Diversity of Tretaments for *H. pylori* Infection Worldwide

**41**

**Chapter 3**

*pylori*

**Abstract**

indene compound

**1. Introduction**

*and Hirofumi Shimomura*

Development of a Novel

Antibacterial Medicine that

Targets a Characteristic Lipid of

*Kiyofumi Wanibuchi, Hisashi Masui, Takashi Takahashi* 

the Cell Membranes of *Helicobacter* 

*Helicobacter pylori* is one of the most prevalent causes of gastritis. This pathogen colonizes for many years human stomach and asymptomatically leads the persons to chronic gastritis. The eradication of *H. pylori* from human stomach is, therefore, important in order to prevent the digestive diseases including peptic ulcers and gastric cancer that develop via chronic atrophic gastritis. Wide-spectrum antibiotics such as amoxicillin and metronidazole are used for the treatment for *H. pylori* infectious diseases. However, the *H. pylori* strains resistant to these antibiotics are increasing year by year around the world. On this basis, we need urgently to develop the antibacterial medicines that act on *H. pylori* with a novel mechanism. Recent studies by our group have demonstrated that *H. pylori* shows susceptibility to the bactericidal action of indene compounds derived from decomposition of vitamin D. The bactericidal action of indene compounds is selective not against commonplace bacteria but against *H. pylori*. The indene compounds turned out to target the *H. pylori*'s phosphatidylethanolamine that retains a myristic acid as the saturated fatty acid side chain. These findings will contribute to the development of new antibacterial medicines specialized to the treatment for *H. pylori* infectious diseases.

**Keywords:** *Helicobacter pylori*, phosphatidylethanolamine, myristic acid, vitamin D,

*Helicobacter pylori* is a Gram-negative microaerophilic helical bacillus equipped with polar flagella as the motility organ. This bacterium colonizes human stomach and causes chronic atrophic gastritis [1]. In addition to gastritis, the patients infected with this pathogen are capable of having various digestive diseases such as gastric ulcer, duodenal ulcer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer [2–7]. Therefore, the eradication of *H. pylori* from human stomach is aggressively carried out around the world. Wide-spectrum

#### **Chapter 3**

## Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell Membranes of *Helicobacter pylori*

*Kiyofumi Wanibuchi, Hisashi Masui, Takashi Takahashi and Hirofumi Shimomura*

#### **Abstract**

*Helicobacter pylori* is one of the most prevalent causes of gastritis. This pathogen colonizes for many years human stomach and asymptomatically leads the persons to chronic gastritis. The eradication of *H. pylori* from human stomach is, therefore, important in order to prevent the digestive diseases including peptic ulcers and gastric cancer that develop via chronic atrophic gastritis. Wide-spectrum antibiotics such as amoxicillin and metronidazole are used for the treatment for *H. pylori* infectious diseases. However, the *H. pylori* strains resistant to these antibiotics are increasing year by year around the world. On this basis, we need urgently to develop the antibacterial medicines that act on *H. pylori* with a novel mechanism. Recent studies by our group have demonstrated that *H. pylori* shows susceptibility to the bactericidal action of indene compounds derived from decomposition of vitamin D. The bactericidal action of indene compounds is selective not against commonplace bacteria but against *H. pylori*. The indene compounds turned out to target the *H. pylori*'s phosphatidylethanolamine that retains a myristic acid as the saturated fatty acid side chain. These findings will contribute to the development of new antibacterial medicines specialized to the treatment for *H. pylori* infectious diseases.

**Keywords:** *Helicobacter pylori*, phosphatidylethanolamine, myristic acid, vitamin D, indene compound

#### **1. Introduction**

*Helicobacter pylori* is a Gram-negative microaerophilic helical bacillus equipped with polar flagella as the motility organ. This bacterium colonizes human stomach and causes chronic atrophic gastritis [1]. In addition to gastritis, the patients infected with this pathogen are capable of having various digestive diseases such as gastric ulcer, duodenal ulcer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer [2–7]. Therefore, the eradication of *H. pylori* from human stomach is aggressively carried out around the world. Wide-spectrum

antibiotics such as amoxicillin, metronidazole, and clarithromycin are used for the treatment for *H. pylori* infectious diseases. However, the *H. pylori* strains resistant to the wide-spectrum antibiotics have been increasing year after year [8]. Especially, almost all *H. pylori* strains clinically isolated from African people have been acquiring the resistance to amoxicillin and metronidazole. In addition, wide-spectrum antibiotics act not only on *H. pylori* but also on commonplace bacteria inhabiting the mucosa of mouth and intestines. Therefore, the patients infected with *H. pylori*, who orally take wide-spectrum antibiotics for the treatment, often suffer from side effects such as stomatitis, constipation, and loose bowels resulted from the collapse of the balance of either oral bacterial flora or enterobacterial flora. When the side effects are serious, the patients develop pseudomembranous colitis accompanied with bloody feces and are compelled to discontinue the eradication of *H. pylori* [9]. To solve the difficult problems on the chemotherapy, we have to develop a novel antibacterial medicine that acts on only *H. pylori* without affecting the survival of human mucosal bacterial flora.

The assimilation of exogenous cholesterol into the cell membranes is one of the unique biological features of *H. pylori*. A part of cholesterol assimilated into the cell membranes is modified with a α-glucose at the carbon position-3 of its steroid framework, and the cholesteryl glucosides generated are used as the bacterial cell membrane constituents [10]. A previous study by our group has revealed that *H. pylori* possesses at least three types of cholesteryl glucosides, cholesteryl-α-D-glucopyranoside (CGL), cholesteryl-6-*O*-tetradecanoyl-α-D-glucopyranoside (CAG), and cholesteryl-6-*O*phosphatidyl-α-D-glucopyranoside (CPG) (**Figure 1**) [11]. In addition to the three cholesteryl glucosides, other researchers have identified the lyso-type of CPG [12]. CGL is synthesized by the catalytic action of cholesterol α-glucosyltransferase (CGT) that localizes to the cytoplasm-side of the inner membrane of *H. pylori* [13–15]. CGT transfers a glucose derived from a uridine diphosphate glucose (UDP-Glc) to the cholesterol. Although the enzyme proteins involved in the synthesis of either CAG or CPG remain to be clarified, a recent study by other group has demonstrated that the enzymatic activities for the synthesis of CAG and CPG are detected in *H. pylori*'s outer membrane and inner membrane, respectively [16]. In addition, both enzymatic activities for the synthesis of CAG and CPG turned out to use phosphatidylethanolamine (PE) as the substrate [16]. In sum, the CGL acyltransferase (CGLAT) transfers a fatty acid derived from PE to the CGL and thereby synthesizes CAG. Meanwhile, the CGL phosphatidyltransferase (CGLPT) transfers a phosphatidyl group derived from PE to the CGL and thereby synthesizes CPG.

#### **Figure 1.**

*Chemical structures of cholesteryl glucosides found in H. pylori cell membranes. In addition to the three types of cholesteryl glucosides, H. pylori possesses the lyso-type of CPG that dissociated a myristic acid. CGL, cholesteryl-α-D-glucopyranoside; CAG, cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside; CPG, cholesteryl-6-O-phosphatidyl-α-D-glucopyranoside; C14, myristic acid; C19, phytomonic acid.*

**43**

**Figure 2.**

*selective high binding affinity only for cholesterol.*

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell…*

A number of studies, including our own, have revealed that *H. pylori* assimilates exogenous cholesterol in order to acquire the resistance to the antibacterial actions of antibiotics and lipophilic compounds [17–20]. Meanwhile, *H. pylori* glucosylates the assimilated cholesterol to evade the host immune systems and/or to detoxify the toxic steroid compounds with 3β-hydroxyl [12, 21]. The mechanism as for cholesterol uptake of *H. pylori*, however, remained for many years to be clarified. In a study in 2012, it has been revealed that PE of *H. pylori* cell membranes functions as a cholesterol-binding lipid [22]. PE is the most predominant glycerophospholipid component composing Gram-negative bacterial cell membranes. The PE of Gram-negative bacteria such as *Enterobacteriaceae* bacteria and *Pseudomonas aeruginosa* retains a palmitic acid (C16:0) as the saturated fatty acid side chain, whereas the PE of *H. pylori* retains a myristic acid (C14:0) as the saturated fatty acid side chain [22–26]. In sum, the PE molecular species composition of *H. pylori* turned out to completely differ from that of typical Gram-negative bacteria. A previous study by our group has demonstrated that the PE accounts for greater than 60% in the total lipids (excluding lipopolysaccharide) of *H. pylori* in the logarithmic growth phase [27]. Moreover, it has been revealed that the PE molecular species (DMPE) with two myristic acids accounts for approximately 30% in the total PE molecular species of *H. pylori* [22]. Intriguingly, DMPE showed higher binding affinity for cholesterol than for cholesteryl ester (**Figure 2**). In sum, the selective intermolecular interaction was found between the low-molecular-weight

Based on a number of studies including our own, the overview from the choles-

*H. pylori*: (1) cholesterol binds at least to DMPE of the outer membrane of *H. pylori* and is assimilated into the membranes; (2) a part of cholesterol is glucosylated by the catalytic action of CGT localized to the cytoplasm-side of the inner membrane, and thereby CGL is generated; (3) CGL is next exchanged to CAG and CPG by the enzymatic actions of CGLAT and CGLPT that localize to the outer membrane and the inner membrane, respectively (**Figure 3**). CGT utilizes an UDP-Glc as the glucose donor of cholesterol. Both enzymes of CGLAT and CGLPT utilize PE (myristoyl-PE) as the acyl group donor and phosphatidyl group donor of CGL,

*Binding affinity of dimyristoyl-phosphatidylethanolamine of H. pylori cell membranes for either cholesterol or cholesteryl ester. Dipalmitoyl-PE with two palmitic acids (C16:0) shows the high binding affinity for both of cholesterol and cholesteryl ester, whereas dimyristoyl-PE (DMPE) with two myristic acids (C14:0) shows the* 

terol assimilation to the cholesterol glucosylation was partially clarified in

*DOI: http://dx.doi.org/10.5772/intechopen.86165*

hydrophobic compounds.

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell… DOI: http://dx.doi.org/10.5772/intechopen.86165*

A number of studies, including our own, have revealed that *H. pylori* assimilates exogenous cholesterol in order to acquire the resistance to the antibacterial actions of antibiotics and lipophilic compounds [17–20]. Meanwhile, *H. pylori* glucosylates the assimilated cholesterol to evade the host immune systems and/or to detoxify the toxic steroid compounds with 3β-hydroxyl [12, 21]. The mechanism as for cholesterol uptake of *H. pylori*, however, remained for many years to be clarified. In a study in 2012, it has been revealed that PE of *H. pylori* cell membranes functions as a cholesterol-binding lipid [22]. PE is the most predominant glycerophospholipid component composing Gram-negative bacterial cell membranes. The PE of Gram-negative bacteria such as *Enterobacteriaceae* bacteria and *Pseudomonas aeruginosa* retains a palmitic acid (C16:0) as the saturated fatty acid side chain, whereas the PE of *H. pylori* retains a myristic acid (C14:0) as the saturated fatty acid side chain [22–26]. In sum, the PE molecular species composition of *H. pylori* turned out to completely differ from that of typical Gram-negative bacteria. A previous study by our group has demonstrated that the PE accounts for greater than 60% in the total lipids (excluding lipopolysaccharide) of *H. pylori* in the logarithmic growth phase [27]. Moreover, it has been revealed that the PE molecular species (DMPE) with two myristic acids accounts for approximately 30% in the total PE molecular species of *H. pylori* [22]. Intriguingly, DMPE showed higher binding affinity for cholesterol than for cholesteryl ester (**Figure 2**). In sum, the selective intermolecular interaction was found between the low-molecular-weight hydrophobic compounds.

Based on a number of studies including our own, the overview from the cholesterol assimilation to the cholesterol glucosylation was partially clarified in *H. pylori*: (1) cholesterol binds at least to DMPE of the outer membrane of *H. pylori* and is assimilated into the membranes; (2) a part of cholesterol is glucosylated by the catalytic action of CGT localized to the cytoplasm-side of the inner membrane, and thereby CGL is generated; (3) CGL is next exchanged to CAG and CPG by the enzymatic actions of CGLAT and CGLPT that localize to the outer membrane and the inner membrane, respectively (**Figure 3**). CGT utilizes an UDP-Glc as the glucose donor of cholesterol. Both enzymes of CGLAT and CGLPT utilize PE (myristoyl-PE) as the acyl group donor and phosphatidyl group donor of CGL,

#### **Figure 2.**

*Gastritis - New Approaches and Treatments*

human mucosal bacterial flora.

the CGL and thereby synthesizes CPG.

antibiotics such as amoxicillin, metronidazole, and clarithromycin are used for the treatment for *H. pylori* infectious diseases. However, the *H. pylori* strains resistant to the wide-spectrum antibiotics have been increasing year after year [8]. Especially, almost all *H. pylori* strains clinically isolated from African people have been acquiring the resistance to amoxicillin and metronidazole. In addition, wide-spectrum antibiotics act not only on *H. pylori* but also on commonplace bacteria inhabiting the mucosa of mouth and intestines. Therefore, the patients infected with *H. pylori*, who orally take wide-spectrum antibiotics for the treatment, often suffer from side effects such as stomatitis, constipation, and loose bowels resulted from the collapse of the balance of either oral bacterial flora or enterobacterial flora. When the side effects are serious, the patients develop pseudomembranous colitis accompanied with bloody feces and are compelled to discontinue the eradication of *H. pylori* [9]. To solve the difficult problems on the chemotherapy, we have to develop a novel antibacterial medicine that acts on only *H. pylori* without affecting the survival of

The assimilation of exogenous cholesterol into the cell membranes is one of the unique biological features of *H. pylori*. A part of cholesterol assimilated into the cell membranes is modified with a α-glucose at the carbon position-3 of its steroid framework, and the cholesteryl glucosides generated are used as the bacterial cell membrane constituents [10]. A previous study by our group has revealed that *H. pylori* possesses at least three types of cholesteryl glucosides, cholesteryl-α-D-glucopyranoside (CGL), cholesteryl-6-*O*-tetradecanoyl-α-D-glucopyranoside (CAG), and cholesteryl-6-*O*phosphatidyl-α-D-glucopyranoside (CPG) (**Figure 1**) [11]. In addition to the three cholesteryl glucosides, other researchers have identified the lyso-type of CPG [12]. CGL is synthesized by the catalytic action of cholesterol α-glucosyltransferase (CGT) that localizes to the cytoplasm-side of the inner membrane of *H. pylori* [13–15]. CGT transfers a glucose derived from a uridine diphosphate glucose (UDP-Glc) to the cholesterol. Although the enzyme proteins involved in the synthesis of either CAG or CPG remain to be clarified, a recent study by other group has demonstrated that the enzymatic activities for the synthesis of CAG and CPG are detected in *H. pylori*'s outer membrane and inner membrane, respectively [16]. In addition, both enzymatic activities for the synthesis of CAG and CPG turned out to use phosphatidylethanolamine (PE) as the substrate [16]. In sum, the CGL acyltransferase (CGLAT) transfers a fatty acid derived from PE to the CGL and thereby synthesizes CAG. Meanwhile, the CGL phosphatidyltransferase (CGLPT) transfers a phosphatidyl group derived from PE to

*Chemical structures of cholesteryl glucosides found in H. pylori cell membranes. In addition to the three types of cholesteryl glucosides, H. pylori possesses the lyso-type of CPG that dissociated a myristic acid. CGL, cholesteryl-α-D-glucopyranoside; CAG, cholesteryl-6-O-tetradecanoyl-α-D-glucopyranoside; CPG, cholesteryl-*

*6-O-phosphatidyl-α-D-glucopyranoside; C14, myristic acid; C19, phytomonic acid.*

**42**

**Figure 1.**

*Binding affinity of dimyristoyl-phosphatidylethanolamine of H. pylori cell membranes for either cholesterol or cholesteryl ester. Dipalmitoyl-PE with two palmitic acids (C16:0) shows the high binding affinity for both of cholesterol and cholesteryl ester, whereas dimyristoyl-PE (DMPE) with two myristic acids (C14:0) shows the selective high binding affinity only for cholesterol.*

**Figure 3.**

*Cholesteryl glucoside synthesis and its enzyme localization in H. pylori cell membranes. CGT, cholesterol α-glucosyltransferase; CGLAT, CGL acyltransferase; CGLPT, CGL phosphatidyltransferase; Cho, cholesterol; MPE, myristoyl phosphatidylethanolamine; LPS, lipopolysaccharide; UDP-Glc, uridine diphosphate-glucose.*

respectively. Incidentally, cholesterol assimilated into *H. pylori* is distributed to both of the inner and outer membranes, whereas cholesteryl glucosides (CGL, CAG, and CPG) synthesized by *H. pylori* predominantly localize to the outer membrane [17].

As described above, it has been revealed that DMPE is one of the most prevalent lipid components of *H. pylori* cell membranes and shows the unique interaction not with cholesteryl ester but with cholesterol. Apart from this, previous studies by our group have demonstrated that a steroid hormone, progesterone acts on the cholesterol-binding site in the *H. pylori* cell membranes and confers the bactericidal action to *H. pylori* [28, 29]. Although it was unclear as for whether the progesterone shows the selective binding affinity for DMPE, this steroid turned out to destabilize the cell membrane structure of *H. pylori* and to ultimately induce the bacteriolysis. These findings drove us to the investigations of the low-molecular-weight hydrophobic compounds that induce the serious structure change to the DMPE molecule through the specific interaction. This chapter mentions the bactericidal activity of the indene compounds against *H. pylori*.

#### **2. Development of new antibacterial medicines for** *H. pylori*

#### **2.1 Finding of an indene compound as the anti-***H. pylori* **substance**

The anti-*H. pylori* activity of various steroidal compounds was investigated. As a consequence, 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of secosteroids turned out to confer the strong bacteriolytic action to *H. pylori* [30]. However, these vitamin D3 derivatives conspicuously attenuated their bactericidal activity by the nonbiological degradation (**Table 1**). In contrast, *H. pylori* did not almost

**45**

**Table 1.**

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell…*

succumb to the bacteriolytic action of vitamin D3. Surprisingly, the nonbiological degradation of vitamin D3 augmented the bactericidal activity of its secosteroid against *H. pylori*. These results indicated that the vitamin D3 derivatives directly act as bactericidal substances on *H. pylori*, and that some decomposition product of vitamin D3 possesses potent bactericidal activity against *H. pylori*. It was, therefore, attempted to extract the anti-*H. pylori* substance from the decomposition products of vitamin D3. As a consequence, the indene compound species (VDP1), otherwise known as Grundmann's ketone, was successfully obtained [31, 32]. VDP1 is a lowmolecular-weight hydrophobic compound in which the indene consisting of 5- and 6-membered rings of hydrocarbons was modified with alkyl, carbonyl, and methyl (**Figure 4**). Intriguingly, *H. pylori* showed high susceptibility to the bacteriolytic action of VDP1, whereas commonplace bacteria such as *Enterobacteriaceae* bacteria, *P. aeruginosa*, and *Staphylococcus aureus* showed insusceptibility to that of VDP1 [30]. In addition, VDP1 conferred the effective bacteriolytic action to *H. pylori* regardless of the assimilation of cholesterol into the cell membranes. These results indicate the possibility that VDP1 is a beneficial fundamental structure for the development of antibacterial medicines to selectively eradicate *H. pylori* without

The collapse induction activity of VDP1 against lipid vesicles was next examined using the unilamellar vesicles prepared with DMPE, dipalmitoyl-PE (DPPE), and dioleoyl-PE (DOPE). Intriguingly, VDP1 turned out to specifically induce the structure collapse of DMPE unilamellar vesicles without affecting the structural stability of either DPPE unilamellar vesicles or DOPE unilamellar vesicles (**Figure 5**). The structure collapse induction activity of VDP1 against DMPE unilamellar vesicles completely corresponded to the bactericidal activity of the indene compound

collapsing the balance of human mucosal bacterial flora.

*Bacteriolytic action of vitamin D3 and its derivatives against H. pylori.*

**2.2 Interaction between VDP1 and PE molecular species**

*DOI: http://dx.doi.org/10.5772/intechopen.86165*

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell… DOI: http://dx.doi.org/10.5772/intechopen.86165*

**Table 1.**

*Gastritis - New Approaches and Treatments*

the indene compounds against *H. pylori*.

**2. Development of new antibacterial medicines for** *H. pylori*

**2.1 Finding of an indene compound as the anti-***H. pylori* **substance**

The anti-*H. pylori* activity of various steroidal compounds was investigated. As a consequence, 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of secosteroids turned out to confer the strong bacteriolytic action to *H. pylori* [30]. However, these vitamin D3 derivatives conspicuously attenuated their bactericidal activity by the nonbiological degradation (**Table 1**). In contrast, *H. pylori* did not almost

respectively. Incidentally, cholesterol assimilated into *H. pylori* is distributed to both of the inner and outer membranes, whereas cholesteryl glucosides (CGL, CAG, and CPG) synthesized by *H. pylori* predominantly localize to the outer membrane [17]. As described above, it has been revealed that DMPE is one of the most prevalent lipid components of *H. pylori* cell membranes and shows the unique interaction not with cholesteryl ester but with cholesterol. Apart from this, previous studies by our group have demonstrated that a steroid hormone, progesterone acts on the cholesterol-binding site in the *H. pylori* cell membranes and confers the bactericidal action to *H. pylori* [28, 29]. Although it was unclear as for whether the progesterone shows the selective binding affinity for DMPE, this steroid turned out to destabilize the cell membrane structure of *H. pylori* and to ultimately induce the bacteriolysis. These findings drove us to the investigations of the low-molecular-weight hydrophobic compounds that induce the serious structure change to the DMPE molecule through the specific interaction. This chapter mentions the bactericidal activity of

*Cholesteryl glucoside synthesis and its enzyme localization in H. pylori cell membranes. CGT, cholesterol α-glucosyltransferase; CGLAT, CGL acyltransferase; CGLPT, CGL phosphatidyltransferase; Cho, cholesterol; MPE, myristoyl phosphatidylethanolamine; LPS, lipopolysaccharide; UDP-Glc, uridine diphosphate-glucose.*

**44**

**Figure 3.**

*Bacteriolytic action of vitamin D3 and its derivatives against H. pylori.*

succumb to the bacteriolytic action of vitamin D3. Surprisingly, the nonbiological degradation of vitamin D3 augmented the bactericidal activity of its secosteroid against *H. pylori*. These results indicated that the vitamin D3 derivatives directly act as bactericidal substances on *H. pylori*, and that some decomposition product of vitamin D3 possesses potent bactericidal activity against *H. pylori*. It was, therefore, attempted to extract the anti-*H. pylori* substance from the decomposition products of vitamin D3. As a consequence, the indene compound species (VDP1), otherwise known as Grundmann's ketone, was successfully obtained [31, 32]. VDP1 is a lowmolecular-weight hydrophobic compound in which the indene consisting of 5- and 6-membered rings of hydrocarbons was modified with alkyl, carbonyl, and methyl (**Figure 4**). Intriguingly, *H. pylori* showed high susceptibility to the bacteriolytic action of VDP1, whereas commonplace bacteria such as *Enterobacteriaceae* bacteria, *P. aeruginosa*, and *Staphylococcus aureus* showed insusceptibility to that of VDP1 [30]. In addition, VDP1 conferred the effective bacteriolytic action to *H. pylori* regardless of the assimilation of cholesterol into the cell membranes. These results indicate the possibility that VDP1 is a beneficial fundamental structure for the development of antibacterial medicines to selectively eradicate *H. pylori* without collapsing the balance of human mucosal bacterial flora.

#### **2.2 Interaction between VDP1 and PE molecular species**

The collapse induction activity of VDP1 against lipid vesicles was next examined using the unilamellar vesicles prepared with DMPE, dipalmitoyl-PE (DPPE), and dioleoyl-PE (DOPE). Intriguingly, VDP1 turned out to specifically induce the structure collapse of DMPE unilamellar vesicles without affecting the structural stability of either DPPE unilamellar vesicles or DOPE unilamellar vesicles (**Figure 5**). The structure collapse induction activity of VDP1 against DMPE unilamellar vesicles completely corresponded to the bactericidal activity of the indene compound

#### **Figure 4.**

*Bacteriolytic action of VDP1 against H. pylori. H. pylori shows high susceptibility to bacteriolytic action of VDP1 derived from decomposition of vitamin D3. Meanwhile, commonplace bacteria such as Escherichia coli and Staphylococcus aureus show insusceptibility to bacteriolytic action of VDP1. VDP1, (1R,3aR,7aR)-1- [(1R)-1,5-dimethylhexyl]octahydro-7a-methyl-4H-inden-4-one.*

#### **Figure 5.**

*Specific intermolecular interaction between VDP1 and DMPE. Dye-containing unilamellar vesicles were prepared with DMPE, dipalmitoyl-PE (DPPE) or dioleoyl-PE (DOPE) and incubated for 5 minutes in the presence or absence of VDP1. The absorbance (A590 nm) of dye released from the PE unilamellar vesicles was measured (left graph). The data were obtained from the three independent experiments and are denoted with the mean A590 nm ± standard deviation. Statistical significance (P < 0.05) was calculated by the Student's t-test. N.S. denotes "no statistical significance." VDP1 induces the selective conformation change to the DMPE unilamellar vesicles. The intermolecular interactions between VDP1 and PE molecular species were simulated by the computational chemistry (right panel). VDP1 induces the conformational change only to a myristic acid side chain in the PE molecule without affecting the conformational stability of a palmitic acid side chain in the PE molecule.*

against *H. pylori* that abundantly contains DMPE in the cell membranes. Based on these results, VDP1 was considered to specifically interact with the DMPE, to induce the serious structure change to the myristic acid side chain in the PE molecule, and to ultimately disrupt the vesicular conformation of DMPE. In addition, these results strongly suggested that VDP1 exerts the bactericidal effect on *H. pylori* by targeting at least DMPE of the cell membranes.

The intermolecular interaction between VDP1, DMPE, and DPPE was, therefore, simulated by the computational chemistry. One of the computer simulations showed that VDP1 induces "the winding-structure change" to a myristic acid side chain in DMPE molecule, while VDP1 induced no structure change to a palmitic acid side chain in DPPE molecule (**Figure 5**). The alkyl of VDP1 seemed to be crucial conformation for the induction of the structure change of the myristic acid side chain of DMPE. In other words, the slight difference of the length of carbon

**47**

**Table 2.**

*\**

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell…*

chain composing the fatty acids in PE molecules appeared to play an important role

As described earlier, VDP1 was considered to confer the bacteriolytic action to *H. pylori* by the disruption of the cell membranes through the induction of the structure change of DMPE that is one of the most prevalent PE molecular species constructing the bacterial cell membranes. To investigate in detail the crucial conformation of VDP1 for exerting the structure collapse effect on DMPE unilamellar vesicles and for exerting the antibacterial effect on *H. pylori*, various VDP1 derivatives were chemically synthesized [33]. The structure collapse induction activity of VDP1 against DMPE unilamellar vesicles was already ascertained to almost completely correspond to the bactericidal activity of the indene compound against *H. pylori*. When the carbonyl of VDP1 was replaced with a hydroxyl, the indene compound (VD3-1) maintained both activities against DMPE unilamellar vesicles and *H. pylori* (**Table 2**). As seen in VDP1, VD3-1 turned out to confer no structure collapse induction activity against DPPE unilamellar vesicles. In addition, VD3-1 also had no influence on the viability of commonplace bacteria such as *Enterobacteriaceae* bacteria, *P. aeruginosa*, and *S. aureus*. Intriguingly, VD2-2 that lacks the alkyl chain of VD3-1 was ascertained to induce no structure collapses of either DMPE unilamellar vesicles or DPPE unilamellar vesicles and to completely forfeit the effective bactericidal activity against *H. pylori*. In combination with the result of computer simulation as for the intermolecular interaction between VDP1 and DMPE, these results indicate that the alkyl structure in the indene compound

*Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Salmonella sp., Pseudomonas aeruginosa, and Staphylococcus aureus. VD3-1, (1R,3aR,7aR)-7a-methyl-1-((R)-6-methylheptan-2-yl)octahydro-1H-inden-4-ol; VD2-2, (1R,3aR,7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyloctahydro-1H-inden-4-ol.*

*Relationship between indene compounds, PE unilamellar vesicles and H. pylori.*

on the specific interaction between VDP1 and PE molecular species.

**2.3 Bactericidal mechanism of the indene compound species**

*DOI: http://dx.doi.org/10.5772/intechopen.86165*

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell… DOI: http://dx.doi.org/10.5772/intechopen.86165*

chain composing the fatty acids in PE molecules appeared to play an important role on the specific interaction between VDP1 and PE molecular species.

#### **2.3 Bactericidal mechanism of the indene compound species**

As described earlier, VDP1 was considered to confer the bacteriolytic action to *H. pylori* by the disruption of the cell membranes through the induction of the structure change of DMPE that is one of the most prevalent PE molecular species constructing the bacterial cell membranes. To investigate in detail the crucial conformation of VDP1 for exerting the structure collapse effect on DMPE unilamellar vesicles and for exerting the antibacterial effect on *H. pylori*, various VDP1 derivatives were chemically synthesized [33]. The structure collapse induction activity of VDP1 against DMPE unilamellar vesicles was already ascertained to almost completely correspond to the bactericidal activity of the indene compound against *H. pylori*. When the carbonyl of VDP1 was replaced with a hydroxyl, the indene compound (VD3-1) maintained both activities against DMPE unilamellar vesicles and *H. pylori* (**Table 2**). As seen in VDP1, VD3-1 turned out to confer no structure collapse induction activity against DPPE unilamellar vesicles. In addition, VD3-1 also had no influence on the viability of commonplace bacteria such as *Enterobacteriaceae* bacteria, *P. aeruginosa*, and *S. aureus*. Intriguingly, VD2-2 that lacks the alkyl chain of VD3-1 was ascertained to induce no structure collapses of either DMPE unilamellar vesicles or DPPE unilamellar vesicles and to completely forfeit the effective bactericidal activity against *H. pylori*. In combination with the result of computer simulation as for the intermolecular interaction between VDP1 and DMPE, these results indicate that the alkyl structure in the indene compound


*\* Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Salmonella sp., Pseudomonas aeruginosa, and Staphylococcus aureus. VD3-1, (1R,3aR,7aR)-7a-methyl-1-((R)-6-methylheptan-2-yl)octahydro-1H-inden-4-ol; VD2-2, (1R,3aR,7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyloctahydro-1H-inden-4-ol.*

#### **Table 2.**

*Relationship between indene compounds, PE unilamellar vesicles and H. pylori.*

*Gastritis - New Approaches and Treatments*

*[(1R)-1,5-dimethylhexyl]octahydro-7a-methyl-4H-inden-4-one.*

**Figure 4.**

**Figure 5.**

*PE molecule.*

against *H. pylori* that abundantly contains DMPE in the cell membranes. Based on these results, VDP1 was considered to specifically interact with the DMPE, to induce the serious structure change to the myristic acid side chain in the PE molecule, and to ultimately disrupt the vesicular conformation of DMPE. In addition, these results strongly suggested that VDP1 exerts the bactericidal effect on *H. pylori*

*Specific intermolecular interaction between VDP1 and DMPE. Dye-containing unilamellar vesicles were prepared with DMPE, dipalmitoyl-PE (DPPE) or dioleoyl-PE (DOPE) and incubated for 5 minutes in the presence or absence of VDP1. The absorbance (A590 nm) of dye released from the PE unilamellar vesicles was measured (left graph). The data were obtained from the three independent experiments and are denoted with the mean A590 nm ± standard deviation. Statistical significance (P < 0.05) was calculated by the Student's t-test. N.S. denotes "no statistical significance." VDP1 induces the selective conformation change to the DMPE unilamellar vesicles. The intermolecular interactions between VDP1 and PE molecular species were simulated by the computational chemistry (right panel). VDP1 induces the conformational change only to a myristic acid side chain in the PE molecule without affecting the conformational stability of a palmitic acid side chain in the* 

*Bacteriolytic action of VDP1 against H. pylori. H. pylori shows high susceptibility to bacteriolytic action of VDP1 derived from decomposition of vitamin D3. Meanwhile, commonplace bacteria such as Escherichia coli and Staphylococcus aureus show insusceptibility to bacteriolytic action of VDP1. VDP1, (1R,3aR,7aR)-1-*

The intermolecular interaction between VDP1, DMPE, and DPPE was, therefore, simulated by the computational chemistry. One of the computer simulations showed that VDP1 induces "the winding-structure change" to a myristic acid side chain in DMPE molecule, while VDP1 induced no structure change to a palmitic acid side chain in DPPE molecule (**Figure 5**). The alkyl of VDP1 seemed to be crucial conformation for the induction of the structure change of the myristic acid side chain of DMPE. In other words, the slight difference of the length of carbon

by targeting at least DMPE of the cell membranes.

**46**

species plays a crucial role on the induction of the structure change of the myristic acid side chain in DMPE molecule. Moreover, the alkyl structure in the indene compound species turned out to be essential for exerting the effective bacteriolytic action to *H. pylori*. The functional groups such as carbonyl and hydroxyl of the indene compound species seem to be significant conformation for bonding to the phosphate head in the PE molecules with an electrostatic attraction. Meanwhile, the indene-ring structure is guessed to be significant to stabilize the hydrophobic interaction between the indene compound species and PE molecules.

A recent study by our group has demonstrated that VDP1 confers the antibacterial action not only to *H. pylori* but also to other *Helicobacter* species [33]. Especially, *Helicobacter felis* showed high susceptibility to the bacteriolytic action of VDP1, as similar to *H. pylori*. *H. felis* is a Gram-negative microaerophilic spiral bacillus possessing bipolar tufts of flagella. This bacterium is isolated from the gastric mucosa of cats and dogs [34–36]. As seen in *H. pylori*, *H. felis* causes chronic gastritis and gastric MALT lymphoma in mouse when it colonizes the mouse stomach [37, 38]. An earlier study by our group has revealed that a myristic acid accounts for approximately 16% in the fatty acid composition of *H. felis* PE, and that the PE molecular species retaining a myristic acid and a palmitic acid accounts for approximately 37% in total PE molecular species of the bacteria [39]. Though *H. felis* completely succumbs to the bacteriolytic action at the same concentration of VDP1 (less than 3 μg/ml) that eradicates *H. pylori*, this *Helicobacter* species did not possess DMPE. On this basis, VDP1 is considered to interact not only with DMPE but also with myristoyl-PE that retains a myristic acid as one of the two fatty acid side chains. In addition, *H. felis* turned out to possess lauryl-PE as the most prevalent PE molecular species. The PE molecular species retaining a lauric acid (C12:0) and a palmitic acid accounted for approximately 40% in total PE molecular species of *H. felis*. In sum, large parts of PE molecular species of *H. felis* bind a palmitic acid and either a myristic acid or a lauric acid as the fatty acid side chains. Given that a lauric acid is shorter in the length of carbon chain than a myristic acid, we can assume that VDP1 collapses the vesicular conformation consisting not only of myristoyl-PE but also of lauryl-PE. In the future, it will need to elucidate the hydrophobic interaction between VDP1 and lauryl-PE in addition to myristoyl-PE.

In contrast, *Helicobacter cinaedi* showed low susceptibility to the bacteriolytic action of VDP1, even though the PE molecular species composition in *H. cinaedi* is similar to the PE molecular species composition in *H. felis* [39]. *H. cinaedi* is a Gram-negative rod-like bacillus equipped with bipolar flagella and isolated from the intestinal tracts and livers of various mammals such as human, dog, cat, and hamster [40–42]. Therefore, this bacterium is classified into the enterohepatic *Helicobacter* species [43, 44]. Meanwhile, *H. pylori* and *H. felis* are classified into the gastric *Helicobacter* species. Most of the persons infected with *H. cinaedi* have no clinical symptoms, but some persons suffer from systematic inflammations, namely phlegmone, arthritis, and meningitis, due to the bacteremia [45]. Although it is unclear as for why *H. cinaedi* is lower in the VDP1-susceptibility than the two *Helicobacter* species, the involvement of lipopolysaccharide (LPS) is considered as one possibility. LPS is a glycolipid constructed of a long polysaccharide chain and fatty acids and is one of the composition components of the outermost layer of the outer membrane of Gram-negative bacteria [46]. The part of polysaccharide chain in LPS comes into direct contact with the outsides of the bacterial cells and limits the membrane permeability of various lipophilic compounds. The LPS contents in *H. cinaedi* may be higher than those in *H. pylori* and *H. felis*. The membrane permeability of VDP1 through the LPS barrier may be, therefore, stricter in *H. cinaedi* than in *H. pylori* and *H. felis*. Further investigation will be necessary to compare the LPS contents between the *Helicobacter* species.

**49**

**Figure 7.**

**Figure 6.**

*destabilization of the membrane conformation.*

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell…*

Based on the current studies, the following bactericidal mechanism of the indene compounds synthetically derived from vitamin D in *H. pylori* was proposed: the indene compounds bind to the myristoyl-PE (including DMPE) of *H. pylori* cell membranes, induce "the winding-structure change" to the myristic acid side chain

*A proposed bactericidal mechanism of the indene compound species for H. pylori. The indene compound species such as VDP1 and VD3-1 bind to the myristoyl-PE of H. pylori cell membranes and induce "the windingstructure change" to the myristic acid side chain of the especially DMPE. H. pylori ultimately lyses via the* 

*Role of cholesterol and cholesteryl glucosides in H. pylori. Cholesterol (Cho) binds to the myristoyl-PE (MPE) including dimyristoyl-PE (DMPE) of the H. pylori's cell membranes but has no influence on the stability of the cell membrane conformation. As similar to cholesterol, no cholesteryl glucosides (CGL, CAG, and CPG) affect the cell membrane stability of H. pylori. These steroidal compounds are assimilated as the membrane lipid constituents of H. pylori and serve to strengthen the cell membrane lipid barrier. Incidentally, VDP1 confers the* 

*bacteriolytic action to H. pylori regardless of the cholesterol assimilation into the cell membranes.*

*DOI: http://dx.doi.org/10.5772/intechopen.86165*

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell… DOI: http://dx.doi.org/10.5772/intechopen.86165*

Based on the current studies, the following bactericidal mechanism of the indene compounds synthetically derived from vitamin D in *H. pylori* was proposed: the indene compounds bind to the myristoyl-PE (including DMPE) of *H. pylori* cell membranes, induce "the winding-structure change" to the myristic acid side chain

#### **Figure 6.**

*Gastritis - New Approaches and Treatments*

species plays a crucial role on the induction of the structure change of the myristic acid side chain in DMPE molecule. Moreover, the alkyl structure in the indene compound species turned out to be essential for exerting the effective bacteriolytic action to *H. pylori*. The functional groups such as carbonyl and hydroxyl of the indene compound species seem to be significant conformation for bonding to the phosphate head in the PE molecules with an electrostatic attraction. Meanwhile, the indene-ring structure is guessed to be significant to stabilize the hydrophobic

A recent study by our group has demonstrated that VDP1 confers the antibacterial action not only to *H. pylori* but also to other *Helicobacter* species [33]. Especially, *Helicobacter felis* showed high susceptibility to the bacteriolytic action of VDP1, as similar to *H. pylori*. *H. felis* is a Gram-negative microaerophilic spiral bacillus possessing bipolar tufts of flagella. This bacterium is isolated from the gastric mucosa of cats and dogs [34–36]. As seen in *H. pylori*, *H. felis* causes chronic gastritis and gastric MALT lymphoma in mouse when it colonizes the mouse stomach [37, 38]. An earlier study by our group has revealed that a myristic acid accounts for approximately 16% in the fatty acid composition of *H. felis* PE, and that the PE molecular species retaining a myristic acid and a palmitic acid accounts for approximately 37% in total PE molecular species of the bacteria [39]. Though *H. felis* completely succumbs to the bacteriolytic action at the same concentration of VDP1 (less than 3 μg/ml) that eradicates *H. pylori*, this *Helicobacter* species did not possess DMPE. On this basis, VDP1 is considered to interact not only with DMPE but also with myristoyl-PE that retains a myristic acid as one of the two fatty acid side chains. In addition, *H. felis* turned out to possess lauryl-PE as the most prevalent PE molecular species. The PE molecular species retaining a lauric acid (C12:0) and a palmitic acid accounted for approximately 40% in total PE molecular species of *H. felis*. In sum, large parts of PE molecular species of *H. felis* bind a palmitic acid and either a myristic acid or a lauric acid as the fatty acid side chains. Given that a lauric acid is shorter in the length of carbon chain than a myristic acid, we can assume that VDP1 collapses the vesicular conformation consisting not only of myristoyl-PE but also of lauryl-PE. In the future, it will need to elucidate the hydrophobic interaction between VDP1 and lauryl-PE in addition to myristoyl-PE. In contrast, *Helicobacter cinaedi* showed low susceptibility to the bacteriolytic action of VDP1, even though the PE molecular species composition in *H. cinaedi* is similar to the PE molecular species composition in *H. felis* [39]. *H. cinaedi* is a Gram-negative rod-like bacillus equipped with bipolar flagella and isolated from the intestinal tracts and livers of various mammals such as human, dog, cat, and hamster [40–42]. Therefore, this bacterium is classified into the enterohepatic *Helicobacter* species [43, 44]. Meanwhile, *H. pylori* and *H. felis* are classified into the gastric *Helicobacter* species. Most of the persons infected with *H. cinaedi* have no clinical symptoms, but some persons suffer from systematic inflammations, namely phlegmone, arthritis, and meningitis, due to the bacteremia [45]. Although it is unclear as for why *H. cinaedi* is lower in the VDP1-susceptibility than the two *Helicobacter* species, the involvement of lipopolysaccharide (LPS) is considered as one possibility. LPS is a glycolipid constructed of a long polysaccharide chain and fatty acids and is one of the composition components of the outermost layer of the outer membrane of Gram-negative bacteria [46]. The part of polysaccharide chain in LPS comes into direct contact with the outsides of the bacterial cells and limits the membrane permeability of various lipophilic compounds. The LPS contents in *H. cinaedi* may be higher than those in *H. pylori* and *H. felis*. The membrane permeability of VDP1 through the LPS barrier may be, therefore, stricter in *H. cinaedi* than in *H. pylori* and *H. felis*. Further investigation will be necessary to compare the

interaction between the indene compound species and PE molecules.

**48**

LPS contents between the *Helicobacter* species.

*A proposed bactericidal mechanism of the indene compound species for H. pylori. The indene compound species such as VDP1 and VD3-1 bind to the myristoyl-PE of H. pylori cell membranes and induce "the windingstructure change" to the myristic acid side chain of the especially DMPE. H. pylori ultimately lyses via the destabilization of the membrane conformation.*

#### **Figure 7.**

*Role of cholesterol and cholesteryl glucosides in H. pylori. Cholesterol (Cho) binds to the myristoyl-PE (MPE) including dimyristoyl-PE (DMPE) of the H. pylori's cell membranes but has no influence on the stability of the cell membrane conformation. As similar to cholesterol, no cholesteryl glucosides (CGL, CAG, and CPG) affect the cell membrane stability of H. pylori. These steroidal compounds are assimilated as the membrane lipid constituents of H. pylori and serve to strengthen the cell membrane lipid barrier. Incidentally, VDP1 confers the bacteriolytic action to H. pylori regardless of the cholesterol assimilation into the cell membranes.*

in the PE molecules, destabilize the membrane conformation, and ultimately confer the bacteriolytic action to *H. pylori* (**Figure 6**).

In the case of the cholesterol assimilation in *H. pylori*, cholesterol is distributed to both membranes of the outer membrane and the inner membrane, and a part of the cholesterol is, thereafter, metabolized to cholesteryl glucosides (CGL, CAG, and CPG), and these metabolites localize to the outer membrane (**Figure 7**). Cholesterol and cholesteryl glucosides have no influence on the stability of the cell membrane conformation of *H. pylori*, and rather these steroidal compounds serve to strengthen the membrane lipid barrier of the bacteria on the limitation of the permeability of lipophilic compounds. A recent study by other group has demonstrated that cholesteryl glucosides are responsible for the morphological maintenance of *H. pylori*, for the acquirement of resistance to antibiotics such as polymyxin B, colistin, and tetracycline, and for the promotion of biofilm formation [47]. This suggests that cholesteryl glucosides of *H. pylori* play an important role to limit the membrane permeability of various low-molecular-weight compounds. However, VDP1 confers the bacteriolytic action even to *H. pylori* retaining cholesterol and cholesteryl glucosides. Further investigation will be necessary to clarify the detailed intermolecular interactions between myristoyl-PE and steroidal compounds.

#### **3. Conclusions**

Almost all hydrophobic drugs are pharmacologically designed to inhibit the functions of either protein molecules or nucleic acids in the target creature species. However, no drugs that target a characteristic lipid molecule in the creatures are discovered for many years. In addition, a number of biochemists on lipid research leave great achievements in the analysis of biosynthetic enzymes of various lipophilic compounds such as fatty acids and complex lipids and in the identification of receptors of various hydrophobic ligands such as steroid hormones and eicosanoids. However, these achievements are not as for lipid itself but as for merely proteins. This chapter described the unique interaction between lipids: the indene compound species specifically disrupt the vesicular conformation consisting of DMPE. These findings will bring the new aspects to the drug discovery research and the lipid biochemistry research.

#### **Acknowledgements**

This work was supported by a Grant-in-Aid from the Adaptable and Seamless Technology Transfer Program through Target-Driven R&A (A-STEP), JSPS KAKENHI (grant number 15 K08006), and JKA promotion funds from KEIRIN RACE.

**51**

**Author details**

Kanagawa, Japan

Kiyofumi Wanibuchi1

and Hirofumi Shimomura2

provided the original work is properly cited.

2 Independent Researcher, Kumamoto, Japan

, Hisashi Masui1

1 Faculty of Pharmaceutical Sciences, Yokohama University of Pharmacy,

\*Address all correspondence to: shimomura20090601@gmail.com

\*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Takashi Takahashi1

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell…*

*DOI: http://dx.doi.org/10.5772/intechopen.86165*

#### **Conflict of interest**

The authors declare no conflict of interest.

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell… DOI: http://dx.doi.org/10.5772/intechopen.86165*

### **Author details**

*Gastritis - New Approaches and Treatments*

**3. Conclusions**

biochemistry research.

**Acknowledgements**

**Conflict of interest**

The authors declare no conflict of interest.

the bacteriolytic action to *H. pylori* (**Figure 6**).

in the PE molecules, destabilize the membrane conformation, and ultimately confer

In the case of the cholesterol assimilation in *H. pylori*, cholesterol is distributed to both membranes of the outer membrane and the inner membrane, and a part of the cholesterol is, thereafter, metabolized to cholesteryl glucosides (CGL, CAG, and CPG), and these metabolites localize to the outer membrane (**Figure 7**). Cholesterol

and cholesteryl glucosides have no influence on the stability of the cell membrane conformation of *H. pylori*, and rather these steroidal compounds serve to strengthen the membrane lipid barrier of the bacteria on the limitation of the permeability of lipophilic compounds. A recent study by other group has demonstrated that cholesteryl glucosides are responsible for the morphological maintenance of *H. pylori*, for the acquirement of resistance to antibiotics such as polymyxin B, colistin, and tetracycline, and for the promotion of biofilm formation [47]. This suggests that cholesteryl glucosides of *H. pylori* play an important role to limit the membrane permeability of various low-molecular-weight compounds. However, VDP1 confers the bacteriolytic action even to *H. pylori* retaining cholesterol and cholesteryl glucosides. Further investigation will be necessary to clarify the detailed

intermolecular interactions between myristoyl-PE and steroidal compounds.

Almost all hydrophobic drugs are pharmacologically designed to inhibit the functions of either protein molecules or nucleic acids in the target creature species. However, no drugs that target a characteristic lipid molecule in the creatures are discovered for many years. In addition, a number of biochemists on lipid research leave great achievements in the analysis of biosynthetic enzymes of various lipophilic compounds such as fatty acids and complex lipids and in the identification of receptors of various hydrophobic ligands such as steroid hormones and eicosanoids. However, these achievements are not as for lipid itself but as for merely proteins. This chapter described the unique interaction between lipids: the indene compound species specifically disrupt the vesicular conformation consisting of DMPE. These findings will bring the new aspects to the drug discovery research and the lipid

This work was supported by a Grant-in-Aid from the Adaptable and Seamless

Technology Transfer Program through Target-Driven R&A (A-STEP), JSPS KAKENHI (grant number 15 K08006), and JKA promotion funds from KEIRIN

**50**

RACE.

Kiyofumi Wanibuchi1 , Hisashi Masui1 , Takashi Takahashi1 and Hirofumi Shimomura2 \*

1 Faculty of Pharmaceutical Sciences, Yokohama University of Pharmacy, Kanagawa, Japan

2 Independent Researcher, Kumamoto, Japan

\*Address all correspondence to: shimomura20090601@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[18] McGee DJ, George AE, Trainor EA, Horton KE, Hildebrandt E, Testerman TL. Cholesterol enhances *Helicobacter pylori* resistance to antibiotics and LL-37. Antimicrobial Agents and Chemotherapy. 2011;**55**:2897-2904

[19] Trainor EA, Horton KE, Savage PE, Testerman TL, McGee DJ. Role of the HefC efflux pump in *Helicobacter pylori* cholesterol-dependent resistance to ceragenins and bile salts. Infection and Immunity. 2011;**79**:88-97

[20] Correia M, Casal S, Vinagre J, Seruca R, Figueiredo C, Touati E, et al. *Helicobacter pylori*'s cholesterol uptake impacts resistance to docosahexanoic acid. International Journal of Medical Microbiology. 2014;**304**:314-320

[21] Shimomura H, Hosoda K, McGee DJ, Hayashi S, Yokota K, Hirai Y. Detoxification of 7-dehydrocholesterol fatal to *Helicobacter pylori* is a novel role of cholesterol glucosylation. Journal of Bacteriology. 2013;**195**:359-367

[22] Shimomura H, Hosoda K, Hayashi S, Yokota K, Hirai Y. Phosphatidylethanolamine of *Helicobacter pylori* functions as a steroidbinding lipid in the assimilation of free cholesterol and 3β-hydroxl steroids into the bacterial cell membrane. Journal of Bacteriology. 2012;**194**:2658-2667

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[24] Kearns DB, Robinson J, Shimkets LJ. *Pseudomonas aeruginosa* exhibits directed twitching motility

up phosphatidylethanolamine gradients. Journal of Bacteriology. 2001;**183**:763-767

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[28] Hosoda K, Shimomura H, Hayashi S, Yokota K, Hirai Y. Steroid hormones as bactericidal agents to *Helicobacter pylori*. FEMS Microbiology Letters. 2011;**318**:68-75

[29] Amgalanbaatar A, Shimomura H, Hosoda K, Hayashi S, Yokota K, Hirai Y. Antibacterial activity of a novel synthetic progesterone species carrying a linoleic acid molecule against *Helicobacter pylori* and the hormonal effect of its steroid on a murine macrophage-like cell line. The Journal of Steroid Biochemistry and Molecular Biology. 2014;**140**:17-25

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**52**

*Gastritis - New Approaches and Treatments*

[1] Marshall B, Warren JR. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet.

[10] Shimomura H, Hosoda K, Hirai Y. Interaction of *Helicobacter pylori* cell membrane with non-esterified cholesterol and other steroids. Open Journal of Medical Microbiology. 2013;**3**:70-79

[11] Hirai Y, Haque M, Yoshida T, Yokota K, Yasuda T, Oguma K. Unique cholesteryl glucosides in *Helicobacter pylori*: Composition and structural analysis. Journal of Bacteriology.

[12] Wunder C, Churin Y, Winau F, Warnecke D, Vieth M, Lindner B, et al. Cholesterol glucosylation promotes immune evasion by *Helicobacter pylori*. Nature Medicine. 2006;**12**:1030-1038

[13] Lebrun AH, Wunder C, Hildebrand J, Churin Y, Zähringer U, Lindner B, et al. Cloning of a cholesterol-αglucosyltransferase from *Helicobacter pylori*. The Journal of Biological Chemistry. 2006;**281**:27765-27772

[14] Lee H, Wang P, Hoshino H, Ito Y, Kobayashi M, Nakayama J, et al. α1,4-GlcNAc-capped mucintype *O*-glycan inhibits cholesterol α-glucosyltransferase from *Helicobacter pylori* and suppress *H. pylori* growth. Glycobiology. 2008;**18**:549-558

[15] Hoshino H, Tsuchida A, Kametani K, Mori M, Nishizawa T, Suzuki T, et al. Membrane-associated activation of cholesterol α-glucosyltransferase, an enzyme responsible for biosynthesis of cholesteryl-α-D-glucopyranoside in *Helicobacter pylori* critical for its survival. Journal of Histochemistry and

Cytochemistry. 2011;**59**:98-105

2016;**7**:6208-6216

[16] Jan HM, Chen YC, Shih YY, Huang YC, Tu Z, Ingle AB, et al. Metabolic labelling of cholesteryl glucosides in *Helicobacter pylori* reveals how the uptake of human lipids enhances bacterial virulence. Chemical Science.

1995;**177**:5327-5333

[2] Graham DY. *Helicobacter pylori*: Its epidemiology and its role in duodenal ulcer disease. Journal of Gastroenterology

[3] Forman D. The Eurogast study group. An international association between *Helicobacter pylori* infection and gastric cancer. Lancet. 1993;**341**:1359-1363

[4] Wotherspoon AC, Oriz-Hidalgo C, Falzon MR, Isaacson PG. *Helicobacter pylori*-associated gastritis and primary B-cell gastric lymphoma. Lancet.

[5] Uemura N, Okamoto S, Yamamoto S, Matsumura M, Yamaguchi S, Yamakido M, et al. *Helicobacter pylori* infection and the development of gastric cancer. The New England Journal of Medicine.

[6] Peek JRM, Blaser MJ. *Helicobacter pylori* and gastrointestinal tract adenocarcinoma. Nature Reviews

[7] Stolte M, Bayerdorffer E, Morgner A, Alpen B, Wundish T, Thiede C, et al. *Helicobacter* and gastric MALT lymphoma. Gut. 2002;**50**:III19-III24

[8] De Francesco V, Giorgio F, Hassan C, Manes G, Vannella L, Panella C, et al. Worldwide *H. pylori* antibiotic resistance: A systematic review. Journal of Gastrointestinal and Liver Diseases.

[9] Trifan A, Girleanu I, Cojocariu C, Sfarti C, Singeap AM, Dorobat C, et al. Pseudomembranous colitis associated with a triple therapy for *Helicobacter pylori* eradication. World Journal of Gastroenterology. 2013;**19**:7476-7479

and Hepatology. 1991;**6**:105-113

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1999;**338**:1175-1176

2001;**345**:829-832

Cancer. 2002;**2**:28-37

2010;**19**:409-414

[31] Windaus A, Grundmann W. Über die konstitution des vitamin D2. II. Justus Liebigs Annalen der Chemie. 1936;**524**:295-299

[32] Sicinski RR, DeLuca HF. Ruthenium tetroxide oxidation of Grundmann's ketone derivative from vitamin D3. Bioorganic and Medical Chemistry Letters. 1995;**5**:159-162

[33] Wanibuchi K, Hosoda K, Ihara M, Tajiri K, Sakai Y, Masui H, et al. Indene compounds synthetically derived from vitamin D have selective antibacterial action on *Helicobacter pylori*. Lipids. 2018;**53**:393-401

[34] Lee A, Hazell SL, O'Rourke J, Kouprach S. Isolation of a spiralshaped bacterium from the cat stomach. Infection and Immunity. 1988;**56**:2843-2850

[35] Paster BJ, Lee A, Fox JG, Dewhirst FE, Tordoff LA, Fraser GJ, et al. Phylogeny of *Helicobacter felis* sp. Nov., *Helicobacter musterae*, and related bacteria. International Journal of Systematic Bacteriology. 1991;**41**:31-38

[36] Hansen TK, Hansen PS, Nørgaard A, Nielsen H, Lee A, Andersen LP. *Helicobacter felis* does not stimulate human neutrophil oxidative burst in contrast to '*Gastrospirillum hominis*' and *Helicobacter pylori*. FEMS Immunology and Medical Microbiology. 2001;**30**:187-195

[37] Enno A, O'Rourke JL, Howlett CR, Jack A, Dixon MF, Lee A. MALTomalike lesions in the murine gastric mucosa after long-term infection with *Helicobacter felis*. The American Journal of Pathology. 1995;**147**:217-222

[38] Mohammadi M, Redline R, Nedrud J, Czinn S. Role of the host in pathogenesis of *Helicobacter*-associated gastritis: *H. felis* infection of inbred and congenic mouse strains. Infection and Immunity. 1996;**64**:238-245

[39] Amgalanbaatar A, Hosoda K, Shimomura H. Phosphatidylethanolamine, but not phosphatidylglycerol-cardiolipin, isolated from two species of *Helicobacter* binds cholesterol over cholesteryl ester. Lipids. 2015;**50**:799-804

[40] Kiehlbauch JA, Brenner DJ, Cameron DN, Steigenwalt AG, Makowski JM, Baker CN, et al. Genotypic and phenotypic characterization of *Helicobacter cinaedi* and *Helicobacter fennelliae* strains isolated from human and animals. Journal of Clinical Microbiology. 1995;**33**:2940-2947

[41] Gebhart CJ, Fennell CL, Murtaugh MP, Stamm WE. *Campylobacter cinaedi* is normal intestinal flora in hamsters. Journal of Clinical Microbiology. 1989;**27**:1692-1694

[42] Fox JG, Handt L, Sheppard BJ, Xu S, Dewhirst FE, Motzel S, et al. Isolation of *Helicobacter cinaedi* from the colon, liver, and mesenteric lymph node of a rhesus monkey with chronic colitis and hepatitis. Journal of Clinical Microbiology. 2001;**39**:1580-1585

[43] Mikkonen TP, Kärenlampi RI, Hänninen ML. Phylogenetic analysis of gastric and enterohepatic helicobacter species based on partial HSP60 gene sequences. International Journal of Systematic and Evolutionary Microbiology. 2004;**54**:753-758

[44] Fowsantear W, Argo E, Pattinson C, Cash P. Comparative proteomics of *Helicobacter* species: The discrimination of gastric and enterohepatic *Helicobacter* species. Journal of Proteomics. 2013;**97**:245-255

[45] Kawamura Y, Tomida J, Morita Y, Fujii S, Okamoto T, Akaike T. Clinical and bacteriological characteristics of *Helicobacter cinaedi* infection. Journal of Infection and Chemotherapy. 2014;**20**:517-526

**55**

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell…*

*DOI: http://dx.doi.org/10.5772/intechopen.86165*

[46] Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, et al. Bacterial endotoxin: Molecular relationship of structure to activity and function. The FASEB Journal.

[47] Qaria MA, Kumar N, Hussain A, Qumar S, Doddam SN, Sepe LP, et al. Roles of cholesteryl-α-glucoside transferase and cholesteryl glucosides in maintenance of *Helicobacter pylori* morphology, cell wall integrity, and resistance to antibiotics. Molecular Biology and Physiology.

1994;**8**:217-225

2018;**9**:e01523-e01518

*Development of a Novel Antibacterial Medicine that Targets a Characteristic Lipid of the Cell… DOI: http://dx.doi.org/10.5772/intechopen.86165*

[46] Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, et al. Bacterial endotoxin: Molecular relationship of structure to activity and function. The FASEB Journal. 1994;**8**:217-225

*Gastritis - New Approaches and Treatments*

[32] Sicinski RR, DeLuca HF. Ruthenium tetroxide oxidation of Grundmann's ketone derivative from vitamin D3. Bioorganic and Medical Chemistry

[39] Amgalanbaatar A, Hosoda K, Shimomura H.

Lipids. 2015;**50**:799-804

1995;**33**:2940-2947

1989;**27**:1692-1694

[40] Kiehlbauch JA, Brenner DJ, Cameron DN, Steigenwalt AG, Makowski JM, Baker CN, et al. Genotypic and phenotypic characterization of *Helicobacter cinaedi* and *Helicobacter fennelliae* strains isolated from human and animals. Journal of Clinical Microbiology.

Phosphatidylethanolamine, but not phosphatidylglycerol-cardiolipin, isolated from two species of *Helicobacter* binds cholesterol over cholesteryl ester.

[41] Gebhart CJ, Fennell CL, Murtaugh MP, Stamm WE. *Campylobacter cinaedi* is normal intestinal flora in hamsters. Journal of Clinical Microbiology.

[42] Fox JG, Handt L, Sheppard BJ, Xu S, Dewhirst FE, Motzel S, et al. Isolation of *Helicobacter cinaedi* from the colon, liver, and mesenteric lymph node of a rhesus monkey with chronic colitis and hepatitis. Journal of Clinical Microbiology. 2001;**39**:1580-1585

[43] Mikkonen TP, Kärenlampi RI, Hänninen ML. Phylogenetic analysis of gastric and enterohepatic helicobacter species based on partial HSP60 gene sequences. International Journal of Systematic and Evolutionary Microbiology. 2004;**54**:753-758

[44] Fowsantear W, Argo E, Pattinson C, Cash P. Comparative proteomics of *Helicobacter* species: The discrimination of gastric and enterohepatic *Helicobacter*

[45] Kawamura Y, Tomida J, Morita Y, Fujii S, Okamoto T, Akaike T. Clinical and bacteriological characteristics of *Helicobacter cinaedi* infection. Journal of Infection and Chemotherapy.

species. Journal of Proteomics.

2013;**97**:245-255

2014;**20**:517-526

[33] Wanibuchi K, Hosoda K, Ihara M, Tajiri K, Sakai Y, Masui H, et al. Indene compounds synthetically derived from vitamin D have selective antibacterial action on *Helicobacter pylori*. Lipids.

[34] Lee A, Hazell SL, O'Rourke J, Kouprach S. Isolation of a spiralshaped bacterium from the cat stomach. Infection and Immunity.

[35] Paster BJ, Lee A, Fox JG, Dewhirst FE, Tordoff LA, Fraser GJ, et al. Phylogeny of *Helicobacter felis* sp. Nov., *Helicobacter musterae*, and related bacteria. International Journal of Systematic Bacteriology. 1991;**41**:31-38

[36] Hansen TK, Hansen PS, Nørgaard A, Nielsen H, Lee A, Andersen LP. *Helicobacter felis* does not stimulate human neutrophil oxidative burst in contrast to '*Gastrospirillum hominis*' and *Helicobacter pylori*. FEMS

Immunology and Medical Microbiology.

[37] Enno A, O'Rourke JL, Howlett CR, Jack A, Dixon MF, Lee A. MALTomalike lesions in the murine gastric mucosa after long-term infection with *Helicobacter felis*. The American Journal

of Pathology. 1995;**147**:217-222

[38] Mohammadi M, Redline R, Nedrud J, Czinn S. Role of the host in pathogenesis of *Helicobacter*-associated gastritis: *H. felis* infection of inbred and congenic mouse strains. Infection and

Immunity. 1996;**64**:238-245

[31] Windaus A, Grundmann W. Über die konstitution des vitamin D2. II. Justus Liebigs Annalen der Chemie.

1936;**524**:295-299

Letters. 1995;**5**:159-162

2018;**53**:393-401

1988;**56**:2843-2850

2001;**30**:187-195

**54**

[47] Qaria MA, Kumar N, Hussain A, Qumar S, Doddam SN, Sepe LP, et al. Roles of cholesteryl-α-glucoside transferase and cholesteryl glucosides in maintenance of *Helicobacter pylori* morphology, cell wall integrity, and resistance to antibiotics. Molecular Biology and Physiology. 2018;**9**:e01523-e01518

**57**

**Chapter 4**

**Abstract**

**1. Introduction**

Pharmacotherapy of Peptic Ulcer

Peptic ulcers have unquestionably been a disease of the twentieth century. Epidemiological data for this disease and its complications have shown striking variation in incidence and prevalence. Various drugs have been used to treat peptic ulcer disease like proton-pump inhibitors, histamine (H2) receptor antagonists, prostaglandin analogues and sucralfate. Because these drugs are complex, expensive and toxic, efforts have been constantly made to find a suitable, palliative and curative agent for the treatment of peptic ulcer disease from natural products of plant and animal origin. Recently, antioxidants are being used to treat peptic ulcer disease. Antioxidants help in scavenging the free radicals and controlling the oxida-

Disease and Latest Research

*Balaji Ommurugan and Vanishree Rao*

tive stress responsible for the progression of peptic ulcer.

**Keywords:** gastritis, gastric ulcers, oxidative stress, antioxidant treatment

Peptic ulcers have unquestionably been a disease of the twentieth century. Epidemiological data for this disease and its complications have shown striking variation in incidence and prevalence. Peptic ulcer is defined as a local defect or excavation on the surface of the stomach with a mucosal break of diameter 5 mm or larger, usually produced by sloughing of the inflammatory necrotic tissue. Aetiology of peptic ulcer is fiercely debated and is believed that peptic ulcers develop due to imbalance between aggressive factors (*Helicobacter pylori*, nonsteroidal anti-inflammatory drugs, gastric acid) and protective factors (mucin, bicarbonate, prostaglandins) leading to interruption of mucosal integrity [1].

The major forms of peptic ulcer include chronic duodenal ulcer, chronic gastric ulcer, Zollinger-Ellison syndrome (ZES), drug-induced ulcers and stress-induced peptic ulcer. Various factors are implicated to play a pivotal role in pathogenesis of ulceration like sedentary life style, alcohol, smoking, spicy food, physiological stress, drugs like non-steroidal anti-inflammatory drugs (NSAIDs) and various bacterial infections [1]. Oxidative stress has emerged as one of the major pathogenic factors in progression of ulcer as it directly impairs the cellular function and promotes cellular organelle damage in mitochondria, lysosomes and nucleus [2]. Stress-induced peptic ulcer is a pathological condition affecting the gastrointestinal tract. Stress ulcers are commonly found in the gastric mucosa anywhere within the stomach to the duodenum. Pathogenesis is mainly due to reduction in mucosal blood flow or a breakdown in other normal mucosal defence mechanisms. Effective therapy remains elusive in the treatment of stress-induced peptic ulcers [3]. One of the common denominators for the occurrence of the disease is involvement of

#### **Chapter 4**

## Pharmacotherapy of Peptic Ulcer Disease and Latest Research

*Balaji Ommurugan and Vanishree Rao*

#### **Abstract**

Peptic ulcers have unquestionably been a disease of the twentieth century. Epidemiological data for this disease and its complications have shown striking variation in incidence and prevalence. Various drugs have been used to treat peptic ulcer disease like proton-pump inhibitors, histamine (H2) receptor antagonists, prostaglandin analogues and sucralfate. Because these drugs are complex, expensive and toxic, efforts have been constantly made to find a suitable, palliative and curative agent for the treatment of peptic ulcer disease from natural products of plant and animal origin. Recently, antioxidants are being used to treat peptic ulcer disease. Antioxidants help in scavenging the free radicals and controlling the oxidative stress responsible for the progression of peptic ulcer.

**Keywords:** gastritis, gastric ulcers, oxidative stress, antioxidant treatment

#### **1. Introduction**

Peptic ulcers have unquestionably been a disease of the twentieth century. Epidemiological data for this disease and its complications have shown striking variation in incidence and prevalence. Peptic ulcer is defined as a local defect or excavation on the surface of the stomach with a mucosal break of diameter 5 mm or larger, usually produced by sloughing of the inflammatory necrotic tissue. Aetiology of peptic ulcer is fiercely debated and is believed that peptic ulcers develop due to imbalance between aggressive factors (*Helicobacter pylori*, nonsteroidal anti-inflammatory drugs, gastric acid) and protective factors (mucin, bicarbonate, prostaglandins) leading to interruption of mucosal integrity [1].

The major forms of peptic ulcer include chronic duodenal ulcer, chronic gastric ulcer, Zollinger-Ellison syndrome (ZES), drug-induced ulcers and stress-induced peptic ulcer. Various factors are implicated to play a pivotal role in pathogenesis of ulceration like sedentary life style, alcohol, smoking, spicy food, physiological stress, drugs like non-steroidal anti-inflammatory drugs (NSAIDs) and various bacterial infections [1]. Oxidative stress has emerged as one of the major pathogenic factors in progression of ulcer as it directly impairs the cellular function and promotes cellular organelle damage in mitochondria, lysosomes and nucleus [2].

Stress-induced peptic ulcer is a pathological condition affecting the gastrointestinal tract. Stress ulcers are commonly found in the gastric mucosa anywhere within the stomach to the duodenum. Pathogenesis is mainly due to reduction in mucosal blood flow or a breakdown in other normal mucosal defence mechanisms. Effective therapy remains elusive in the treatment of stress-induced peptic ulcers [3]. One of the common denominators for the occurrence of the disease is involvement of

free radicals, an increase in histamine release and decreased mucous production. Reactive oxygen species are generated by various metabolic activities, and antioxidant enzymes like superoxide dismutase, catalase, lipid peroxidase and glutathione peroxidase control their accumulation. Any imbalance in the activity of these enzymes leads to faulty disposal of free radical and their accumulation [4].

Alcohol is one of the leading causes of peptic ulcer disease. The mechanism of ethanol-induced gastric lesions is varied including the depletion of gastric mucus content, damaged mucosal blood flow and mucosal cell injury. It decreases bicarbonate and mucus production by which it produces necrotic lesion in gastric mucosa. Ethanol initiates apoptosis which leads to cell death. It also releases superoxide dismutase and hydroperoxyl free radical species in the biological system [4].

Various drugs have been used to treat peptic ulcer disease like proton-pump inhibitors, histamine (H2) receptor antagonists, prostaglandin analogues and sucralfate. Because these drugs are complex, expensive and toxic, efforts have been constantly made to find a suitable, palliative and curative agent for the treatment of peptic ulcer disease from natural products of plant and animal origin. Recently antioxidants are being used to treat peptic ulcer disease. Antioxidants help in scavenging the free radicals and controlling the oxidative stress responsible for the progression of peptic ulcer [2]. Coenzyme Q10 (CoQ10) and L-glutamine have antioxidant property, and their role as antioxidants has been documented in the literature in treating medical conditions [5–8].

#### **2. Historical aspect**

Gastric acid secretion had always been the topic of debate for the last 100 years with greater emphasis thrown on molecular as well cellular mechanisms involved in gastric acid secretion. Gastric juice was chemically analysed, and hydrochloric acid (HCL) was first isolated from gastric juice in 1824 by William Prout [9]. After the discovery of histamine (H2) receptor by James Black in 1971, antagonists were available for the treatment of peptic ulcer [10]. After the scintillating discovery of proton-pump inhibitors in 1989, the treatment of peptic ulcer was revolutionized as it blocks the final step of acid synthesis in the stomach lumen.

#### **2.1 Gastric acid regulation**

#### *2.1.1 Central regulation*

The central nervous system and enteric nervous system play a major role in the regulation of acid secretion along with hormones, paracrine agents as well as second messengers. The acid secretion occurs in three phases, namely, the cephalic, gastric, and intestinal phases [11]. The dorsal motor nucleus of the vagus (DMNV), the nucleus tractus solitarius (NTS) and the hypothalamus play a major role in central regulation of acid secretion. The DMNV plays a crucial role in integrating the sensory input from the hypothalamus and visceral input from the NTS and supplies efferent fibres to the stomach via the vagus, thereby primarily helping in motility rather than secretion. The ventromedial hypothalamus exerts an inhibitory influence on acid secretion with its stimulation causing decreased acid secretion and vice versa [11]. The sensory receptors of the stomach present within the muscle layer as well as mucosa of the stomach help in detecting the mechanical, chemical as well as the thermal stimuli, and these sensory impulses are carried to the central nervous system via sympathetic afferent as well as the vagal nerve fibres [11].

**59**

*Pharmacotherapy of Peptic Ulcer Disease and Latest Research*

and calcium-sensitive pathway resulting in stimulation of H<sup>+</sup>

epithelial barrier with parietal cells at the base of the gland [19].

*2.2.1 Stimulation of mucus and bicarbonate secretion*

*2.2.2 Strengthening of gastric mucosal barrier*

*2.2.3 Regulation of mucosal blood flow*

neutralisation and in absorption of injurious agents [25].

Intrinsic mechanisms of the stomach regulate acid secretion, and these include neural stimulation via the vagus and gastrin and histamine release from G cells and enterochromaffin-like (ECL) cells, respectively. All these stimuli directly act on the parietal cells. Acetylcholine also helps in the regulation of acid secretion [12]. The histamine released acts on the histamine receptor type 2 (H2) on the parietal cells, leading to activation of cyclic adenosine monophosphate pathway

The term cytoprotection coined by Robert is defined as protection against gastric mucosal injury by mechanisms other than neutralisation of gastric acid [14]. An explosion of investigations led to the discovery that endogenous prostaglandins are involved in cytoprotection via putative mechanisms which includes mucus secretion, release of bicarbonate, maintenance and strengthening of mucosal blood flow and free radical scavenging [15–18]. The normal gastric mucosa without exogenous insult remains hostile to the acidic milieu of gastric lumen. Gastric mucosal defence can be categorised into pre-epithelial defence which is secretion of mucus gel, epithelial defence with surface epithelial cells withstanding pH <2.5 and the post-

The mucus barrier is made of mucus, lipids and proteins. These form a continuous gel and along with bicarbonate secretion protect the stomach from acidic insult [20]. Cytoprotective agents like prostaglandins have shown to increase the mucus gel thickness but does not protect the surface epithelium in contrast to protection of the deeper layers [21]. Mucin also helps in reepithelization of mucosa. It was identified that bicarbonate helps in cytoprotection and acts by metabolically dependent process as well as by passive diffusion [22]. Prostaglandins help in increasing the bicarbonate secretion, and bicarbonate in turn forms the mucus bicarbonate barrier [23]. Bicarbonate also directly helps in lowering the hydrogen ion concentration in

The apical membrane, the so-called tight junctions between the surface epithelial cells, prevents back diffusion of acid and hence forms a major mucosal barrier. Phospholipids on the luminal surface of gastric epithelium form a hydrophobic lining and thereby contribute in preventing the water-soluble hydrogen ions to pass through. Prostaglandins increase concentration of these

Vascular injuries to sub-epithelial capillaries with increased vascular permeability and circulatory stasis lead to functional impairment of gastric microcirculation. Upregulation of mucosal blood flow maintains oxygenation and nutrient supply. Increase in blood supply to mucosa helps in regulating bicarbonate mediated acid

K<sup>+</sup>


*DOI: http://dx.doi.org/10.5772/intechopen.86386*

**2.2 Mechanisms of cytoprotection**

*2.1.2 Peripheral mechanism*

parietal cells [13].

the gastric mucosa [14].

phospholipids [24].

#### *2.1.2 Peripheral mechanism*

*Gastritis - New Approaches and Treatments*

literature in treating medical conditions [5–8].

it blocks the final step of acid synthesis in the stomach lumen.

system via sympathetic afferent as well as the vagal nerve fibres [11].

system [4].

**2. Historical aspect**

**2.1 Gastric acid regulation**

*2.1.1 Central regulation*

free radicals, an increase in histamine release and decreased mucous production. Reactive oxygen species are generated by various metabolic activities, and antioxidant enzymes like superoxide dismutase, catalase, lipid peroxidase and glutathione peroxidase control their accumulation. Any imbalance in the activity of these enzymes leads to faulty disposal of free radical and their accumulation [4].

Alcohol is one of the leading causes of peptic ulcer disease. The mechanism of ethanol-induced gastric lesions is varied including the depletion of gastric mucus content, damaged mucosal blood flow and mucosal cell injury. It decreases bicarbonate and mucus production by which it produces necrotic lesion in gastric mucosa. Ethanol initiates apoptosis which leads to cell death. It also releases superoxide dismutase and hydroperoxyl free radical species in the biological

Various drugs have been used to treat peptic ulcer disease like proton-pump inhibitors, histamine (H2) receptor antagonists, prostaglandin analogues and sucralfate. Because these drugs are complex, expensive and toxic, efforts have been constantly made to find a suitable, palliative and curative agent for the treatment of peptic ulcer disease from natural products of plant and animal origin. Recently antioxidants are being used to treat peptic ulcer disease. Antioxidants help in scavenging the free radicals and controlling the oxidative stress responsible for the progression of peptic ulcer [2]. Coenzyme Q10 (CoQ10) and L-glutamine have antioxidant property, and their role as antioxidants has been documented in the

Gastric acid secretion had always been the topic of debate for the last 100 years with greater emphasis thrown on molecular as well cellular mechanisms involved in gastric acid secretion. Gastric juice was chemically analysed, and hydrochloric acid (HCL) was first isolated from gastric juice in 1824 by William Prout [9]. After the discovery of histamine (H2) receptor by James Black in 1971, antagonists were available for the treatment of peptic ulcer [10]. After the scintillating discovery of proton-pump inhibitors in 1989, the treatment of peptic ulcer was revolutionized as

The central nervous system and enteric nervous system play a major role in the regulation of acid secretion along with hormones, paracrine agents as well as second messengers. The acid secretion occurs in three phases, namely, the cephalic, gastric, and intestinal phases [11]. The dorsal motor nucleus of the vagus (DMNV), the nucleus tractus solitarius (NTS) and the hypothalamus play a major role in central regulation of acid secretion. The DMNV plays a crucial role in integrating the sensory input from the hypothalamus and visceral input from the NTS and supplies efferent fibres to the stomach via the vagus, thereby primarily helping in motility rather than secretion. The ventromedial hypothalamus exerts an inhibitory influence on acid secretion with its stimulation causing decreased acid secretion and vice versa [11]. The sensory receptors of the stomach present within the muscle layer as well as mucosa of the stomach help in detecting the mechanical, chemical as well as the thermal stimuli, and these sensory impulses are carried to the central nervous

**58**

Intrinsic mechanisms of the stomach regulate acid secretion, and these include neural stimulation via the vagus and gastrin and histamine release from G cells and enterochromaffin-like (ECL) cells, respectively. All these stimuli directly act on the parietal cells. Acetylcholine also helps in the regulation of acid secretion [12]. The histamine released acts on the histamine receptor type 2 (H2) on the parietal cells, leading to activation of cyclic adenosine monophosphate pathway and calcium-sensitive pathway resulting in stimulation of H<sup>+</sup> K<sup>+</sup> -ATPase on parietal cells [13].

#### **2.2 Mechanisms of cytoprotection**

The term cytoprotection coined by Robert is defined as protection against gastric mucosal injury by mechanisms other than neutralisation of gastric acid [14]. An explosion of investigations led to the discovery that endogenous prostaglandins are involved in cytoprotection via putative mechanisms which includes mucus secretion, release of bicarbonate, maintenance and strengthening of mucosal blood flow and free radical scavenging [15–18]. The normal gastric mucosa without exogenous insult remains hostile to the acidic milieu of gastric lumen. Gastric mucosal defence can be categorised into pre-epithelial defence which is secretion of mucus gel, epithelial defence with surface epithelial cells withstanding pH <2.5 and the postepithelial barrier with parietal cells at the base of the gland [19].

#### *2.2.1 Stimulation of mucus and bicarbonate secretion*

The mucus barrier is made of mucus, lipids and proteins. These form a continuous gel and along with bicarbonate secretion protect the stomach from acidic insult [20]. Cytoprotective agents like prostaglandins have shown to increase the mucus gel thickness but does not protect the surface epithelium in contrast to protection of the deeper layers [21]. Mucin also helps in reepithelization of mucosa. It was identified that bicarbonate helps in cytoprotection and acts by metabolically dependent process as well as by passive diffusion [22]. Prostaglandins help in increasing the bicarbonate secretion, and bicarbonate in turn forms the mucus bicarbonate barrier [23]. Bicarbonate also directly helps in lowering the hydrogen ion concentration in the gastric mucosa [14].

#### *2.2.2 Strengthening of gastric mucosal barrier*

The apical membrane, the so-called tight junctions between the surface epithelial cells, prevents back diffusion of acid and hence forms a major mucosal barrier. Phospholipids on the luminal surface of gastric epithelium form a hydrophobic lining and thereby contribute in preventing the water-soluble hydrogen ions to pass through. Prostaglandins increase concentration of these phospholipids [24].

#### *2.2.3 Regulation of mucosal blood flow*

Vascular injuries to sub-epithelial capillaries with increased vascular permeability and circulatory stasis lead to functional impairment of gastric microcirculation. Upregulation of mucosal blood flow maintains oxygenation and nutrient supply. Increase in blood supply to mucosa helps in regulating bicarbonate mediated acid neutralisation and in absorption of injurious agents [25].

#### *2.2.4 Effects on gastric motility*

Mucosal compression is said to play an important role in epithelial necrosis and ulceration. Gastric hypercontraction accounts for mucosal compression. The gastric mucosa is protected by the action of circular muscles which causes flattening of gastric mucosal folds, thereby leading to increase in mucosal surface area ultimately reducing volume of irritants coming in contact with the mucosa. Various substances like prostaglandins and mast cell stabilisers aid in this process adding to cytoprotection [26].

#### *2.2.5 Scavenging free radicals*

Free radicals cause lipid peroxidation and damage to intracellular components. It leads to ischemia of gastric mucosa, thereby causing severe damage to the mucosa. Vitamin E and selenium are well-known antioxidants shown to have protective effect on stress and chemical-induced gastric lesions [27].

#### *2.2.6 Endogenous mediators on gastric cytoprotection*

Prostaglandins, L-cysteine, methionine and epidermal growth factor are said to be cytoprotective. Imbalance between two metabolites of arachidonic pathway is also said to contribute to gastric injury. Literature data suggests prostaglandins help in gastric protection by increasing the gastric blood supply and decreasing the synthesis of leukotrienes, thus playing a significant role in cytoprotection [28]. Therefore, cytoprotection is a multifactorial phenomenon.

#### **2.3 Pathogenesis of peptic ulcer**

Peptic ulcers are chronic with ~99% ulcers occurring in the duodenum and stomach with the former being four times higher than the latter [29]. Factors causing peptic ulcers include increased acid secretion, impaired mucosal defence, free radical and lipid peroxidation.

#### *2.3.1 Increased acid secretion*

Pepsin activity in gastric juice and acidity of gastric juice are important determinants of ulcer formation. The famous Schwartz's dictum "no acid-no ulcer" becomes accurate when amplified to "no acid and peptic activity", as pepsin contributes to the digestive power of the stomach. This dictum is supported by various therapeutic drugs like antacids and anti-secretory drugs, but much to everyone's anguish, ulcer recurs once therapy is stopped [30].

#### *2.3.2 Impaired mucosal defence*

The tight epithelial junctions form a barrier preventing hydrogen ion back diffusion. Recent evidences suggest surface phospholipids form a hydrophobic lining on the gastric epithelium and hence retard the passage of hydrogen ions. NSAIDS and *Helicobacter pylori* infection disrupt the mucosal barrier and are known to increase the diffusion of hydrogen ions [31].

#### *2.3.3 Free radical and peroxidation*

Free radical contains unpaired electrons, and it plays an important role in pathogenesis of ischemia/reperfusion injury. Free radicals can nick deoxyribonucleic acid

**61**

*2.4.5 Alcohol*

*Pharmacotherapy of Peptic Ulcer Disease and Latest Research*

**2.4 Predisposing factors for peptic ulceration**

(DNA) and provoke uncontrolled chain reactions like lipid peroxidation. Acute and chronic gastric ulcers are caused by oxygen-derived free radicals, and in one study, infusion of superoxide-generating system into rat celiac artery-induced gastrointes-

*Helicobacter pylori* causes antral gastritis in more than 95% of patients with duodenal ulcer than 75% with gastric ulcer. This organism adheres to the mucosal epithelium close to the gap junctions and releases urea and ammonia producing an alkaline environment with raised pH. This creates an environment for the organism to survive, and release of ammonia is cytotoxic to the gastric cells. Gastric metaplasia occurs, and colonisation of these heterotrophic islands results in mucosal injury and gastric ulceration. Oxidative stress has been implicated in the pathogenesis of *Helicobacter pylori* infections, and increased oxidative damage by *Helicobacter pylori* is responsible for epithelial injury, altered epithelial prolifera-

NSAIDs are known to cause various injuries in the gastric tract ranging from haemorrhages and petechiae to erosions with ulcers. These drugs are known to cause mucus glycoprotein denaturation in the stomach and sloughing of epithelial cells. Also, drugs like aspirin causes intracellular protons to accumulate in the parietal cells and leads to localised acid accumulation by the process called back diffusion of acid. These drugs also cause labialization of lysosomes leading to cellular autolytic reactions, inhibition of prostaglandins and mast cell degranulation leading to histamine release, inhibition of glucose oxidation and enzymes involved

in anabolic reactions. It also increases the production of free radicals [34].

Healing of ulcers is affected by smoking, and it is a known fact that gastric ulcers occur more frequently in smokers. Various theories are put forward as to why cigarette smoking causes ulcers, and some of them includes stimulation of acid secretion, blood flow alteration to gastric mucosa, induction of bile reflux and

The CNS and brain gut axis play an important role in stress ulcerogenesis. Various conditions like shock, sepsis, trauma and neurological disorders are now regarded as multifactorial phenomenon. Various interactions between vascular, mucosal and neurohumoral factors and the autonomic nervous system play a critical role in stress ulcerogenesis. Limbic area plays a pertinent role in modulating acid

Ethanol causes cell and plasma membrane damage leading to increased membrane permeability finally causing accumulation of sodium and water. It also causes

*DOI: http://dx.doi.org/10.5772/intechopen.86386*

tinal bleeding was shown [32].

tion and increased apoptosis [33].

*2.4.3 Cigarette smoking*

*2.4.4 Psychological stress*

reduced prostaglandin synthesis [35].

secretion, motility and blood flow [36].

*2.4.2 Non-steroidal anti-inflammatory drugs*

*2.4.1 Helicobacter infection*

(DNA) and provoke uncontrolled chain reactions like lipid peroxidation. Acute and chronic gastric ulcers are caused by oxygen-derived free radicals, and in one study, infusion of superoxide-generating system into rat celiac artery-induced gastrointestinal bleeding was shown [32].

#### **2.4 Predisposing factors for peptic ulceration**

#### *2.4.1 Helicobacter infection*

*Gastritis - New Approaches and Treatments*

Mucosal compression is said to play an important role in epithelial necrosis and ulceration. Gastric hypercontraction accounts for mucosal compression. The gastric mucosa is protected by the action of circular muscles which causes flattening of gastric mucosal folds, thereby leading to increase in mucosal surface area ultimately reducing volume of irritants coming in contact with the mucosa. Various substances like prostaglandins and mast cell stabilisers aid in this process adding to cytoprotection [26].

Free radicals cause lipid peroxidation and damage to intracellular components. It leads to ischemia of gastric mucosa, thereby causing severe damage to the mucosa. Vitamin E and selenium are well-known antioxidants shown to have protective

Prostaglandins, L-cysteine, methionine and epidermal growth factor are said to be cytoprotective. Imbalance between two metabolites of arachidonic pathway is also said to contribute to gastric injury. Literature data suggests prostaglandins help in gastric protection by increasing the gastric blood supply and decreasing the synthesis of leukotrienes, thus playing a significant role in cytoprotection [28].

Peptic ulcers are chronic with ~99% ulcers occurring in the duodenum and stomach with the former being four times higher than the latter [29]. Factors causing peptic ulcers include increased acid secretion, impaired mucosal defence, free

Pepsin activity in gastric juice and acidity of gastric juice are important determinants of ulcer formation. The famous Schwartz's dictum "no acid-no ulcer" becomes accurate when amplified to "no acid and peptic activity", as pepsin contributes to the digestive power of the stomach. This dictum is supported by various therapeutic drugs like antacids and anti-secretory drugs, but much to everyone's

The tight epithelial junctions form a barrier preventing hydrogen ion back diffusion. Recent evidences suggest surface phospholipids form a hydrophobic lining on the gastric epithelium and hence retard the passage of hydrogen ions. NSAIDS and *Helicobacter pylori* infection disrupt the mucosal barrier and are known to increase

Free radical contains unpaired electrons, and it plays an important role in pathogenesis of ischemia/reperfusion injury. Free radicals can nick deoxyribonucleic acid

effect on stress and chemical-induced gastric lesions [27].

Therefore, cytoprotection is a multifactorial phenomenon.

anguish, ulcer recurs once therapy is stopped [30].

*2.2.6 Endogenous mediators on gastric cytoprotection*

*2.2.4 Effects on gastric motility*

*2.2.5 Scavenging free radicals*

**2.3 Pathogenesis of peptic ulcer**

radical and lipid peroxidation.

*2.3.1 Increased acid secretion*

*2.3.2 Impaired mucosal defence*

the diffusion of hydrogen ions [31].

*2.3.3 Free radical and peroxidation*

**60**

*Helicobacter pylori* causes antral gastritis in more than 95% of patients with duodenal ulcer than 75% with gastric ulcer. This organism adheres to the mucosal epithelium close to the gap junctions and releases urea and ammonia producing an alkaline environment with raised pH. This creates an environment for the organism to survive, and release of ammonia is cytotoxic to the gastric cells. Gastric metaplasia occurs, and colonisation of these heterotrophic islands results in mucosal injury and gastric ulceration. Oxidative stress has been implicated in the pathogenesis of *Helicobacter pylori* infections, and increased oxidative damage by *Helicobacter pylori* is responsible for epithelial injury, altered epithelial proliferation and increased apoptosis [33].

#### *2.4.2 Non-steroidal anti-inflammatory drugs*

NSAIDs are known to cause various injuries in the gastric tract ranging from haemorrhages and petechiae to erosions with ulcers. These drugs are known to cause mucus glycoprotein denaturation in the stomach and sloughing of epithelial cells. Also, drugs like aspirin causes intracellular protons to accumulate in the parietal cells and leads to localised acid accumulation by the process called back diffusion of acid. These drugs also cause labialization of lysosomes leading to cellular autolytic reactions, inhibition of prostaglandins and mast cell degranulation leading to histamine release, inhibition of glucose oxidation and enzymes involved in anabolic reactions. It also increases the production of free radicals [34].

#### *2.4.3 Cigarette smoking*

Healing of ulcers is affected by smoking, and it is a known fact that gastric ulcers occur more frequently in smokers. Various theories are put forward as to why cigarette smoking causes ulcers, and some of them includes stimulation of acid secretion, blood flow alteration to gastric mucosa, induction of bile reflux and reduced prostaglandin synthesis [35].

#### *2.4.4 Psychological stress*

The CNS and brain gut axis play an important role in stress ulcerogenesis. Various conditions like shock, sepsis, trauma and neurological disorders are now regarded as multifactorial phenomenon. Various interactions between vascular, mucosal and neurohumoral factors and the autonomic nervous system play a critical role in stress ulcerogenesis. Limbic area plays a pertinent role in modulating acid secretion, motility and blood flow [36].

#### *2.4.5 Alcohol*

Ethanol causes cell and plasma membrane damage leading to increased membrane permeability finally causing accumulation of sodium and water. It also causes

**Figure 1.** *Pathogenesis of peptic ulcer.*

free radical release leading to lipid peroxidation causing gastric lesions. Patients with cirrhosis due to alcohol also have increased incidence of peptic ulcer [37] (**Figure 1**).

#### **2.5 Therapy for acute peptic ulcer**

Gastric acid secretion and mucosal defence mechanism have been the target to treat peptic ulcer disease. This has led to discovery of many drugs to treat peptic ulcer disease, and few treatment options have stood the test of time as shown in **Table 1** [38].

#### *2.5.1 H+ /K+ ATPase inhibitors*

It acts by directly blocking the gastric proton pump rather than blocking histamine and cholinergic receptors. There are many drugs available in this class, namely, omeprazole, lansoprazole, rabeprazole and pantoprazole. They block the final step in the acid secretion and thereby have better control over basal as well as nocturnal acid secretion. They are also known to inhibit the growth of *Helicobacter pylor*i [38]. They are now used as first-line agents in the treatment of peptic ulcer, and it has replaced H2 antagonists.

#### *2.5.2 Prostaglandins*

Robert in 1979 showed prostaglandins inhibit gastric acid secretion and help in protection against ulcers caused by NSAIDs, diet, alcohol, smoking and stress. Misoprostol, a prostaglandin analogue, acts by increasing the secretion of mucus as well as bicarbonate, thereby protecting against chronic ulcers. But it helps only in protection against gastric ulcer and not against duodenal ulcers [39]. It is contraindicated in pregnancy due to its abortifacient property. Enprostil, rioprostil and arbaprostil are other known compounds. Other drugs in clinical trials are nocloprost, enisoprost and mexiprost [39].

**63**

*Pharmacotherapy of Peptic Ulcer Disease and Latest Research*

**Class of drugs Mechanisms Use**

*PPI = proton-pump inhibitor, NSAID = non-steroidal anti-inflammatory drug\**

*DOI: http://dx.doi.org/10.5772/intechopen.86386*

**H2 receptor antagonists** (cimetidine, ranitidine, famotidine, nizatidine, roxatidine)

**Prostaglandin analogues**

)

**Bismuth salts** (subcitrate,

*H. pylori* **eradication regimens** (PPI plus two antibiotics)

esomeprazole)

(misoprostol\*

subsalicylate)

**Table 1.**

**PPI** (omeprazole, pantoprazole, lansoprazole, rabeprazole,

*2.5.3 H2 receptor antagonists*

healing is a frequent complication [40].

*Class of drugs with effect on healing of peptic ulcer.*

*2.5.4 Muscarinic receptor antagonists*

well as stimulated acid secretion [41].

*2.5.5 Mucosal coating agents*

*Helicobacter pylori* infection [42].

**3. Coenzyme Q10**

These drugs act by blocking the H2 receptor and thereby reduce the release of gastric acid. It is very helpful in reducing 90% of the basal, food-stimulated and nocturnal secretion of gastric acid as well. Literature evidence says it also helps in prevention of stress-induced gastric ulcers. They are used in combination with antacids in the treatment of stress-induced ulcers. These drugs include mainly ranitidine, cimetidine, famotidine and nizatidine. One of the major drawbacks is long duration of administration for ulcer therapy, and recurrence of ulcer after

Increase mucosal resistance; weak acid inhibition

Weak antibacterial effect; increase of mucosal prostaglandin synthesis

Acid inhibition *H. pylori*-negative peptic ulcer; replaced

Cure of *H. pylori* infection Standard therapy in all *H. pylori*-positive ulcers

eradication

Most potent acid inhibition Standard treatment for all *H. pylori*-

suppression

by PPI because of inferiority in acid

negative peptic ulcers; prevention of NSAID or aspirin ulcers; essential component in eradication regimen; given intravenously in bleeding ulcers

*H. pylori*-negative gastric ulcer; prevention of NSAID ulcers

In quadruple therapy for *H. pylori*

*Contraindicated in pregnancy*

Pirenzepine has more cytoprotective effects when compared with histamine receptor antagonists. It helps in protection against gastric mucosal lesions induced by alcohol, sodium hydroxide (NAOH) and taurocholate. It exerts its action via inhibition of muscarinic (M1) receptor present in the stomach and reduces basal as

Sucralfate is a basic sulphated disaccharide with aluminium sulphate complex. It helps in forming an adherent coating at the mucosal sites which are ulcerated. It acts by reducing pepsin activity, adsorbs bile salts and acts as barrier to hydrogen ion diffusion. It also binds to both epidermal growth factor (EGF) and fibroblast growth factor (FGF) and helps in enhancing ulcer healing. It is found effective in

Morton in 1955 in Liverpool identified a quinone-like substance with an ultraviolet absorption at 272 nm from intestinal mucosa of horses and named it as ubiquinone.

*Pharmacotherapy of Peptic Ulcer Disease and Latest Research DOI: http://dx.doi.org/10.5772/intechopen.86386*


#### **Table 1.**

*Gastritis - New Approaches and Treatments*

**2.5 Therapy for acute peptic ulcer**

 *ATPase inhibitors*

and it has replaced H2 antagonists.

prost, enisoprost and mexiprost [39].

in **Table 1** [38].

*/K+*

*2.5.2 Prostaglandins*

*2.5.1 H+*

**Figure 1.**

*Pathogenesis of peptic ulcer.*

free radical release leading to lipid peroxidation causing gastric lesions. Patients with cirrhosis due to alcohol also have increased incidence of peptic ulcer [37] (**Figure 1**).

Gastric acid secretion and mucosal defence mechanism have been the target to treat peptic ulcer disease. This has led to discovery of many drugs to treat peptic ulcer disease, and few treatment options have stood the test of time as shown

It acts by directly blocking the gastric proton pump rather than blocking histamine and cholinergic receptors. There are many drugs available in this class, namely, omeprazole, lansoprazole, rabeprazole and pantoprazole. They block the final step in the acid secretion and thereby have better control over basal as well as nocturnal acid secretion. They are also known to inhibit the growth of *Helicobacter pylor*i [38]. They are now used as first-line agents in the treatment of peptic ulcer,

Robert in 1979 showed prostaglandins inhibit gastric acid secretion and help in protection against ulcers caused by NSAIDs, diet, alcohol, smoking and stress. Misoprostol, a prostaglandin analogue, acts by increasing the secretion of mucus as well as bicarbonate, thereby protecting against chronic ulcers. But it helps only in protection against gastric ulcer and not against duodenal ulcers [39]. It is contraindicated in pregnancy due to its abortifacient property. Enprostil, rioprostil and arbaprostil are other known compounds. Other drugs in clinical trials are noclo-

**62**

*Class of drugs with effect on healing of peptic ulcer.*

#### *2.5.3 H2 receptor antagonists*

These drugs act by blocking the H2 receptor and thereby reduce the release of gastric acid. It is very helpful in reducing 90% of the basal, food-stimulated and nocturnal secretion of gastric acid as well. Literature evidence says it also helps in prevention of stress-induced gastric ulcers. They are used in combination with antacids in the treatment of stress-induced ulcers. These drugs include mainly ranitidine, cimetidine, famotidine and nizatidine. One of the major drawbacks is long duration of administration for ulcer therapy, and recurrence of ulcer after healing is a frequent complication [40].

#### *2.5.4 Muscarinic receptor antagonists*

Pirenzepine has more cytoprotective effects when compared with histamine receptor antagonists. It helps in protection against gastric mucosal lesions induced by alcohol, sodium hydroxide (NAOH) and taurocholate. It exerts its action via inhibition of muscarinic (M1) receptor present in the stomach and reduces basal as well as stimulated acid secretion [41].

#### *2.5.5 Mucosal coating agents*

Sucralfate is a basic sulphated disaccharide with aluminium sulphate complex. It helps in forming an adherent coating at the mucosal sites which are ulcerated. It acts by reducing pepsin activity, adsorbs bile salts and acts as barrier to hydrogen ion diffusion. It also binds to both epidermal growth factor (EGF) and fibroblast growth factor (FGF) and helps in enhancing ulcer healing. It is found effective in *Helicobacter pylori* infection [42].

#### **3. Coenzyme Q10**

Morton in 1955 in Liverpool identified a quinone-like substance with an ultraviolet absorption at 272 nm from intestinal mucosa of horses and named it as ubiquinone.

Crane and his colleagues in the University of Wisconsin isolated quinone in lipid extracts of mitochondria and named it coenzyme Q because of its unique role in cellular metabolism and energy production. Ernster, a Swedish scientist, expanded the benefits of this molecule as an antioxidant and free radical scavenger. Coenzyme Q10 also plays a major proton-motive role in the energy transfer systems [43].

Coenzyme Q10 is an active quinone with a benzoquinone ring along with 10 isoprenoid side chains. It is structurally related to vitamin K and vitamin E. Naturally it is orange in colour without odour and taste with a molecular weight of 863.34 g/mol. It is stable at temperatures below 46°C. CoQ10 is the prevalent form in humans in contrast to CoQ9 in rats and Q6, Q7 and Q8 in yeast and bacteria. It exists in three forms, the fully oxidised ubiquinone; semiquinone, the free radical form; and ubiquinol, the reduced form [44].

CoQ10 is found in every cell of the human body, mainly located in the phospholipid bilayer of various membranes. It is found in higher concentrations in the heart, liver, muscles and pancreas, which have high energy requirements. It is derived from tyrosine with several vitamins and trace elements as cofactors. Because of this complex biosynthesis, human enzyme and protein defects may cause deficiency of CoQ10 in infants as well as adults. Cellular functions depend on production of adenosine triphosphate (ATP) in mitochondria making electron and proton transfer functions of quinone ring very important in all life forms [43].

Coenzyme Q10 is usually absorbed from the small intestine, and bioavailability depends on the type of preparation and on the route of administration. Evidence says it is absorbed orally with almost 178% increase in serum levels. Some studies also say it is absorbed very minimally due to its lipophilic nature and huge molecular weight. Oil-based preparations of CoQ10 have better absorption [44].

It plays a vital role as intermediate in mitochondrial electron transport chain. CoQ10, an endogenously synthesised lipid-soluble antioxidant along with alphatocopherol, acts in scavenging the free radicals generated in the inner mitochondrial membrane. CoQ10 also prevents lipid peroxidation in cells depleted of alpha-tocopherol. It helps in protection of DNA from free radical injury, in recycling of antioxidants such as tocopherol and ascorbate with additional role in cell signalling and gene expression. A direct evidence for the antioxidant property of CoQ10 is shown in literature, where luminescence is eliminated from free radicals when skin cream containing coenzyme Q10 is applied demonstrating the elimination of free radicals by CoQ10. It also helps in maintaining cellular respiration and ATP synthesis. It also helps in decreasing calcium overload in tissues by indirectly stabilising calcium channels [45].

CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, ageing-related oxidative stress, carcinogenesis processes and also treatment with statins. Many neurodegenerative disorders, diabetes, cancer and muscular and cardiovascular diseases have been associated with low CoQ10 levels as well as different ataxias and encephalomyopathies [45, 46]. CoQ10 is generally very well tolerated at doses not exceeding 500 mg. Gastrointestinal (digestive) distress is reported with doses up to 3000 mg daily [45]. Recent evidence also says coenzyme Q10 is used in treatment of peptic ulcer. Few animal studies have tried the use of coenzyme Q10; in one study, indomethacin-induced ulcer in Wistar rats was treated using coenzyme Q10, and favourable results were obtained [47]. CoQ10-mediated gastroprotective effect involves preservation of microvascular permeability, elevation of prostaglandin E₂, improvement of redox status as well as boosting of nitric oxide.

#### **4. Glutamine**

Glutamine is one of the 20 amino acids encoded by standard genetic code. It is considered a conditionally essential amino acid. Its side chain is an amide formed by

**65**

*Pharmacotherapy of Peptic Ulcer Disease and Latest Research*

be positive, yet human trials have not been done in large [52, 53].

2.Variety of animal species should be made use of.

Clinical ulcers are usually chronic and are penetrating lesions in comparison with experimentally induced lesions which are acute non-penetrating ulcers healing at faster rates without scar formation. Even though experimental lesions have some limitation, it is still possible to evaluate the therapeutic agents rapidly with reasonable predictability for their therapeutic use. There are various animal models used for evaluating gastric ulcers, and some of the most important will be described below. Criteria for experimental ulcers proposed by Lee and Bianchi are as follows [54]:

1.It should be simple and easily reproducible with easy quantification of results.

3.Ulcer should be produced in characteristic sites like the stomach and the first

4.Models should include different mechanisms by which ulcers are produced.

The various methods available are discussed in the next subsections.

5.There should not be any spontaneous healing of ulcers during the observation

Ulcers produced by this method are also called as Shay ulcers as it was first demonstrated by Shay in 1945. In this model, the animals are usually housed in individual

**4.1 Ulcer induction methods**

part of the duodenum.

period.

*4.1.1 Pylorus ligated rat*

replacing hydroxyl side chain of glutamic acid. In humans, blood glutamine is the most abundant free amino acid, with concentration of about 500–900 μmol/L. It is mainly helpful in protein synthesis, acid base balance, cellular energy (next to glucose), nitrogen donation for anabolic process, carbon donation in citric acid cycle and ammonia transporter in blood circulation. It is produced by enzyme glutamine synthetase from glutamate/ammonia in muscles. Almost 90% of glutamine is synthesized in the muscles [48]. Consumers are cells of the intestine, kidney cells and immune/cancer cells. It is used in cachexia, to reduce infections and to control gut leak after surgery. It also increased intestinal barrier and intestinal permeability. As a preferred substrate for enterocytes, glutamine has shown to support the normal immunological structure and function of the gastrointestinal tract. In animal studies glutamine deprivation is associated with loss of intestinal epithelial integrity, while glutamine supplementation decreases gastrointestinal tract mucosal atrophy. Glutamine also restored ATP levels and reduces cell apoptosis. It is very important during stress and catabolic conditions [49]. So far only one animal study has evaluated the use of L-glutamine in aspirin-induced peptic ulcer model. They found out the L-glutamine was effective in protecting against aspirin-induced gastric lesions in rats [50]. L-Glutamine, commonly used in sports medicine for muscle recovery, has gained medical importance because of its antioxidant properties [51]. The antioxidant properties of L-glutamine has been claimed to be useful in the treatment of peptic ulcer disease in animal studies as well as in very few human studies. Only a few animal studies have been done so far to investigate the role of L-glutamine in the treatment of *Helicobacter pylori* infections, and it was found to

*DOI: http://dx.doi.org/10.5772/intechopen.86386*

#### *Pharmacotherapy of Peptic Ulcer Disease and Latest Research DOI: http://dx.doi.org/10.5772/intechopen.86386*

*Gastritis - New Approaches and Treatments*

Crane and his colleagues in the University of Wisconsin isolated quinone in lipid extracts of mitochondria and named it coenzyme Q because of its unique role in cellular metabolism and energy production. Ernster, a Swedish scientist, expanded the benefits of this molecule as an antioxidant and free radical scavenger. Coenzyme Q10

Coenzyme Q10 is an active quinone with a benzoquinone ring along with 10 isoprenoid side chains. It is structurally related to vitamin K and vitamin E. Naturally it is orange in colour without odour and taste with a molecular weight of 863.34 g/mol. It is stable at temperatures below 46°C. CoQ10 is the prevalent form in humans in contrast to CoQ9 in rats and Q6, Q7 and Q8 in yeast and bacteria. It exists in three forms, the fully oxidised ubiquinone; semiquinone, the free radical form; and ubiquinol, the reduced form [44]. CoQ10 is found in every cell of the human body, mainly located in the phospholipid bilayer of various membranes. It is found in higher concentrations in the heart, liver, muscles and pancreas, which have high energy requirements. It is derived from tyrosine with several vitamins and trace elements as cofactors. Because of this complex biosynthesis, human enzyme and protein defects may cause deficiency of CoQ10 in infants as well as adults. Cellular functions depend on production of adenosine triphosphate (ATP) in mitochondria making electron and proton transfer

Coenzyme Q10 is usually absorbed from the small intestine, and bioavailability depends on the type of preparation and on the route of administration. Evidence says it is absorbed orally with almost 178% increase in serum levels. Some studies also say it is absorbed very minimally due to its lipophilic nature and huge molecu-

also plays a major proton-motive role in the energy transfer systems [43].

functions of quinone ring very important in all life forms [43].

lar weight. Oil-based preparations of CoQ10 have better absorption [44].

ing calcium overload in tissues by indirectly stabilising calcium channels [45].

din E₂, improvement of redox status as well as boosting of nitric oxide.

Glutamine is one of the 20 amino acids encoded by standard genetic code. It is considered a conditionally essential amino acid. Its side chain is an amide formed by

CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, ageing-related oxidative stress, carcinogenesis processes and also treatment with statins. Many neurodegenerative disorders, diabetes, cancer and muscular and cardiovascular diseases have been associated with low CoQ10 levels as well as different ataxias and encephalomyopathies [45, 46]. CoQ10 is generally very well tolerated at doses not exceeding 500 mg. Gastrointestinal (digestive) distress is reported with doses up to 3000 mg daily [45]. Recent evidence also says coenzyme Q10 is used in treatment of peptic ulcer. Few animal studies have tried the use of coenzyme Q10; in one study, indomethacin-induced ulcer in Wistar rats was treated using coenzyme Q10, and favourable results were obtained [47]. CoQ10-mediated gastroprotective effect involves preservation of microvascular permeability, elevation of prostaglan-

It plays a vital role as intermediate in mitochondrial electron transport chain. CoQ10, an endogenously synthesised lipid-soluble antioxidant along with alphatocopherol, acts in scavenging the free radicals generated in the inner mitochondrial membrane. CoQ10 also prevents lipid peroxidation in cells depleted of alpha-tocopherol. It helps in protection of DNA from free radical injury, in recycling of antioxidants such as tocopherol and ascorbate with additional role in cell signalling and gene expression. A direct evidence for the antioxidant property of CoQ10 is shown in literature, where luminescence is eliminated from free radicals when skin cream containing coenzyme Q10 is applied demonstrating the elimination of free radicals by CoQ10. It also helps in maintaining cellular respiration and ATP synthesis. It also helps in decreas-

**64**

**4. Glutamine**

replacing hydroxyl side chain of glutamic acid. In humans, blood glutamine is the most abundant free amino acid, with concentration of about 500–900 μmol/L. It is mainly helpful in protein synthesis, acid base balance, cellular energy (next to glucose), nitrogen donation for anabolic process, carbon donation in citric acid cycle and ammonia transporter in blood circulation. It is produced by enzyme glutamine synthetase from glutamate/ammonia in muscles. Almost 90% of glutamine is synthesized in the muscles [48]. Consumers are cells of the intestine, kidney cells and immune/cancer cells. It is used in cachexia, to reduce infections and to control gut leak after surgery. It also increased intestinal barrier and intestinal permeability. As a preferred substrate for enterocytes, glutamine has shown to support the normal immunological structure and function of the gastrointestinal tract. In animal studies glutamine deprivation is associated with loss of intestinal epithelial integrity, while glutamine supplementation decreases gastrointestinal tract mucosal atrophy. Glutamine also restored ATP levels and reduces cell apoptosis. It is very important during stress and catabolic conditions [49]. So far only one animal study has evaluated the use of L-glutamine in aspirin-induced peptic ulcer model. They found out the L-glutamine was effective in protecting against aspirin-induced gastric lesions in rats [50]. L-Glutamine, commonly used in sports medicine for muscle recovery, has gained medical importance because of its antioxidant properties [51]. The antioxidant properties of L-glutamine has been claimed to be useful in the treatment of peptic ulcer disease in animal studies as well as in very few human studies. Only a few animal studies have been done so far to investigate the role of L-glutamine in the treatment of *Helicobacter pylori* infections, and it was found to be positive, yet human trials have not been done in large [52, 53].

#### **4.1 Ulcer induction methods**

Clinical ulcers are usually chronic and are penetrating lesions in comparison with experimentally induced lesions which are acute non-penetrating ulcers healing at faster rates without scar formation. Even though experimental lesions have some limitation, it is still possible to evaluate the therapeutic agents rapidly with reasonable predictability for their therapeutic use. There are various animal models used for evaluating gastric ulcers, and some of the most important will be described below.

Criteria for experimental ulcers proposed by Lee and Bianchi are as follows [54]:


The various methods available are discussed in the next subsections.

#### *4.1.1 Pylorus ligated rat*

Ulcers produced by this method are also called as Shay ulcers as it was first demonstrated by Shay in 1945. In this model, the animals are usually housed in individual cages and fasted for 36 h before ligating the pylorus. The abdomen is opened after anesthetising the rats by a small midline incision just below the xiphoid process. Then the pyloric part of the stomach is ligated without compromising its vascularity. Later the abdomen is closed in layers using interrupted sutures. The animal is made to starve completely without water and is sacrificed after 19 h. The stomach is then dissected out, and the contents of the stomach are used to determine the pH, volume of gastric juice and free and total acidity. The stomach is then cut open along the greater curvature and examined for ulceration. Circular lesions and linear lesions are observed. This model usually has a greater predictive value for antiulcer agents though ulcers in this model are usually localised in the ruminal area of the stomach in comparison to human ulcers which are usually located in the glandular portion of the stomach and duodenal region [55].

#### *4.1.2 Stress ulcers*

These ulcers are usually produced by subjecting any species to different types of stress. This model is very easy as it is devoid of any experimental surgery and usage of anaesthesia. It mainly involves the central nervous system, and produced lesions are located in the glandular portion of the stomach.

#### **5. Restraint ulcers**

This method was first used by Brodie and Hansen in 1960. Rats are usually fasted for 36 h before the experiment. Later each rat is placed in a piece of galvanised steel window screen of appropriate size. The screen is then moulded around each rat and is held together with wire staples. The animals are made immobile by tightening the limbs together. The test drug is administered 30 min before subjecting the animals to restraint. After 24 h the animals are sacrificed, and their stomach is dissected out along the greater curvature and is subjected to assessment. One drawback of this method was the ulcers were not deep as they did not penetrate the muscularis mucosa and penetrating ulcers were not produced. Some commonly used modifications of this method to overcome the drawbacks include water immersion-induced restraint ulcer, cold and restraint ulcer, swimming stress ulcers and also stress with concurrent administration of NSAIDs and also haemorrhagic shock-induced gastric ulcers in rats [56].

#### **5.1 NSAID-induced gastric mucosal damage**

The routinely used drug for experimental induction of ulcers includes diclofenac, ibuprofen, indomethacin, phenylbutazone and aspirin. Usually the test agents are administered 30 min–1 h before the noxious challenge. Later after 4 h the animals are sacrificed and examined for mucosal lesions in the stomach [57].

#### *5.1.1 Histamine-induced gastric ulcers*

The vasospastic and the gastric secretion increases shown via the histamine receptors attribute to ulcer formation in this model. It was first described in 1947 in guinea pigs. It was noted that in this model 100% ulceration was produced with notable increase in volume of gastric secretion as well as increment in free and total acidity. Usually the animals are fasted for 36 h, and ulcers are induced by injecting 1 ml of histamine acid phosphate (50 mg base) via intraperitoneal route. Histamine toxicity to animals are prevented using promethazine hydrochloride

**67**

*Pharmacotherapy of Peptic Ulcer Disease and Latest Research*

done after dissection, and various indices are calculated [58].

kg, and with this dose, moderate gastric lesions are noted [60].

and usually animals are observed for a period of 7–14 days [61].

5 mg intraperitoneally 15 min prior to and 15 min after histamine administration, respectively. The investigational drug is usually administered 45 min before injecting histamine. After 4 h the animals are sacrificed; and assessment of the stomach is

Acetic acid at a concentration of 1–30% is used, and usually 0.05 ml per rat is used. It is injected to the submucosal layer of the stomach, penetrating ulcers usually produced can be noted with gross examination, and ulcers are mostly confined by adhesion to contiguous organs. It can be successfully used to screen new antiul-

Wilhelmi, Wedinger and Veraguth described this method in Wistar rats. Usually rats are fasted for 24 h, and later serotonin creatinine sulphate is dissolved in saline and injected subcutaneously into rats. Usually serotonin is used at a dose of 20 mg/

Eighty percent of ethanol in a dose of 5 ml/kg of body weight is usually given orally to the albino rats. If administered intraperitoneally, 40% of ethanol is given,

Peptic ulcer being a global problem proper treatment is warranted. Proper screening of *Helicobacter pylori* and ruling out other possible causes could benefit the patient in getting cured with the correct treatment. The latest research proves oxidative stress as one of the major contributing factors for peptic ulcer disease, so the use of antioxidants as a potential agent is highly warranted. Further clinical trials can be done to elicit the efficacy of these antioxidants as potential anti-peptic

*DOI: http://dx.doi.org/10.5772/intechopen.86386*

*5.1.2 Acetic acid-induced chronic gastric ulcers*

*5.1.3 Serotonin-induced gastric ulcers*

*5.1.4 Ethanol-induced gastric ulcers.*

cer agents [59].

**6. Conclusion**

ulcer drugs.

5 mg intraperitoneally 15 min prior to and 15 min after histamine administration, respectively. The investigational drug is usually administered 45 min before injecting histamine. After 4 h the animals are sacrificed; and assessment of the stomach is done after dissection, and various indices are calculated [58].

#### *5.1.2 Acetic acid-induced chronic gastric ulcers*

Acetic acid at a concentration of 1–30% is used, and usually 0.05 ml per rat is used. It is injected to the submucosal layer of the stomach, penetrating ulcers usually produced can be noted with gross examination, and ulcers are mostly confined by adhesion to contiguous organs. It can be successfully used to screen new antiulcer agents [59].

#### *5.1.3 Serotonin-induced gastric ulcers*

Wilhelmi, Wedinger and Veraguth described this method in Wistar rats. Usually rats are fasted for 24 h, and later serotonin creatinine sulphate is dissolved in saline and injected subcutaneously into rats. Usually serotonin is used at a dose of 20 mg/ kg, and with this dose, moderate gastric lesions are noted [60].

#### *5.1.4 Ethanol-induced gastric ulcers.*

Eighty percent of ethanol in a dose of 5 ml/kg of body weight is usually given orally to the albino rats. If administered intraperitoneally, 40% of ethanol is given, and usually animals are observed for a period of 7–14 days [61].

### **6. Conclusion**

*Gastritis - New Approaches and Treatments*

the stomach and duodenal region [55].

shock-induced gastric ulcers in rats [56].

*5.1.1 Histamine-induced gastric ulcers*

**5.1 NSAID-induced gastric mucosal damage**

are located in the glandular portion of the stomach.

*4.1.2 Stress ulcers*

**5. Restraint ulcers**

cages and fasted for 36 h before ligating the pylorus. The abdomen is opened after anesthetising the rats by a small midline incision just below the xiphoid process. Then the pyloric part of the stomach is ligated without compromising its vascularity. Later the abdomen is closed in layers using interrupted sutures. The animal is made to starve completely without water and is sacrificed after 19 h. The stomach is then dissected out, and the contents of the stomach are used to determine the pH, volume of gastric juice and free and total acidity. The stomach is then cut open along the greater curvature and examined for ulceration. Circular lesions and linear lesions are observed. This model usually has a greater predictive value for antiulcer agents though ulcers in this model are usually localised in the ruminal area of the stomach in comparison to human ulcers which are usually located in the glandular portion of

These ulcers are usually produced by subjecting any species to different types of stress. This model is very easy as it is devoid of any experimental surgery and usage of anaesthesia. It mainly involves the central nervous system, and produced lesions

This method was first used by Brodie and Hansen in 1960. Rats are usually fasted for 36 h before the experiment. Later each rat is placed in a piece of galvanised steel window screen of appropriate size. The screen is then moulded around each rat and is held together with wire staples. The animals are made immobile by tightening the limbs together. The test drug is administered 30 min before subjecting the animals to restraint. After 24 h the animals are sacrificed, and their stomach is dissected out along the greater curvature and is subjected to assessment. One drawback of this method was the ulcers were not deep as they did not penetrate the muscularis mucosa and penetrating ulcers were not produced. Some commonly used modifications of this method to overcome the drawbacks include water immersion-induced restraint ulcer, cold and restraint ulcer, swimming stress ulcers and also stress with concurrent administration of NSAIDs and also haemorrhagic

The routinely used drug for experimental induction of ulcers includes diclofenac, ibuprofen, indomethacin, phenylbutazone and aspirin. Usually the test agents are administered 30 min–1 h before the noxious challenge. Later after 4 h the

The vasospastic and the gastric secretion increases shown via the histamine receptors attribute to ulcer formation in this model. It was first described in 1947 in guinea pigs. It was noted that in this model 100% ulceration was produced with notable increase in volume of gastric secretion as well as increment in free and total acidity. Usually the animals are fasted for 36 h, and ulcers are induced by injecting 1 ml of histamine acid phosphate (50 mg base) via intraperitoneal route. Histamine toxicity to animals are prevented using promethazine hydrochloride

animals are sacrificed and examined for mucosal lesions in the stomach [57].

**66**

Peptic ulcer being a global problem proper treatment is warranted. Proper screening of *Helicobacter pylori* and ruling out other possible causes could benefit the patient in getting cured with the correct treatment. The latest research proves oxidative stress as one of the major contributing factors for peptic ulcer disease, so the use of antioxidants as a potential agent is highly warranted. Further clinical trials can be done to elicit the efficacy of these antioxidants as potential anti-peptic ulcer drugs.

*Gastritis - New Approaches and Treatments*

#### **Author details**

Balaji Ommurugan1 \* and Vanishree Rao2

1 Drug Safety Physician, Bioclinica Private Limited, India

2 Research Scholar, Mcops, Manipal Academy of Higher Education, India

\*Address all correspondence to: puntermmc@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**69**

*Pharmacotherapy of Peptic Ulcer Disease and Latest Research*

lesions. Bratislavské Lekárske Listy.

[9] Heinz E, Öbrink KJ. Acid formation and acidity control in the stomach. Physiological Reviews. 1954;**34**(4):643-673

[10] Angus JA, Black JW. The interaction of choline esters, vagal stimulation, and H2-receptor blockade on acid secretion in vitro. European Journal of Pharmacology. 1982;**80**(2-3):217-224

[11] Hersey SJ, Sachs G. Gastric acid secretion. Physiological Reviews.

[12] Goldschmiedt M, Feldman M. Gastric secretion in health and disease. In: Sleisenger MH, editor. Gastrointestinal Disease. Philadelphia: WB Saunders

2015;**116**(1):51-56

1995;**75**(1):155-190

Company; 1993. pp. 521-544

1990;**322**(13):909-916

1979;**77**(3):433-443

1987;**8**(4):149-154

1988;**16**(2):223-236

[13] Soll AH. Pathogenesis of peptic ulcer and implications for therapy. New England Journal of Medicine.

[14] Robert A, Nezamis JE, Lancaster C,

prostaglandins in rats. Gastroenterology.

[15] Lacy ER, Ito S. Microscopic analysis of ethanol damage to rat gastric mucosa after treatment with a prostaglandin. Gastroenterology. 1982;**83**(3):619-625

[16] Szabo S, Szelenyi I. Cytoprotection'in

[17] Schmidt KL, Miller TA. Morphological

gastrointestinal pharmacology. Trends in Pharmacological Sciences.

characteristics of prostaglandin cytoprotection. Toxicologic Pathology.

[18] Soll AH, Weinstein WM, Kurata J, McCarthy D. Nonsteroidal anti-inflammatory drugs and peptic

Hanchar AJ. Cytoprotection by

*DOI: http://dx.doi.org/10.5772/intechopen.86386*

[1] Prabhu V, Shivani A. An overview of history, pathogenesis and treatment of perforated peptic ulcer disease with evaluation of prognostic scoring in adults. Annals of Medical and Health Sciences Research. 2014;**4**(1):22-29

[2] Tandon R, Khanna RD, Dorababu M,

Bhattacharjee M, Banerjee RK. Hydroxyl radical is the major causative factor in stress-induced gastric ulceration. Free Radical Biology and Medicine.

[4] Ko JK, Cho CH. Alcohol drinking and cigarette smoking: A "partner" for gastric ulceration. Chinese Medical Journal; Free China ed.

[5] Denny N, Chapple IL, Matthews JB. Antioxidant, and anti-inflammatory effects of coenzyme Q10: A preliminary study. Journal of Dental Research.

[6] Heyland DK, Elke G, Cook D, Berger MM, Wischmeyer PE, Albert M, et al. Glutamine and antioxidants in the critically ill patient: A post hoc analysis of a large-scale randomized trial. Journal of Parenteral and Enteral

Nutrition. 2015;**39**(4):401-409

[7] Okabe S, Ohtsu K, Takeuch K, Takhal K. Effect of L-glutamine on indomethacin induced gastric lesions in the rat. The Japanese Journal of Pharmacology. 1974;**24**:169-171

[8] Karkaya K, Barut F, Hanci V, Can M, Comert M, Ucan HB, et al. Gastroprotective effects of CoQ10 on ethanol-induced acute gastric

Goel RK. Oxidative stress and antioxidants status in peptic ulcer and gastric carcinoma. Indian Journal of Physiology and Pharmacology.

[3] Das D, Bandyopadhyay D,

2004;**48**(1):115-118

1997;**23**(1):8-18

2000;**63**(12):845-854

1999;**78**(543):00008

**References**

*Pharmacotherapy of Peptic Ulcer Disease and Latest Research DOI: http://dx.doi.org/10.5772/intechopen.86386*

#### **References**

*Gastritis - New Approaches and Treatments*

**68**

**Author details**

Balaji Ommurugan1

\* and Vanishree Rao2

2 Research Scholar, Mcops, Manipal Academy of Higher Education, India

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Drug Safety Physician, Bioclinica Private Limited, India

\*Address all correspondence to: puntermmc@gmail.com

provided the original work is properly cited.

[1] Prabhu V, Shivani A. An overview of history, pathogenesis and treatment of perforated peptic ulcer disease with evaluation of prognostic scoring in adults. Annals of Medical and Health Sciences Research. 2014;**4**(1):22-29

[2] Tandon R, Khanna RD, Dorababu M, Goel RK. Oxidative stress and antioxidants status in peptic ulcer and gastric carcinoma. Indian Journal of Physiology and Pharmacology. 2004;**48**(1):115-118

[3] Das D, Bandyopadhyay D, Bhattacharjee M, Banerjee RK. Hydroxyl radical is the major causative factor in stress-induced gastric ulceration. Free Radical Biology and Medicine. 1997;**23**(1):8-18

[4] Ko JK, Cho CH. Alcohol drinking and cigarette smoking: A "partner" for gastric ulceration. Chinese Medical Journal; Free China ed. 2000;**63**(12):845-854

[5] Denny N, Chapple IL, Matthews JB. Antioxidant, and anti-inflammatory effects of coenzyme Q10: A preliminary study. Journal of Dental Research. 1999;**78**(543):00008

[6] Heyland DK, Elke G, Cook D, Berger MM, Wischmeyer PE, Albert M, et al. Glutamine and antioxidants in the critically ill patient: A post hoc analysis of a large-scale randomized trial. Journal of Parenteral and Enteral Nutrition. 2015;**39**(4):401-409

[7] Okabe S, Ohtsu K, Takeuch K, Takhal K. Effect of L-glutamine on indomethacin induced gastric lesions in the rat. The Japanese Journal of Pharmacology. 1974;**24**:169-171

[8] Karkaya K, Barut F, Hanci V, Can M, Comert M, Ucan HB, et al. Gastroprotective effects of CoQ10 on ethanol-induced acute gastric

lesions. Bratislavské Lekárske Listy. 2015;**116**(1):51-56

[9] Heinz E, Öbrink KJ. Acid formation and acidity control in the stomach. Physiological Reviews. 1954;**34**(4):643-673

[10] Angus JA, Black JW. The interaction of choline esters, vagal stimulation, and H2-receptor blockade on acid secretion in vitro. European Journal of Pharmacology. 1982;**80**(2-3):217-224

[11] Hersey SJ, Sachs G. Gastric acid secretion. Physiological Reviews. 1995;**75**(1):155-190

[12] Goldschmiedt M, Feldman M. Gastric secretion in health and disease. In: Sleisenger MH, editor. Gastrointestinal Disease. Philadelphia: WB Saunders Company; 1993. pp. 521-544

[13] Soll AH. Pathogenesis of peptic ulcer and implications for therapy. New England Journal of Medicine. 1990;**322**(13):909-916

[14] Robert A, Nezamis JE, Lancaster C, Hanchar AJ. Cytoprotection by prostaglandins in rats. Gastroenterology. 1979;**77**(3):433-443

[15] Lacy ER, Ito S. Microscopic analysis of ethanol damage to rat gastric mucosa after treatment with a prostaglandin. Gastroenterology. 1982;**83**(3):619-625

[16] Szabo S, Szelenyi I. Cytoprotection'in gastrointestinal pharmacology. Trends in Pharmacological Sciences. 1987;**8**(4):149-154

[17] Schmidt KL, Miller TA. Morphological characteristics of prostaglandin cytoprotection. Toxicologic Pathology. 1988;**16**(2):223-236

[18] Soll AH, Weinstein WM, Kurata J, McCarthy D. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Annals of Internal Medicine. 1991;**114**(4):307-319

[19] Sanders MJ, Ayalon A, Roll M, Soll AH. The apical surface of canine chief cell monolayers resists H+ backdiffusion. Nature. 1985;**313**(5997):52-54

[20] Younan F, Pearson J, Allen A, Venables C. Changes in the structure of the mucous gel on the mucosal surface of the stomach in association with peptic ulcer disease. Gastroenterology. 1982;**82**(5):827-831

[21] Bickel M, Kauffman GL. Gastric gel mucus thickness: Effect of distention, 16,16-dimethyl prostaglandin E2, and carbenoxolone. Gastroenterology. 1981;**80**(4):770-775

[22] Rees WD, Turnberg LA. Mechanisms of gastric mucosal protection: A role for the 'mucusbicarbonate' barrier. Clinical Science. 1982;**62**(4):343-348

[23] Allen A, Garner A. Mucus and bicarbonate secretion in the stomach and their possible role in mucosal protection. Gut. 1980;**21**(3):249

[24] Fromm D. Gastric mucosal "barrier". Gastroenterology. 1979;**77**(2):396-398

[25] Pihan G, Rogers C, Szabo S. Vascular injury in acute gastric mucosal damage. Digestive Diseases and Sciences. 1988;**33**(5):625-632

[26] Takeuchi K, Nobuhara Y. Inhibition of gastric motor activity by 16,16-dimethyl prostaglandin E 2. Digestive Diseases and Sciences. 1985;**30**(12):1181-1188

[27] Itoh M, Guth PH. Role of oxygenderived free radicals in hemorrhagic shock-induced gastric lesions in the rat. Gastroenterology. 1985;**88**(5):1162-1167

[28] Peskar BM, Hoppe U, Lange K, Peskar BA. Effect of nonsteroidal anti-inflammatory drugs (NSAID) on rat gastric leukotriene formation. Gastroenterology. 1987;**92**(5):1573-1573

[29] Desai JK, Goyal RK, Parmar NS. Pathogenesis of peptic ulcer disease and current trends in therapy. Indian Journal of Physiology and Pharmacology. 1997;**41**(1):3-15

[30] Du Plessis DJ. Pathogenesis of gastric ulceration. The Lancet. 1965;**285**(7393):974-978

[31] Isenberg JI, Selling JA, Hogan DL, Koss MA. Impaired proximal duodenal mucosal bicarbonate secretion in patients with duodenal ulcer. New England Journal of Medicine. 1987;**316**(7):374-379

[32] Demir S, Yilmaz M, Koseoglu M, Akalin N, Aslan D, Aydin A. Role of free radicals in peptic ulcer and gastritis. Turkish Journal of Gastroenterology. 2003;**14**(1):39-43

[33] Kuipers EJ, Thijs JC, Festen HP. The prevalence of *Helicobacter pylori* in peptic ulcer disease. Alimentary Pharmacology & Therapeutics. 1995;**9**:59-69

[34] Huang JQ, Sridhar S, Hunt RH. Role of *Helicobacter pylori* infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: A meta-analysis. The Lancet. 2002;**359**(9300):14-22

[35] Kurata JH, Nogawa AN. Metaanalysis of risk factors for peptic ulcer: Nonsteroidal antiinflammatory drugs, *Helicobacter pylori*, and smoking. Journal of Clinical Gastroenterology. 1997;**24**(1):2-17

[36] Levenstein S, Ackerman S, Kiecolt-Glaser JK, Dubois A. Stress and peptic ulcer disease. JAMA. 1999;**281**(1):10-11

[37] Friedman GD, Siegelaub AB, Seltzer CC. Cigarettes, alcohol, coffee

**71**

*Pharmacotherapy of Peptic Ulcer Disease and Latest Research*

efficacy of coenzyme Q10 in

[48] Miller AL. Therapeutic considerations of L-glutamine: A review of the literature. Alternative Medicine Review: A Journal of Clinical Therapeutic. 1999 Aug;**4**(4):239-248

[49] Novak F, Heyland DK,

supplementation in serious illness: A systematic review of the evidence. Critical Care Medicine.

2002;**30**(9):2022-2029

1974;**26**(8):605-611

[50] Okabe S, Takeuchi K,

Nakamura K, Takagi K. Inhibitory effects of L-glutamine on the aspirininduced gastric lesions in the rat.

Journal of Pharmacy and Pharmacology.

[51] Heyland DK, Dhaliwal R, Day AG, Muscedere J, Drover J, Suchner U, et al. Reducing deaths due to oxidative

stress (The REDOXS© Study): Rationale and study design for a randomized trial of glutamine and antioxidant supplementation in critically-ill patients. Proceedings

[52] Hagen SJ, Ohtani M, Zhou JR, Taylor NS, Rickman BH, Blackburn GL,

et al. Inflammation and foveolar hyperplasia are reduced by supplemental dietary glutamine during *Helicobacter pylori* infection in mice. The Journal of Nutrition.

[53] Amagase K, Nakamura E, Endo T, Hayashi S, Hasumura M, Uneyama H, et al. New frontiers in gut nutrient sensor research: Prophylactic effect of glutamine against *Helicobacter pylori*induced gastric diseases in Mongolian gerbils. Journal of Pharmacological

of the Nutrition Society. 2006;**65**(3):250-263

2009;**139**(5):912-918

Sciences. 2010;**112**(1):25-32

Avenell A, Drover JW, Su X. Glutamine

2012;**6**:2012

indomethacin-induced gastropathy: Other potential mechanisms. Ulcers.

*DOI: http://dx.doi.org/10.5772/intechopen.86386*

and peptic ulcer. New England Journal of Medicine. 1974;**290**(9):469-473

[39] Freston JW. Overview of medical therapy of peptic ulcer disease. Gastroenterology Clinics of North America. 1990;**19**(1):121-140

[40] Nash J, Lambert L, Deakin M. Histamine H2-receptor antagonists in peptic ulcer disease. Drugs.

[41] Giorgi-Conciato M, Daniotti S, Ferrari PA, Gaetani M, Petrin G, Sala P, et al. Efficacy and safety of pirenzepine in peptic ulcer and in non-ulcerous gastroduodenal diseases. A multicentre controlled clinical trial. Scandinavian

Journal of Gastroenterology. Supplement. 1982;**81**:1

[42] Guth PH. Mucosal coating agents and other non-anti-secretory agents. Digestive Diseases and Sciences.

[43] Crane FL. Discovery of ubiquinone (coenzyme Q ) and an overview of function. Mitochondrion. 2007;**7**:S2-S7

[44] Bhagavan HN, Chopra RK. Coenzyme

metabolism and pharmacokinetics. Free Radical Research. 2006;**40**(5):445-453

Q10: Absorption, tissue uptake,

[45] Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. European Journal of Clinical Nutrition. 1999;**53**(10):764-770

[46] Shults CW. Coenzyme Q10 in neurodegenerative diseases. Current Medicinal Chemistry.

[47] Malash AM, Abdallah DM,

Agha AM, Kenawy SA. Gastroprotective

2003;**10**(19):1917-1921

1994;**47**(6):862-871

1987;**32**(6):647-654

[38] Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. The Lancet. 2009;**374**(9699):1449-1461

*Pharmacotherapy of Peptic Ulcer Disease and Latest Research DOI: http://dx.doi.org/10.5772/intechopen.86386*

and peptic ulcer. New England Journal of Medicine. 1974;**290**(9):469-473

*Gastritis - New Approaches and Treatments*

anti-inflammatory drugs (NSAID) on rat gastric leukotriene formation. Gastroenterology. 1987;**92**(5):1573-1573

[30] Du Plessis DJ. Pathogenesis of gastric ulceration. The Lancet.

mucosal bicarbonate secretion in patients with duodenal ulcer. New England Journal of Medicine.

[31] Isenberg JI, Selling JA, Hogan DL, Koss MA. Impaired proximal duodenal

[32] Demir S, Yilmaz M, Koseoglu M, Akalin N, Aslan D, Aydin A. Role of free radicals in peptic ulcer and gastritis. Turkish Journal of Gastroenterology.

[33] Kuipers EJ, Thijs JC, Festen HP. The prevalence of *Helicobacter pylori* in peptic ulcer disease. Alimentary Pharmacology & Therapeutics.

[34] Huang JQ, Sridhar S, Hunt RH. Role of *Helicobacter pylori* infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: A meta-analysis. The Lancet. 2002;**359**(9300):14-22

[35] Kurata JH, Nogawa AN. Metaanalysis of risk factors for peptic ulcer: Nonsteroidal antiinflammatory drugs, *Helicobacter pylori*, and smoking. Journal of Clinical Gastroenterology.

[36] Levenstein S, Ackerman S, Kiecolt-Glaser JK, Dubois A. Stress and peptic ulcer disease. JAMA.

[37] Friedman GD, Siegelaub AB, Seltzer CC. Cigarettes, alcohol, coffee

Parmar NS. Pathogenesis of peptic ulcer disease and current trends in therapy. Indian Journal of Physiology and Pharmacology. 1997;**41**(1):3-15

[29] Desai JK, Goyal RK,

1965;**285**(7393):974-978

1987;**316**(7):374-379

2003;**14**(1):39-43

1995;**9**:59-69

1997;**24**(1):2-17

1999;**281**(1):10-11

ulcer disease. Annals of Internal Medicine. 1991;**114**(4):307-319

[19] Sanders MJ, Ayalon A, Roll M, Soll AH. The apical surface of canine chief cell monolayers resists H+ backdiffusion. Nature. 1985;**313**(5997):52-54

[20] Younan F, Pearson J, Allen A, Venables C. Changes in the structure of the mucous gel on the mucosal surface of the stomach in association with peptic ulcer disease. Gastroenterology.

[21] Bickel M, Kauffman GL. Gastric gel mucus thickness: Effect of distention, 16,16-dimethyl prostaglandin E2, and carbenoxolone. Gastroenterology.

1982;**82**(5):827-831

1981;**80**(4):770-775

1982;**62**(4):343-348

1988;**33**(5):625-632

of gastric motor activity by 16,16-dimethyl prostaglandin E 2. Digestive Diseases and Sciences.

1985;**30**(12):1181-1188

[28] Peskar BM, Hoppe U,

[22] Rees WD, Turnberg LA. Mechanisms of gastric mucosal protection: A role for the 'mucusbicarbonate' barrier. Clinical Science.

[23] Allen A, Garner A. Mucus and bicarbonate secretion in the stomach and their possible role in mucosal protection. Gut. 1980;**21**(3):249

[24] Fromm D. Gastric mucosal "barrier". Gastroenterology. 1979;**77**(2):396-398

[25] Pihan G, Rogers C, Szabo S. Vascular injury in acute gastric mucosal damage. Digestive Diseases and Sciences.

[26] Takeuchi K, Nobuhara Y. Inhibition

[27] Itoh M, Guth PH. Role of oxygenderived free radicals in hemorrhagic shock-induced gastric lesions in the rat. Gastroenterology. 1985;**88**(5):1162-1167

Lange K, Peskar BA. Effect of nonsteroidal

**70**

[38] Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. The Lancet. 2009;**374**(9699):1449-1461

[39] Freston JW. Overview of medical therapy of peptic ulcer disease. Gastroenterology Clinics of North America. 1990;**19**(1):121-140

[40] Nash J, Lambert L, Deakin M. Histamine H2-receptor antagonists in peptic ulcer disease. Drugs. 1994;**47**(6):862-871

[41] Giorgi-Conciato M, Daniotti S, Ferrari PA, Gaetani M, Petrin G, Sala P, et al. Efficacy and safety of pirenzepine in peptic ulcer and in non-ulcerous gastroduodenal diseases. A multicentre controlled clinical trial. Scandinavian Journal of Gastroenterology. Supplement. 1982;**81**:1

[42] Guth PH. Mucosal coating agents and other non-anti-secretory agents. Digestive Diseases and Sciences. 1987;**32**(6):647-654

[43] Crane FL. Discovery of ubiquinone (coenzyme Q ) and an overview of function. Mitochondrion. 2007;**7**:S2-S7

[44] Bhagavan HN, Chopra RK. Coenzyme Q10: Absorption, tissue uptake, metabolism and pharmacokinetics. Free Radical Research. 2006;**40**(5):445-453

[45] Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. European Journal of Clinical Nutrition. 1999;**53**(10):764-770

[46] Shults CW. Coenzyme Q10 in neurodegenerative diseases. Current Medicinal Chemistry. 2003;**10**(19):1917-1921

[47] Malash AM, Abdallah DM, Agha AM, Kenawy SA. Gastroprotective efficacy of coenzyme Q10 in indomethacin-induced gastropathy: Other potential mechanisms. Ulcers. 2012;**6**:2012

[48] Miller AL. Therapeutic considerations of L-glutamine: A review of the literature. Alternative Medicine Review: A Journal of Clinical Therapeutic. 1999 Aug;**4**(4):239-248

[49] Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: A systematic review of the evidence. Critical Care Medicine. 2002;**30**(9):2022-2029

[50] Okabe S, Takeuchi K, Nakamura K, Takagi K. Inhibitory effects of L-glutamine on the aspirininduced gastric lesions in the rat. Journal of Pharmacy and Pharmacology. 1974;**26**(8):605-611

[51] Heyland DK, Dhaliwal R, Day AG, Muscedere J, Drover J, Suchner U, et al. Reducing deaths due to oxidative stress (The REDOXS© Study): Rationale and study design for a randomized trial of glutamine and antioxidant supplementation in critically-ill patients. Proceedings of the Nutrition Society. 2006;**65**(3):250-263

[52] Hagen SJ, Ohtani M, Zhou JR, Taylor NS, Rickman BH, Blackburn GL, et al. Inflammation and foveolar hyperplasia are reduced by supplemental dietary glutamine during *Helicobacter pylori* infection in mice. The Journal of Nutrition. 2009;**139**(5):912-918

[53] Amagase K, Nakamura E, Endo T, Hayashi S, Hasumura M, Uneyama H, et al. New frontiers in gut nutrient sensor research: Prophylactic effect of glutamine against *Helicobacter pylori*induced gastric diseases in Mongolian gerbils. Journal of Pharmacological Sciences. 2010;**112**(1):25-32

[54] Lee YH, Bianchi RG. Use of experimental peptic ulcer models for drug screening. Peptic Ulcer. 1971:329-348

[55] Shay H. A simple method for the uniform production of gastric ulceration in rat. Gastroenterology. 1945;**5**:43-61

[56] Levine RJ. A method for rapid production of stress ulcers in rats. In: Peptic Ulcer. Copenhagen: Munksgaard; 1971. pp. 92-97

[57] Djahanguiri B. The production of acute gastric ulceration by indomethacin in the rat. Scandinavian Journal of Gastroenterology. 1968;**4**(3):265-267

[58] Hay LJ, Varco RL, Code CF, Wangensteen OH. The experimental production of gastric and duodenal ulcers in laboratory animals by the intramuscular injection of histamine in beeswax. Surgery, Gynecology & Obstetrics. 1942;**75**:170-182

[59] Okabe S, Pfeiffer CJ. Chronicity of acetic acid ulcer in the rat stomach. Digestive Diseases and Sciences. 1972;**17**(7):619-629

[60] LePard KJ, Stephens RL. Serotonin inhibits gastric acid secretion through a 5-hydroxytryptamine1-like receptor in the rat. Journal of Pharmacology and Experimental Therapeutics. 1994;**270**(3):1139-1144

[61] Oates PJ, Hakkinen JP. Studies on the mechanism of ethanol-induced gastric damage in rats. Gastroenterology. 1988;**94**(1):10-21

**73**

been paid to gastritis clinically.

**Chapter 5**

**Abstract**

Medicine

Gastritis Treated by Chinese

Chronic gastritis is one of the common diseases of the digestive system characterized by many uncomfortable clinical symptoms, and the patient with chronic gastritis has a lower quality of life. Chinese medicine is a branch of medicine in the world, and it has special theory; different methods have been used to treat gastritis for more than 1000 years. We aimed to introduce the special theory and the different methods of Chinese medicine and about its syndrome classification, syndrome differentiation and treatment, diagnosis and treatment process, and criterion of therapeutic effect of chronic gastritis. The mechanism of Chinese medicine on

**Keywords:** gastritis, Chinese medicine, diagnosis, syndrome classification, syndrome

Chronic gastritis is one of the common diseases of the digestive system and a chronic inflammatory reaction of gastric mucosa caused by several factors, such as *Helicobacter pylori* infection, alcoholism, smoking, stress conditions, and the use of some conventional medicines such as some anti-inflammatory drugs; the infection of *Helicobacter pylori* is its main cause [1, 2]. Chronic non-atrophic gastritis, atrophic gastritis (atrophy, intestinal metaplasia), dysplasia, and carcinogenesis may

Chronic gastritis is usually divided into chronic superficial gastritis and chronic atrophic gastritis. Chronic superficial gastritis is characterized by no obviously pathological changes. Its common symptoms are abdominal discomfort after eating, dull pain, accompanying belching, and pantothenic acid. Chronic atrophic gastritis is characterized by atrophy and decrease of gastric mucosal epithelium and glands, thinness of gastric mucosa, thickening of the mucosal base, or metaplasia of pyloric gland and intestinal gland or atypical hyperplasia. Chronic atrophic gastritis occurs in approximately 2% of the general population in the United States [5], particularly those older than 60 years and with higher prevalence in females [5, 6], and a Swedish study reported an increased incidence in the population aged between 35 and 45 years [6]. The common symptoms of chronic gastritis are a dull pain in the upper abdomen, abdominal fullness and distention, belching, inappetence, or being thin and anemic. The symptoms of gastritis are easy to relapse which seriously affect their quality of life. Chronic atrophic gastritis with intestinal metaplasia and intraepithelial neoplasia increases the risk of gastric cancer, and more attention has

*Xiaomei Wang, Guang Ji and Huangan Wu*

chronic gastritis needs further research.

occur after *Helicobacter pylori* infection [3, 4].

differentiation, treatment

**1. Introduction**

#### **Chapter 5**

*Gastritis - New Approaches and Treatments*

[55] Shay H. A simple method for the uniform production of gastric ulceration in rat. Gastroenterology. 1945;**5**:43-61

[56] Levine RJ. A method for rapid production of stress ulcers in rats. In: Peptic Ulcer. Copenhagen: Munksgaard;

[57] Djahanguiri B. The production of acute gastric ulceration by indomethacin in the rat. Scandinavian Journal of Gastroenterology. 1968;**4**(3):265-267

[58] Hay LJ, Varco RL, Code CF, Wangensteen OH. The experimental production of gastric and duodenal ulcers in laboratory animals by the intramuscular injection of histamine in beeswax. Surgery, Gynecology &

Obstetrics. 1942;**75**:170-182

1972;**17**(7):619-629

1994;**270**(3):1139-1144

1988;**94**(1):10-21

[59] Okabe S, Pfeiffer CJ. Chronicity of acetic acid ulcer in the rat stomach. Digestive Diseases and Sciences.

[60] LePard KJ, Stephens RL. Serotonin inhibits gastric acid secretion through a 5-hydroxytryptamine1-like receptor in the rat. Journal of Pharmacology and Experimental Therapeutics.

[61] Oates PJ, Hakkinen JP. Studies on the mechanism of ethanol-induced gastric damage in rats. Gastroenterology.

[54] Lee YH, Bianchi RG. Use of experimental peptic ulcer models for drug screening. Peptic Ulcer.

1971:329-348

1971. pp. 92-97

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## Gastritis Treated by Chinese Medicine

*Xiaomei Wang, Guang Ji and Huangan Wu*

#### **Abstract**

Chronic gastritis is one of the common diseases of the digestive system characterized by many uncomfortable clinical symptoms, and the patient with chronic gastritis has a lower quality of life. Chinese medicine is a branch of medicine in the world, and it has special theory; different methods have been used to treat gastritis for more than 1000 years. We aimed to introduce the special theory and the different methods of Chinese medicine and about its syndrome classification, syndrome differentiation and treatment, diagnosis and treatment process, and criterion of therapeutic effect of chronic gastritis. The mechanism of Chinese medicine on chronic gastritis needs further research.

**Keywords:** gastritis, Chinese medicine, diagnosis, syndrome classification, syndrome differentiation, treatment

#### **1. Introduction**

Chronic gastritis is one of the common diseases of the digestive system and a chronic inflammatory reaction of gastric mucosa caused by several factors, such as *Helicobacter pylori* infection, alcoholism, smoking, stress conditions, and the use of some conventional medicines such as some anti-inflammatory drugs; the infection of *Helicobacter pylori* is its main cause [1, 2]. Chronic non-atrophic gastritis, atrophic gastritis (atrophy, intestinal metaplasia), dysplasia, and carcinogenesis may occur after *Helicobacter pylori* infection [3, 4].

Chronic gastritis is usually divided into chronic superficial gastritis and chronic atrophic gastritis. Chronic superficial gastritis is characterized by no obviously pathological changes. Its common symptoms are abdominal discomfort after eating, dull pain, accompanying belching, and pantothenic acid. Chronic atrophic gastritis is characterized by atrophy and decrease of gastric mucosal epithelium and glands, thinness of gastric mucosa, thickening of the mucosal base, or metaplasia of pyloric gland and intestinal gland or atypical hyperplasia. Chronic atrophic gastritis occurs in approximately 2% of the general population in the United States [5], particularly those older than 60 years and with higher prevalence in females [5, 6], and a Swedish study reported an increased incidence in the population aged between 35 and 45 years [6]. The common symptoms of chronic gastritis are a dull pain in the upper abdomen, abdominal fullness and distention, belching, inappetence, or being thin and anemic. The symptoms of gastritis are easy to relapse which seriously affect their quality of life. Chronic atrophic gastritis with intestinal metaplasia and intraepithelial neoplasia increases the risk of gastric cancer, and more attention has been paid to gastritis clinically.

Traditional Chinese medicine (TCM) has accumulated many years of clinical experience in the diagnosis and treatment of this disease. In 2009, spleen-stomach disease branch of China Association of Chinese Medicine (CACM) organized and formulated the "consensus opinions on TCM diagnosis and treatment of chronic superficial gastritis" and "consensus opinions on TCM diagnosis and treatment of chronic atrophic gastritis," which played a normative role in the diagnosis and treatment of chronic gastritis. In recent years, there are a lot of progress of TCM in the diagnosis and treatment of chronic gastritis. It is necessary to update the consensus opinions to meet clinical needs and better guide clinical work.

Based on the principles of evidence-based medicine, team members of spleenstomach disease branch of CACM extensively collected evidence-based information, and they successively organized domestic experts of spleen and stomach diseases to summarize and discuss a series of key issues such as syndrome classification, syndrome differentiation and treatment, diagnosis and treatment process, and criterion of therapeutic effect for chronic gastritis. Based on an expert opinion, three rounds of voting followed under internationally accepted Delphi law, the drafting group has fully discussed, revised, and approved the consensus in 2017 (Consensus opinions of TCM diagnosis and treatment experts on chronic gastritis, 2017 edition) [7].

#### **2. TCM diagnosis of chronic gastritis**

TCM diagnosis of chronic gastritis is mainly based on symptom diagnosis. Patients with stomachache as the main symptom were diagnosed as "epigastric pain," and patients with epigastric distention as the main symptom were diagnosed as "distention and fullness." If the symptoms of stomachache or epigastric distention are not obvious, it can be diagnosed as "acid regurgitation," "hubbub," and other diseases according to the main symptoms [8, 9].

#### **3. Diagnosis of chronic gastritis by western medicine**

The diagnosis of chronic gastritis mainly depends on endoscopy and pathological examination, especially the latter is of greater value. The etiology of chronic gastritis should be determined as far as possible, and endoscopic diagnosis of special gastritis must combine etiology and pathology [10].

#### **3.1 Clinical manifestations**

Chronic gastritis is a chronic inflammatory reaction of the gastric mucosa, and most patients with chronic gastritis may have no obvious clinical symptoms. Patients with symptoms mainly manifested a non-specific dyspepsia, such as discomfort in the upper abdomen, fullness, pain, loss of appetite, belching, acid regurgitation, etc. A part also can have forgetfulness, anxiety, depression, and other psychological symptoms [8–10]. There was no significant correlation between the presence and severity of dyspepsia and the histological findings and endoscopic grading of chronic gastritis [8–10].

#### **3.2 Endoscopic and pathological examination**

Endoscopic diagnosis: For non-atrophic gastritis, endoscopic examination showed the basic manifestations of mucosal erythema, mucosal hemorrhagic spots or plaques, rough mucosa with or without edema, hyperemia, and exudation. For atrophic

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*Gastritis Treated by Chinese Medicine*

the degree judgment [10].

**3.3 Lab examination**

**4.1 Etiology**

**4.2 Disease location**

spleen in TCM theory.

**4.4 Change of pathogenesis**

**4.3 Pathogenesis**

*DOI: http://dx.doi.org/10.5772/intechopen.88504*

gastritis, endoscopic examination showed that the mucosa was red and white, mainly white, with folds flattened or even disappeared. Some mucosal vessels were exposed, which may be accompanied by mucosal granules or nodules. It is described as atrophic gastritis or non-atrophic gastritis with bile reflux, erosion and mucosal bleeding, etc. Histopathologic diagnosis: Two or more biopsy tissues can be selected as required. The endoscopic physician should provide the site of sampling, endoscopic examination results, and brief medical history to the pathology department. The pathological changes should be reported in each biopsy specimen in each biopsy specimen, such as the grade of *Helicobacter pylori* infection, chronic inflammatory response, activity, atrophy, intestinal metaplasia, and dysplasia (intraepithelial neoplasia). Chronic gastritis biopsy shows atrophy of the inherent glands (including metaplasia atrophy and non-metaplasia atrophy), which can be diagnosed as atrophic gastritis, regardless of the number and degree of atrophy of the biopsy specimen. The clinician may combine the pathological result and the endoscopic view, making the lesion scope and

*Helicobacter pylori* is the most important cause of chronic gastritis. Routine detection is recommended. Vitamin B12 and autoantibodies are recommended for diagnosis of atrophic gastritis. Serum gastrin G17, pepsin I and II may help deter-

The stomach is physiologically harmonious, but pathologically it is sluggish [11]. This disease is mainly related to the weakness of spleen and stomach, emotional disorders, improper diet, drugs, exogenous pathogens (*Helicobacter pylori* infection), and other factors; the above factors damage the spleen and stomach, resulting in transport and loss of division, rise and fall disorders, and the occurrence of Qi stagnation, wet resistance, cold coagulation, fire depression, blood stasis, etc.,

Chronic gastritis is located in the stomach and is closely related to the liver and

The pathogenesis of chronic gastritis can be divided into two aspects: deficient

The syndrome differentiation of chronic gastritis should examine the evidence and seek the cause. The pathogenesis is related to the specific clinical type. In general, it is

essential and excessive superficial. This deficiency is mainly manifested as qi (Yang) deficiency and stomach yin deficiency. The main manifestations of excessive superficial are stagnation of qi, dampness and heat, and blood stasis. Spleen deficiency and qi stagnation are the basic pathogenesis of chronic gastritis.

mine whether gastric mucosa atrophy and atrophy [10].

**4. Etiology and pathogenesis of chronic gastritis**

manifested as stomachache, bloating, and other symptoms.

*Gastritis Treated by Chinese Medicine DOI: http://dx.doi.org/10.5772/intechopen.88504*

*Gastritis - New Approaches and Treatments*

**2. TCM diagnosis of chronic gastritis**

other diseases according to the main symptoms [8, 9].

**3. Diagnosis of chronic gastritis by western medicine**

special gastritis must combine etiology and pathology [10].

**3.1 Clinical manifestations**

grading of chronic gastritis [8–10].

**3.2 Endoscopic and pathological examination**

Traditional Chinese medicine (TCM) has accumulated many years of clinical experience in the diagnosis and treatment of this disease. In 2009, spleen-stomach disease branch of China Association of Chinese Medicine (CACM) organized and formulated the "consensus opinions on TCM diagnosis and treatment of chronic superficial gastritis" and "consensus opinions on TCM diagnosis and treatment of chronic atrophic gastritis," which played a normative role in the diagnosis and treatment of chronic gastritis. In recent years, there are a lot of progress of TCM in the diagnosis and treatment of chronic gastritis. It is necessary to update the consensus

Based on the principles of evidence-based medicine, team members of spleenstomach disease branch of CACM extensively collected evidence-based information, and they successively organized domestic experts of spleen and stomach diseases to summarize and discuss a series of key issues such as syndrome classification, syndrome differentiation and treatment, diagnosis and treatment process, and criterion of therapeutic effect for chronic gastritis. Based on an expert opinion, three rounds of voting followed under internationally accepted Delphi law, the drafting group has fully discussed, revised, and approved the consensus in 2017 (Consensus opinions of

TCM diagnosis and treatment experts on chronic gastritis, 2017 edition) [7].

TCM diagnosis of chronic gastritis is mainly based on symptom diagnosis. Patients with stomachache as the main symptom were diagnosed as "epigastric pain," and patients with epigastric distention as the main symptom were diagnosed as "distention and fullness." If the symptoms of stomachache or epigastric distention are not obvious, it can be diagnosed as "acid regurgitation," "hubbub," and

The diagnosis of chronic gastritis mainly depends on endoscopy and pathological examination, especially the latter is of greater value. The etiology of chronic gastritis should be determined as far as possible, and endoscopic diagnosis of

Chronic gastritis is a chronic inflammatory reaction of the gastric mucosa, and most patients with chronic gastritis may have no obvious clinical symptoms. Patients with symptoms mainly manifested a non-specific dyspepsia, such as discomfort in the upper abdomen, fullness, pain, loss of appetite, belching, acid regurgitation, etc. A part also can have forgetfulness, anxiety, depression, and other psychological symptoms [8–10]. There was no significant correlation between the presence and severity of dyspepsia and the histological findings and endoscopic

Endoscopic diagnosis: For non-atrophic gastritis, endoscopic examination showed the basic manifestations of mucosal erythema, mucosal hemorrhagic spots or plaques, rough mucosa with or without edema, hyperemia, and exudation. For atrophic

opinions to meet clinical needs and better guide clinical work.

**74**

gastritis, endoscopic examination showed that the mucosa was red and white, mainly white, with folds flattened or even disappeared. Some mucosal vessels were exposed, which may be accompanied by mucosal granules or nodules. It is described as atrophic gastritis or non-atrophic gastritis with bile reflux, erosion and mucosal bleeding, etc.

Histopathologic diagnosis: Two or more biopsy tissues can be selected as required. The endoscopic physician should provide the site of sampling, endoscopic examination results, and brief medical history to the pathology department. The pathological changes should be reported in each biopsy specimen in each biopsy specimen, such as the grade of *Helicobacter pylori* infection, chronic inflammatory response, activity, atrophy, intestinal metaplasia, and dysplasia (intraepithelial neoplasia). Chronic gastritis biopsy shows atrophy of the inherent glands (including metaplasia atrophy and non-metaplasia atrophy), which can be diagnosed as atrophic gastritis, regardless of the number and degree of atrophy of the biopsy specimen. The clinician may combine the pathological result and the endoscopic view, making the lesion scope and the degree judgment [10].

#### **3.3 Lab examination**

*Helicobacter pylori* is the most important cause of chronic gastritis. Routine detection is recommended. Vitamin B12 and autoantibodies are recommended for diagnosis of atrophic gastritis. Serum gastrin G17, pepsin I and II may help determine whether gastric mucosa atrophy and atrophy [10].

#### **4. Etiology and pathogenesis of chronic gastritis**

#### **4.1 Etiology**

The stomach is physiologically harmonious, but pathologically it is sluggish [11]. This disease is mainly related to the weakness of spleen and stomach, emotional disorders, improper diet, drugs, exogenous pathogens (*Helicobacter pylori* infection), and other factors; the above factors damage the spleen and stomach, resulting in transport and loss of division, rise and fall disorders, and the occurrence of Qi stagnation, wet resistance, cold coagulation, fire depression, blood stasis, etc., manifested as stomachache, bloating, and other symptoms.

#### **4.2 Disease location**

Chronic gastritis is located in the stomach and is closely related to the liver and spleen in TCM theory.

#### **4.3 Pathogenesis**

The pathogenesis of chronic gastritis can be divided into two aspects: deficient essential and excessive superficial. This deficiency is mainly manifested as qi (Yang) deficiency and stomach yin deficiency. The main manifestations of excessive superficial are stagnation of qi, dampness and heat, and blood stasis. Spleen deficiency and qi stagnation are the basic pathogenesis of chronic gastritis.

#### **4.4 Change of pathogenesis**

The syndrome differentiation of chronic gastritis should examine the evidence and seek the cause. The pathogenesis is related to the specific clinical type. In general, it is

often clinically manifested as the syndrome of the combination of the original and the false and the real [8, 9]. In the early stage, the patients were mainly positivistic, while the patients who had been ill for a long time became the deficiency syndrome or the mixture of deficiency and reality. Chronic non-atrophic gastritis is characterized by weakness of the spleen and stomach and disharmony of the liver and stomach [12]. Chronic atrophic gastritis is characterized by weakness of the spleen and stomach, qi stagnation, and blood stasis [13, 14]. Chronic gastritis with bile reflux is more common with disharmony between the liver and stomach [15]. Spleen and stomach dampnessheat syndrome is common in patients with *Helicobacter pylori* infection [16, 17]. For patients with precancerous lesions, qi and yin deficiency, qi stagnation and blood stasis, and damp-heat internal obstruction syndromes are common [18, 19].

#### **5. Syndrome differentiation type of chronic gastritis**

Combined with existing consensus and standards, quantitative literature statistical methods were used to conduct statistics on the relatively common clinical single syndromes. The common syndromes were identified as the syndrome of liverstomach disharmony which includes the syndrome of liver-stomach qi stagnation and the syndrome of liver-stomach heat retention, the syndrome of damp-heat of the spleen and stomach, the syndrome of spleen-stomach weakness including the syndrome of spleen-stomach qi deficiency and the syndrome of spleen-stomach cold syndrome, the syndrome of deficiency of stomach yin, and the syndrome of obstruction of stomach collaterals. The above syndromes can appear alone or in combination, and the clinical diagnosis should be based on the identification of single syndromes.

#### **5.1 Standard of syndrome differentiation**

#### *5.1.1 Syndrome of liver-stomach disharmony*

#### *5.1.1.1 Syndrome of liver-stomach qi stagnation*

Main symptoms are full or painful epigastric distention, distension, or pain in the flanks. Minor symptoms are induced or exacerbated by emotional factors and frequent belching. Symptoms in the tongue and pulse include pink tongue, thin and white moss, and wiry pulse.

#### *5.1.1.2 Syndrome of liver-stomach heat retention*

Main symptoms are epigastric burning pain, distension, or pain in the flanks. Minor symptoms are upset and irritability, acid reflux, dry mouth, bitter mouth, and dry stool. Symptoms in the tongue and pulse include red tongue, yellow moss, wiry pulse, or rapid pulse.

#### *5.1.2 Syndrome of damp-heat of the spleen and stomach*

Main symptoms are distention and fullness of stomach and abdomen, trapped and heavy body, and loose or sticky stool. Minor symptoms include eating less, anorexia, bitter mouth, bad breath, and drowsy mental. Symptoms in the tongue and pulse include red tongue, yellow and greasy moss, slippery pulse, or rapid pulse.

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*DOI: http://dx.doi.org/10.5772/intechopen.88504*

*5.1.3.1 Syndrome of spleen-stomach qi deficiency*

Main symptoms are epigastric distension or faint stomachache, postprandial aggravation, tired, and weak. Minor symptoms are indigestion and loss of appetite, cold limbs, and thin and sloppy stool. Symptoms in the tongue and pulse include

The main symptom is dull and insistent stomachache, preferring warmth and pressure. Minor disease: stomachache attack or aggravation after fatigue or take cold, spit water, mental fatigue, limb lassitude, diarrhea or with indigestible food. Symptoms in the tongue and pulse include pale and fat tongue with tooth mark,

Major symptoms include epigastric burning pain and noise in the stomach. Minor symptoms include hunger and not wanting to eat, dry mouth, and dry stool. Symptoms in the tongue and pulse include red tongue and little saliva, no or little

Main symptoms are fullness in the stomach or pain with definite location. Minor symptoms are stomach pain for a long time and sting pain. Symptoms in the tongue and pulse include dark red tongue or petechiae, ecchymosis, and wiry and

Syndrome diagnosis: with two main symptoms and two minor symptoms, the

Gastroscope is a tool to observe the color, texture, secretion, peristalsis of gastric mucosa, and mucosal blood vessels to identify the type of syndrome differentiation. Syndrome differentiation under gastroscopy has certain clinical value, especially for patients with no clinical symptoms or poor efficacy after long-term treatment. The classification standards of microscopic syndrome differentiation

Syndromes are acute and active inflammatory reaction in gastric mucosa, or

Syndromes are congestion and edema in gastric mucosa and obvious erosion of

pale tongue or tooth marks, thin and white moss, and weak pulse.

*5.1.3.2 Syndrome of deficiency of the spleen and stomach*

white and slippery moss, and deep and weak pulse.

diagnosis can be made by referring to tongue and pulse.

*5.2.1 Syndrome of disharmony between liver and stomach*

*5.2.2 Syndrome of spleen-stomach dampness and heat*

with bile reflux, gastric peristalsis faster.

**5.2 Microscopic syndrome differentiation of chronic gastritis**

*5.1.4 Syndrome of deficiency of stomach yin*

*5.1.5 Syndrome of stomach collateral stasis*

moss, and thin or rapid pulse.

unsmooth pulse.

are as follows [20].

thick and turbid mucus.

*5.1.3 Weakness of the spleen and stomach*

*Gastritis - New Approaches and Treatments*

often clinically manifested as the syndrome of the combination of the original and the false and the real [8, 9]. In the early stage, the patients were mainly positivistic, while the patients who had been ill for a long time became the deficiency syndrome or the mixture of deficiency and reality. Chronic non-atrophic gastritis is characterized by weakness of the spleen and stomach and disharmony of the liver and stomach [12]. Chronic atrophic gastritis is characterized by weakness of the spleen and stomach, qi stagnation, and blood stasis [13, 14]. Chronic gastritis with bile reflux is more common with disharmony between the liver and stomach [15]. Spleen and stomach dampnessheat syndrome is common in patients with *Helicobacter pylori* infection [16, 17]. For patients with precancerous lesions, qi and yin deficiency, qi stagnation and blood stasis, and damp-heat internal obstruction syndromes are common [18, 19].

Combined with existing consensus and standards, quantitative literature statistical methods were used to conduct statistics on the relatively common clinical single syndromes. The common syndromes were identified as the syndrome of liverstomach disharmony which includes the syndrome of liver-stomach qi stagnation and the syndrome of liver-stomach heat retention, the syndrome of damp-heat of the spleen and stomach, the syndrome of spleen-stomach weakness including the syndrome of spleen-stomach qi deficiency and the syndrome of spleen-stomach cold syndrome, the syndrome of deficiency of stomach yin, and the syndrome of obstruction of stomach collaterals. The above syndromes can appear alone or in combination, and the clinical diagnosis should be based on the identification of single syndromes.

Main symptoms are full or painful epigastric distention, distension, or pain in the flanks. Minor symptoms are induced or exacerbated by emotional factors and frequent belching. Symptoms in the tongue and pulse include pink tongue, thin and

Main symptoms are epigastric burning pain, distension, or pain in the flanks. Minor symptoms are upset and irritability, acid reflux, dry mouth, bitter mouth, and dry stool. Symptoms in the tongue and pulse include red tongue, yellow moss,

Main symptoms are distention and fullness of stomach and abdomen, trapped and heavy body, and loose or sticky stool. Minor symptoms include eating less, anorexia, bitter mouth, bad breath, and drowsy mental. Symptoms in the tongue and pulse include red tongue, yellow and greasy moss, slippery

**5. Syndrome differentiation type of chronic gastritis**

**5.1 Standard of syndrome differentiation**

*5.1.1 Syndrome of liver-stomach disharmony*

white moss, and wiry pulse.

wiry pulse, or rapid pulse.

pulse, or rapid pulse.

*5.1.1.1 Syndrome of liver-stomach qi stagnation*

*5.1.1.2 Syndrome of liver-stomach heat retention*

*5.1.2 Syndrome of damp-heat of the spleen and stomach*

**76**

#### *5.1.3 Weakness of the spleen and stomach*

#### *5.1.3.1 Syndrome of spleen-stomach qi deficiency*

Main symptoms are epigastric distension or faint stomachache, postprandial aggravation, tired, and weak. Minor symptoms are indigestion and loss of appetite, cold limbs, and thin and sloppy stool. Symptoms in the tongue and pulse include pale tongue or tooth marks, thin and white moss, and weak pulse.

#### *5.1.3.2 Syndrome of deficiency of the spleen and stomach*

The main symptom is dull and insistent stomachache, preferring warmth and pressure. Minor disease: stomachache attack or aggravation after fatigue or take cold, spit water, mental fatigue, limb lassitude, diarrhea or with indigestible food. Symptoms in the tongue and pulse include pale and fat tongue with tooth mark, white and slippery moss, and deep and weak pulse.

#### *5.1.4 Syndrome of deficiency of stomach yin*

Major symptoms include epigastric burning pain and noise in the stomach. Minor symptoms include hunger and not wanting to eat, dry mouth, and dry stool. Symptoms in the tongue and pulse include red tongue and little saliva, no or little moss, and thin or rapid pulse.

#### *5.1.5 Syndrome of stomach collateral stasis*

Main symptoms are fullness in the stomach or pain with definite location. Minor symptoms are stomach pain for a long time and sting pain. Symptoms in the tongue and pulse include dark red tongue or petechiae, ecchymosis, and wiry and unsmooth pulse.

Syndrome diagnosis: with two main symptoms and two minor symptoms, the diagnosis can be made by referring to tongue and pulse.

#### **5.2 Microscopic syndrome differentiation of chronic gastritis**

Gastroscope is a tool to observe the color, texture, secretion, peristalsis of gastric mucosa, and mucosal blood vessels to identify the type of syndrome differentiation. Syndrome differentiation under gastroscopy has certain clinical value, especially for patients with no clinical symptoms or poor efficacy after long-term treatment. The classification standards of microscopic syndrome differentiation are as follows [20].

#### *5.2.1 Syndrome of disharmony between liver and stomach*

Syndromes are acute and active inflammatory reaction in gastric mucosa, or with bile reflux, gastric peristalsis faster.

#### *5.2.2 Syndrome of spleen-stomach dampness and heat*

Syndromes are congestion and edema in gastric mucosa and obvious erosion of thick and turbid mucus.

#### *5.2.3 Syndrome of spleen-stomach weakness*

Syndromes include pale gastric mucosa, thinning mucosa, thin and more mucus or mucosal edema, visible submucosal blood vessels, and decreased gastric motility.

#### *5.2.4 Syndrome of stomach yin deficiency*

Syndromes are rough mucosal surface, thin and brittle, less secretion, thinner or disappeared plica, fissure-like changes, or visible small vascular network under the mucous membrane.

#### *5.2.5 Syndrome of stomach collateral stasis*

Syndromes are granular or nodular gastric mucosa, with intramucosal hemorrhage; gray or brown mucus; visible vascular network; and dark red vascular veins.

#### **6. Clinical treatment of chronic gastritis**

The main aim to treat chronic gastritis with traditional Chinese medicine focuses on improving the symptoms and quality of life of the patients and paying close attention to the lesions of erosion and atrophy of gastric mucosa, intestinal metaplasia, and intraepithelial neoplasia (dysplasia).

#### **6.1 Therapeutic principles**

The main therapeutic methods of TCM for chronic gastritis include medication, acupuncture, moxibustion therapy, etc. In clinic, appropriate treatment methods can be selected according to the specific situation and combined with dietary adjustment, psychological counseling, and other methods of comprehensive treatment. In the course of treatment, etiologic factors based on differentiation and treatment based on syndrome differentiation should be determined.

#### **6.2 Treatment based on syndrome differentiation**

#### *6.2.1 Syndrome of disharmony between the liver and stomach*

#### *6.2.1.1 Syndrome of qi stagnation between the liver and stomach*

The therapeutic principle is to soothe the liver to smoothen qi and harmonize the stomach. Main prescription includes Chaihu Shugan powder (*Jingyue Quanshu*). Chinese herbal medicine include Bupleurum, tangerine peel, *Fructus aurantii*, peony, *Rhizoma cyperi*, *Ligusticum striatum*, and liquorice. Patient with epigastric pain can add Sichuan neem seed and *Rhizoma corydalis*. Patient with apparent belch can add agarwood and inula flower.

#### *6.2.1.2 Syndrome of heat stagnation in the liver and stomach*

Treatment includes cooling the liver and soothing the stomach. Main prescription includes Huagan decoctum (*Jingyue Quanshu*) and Zuo Jin Wan (*Danxi Xinfa*). Medication includes Pericarpium citri reticulatae viride, tangerine peel, white peony root, peony peel, Gardenia, *Alisma*, fritillary bulb of Zhejiang, *Rhizoma coptidis*, and *Evodia officinalis*. Patient with obvious acid reflux can add squid bone and

**79**

*Angelica*.

aconite.

semen cannabis.

*Gastritis Treated by Chinese Medicine*

*DOI: http://dx.doi.org/10.5772/intechopen.88504*

can add Bupleurum and Radix curcumae.

*6.2.2 Syndrome of damp-heat in the spleen and stomach*

*6.2.3 Syndrome of deficiency of the spleen and stomach*

*6.2.3.1 Syndrome of the spleen and stomach qi deficiency*

*6.2.3.2 Syndrome of deficiency and cold in spleen and stomach*

*6.2.4 Syndrome of yin deficiency of stomach*

*6.2.5 Syndrome of stomach collaterals stasis*

ing acid decay can add radish seed, Divine comedy, and hawthorn.

concha arcae. Patient with fullness and discomfort in the chest and hypochondrium

Treatment includes clearing heat and removing dampness. Main prescription includes the soup of Huanglian Wendan (Discrimination of Six Causes). Chinese herbal medicine include *Pinellia ternata*, orange peel, *Poria cocos*, immature bitter orange, bamboo shavings, *Rhizoma coptidis*, jujube, and liquorice. Patient with abdominal distension can add *Magnolia officinalis* and betel nut. Patient with belch-

Treatment includes reinforcing qi to strengthen the spleen. Main prescription includes Xiangsha Liujunzi decoction (*Ancient and Modern Famous Medical Prescription*). Chinese herbal medicine includes costustoot, orange peel, *Pinellia ternata*, *Codonopsis*, *Atractylodes*, *Poria cocos*, and liquorice. Patient with fullness and distention can add citron. Patient with shortness of breath and sweating can add Radix Astragali Preparata. Patient with cold limbs can add cassia twig and

Treatment includes warming and strengthening the spleen. Prescription includes Huangqi Jianzhong decoction (*Synopsis of the Golden Chamber*) and Lizhong decoction (*Treatise on Febrile Diseases*). Chinese herbal medicines include *Astragalus*, peony, cassia twig, ginger, jujube, maltose, *Codonopsis*, white *Atractylodes rhizome*, dried ginger, and liquorice. Patient with loose stool can add cannon ginger charcoal and fried coix seed. Patient with obvious chills can add

Treatment includes nourishing yin, benefiting the stomach. The main prescription is Yiguan Decoction (*Xu Mingyi Lei'an*). Chinese herbal medicines include radix ginseng, Radix ophiopogonis, Rehmanniae, *Angelica sinensis*, *Fructus lycii*, and Szechwan Chinaberry fruit. Patient with obvious stomachache can add *Paeonia lactiflora* and liquorice. Patient with constipation can add snake gourd fruit and

The treatment includes activating blood circulation and removing blood stasis. Main prescription includes Shixiao powder (*Taiping Huimin Heji Jufang*) and Danshen decoction (*Shifang Gekuo*). Chinese herbal medicines include Wuling zhi, Typhae pollen, *Salvia miltiorrhiza*, Sandalwood, and *Amomum*. Patient with obvious pain can add *Rhizoma corydalis* and *Radix curcumae*. Patient who has shortness of breath and is weak can add *Astragalus* and *Codonopsis*. For patients with complex clinical symptoms and multiple syndromes, the combination of prescriptions corresponding to the pathogenesis can improve the treatment effect. For example,

*Gastritis - New Approaches and Treatments*

*5.2.3 Syndrome of spleen-stomach weakness*

*5.2.4 Syndrome of stomach yin deficiency*

*5.2.5 Syndrome of stomach collateral stasis*

**6. Clinical treatment of chronic gastritis**

plasia, and intraepithelial neoplasia (dysplasia).

**6.2 Treatment based on syndrome differentiation**

*6.2.1 Syndrome of disharmony between the liver and stomach*

*6.2.1.2 Syndrome of heat stagnation in the liver and stomach*

*6.2.1.1 Syndrome of qi stagnation between the liver and stomach*

**6.1 Therapeutic principles**

mucous membrane.

Syndromes include pale gastric mucosa, thinning mucosa, thin and more mucus or mucosal edema, visible submucosal blood vessels, and decreased gastric motility.

Syndromes are rough mucosal surface, thin and brittle, less secretion, thinner or disappeared plica, fissure-like changes, or visible small vascular network under the

Syndromes are granular or nodular gastric mucosa, with intramucosal hemorrhage; gray or brown mucus; visible vascular network; and dark red vascular veins.

The main aim to treat chronic gastritis with traditional Chinese medicine focuses

on improving the symptoms and quality of life of the patients and paying close attention to the lesions of erosion and atrophy of gastric mucosa, intestinal meta-

The main therapeutic methods of TCM for chronic gastritis include medication, acupuncture, moxibustion therapy, etc. In clinic, appropriate treatment methods can be selected according to the specific situation and combined with dietary adjustment, psychological counseling, and other methods of comprehensive treatment. In the course of treatment, etiologic factors based on differentiation and

The therapeutic principle is to soothe the liver to smoothen qi and harmonize the stomach. Main prescription includes Chaihu Shugan powder (*Jingyue Quanshu*). Chinese herbal medicine include Bupleurum, tangerine peel, *Fructus aurantii*, peony, *Rhizoma cyperi*, *Ligusticum striatum*, and liquorice. Patient with epigastric pain can add Sichuan neem seed and *Rhizoma corydalis*. Patient with apparent belch can add agarwood and

Treatment includes cooling the liver and soothing the stomach. Main prescription includes Huagan decoctum (*Jingyue Quanshu*) and Zuo Jin Wan (*Danxi Xinfa*). Medication includes Pericarpium citri reticulatae viride, tangerine peel, white peony root, peony peel, Gardenia, *Alisma*, fritillary bulb of Zhejiang, *Rhizoma coptidis*, and *Evodia officinalis*. Patient with obvious acid reflux can add squid bone and

treatment based on syndrome differentiation should be determined.

**78**

inula flower.

concha arcae. Patient with fullness and discomfort in the chest and hypochondrium can add Bupleurum and Radix curcumae.

#### *6.2.2 Syndrome of damp-heat in the spleen and stomach*

Treatment includes clearing heat and removing dampness. Main prescription includes the soup of Huanglian Wendan (Discrimination of Six Causes). Chinese herbal medicine include *Pinellia ternata*, orange peel, *Poria cocos*, immature bitter orange, bamboo shavings, *Rhizoma coptidis*, jujube, and liquorice. Patient with abdominal distension can add *Magnolia officinalis* and betel nut. Patient with belching acid decay can add radish seed, Divine comedy, and hawthorn.

#### *6.2.3 Syndrome of deficiency of the spleen and stomach*

#### *6.2.3.1 Syndrome of the spleen and stomach qi deficiency*

Treatment includes reinforcing qi to strengthen the spleen. Main prescription includes Xiangsha Liujunzi decoction (*Ancient and Modern Famous Medical Prescription*). Chinese herbal medicine includes costustoot, orange peel, *Pinellia ternata*, *Codonopsis*, *Atractylodes*, *Poria cocos*, and liquorice. Patient with fullness and distention can add citron. Patient with shortness of breath and sweating can add Radix Astragali Preparata. Patient with cold limbs can add cassia twig and *Angelica*.

#### *6.2.3.2 Syndrome of deficiency and cold in spleen and stomach*

Treatment includes warming and strengthening the spleen. Prescription includes Huangqi Jianzhong decoction (*Synopsis of the Golden Chamber*) and Lizhong decoction (*Treatise on Febrile Diseases*). Chinese herbal medicines include *Astragalus*, peony, cassia twig, ginger, jujube, maltose, *Codonopsis*, white *Atractylodes rhizome*, dried ginger, and liquorice. Patient with loose stool can add cannon ginger charcoal and fried coix seed. Patient with obvious chills can add aconite.

#### *6.2.4 Syndrome of yin deficiency of stomach*

Treatment includes nourishing yin, benefiting the stomach. The main prescription is Yiguan Decoction (*Xu Mingyi Lei'an*). Chinese herbal medicines include radix ginseng, Radix ophiopogonis, Rehmanniae, *Angelica sinensis*, *Fructus lycii*, and Szechwan Chinaberry fruit. Patient with obvious stomachache can add *Paeonia lactiflora* and liquorice. Patient with constipation can add snake gourd fruit and semen cannabis.

#### *6.2.5 Syndrome of stomach collaterals stasis*

The treatment includes activating blood circulation and removing blood stasis. Main prescription includes Shixiao powder (*Taiping Huimin Heji Jufang*) and Danshen decoction (*Shifang Gekuo*). Chinese herbal medicines include Wuling zhi, Typhae pollen, *Salvia miltiorrhiza*, Sandalwood, and *Amomum*. Patient with obvious pain can add *Rhizoma corydalis* and *Radix curcumae*. Patient who has shortness of breath and is weak can add *Astragalus* and *Codonopsis*. For patients with complex clinical symptoms and multiple syndromes, the combination of prescriptions corresponding to the pathogenesis can improve the treatment effect. For example,

if the pathogenesis of gastritis patient is the deficiency of the spleen and stomach and the disharmony between the liver and stomach, the main prescription should be Xiangsha Liujunzi decoction and Bupleurum Shugan powder.

#### **6.3 Treatment based on disease differentiation**

Treating chronic gastritis by disease differentiation is an important part of TCM clinical practice. The principle is to formulate the prescription based on the understanding of the basic pathogenesis of chronic gastritis and then prescribe the prescription according to the syndrome. From the composition of clinical prescriptions, most of them are composed of single syndrome prescriptions. For those without obvious clinical symptoms, treatment can be carried out based on disease differentiation combined with the syndrome differentiation results of the tongue and pulse and gastric mucosa manifestation under endoscope.

In chronic gastritis patients with positive *Helicobacter pylori*, eradication of *Helicobacter pylori* is necessary if there are obvious clinical symptoms or accompanied by atrophy, erosion, intestinal metaplasia, intraepithelial neoplasia, or family history of gastric cancer [8, 10]. The eradication of *Helicobacter pylori* guidelines and drug regimen were need.

Based on the syndrome differentiation, when chronic gastritis is accompanied by gastric mucosa congestion and erosion, Notoginseng powder, *Rhizoma bletillae* powder, and Pearl powder can be added for treatment, and it can be taken with decoction or with warm water after making a paste and taken on an empty stomach. For patients with intramucosal hemorrhage, the herbs to remove blood stasis and stop bleeding can be added, such as *Panax notoginseng* powder and *Rhizoma bletillae* powder. For chronic gastritis patient with precancerous lesions and syndrome of non-spleen-stomach deficient cold can add *Hedyotis diffusa*, *Scutellariae barbatae*, and Chinese lobelia into the compound prescription or use the herbs for promoting circulation and removing stasis, such as *Salvia miltiorrhiza*, *Panax notoginseng*, and Zedoary turmeric.

#### **6.4 Commonly used Chinese patent medicine**

#### *6.4.1 Qizhi Weitong granules*

It can smooth liver qi and harmonize the stomach to alleviate stomachache. It was usually used for patients with depression or irritability, sigh, belching, chest stuffiness and fullness, and epigastric pain.

#### *6.4.2 Weishu granules*

It can regulate qi and eliminate distension and alleviate stomachache. It was usually used for patients with epigastric pain caused by qi stagnation with epigastric distension pain, which extends to two sides, pain relief after belching or flatus, pain aggravation after emotional depression and anger, eating less food, chest distress, and poor defecation.

#### *6.4.3 Wenweishu capsule*

It can nourish the stomach and promote Qi circulation to relieve pain. It was usually used for patients with stomachache caused by deficiency and cold in the middle Jiao with epigastric cold pain, abdominal distension and belching, poor appetite, less food, intolerance of cold, and weakness.

**81**

*Gastritis Treated by Chinese Medicine*

*6.4.4 Xuhan Weitong granule*

*6.4.5 Jianwei Xiaoshi oral liquid*

*6.4.6 Yangweishu capsule*

appetite, and emaciation.

*6.4.7 Cubeb Weitong granules*

stagnation and blood stasis.

loss of appetite and belching.

*6.4.9 Wei Fuchun capsule*

*6.4.10 Dalitong granules*

*6.4.11 Weitai granules*

*6.4.8 Molodan (concentrated pills)*

distention.

*DOI: http://dx.doi.org/10.5772/intechopen.88504*

tion after catch cold, eating cold food, or stomach empty.

It can tonify Qi and the spleen and warm the stomach to relieve pain. It is usually used for patients with stomachache caused by deficiency of the spleen and stomach. The symptoms are epigastric dull pain, tolerance of warmth and pressure, aggrava-

It can tonify the stomach and improves digestion. It was usually used for patients with dyspepsia caused by deficiency of the spleen and stomach. The symptoms are dyspepsia, belching, putrid belching and acid swallowing, abdominal fullness, and

It can nourish the yin and stomach. It was usually used for patients with epigastric burning pain caused by deficiency of the yin and stomach. The further symptoms are dull pain, feverishness in palms and soles, dry mouth, bitter mouth, poor

It can activate Qi to promote blood circulation and harmonize stomach to relieve pain. It was usually used for epigastric distension and pricking pain caused by Qi

It can harmonize the stomach and calms the adverse-rising energy, strengthens the spleen to relieve distension and dredge collateral to relieve pain. It was usually used for patients with symptoms of stomachache, fullness, stuffy, indigestion, and

It can strengthen the spleen and nourish qi and promote blood circulation and detoxification. It was usually used for patients with the precancerous lesions of gastric cancer of chronic atrophic gastritis or adjuvant treatment after gastric cancer surgery.

It can clear heat and relieve depression, regulate the stomach and calm the adverserising energy, and eliminate stagnation. It was usually used for patients with epigastric fullness and distention syndrome caused by heat stagnation of the liver and stomach. The symptoms include epigastric distension and fullness, belching, poor appetite, heartburn in the stomach, noisy pantothenic acid, epigastric pain, and dry and bitter

It can promote Qi circulation and relieve stomachache. It is usually used for patients with stomachache caused by qi stagnation and blood stasis and dampness

mouth. The dyskinetic type of functional dyspepsia seen above symptoms.

#### *6.4.4 Xuhan Weitong granule*

*Gastritis - New Approaches and Treatments*

and drug regimen were need.

Zedoary turmeric.

*6.4.1 Qizhi Weitong granules*

*6.4.2 Weishu granules*

and poor defecation.

*6.4.3 Wenweishu capsule*

**6.4 Commonly used Chinese patent medicine**

stuffiness and fullness, and epigastric pain.

less food, intolerance of cold, and weakness.

if the pathogenesis of gastritis patient is the deficiency of the spleen and stomach and the disharmony between the liver and stomach, the main prescription should

Treating chronic gastritis by disease differentiation is an important part of TCM clinical practice. The principle is to formulate the prescription based on the understanding of the basic pathogenesis of chronic gastritis and then prescribe the prescription according to the syndrome. From the composition of clinical prescriptions, most of them are composed of single syndrome prescriptions. For those without obvious clinical symptoms, treatment can be carried out based on disease differentiation combined with the syndrome differentiation results of the tongue

In chronic gastritis patients with positive *Helicobacter pylori*, eradication of *Helicobacter pylori* is necessary if there are obvious clinical symptoms or accompanied by atrophy, erosion, intestinal metaplasia, intraepithelial neoplasia, or family history of gastric cancer [8, 10]. The eradication of *Helicobacter pylori* guidelines

Based on the syndrome differentiation, when chronic gastritis is accompanied by gastric mucosa congestion and erosion, Notoginseng powder, *Rhizoma bletillae* powder, and Pearl powder can be added for treatment, and it can be taken with decoction or with warm water after making a paste and taken on an empty stomach. For patients with intramucosal hemorrhage, the herbs to remove blood stasis and stop bleeding can be added, such as *Panax notoginseng* powder and *Rhizoma bletillae* powder. For chronic gastritis patient with precancerous lesions and syndrome of non-spleen-stomach deficient cold can add *Hedyotis diffusa*, *Scutellariae barbatae*, and Chinese lobelia into the compound prescription or use the herbs for promoting circulation and removing stasis, such as *Salvia miltiorrhiza*, *Panax notoginseng*, and

It can smooth liver qi and harmonize the stomach to alleviate stomachache. It was usually used for patients with depression or irritability, sigh, belching, chest

It can regulate qi and eliminate distension and alleviate stomachache. It was usually used for patients with epigastric pain caused by qi stagnation with epigastric distension pain, which extends to two sides, pain relief after belching or flatus, pain aggravation after emotional depression and anger, eating less food, chest distress,

It can nourish the stomach and promote Qi circulation to relieve pain. It was usually used for patients with stomachache caused by deficiency and cold in the middle Jiao with epigastric cold pain, abdominal distension and belching, poor appetite,

be Xiangsha Liujunzi decoction and Bupleurum Shugan powder.

and pulse and gastric mucosa manifestation under endoscope.

**6.3 Treatment based on disease differentiation**

**80**

It can tonify Qi and the spleen and warm the stomach to relieve pain. It is usually used for patients with stomachache caused by deficiency of the spleen and stomach. The symptoms are epigastric dull pain, tolerance of warmth and pressure, aggravation after catch cold, eating cold food, or stomach empty.

#### *6.4.5 Jianwei Xiaoshi oral liquid*

It can tonify the stomach and improves digestion. It was usually used for patients with dyspepsia caused by deficiency of the spleen and stomach. The symptoms are dyspepsia, belching, putrid belching and acid swallowing, abdominal fullness, and distention.

#### *6.4.6 Yangweishu capsule*

It can nourish the yin and stomach. It was usually used for patients with epigastric burning pain caused by deficiency of the yin and stomach. The further symptoms are dull pain, feverishness in palms and soles, dry mouth, bitter mouth, poor appetite, and emaciation.

#### *6.4.7 Cubeb Weitong granules*

It can activate Qi to promote blood circulation and harmonize stomach to relieve pain. It was usually used for epigastric distension and pricking pain caused by Qi stagnation and blood stasis.

#### *6.4.8 Molodan (concentrated pills)*

It can harmonize the stomach and calms the adverse-rising energy, strengthens the spleen to relieve distension and dredge collateral to relieve pain. It was usually used for patients with symptoms of stomachache, fullness, stuffy, indigestion, and loss of appetite and belching.

#### *6.4.9 Wei Fuchun capsule*

It can strengthen the spleen and nourish qi and promote blood circulation and detoxification. It was usually used for patients with the precancerous lesions of gastric cancer of chronic atrophic gastritis or adjuvant treatment after gastric cancer surgery.

#### *6.4.10 Dalitong granules*

It can clear heat and relieve depression, regulate the stomach and calm the adverserising energy, and eliminate stagnation. It was usually used for patients with epigastric fullness and distention syndrome caused by heat stagnation of the liver and stomach. The symptoms include epigastric distension and fullness, belching, poor appetite, heartburn in the stomach, noisy pantothenic acid, epigastric pain, and dry and bitter mouth. The dyskinetic type of functional dyspepsia seen above symptoms.

#### *6.4.11 Weitai granules*

It can promote Qi circulation and relieve stomachache. It is usually used for patients with stomachache caused by qi stagnation and blood stasis and dampness and heat stasis. The symptoms are abdominal dull pain, fullness, sour regurgitation, nausea, and vomiting; the discomfort is lessened after eating.

#### *6.4.12 Jin Weitai capsule*

It can promote qi circulation and relieve pain in the stomach. It is usually used for patients with acute and chronic gastroenteritis, ulcer in the stomach and duodenum caused by qi stagnation of the liver and stomach or dampness and heat stasis.

#### *6.4.13 Weikang capsule*

It can promote Qi circulation and invigorate the stomach, remove blood stasis and hemostasis, and relieve hyperacidity and pain. It is usually used for patients with epigastric pain caused by Qi stagnation and blood stasis. The further symptoms are pain fixation, acid swallowing noise, and gastric and duodenal ulcers.

#### *6.4.14 Jinghua Weikang Jiaowan*

It can regulate Qi to dissipate cold and clear heat and disperse blood stasis. It is usually used for patients with epigastric distension pain or duodenal ulcer caused by mixed coldness and heat syndrome and Qi stagnation and blood stasis and belching; the further symptoms are acid regurgitation, noise, and bitter mouth.

#### *6.4.15 Ganhai Weikang capsule*

It can strengthen the spleen and stomach and relieve pain with convergence. It was usually used for patients with chronic gastritis stomach and duodenal ulcer and reflux esophagitis caused by spleen deficiency and qi stagnation.

#### *6.4.16 Dongfang Weiyao capsule*

It can soothe the liver and harmonize stomach, regulate Qi and promote blood circulation, clear heat, and relieve pain. It is usually used for patients with epigastric pain caused by liver-stomach disharmony and heat stasis blocking collaterals; the symptoms are stomachache, belching, acid swallowing, noise, poor appetite, and irritability.

#### *6.4.17 Yanshen Jianwei capsule*

It can strengthen the spleen and harmonize the stomach, regulate cold and heat, and relieve fullness and pain. It was usually used for patients with stomachache caused by deficiency in origin and enrichment in symptom and mixed coldness and heat; the symptoms are epigastric fullness, stomachache, poor appetite, belching, noise, fatigue, and weakness.

#### *6.4.18 Danweikang capsule*

It can soothe the liver and gallbladder and clear dampness and heat. It was usually used for patients with hypochondriac pain and jaundice caused by the dampheat in the liver and gallbladder. It can also be used for patients with bile reflux gastritis and cholecystitis that have the same symptoms.

**83**

*Gastritis Treated by Chinese Medicine*

**6.6 Psychological intervention**

**7. Criterion of therapeutic effect**

*7.1.1 Evaluation of syndrome efficacy*

tive effect index or smaller than 70%.

*DOI: http://dx.doi.org/10.5772/intechopen.88504*

**6.5 Acupuncture and moxibustion therapy**

stomach and improve their quality of life [21–24].

Acupuncture and moxibustion therapy have an effect on improving the symptoms of chronic gastritis. Acupuncture and moxibustion can effectively relieve the symptoms of gastritis in patients with syndrome of deficiency of the spleen and

Acupoints in acupuncture treatment include Zusanli (ST36), Zhongwan (RN12), Weishu (BL21), Pishu (BL20), and Neiguan (PC6). Patient with liver-stomach disharmony syndrome plus Ganshu (BL17), Taichong (LR4), Qimen (LR14). Patient with hot stasis syndrome plus Tianshu (ST25), Fenglong (ST40). Patient with weakness of spleen and stomach syndrome should add Pishu (BL20), Liang qiu (ST34), Qihai (RN6). Patient with deficiency of stomach Yin syndrome should add Sanyinjiao (SP6), Taixi (KI3). For those with severe cold and deficiency of spleen and stomach syndrome, moxibustion should be performed at Shangwan (RN13), Zhongwan (RN12), Xiawan (RN10), and Zusanli (ST36). Patient with nausea, vomiting, or belching should add Shangwan (RN13), Neiguan (PC6), Geshu (BL17). Patient with severe pain plus Liangmen (ST21), Neiguan (PC6), Gongsun (SP4). Patient with dyspepsia should add Hegu (LI4), Tian shu (ST25), Guanyuan (ST34), Sanyinjiao (SP6). Patient with Qi stagnation and blood stasis syndrome should add Taichong (LR4), Xuehai (SP10), Hegu (LI4). Patient with qi deficiency and blood stasis syndrome should add Xuehai (SP10) and Geshu (BL17). Acupuncture was used for patient with excess syndrome and moxibustion for those with deficiency syndrome. Patient with intermingled deficiency and excess syndrome, acupuncture should combine moxibustion.

Mental stimulation is an important factor causing chronic gastritis, and the scores of anxiety and depression of patients with chronic gastritis are also higher than normal people. Common psychological disorders include loss of confidence in treatment, fear of cancer, and fear of special examinations. Strengthening psychological counseling for gastritis patients is helpful for alleviating the incidence of chronic gastritis, alleviating symptoms, and improving the quality of life [25–27].

**7.1 The criteria of therapeutic effect of chronic gastritis include evaluation of syndrome efficacy, symptom evaluation, endoscopic evaluation of gastric mucosa, histopathological evaluation, and evaluation of quality of life**

It reflects the characteristics of clinical efficacy evaluation of TCM, and the efficacy is often evaluated by nimodipine method according to the clinical symptoms and manifestations of the tongue and pulse. Clinical recovery: The main symptoms and signs disappear or almost disappear, and the curative effect index was equal or greater than 95%. Significant efficacy: The main symptoms and signs were significantly improved, and curative effect index was equal or greater than 70% or smaller than 95%. Clinical effective: The main symptoms and signs improved, and curative effect index was equal or greater than 30% or smaller than 70%. Ineffectiveness: The main symptoms and signs have no obvious improvement or even worse, cura*Gastritis - New Approaches and Treatments*

*6.4.12 Jin Weitai capsule*

*6.4.13 Weikang capsule*

*6.4.14 Jinghua Weikang Jiaowan*

*6.4.15 Ganhai Weikang capsule*

*6.4.16 Dongfang Weiyao capsule*

*6.4.17 Yanshen Jianwei capsule*

noise, fatigue, and weakness.

*6.4.18 Danweikang capsule*

irritability.

heat stasis.

and heat stasis. The symptoms are abdominal dull pain, fullness, sour regurgitation,

It can promote qi circulation and relieve pain in the stomach. It is usually used for patients with acute and chronic gastroenteritis, ulcer in the stomach and duodenum caused by qi stagnation of the liver and stomach or dampness and

It can promote Qi circulation and invigorate the stomach, remove blood stasis and hemostasis, and relieve hyperacidity and pain. It is usually used for patients with epigastric pain caused by Qi stagnation and blood stasis. The further symptoms are pain fixation, acid swallowing noise, and gastric and duodenal ulcers.

It can regulate Qi to dissipate cold and clear heat and disperse blood stasis. It is usually used for patients with epigastric distension pain or duodenal ulcer caused by mixed coldness and heat syndrome and Qi stagnation and blood stasis and belching; the further symptoms are acid regurgitation, noise, and bitter mouth.

It can strengthen the spleen and stomach and relieve pain with convergence. It was usually used for patients with chronic gastritis stomach and duodenal ulcer and

It can soothe the liver and harmonize stomach, regulate Qi and promote blood circulation, clear heat, and relieve pain. It is usually used for patients with epigastric pain caused by liver-stomach disharmony and heat stasis blocking collaterals; the symptoms are stomachache, belching, acid swallowing, noise, poor appetite, and

It can strengthen the spleen and harmonize the stomach, regulate cold and heat,

It can soothe the liver and gallbladder and clear dampness and heat. It was usually used for patients with hypochondriac pain and jaundice caused by the dampheat in the liver and gallbladder. It can also be used for patients with bile reflux

gastritis and cholecystitis that have the same symptoms.

and relieve fullness and pain. It was usually used for patients with stomachache caused by deficiency in origin and enrichment in symptom and mixed coldness and heat; the symptoms are epigastric fullness, stomachache, poor appetite, belching,

reflux esophagitis caused by spleen deficiency and qi stagnation.

nausea, and vomiting; the discomfort is lessened after eating.

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#### **6.5 Acupuncture and moxibustion therapy**

Acupuncture and moxibustion therapy have an effect on improving the symptoms of chronic gastritis. Acupuncture and moxibustion can effectively relieve the symptoms of gastritis in patients with syndrome of deficiency of the spleen and stomach and improve their quality of life [21–24].

Acupoints in acupuncture treatment include Zusanli (ST36), Zhongwan (RN12), Weishu (BL21), Pishu (BL20), and Neiguan (PC6). Patient with liver-stomach disharmony syndrome plus Ganshu (BL17), Taichong (LR4), Qimen (LR14). Patient with hot stasis syndrome plus Tianshu (ST25), Fenglong (ST40). Patient with weakness of spleen and stomach syndrome should add Pishu (BL20), Liang qiu (ST34), Qihai (RN6). Patient with deficiency of stomach Yin syndrome should add Sanyinjiao (SP6), Taixi (KI3). For those with severe cold and deficiency of spleen and stomach syndrome, moxibustion should be performed at Shangwan (RN13), Zhongwan (RN12), Xiawan (RN10), and Zusanli (ST36). Patient with nausea, vomiting, or belching should add Shangwan (RN13), Neiguan (PC6), Geshu (BL17). Patient with severe pain plus Liangmen (ST21), Neiguan (PC6), Gongsun (SP4). Patient with dyspepsia should add Hegu (LI4), Tian shu (ST25), Guanyuan (ST34), Sanyinjiao (SP6). Patient with Qi stagnation and blood stasis syndrome should add Taichong (LR4), Xuehai (SP10), Hegu (LI4). Patient with qi deficiency and blood stasis syndrome should add Xuehai (SP10) and Geshu (BL17). Acupuncture was used for patient with excess syndrome and moxibustion for those with deficiency syndrome. Patient with intermingled deficiency and excess syndrome, acupuncture should combine moxibustion.

#### **6.6 Psychological intervention**

Mental stimulation is an important factor causing chronic gastritis, and the scores of anxiety and depression of patients with chronic gastritis are also higher than normal people. Common psychological disorders include loss of confidence in treatment, fear of cancer, and fear of special examinations. Strengthening psychological counseling for gastritis patients is helpful for alleviating the incidence of chronic gastritis, alleviating symptoms, and improving the quality of life [25–27].

### **7. Criterion of therapeutic effect**

#### **7.1 The criteria of therapeutic effect of chronic gastritis include evaluation of syndrome efficacy, symptom evaluation, endoscopic evaluation of gastric mucosa, histopathological evaluation, and evaluation of quality of life**

#### *7.1.1 Evaluation of syndrome efficacy*

It reflects the characteristics of clinical efficacy evaluation of TCM, and the efficacy is often evaluated by nimodipine method according to the clinical symptoms and manifestations of the tongue and pulse. Clinical recovery: The main symptoms and signs disappear or almost disappear, and the curative effect index was equal or greater than 95%. Significant efficacy: The main symptoms and signs were significantly improved, and curative effect index was equal or greater than 70% or smaller than 95%. Clinical effective: The main symptoms and signs improved, and curative effect index was equal or greater than 30% or smaller than 70%. Ineffectiveness: The main symptoms and signs have no obvious improvement or even worse, curative effect index or smaller than 70%.

#### *7.1.2 Symptom evaluation*

It is mainly aimed at the evaluation of dyspepsia symptoms of chronic gastritis, such as upper abdominal pain, fullness or early fullness, loss of appetite, etc. The method was that the symptoms were classified into main symptoms and minor symptoms according to degree and frequency and assign the value according to the weight function, further specification was needed.

#### *7.1.3 Endoscopic evaluation of gastric mucosa*

Level I: Branch of Digestive endoscopy of Chinese Medical Association [28] Scattered or discontinuous linear erythema, single erosion, local mucosal hemorrhage, granular gastric mucosal atrophy, partial visible blood vessel, or single gray nodules of intestinal metaplasia. Level II: Dense or continuous linear erythema, more than five local multiple erosion, multiple mucosal hemorrhage, medium gastric mucosal atrophy, continuous visible blood vessel, or multiple gray nodules of intestinal metaplasia. Level III: Extensive fused erythema, more than five extensive multiple erosion, diffuse mucosal hemorrhage, big gastric mucosal atrophy, disappeared mucosal folds, visible blood vessel to mucosa surface, or diffused gray nodules of intestinal metaplasia.

#### *7.1.4 Histopathological evaluation*

It includes mucosal trophy, intestinal metaplasia, intraepithelial neoplasia, inflammatory response, and disease activity. They were divided to none, mild level, medium level, and severe level [10]. None level: There are no more than five mononuclear cells in each high-power field. Mild level: There are a few neutrophils in the lamina propria of the gastric mucosa. Chronic inflammatory cells are few and limited to the superficial mucosa, no more than one third of the mucosa. The number of proper mucosal glands decreased by no more than one third of the original glands. Intestinal metaplasia accounts for less than one third of the total glandular and surface epithelial area. Medium level: Neutrophils are more common in the mucosa and can be found in surface epithelial cells, small concave epithelial cells, or glandular epithelium. Chronic inflammatory cells are relatively dense, no more than two thirds of the mucosal layer. The number of proper mucosal glands decreased between one third and two thirds of the original glands. Intestinal metaplasia accounts for one third-two thirds of the total glandular and surface epithelial area. Severe level: The neutrophils are more dense, or pit abscesses may be seen in addition to the medium. Chronic inflammatory cells are dense and occupy the entire mucosal layer. The number of proper glands decreased by more than two thirds, and only a few glands remained or even disappeared completely. Intestinal metaplasia accounts for more than two thirds of the total glandular and epithelial surface area. The visual analogue scoring method combined with histopathological evaluation can be referred to for grading of each lesion.

#### *7.1.5 Evaluation of quality of life*

The patient reported outcomes (PRO), and SF-36 health questionnaire scales can be used to evaluate the quality of life. PRO proceeds from the characteristics of TCM treatment of spleen and stomach diseases. Patients were evaluated from six dimensions including dyspepsia, reflux, defecation, social, psychological, and general state [29, 30].

**85**

*Gastritis Treated by Chinese Medicine*

and depression.

**7.2 Long-term efficacy**

**7.3 Marking targeting biopsy**

and intraepithelial neoplasia.

**8.1 Alimentary control**

**8.2 Psychological adjustment**

**8.3 Lifestyle adjustment**

**8.4 Follow-up monitoring**

**8. Prevention and maintenance**

*DOI: http://dx.doi.org/10.5772/intechopen.88504*

Hospital anxiety and depression scale (HAD), anxiety self-rating scale (SAS), and depression self-rating scale (SDS) can be used to evaluate the state of anxiety

Clinical efficacy evaluation of chronic gastritis should combine short-term efficacy with long-term efficacy evaluation. The course of chronic gastritis is a longterm, chronic, and repeated process. In addition to symptoms, atrophy, intestinal metaplasia, intraepithelial neoplasia, and other lesions should be the important content of observation. The clinical efficacy evaluation time of chronic gastritis is recommended to be more than 3 months in order to accurately evaluate the efficacy. Long-term follow-up was conducted after the treatment to observe the incidence of gastric cancer and other endpoint outcome indicators and disease recurrence.

Marking targeting biopsy of gastric mucosa is of high value for the evaluation of chronic atrophic gastritis and chronic atrophic gastritis with intestinal metaplasia

Research on the relationship between eating behavior and chronic gastritis shows that habits of irregular meals, eating too fast, overeating, eating hot food, eating and drinking too much, salty taste are risk factors for chronic gastritis [29, 30]. Chronic gastritis patients should try to avoid taking stimulating food, such as spicy food, food containing nitrite, etc., and drugs, such as nonsteroidal anti-

Patients with chronic gastritis should keep a good mood and avoid the stimula-

Patients with chronic gastritis should avoid long-term overwork. In winter and

Patients with chronic atrophic gastritis accompanied by intraepithelial neoplasia and intestinal metaplasia were followed up and monitored to have a certain probability of cancer. Studies have shown that the time required for 95% of the population with precancerous lesions to become cancerous is 11.6 years for atrophic gastritis, 11.4 years for intestinal metaplasia, 5.7 years for dysplasia, and 4.5 years for moderate to severe intestinal metaplasia with moderate to severe dysplasia [31].

inflammatory drugs, that may damage the gastric mucosa.

spring, we need to pay special attention to life adjustment.

tion of bad emotions. If necessary, they can consult a psychologist.

*7.1.6 Anxiety and depression evaluation*

#### *7.1.6 Anxiety and depression evaluation*

Hospital anxiety and depression scale (HAD), anxiety self-rating scale (SAS), and depression self-rating scale (SDS) can be used to evaluate the state of anxiety and depression.

#### **7.2 Long-term efficacy**

*Gastritis - New Approaches and Treatments*

weight function, further specification was needed.

*7.1.3 Endoscopic evaluation of gastric mucosa*

nodules of intestinal metaplasia.

*7.1.4 Histopathological evaluation*

referred to for grading of each lesion.

*7.1.5 Evaluation of quality of life*

general state [29, 30].

It is mainly aimed at the evaluation of dyspepsia symptoms of chronic gastritis, such as upper abdominal pain, fullness or early fullness, loss of appetite, etc. The method was that the symptoms were classified into main symptoms and minor symptoms according to degree and frequency and assign the value according to the

Level I: Branch of Digestive endoscopy of Chinese Medical Association [28] Scattered or discontinuous linear erythema, single erosion, local mucosal hemorrhage, granular gastric mucosal atrophy, partial visible blood vessel, or single gray nodules of intestinal metaplasia. Level II: Dense or continuous linear erythema, more than five local multiple erosion, multiple mucosal hemorrhage, medium gastric mucosal atrophy, continuous visible blood vessel, or multiple gray nodules of intestinal metaplasia. Level III: Extensive fused erythema, more than five extensive multiple erosion, diffuse mucosal hemorrhage, big gastric mucosal atrophy, disappeared mucosal folds, visible blood vessel to mucosa surface, or diffused gray

It includes mucosal trophy, intestinal metaplasia, intraepithelial neoplasia, inflammatory response, and disease activity. They were divided to none, mild level, medium level, and severe level [10]. None level: There are no more than five mononuclear cells in each high-power field. Mild level: There are a few neutrophils in the lamina propria of the gastric mucosa. Chronic inflammatory cells are few and limited to the superficial mucosa, no more than one third of the mucosa. The number of proper mucosal glands decreased by no more than one third of the original glands. Intestinal metaplasia accounts for less than one third of the total glandular and surface epithelial area. Medium level: Neutrophils are more common in the mucosa and can be found in surface epithelial cells, small concave epithelial cells, or glandular epithelium. Chronic inflammatory cells are relatively dense, no more than two thirds of the mucosal layer. The number of proper mucosal glands decreased between one third and two thirds of the original glands. Intestinal metaplasia accounts for one third-two thirds of the total glandular and surface epithelial area. Severe level: The neutrophils are more dense, or pit abscesses may be seen in addition to the medium. Chronic inflammatory cells are dense and occupy the entire mucosal layer. The number of proper glands decreased by more than two thirds, and only a few glands remained or even disappeared completely. Intestinal metaplasia accounts for more than two thirds of the total glandular and epithelial surface area. The visual analogue scoring method combined with histopathological evaluation can be

The patient reported outcomes (PRO), and SF-36 health questionnaire scales can be used to evaluate the quality of life. PRO proceeds from the characteristics of TCM treatment of spleen and stomach diseases. Patients were evaluated from six dimensions including dyspepsia, reflux, defecation, social, psychological, and

*7.1.2 Symptom evaluation*

**84**

Clinical efficacy evaluation of chronic gastritis should combine short-term efficacy with long-term efficacy evaluation. The course of chronic gastritis is a longterm, chronic, and repeated process. In addition to symptoms, atrophy, intestinal metaplasia, intraepithelial neoplasia, and other lesions should be the important content of observation. The clinical efficacy evaluation time of chronic gastritis is recommended to be more than 3 months in order to accurately evaluate the efficacy. Long-term follow-up was conducted after the treatment to observe the incidence of gastric cancer and other endpoint outcome indicators and disease recurrence.

#### **7.3 Marking targeting biopsy**

Marking targeting biopsy of gastric mucosa is of high value for the evaluation of chronic atrophic gastritis and chronic atrophic gastritis with intestinal metaplasia and intraepithelial neoplasia.

#### **8. Prevention and maintenance**

#### **8.1 Alimentary control**

Research on the relationship between eating behavior and chronic gastritis shows that habits of irregular meals, eating too fast, overeating, eating hot food, eating and drinking too much, salty taste are risk factors for chronic gastritis [29, 30]. Chronic gastritis patients should try to avoid taking stimulating food, such as spicy food, food containing nitrite, etc., and drugs, such as nonsteroidal antiinflammatory drugs, that may damage the gastric mucosa.

#### **8.2 Psychological adjustment**

Patients with chronic gastritis should keep a good mood and avoid the stimulation of bad emotions. If necessary, they can consult a psychologist.

#### **8.3 Lifestyle adjustment**

Patients with chronic gastritis should avoid long-term overwork. In winter and spring, we need to pay special attention to life adjustment.

#### **8.4 Follow-up monitoring**

Patients with chronic atrophic gastritis accompanied by intraepithelial neoplasia and intestinal metaplasia were followed up and monitored to have a certain probability of cancer. Studies have shown that the time required for 95% of the population with precancerous lesions to become cancerous is 11.6 years for atrophic gastritis, 11.4 years for intestinal metaplasia, 5.7 years for dysplasia, and 4.5 years for moderate to severe intestinal metaplasia with moderate to severe dysplasia [31].

So, the advice of "Chronic gastritis consensus in China" is patients of chronic atrophic gastritis with moderate to severe atrophy and intestinal metaplasia need around 1-year follow-up. Patients of chronic atrophic gastritis without intestinal metaplasia or intraepithelial neoplasia need appropriate follow-up of endoscopy and pathology. Patient accompanied by low-level intraepithelial neoplasia and proved that it doesn't come from adjacent tissues of cancer need once endoscopy every 3 months follow-up according to the endoscopic and clinical situation. However, high-grade intraepithelial neoplasia requires immediate confirmation and endoscopic or surgical treatment after confirmation.

#### **9. Conclusions**

The core contents of traditional Chinese medicine (TCM) theory are holism concept and syndrome differentiation; the treatment based on syndrome differentiation is the basic principle of TCM in understanding and treating diseases. So based on the treatment of *Helicobacter pylori* infection, chronic gastritis was treated by Chinese medicine based on disease differentiation. Patients with different syndromes are treated differently with different medicines. Usually, Chinese medicine to treat chronic gastritis is administered orally in decoction or proprietary Chinese medicine. In the recent years, improvement of gastritis drug dosage forms appeared [32], and it was a modern directed drug release preparation with gastric organ flotation and adhesion functions, but more clinical evidence of its effectiveness is lacking.

In conclusion, TCM plays a certain role in improving the clinical symptoms and signs of chronic gastritis. Although the mechanism of its action is not very clear, it still has important clinical value and needs further research and discussion.

#### **Acknowledgements**

Authors thank Spleen and Stomach Disease Branch of China Association of Chinese Medicine for the Consensus opinions of TCM diagnosis and treatment experts on chronic gastritis.

Authors thank for the support of National Basic Research Programme of China (973 programme, grant number 2015CB554501).

**87**

**Author details**

Xiaomei Wang\*, Guang Ji and Huangan Wu

provided the original work is properly cited.

\*Address all correspondence to: wxm123@vip.sina.com

Shanghai University of Traditional Chinese Medicine, Shanghai, China

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Gastritis Treated by Chinese Medicine*

*DOI: http://dx.doi.org/10.5772/intechopen.88504*

#### **Conflict of interest**

There is no conflict of interest among authors.

*Gastritis Treated by Chinese Medicine DOI: http://dx.doi.org/10.5772/intechopen.88504*

*Gastritis - New Approaches and Treatments*

**9. Conclusions**

ness is lacking.

**Acknowledgements**

**Conflict of interest**

experts on chronic gastritis.

(973 programme, grant number 2015CB554501).

There is no conflict of interest among authors.

endoscopic or surgical treatment after confirmation.

So, the advice of "Chronic gastritis consensus in China" is patients of chronic atrophic gastritis with moderate to severe atrophy and intestinal metaplasia need around 1-year follow-up. Patients of chronic atrophic gastritis without intestinal metaplasia or intraepithelial neoplasia need appropriate follow-up of endoscopy and pathology. Patient accompanied by low-level intraepithelial neoplasia and proved that it doesn't come from adjacent tissues of cancer need once endoscopy every 3 months follow-up according to the endoscopic and clinical situation.

However, high-grade intraepithelial neoplasia requires immediate confirmation and

The core contents of traditional Chinese medicine (TCM) theory are holism concept and syndrome differentiation; the treatment based on syndrome differentiation is the basic principle of TCM in understanding and treating diseases. So based on the treatment of *Helicobacter pylori* infection, chronic gastritis was treated by Chinese medicine based on disease differentiation. Patients with different syndromes are treated differently with different medicines. Usually, Chinese medicine to treat chronic gastritis is administered orally in decoction or proprietary Chinese medicine. In the recent years, improvement of gastritis drug dosage forms appeared [32], and it was a modern directed drug release preparation with gastric organ flotation and adhesion functions, but more clinical evidence of its effective-

In conclusion, TCM plays a certain role in improving the clinical symptoms and signs of chronic gastritis. Although the mechanism of its action is not very clear, it still has important clinical value and needs further research and discussion.

Authors thank Spleen and Stomach Disease Branch of China Association of Chinese Medicine for the Consensus opinions of TCM diagnosis and treatment

Authors thank for the support of National Basic Research Programme of China

**86**

#### **Author details**

Xiaomei Wang\*, Guang Ji and Huangan Wu Shanghai University of Traditional Chinese Medicine, Shanghai, China

\*Address all correspondence to: wxm123@vip.sina.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[17] Changhong W, Yuping L, Lixin W, et al. Control observation of correlation between *Helicobacter pylori* infection and inflammatory cell coating on the tongue and syndrome of TCM of 1052 cases of gastritis. Chinese Archives of Traditional Chinese Medicine. 2004;**22**(8):1396-1397. DOI: 10.3969/j. issn.1673-7717.2004.08.017

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[19] Ling H, Jianying M. Professor Lao shaoxian's experience in the diagnosis and treatment of precancerous diseases of gastric cancer. Journal of New Chinese Medicine. 2006;**38**(5):7-9. DOI: 10.3969/j. issn.0256-7415.2006.05.004

[20] Branch of Digestive System Disease of Chinese Association of Integrative Medicine. Consensus on the diagnosis and treatment of chronic gastritis with integrated Chinese and western medicine. Chinese Journal of Integrative Medicine. 2012;**32**(6):738-743

[21] Wenjie J, Lianying C, Jing L, et al. Meta analysis of acupuncture treatment for chronic atrophic gastritis. Shanghai Journal of Acupuncture and Moxibustion. 2016;**35**(7):886-892

[22] Juan X, Zhihui X, Guo C, et al. Meta analysis of acupuncture in the treatment of chronic atrophic gastritis. Guiding Journal of Traditional Chinese Medicine and Pharmacology. 2016;**22**(15):75-78,83

[23] Yinhu X, Xiaoling C. Treating 52 cases of chronic superficial gastritis with deficiency of spleen and stomach. Shaanxi Journal of Traditional Chinese Medicine. 2005;**26**(9):959-960. DOI: 10.3969/j. issn.1000-7369.2005.09.073

[24] Yun Q. Clinical observation on 78 cases of epigastric pain due to deficiency of spleen and stomach with warm acupuncture and ginger moxibustion. Journal of Guiyang College of Traditional Chinese Medicine. 2004;**26**(4):37-38. DOI: 10.3969/j. issn.1002-1108.2004.04.028

[25] Xianling P, Jing M, Houzhi M. Effects of psychological intervention on the curative effect of chronic atrophic gastritis in the elderly. West China Medical Journal. 2014;**29**(4):751-753. DOI: 10.7507/1002-0179.20140226

[26] Xiaoju Z, Xia Z. Effect of nursing intervention on curative effect and mental state of patients with chronic atrophic gastritis. Modern Journal of Integrated Traditional Chinese and Western Medicine. 2015;**24**(10):1130-1132. DOI: 10.3969/j. issn.1008-8849.2015.10.042

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*Gastritis - New Approaches and Treatments*

[1] González CA, Figueiredo C, Lic CB, et al. *Helicobacter pylori* cagA and vacA genotypes as predictors of progression of gastric preneoplastic lesions: A long-term follow-up in a high-risk area in Spain. The American Journal of Gastroenterology. 2011;**106**(5):867-874. chronic gastritis (2017). Chinese Journal of Traditional Chinese Medicine.

[8] Tang XD, Li BS, Zhou LY, et al. Clinical practice guideline of Chinese medicine for chronic gastritis. Chinese Journal of Integrative Medicine.

[9] Spleen-stomach disease branch of Chinese medical association. Consensus opinions on TCM diagnosis and treatment of chronic atrophic gastritis. Chinese Journal of Integrative Chinese and West Medicine Digestion.

[10] Gastroenterology breach of Chinese medical association. Consensus on chronic gastritis in China. Chinese Journal of Gastroenterology.

[11] Xudong T. Academic thoughts on health of Dong Jianhua. Journal of Peking University of Traditional Chinese Medicine. 1995;**18**(2):45-48. DOI: 10.3321/j. issn:1006-2157.1995.02.015

[12] Shengsheng Z. Clinical Study on TCM Syndrome of Chronic Gastritis. Beijing: Peking University of Traditional

Chinese Medicine; 2005

[13] Xuewen Z. TCM syndrome

[14] Xudong T. Discussion on pathogenesis of blood stasis and treatment of chronic atrophic gastritis.

Journal of Traditional Chinese Medicine. 1998;**39**(11):687-689

[15] Li H. Discussion on etiology and pathogenesis of bile reflux gastritis. Shandong Journal of

treatment of chronic atrophic gastritis. Chinese Archives of Traditional Chinese Medicine. 2002;**20**(5):558-559,587. DOI: 10.3969/j.issn.1673-7717.2002.05.005

2017;**32**(7):3060-3064

2012;**18**(1):56-71

2010;**18**(5):345-349

2013;**18**(1):24-36

[2] Sharma PK, Suri TM, Venigalla PM, et al. Atrophic gastritis with high prevalence of *Helicobacter pylori* is a predominant feature in patients with dyspepsia in a high altitude area. Tropical Gastroenterology.

[3] de Vries AC, van Grieken NC, Looman CW, et al. Gastric cancer risk in patients with premalignant gastric lesions: A nationwide cohort study in the Netherlands. Gastroenterology. 2008;**134**(4):945-952. DOI: 10.1053/j.

[4] Song H, Ekheden IG, Zheng Z, et al. Incidence of gastric cancer among patients with gastric precancerous lesions: Observational cohort study in a low risk Western population. BMJ. 2015;**351**:h3867. DOI: 10.1136/bmj.h3867

[5] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and

[6] Song H, Held M, Sandin S, et al. Increase in the prevalence of atrophic gastritis among adults age 35 to 44 years old in Northern Sweden between 1990 and 2009. Clinical Gastroenterology and Hepatology. 2015;**13**(9):1592-1600.e1. DOI: 10.1016/j.cgh.2015.04.001

[7] Spleen and Stomach Disease Branch of China Association of Chinese Medicine. Consensus opinions of TCM diagnosis and treatment experts on

estimated population burden of selected autoimmune diseases in the United States. Clinical Immunology and Immunopathology. 1997;**84**(3):223-243

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**91**

Section 3

Autoimmune Gastritis

Section 3
