Anti Asthma Drug

Asthma Protocol Version 1.4

A Randomized, Double-Blind, Controlled Study of A Herbomineral Preparation of Divya Pharmacy in Adult Patients of mild to moderate

Bronchial Asthma

Avnish K. Upadhyay

Department of Clinical Research & Drug DevelopmentDivya Yog Mandir Trust,

Patanjali Yog Peeth , Haridwar

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TABLE OF CONTENTS

1. INTRODUCTION

1.1. Background1.2. Hypothesis

2. STUDY OBJECTIVES

3. STUDY DESIGN

3.1. Study population3.1.1. Inclusion Criteria3.1.2. Exclusion Criteria

3.2. Study Observations3.2.1. Screening Visit3.2.2. Visit One3.2.3. Subsequent three monthly visits

4. PATIENT WITHDRAWAL

5. TREATMENT ADMINISTERED

5.1. Randomization of Subjects5.2. Dosage and Administration

5.2.1. Control Group5.2.2. Swasnashini (An Ayurvedic Preparation by Divya Pharmacy)

6. EFFICACY VARIABLES

6.1. Primary Endpoints6.2. Secondary Endpoints

7. DATA ANALYSIS METHODS

7.1. Sample Size7.2. Randomization7.3. General Consideration7.4. Statistical Methods

8. DATA COLLECTION

8.1 Demographics

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9. CLINICAL AND LAB PROCEDURES

9.1. Clinical Laboratory Assesments

10. REFERENCES

11. TABLE. TIME AND EVENT SCHEDULE

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1. INTRODUCTION

1.1. Background

Asthma is a chronic illness involving the respiratory system in which the airway occasionally constricts, becomes inflamed, and is lined with excessive amounts of mucus, often in response to one or more triggers. These episodes may be triggered by such things as exposure to an environmental stimulant (or allergen), cold air, warm air, moist air, exercise or exertion, or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold.(1) This airway narrowing causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing. The airway constriction responds to bronchodilators. Between episodes, most patients feel well but can have mild symptoms and they may remain short of breath after exercise for longer periods of time than the unaffected individual. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and environmental changes.

Public attention in the developed world has recently focused on asthma because of its rapidly increasing prevalence, affecting up to one in four urban children.(2)

The word 'asthma' is derived from the Greek aazein, meaning "sharp breath." The word first appears in Homer's Iliad;(3) Hippocrates was the first to use it in reference to the medical condition, in 450 BC. Hippocrates thought that the spasms associated with asthma were more likely to occur in tailors, anglers, and metalworkers. Six centuries later, Galen wrote much about asthma, noting that it was caused by partial or complete bronchial obstruction. In 1190 AD, Moses Maimonides, an influential medieval rabbi, philosopher, and physician, wrote a treatise on asthma, describing its prevention, diagnosis, and treatment/(4) In the 17th century, Bernardino Ramazzini noted a connection between asthma and organic dust. The use of bronchodilators started in 1901, but it was not until the 1960s that the inflammatory component of asthma was recognized, and anti-inflammatory medications were added to the regimens.

In some individuals asthma is characterized by chronic respiratory impairment. In others it is an intermittent illness marked by episodic symptoms that may result from a number of triggering events, including upper respiratory infection, stress, airborne allergens, air pollutants (such as smoke or traffic fumes), or exercise. Some or all of the following symptoms may be present in those with asthma: dyspnea, wheezing, stridor, coughing, an inability for physical exertion. Some asthmatics that have severe shortness of breath and tightening of the lungs never wheeze or have stridor and their symptoms may be confused with a COPD-type disease.

An acute exacerbation of asthma is referred to as an asthma attack. The clinical hallmarks of an attack are shortness of breath (dyspnea) and either wheezing or stridor.(6) Although the former is "often regarded as the sine qua non of asthma,(5) some patients

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present primarily with coughing, and in the late stages of an attack, air motion may be so impaired that no wheezing may be heard. When present the cough may sometimes produce clear sputum. The onset may be sudden, with a sense of constriction in the chest, breathing becomes difficult, and wheezing occurs (primarily upon expiration, but can be in both respiratory phases). An asthma attack may spread the mold to others through the air.

Signs of an asthmatic episode include wheezing, rapid breathing (tachypnea), prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), and over-inflation of the chest. During a serious asthma attack, the accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck) may be used, shown as in-drawing of tissues between the ribs and above the sternum and clavicles, and the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation).

During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Just before loss of consciousness, there is a chance that the patient will feel numbness in the limbs and palms may start to sweat. Feet may become icy cold. Severe asthma attacks, which may not be responsive to standard treatments (status asthmaticus), are life-threatening and may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few signs of the disease.(6)

Asthma is defined simply as reversible airway obstruction. Reversibility occurs either spontaneously or with treatment. The basic measurement is peak flow rates and the following diagnostic criteria are used by the British Thoracic Society.(7)

≥20% difference on at least three days in a week for at least two weeks;

≥20% decrease in peak flow following exposure to a trigger (e.g., exercise).

In many cases, a physician can diagnose asthma on the basis of typical findings in a patient's clinical history and examination. Asthma is strongly suspected if a patient suffers from eczema or other allergic conditions—suggesting a general atopic constitution—or has a family history of asthma. While measurement of airway function is possible for adults, most new cases are diagnosed in children who are unable to perform such tests. Diagnosis in children is based on a careful compilation and analysis of the patient's medical history and subsequent improvement with an inhaled bronchodilator medication. In adults, diagnosis can be made with a peak flow meter (which tests airway restriction), looking at both the diurnal variation and any reversibility following inhaled bronchodilator medication.

Asthma is categorized by the United States National Heart, Lung and Blood Institute as falling into one of four categories: mild intermittent, mild persistent, moderate persistent and severe persistent. The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent nighttime symptoms, result in

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limited physical activity and when lung function as measured by PEV or FEV1 tests is less than 60% predicted with PEF variability greater than 30%.

During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus, making it difficult to breathe. In essence, asthma is the result of an immune response in the bronchial airways.(8)

Many asthmatics, like those who suffer from other chronic disorders, use alternative treatments; surveys show that roughly 50% of asthma patients use some form of unconventional therapy.(9,10) There are little data to support the effectiveness of most of these therapies. A Cochrane systematic review of acupuncture for asthma found no evidence of efficacy.(11) A similar review of air ionisers found no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.(12) A study of "manual therapies" for asthma, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic manoeuvers, found there is insufficient evidence to support or refute their use in treating asthma;(13) these manoeuvers include various osteopathic and chiropractic techniques to "increase movement in the rib cage and the spine to try and improve the working of the lungs and circulation"; chest tapping, shaking, vibration, and the use of "postures to help shift and cough up phlegm." On the other hand, one meta-analysis found that homeopathy has a potentially mild benefit in reducing symptom intensity.(14) however, the number of patients involved in the analysis was small, and subsequent studies have not supported this finding.(15) Several small trials have suggested some benefit from various yoga practices, ranging from integrated yoga programs(16) —"yogasanas, Pranayama, meditation, and kriyas"—to sahaja yoga,(17) a form of meditation.

In Ayurveda, Asthma is known as 'Swas Roga'. Samprapti (Pathogenesis) of the swas roga according to Ayurveda is "The vitiated 'Pranvayu' combines with deranged 'Kapha dosha' in the lungs causing obstruction in the 'Pranavaha srotasa'(Respiratory passage). This results in gasping and laboured breathing. This condition is known as 'Swas Roga'"Five types of 'Swas Roga' are described in Ayurvedic texts1]Maha-shwas2]Urdhva-shwas3]Chinna-shwas4]Tamak-shwas5]Kshudra-shwasAmong these five types first three are not curable. 'Tamak-shwas is 'yapya'(Controllable) and is difficult to cure. The last one is curable. More than 75% of the cases belong to last two catagories.(18)

Ayurvedic medicines are very safe and cure the problem to a great extent. Scholars of various disciplines are working on the problem and various modern means and measures have been discovered. Even then the effective drug without any reaction couldn’t be established. Ayurveda is the reach source of the therapeutic measures that can control the

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disease. Out of such therapeutic measures a poly-herbal compound is selected for the benefit of the increasing number of asthma patients.

A Herbomineral combination of Divya Pharmacy found very much effective in Asthama patients in General Practice containing Glycyrhiza glabra, Justicia gendarussa, Solanum surattenes, Adhatoda vasica, Ocimum sanctum, Cinnamomum zeylanicum, Zingiber officinale, Abhrak Bhasma, Swarn Basant Malti, Sanjivani Vati etc.To treat this widespread disease there is a high prevalence of usage of herbal medicine. The use of plants is as old as humankind and it has been steadily increasing over the past 10 years. Plant-based remedies are now one of the most popular complementary treatments. Herbal supplements are receiving increasing exposure through media, including the Internet, in lay journals and more recently in the scientific press. Interest in herbal medicine has been facilitated by multiple factors, including the perception that pharmaceutical medications are expensive, overprescribed and may often be dangerous. Alternatively, herbal medicine is often perceived as being "natural" and therefore is considered safe. (19)

The antitussive activity of Adhatoda vasica (AV) extract was evaluated in anaesthetized guinea pigs and rabbits and in unanaesthetized guinea pigs. AV was shown to have a good antitussive activity. Intravenously, it was 1/20–1/40 as active as codeine on mechanically and electrically induced coughing in rabbits and guinea-pigs. After oral administration to the guinea-pig the antitussive activity of AV was similar to codeine against coughing induced by irritant aerosols. Adhatoda vasica (L.) Nees is a well-known plant drug in Ayurvedic and Unani medicine. It has been used for the treatment of various diseases and disorders, particularly for the respiratory tract ailments. During the last 20 years, several scientific reports on oxytocic and abortifacient effects of vasicine and alkaloid derived from the plant have appeared. This leads to questions concerning the safety of A. vasica as a herbal medicine. In this article, the major data on traditional uses as well as ethnopharmacological and toxicological studies, both published and unpublished, are reviewed and commented upon. The data have been evaluated from the point of view of correctness, reliability, relevance and importance for the overall evaluation of the safety of A. vasica. (20, 21)

Several plants are used in traditional medicine for the treatment of bronchial asthma. We are trying to identify the active compound(s) and their mode of action. For the isolation and identification of the active principles, different chromatographic methods, HPLC, MPLC, elementary analysis, UV, mass, 1H- and 13C-NMR spectroscopy are used. Whole plant extracts, fractionated extracts and pure compounds are tested in the following pharmacological systems: cyclooxygenase and lipoxygenase pathway of arachidonic acid metabolism, bronchial obstruction of guinea pigs after inhalation of allergens, platelet-activating factor (PAF), histamine or acetylcholine, PAF-induced bronchial hyperreactivity of guinea pigs, histamine release, chemoluminescence and chemotaxis of human polymorphonuclear leukocytes as well as thromboxane biosynthesis of human platelets. As active compounds in onion extracts, thiosulfinates and cepaenes could be identified. They exert a wide spectrum of pharmacologic activities, both in vitro and in vivo. Tetragalloyl quinic acid from Galphimia glauca, suppressed allergen- and PAF-induced bronchial obstruction, PAF-induced bronchial

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hyperreactivity (5 mg/kg orally) in vivo and thromboxane biosynthesis in vitro. Hitherto unknown alkaloids from Adhatoda vasica showed pronounced protection against allergen-induced bronchial obstruction in guinea pigs (10 mg/ml aerosol). Androsin from Picrorhiza kurroa prevented allergen- and PAF-induced bronchial obstruction (10 mg/kg orally; 0.5 mg inhalative). Histamine release in vitro was inhibited by other compounds of the plant extract yet to be identified. Pharmacological effects of plant extracts and pure compounds in man are under investigation. (22)

To identify the inhibitor of prednisolone metabolism contained in Saiboku-To, we conducted in-vitro experiments of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), using rat liver homogenate and cortisol as a typical substrate. We studied the effects of ten herbal constituents on 11 beta-HSD. Five herbal extracts showed inhibitory activity with Glycyrrhiza glabra > Perillae frutescens > Zizyphus vulgaris > Magnolia officinalis > Scutellaria baicalensis. This suggests that unknown 11 beta-HSD inhibitors are contained in four herbs other than G. glabra which contains a known inhibitor, glycyrrhizin (and glycyrrhetinic acid). Seven chemical constituents which have been identified as the major urinary products of Saiboku-To in healthy and asthmatic subjects were studied; magnolol derived from M. officinalis showed the most potent inhibition of the enzyme (IC50, 1.8 x 10(-4) M). Although this activity was less than that of glycyrrhizin, the inhibition mechanism (non-competitive) was different from a known competitive mechanism. These results suggest that magnolol might contribute to the inhibitory effects of Saiboku-To on prednisolone metabolism through inhibition of 11 beta-HSD. (23)

Ocimum sanctum (OS) has been mentioned in Indian system of traditional medicine to be of value in the treatment of diabetes mellitus. We have previously shown that OS shows a dose-dependent hypoglycemic effect and prevented rise in plasma glucose in normal rats. It also showed significant antihyperglycemic effect in STZ-induced diabetes. The present study was undertaken to assess the effect of OS on three important enzymes of carbohydrate metabolism [glucokinase (GK) (EC 2.7.1.2), hexokinase (HK) (EC 2.7.1.1) and phosphofructokinase (PFK) (EC 2.7.1.11)] along with glycogen content of insulin-dependent (skeletal muscle and liver) and insulin-independent tissues (kidneys and brain) in STZ (65 mg/kg) induced model of diabetes for 30 days. Administration of OS extract 200 mg/kg for 30 days led to decrease in plasma glucose levels by approximately 9.06 and 26.4% on 15th and 30th day of the experiment. Liver and two-kidney weight expressed as percentage of body weight significantly increased in diabetics (P<0.0005) versus normal controls. OS significantly decreased renal (P<0.0005) but not liver weight. Renal glycogen content increased by over 10 folds while hepatic and skeletal muscle glycogen content decreased by 75 and 68% in diabetic controls versus controls. OS did not affect glycogen content in any tissue. Activity of HK, GK and PFK in diabetic controls was 35, 50 and 60% of the controls and OS partially corrected this alteration.(24)

In another study the ethanolic extract of the leaves exhibited a hypoglycemic effect in rats and an antispasmodic effect in isolated guinea pig ileum. Tulsi extract was administered to 20 patients with shortness of breath secondary to tropical eosinophia in an oral dosage

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of 500 mg TID and an improvement in breathing was noted. The aqueous extract showed a hypotensive effect on anesthetised dogs and cats and negative inotropic and chronotropic activity (reduces the force and rate, respectively) on rabbit's heart. Antibacterial activity has been shown against Staphlococcus aureus and Mycoplasma tuberculosis in vitro as well as against several other species of pathogens including fungi. The plant has had general adaptogenic effects in mice and rats and has been shown to protect against stress-induced ulcers. It has also shown to be protective against histamine-induced bronchospasm in animals. The leaf infusion or fresh leaf juice is commonly used in cough, mild upper respiratory infections, bronchospasm, stress-related skin disorders and indigestion. It is combined with ginger and maricha (black pepper) in bronchial asthma. It is given with honey in bronchitis and cough. The leaf juice is taken internally and also applied directly on cutaneous lesions in ringworm. The essential oil has been used in ear infections. The seeds are considered a general nutritious tonic.(25,26,27)

Spices are the most attractive ingredients to confer an authentic taste to food. As they are derived from plants, they harbour allergenic potency and can induce symptoms ranging from mild local to severe systemic reactions. Due to the content of pharmacologically active substances of spices, the diagnosis of allergy and the differentiation from intolerance reactions may be difficult. Association with inhalative allergies via IgE cross-reactivity, but also direct gastrointestinal sensitization plays a role. This article is a botanical and allergological overview of the most important spices and molecules responsible for eliciting IgE-mediated reactions or cross-reactions. As no curative treatments are known at present, strict avoidance is recommended and, therefore, accurate labelling of pre-packed food is necessary. (28)

In a placebo-controlled study the effect of ginger and fenugreek was examined on blood lipids, blood sugar, platelet aggregation, fibrinogen and fibrinolytic activity. The subjects included in this study were healthy individuals, patients with coronary artery disease (CAD), and patients with non-insulin-dependent diabetes mellitus (NIDDM) who either had CAD or were without CAD. In patients with CAD powdered ginger administered in a dose of 4 g daily for 3 months did not affect ADP- and epinephrine-induced platelet aggregation. Also, no change in the fibrinolytic activity and fibrinogen level was observed. However, a single dose of 10 g powdered ginger administered to CAD patients produced a significant reduction in platelet aggregation induced by the two agonists. Ginger did not affect the blood lipids and blood sugar. Fenugreek given in a dose of 2.5 g twice daily for 3 months to healthy individuals did not affect the blood lipids and blood sugar (fasting and post prandial). However, administered in the same daily dose for the same duration to CAD patients also with NIDDM, fenugreek decreased significantly the blood lipids (total cholesterol and triglycerides) without affecting the HDL-c. When administered in the same daily dose to NIDDM (non-CAD) patients (mild cases), fenugreek reduced significantly the blood sugar (fasting and post prandial). In severe NIDDM cases, blood sugar (both fasting and post prandial) was only slightly reduced. The changes were not significant. Fenugreek administration did not affect platelet aggregation, fibrinolytic activity and fibrinogen.(29)

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DCBT4567-Astha-15 (Plant based formulation for Bronchial Asthma), salbutamol and sal- butamol + theophylline patients showed statistically significant improvement in FEV 1 , while placebo patients did not show any improvement. Fifty percent of DCBT4567-Astha-15, 48% of salbutamol, 58% of salbutamol + theophylline and 26% of placebo patients showed the desired 15% improvement in FEV 1 . Improved mean FEV 1 values at the end of the trial indicated that the salbutamol - theophylline combination was superior followed by salbutamol and DCBT4567-Astha-15. Clinical symptoms like dyspnoea, wheezing, cough, expectoration,disability, and sleep disturbances were significantly reduced in DCBT4567-Astha-15 patients compared to patients of the other three arms.(30)

Herbs and spices have been used for generations by humans as food and to treat ailments. Scientific evidence is accumulating that many of these herbs and spices do have medicinal properties that alleviate symptoms or prevent disease. A growing body of research has demonstrated that the commonly used herbs and spices such as garlic, black cumin, cloves, cinnamon, thyme, allspices, bay leaves, mustard, and rosemary, possess antimicrobial properties that, in some cases, can be used therapeutically. Other spices, such as saffron, a food colorant; turmeric, a yellow colored spice; tea, either green or black, and flaxseed do contain potent phytochemicals, including carotenoids, curcumins, catechins, lignan respectively, which provide significant protection against cancer. This review discusses recent data on the antimicrobial and chemopreventive activities of some herbs and spices and their ingredients. (31)

Datura contains tropane alkaloids that are sometimes used as a hallucinogen. The active ingredients are atropine, hyoscyamine and scopolamine which are classified as deliriants, or anticholinergics. (32)

Cassia fistula is a deciduous tree with exfoliating bark. The pulp contains sennosides A and B, Rhein and its glucoside, barbaloin, aloin, formic acid, butyric acid, their ethyl esters and oxalic acid. It is a safe purgative given even to pregnant women. The pulp is also given for biliousness and in disorders of the liver. It is applied in gout and rheumatism. It is utilized in blood-poisoning, anthrax and dysentery, also given in leprosy and diabetes and for the removal of abdominal obstructions. It is used in the treatment of varicose veins. It helps in shrinking engorged veins and has a powerful anti-inflammatory effect. (33)

Abhrak (Bhasma Biotite) Abhrak is considered to be a tonic. In combination with iron preparation, it is used in chronic diseases. Prepared from black mica with the juice of various indegenous drugs. Tonic, Alterative, Haematinic and Aphrodisiac. Gives strength to the body.(34) Shringa Bhasma is expectorant and diaphoretic, indicated in bronchitis, pneumonia, tuberculosis, cough and cold widely used by ancient traditional practitioners.(34)

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In so many clinical studies herbs and herbomineral preparations of Ayurveda found useful in different type of Respiratory disorders like Bronchial Asthma. (35-60)

1.2. Hypothesis

Allergic respiratory disorders, in particular asthma are increasing in prevalence, which is a global phenomenon. Even though genetic predisposition is one of the factors in children for the increased prevalence - urbanisation, air pollution and environmental tobacco smoke contribute more significantly. Our hospital based study on 20,000 children under the age of 18 years from 1979,1984,1989,1994 and 1999 in the city of Bangalore showed a prevalence of 9%,10.5%,18.5%, 24.5% and 29.5% respectively. The increased prevalence correlated well with demographic changes of the city. Further to the hospital study, a school survey in 12 schools on 6550 children in the age group of 6 to 15 years was undertaken for prevalence of asthma and children were categorized into three groups depending upon the geographical situation of the school in relation to vehicular traffic and the socioeconomic group of children. Group I-Children from schools of heavy traffic area showed prevalence of 19.34%, Group II-Children from heavy traffic region and low socioeconomic population had 31.14% and Group III-Children from low traffic area school had 11.15% respectively. (P: I & II; II & III <0.001). A continuation of study in rural areas showed 5.7% in children of 6-15 years. The persistent asthma also showed an increase from 20% to 27.5% and persistent severe asthma 4% to 6.5% between 1994-99. Various epidemiological spectra of asthma in children are discussed here. (61)

The concept delineated in the project will be elucidated by scientific insight and investigation. Thus a number of basic concepts may emerge which are academically significant. The broad and in depth study spectrum will raise many problems as well as their solution. Ultimately the results will come out as substantial scientific contributions. It is also envisaged that this project will help the developing countries like India to treat the Asthma at very low cost.

2. STUDY OBJECTIVES

The assessment of Effect of Herbomineral Preparation in patients of Bronchial Asthma. The result of this study will decide long term study on different type of Asthmatic patients.

3. STUDY DESIGN 3.1. Study population

3.1.1. Inclusion Criteria

1. Male or female 18-50 years of age (inclusive).2. Diagnosis of asthma for at least 6 months.3. Morning FEV1 of 40-80% normal.4. Demonstrated reversible airflow restriction.

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5. Non-smokers.6. On moderate doses of ICS with inadequate asthma control.7. Signed ICF

3.1.2. Exclusion Criteria

1. Diagnosis of COPD.2. Uncontrolled systemic illness.3. Hypersensitivity to any component of Investigational Drug.4. Any patient with an unscheduled visit to an ER or hospital for asthma

exacerbation within past 3 months.5. History of hepatitis or active liver disease.6. ALT greater than 3xULN.7. History of HIV infection8. Recent history of drug or alcohol abuse.9. Oral corticosteroids within one month, cromolyn sodium or nedocromil within 14

days, theophylline, LABA, ZYFLO, or leukotriene modifiers, warfarin or propranolol, inhaled anti-cholinergics, or combination LABA/ICS.

10. Omalizumab within 3 months.11. Pregnant female.12. Participation with 30 days in investigational study.

3.2. Study Observations

3.2.1. Screening Visit

A maximum of 7-8 days elapse between screening and the start of treatment. Patients will be randomized and assigned an identification number during the screening visit.

The following procedure will be performed:

1. Patient must sign informed consent form.

2. Physical examination.

3. Collection of blood for cytochemistry, biochemistry and haematology analysis.

4. Record of Vital signs

The following information will be recorded:

1. Demographics including – Date of birth, Gender and race.

2. Height, Weight

3. Primary disease.

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3.2.2. Visit One

Visit one will take place around 30 days after treatment starts.

The following procedure will be performed:

1. Physical examination.

2. Collection of blood for cytochemistry, biochemistry and haematology analysis.

3. Record of Vital signs

The following information will be recorded:

1. Date treatment started

2. Weight

3.2.3. Subsequent three monthly visits

Treatment period continues for twelve months. Patients will be with drawn from the study if they have life threatening problem.

The following procedure will be performed:

1. Physical examination.

2. Collection of blood for cytochemistry, biochemistry and haematology analysis.

3. Record of Vital signs

The following information will be recorded:

1. Treatment regime

2. Weight

4. PATIENT WITHDRAWAL

Patients are withdrawn from the study for any of the following reasons:

1. Completion of study

2. Patient preference

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3. Death

4. Physician discretion

5. TREATMENT ADMINISTERED

5.1. Randomization of Subjects

Patients will be randomized 1:1

1 (Control group) : Standard Life Style1 Treatment Group (Herbomineral Preparation By Divya Pharmacy) fashion and followed for one year.

5.2. Dosage and Administration

5.2.1. Control Group

The Control group will not receive any type of treatment. This group will receive Standard Life Style (SLS)

5.2.1. Treatment Group (Herbomineral Preparation by Divya Pharmacy)

The ingredients is as followes: Each 750 mg Capsule or Tablet contains

Name Botanical/English Name/Reference Qty. (mg.)

Extract ofMadhuyashti Glycyrhiza glabra 220

Kateli Choti Solanum surattenes 110

Kala Vasa Justicia gendarussa 110

Safed Vasa Adhatoda vasica 110

Vanafsa Panchang Viola odorata 110

Desi Tulsi Panchang Ocimum sanctum 110

Choti Peepal Piper peepuloids 110

Dal Chini Cinnamomum zeylanicum 220

Lavang Syzygium aromaticum 220

Saunth Zingiber officinale 110

Dhatura Panchang Datura stramonium 110

Tej Patra Cinnamomum tamala 110

Bharangi Clerodendrum serratum 110

Lisoda Cordia dichotoma 110

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Amaltas Cassia fistula 110

Kakrasringi Pistacia integrrima 110Rudanti Phal Capparis moon 110Akarkara mool Anacyclus pyrethrum 110Powders of

Abhrak Bhasma AFI Page 9 40

Praval Pishti RT Page 177 40

Trikatu Churna Bh.R. 200

Srnga Bhasma ****** 85

Swarn Basant Malti ASS Page 407 17

Godanti Bhasm AFI Page 185 40

Muktasukti Bhasm RT Page 296 40

Laxmi Vilas Ras AFI Page 214 165

Sanjivani Vati RTS Page 189 85

Two tablets will be given to subjects in treatment group before meal at 7.00AM Morning and 6.00PM evening with simple water or should be chewed. The subjects in both group will be on control diet.

6. EFFICACY VARIABLES

6.1. Primary Endpoints

Pulmonary function measures [Time Frame: 3 and 6 months]

(A) Breath holding time – measured by stop watch.

(B) Vital capacity-measured by an instrument called Spirometer.

(C) Peak expiratory flow rate measured with help of Peak flow meter.

6.2. Secondary Endpoints

1. Asthma exacerbations, ACQ, AQLQ, safety [Time Frame: 3 and 6 months]

2. BLOOD : T.L.C. ; D.L.C. ; Hb% ; E.S.R. ; P.P.B.S., URINE : RE / ME , CHEST : X-Ray

7. DATA ANALYSIS METHODS

7.1. Sample Size

A minimum of ********* patients will be recruited to commence the study in order to detect the minimum relevant clinical difference at a statistical power of 80 % and p=0.05.

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7.2. Randomization

Patients will be randomized 1:1

1 (Control group) : Standard Life Style1 Treatment Group (Herbomineral Preparation) fashion and followed for one year.

7.3. General Consideration

As this is a randomized controlled trial, the primary analysis will be an intend-to-treat (ITT) analysis whereby all comparisons will be made on the basis of the treatment group to which patients are initially randomized.

A secondary as-treated analysis will also be performed based solely on those patients deemed to be evaluable throughout the study. This as-treated analysis will directly access the effectiveness of treatment regimes with respect to the primary and secondary outcome variables.

7.4. Statistical Methods

Student‘t’ test and repeated measure ANOVA.

8. DATA COLLECTION

8.1. Demographics

Demographic measure includes age, gender and race.

9. CLINICAL AND LAB PROCEDURES

9.1. Clinical Laboratory Assesments

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10. REFERENCES

1. Zhao J, Takamura M, Yamaoka A, Odajima Y, Iikura Y. Altered eosinophil levels as a result of viral infection in asthma exacerbation in childhood. J Pediatr Allergy Immunol. 2002 Feb;13(1):47–50. PMID 12000498

2. Lilly CM. Diversity of asthma: Evolving concepts of pathophysiology and lessons from genetics. J Allergy Clin Immunol. 2005;115 (4 Suppl):S526-31. PMID 15806035

3. Marketos SG, Ballas CN. Bronchial asthma in the medical literature of Greek antiquity. J Asthma. 1982;19(4):263-9. PMID 6757243

4. Rosner F. Moses Maimonides' treatise on asthma. Thorax. 1981;36:245–251. PMID 7025335

5. McFadden ER, Jr (2004). "Asthma", Harrison's Principles of Internal Medicine (Kasper DL, Fauci AS, Longo DL, et al (eds)), 16th ed., New York: McGraw-Hill, 1508–16. 

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48. Mahadeva, K., H.I. Chandrasekara, D.H. Rajapaksa, K.D. Dharmasena, E. Karunanayake, S. Weerakoon, J. Thilainathan, S. Arunachalam and S. Goonetilleke (1969) - Evaluation of the effect of Ayurvedic drugs in the treatment of bronchial asthma, Ayurveda Pradeepika.

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53. Saily, A., R. Sahu, B. Gupta and S.M. Sondhi (1994) - Analysis for mineral elements of medicinal plants used for the treatment of asthma, syphilis, diarrhoea, skin diseases and rheumatism, Hamdard Medicus 37, 4, 18-22.

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57. Sharma, P.P. and J.M. Sharma (1992) - Therapeutic evaluation of Calotropis spp. in management of bronchial asthma - a clinical study, International Seminar on Traditional Medicine, Calcutta, 7-9th Dec., 1992, 86-87.

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60. Upadhyay, S.D. and N.N. Pandey (1990) - Clinical evaluation of pippali (Piper longum Linn.) kshirpaka in the treatment of bronchial asthma - a preliminary study, =Aryavaidyan 11, 133-136; also in Nagarjun 25, 11, 1982, 250-258.

61. Paramesh H, Epidemiology of asthma in India., Year : 2002 Volume : 69 Issue : 4  Page : 309-12

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