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Phase I tolerability study of Yogaraj-guggulu--a popular ayurvedic drug.
Yogaraj-guggulu is a widely used Ayurvedic formulation. In a retrospective study for the frequency of, usage, Yogaraj-guggulu ranked first in the hospital practice and second in the private practice.[1] This formulation is used in conditions like arthritis, myalgia and hyperlipidemia. It has been shown to have significant anti-inflammatory activity in formaldehyde-induced arthritis and in croton oil granuloma.[4] Guggulu, the resinous material of Commiphora mukul, the largest single ingredient of Yogaraj-guggulu has been mentioned to be useful in disorders of lipid metabolism in Ayurvedic literature 600 B.C.[8] Hypolipidemic activity of Guggulu has been shown by various workers;[5],[6],[9] However, guggulu as a single drug is rarely used in practice. Yogaraj-guggulu is the commonly used formulation. A large dose of 12 gm/day has been prescribed in ancient Ayurvedic texts.[7] Smaller doses from 3 to 5 gm/day are usual in the present day practice. It was therefore of interest to study the tolerability of large doses of Yogaraj-guggulu in healthy human volunteers. The results of the Phase 1 study are presented in this paper.
Subjects Eight male students volunteered for the Phase 1 study. They were divided into four groups of two each for different dose schedules. A careful history, thorough physical examination and laboratory investigations were carried out to exclude any systemic disease. The age of the volunteers ranged from 22 to 28 years. The body weight ranged from 45 to 63 kg. Tolerability profile Tolerability was monitored by recording baseline symptoms. The checklist covered 22 symptoms and two blanks. The grading of the severity of symptoms was done as Absent = 0, Mild = 1, Moderate = 2, Severe = 3. Positive signs were recorded under each system. The examination and recording was done on -1 day and 0 day basally and on the 2nd and 7th days after the drug. Pulse rate, and systolic and diastolic blood pressures in supine and upright positions were recorded twice a day from -1 day upto 7 days. Weight was recorded initially and on the 7th day. The organ function tolerability was monitored basally and at the end of the treatment by laboratory investigations which included the estimation of haemoglobin, red cell count, total and differential leucocyte count, erythrocyte sedimentation rate, serum proteins, serum enzymes (transaminases and alkaline phosphatase), total and direct serum bilirubin, serum cholesterol, blood urea, fasting blood sugar, serum electrolytes (sodium, potassium and chloride), routine urine analysis and stool examination. Electrocardiogram for standard and chest leads was taken before and after the treatment. Side effects if any were carefully watched and recorded. Drug A batch of Yogaraj-guggulu was specially prepared by Dhootapapeshwar Limited, Panvel. Formula of Yogaraj-guggulu modified by Dhootapapeshwar contains 39.87% plant material (24 plants), 39.87% guggulu and 20.24% inorganic material in the form of Loha Bhasma and Mandoora Bhasma. It was constituted in the form of a tablet of 250 mg each. Disintegration time of the tablet was 20 minutes. Four dose schedules were studied: 4 tablets x 3, 6 tablets x 3, 8 tablets x 3 and 12 tablets x 3 for one week. The dose of the formulation calculated as mg/kg and mg/m2 of body surface is showy. in Figure 1. No other drug was allowed during the period of trial. No stringent dietary restrictions were observed.
The general tolerability of Yogaraj-guggulu was good in volunteers even at the dose of 9 gm per day. [Table - 1] shows the details of volunteers, total dose per day and clinical tolerability of the formulation. Fourteen baseline symptoms were present initially; four symptoms-anorexia, joint pain, drowsiness and headache were absent on the second day of the treatment. Total score of each of the ten baseline symptoms initially and on the 2nd and 7th days is shown in [Table - 2]. No aggravation of baseline symptoms was seen in any volunteer. Three volunteers reported diarrhoea. One volunteer (RSG) had five motions only on the fourth day of the therapy. He was on a dose of 4.5 gm/day. His stools showed ova of Trichuris trichiura. Another volunteer (SRT) had mild diarrhoea for three days. Ova of T. saginatta were detected in his stool examination basally. He received a dose of 9 gm/day of Yogaraj-guggulu. Third volunteer (ASB) passed two to three semi-solid motions almost throughout the trial period. Diarrhoea was controlled on the day following the trial. A dose of 4.5 gm/day was administered to him. Stomatitis was developed on the second day after drug administration in one volunteer. Significant relief in stomatitis was observed on the fifth day though the drug was continued. The subject had history of recurrent stomatitis in the past. Mild constipation was reported by one subject. The volunteer CVP developed pruritus and patchy maculo-papular rash on the hands and feet on the fifth day of the treatment. Drug was discontinued. The lesions disappeared within 36 hours. In the same volunteer, a rechallange with an identical dose did not result in rash. The volunteer had a past history of urticaria of unknown etiology. The basal mean values of blood pressure and pulse rate in supine and upright positions did not show any change. The weight did not show any significant change. ECG showed an increase in the amplitude of T-wave in three volunteers. Such a change in T-wave was considered to be non-specific. Mild increase in the mean leucocyte count from basal 6787 ± 513.22 (S.E.) to post-therapy 7012 ± 443.49 (S.E.) is within normal limits and statistically insignificant. The mean basal S.G.P.T. was 14.37 ± 2.75 (S.E.) which increased to 22.60 ± 2.20 (S.E.) after treatment. The change is within normal limits. No significant change was observed in any other investigation.
There is a general consensus that Ayurvedic drugs are well tolerated and side effects if any are mild. We observed burning sensation of eyes, palms and soles in 21 out of 111 patients of acute viral hepatitis treated with Trikatu-a mixture of powder of Zingibar officinale, Piper longum and Piper nigrum in a dose of 2 gm T.D.S.[2] No severe side effects have been observed with Yogaraj-guggulu during the clinical practice for the last twenty-five years, however, systematic Phase 1 study with this drug is carried out for the first time. General tolerability of Yogaraj-guggulu in volunteers was good. Out of three volunteers who developed diarrhoea, one had ova of Trichuris trichiura and another had ova of tape worm. A possibility of irritating the intestinal parasites by Yogaraj-guggulu could not be ruled out. Third volunteer had mild diarrhoea throughout the period of study and was controlled after the discontinuation of the drug. Iron intolerance may be responsible for diarrhoea in this volunteer. One subject developed rash and pruritus after Yogaraj-guggulu. However a rechallange did not reproduce the symptoms; as the subject also gave a past history of urticaria, it was probably a non drug phenomenon. Eight different formulations of Yogaraj-guggulu are cited in Ayurvedic literature.[7] This number further increases by the arbitrary modification of the formulation by manufacturers. [Table - 3] shows the number of plants, the percentage of guggulu and inorganic ingredients in each formulation. Maximum number of plants in a formulation is 53 and minimum is 14. Percentage of guggulu is 50 in seven formulations; only one formulation contains 25.86% of guggulu. Percentage of inorganic ingredients like Loha Bhasma, Mandoor Bhasma, Abhraka Bhasma etc. also is 48.27 in this formulation. Tolerability of the formulation with variable ingredients may not be similar. Yogaraj-guggulu is marketed in the form of tablets or pills weighing from 100 to 500 mg. Disintegration time of several market preparations varies from 20 to over 140 minutes.[3] Such variable dosage form may also affect the tolerability. Manufacturing processes, the ingredients and dosage form need to be standardised for a rational evaluation of safety of Ayurvedic drugs.
We thank Dr. K. N. Mehta, Dean, M. A. Podar Ayurvedic Hospital for clinical facilities and for permitting us to publish the paper. We are also thankful to Dhootapapeshwar Limited for the supply of Yogaraj-guggulu. Authors are also grateful to Shree Taher and Shree Relekar for their technical assistance.
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