**Evaluation of** *Glycyrrhiza glabra* **Cream as Treatment for Melasma**

Amina Hamed Alobaidi, Eqbal Salih Hamad, Abdulghani Mohamed Alsamarai and Kudair Abass Kudair

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/58918

**1. Introduction**

[50] Wallis T. E.; (1967), "*Text book of Pharmacognosy*", 5th Ed., J. & A. Churchill Ltd., pp.

[51] Wildfeuer A., Neu I. S., Safayhi H., Metzger G., Wehrmann M., Vogel U., and Am‐

mon H. P. (1998), T.; *Arzneimittel Forschung/Drug research*, 48, 668.

22 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine

500-501.

Melasma is a common cosmetic problem in our community [1], with social and psychological burden. It is a disorder of pigmentary system characterized by irregular brown or grayishbrown, acquired hypermelanosis of sun-exposed areas especially the face [2]. Many prepara‐ tions were used for treatment of melasma, but none of them was ideal [3].

Researchers recently are more involved in performing a research that evaluated the therapeutic effects of formulation that with active substance of plant origin [4]

Recently, topical polyherbal formulations are the latest additions to the treatment approaches list of melasma, with a reducing and diverting the production of melanin [5]. The therapeutic effect of such preparation was enhanced when cosmetic emulsion contained antioxidants are used as active ingredients [6]. Natural herbs are a rich source of many antioxidatively acting compounds [7]. *Glycyrrhiza glabra* is a medicinal plant with rich natural antioxidants [8].The best natural antioxidants in extract of *Glycyrrhiza glabra* are glycyrrhizin (glycyrrhizic acid) and flavonoids [9]. The role of plant extract of *Glycyrrhiza glabra* on skin is mainly attributed to its antioxidant activity particularly to its potent antioxidants triterpene, saponins and flavonoids [10]. G. glabra extract are with therapeutic effects in skin whitening [11], skin depigmenting [12], skin lightening [3], antiaging [14], anti-erythemic [14], emollient [15], anti-acne [16] and photoprotection effects [17,18]. A 2.5% G. glabra extract cream was formulated and it was with

© 2015 The Author(s). Licensee InTech. 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 eproduction in any medium, provided the original work is properly cited.

sound chemical and physical stability [19]. In this study, 2.5% of G. glabra extract was evaluated as treatment of melasma in female.

### **2. Materials and methods**

#### **2.1. Study design**

Double blind placebo controlled study. The study population stratified to active or placebo treatment randomly. The female with even code number receiving cream with active ingre‐ dient while female with odd code number receiving placebo. The cream distributed by a pharmacist, while the clinical evaluation was performed by a dermatologist clinician.

#### **2.2. Study population**

Hundred female volunteers were enrolled in this study between the ages of 20 and 45 years. They were recruited from Dermatology Clinic in Samarra Teaching Hospital and daily dermatology clinics. Prior to the tests, the volunteers were examined for any serious skin disease or damage especially on cheeks and forearms. Before the study, every volunteer was provided with a volunteer protocol. This protocol stating the terms and conditions of the testing were to be signed by every volunteer individually. Blood samples were collected from the 100 volunteer females suffering from melasma.They were diagnosed by consultant dermatologists. Wood's lamp (340-400) nm was used to identify the types of melasma whether epidermal, dermal or mixed (dermoepidermal). Of the total 76%were married and 24% were single. Serum of the patients and controls were investigated for levels of TSH, estrogen, progesterone, prolactin, ALT (SGPT), AST (SGOT), total protein, blood urea and S. albumin before and after treatment.

The history as well as personal information about patients was obtained by questionnaire. Volunteers were not informed about the contents of formulations. All the skin tests have been done at 25°C. Erythema of the skin are determined on the first day before application of any cream and then on days 7, 14, 21 and 28 after treatment. Fifty female from patients group received the treatment for 28 days, 7 patients were lost to follow up. The above parameters for forty three patients were determined after treatment. As well as fifty female suffering from melasma took the placebo, the same above parameters were measured before and after treatment.

None of the patients or control subjects was on any oral and/or local medication. The pregnant and lactating females or patients on any hormonal therapy (contraceptive pills) were excluded from the study. Patients with other systemic diseases like diabetes, hypertension, or on drugs for any underlying disease were also excluded.

#### **2.3. Formulation**

sound chemical and physical stability [19]. In this study, 2.5% of G. glabra extract was

24 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine

Double blind placebo controlled study. The study population stratified to active or placebo treatment randomly. The female with even code number receiving cream with active ingre‐ dient while female with odd code number receiving placebo. The cream distributed by a

Hundred female volunteers were enrolled in this study between the ages of 20 and 45 years. They were recruited from Dermatology Clinic in Samarra Teaching Hospital and daily dermatology clinics. Prior to the tests, the volunteers were examined for any serious skin disease or damage especially on cheeks and forearms. Before the study, every volunteer was provided with a volunteer protocol. This protocol stating the terms and conditions of the testing were to be signed by every volunteer individually. Blood samples were collected from the 100 volunteer females suffering from melasma.They were diagnosed by consultant dermatologists. Wood's lamp (340-400) nm was used to identify the types of melasma whether epidermal, dermal or mixed (dermoepidermal). Of the total 76%were married and 24% were single. Serum of the patients and controls were investigated for levels of TSH, estrogen, progesterone, prolactin, ALT (SGPT), AST (SGOT), total protein, blood urea and S. albumin

The history as well as personal information about patients was obtained by questionnaire. Volunteers were not informed about the contents of formulations. All the skin tests have been done at 25°C. Erythema of the skin are determined on the first day before application of any cream and then on days 7, 14, 21 and 28 after treatment. Fifty female from patients group received the treatment for 28 days, 7 patients were lost to follow up. The above parameters for forty three patients were determined after treatment. As well as fifty female suffering from melasma took the placebo, the same above parameters were measured before and after

None of the patients or control subjects was on any oral and/or local medication. The pregnant and lactating females or patients on any hormonal therapy (contraceptive pills) were excluded from the study. Patients with other systemic diseases like diabetes, hypertension, or on drugs

pharmacist, while the clinical evaluation was performed by a dermatologist clinician.

evaluated as treatment of melasma in female.

**2. Materials and methods**

**2.1. Study design**

**2.2. Study population**

before and after treatment.

for any underlying disease were also excluded.

treatment.

Water in oil (W/O) active cream (2.5% G. glabra) and base were prepared as described previously [19].

#### **3. Results**

#### **3.1. Age and marital status**

A 100 female suffering from melasma, 93 completed the study while 7 patients were lost to follow up. The distribution of these two groups is shown in Table (1). They were divided into 3 age groups. The highest percentages (50%) and (56%) were found in the age group of (30-39) years for active cream and control patient groups respectively. The lowest percentage of incidence for active treatment females was (12%) in the age group of (40-50) years, and for control, the lowest percentage was (4%) in the age group of (40-50) years. The highest incidence of melasma was found in married women than in singles of both groups, Table (1).


**Table 1.** Distribution of melasma percentage in females according to age and marital status.

#### **3.2. Clinical response**

Comparison between formulation treated group and placebo treated group indicated a significant differences for overall response to treatment. The improvement in active treatment group was 93% (40/43), while the corresponding value in placebo treated group was 4% (2/50), (P=0.001). Table 2. The effect of the formulated cream was demonstrated from the 1st week of treatment course (6.9%), with subsequent increase in improvement rate for week 2 (20.9%), week 3 (30.2%) and week 4 (34.8%)(P=0.007).


**Table 2.** Clinical results of studied and control females with melasma after treatment with the product.

Comparison between the active treated cream and placebo on week interval indicated anon significant improvement for the first week of the treatment course (P=0.18). However, there was a significant difference in the improvement rate between the two treatment groups for week 2 (P=0.009), week 3 (P=0.005) and week 4 (P=0.001), Table 2.

#### **4. Discussion**

This clinical trial indicated that 2.5% G. glabra cream was effective as treatment for melasma in a 28 days course with minimal side effects. However, this finding needs to be strengthening in a large scale clinical trial. Licorice is an extract with an important depigmenting property, obtained from *Glycyrrhiza glabra.* Known as "alcacus", it contains many compounds, of which saponins and flavonoids have the greatest antiphlogistic action [20]. In mouse cell culture, it was observed that Licorice has glabridine, the main component of the hydrophobic fraction of the extract, with the ability to inhibit tyrosinase without affecting DNA synthesis. The *in vivo* results were compatible with those *in vitro,* and immunohistochemical analysis showed a reduction of DOPA-positive melanocytes [21]. Moreover, Licorice has anti-inflammatory action by inhibiting some enzymes of the arachidonic acid cascade, especially cyclooxigenase, released after exposure to UV rays [22]. Due to these properties, glabridine is an important depigmenting component of the extract.

Nonetheless, Licorice has other components with depigmenting effects, such as liquiritin, which disperses melanin. In addition, Licorice has other active ingredient which exert antioxidant activity and thus Licorice cosmetic properties are attributed to its wide spectrum of antioxidant activity [23].Ultraviolet radiation in the skin leads to the formation of peroxides that induce the development of free radicals [24]. Certain licorice constituents possess significant antioxidant properties. Glycyrrhizin and glabridin inhibit the generation of reactive oxygen species (ROS) by neutrophils at the site of inflammation [6].

Traditionally, the use of depigmenting topical substances is without a doubt the best thera‐ peutic option for the clinical treatment of melasma. Hydroquinone, although having some disadvantages, is the most used therapeutic alternative. [25,26] Nonetheless, many other substances, mostly of plant origin, have become more popular in dermatologic treatment [27]. In this study, the use of 2.5% *G. glabra* extract cream shows a reduction in melasma depending on digital evaluation and size of the lesion.

This study strengthens the clinical benefits of the *G. glabra* extract substances in the literature due to their melanin-dependent action (inhibiting tyrosinase, depleting or preventing the migration of melanosomes) and/or free radical-dependent action (melanogenic inhibition by preventing radical action on the melanocytes). The active group showed a reduction in the absolute number of lesions, according to the results obtained by digital photographic imaging, with significant statistical differences between the active and placebo group.

The adverse effects observed in both groups (Active and placebo) were well tolerated, spontaneously regressing with the use of the products. We observed, however, that these effects were less noticed in women using our formulation as only one lady developed allergic contact dermatitis. However, the side effect in the present study was less than that reported in subjects using hydroquinone (2%) [28]. Such data suggest the higher safety of *G. glabra* extract at 2.5% concentration product used by our patients as compared with hydroquinone, whose degree of tolerance has already been questioned in the literature [26,29].

The superiority of this greater depigmenting tendency could be better assessed in a prospective clinical study with a higher number of volunteers. Thus this study indicates that, depending on the concentrations used, plant extracts can be as efficient as hydroquinone in the treatment of melasma, without the side effect of hydroquinone. This confirms the viability of future competitive clinical studies to accurately elucidate a possible clinical superiority and ratify a tendency of higher tolerability of this new depigmenting alternative. In addition, combination of G. glabra extract with sun screen in a single formulated is recommended.

## **Author details**

**Variable**

Treatment period

**4. Discussion**

depigmenting component of the extract.

**Number improved [%]**

26 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine

Cumulative improvement

**Table 2.** Clinical results of studied and control females with melasma after treatment with the product.

Comparison between the active treated cream and placebo on week interval indicated anon significant improvement for the first week of the treatment course (P=0.18). However, there was a significant difference in the improvement rate between the two treatment groups for

This clinical trial indicated that 2.5% G. glabra cream was effective as treatment for melasma in a 28 days course with minimal side effects. However, this finding needs to be strengthening in a large scale clinical trial. Licorice is an extract with an important depigmenting property, obtained from *Glycyrrhiza glabra.* Known as "alcacus", it contains many compounds, of which saponins and flavonoids have the greatest antiphlogistic action [20]. In mouse cell culture, it was observed that Licorice has glabridine, the main component of the hydrophobic fraction of the extract, with the ability to inhibit tyrosinase without affecting DNA synthesis. The *in vivo* results were compatible with those *in vitro,* and immunohistochemical analysis showed a reduction of DOPA-positive melanocytes [21]. Moreover, Licorice has anti-inflammatory action by inhibiting some enzymes of the arachidonic acid cascade, especially cyclooxigenase, released after exposure to UV rays [22]. Due to these properties, glabridine is an important

Nonetheless, Licorice has other components with depigmenting effects, such as liquiritin, which disperses melanin. In addition, Licorice has other active ingredient which exert antioxidant activity and thus Licorice cosmetic properties are attributed to its wide spectrum of antioxidant activity [23].Ultraviolet radiation in the skin leads to the formation of peroxides that induce the development of free radicals [24]. Certain licorice constituents possess

Week 1 3 [6.9] 3 [6.9] 0 [0] 0 [0] 0.18 Week 2 9 [20.9] 12 [27.9] 1 [2] 1 [2] 0.009 Week 3 13 [30.2] 25 [58.13] 1 [2] 2 [4] 0.005 Week 4 15 [34.8] 40 [93.00] 0 [0] 2 [4] 0.001

Placebo [50 subject]

Weekly improved **Cumulative improvement**

Formulation [43 Patient]

P value 0.007 0.58 Total response [%] 40 [93] 2 [4]

No response [%] 3 [6.9] 48 [96]

week 2 (P=0.009), week 3 (P=0.005) and week 4 (P=0.001), Table 2.

**Weekly improved** **P value**

0.001

Amina Hamed Alobaidi1\*, Eqbal Salih Hamad1,2, Abdulghani Mohamed Alsamarai1 and Kudair Abass Kudair1

\*Address all correspondence to: aminahamed2006@gmail.com

1 Departments of Biochemistry and Medicine, Tikrit University College of Medicine, Tikrit Teaching Hospital, Tikrit, Iraq

2 State Company for Drugs Industries, Samara, Salahuldean, Iraq

#### **References**


[15] Mayo Clinic: Moisturizers: Options for softer skin Dec. 16, 2010.

**References**

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10.1186/1472-6882-13-143.

Academic Press. 1, (53) 2003.

erties of natural spices. Food Res.2001, 17, 46-55.

nent of licorice roots. Plant Physiol, 2004;121:821-8.

2000;52:219-223.

2005;111:40–8.

(2): 223–8.

Health 2001;118:300-304.

[1] Alsamarai AGM. Prevalence of skin diseases in Iraq. Int J Dermatol 2009; 48: 734-739.

[2] Ortonne JP, Arellano I, Berneburg M, Cestari T, Chan H, Grimes P, et al. A global survey of the role of ultraviolet radiation and hormonal influences in the develop‐

[3] Olumide, Y. M. "Use of skin lightening creams".2010; BMJ 341 (nov23 2): c6102–

[4] Shabbir M, Khan MR, Saeed N. Assessment of phytochemicals, antioxidant, anti-lip‐ id peroxidation and anti-hemolytic activity of extract and various fractions of Mayte‐ nus royleanus leaves. BMC Complement Altern Med. 2013 Jun 22;13:143. doi:

[5] Hikino H., Recent Research on Oriental Medicinal Plants, in Wagner H., Hikino H.,and Farnsworth NR. (eds.), Economic and medicinal Plant Research; London:

[6] Haraguchi H, Yoshida N, Ishikawa H, et al. Protection of mitochondrial functions against oxidative stresses by isoflavans from Glycyrrhiza glabra. J Pharm Pharmacol

[7] Chipault, J. R.; Mizuno, G. R.; Hawkins, J. M.; Lundberg, W.O. The antioxidant prop‐

[8] Olukoga A, Donaldson D. Historical perspectives on health. The history of liquorice: the plant, its extract, cultivation, and commercialisation and etymology. J R Soc

[9] Utsunomiya T, Kobayashi M, Pollard RB, Suzuki F. Glycyrrhizin, an active compo‐

[10] Mabberley, D. J. a Portable Dictionary of Plants, their Classification and Uses. Mab‐

[11] Hearing, V. J. The regulation of melanin production. Hori, W. eds.Drug Discovery Approaches for Developing Cosmeceuticals, Advanced Skin Care and Cosmetic

[12] Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol.

[13] Holliday, R. The extreme arrogance of anti-aging medicine. Biogerontology. 2009;10

[14] Draelos ZD. Cosmetic therapy. In: Wolverton SE, editor. Comprehensive Dermato‐

logic Drug Therapy. 2nd ed. Philadelphia: Saunders; 2007. pp. 761–74.

Products.1997,3.1.1-3.1.21 IBC Library Series Southborough, Massachusetts.

berley's Plant-book: 3rd Edition. Cambridge University Press, (2008).

ment of melasma. J Eur Acad Dermatol Venereol. 2009;23:1254–1262.

28 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine


**Evaluation of the Therapeutic Effect of Combined Conventional Asthma Drugs with Tianeptine in Treatment of Asthma — Double-Blind Controlled Trial Pilot Study**

Abdulghani Mohamad Alsamarai, Mohammad Ghiyath Alhelwani and Amina Hamed Ahmed Alobaidi

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/58917

**1. Introduction**

Asthma is a chronic inflammatory and immunologic common which associated with revers‐ able obstruction of airflow. Arab countries are with 20% prevalence rate and ambient air pollution may contribute to rise in this rate with time. Environmental factors are known to play an important role in the elicitation of asthma in genetically predisposed individuals. Although there has also been an increase in the awareness among doctors to diagnose asthma, a combination of various other factors may also be involved in the increased prevalence of asthma. Further investigations are recommended to identify the etiologic factors contributing to the rising prevalence of this disorder in Arab countries [1].

Asthma is common with an increasing prevalence and mortality especially in low-income and minority populations. The National Heart, Lung, and Blood Institute (NHLBI) defined asthma as *"recurrent episodes of respiratory symptoms; variable airflow obstruction that is often reversible, either spontaneously or with treatment; presence of airway hyper reactivity; and, importantly, chronic airway inflammation in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T- lymphocytes, macrophages, neutrophils, and epithelial cells"*[2]

Asthma is an important worldwide health priority because of its high and increasing preva‐ lence, high morbidity and mortality, and direct and indirect costs. Asthma is with a prevalence

© 2015 The Author(s). Licensee InTech. 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 eproduction in any medium, provided the original work is properly cited.

of 12% of the population [3] with significant impact on quality of life and cost. [4]. The most important thing that relialized is asthma has been associated with significant comorbidities, especially depression [5-10]*.* Although stress triggered asthma symptoms, does not all of a sudden cause a person to develop the disease of asthma. [11,12]. The course of asthma appears to be influenced by mood and emotions and there is a high prevalence of depression or depressive symptoms in both children and adults with asthma.[11,12]

Recent studies indicated a positive association between stress and asthma exacerbation [13].

The chronicity of asthma course and episodic recurrences may lead to development of depression in asthmatic patients, specially in subjects with severe uncontrolled asthma [14]. Depression is associated with increased use of asthma-related urgent care services, emergency rooms, hospitals, and unscheduled appointments for asthma. as well as a variety of unfavor‐ able asthma outcomes. Despite data on the frequency of depression in asthma and its adverse consequences, it is generally not recognized or treated.

Combination of conventional treatment drugs with antidepressants may amliorate asthma course and attack severity [15]. Both asthma and depression shared some biological linkage and antidepressant may be of therapeutic benefit through induction of bronchodilatation and reduction in cytokines production in asthmatic patients [16,17,18]. Immune and inflammatory responses in asthmatic patients may be modulated by antidepressants [18,19]. The ideal antidepressant to be used for treatment of asthma in combination with convention‐ al drugs should have bronchodilator and anti-inflammatory activity and non-sedating such as tianeptine [20].

The present study was conducted to determine the therapeutic efficacy of Tianeptine in patients with asthma. Informed cosent taken from each subject included in the study and the study protocol was approved by the ethical committee.

**Objectives: To** determine the therapeutic efficacy of Tianeptine in patients with asthma.

## **2. Patients and methods**

#### **2.1. Study population**

The study was performed on asthmatic patients. The subjects included in the study were recruited from the Habib Hospital outpatients Clinic in the Kingdom of Saudi Arabia. [Table 1]. The sample size in the study was 82 adult patients suffering from asthma for at least one year duration, and their age range was from 18 to 70 years, with a mean age of 35.8 years. The diagnosis and classification of asthma was performed by specialist physi‐ cian and was established according to the National Heart Blood and Lung Institute / World Health Organization (NHLBI/WHO) workshop on the Global Strategy for Asthma [21]. The diseases severity classification was performed according to GIN criteria [22]. Patients were excluded if they were smokers, if they had malignancy, heart failure, history of venous

embolisms, coronary heart disease and liver or kidney diseases..Current substance or alcohol Abuse/dependence, MDD with psychotic features (delusions, hallucinations, disorganized thought processes) or schizophrenia or schizoaffective disorder or if they had mental retardation or other severe cognitive impairment or if they were on current antipsychotic or antidepressant therapy or psychotherapy. Initiation of other psychotropic medications or psychotherapy within past 2 weeks (e.g., anxiolytics, hypnotics) and if they were pregnant or nursing women.


**Table 1.** Study population

of 12% of the population [3] with significant impact on quality of life and cost. [4]. The most important thing that relialized is asthma has been associated with significant comorbidities, especially depression [5-10]*.* Although stress triggered asthma symptoms, does not all of a sudden cause a person to develop the disease of asthma. [11,12]. The course of asthma appears to be influenced by mood and emotions and there is a high prevalence of depression or

Recent studies indicated a positive association between stress and asthma exacerbation [13].

The chronicity of asthma course and episodic recurrences may lead to development of depression in asthmatic patients, specially in subjects with severe uncontrolled asthma [14]. Depression is associated with increased use of asthma-related urgent care services, emergency rooms, hospitals, and unscheduled appointments for asthma. as well as a variety of unfavor‐ able asthma outcomes. Despite data on the frequency of depression in asthma and its adverse

Combination of conventional treatment drugs with antidepressants may amliorate asthma course and attack severity [15]. Both asthma and depression shared some biological linkage and antidepressant may be of therapeutic benefit through induction of bronchodilatation and reduction in cytokines production in asthmatic patients [16,17,18]. Immune and inflammatory responses in asthmatic patients may be modulated by antidepressants [18,19]. The ideal antidepressant to be used for treatment of asthma in combination with convention‐ al drugs should have bronchodilator and anti-inflammatory activity and non-sedating such

The present study was conducted to determine the therapeutic efficacy of Tianeptine in patients with asthma. Informed cosent taken from each subject included in the study and the

The study was performed on asthmatic patients. The subjects included in the study were recruited from the Habib Hospital outpatients Clinic in the Kingdom of Saudi Arabia. [Table 1]. The sample size in the study was 82 adult patients suffering from asthma for at least one year duration, and their age range was from 18 to 70 years, with a mean age of 35.8 years. The diagnosis and classification of asthma was performed by specialist physi‐ cian and was established according to the National Heart Blood and Lung Institute / World Health Organization (NHLBI/WHO) workshop on the Global Strategy for Asthma [21]. The diseases severity classification was performed according to GIN criteria [22]. Patients were excluded if they were smokers, if they had malignancy, heart failure, history of venous

**Objectives: To** determine the therapeutic efficacy of Tianeptine in patients with asthma.

depressive symptoms in both children and adults with asthma.[11,12]

32 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine

consequences, it is generally not recognized or treated.

study protocol was approved by the ethical committee.

as tianeptine [20].

**2. Patients and methods**

**2.1. Study population**

Inclusion criteria includes: Out patients; Bronchial asthma has been known at least for 1 year ; Absene of long-term remissions of asthma (lasting more than 3 months) ; Poorly controlled asthma, due to various reasons ; No changes in asthma medications. ; and Both male and female

#### **2.2. Study design**

This study is randomized controlled trial to evaluate the therapeutic activity of tianeptine for treatment of asthma. The patients were distributed randomly to the groups. Patients who were eligible for entry in the study were included and follow-up for 8 weeks. Each patient had three visits, the first when introduce him\her in the study then the second after a month and the third was after two months

#### **2.3. Measurement of stress**

Perceived Stress Scale (PSS)[23] was used to measure the perception of stress in our study population. The Perceived Stress Scale is the only empirically established index of general stress appraisal. "The PSS measures the degree to which situations in one's life is appraised as stressful [24]. The PSS is not a diagnostic instrument, so there are no cut-offs. There are only comparisons between people in a given sample relationship between PSS scores and health behaviors and relationship among performance appraisal discomfort and belief, core selfevaluation and perceived stress.

There are three versions of the PSS: One with 4, one with 10, and one with 14 items. The 14 item version, which is the version that was adapted culturally to our study, as it had been used in previous studies and, at that time. Thus, the version we used has 14 items and is rated on a 5-point Liker type scale, ranging from 0 (*never*) to 4 (*very frequently*). Scores of items 4, 5, 6, 7, 9, 10, and 13 are reversed. Higher scores correspond to higher perceived stress. Internal consistency and factor structure data are mentioned in the introduction.[25]

#### **2.4. Treatment schedule**

The patients were distributed randomly into four groups each one include 25 patients. Selection of patients and distribution of them in the groups will be equally matched in gender, severity and presence of attack.


#### **2.5. Research methodolog**


ble, accessible, and easy to use by the patient and it will detect moderate or severe disease. The simplicity of the method is its main advantage. It is measured using a standard Wright Peak Flow Meter or mini Wright Meter. The needle must always be reset to zero before PEF is measured. The measurement of peak expiratory flow rate (PEFR) three to four times allows the diagnosis and assessment of the severity of asthma. [26]. It will be studied for all patients, and the stress and anxiety status of patients will determined for all patients included in the study by using Perceived Stress Scale. Arabic version of the questions set prepared and used through the study.

**c.** Patients evaluation performed at interval of the study and at least to attend the chest clinic 3 times during the study period.

#### **Visit 1: Screening visit:**

stressful [24]. The PSS is not a diagnostic instrument, so there are no cut-offs. There are only comparisons between people in a given sample relationship between PSS scores and health behaviors and relationship among performance appraisal discomfort and belief, core self-

There are three versions of the PSS: One with 4, one with 10, and one with 14 items. The 14 item version, which is the version that was adapted culturally to our study, as it had been used in previous studies and, at that time. Thus, the version we used has 14 items and is rated on a 5-point Liker type scale, ranging from 0 (*never*) to 4 (*very frequently*). Scores of items 4, 5, 6, 7, 9, 10, and 13 are reversed. Higher scores correspond to higher perceived stress. Internal

The patients were distributed randomly into four groups each one include 25 patients. Selection of patients and distribution of them in the groups will be equally matched in gender,

**• The first group** given conventional asthma treatment [SYMBICORT (budesonide and formoterol inhalation) or SEROTID (Salmeterol, fluticasone propionate).with or without

**• The second group** given conventional asthma treatment plus tianeptine12.5mg three times

**• The fourth group** is given conventional treatment with fexofenadine180 mg once daily plus

**a.** After making sure of the status of each individual from the patients have asthma and they are eligible for this study design and did not have any of the exceptions for the study will be admitted to one of the study groups. Informed written consent taken from all patients

**b.** Baseline assessment conducted for each patient at the time of enrollment in the study,also recording the number of attacks suffered by the patient during the week and the number of times where he \she wake up because of shortness of breath and the number of times sprays ventolen during the week and the number of absences from school or work during the month due to asthma and assessing the severity of cough and the severity of breathing difficulty suffered by the patient that were divided to three degrees,simple, moderate and severe. Also study and record presence of wheezing or not. As spirometry remains an essential diagnostic tool in assessment of asthmatic patient But we will limit ourselves to study Peak Expiratory Flow Rate (PEFR) because it is a simple method of measuring airway obstruction the device is availa‐

**• The third group** given Singulair 10mg once daily (montelukast) plus tianeptine

consistency and factor structure data are mentioned in the introduction.[25]

34 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine

evaluation and perceived stress.

**2.4. Treatment schedule**

salbutamol].

daily

tianeptine

**2.5. Research methodolog**

included in the study.

severity and presence of attack.

The following actions were taken


**Visit 2:** 4weeks after visit 1

The following actions were taken


**Visit 3:** 4weeks after visit 2

Repeat all the actions taken in the visit 2

At each study visit the peak expiratory flow (PEF) will be performed, the best of three measurements will be recorded [27].

#### **2.6. Asthma control questionnaire**

International guidelines for the treatment of asthma have identified that the primary clinical goal of asthma management is to optimise asthma control (minimisation of symptoms, activity limitation, and bronchoconstriction and rescue β<sup>2</sup> -agonist use) and thus reduce the risk of life-threatening exacerbations and long-term morbidity. The Asthma Control Questionnaire (ACQ) was developed to meet these criteria. It measures both the adequa‐ cy of asthma control and change in asthma control, which occurs either spontaneously or as a result of treatment [28]. We have developed a schedule for each patient where the following questions is registered for all visits to facilitate consideration of the patient's condition fully [29].


#### **2.7. Statistical analysis**

SPSS package (version 17) was used for statistical analysis.

#### **3. Results**

Out of the total (82) patients with asthma included in the study, 79% (65 patients) of them continued until the end of the study and are eligiable for analysis. The subjects suitable for analysis are consisted of 33 men (52%) and 32 women (48%). The mean age was 35.8 years (Table 1).

#### **3.1. Role of conventional asthma treatment in the first group**

In this study 22 patients has been selected for the first group, 18 patients (81.8%) of them continued until the end of the study. Of the total, 9 patients were male and 9 were female and they were given conventional asthma treatment only [SYMBICORT (budesonide and formo‐ terol inhalation) or SEROTID (Salmeterol, fluticasone propionate) with or without salbutamol]. Their results are shown in Table 3. The average age of patients was 35.8 year, average severity of symptoms was 2.78, medication score was 3.94 and PSS value was 22.94. There was significant clinical impact of ventolin, Symbicort and Seretide conventional in treatment of asthma. Then average of improvement after a month was 1.94 and increased to 2.11 after 2 months period (P= 0.001) from the base line and PEFR increased from 72.6% at the time of enrollement in the study to 83.6% at the end of the study (P=0.0001).


**Table 2.** Combined rates of all data for patients of Conventional treatment (group 1)

as a result of treatment [28]. We have developed a schedule for each patient where the following questions is registered for all visits to facilitate consideration of the patient's

**1.** In the past 4 weeks, how much of the time did your asthma keep you from getting as much

**3.** During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, and shortness of breath, chest tightness or pain) wake you up at night or earlier than usual in

**4.** During the past 4 weeks, how often have you used your rescue inhaler or nebulizer

Out of the total (82) patients with asthma included in the study, 79% (65 patients) of them continued until the end of the study and are eligiable for analysis. The subjects suitable for analysis are consisted of 33 men (52%) and 32 women (48%). The mean age was 35.8 years

In this study 22 patients has been selected for the first group, 18 patients (81.8%) of them continued until the end of the study. Of the total, 9 patients were male and 9 were female and they were given conventional asthma treatment only [SYMBICORT (budesonide and formo‐ terol inhalation) or SEROTID (Salmeterol, fluticasone propionate) with or without salbutamol]. Their results are shown in Table 3. The average age of patients was 35.8 year, average severity of symptoms was 2.78, medication score was 3.94 and PSS value was 22.94. There was significant clinical impact of ventolin, Symbicort and Seretide conventional in treatment of asthma. Then average of improvement after a month was 1.94 and increased to 2.11 after 2 months period (P= 0.001) from the base line and PEFR increased from 72.6% at the time of

**2.** During the past 4 weeks, how often have you had attacks of shortness of breath?

**7.** How would you rate your asthma control during the past 4 weeks?

36 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine

SPSS package (version 17) was used for statistical analysis.

**3.1. Role of conventional asthma treatment in the first group**

enrollement in the study to 83.6% at the end of the study (P=0.0001).

condition fully [29].

the morning?

**6.** Is there wheezing or no?

**2.7. Statistical analysis**

**3. Results**

(Table 1).

**8.** Recording peak expiratory flow

done at work, school or at home?

medication (such as salbutamol)? **5.** Assessment of severity of cough, SOB.

#### **3.2. Role of conventional asthma treatment plus Tianeptine in the second group**

These patients were given the same of traditional medicines which given to the first group, but was added Tianeptine to each patients in this group. The average patients age was 36.4 year, average severity of symptoms was 3.06, medication score was 3.9 and PSS value was 22.33. The treatment lead to improvement of 1.93 after a month and this increased to 2.4 after 2 months with significant difference (P= 0.001) from the baseline. In addition, PEFR increased from 77.4% at study enrollement to 89.13% at the end of the study (P= 0.0001).


**Table 3.** Combined rates of all data for patients of Conventional treatment with Tianeptine [group 2]

#### **3.3. Role of Tianeptine ± Singulair in asthmath in the third group**

These patients were given Tianeptine12.5+Singulair10mg without addition or modification of traditional medicines. The average of patient's age was 35.53, average severity of symptoms was 2.46, medication score was 6, and average of PSS of this group was 23.06. The improvement after a month was 1.00 and increased to 2.13 after 2 months (P=0.001) from the baseline. Furthermore, average of Rate of peak expiratory flow at onset of study was 80.4% and increased to 88.4% at the end of the study (P=0.001).


**Table 4.** Combined rates of all data for patients of Singulair with Tianeptine [group3]:

#### **3.4. Role of conventional medicines ± fexofenadine ± tianeptine in asthma in the fourth group**

In this group, 17 patients continued until the end of the study, including 8 patients were male and 9 were female. The patients were given the same of traditional medicines given to the first group, but was added Tianeptine (12.5 mg) three time daily and fexofenadine (180 mg) once daily to each patients in this group. Average of patient's age of fourth group was 35.7, average of severity of symptoms was 3.17, medication score was 7, and average of PSS of this group was 26.67. The average of improvement after a month was 2.41and this increased to 2.58 after 2 month of treatment (P=0.0001). In addition, PEFR was increased to 88.41% at the end of the study (P=0.0001)


**Table 5.** Combinee rates of all data for patients of Conventional treatment with Fexofenadine + Tianeptine [group 4]:

#### **3.5. Comparison between the rates of the key points for all groups**

**3.3. Role of Tianeptine ± Singulair in asthmath in the third group**

38 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine

to 88.4% at the end of the study (P=0.001).

P value 0.001

P value 0.001

**Table 4.** Combined rates of all data for patients of Singulair with Tianeptine [group3]:

Rate of improvement

PEFR

**group**

study (P=0.0001)

These patients were given Tianeptine12.5+Singulair10mg without addition or modification of traditional medicines. The average of patient's age was 35.53, average severity of symptoms was 2.46, medication score was 6, and average of PSS of this group was 23.06. The improvement after a month was 1.00 and increased to 2.13 after 2 months (P=0.001) from the baseline. Furthermore, average of Rate of peak expiratory flow at onset of study was 80.4% and increased

Age 35.53 12.72 3.28 28.50 – 42.56

Severity of asthma 2.47 0.92 0.24 1.96 – 2.98

Medication score 6.00 0.00 0.00 6.00 – 6.00

PSS score 23.07 5.88 1.52 19.82 – 26.32

1 month 1.00 0.38 0.10 0.81-1.19

2 month 2.13 0.74 0.19 1.83-2.44

Study onset 80.40 5.55 1.43 77.33 – 83.47

End of study 88.40 7.34 1.89 83.34 – 92.46

**3.4. Role of conventional medicines ± fexofenadine ± tianeptine in asthma in the fourth**

In this group, 17 patients continued until the end of the study, including 8 patients were male and 9 were female. The patients were given the same of traditional medicines given to the first group, but was added Tianeptine (12.5 mg) three time daily and fexofenadine (180 mg) once daily to each patients in this group. Average of patient's age of fourth group was 35.7, average of severity of symptoms was 3.17, medication score was 7, and average of PSS of this group was 26.67. The average of improvement after a month was 2.41and this increased to 2.58 after 2 month of treatment (P=0.0001). In addition, PEFR was increased to 88.41% at the end of the

**Variable Mean SD St. Error of mean 95% confidence interval**

The averages of PSS for all groups were roughly convergent (P>0.05). All patients in the four groups have made improvement with lightly varying degrees in the first month, with the exception of the third group. However, the percentage of improvement in patients of this group in the first month was relatively low, but after two months the improvement became well. Furthermore, the average improvement after a month of treatment course was with highly significant differences between the groups (P=0.000). However, the average improvement after 2 month was with non significant differences between the groups (P=0.06). The same pattern of differences was achieved for PEFR, however, the changes in PEFR were significantly different between the groups. Although the severity of asthma was more in group 4, the increase change was more prominent in this group as compared to other 3 groups.Table 6.


Improvment1: Mean rate of overall improvement in the group after the first month

Improvment2: Mean rate of overall improvement in the group after the second month

PEFR1: Mean rate of peak expiratory flow of the group at the beginning of the study

PEFR2: Mean rate of peak expiratory flow of the group at the end of the study

Change: Mean the difference between the rate of peak expiratory flow between the beginning and end of the study

**Table 6.** Improvement comparison between the treatment groups

The proportion of decreasing of the mean percentage change of daily "as-needed" inhaled βagonist using for patients of each group were 25.5%, 31.1%, 26.6% and 35.8% for groups1,2,3,and 4 respectively. The present study demonstrated non significant differences in proportion of decreasing between the 4 groups. However, all groups demonstrated significant differences in proportion of decreasing inhaled β-agonist use at the end of the study as compared to enrollement time. Table 7.


**Table 7.** Proportion of decreasing of the mean percentage change of daily "as-needed" inhaled β-agonist using for patients of for treatment groups

**In conclusion**, the 4 treatment course were effective therapeutic approaches for asthma treatment, however, the combination of SYMBICORT (budesonide and formoterol inhalation) or SEROTID (Salmeterol, fluticasone propionate) plus Tianeptine (12.5 mg) three time daily and fexofenadine (180 mg) once daily was superior in treating severe asthma.

#### **4. Discussion**

Individuals with asthma have twice the risk of developing mood and anxiety disorders as individuals without asthma and these psychological factors are associated with worse outcomes and greater need for medical intervention. Similarly, asthma symptom onset and exacerbation often occur during times of increased psychological stress. Remission from depression, on the other hand, is associated with improvement in asthma symptoms and decreased usage of asthma medication. Yet research aimed at understanding the biological underpinnings of asthma has focused almost exclusively on the periphery. An extensive literature documents the relationship between emotion and asthma, but little work has explored the function of affective neural circuitry in asthma symptom expression.[30]

The present study indicated that in patients receiving Tianeptine plus conventional asthma treatment (group 2) demonstrate a hsigigher decrease in the mean percentage change in daily "as-needed" inhaled β-agonist use (31.1%) as compared to patients group receiving conven‐ tional asthma treatment (group 1) only (25.5%). Also, there was a higher decrease in the mean percentage change in daily "as-needed" inhaled β-agonist use (35.8%) in the fourth group which given conventional treatment with fexofenadine plus tianeptine as compared to the other 3 groups of treatment. However, using ANOVA analysis, the differences in percentage change in daily "as –needed'' between the four groups were not statistically significant. Furthermore, the percentage of change was highly significant for the four groups of treatment.

The proportion of decreasing of the mean percentage change of daily "as-needed" inhaled βagonist using for patients of each group were 25.5%, 31.1%, 26.6% and 35.8% for groups1,2,3,and 4 respectively. The present study demonstrated non significant differences in proportion of decreasing between the 4 groups. However, all groups demonstrated significant differences in proportion of decreasing inhaled β-agonist use at the end of the study as

40 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine

Group 1 18 2.56 2.57 1.27 - 3.83 25.5% 0.001 Group 2 15 3.13 1.58 2.86 - 4.61 31.1% 0.000 Group 3 15 2.67 1.05 2.09 - 3.25 26.6% 0.000 Group 4 17 3.59 1.94 2.59 - 4.58 35.8% 0.000

>0.05 >0.05

**Table 7.** Proportion of decreasing of the mean percentage change of daily "as-needed" inhaled β-agonist using for

and fexofenadine (180 mg) once daily was superior in treating severe asthma.

**In conclusion**, the 4 treatment course were effective therapeutic approaches for asthma treatment, however, the combination of SYMBICORT (budesonide and formoterol inhalation) or SEROTID (Salmeterol, fluticasone propionate) plus Tianeptine (12.5 mg) three time daily

Individuals with asthma have twice the risk of developing mood and anxiety disorders as individuals without asthma and these psychological factors are associated with worse outcomes and greater need for medical intervention. Similarly, asthma symptom onset and exacerbation often occur during times of increased psychological stress. Remission from depression, on the other hand, is associated with improvement in asthma symptoms and decreased usage of asthma medication. Yet research aimed at understanding the biological underpinnings of asthma has focused almost exclusively on the periphery. An extensive literature documents the relationship between emotion and asthma, but little work has

explored the function of affective neural circuitry in asthma symptom expression.[30]

The present study indicated that in patients receiving Tianeptine plus conventional asthma treatment (group 2) demonstrate a hsigigher decrease in the mean percentage change in daily "as-needed" inhaled β-agonist use (31.1%) as compared to patients group receiving conven‐

**Difference number of salbutamol using between onset and end study**

**Mean SD 95% Confidence interval Rate of decrease**

**P value**

compared to enrollement time. Table 7.

**Variable Number**

patients of for treatment groups

**4. Discussion**

P value ANOVA PEFR was improved significantly in the four groups, however, there was a significant differences in changes between the four ngroups of treatment. Furthermore, the PEFR change was more in group four (conventional + tianeptine + fexofenadine) and lowest in group 3 (singulair plus Tianeptine). The rate of improvement was highest in group 4 and lowest in group 3 after one month of treatment course and the there was a highly significant differences between the 4 groups in their rate of improvement. However, after 2 months of treatment there was no significant differences between the groups in their rate of improvement. This could be explasined on the basis that fexofenadine may exert antiinflammatory action that may influence the clinical improvement [31-38]

In this study the impact of Tianeptine was clear through the big improvement in patients who receice this medicine, as demonstrated in reduction of daily use and percent reduction of salbutamol, percent changes in PEFR and rate of improvement in group 2,3 and 4. However, the above parameters changes were lower in group of patients (group 3) receiving singulair with Tianeptine. This could be due to that singulair acts as antiinflammatory, it does prevent bronchoconstriction, but not relieve the present bronchoconstriction. In addition, it takes 3 -4 to reach high peak blood mean (Tmax)[39].

The therapeutic effect of Tianeptine in treatment of asthma may be contributed to its ability to suppress proinflammatory cytokines, interference with cholinergic and serotoninergic pathways, modulation of immune response and/or serotonin uptake by platelets and seroto‐ nergic axons at the central nervous system [40,41]. Serotonin induces bronchoconstriction via peripheral and central pathways resulting in increasing colinergic activity and histamine release[42]. These changes may explain why tianeptine has proven to be a powerful therapeutic tool in controlling asthma as this study indicated of better improvement in groups (groups 2,3,and 4) receiving tinaneptine. During asthma attack, catacholamines and free serotonin (f-5- HT), only f-5-HT levels correlated positively with pulmonary function clinical severity [43,44]. f-5-HT was taken up by pulmonary endocrine cells that were located at the parasympathetic terminals. Pulmonary endocrine cells located at the parasympathetic terminals taken up f-5- HT. Bronchial smooth muscle contracted due to effect of serotonin through potententiation of acetylcholine [39]. However, postsynaptic receptors (5-HT3 and 5-HT4) that located at the bronchial muscle mediated serotonin effects.

A reported studies [45,46] suggested that tinaneptine therapy reduce plasma f-5-HT, clinical rating and increase in pulmonary function. While, asthma attach triggered by drugs that increase f-5HT such as buspirone and serotonin-uptake inhibitors (like sertraline, paroxetine, etc).[47-50]. However, the side effects of buspirone and serotonin inhibitors may be controlled by atropine [51]. Dupon et al.[52] suggested that serotonin produced frequency- and concen‐ tration-dependent facilitation of cholinergic contractions of human airways, which was mimicked by both 5-HT3 and 5-HT4 agonists, and subsequently 5-HT facilitates cholinergic contractions in the human airways. In addition, Tianeptine greatlly annulated pulmonary vasoconstriction and bronchoconstriction that induced by drugs through their ability to increase f-5HT serum levels [53-59]. Neuroepithelial autocrine serotonergic cells located at the bronchopulmonary system release 5-HT under the effect of acetylcholine stimulation, while, serotonin triggers acetylcholine release from the parasympathetic terminals [60].

Mood disordera are more common in individuals with atopy [13]. Through our study, we can say Tianeptine definitely seems to improve the asthma as it reduced the severity of symptoms and improved the daily functioning of a asthmatic patient and reduced absences from school or work, with increase PEFR, whether that it was added to traditional medicines (budesonide and formoterol inhalation or Salmeterol, fluticasone propionate)or Singulair or fexofenadine. But Group who took the traditional medicines for asthma with the addition of tianeptine and fexofenadine was better and their symptoms responded to treatment better than others. This finding may be due to synergistic antiinflamatory effects that induced by combination of Tianeptine and fexofenadine.

Tianeptine led to a clinical improvement of asthmatic symptoms in the second group, patients who were given the tianeptine in addition to traditional medicine has with better improvement as compared to the first group who took traditional medicines only. This suggests the positive effect of this drug for patients with asthma, of course not as a single medicine, but certainly as adjuvant drug to the essential approved medicines. The mechanism by which this positive impact was induced may be due to its significant anxiolytic properties for patients with asthma who worry more than others or due to positive association between free serotonin in plasma and severity of asthma in symptomatic patients. As tianeptine was the only agent known to both reduce free serotonin in plasma and enhance uptake in platelets,[45,46]. Previous studies have shown that antidepressants may be of therapeutic value in asthma [61,62] as there is increasing evidence that a biological linkage may exist between asthma and depression [61,63,64]. A defect in the function of the autonomic nervous system such as alpha-adrenergic and cholinergic hyperresponsiveness and beta-adrenergic hyporesponsiveness even distal from the airways has been demonstrated in asthmatic patients, as well as in depression [61,64]. Antidepressants may have a therapeutic role in asthma by supressing proinflammatory cytokines and preventing their brain effects [61,65]. They also interfere with cholinergic and serotoninergic pathways, both centrally and peripherally. Most antidepressants also induce adaptive changes in central monoaminergic neurotransmission, which itself might modulate immune reactivity [61,65]. Tianeptine is an antidepressant drug that has been recently used with success in the treatment of asthma. Tianeptine treats depression through the enhancement of serotonin reuptake from the synaptic cleft by serotoninergic terminals. It works by a mechanism that is just the pollar opposite of selective serotonin reuptake inhibition. It has been reported that this substance provoked a dramatic disappearance of clinical symptoms and improved the pulmonary function in asthmatic patients [61,66].

Without the slightest doubt, the modern conventional medicine such as SYMBICORT (bude‐ sonide and formoterol inhalation) or SEROTID (Salmeterol, fluticasone propionate has provided great benefit for patients with asthma and It shall be the basis of good treatment for asthmatic patients in various degrees and severity. In the present study, these drugs had good results and improved symptoms of patient and their live quality. These treatment approach showed improvement in PEFR from 72.6% to 83.7%, with difference in the amount of 11% and significant decrease in the mean percentage change in daily "as-needed" inhaled β-agonist use of about 25%. Some randomised controlled trial comparing stable dose Seretide with Symbi‐ cort, given as an adjustable maintenance dose, in 706 adults with persistent asthma [67]. Over one year, those taking Serotide experienced the equivalent of 24 more symptom-free days compared to those taking symbicort. The overall incidence of asthma exacerbations (a severe attack) was 47% lower in the Seretide group. Overall, the majority of exacerbations did not result in hospitalisation. Morning peak expiratory flow was significantly higher with Seretide and those taking Seretide experienced a significantly higher proportion of days free of rescue medication use [67].

tration-dependent facilitation of cholinergic contractions of human airways, which was mimicked by both 5-HT3 and 5-HT4 agonists, and subsequently 5-HT facilitates cholinergic contractions in the human airways. In addition, Tianeptine greatlly annulated pulmonary vasoconstriction and bronchoconstriction that induced by drugs through their ability to increase f-5HT serum levels [53-59]. Neuroepithelial autocrine serotonergic cells located at the bronchopulmonary system release 5-HT under the effect of acetylcholine stimulation, while,

Mood disordera are more common in individuals with atopy [13]. Through our study, we can say Tianeptine definitely seems to improve the asthma as it reduced the severity of symptoms and improved the daily functioning of a asthmatic patient and reduced absences from school or work, with increase PEFR, whether that it was added to traditional medicines (budesonide and formoterol inhalation or Salmeterol, fluticasone propionate)or Singulair or fexofenadine. But Group who took the traditional medicines for asthma with the addition of tianeptine and fexofenadine was better and their symptoms responded to treatment better than others. This finding may be due to synergistic antiinflamatory effects that induced by combination of

Tianeptine led to a clinical improvement of asthmatic symptoms in the second group, patients who were given the tianeptine in addition to traditional medicine has with better improvement as compared to the first group who took traditional medicines only. This suggests the positive effect of this drug for patients with asthma, of course not as a single medicine, but certainly as adjuvant drug to the essential approved medicines. The mechanism by which this positive impact was induced may be due to its significant anxiolytic properties for patients with asthma who worry more than others or due to positive association between free serotonin in plasma and severity of asthma in symptomatic patients. As tianeptine was the only agent known to both reduce free serotonin in plasma and enhance uptake in platelets,[45,46]. Previous studies have shown that antidepressants may be of therapeutic value in asthma [61,62] as there is increasing evidence that a biological linkage may exist between asthma and depression [61,63,64]. A defect in the function of the autonomic nervous system such as alpha-adrenergic and cholinergic hyperresponsiveness and beta-adrenergic hyporesponsiveness even distal from the airways has been demonstrated in asthmatic patients, as well as in depression [61,64]. Antidepressants may have a therapeutic role in asthma by supressing proinflammatory cytokines and preventing their brain effects [61,65]. They also interfere with cholinergic and serotoninergic pathways, both centrally and peripherally. Most antidepressants also induce adaptive changes in central monoaminergic neurotransmission, which itself might modulate immune reactivity [61,65]. Tianeptine is an antidepressant drug that has been recently used with success in the treatment of asthma. Tianeptine treats depression through the enhancement of serotonin reuptake from the synaptic cleft by serotoninergic terminals. It works by a mechanism that is just the pollar opposite of selective serotonin reuptake inhibition. It has been reported that this substance provoked a dramatic disappearance of clinical symptoms and

improved the pulmonary function in asthmatic patients [61,66].

serotonin triggers acetylcholine release from the parasympathetic terminals [60].

42 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine

Tianeptine and fexofenadine.

In the present study, the two drugs had similar results in controling asthma and these results were better in group 4 (given conventional treatment with fexofenadine plus tianeptine). As table 6 shows the extent of improvement after 2 months of treatment comparison between the four groups, the improvement of patients in fourth group was significant. This finding support existence of the synergistic role of fexofenadine with tianeptine and conventional asthma treatment, where the improvement in PEFR was greater in fourth group patients who took the both of drugs together with conventional course. In addition to traditional medicine fexofe‐ nadine has been shown to have an impact on inflammatory mediators, other than histamine, such as decreasing the production of LTC4, LTD4, LTE4, PGE2, and PGF2α; and diminishing eosinophil adherence, chemotaxis, and opsonization of particles.[68] These effects may provide benefit to some of the inflammatory responses of an acute allergic reaction and provide a basis for future development of H1 antagonists with stronger anti-inflammatory effects.[68]

Repeated dosing with fexofenadine (180mg) and montelukast (10 mg) as add-on therapy improved AMP PC20 and other surrogate inflammatory markers along with asthma diary outcomes in ICS-treated atopic asthmatic patients. [69]. However, in our study the patients of third group [given Singulair (montelukast) plus Tianeptine] were less responsive and less improved compared with other groups especially in the first month. This may be due to the combination of Singulair (montelukast) plus tianeptine only without the addition of drugs such as SYMBICORT or SEROTID. However, results of imrovement in group thee at the end of second month was better compared with the same group in the first month. This confirms preventive influence of Singulair, Montelukast in a long term-controller medication which should not be substituted for short acting β-agonists. Furthermore, this finding suggest not to use Singulair alone and to be used in combination with other prophylactic agent.

Montelukast is a preventive agent, which should be used in addition to other drugs for the management of asthma. [39] Therefore, as it is well known and previously confirmed, monte‐

lukastis effective asprophylacticdrug andcontrol of chronic asthmatic course for subjects aged ≥ 15 years, however, of no value as rescue treatment approach in acute attacks.[39]

The clinical benefit from adding Tianeptine to asthma therapy course may actually result in new indications for antidepressants. They could also help in understanding some common pathophysiological mechanisms existing between asthma and depression.[19]

*The treatment for asthma and depression involves a coordinated approach that monitors both the symptoms of asthma and depression including using an asthma action plan. It is important to find the treatment that works best for each person. The most effective treatments are those that combine psychological and medical care, medical monitoring, individualised asthma education and adequate community support. It should be noted that while antidepressants seem to have no specific effect on asthma symptoms or medication, the National Asthma Council recommends that people should not take sedatives when having an acute attack of asthma as it may have an effect on breathing [70]*

The natural course of asthma include a scenario of triggering phase followed by generation of symptom and inflammation phase to form a vicious cycle of subsequent phases [71]. Consti‐ tutional predisposition to the development of neurogenic generator component is necessary for asthma development. Although stress does not cause asthma, stress and asthma are definitely linked. Asthma causes stress, and stress makes it more difficult to control asthma. Even daily stress can make asthma symptoms worsen. The learning to change stress response to decrease asthma symptoms is important. Equally important is prioritizing patient daily schedule so he allow enough time to accomplish what the patient needs to do without feeling pressured or overwhelmed [71]

The study limitation is the small numbers of patients in each group. However, the power analysis calculated to determine the effect of sample size in each group. The power of analysis was 0.89 for reduction in PEFR for all groups, while that of rate improvement were 0.54 for group 2, 0.10 for group 3 and 0.72 for group 4. These findings indicated that sample size with influence on the finding of group 3 only. However, the power of analysis for the differences between the groups indicated a values of >0.97 for the 4 groups indicating non influence of sample sizes on the results.

**In conclusion,** the present study indicated the therapeutic activity of Tianeptine as add on drug in asthma control and treatment. The most effective combination course is that of fexofenadine, Tianeptine and conventional beta agonist such as symbicort or serotid. Until today, management of bronchial asthma was held in two main directions:Modification of factors inducing allergic reaction and interference on the certain stages of allergic reaction; and Interference with peripheral bronchial receptors. Both these directions do finally affect the trigger factors. Based on the present study findings, We suggest a 3rd direction in the man‐ agement of bronchial asthma: application of antidepresion agents for the control of activity of generator neurogenic mechanisms of bronchial asthma. This new approach leads to the prevention of asthmatic attacks and opens up new perspectives for the management of this disease

## **Author details**

lukastis effective asprophylacticdrug andcontrol of chronic asthmatic course for subjects aged

The clinical benefit from adding Tianeptine to asthma therapy course may actually result in new indications for antidepressants. They could also help in understanding some common

*The treatment for asthma and depression involves a coordinated approach that monitors both the symptoms of asthma and depression including using an asthma action plan. It is important to find the treatment that works best for each person. The most effective treatments are those that combine psychological and medical care, medical monitoring, individualised asthma education and adequate community support. It should be noted that while antidepressants seem to have no specific effect on asthma symptoms or medication, the National Asthma Council recommends that people should not take*

The natural course of asthma include a scenario of triggering phase followed by generation of symptom and inflammation phase to form a vicious cycle of subsequent phases [71]. Consti‐ tutional predisposition to the development of neurogenic generator component is necessary for asthma development. Although stress does not cause asthma, stress and asthma are definitely linked. Asthma causes stress, and stress makes it more difficult to control asthma. Even daily stress can make asthma symptoms worsen. The learning to change stress response to decrease asthma symptoms is important. Equally important is prioritizing patient daily schedule so he allow enough time to accomplish what the patient needs to do without feeling

The study limitation is the small numbers of patients in each group. However, the power analysis calculated to determine the effect of sample size in each group. The power of analysis was 0.89 for reduction in PEFR for all groups, while that of rate improvement were 0.54 for group 2, 0.10 for group 3 and 0.72 for group 4. These findings indicated that sample size with influence on the finding of group 3 only. However, the power of analysis for the differences between the groups indicated a values of >0.97 for the 4 groups indicating non influence of

**In conclusion,** the present study indicated the therapeutic activity of Tianeptine as add on drug in asthma control and treatment. The most effective combination course is that of fexofenadine, Tianeptine and conventional beta agonist such as symbicort or serotid. Until today, management of bronchial asthma was held in two main directions:Modification of factors inducing allergic reaction and interference on the certain stages of allergic reaction; and Interference with peripheral bronchial receptors. Both these directions do finally affect the trigger factors. Based on the present study findings, We suggest a 3rd direction in the man‐ agement of bronchial asthma: application of antidepresion agents for the control of activity of generator neurogenic mechanisms of bronchial asthma. This new approach leads to the prevention of asthmatic attacks and opens up new perspectives for the management of this

≥ 15 years, however, of no value as rescue treatment approach in acute attacks.[39]

44 Evidence-based Strategies in Herbal Medicine, Psychiatric Disorders and Emergency Medicine

pathophysiological mechanisms existing between asthma and depression.[19]

*sedatives when having an acute attack of asthma as it may have an effect on breathing [70]*

pressured or overwhelmed [71]

sample sizes on the results.

disease

Abdulghani Mohamad Alsamarai2,3\*, Mohammad Ghiyath Alhelwani1 and Amina Hamed Ahmed Alobaidi1

\*Address all correspondence to: galsamarrai@yahoo.com

1 Department of Medicine, Tikrit University College of Medicine, Tikrit, Iraq; College of Ap‐ plied Medical Sciences, Netherland

2 Asthma and Allergy Centre, Tikrit Teaching Hospital, Tikrit, Iraq

3 Habib Hospital Outpatients Clinic, Saudi Arabia

Department of Biochemistry, Tikrit University College of Medicine, Tikrit, Iraq

#### **References**


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## **Chapter 4**
