**3. Some biomedical application for some plant used in treating hypoglycemic and hyperglycemic conditions**

### **A- Amelioration of hyperglycemia in STZ-diabetic rats.**

Several approaches were conducted in order to investigate the hypoglycemic and hypolipidemic activities of plant extract on experimental animals (STZ-diabetic rats). The derived data showed that some extracts are potent in the amelioration of hyperglycemia in STZ-diabetic rats and is a potential source for the isolation of new per os active agent(s) for anti-diabetic therapy like what observed in Averrhoa bilimbi ethanolic extract which has hypoglycemic, hypotriglyceridemic, anti-lipid peroxidative and anti-atherogenic properties in STZ-diabetic rats (Purshparaj et al., 2001). Another way was by the inhibition of myeloperoxidase activity and decreased lipid peroxidation, induced by ascorbyl radical either in microsomes or in asolectin and phosphatidylcholine liposomes as what observed in Bauhinia forficate due to the kaempferitrin effect .that showed high reactivity with the free radical 1,1-diphenyl-2-picryl hydrazyl (DPPH),

In the plant *Beta vulgaris L. var. cicla (Chenopodiaceae*) the anti-diabetic effect in experimental animals may be to the reduction in blood glucose levels by the regeneration of the β cells (Bolkent et al., 2000). Betavulgarosides I, II, III, IV and oleanolic acid oligoglycosides produced hypoglycemic effects that was demonstrated by a per os glucose tolerance test in rats after their per os administration (Yoshikawa et al., 1996). Or through stimulating the synthesis/release of insulin from the β cells of Langerhans like the effect of *Biophytum sensitivum* and/or also mediated through enhance secretion of insulin from the β cells of Langerhans or through an Extra pancreatic mechanism (*Catharanthus roseus L. (Apocynaceae*)). Or by increasing the number of islet β cells and that of islet α cells was decreased in STZ-diabetic rats like what happen in Dendrobium candidum (Orchidaceae), Its mechanism of action probably involves the stimulation of the secretion of insulin from β cells and the inhibition of the secretion of glucagons from α cells and it can probably decrease the decomposition of liver glycogen and increase the synthesis of liver glycogen.

The Administration of *Coccinia indica (Cucurbitaceae*) leaf extract, an indigenous plant used in Ayurvedic medicine in India, to normal and STZ-diabetic animals exhibited significant hypoglycemic and antihyperglycemic effect and reversed the associated with diabetes biochemical alterations (Venkateswaran & Pari 2002). The results indicated that the per os administration of Coccinia indica leaf extract to diabetic animals normalized blood glucose and caused marked improvement of altered carbohydrate metabolizing enzymes during diabetes. The antioxidant effects of an ethanolic extract of Coccinia indica leaves was studied in STZ-diabetic rats (Venkateswaran & Pari 2003). Per os administration of Coccinia indica leaf extract resulted in a significant reduction in thiobarbituric acid reactive substances and hydroperoxides and a significant increase in reduced GSH, SOD, CAT, glutathione peroxidase and glutathione-S-transferase in liver and kidney of STZ-diabetic rats, which clearly showed the extract's antioxidant property. The ethnopharmacological use of *Gongronema latifolium* in ameliorating the oxidative stress found in diabetics and indicating promise of possible use in lessening morbidity in affected individuals.

The obtained result by Kim et al 2006 suggest that the administration of *Chrysanthemum coronarium* and *Morus alba,* have a hypoglycemic effect in diabetic rats and their effect was equivalent to that of glibenclamide. The administration of *C.unshiu* shows more antihyperlipidemic effect than antidiabetic effect. The effect of aqueous extracts from four medicinal plants on the blood glucose levels of experimental animals was determined at various time intervals for 9 h after oral administration at 100 mg dose kg-1 b.wt. (Fig. 2). There was a significant elevation in the blood glucose level by 3.3-5 times during experimental time period in alloxan-induced diabetic rats, when compared to normal rats. The administration of *C. coronarium* extract caused the blood glucose levels of diabetic rats to 83.4, 67.6, 75.1, 81.1 and 74.3% at the time interval of 1, 3, 5, 7 and 9 h, respectively (p<0.05). Maximum reduction of 32.4% was observed 3 h after treatment. The administration of *M. alba* extract produced the most significant reduction (p<0.05) among four medicinal plants in the blood glucose levels of 34, 41, 33 and 35% at 3, 5, 7 and 9 h respectively.

Fig. 2. Percentage of effect of experimental plants on plasma glucose levels compared with 0 h data in alloxaninduced diabetic rats (%). Values are mean percent of blood glucose concentration (n= 6). According to the study obtained by Kim et al., 2006.

### **B- Hypoglycemic, hypolipidemic hypotriglyceridemic, anti-lipid peroxidative and antiatherogenic properties of these agents in different medicinal plant:**

Insulin resistance (hyperinsulinemia) is now recognized as a major contributor to the development of glucose intolerance, dyslipidemia and hypertension in type II diabetic patients. Aqueous extracts of Pterocarpus marsupium bark (Fbaceae) and Trigonella foenum-graecum. (Leguminosae) seeds have been shown to exert hypoglycemic/antihyperglycemic effect in experimental as well as in clinical settings (Grover et al., 2005). Results of this study, in addition to previous clinical benefits of

equivalent to that of glibenclamide. The administration of *C.unshiu* shows more antihyperlipidemic effect than antidiabetic effect. The effect of aqueous extracts from four medicinal plants on the blood glucose levels of experimental animals was determined at various time intervals for 9 h after oral administration at 100 mg dose kg-1 b.wt. (Fig. 2). There was a significant elevation in the blood glucose level by 3.3-5 times during experimental time period in alloxan-induced diabetic rats, when compared to normal rats. The administration of *C. coronarium* extract caused the blood glucose levels of diabetic rats to 83.4, 67.6, 75.1, 81.1 and 74.3% at the time interval of 1, 3, 5, 7 and 9 h, respectively (p<0.05). Maximum reduction of 32.4% was observed 3 h after treatment. The administration of *M. alba* extract produced the most significant reduction (p<0.05) among four medicinal plants in the blood glucose levels of 34, 41, 33 and 35% at 3, 5, 7 and 9 h

Fig. 2. Percentage of effect of experimental plants on plasma glucose levels compared with 0 h data in alloxaninduced diabetic rats (%). Values are mean percent of blood glucose

**B- Hypoglycemic, hypolipidemic hypotriglyceridemic, anti-lipid peroxidative and anti-**

Insulin resistance (hyperinsulinemia) is now recognized as a major contributor to the development of glucose intolerance, dyslipidemia and hypertension in type II diabetic patients. Aqueous extracts of Pterocarpus marsupium bark (Fbaceae) and Trigonella foenum-graecum. (Leguminosae) seeds have been shown to exert hypoglycemic/antihyperglycemic effect in experimental as well as in clinical settings (Grover et al., 2005). Results of this study, in addition to previous clinical benefits of

concentration (n= 6). According to the study obtained by Kim et al., 2006.

**atherogenic properties of these agents in different medicinal plant:** 

respectively.

Pterocarpus marsupium seen in type II diabetic subjects, are suggestive of usefulness of its bark in insulin resistance, the associated disorder of type II diabetes. Though several antidiabetic principles (epicatechin, pterosupin, marsupin and pterostilbene) have been identified.

The administration of trihydroxyoctadecadienoic acid and its derivatives obtained from the roots of the native Armenian plant *Bryonia alba (Curcubiaceae*) was found to restore the disordered lipid metabolism of alloxan-diabetic rats (Karageuzyan et al., 1998). These derivatives of trihydroxyoctadecadienoic acid can correct major metabolic abnormalities typical of severe diabetes mellitus they can influence the profile of the formation of stable prostaglandins by actions such as downstream of prostaglandin endoperoxides. In *Camellia sinensis (Theaceae*) species, the blood glucose lowering activity of Camellia sinensis was studied by many workers. It has recently been reported that the major green tea polyphenolic constituent, epigallocatechin 3- gallate, mimics the cellular effects of insulin including the reductive effect on the gene expression of rate-limiting gluconeogenic enzymes in a cell culture system (Koyama et al., 2004). Per os administration of green tea that contains this polyphenolic constituent caused a reduction in the levels of mRNAs for gluconeogenic enzymes, PEPCK and G6Pase in the mouse liver. Epigallocatechin 3-gallate alone was also found to down-regulate the gene expression of these enzymes in vitro.

*Bumelia sartorum (Sapotaceae),* the hypoglycemic effect may be similar to chlorpropamide and possibly due to an enhanced secretion of insulin from the islets of Langerhans or an increased utilization of glucose by peripheral tissues. Besides hypoglycemic activity, the ethanol extract also elicited significant anti-inflammatory activity, but did not show any significant effects on blood pressure, respiration or on the various isolated tissue preparations studied. Bassic acid, an unsaturated triterpene acid isolated from an ethanol extract of Bumelia sartorum root bark, elicited significant hypoglycemic activity in alloxandiabetic rats and altered the pattern of glucose tolerance in these animals when administered per os (Naik et al., 1991). In addition, bassic acid treatment increased significantly the glucose uptake process and glycogen synthesis in isolated rat diaphragm. Bassic acid treatment increased plasma insulin levels significantly in alloxandiabetic rats. It was therefore suggested that the hypoglycemia activity of bassic acid may be mediated through enhanced secretion of insulin from the pancreatic β cells.

Compelling evidence of *Bidens pilosa (Asteraceae)* suggests that infiltrating CD4 type I helper T (Th1) cells in the pancreatic islets play a pivotal role in the progression of diabetes in nonobese diabetic mice. Treatment with a butanol fraction of Bidens blood glucose and insulin in non-obese diabetic mice in a dose-dependent manner and elevated the serum IgE levels regulated by Th2 cytokines (Chang et al., 2004). Moreover, the butanol fraction inhibited the differentiation of naive helper T cells (Th0) into Th1 cells but enhanced their transition into type II helper T (Th2) cells using an in vitro T cell differentiation assay. The butanol fraction of *Biderns pilosa* and its polyacetylenes can prevent diabetes possibly via suppressing the differentiation of Th0 cells into Th1 cells and promoting that of Th0 cells into Th2 cells.

The results of a reported study of *Gongronema latifolium (Asclepiadaceae)* suggest that the extracts from leaves could exert their antidiabetic activities through their antioxidant properties (Ugochukwu & Bababy 2002). The aqueous and ethanolic extracts were tested in order to evaluate their effect on renal oxidative stress and lipid peroxidation in non-diabetic and STZ-diabetic rats after per os administration (Ugochukwu & Makini 2003). The ethanolic extract appeared to be more effective in reducing oxidative stress, lipid peroxidation, and increasing the GSH/GSSG ratio, The antihyperglycemic effects of aqueous and ethanolic extracts from Gongronema latifolium leaves was also investigated on glucose and glycogen metabolism in liver of non-diabetic and STZ-diabetic rats (Ugochukwu & Bababy 2003). The data showed that the ethanolic extract from the plant's leaves had antihyperglycemic potency, which was suggested to be mediated through the activation of HK, PFK, G6PD and inhibition of GK in the liver.

According to the study occurred by Mohammad Khalil, et al. (2010), it is found found that, the treatment of the diabetic rats with *Citrullus colocynthis* pulp extract, in the livers showed, more or less, an improvement in the histological architecture with persistence of the cytoplasmic vacuoles in some hepatocytes that could be attributed to the residual adverse effect of the diabetic affliction. But the noticed apparent general improvement signifies that *Citrullus colocynthis* could possess cyto-protective abilities on the hepatocytes. The present findings are supported by those announced by Aburjai *et al*. (2007) who confirmed the antidiabetic properties of *Citrullus colocynthis* extract. Also, Sebbagh *et al*. (2009) stated that this plant could improve the streptozotosin-induced diabetes in rats. Bujanda *et al*. (2008) owed the similar steatotic inhibitory effect of resveratol to inhibition of the tumor necrosis factor alpha production, lipid per-oxidation and oxidative stress.

The damaged sinusoids, the aemorrhage and the inflammatory cell infiltration encountered in the liver of the diabetic animals, might be due to the hyperglycemic state. Seifalian *et al*. (1999), in an analogous study in rabbits, stressed on that the sinusoidal affection is correlated with the severity of fat accumulation in the parenchymal cells. According to the findings of Khan and Chakarabarti (2003); Hayden *et al*. (2005) and Ban and Twigg (2008), hyperglycemia is the main offending factor in the onset of the micro-vascular diabetic complications. Fortunately, following *Citrullus colocynthis* intake, in their study, the damaged sinusoids, the haemorrhage and the inflammatory cell infiltration subsided indicating a beneficial role of such a remedy. These findings are supported by those claimed by Alarcon-Aguilar *et al*. (2000). Despite the obvious antidiabetic effect of *Citrullus colocynthis* pulp extract, its use in normal rats, in the current work, caused hepatocytic poration and few hapatocytes had condensed or fragmented nuclei indicating minimal hepatotoxicity.

This herbal therapy of *Gymnema sylvestre (Asclepiadaceae*) appears to bring about blood glucose homeostasis through increased serum insulin levels provided by repair/regeneration of the endocrine pancreas. Also, the effectiveness of the water extract from the leaves of *Gymnema sylvestre*, in controlling hyperglycemia was investigated in type II diabetic patients as conventional per os anti-hyperglycemic agents (Baskaran et al., 1990). The obtained data suggested that the β cells may be regenerated / repaired in type II diabetic patients on the extract's supplementation. This was supported by the raised insulin levels in the serum of patients after the supplementation. Furthermore, the antihyperglycemic action of a crude saponin fraction and five triterpene glycosides (gymnemic acids I-IV and gymnemasaponin V) derived from the methanol extract of leaves of *Gymnema sylvestre* was investigated in STZ-diabetic mice (Sugihara et al., 2000).

The results indicated that insulin-releasing action of gymnemic acid IV, administered i.p., may contribute to the antihyperglycemic effect by the leaves of Gymnema sylvestre.

and STZ-diabetic rats after per os administration (Ugochukwu & Makini 2003). The ethanolic extract appeared to be more effective in reducing oxidative stress, lipid peroxidation, and increasing the GSH/GSSG ratio, The antihyperglycemic effects of aqueous and ethanolic extracts from Gongronema latifolium leaves was also investigated on glucose and glycogen metabolism in liver of non-diabetic and STZ-diabetic rats (Ugochukwu & Bababy 2003). The data showed that the ethanolic extract from the plant's leaves had antihyperglycemic potency, which was suggested to be mediated through the

According to the study occurred by Mohammad Khalil, et al. (2010), it is found found that, the treatment of the diabetic rats with *Citrullus colocynthis* pulp extract, in the livers showed, more or less, an improvement in the histological architecture with persistence of the cytoplasmic vacuoles in some hepatocytes that could be attributed to the residual adverse effect of the diabetic affliction. But the noticed apparent general improvement signifies that *Citrullus colocynthis* could possess cyto-protective abilities on the hepatocytes. The present findings are supported by those announced by Aburjai *et al*. (2007) who confirmed the antidiabetic properties of *Citrullus colocynthis* extract. Also, Sebbagh *et al*. (2009) stated that this plant could improve the streptozotosin-induced diabetes in rats. Bujanda *et al*. (2008) owed the similar steatotic inhibitory effect of resveratol to inhibition of the tumor necrosis factor

The damaged sinusoids, the aemorrhage and the inflammatory cell infiltration encountered in the liver of the diabetic animals, might be due to the hyperglycemic state. Seifalian *et al*. (1999), in an analogous study in rabbits, stressed on that the sinusoidal affection is correlated with the severity of fat accumulation in the parenchymal cells. According to the findings of Khan and Chakarabarti (2003); Hayden *et al*. (2005) and Ban and Twigg (2008), hyperglycemia is the main offending factor in the onset of the micro-vascular diabetic complications. Fortunately, following *Citrullus colocynthis* intake, in their study, the damaged sinusoids, the haemorrhage and the inflammatory cell infiltration subsided indicating a beneficial role of such a remedy. These findings are supported by those claimed by Alarcon-Aguilar *et al*. (2000). Despite the obvious antidiabetic effect of *Citrullus colocynthis* pulp extract, its use in normal rats, in the current work, caused hepatocytic poration and few hapatocytes had condensed or fragmented nuclei indicating minimal

This herbal therapy of *Gymnema sylvestre (Asclepiadaceae*) appears to bring about blood glucose homeostasis through increased serum insulin levels provided by repair/regeneration of the endocrine pancreas. Also, the effectiveness of the water extract from the leaves of *Gymnema sylvestre*, in controlling hyperglycemia was investigated in type II diabetic patients as conventional per os anti-hyperglycemic agents (Baskaran et al., 1990). The obtained data suggested that the β cells may be regenerated / repaired in type II diabetic patients on the extract's supplementation. This was supported by the raised insulin levels in the serum of patients after the supplementation. Furthermore, the antihyperglycemic action of a crude saponin fraction and five triterpene glycosides (gymnemic acids I-IV and gymnemasaponin V) derived from the methanol extract of leaves

of *Gymnema sylvestre* was investigated in STZ-diabetic mice (Sugihara et al., 2000).

The results indicated that insulin-releasing action of gymnemic acid IV, administered i.p., may contribute to the antihyperglycemic effect by the leaves of Gymnema sylvestre.

activation of HK, PFK, G6PD and inhibition of GK in the liver.

alpha production, lipid per-oxidation and oxidative stress.

hepatotoxicity.

Fig. 3. Photomicrographs of the livers of control, *Citrullus colocynthis*- treated, diabetic and *Citrullus colocynthis*treated diabetic rats, H&E stain; (a) Liver of control rats, ×40; (b) Liver of *Citrullus colocynthis* treated rats, showing few hapatocytes had condensed or fragmented nuclei ×40; (c) Liver of diabetic rats, showing disorganized hepatic cords, reduced sinusoids and many hepatocytes having cytoplasmic vacuolization, ×20; (d) Higher magnification of (c), showing most hepatocytes with cytoplasmic vacuolar degeneration and pyknotic nuclei (arrows), ×40; (e) Liver diabetic rats, showing a central inflammatory cell infiltration (white arrows) and hepatocytes with cytoplasmic vacuolar degeneration and pyknotic nuclei (black arrows), ×40; (f) Liver of diabetic rats treated with *Citrullus colocynthis*, showing recovered hepatocytes with less cytoplasmic vacuolization compared with diabetic animals. Few hepatocytes with cytoplasmic vacuolization and pyknotic nuclei are still seen (arrows), ×40. According to the study occurred by Mohammad Khalil, et al. (2010).

Fig. 4. Scanning electron micrographs of livers of control and *Citrullus colocynthis*-treated rats. (a) SEM of the liverof control rats showing normal hepatic cord around a Central Vein (CV), ×450; (b) Larger magnification of (a) showing normal Sinusoids (S) and normal Hepatocytes (H) with normal intercellular boundaries (arrows), ×1500 (c); SEM of the liver of *Citrullus colocynthis*-treated rats, showing rows of Hepatocytes (H) containing few pores (white arrows). Note the blood Sinusoids (S) and the intercellular boundaries (black arrows), ×1100; (d) Higher magnification of (c), showing blood Sinusoids (S), Hepatocytes (H), intercellular spaces (black arrows) and erythrocytes (R), ×1500. According to the study occurred by Mohammad Khalil, et al. (2010).

Gymnemic acid IV may be an anti-obese and antihyperglycemic prodrug. The inhibitory activity of each triterpene glycoside on the glucose uptake in rat small intestine fragments was examined, in order to determine its impact on the increase of serum glucose level in glucose-loaded rats (Yoshikawa et al., 1997). It was found that Gymnemic acids II and III showed potent inhibitory activity on glucose uptake. Gymnemoside b and gymnemic acids III, V, VII were found to exhibit a little inhibitory activity against glucose uptake, and the principal constituents, gymnemic acid I and gymnemasaponin V, lacked this activity. It is noteworthy that, although Gymnema saponin constituents such as Gymnemic acids II and III show no effect on serum glucose levels in oral-loaded rats, they exhibit potent inhibitory activity on the glucose uptake and further studies need to be contacted.

The hypoglycemic activity of a decoction from *Juniperus communis* (juniper berries) both in normal glycemic and in STZ-diabetic rats was studied (Sanchez et al., 1994). Juniper decoction decreased glycemic levels in normal glycemic rats through an increase of peripheral glucose utilization or a potentiation of glucose induced insulin secretion.

The per os administration of the decoction to STZ diabetic rats resulted in a significant reduction both in blood glucose levels and in the mortality index, as well as the prevention

Fig. 4. Scanning electron micrographs of livers of control and *Citrullus colocynthis*-treated rats. (a) SEM of the liverof control rats showing normal hepatic cord around a Central Vein (CV), ×450; (b) Larger magnification of (a) showing normal Sinusoids (S) and normal Hepatocytes (H) with normal intercellular boundaries (arrows), ×1500 (c); SEM of the liver of *Citrullus colocynthis*-treated rats, showing rows of Hepatocytes (H) containing few pores (white arrows). Note the blood Sinusoids (S) and the intercellular boundaries (black arrows), ×1100; (d) Higher magnification of (c), showing blood Sinusoids (S), Hepatocytes (H), intercellular spaces (black arrows) and erythrocytes (R), ×1500. According to the study

Gymnemic acid IV may be an anti-obese and antihyperglycemic prodrug. The inhibitory activity of each triterpene glycoside on the glucose uptake in rat small intestine fragments was examined, in order to determine its impact on the increase of serum glucose level in glucose-loaded rats (Yoshikawa et al., 1997). It was found that Gymnemic acids II and III showed potent inhibitory activity on glucose uptake. Gymnemoside b and gymnemic acids III, V, VII were found to exhibit a little inhibitory activity against glucose uptake, and the principal constituents, gymnemic acid I and gymnemasaponin V, lacked this activity. It is noteworthy that, although Gymnema saponin constituents such as Gymnemic acids II and III show no effect on serum glucose levels in oral-loaded rats, they exhibit potent inhibitory

The hypoglycemic activity of a decoction from *Juniperus communis* (juniper berries) both in normal glycemic and in STZ-diabetic rats was studied (Sanchez et al., 1994). Juniper decoction decreased glycemic levels in normal glycemic rats through an increase of

The per os administration of the decoction to STZ diabetic rats resulted in a significant reduction both in blood glucose levels and in the mortality index, as well as the prevention

peripheral glucose utilization or a potentiation of glucose induced insulin secretion.

activity on the glucose uptake and further studies need to be contacted.

occurred by Mohammad Khalil, et al. (2010).

Fig. 5. Scanning electron micrographs of livers of diabetic and *Citrullus colocynthis*-treated diabetic rats. (a) SEM of the liver of diabetic rats showing degenerating Hepatocytes (H) having a plenty of lipid droplets (white arrows). Damaged blood Sinusoids (S) are also seen as well as some erythrocytes (R) are spread inside hepatocytes, ×450; (b) SEM of the liver of diabetic rats showing hemorrhage of erythrocytes (R) between Hepatocytes (H). Lipid degeneration (black arrows) of hepatocytes is also seen, ×450; (c) SEM of the liver of *Citrullus colocynthis*-treated diabetic rats, showing intact Hepatocytes (H) and blood Sinusoids (S). Only fewhepatocytes around the central vein have some vacuoles, ×450; (d) SEM of the liver of *Citrullus colocynthis* treated diabetic rats (300 mg) with higher magnification, showing intact Hepatocytes (H) and a Central Vein (CV) containing a lot of erythrocytes. A few hepatocytes around the central vein have a few lipid droplets (arrows), ×1100. According to the study occurred by Mohammad Khalil, et al. (2010).

of the loss of body weight. This effect seemed to be mediated by the peripheral action of juniper while in Olea europaea (Oleaceae) plant species, the hypoglycemic activity may result from two mechanisms: (a) potentiation of glucose induced insulin release, and (b) increased peripheral uptake of glucose.

The hypoglycemic effect of the rhizomes of *Polygala senega* (Polygalaceae) was proposed that after i.p. administration was without altering the insulin levels and with the need of the presence of insulin in order to act. In addition, one of the active components of this hypoglycemic effect was identified as a triterpenoid glycoside, senegin-II (as a mixture of isomers). *Solanum lycocarpum (Solanaceae***)** has been widely employed for diabetes management, obesity and to decrease cholesterol levels. Some of the polysaccharides slowed gastric emptying and act on the endocrinous system affecting the liberation of gastrointestinal hormones, lowering blood glucose levels. The hypocholesterolemic activity could be due to the increased fecal bile acid excretion as well as to the action of the shortchain fatty acids, coming from fermentation, on the synthesis of deltaaminolevulinate and by the increase of the cholesterol 7-alpha-hydroxylase and 3-hydroxy-3-methylglutaryl CoA reductase synthesis (DalAgnol & Lino von Poser 2000).

## **4. Conclusions and future directions**

Scientists from divergent fields are investigating plants anew with an eye to their antimicrobial usefulness. A sense of urgency accompanies the search as the pace of species extinction continues. Laboratories of the world have found literally thousands of phytochemicals which have inhibitory effects on all types of microorganisms in vitro. More of these compounds should be subjected to animal and human studies to determine their effectiveness in whole-organism systems, including in particular toxicity studies as well as an examination of their effects on beneficial normal microbiota. It would be advantageous to standardize methods of extraction and in vitro testing so that the search could be more systematic and interpretation of results would be facilitated. Also, alternative mechanisms of infection prevention and treatment should be included in initial activity screenings. Disruption of adhesion is one example of an anti-infection activity not commonly screened for currently. Attention to these issues could usher in a badly needed new era of chemotherapeutic treatment of infection by using plant-derived principles.

### **5. References**


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