Divya Mukta Vati

HTN Protocol Version 1.5

Effects of Mukta Vati (A Nobel Herbomineral Preparation of Divya Pharmacy) in Patients With High-Normal to Stage I Hypertension : A

randomized controlled comparative study

Principle Investigator(s):1. Nayak,S.C., BAMS, MSc (Yoga)Consultant Physician & Research Personnel2. Upadhyay,A.K., BAMS, PGD Clinical ResearchClinical Research Scientist

Divya Yog Mandir Trust,(A Recognized R & D Institution by DSIR)

Patanjali Yog Peeth , Delhi-Haridwar National Highway, Near Bahadarabad, Haridwar

RCT Hypertension 1

Divya Mukta Vati

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 two monthly visits

4. PATIENT WITHDRAWAL

5. TREATMENT ADMINISTERED

5.1. Randomization of Subjects5.2. Dosage and Administration

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

6. EFFICACY VARIABLES

RCT Hypertension 2

Divya Mukta Vati

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

9. CLINICAL AND LAB PROCEDURES

9.1. Clinical Laboratory Assesments

10. REFERENCES

11. TABLE. TIME AND EVENT SCHEDULE

RCT Hypertension 3

Divya Mukta Vati

1. INTRODUCTION

1.1. Background

In normal course of blood circulation, the heart received impure blood in its right atrium and sends it to the right ventricle which further sends it to the lungs for purification. The purified blood from the lungs is sent back to the left atrium of the heart which passes it to the left ventricle. Then the blood is distributed to various body organs. Every bit of this blood transport step requires stipulated amount of pressure to carry the blood further. This is called blood pressure.

Due to certain physiological disorders of the lumen of the arteries constrict, their volume also reduces. This creates increased pressure inside the arteries which is then referred to as “Hypertension”. Normally the blood pressure during systole (when the left ventricle contracts) should be not more than 120 to 130 mm / Hg. During Diastole (when the left ventricle relaxes) the pressure should be about 80 to 85 mm / Hg. When these values remain elevated for a considerable amount of time, the person is said to be “Hypertensive”. High B.P. may have an hormonal cause among other causes leading to disruption of renin – angiotensin – aldosterone actions, high B.P. may also be as a result of renal disorders. The so called essential hypertension does not show definite correlation to any factor as yet.

Hypertension places patients at high risk for target organ damage including, retina, brain, heart, kidneys etc.

The BP is not same everywhere; it is maximum close to heart from where the blood comes out and lowest where blood comes in to the heart. So always the BP is measured on the hands. There are 2 types of pressures, systolic and diastolic. Systolic Pressure is higher and indicates the contraction of heart and diastolic is when heart expands. The BP in healthy person is 120 mm / 80 mm, that is systolic 120mm and diastolic is 80mm. If

RCT Hypertension 4

Divya Mukta Vati

the BP is greater or less by 15 mm to 20 mm than the normal range, it is considered as disease.

There are various reasons for this high BP. Sometimes because of improper functioning of kidneys, heart related problems or diabetes BP can go high, so if these diseases are treated then BP also comes to normal. But in 80 % of the cases there is no apparent reason, and then it is called "Essential Hypertension".The reason for this High BP is cannot be found on physical plane but can be traced to mental activities. High mental strain results in high BP. Modern medical science treats the BP but not the underlying reason that is mental strain. When you take medicines, the BP comes to normal for sometime but when the effect of the medicines is over, the BP again rises. So the best remedy is to remove all underlying reasons for mental stress and strain.

MuktaVati is a unique herbal remedy for hypertension containing ayurvedic time-tested herbs known to help patients with high blood pressure, anxiety and insomnia. When added to an individual's diet, MuktaVati acts extremely fast and it is not uncommon to see results within 2-3 days. Muktavati provides fast effective treatment to relieve all symptoms of high blood pressure like sleeplessness, anxiety, restless legs syndrome, anxiety etc. A completely natural, safe fast acting and supremely effective hypertension remedy.

According to Ayurveda, which terms this disorder as `rakta vata', it is due to disturbance in one of the three doshas, vata. Instability in vata leads to problems such as metabolic and circulatory diseases, depression and emotional problems, and illnesses related to the stresses and strains and tension in the mind. One of these illnesses is hypertension.

Mukta Vati is made up of various herbs and minerals having potent anti stress, anti hypertensive and rejuvenating properties.

Brahmi (Centella Asiatica) : Brahmi has been traditionally used for nervous disorders, epilepsy, senility, premature aging, hair loss, obstinate skin conditions and venereal diseases. It is considered the primary Ayurvedic nerve and cardiac tonic. It pacifies high vata or pitta. Brahmi relieves mental fatigue, brings undisturbed sleep and treats convulsions. Scientific research suggests that Brahmi (Centella asiatica) improves memory, mental functions and reduces learning time. (1,2) Several other clinical studies have further confirmed the efficacy of Brahmi (Centella asiatica) extract in venous insufficiency (3).

Ashwagandha (Withania Somnifera) : Ashwagandha is highly valued for its restorative action on the functioning of nervous system and counteracting high blood pressure. It corrects loss of memory arising out of long term stress, illness and overwork. Restores vitality in those suffering from overwork and nervous exhaustion. In fact having the ability to nurture the nervous system, counteract anxiety and stress to promote a calm state of mind, the same Ashvagandha having powerful anti-inflammatory properties, is specific for treating arthritic and rheumatic conditions.(4)

RCT Hypertension 5

Divya Mukta Vati

Shankhapushpi (Convolvulus pluricaulis L.) : Popularly known to treat sleep disorders - stress and anxiety, Shankapushpi is quoted in Charaka to be the single greatest herb for enhancing all three aspects of mind power -- learning (Dhi), memory (Driti), and recall (Smriti). Thus it is called the greatest Medhya Rasayana (that which enhances the mind). It helps the quality of sleep by improving mind-body coordination. Shankapushpi is also very beneficial for the nervous system, enhancing the quality of bone marrow and nerve tissue (Majja Dhatu).(5)

Vacha (Acorus Calamus) : Acorus calamus is a semi-aquatic herb with creeping rhizomes traditionally used for treating high blood pressure. The rhizomes are considered to possess anti-spasmodic, carminative and anthelmentic properties. In Ayurveda, they are used for the treatment of epilepsy, chronic diarrhoea and dysentery, bronchial catarrh, fever, glandular and abdominal tumours, kidney and liver complaints, rheumatism and eczema. It has also been used in Ayurveda to improve memory retention and recall. A combination of B. monnier i(Brahmi) and A. calamus significantly increases memory and controls hyperactivity in children.(6)

Jyotishmati (Celastrus Paniculatus) : In India this is a well known woody climbing vine and grows almost all over India, especially in the hilly areas. Seeds are also used to increase memory and are used in loss of appetite, fever and rheumatism. Ayurvedic practitioners have used Jyotishmati widely in psychosomatic disorders. It activates healthier functioning of brain and also strengthens a persons ability to endure stress whether emotional or physical. It has been reported to show a relaxing effect on the central nervous system resulting in a significant reduction in anxiety and nervous tension.(7)

Guduchi (Tinospora Cordifolia) : Guduchi is both a tonic and powerful immuno-modulator. It is regarded as a blood purifier and liver protector and is considered very helpful and effective in eye disorders whilst supporting the mental actions of the above elements.(8)

Red Clover Powder (Trifolium Pratense) : An effective astringent, nervine tonic, antacid, diuretic and cardio-tonic. It is also used as a nervine tonic in headache, giddiness and vertigo. Can be used as heart tonic also.(8.1)

Pearl Powder (Mukta Pishti) : Pearl is a very special compound for hypertension treatment. Powdered Pearl is used as a Shen tonic to stabilize the emotions, allay fright, ease frustration and anger, brighten the eyes and help regenerate tissue.(8.2)

Brahmi (Centella asiatica) is effective in the treatment of venous insufficiency and has been shown to reduce ankle oedema, foot swelling and capillary filtration rate, and to improve microcirculatory parameters (9-11).

A randomised, placebo-controlled, double-blind multi-centre trial investigated the effect of a Brahmi (Centella asiatica) extract (60 mg or 120 mg/day for 2 months) in 94 patients with venous insufficiency (12).

RCT Hypertension 6

Divya Mukta Vati

Significant and dose-dependant improvements in subjective and plethysmographic (extremity volume) parameters were seen with both dosages of Brahmi (Centella asiatica) treatment.

Another double-blind study with 40 patients suffering chronic venous insufficiency found that Brahmi (Centella asiatica) extract (60 mg/day for 30 days) significantly improved ankle circumference, vascular tone and leg volume compared with baseline (13).

The valuable contribution of Brahmi (Centella asiatica) extract in the treatment of venous hypertension has been confirmed in randomised, double-blind controlled trials.

In one trial, 62 patients with venous hypertension took Brahmi (Centella asiatica) extract (90 mg or 180 mg daily) or placebo (11) . A dose-dependant reduction in capillary filtration rate and ankle circumference was seen at the end of the 4-week study period, and changes were significant compared with placebo.

Another study involving 87 patients with chronic venous hypertensive microangiopathy found that microcirculatory parameters were significantly improved compared with placebo in patients taking Brahmi (Centella asiatica) extract (60 mg or 120 mg daily) after 60 days (14).

The ability of Brahmi (Centella asiatica) extract to reduce capillary permeability in patients with venous hypertension has also been demonstrated in a placebo-controlled study (10).

The neuroprotective potential of ethanol:water (1:1) extract of rhizomes of Acorus calamus (AC-002) has been investigated in middle cerebral artery occlusion (MCAO)-induced ischaemia in rats. A significant behavioural impairment in Rota-Rod performance and grid walking was observed in rats, 72 hours after MCAO as compared to sham-operated animals. These rats also exhibited an increase in lipid peroxidation (cortex -157%, corpus striatum - 58%) and a decrease in glutathione levels (cortex - 59%, corpus striatum - 34%) and superoxide dismutase (SOD) activity (cortex - 64%, corpus striatum - 32%) as compared to sham-operated animals. Ischaemic rats treated with AC-002 (25 mg/kg, p.o.) exhibited a significant improvement in neurobehavioural performance viz. Rota-Rod performance and grid walking as compared to the MCAO group. Interestingly, treatment with AC-002 in MCAO rats significantly decreased malonaldialdehyde levels in cortex as compared to ischaemic rats. A significant increase in reduced glutathione levels and SOD activity was also observed both in cortex and corpus striatum in MCAO rats treated with AC-002 in comparison to MCAO rats. Treatment with AC-002 in MCAO rats also reduced the contralateral cortical infarct area (19%) as compared to MCAO rats (33%). Neurological function score was improved in the AC-002-treated rats as compared to the MCAO group. The results of the present study indicate the neuroprotective efficacy of A. calamus in the rat model of ischaemia. (15)

RCT Hypertension 7

Divya Mukta Vati

The effect of Withania somnifera extract on arterial blood pressure in normotensive pentobarbital anaesthetized dogs was studied. Also a possible effect of Withania somnifera on blood pressure in dogs administered either with adrenaline and acetylcholine was investigated. Thirty mongrel dogs of both sexes were distributed randomly in three series of ten animals each. Each animal was adminstered at intervals of 4 min with either a neurotransmitter, saline or the extract until a cycle of 32 minutes was completed. It is concluded that the Withania somnifera extract induced a significant decrease (p < 0.05) in the arterial and diastolic blood pressure in normotensive pentobarbital anaesthetized dogs. Withania also significantly prevented the hypotensive effect of acetyltholine and increased the hypertensive effect of adrenaline. (16)

Several Studies indicate ashwagandha possesses anti-inflammatory, antitumor, antistress, antioxidant, immunomodulatory, hemopoetic, and rejuvenating properties. It also appears to exert a positive influence on the endocrine, cardiopulmonary, and central nervous systems. The mechanisms of action for these properties are not fully understood. Toxicity studies reveal that ashwagandha appears to be a safe compound. (17)

To evaluate the antistress effect of WS, an alcohol extract from defatted seeds of WS dissolved in normal saline was given (100 mg/ kg intraperitoneally as a single dose) to 20-25 g mice in a swimming performance test in water at 28 [degrees]-30 [degrees] C.(18) Controls were given saline. The extracts approximately doubled the swimming time when compared to controls. In another study, WS prevented both a weight increase of the adrenals and a reduction in ascorbic acid content of the adrenals normally caused by this swimming test. The authors suggested that WS induced a state of nonspecific increased resistance during stress.

Glycosides of WS (sitoindosides VII and VIII, 50 to 100 mg/kg) exhibited significant antistress activity in forced swimming-induced immobility in mice, restraint stress-induced gastric ulcers in rats, restraint-induced auto-analgesia in rats, restraint stress effect on thermic response of morphine in rats, and morphine-induced toxicity in aggregated mice. (19) The alcohol extract of WS (100 mg/kg, twice daily orally on day 1, 4 or 7) reduced stress-induced increases in blood urea nitrogen levels, blood lactic acid, and adrenal hypertrophy, but did not affect changes in thymus weight and hyperglycemia in rats. (20) WS reversed the cold swimming-induced increases in plasma corticosterone, phagocytic index, and avidity index to control levels. WS root powder (100 mg/kg orally as an aqueous suspension daily for seven days) given before the swimming test in water at 10 [degrees] C also increased total swimming time, indicating better stress tolerance in rats.(21) These results indicated a significant increase in plasma corticosterone level, phagocytic index, and avidity index in control rats, whereas these levels were near normal in WS rats subjected to the same test.

In a comparative study for antistress activity, finely powdered roots of WS and Panax ginseng (PG), suspended in 2-percent acacia (100 mg/kg in 1.00 mL orally) were given to 18-20 g mice daily for seven days; the swimming test was given on day 8.(22) Significant antistress activity, as measured by the swimming endurance test, was found for both compounds. The swimming time was 536.6 minutes for PG, 474.1 minutes for WS, and

RCT Hypertension 8

Divya Mukta Vati

163.3 minutes for controls; all differences between groups were significant (p [is less than] 0.05). Anabolic activity, measured as an increase in body weight, was significant for both herbal extracts but was better in the WS group than in the PG group. If these results could be reproduced in humans, it would support the use of WS in nervous exhaustion due to stress and in cachexia to increase body weight.

The chloroform fraction of the total ethanolic extract of Convolvulus pluricaulis elicited a significant antidepressant-like effect in mice by interaction with the adrenergic, dopaminergic, and serotonergic systems. (23)

In a study a herbomineral compound like Mukta Vati, acclaimed for its action of down-grading β-receptors and protecting the heart against sympathetic outbursts, was tried in 22 cases of mild to moderate hypertension, of whom 8 had associated anxiety neurosis (36.36 per cent). Sixteen patients (72.7 per cent) were taking some antihypertensive agents irregularly and hence their blood pressure was not controlled, whereas 6 cases (27.27 per cent) were not taking any antihypertensive agent. After herbomineral compound, 19 cases (86.36 per cent) did not require any other drug except herbomineral compound, whereas 3 cases (13.63 per cent) required the addition of other antihypertensive agents as these had high diastolic pressures, i.e. above 120 mm Hg. herbomineral compound also produced a fall in the pulse rate. The mean value fell from 90.45 ± 9.54 to 76.27 ± 5.95/mt after herbomineral compound, which is statistically significant.

The mean systolic blood pressure before herbomineral compound was 153 ± 11.133 mm Hg which fell to 130 ± 9.3 mm Hg after 6 weeks of herbomineral compound therapy. This systolic fall is statistically significant (p<0.01). Similarly there was a fall in mean diastolic blood pressure from 104 ± 8.8 to 88 ± 6.41 mm Hg after 6 weeks of herbomineral compound, which is also highly significant (p<0.01). However, 3 cases (13.6 per cent) with initial diastolic pressures above 120 mm Hg, continued to have diastolic pressure in the range of 94 to 100 mm Hg. (24)

The effect of a herbomineral compound and propranolol on left ventricular hypertrophy in hypertensive individuals was studied by echocardiography. The study showed an improvement in cardiac function as indicated by an increase in ejection fraction and fractional shortening in both the Abana- and propranolol-treated groups.(25)

The plant Onosma Bracteatum is alterative, demulcent, refrigerant and tonic. A decoction is used in the treatment of rheumatism, syphilis and leprosy. The plant is considered to be useful in relieving excessive thirst and restlessness in febrile excitement, and also to be useful in relieving functional palpitation of the heart, irritation of the bladder and stomach, and strangury (26).

1.2. Hypothesis

Hypertension and diabetes mellitus are prevalent disorders of middle class population. Hypertension is the major silent killer of mankind. The herbal formulation used in this

RCT Hypertension 9

Divya Mukta Vati

project certainly helps to control and cure the hypertension. There are many drugs in different pathies but it is quite effective and less toxic in comparison to other drug. The entire work of this project is designed in such way that it will cover all the aspects of the process i.e., chemical, botanical, microbiological, pharmacological screening as well as clinical trial. Special attention will be given on the evaluation of modern technique i.e., quality and quantity assurance at each step of the process.

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 hypertension at very low cost.

2. STUDY OBJECTIVES

The assessment of Effect of Mukta vati in patients of High-Normal to Stage I hypertension especially cardiovascular effects. The result of this study will decide long term study on different type of Hypertensive patients.

3. STUDY DESIGN 3.1. Study population

3.1.1. Inclusion Criteria

1. Subjects must be willing to and have the capacity for giving written informed consent.

2. between the ages of 18 and 70

3. BP criteria: SBP of > 130 but < 160 mm Hg and DBP < 100 mmHg

4. All subjects must be willing to comply with all study-related procedures

3.1.2. Exclusion Criteria

1. Females subjects who are pregnant or post partum < 3 months

2. Subjects currently taking blood pressure lowering medications or dietary supplements (magnesium, potassium, calcium>1200 mg/day, fish oils > 2000 mg/day, ephedra, hawthorn, forskolin)

4. Non-dominant arm circumference > 40.0 or50 cm

5. Subjects with BMI < 18.5 kg/m2

RCT Hypertension 10

Divya Mukta Vati

6. Subjects who have received an experimental drug, used an experimental medical device within 30 days prior to screening, or who gave a blood donation of greater that or equal to one pint within 8 weeks prior to screening.

7. Subjects with diabetes mellitus

8. Subjects with established cardiovascular disease

9. Subjects with known arrthymias such as atrial flutter or fibrillation or those with cardiac pacemakers

10. Current users (within the previous 30 days) of any tobacco products

11. History of renal insufficiency based on estimated glomerular filtration rate < 60 ml/min

12. Women who consume > 10 alcoholic drinks per week and men who consume > 15 drinks per week.

13. Subjects with known autonomic neuropathy (e.g: Shy-Drager, orthostatic hypotension)

14. Subjects with known secondary causes of hypertension (renal artery stenosis, pheochromocytoma, coarctation of aorta, hyperaldosteronemia)

15. Regular use of benzodiazepines, anti-psychotic drugs or corticosteroids (> 1x per month). Stable doses (3 months) of antidepressants (SSRIs or TCAs) will be allowed.

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:

RCT Hypertension 11

Divya Mukta Vati

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

2. Height, Weight

3. Primary disease.

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 two 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

RCT Hypertension 12

Divya Mukta Vati

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

1. Completion of study

2. Patient preference

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 (Mukta Vati) 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 (Mukta Vati)

The ingredients in Mukta vati is as followes: Each 300 mg Tablet contains

Name Botanical/English Name Qty. (mg.)Extract of

1 Brahmi Centella asiatica >>>>46mg EachUgragandha Acorus calamus --Ashwagandha Withania somnifera --Shankhpushpi Convolvulus pluricaulis --Jyotishmati Celastrus paniculatus >>>>19mgGajwan Onosma bracteatum >>>>69mgGiloy Tinospora cordifolia >>>>20mgPowders of

RCT Hypertension 13

Divya Mukta Vati

2 Praval Pishti >>>>6.0mgMukta Pishti >>>>2.0mgProcessed with Fresh juices of

3 Giloy Tinospora cordifolia qs.Brahmi Centella asiatica qs.Shankhpushpi Convolvulus pluricaulis qs.

Two tablets of Mukta Vati 300mg 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

Average systolic blood pressure (SBP) as measured by 24 hour ambulatory blood pressure monitoring (ABPM) before treatment, after eight weeks of treatment and after 16 weeks of treatment.

6.2. Secondary Endpoints Mean daytime SBP and DBP derived from 24 hour ABPM Nocturnal BP suppression as measured by ABPM Clinic blood pressure and pulse pressure Durability of any blood pressure effects 4 weeks after the termination of the

intervention ECG for LV Hypertrophy and evidence of IHD, LV systolic & diastolic function. Heart rate variability as measured by 24 hour Holter monitoring Psychological measures of mood, stress and QOL using: POMS, PSS-10, Cook-

Medley and SF-36 questionnaires. Physiologic markers of stress using 24 hour urinary cortisol and catecholamines.

Urinalysis - Proteinuria >200 mg/day & hematuria.

7. DATA ANALYSIS METHODS

7.1. Sample Size

A minimum of 60 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. 7.2. Randomization

Patients will be randomized 1:1

1 (Control group) : Standard Life Style

RCT Hypertension 14

Divya Mukta Vati

1 Treatment Group (Mukta Vati) 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

RCT Hypertension 15

Divya Mukta Vati

10. REFERENCES

1. Prof. P.V. Sharma, Dravya Guna Vigyan, Chapter 1, Medhyadi Varga Page 2-6.

2. Acharya Sushruta, Sushruta Samhita, Sutra Sthan Chapter 46, Chikitsa Sthan Chapter 28.

3. Brinkhaus B et al. Centella asiatica in traditional and modern phytomedicine - A pharmacological and clinical profile -Part II: Pharmacological and therapeutical profile, conclusions. Perfusion 1998; 11:508-20.

4. Wealth of .India (Raw Materials) C.S.I.R. Volune-X,581-585, Prof. P.V. Sharma, Dravya Guna Vigyan, Chapter 9, Jwaradhnadi Varga Page 762-765. C.K.Atal, Phytochemistry and Pharmacognosy of Withania somnifera (Linn.) (Ashwagandha) CCRIM & H, Monograph, New Delhi 1975.

5. Prof. P.V. Sharma, Dravya Guna Vigyan, Chapter 1, Medhyadi Varga Page 9-11.

6. Medicinal Plants of India Volume -1 , I.C.M.R. New Delhi (1976) Page 18-22 Prof. P.V. Sharma, Dravya Guna Vigyan, Chapter 1, Medhyadi Varga Page 28-31.

7. Jogleker G.V. et al. JRIM (Journal of Research in Indian Medicine) Volume I, Issue 2,Page 190-195, (1966)

8. Wealth of .India (Raw Materials) C.S.I.R. Volune-X,251-252, B.B.O.(Haine's Botany of Bihar & Orissa) Volume I, Page 18,19., Botanical Survey of India, Calcutta (1961)

8.1. Ayurvedic Formulary of India (AFI) Volume I, Group No 17, PISHTI Page 223-224 Ayurveda Sara Samgraha Sodhan Maran Prakaran Page-119

8.2. Ayurvedic Formulary of India (AFI) Volume I, Group No 17, PISHTI Page 224 Ayurveda Sara Samgraha Sodhan Maran Prakaran Page-145

9. Cesarone MR et al. [Activity of Centella asiatica in venous insufficiency]. Minerva Cardioangiologica 1992; 40:137-43.

RCT Hypertension 16

Divya Mukta Vati

10. Belcaro GV et al. Improvement of capillary permeability in patients with venous hypertension after treatment with TTFCA. Angiology 1990; 41:533-40.

11. Belcaro GV et al. Capillary filtration and ankle edema in patients with venous hypertension treated with TTFCA. Angiology 1990; 41:12-8. 12. Pointel JP et al. Titrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology 1987; 38:46-50.

13. Monteverde A et al. Comparison between extract of Centella asiatica and O-(b-Hydroxyethyl) rutoside in the treatment of venous insufficiency of the lower limbs. Acta Therapeutica 1987; 13:629-36.

14. Cesarone MR et al. [The microcirculatory activity of Centella asiatica in venous insufficiency. A double-blind study]. Minerva Cardioangiologica 1994; 42:299-304.

15. Shukla PK, Khanna VK, Ali MM, Maurya R, Khan MY, Srimal RC Neuroprotective effect of Acorus calamus against middle cerebral artery occlusion-induced ischaemia in rat. Hum Exp Toxicol. 2006 Apr;25(4):187-94. Industrial Toxicology Research Centre, PO Box 80, M.G. Marg, Lucknow 226001, India.

16. F. Ahumada , F. Aspee , G. Wikman , J. Hancke, Withania somnifera extract. Its effect on arterial blood pressure in anaesthetized dogs, Phytotherapy Research, Volume 5, Issue 3 Pages 111 – 114.

17. Lakshmi-Chandra Mishra, Scientific Basis for the Therapeutic Use of Withania somnifera : A Review – Ashwagandha (Altern Med Rev 2000;5(4) 334-346)

18. Singh N, Nath R, Lata A, et al. Withania somnifera (ashwagandha), a rejuvenating herbal drug which enhances survival during stress (an adaptogen). Int J Crude Drug Res 1982;20:29-35.

19. Bhattacharya SK, Goel RK, Kaur R, Ghosal S. Antistress activity of sitoindosides VII and VIII, new acylsterylglucosides from Withania somnifera. Phytotherapy Res 1987;1:32-39.

20. Dadkar VN, Ranadive NU, Dhar HL. Evaluation of antistress (adaptogen) activity of Withania somnifera (Ashwagandha). Ind J Clin Biochem 1987,2:101-108.

21. Archana R, Namasivayan A. Antistressor effect of Withania somnifera. J Ethnopharmacol 1999;64:91-93.

RCT Hypertension 17

Divya Mukta Vati

22. Grandhi A, Mujumdar AM, Patwardhan B. A comparative pharmacological investigation of Ashwagandha and Ginseng. J Ethnopharmacol 1994;44:131-135.

23. Dhingra D, Valecha R. Evaluation of the antidepressant-like activity of Convolvulus pluricaulischoisy in the mouse forced swim and tail suspension tests. Med Sci Monit. 2007 Jul;13(7):BR155-161.

24. Salkar, R.G., Mrs. Salkar, H.R., Deshmukh, P.Y., Role of Abana in Hypertension, Department of Medicine, Government Medical College, Nagpur, India. [Antiseptic (1987): 12, 719]

25. Radha Yegnanarayan , S. A. Sangle, S. S. Sirsikar, D. K. Mitra, Regression of cardiac hypertrophy in hypertensive patients - comparison of Abana with propranolol, Phytotherapy Research Volume 11, Issue 3 , Pages 257 – 259

26. Chopra. R. N., Nayar. S. L. and Chopra. I. C. Glossary of Indian Medicinal Plants (Including the Supplement). Council of Scientific and Industrial Research, New Delhi. 1986

RCT Hypertension 18