Indian Journal of Pharmacology 1992; 24: 98-101.

EFFICACY OF AN AYURVEDIC FORMULATION IN RHEUMATOID ARTHRIT S A DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSS-OVER STUDY

RR. KULKARNI, P.S. PATKI, V.P. JOG, GANDAGE AND B. PATWARDHAN*
Byramjee Jeejeebhoy Medical College and Sasson General Hospital and *Interdisciplinary School of Health Sciences, University of Poona, Pune. Accepted for publication February 12, 1992. Summary The clinical efficacy of an Ayurvedic indigenous formulation containing Withania somnifera, Boswellia serrata, Curcuma longa and zinc, was evaluated in a randomized, double-blind, placebo controlled, cross-over study in 20 patients of rheumatoid arthritis. Treatment with the indigenous formulation for the period of 3 months produced significantly greater relief of pain, decreased morning stiffness, decrease in Ritche articular index and joint score. A significant drop in erythrocyte sedimentation rate was observed in the drug treated patients (P < 0.01). Nine out of 20 patients showed seroconversion at the end of three months treatment with indigenous drug. Radiological assessment, however, did not show any significant changes in both the groups. Side effects observed with this formulation did not necesitate withdrawal of treatment. Rheumatoid arthritis seroconversion ayurvedic medicine clinial trial

Key words

Rheumatoid arthritis is a common disorder with varied clinical signs and symptoms related to multiple anatomical sites, both articular and extra-articular. Presently, the non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay in this condition, however, they have serious adverse effects and have limitationsfora long term therapy.,The immunosuppressive drugs are reserved for selected cases, while the disease modifying drugs like gold-salts are costly and have low benefit risk ratio.4 Hence, there is a need for drugs having good efficacy with low toxic profile in this debilitating disorder. A number of indigenous drugs have been claimed to be effective in the treatment of rheumatic disorder!x5 but their claims have not been largely substantiated in well controlled clinical trials. The formulation under investigation (Articulin-F), is one such preparation which has been prepared on the basis of Indian medicinal system of Ayurveda.The ingredients used in this formulation have been claimed to be effective in rheumatic disorders and the efficacy of these ingredients have been evaluated in both, animal models and clinical trials.7-10 We now report the result of a prospective double blind, placebo controlled trial of this indigenous formulation in the treatment of rheumatoid arthritis.

MATERIALS AND METHODS Patients Twenty patients (14 females, 6 males) attending the Rheumatology Clinic of Sassoon General Hospital with symptoms of rheumatoid arthritis were included in this study. Their mean (SEM) age and duration of illness were 30.4 (1.8) and 2.1 (0.4) years respectively. The inclusion criterias were morning stiffness, joint swelling and tenderness, disability and/or loss of function due to joint deformity, spells of remission and exacerbations with radiological changes and serologically positive rheumatoid arthritis factor. Patients having diabetes mellitus, hypertension, peptic ulcer, renal failure, liver disorders, pregnancy, were excluded from the study. Study Design After informed consent, the patients entered into a double-blind, randomized, cross-over study of treatment with the indigenous formulation or a matching placebo In the dose of 2 capsules 8 hourly after food. Each treatment was given for a period of three months and then after a wash-out period of two weeks the patients were transferred to the other treatment limb for the final three months.

Correspondence: Dr.P.S.Patki, Department of Pharmacology, B.J.Medical College, Pune-411 001.

99 R.R. KULKARNI et al.

Assessment of Patients After entry into the study, the patients were evaluated weekly in a run-in period of one month during which all their previous drug therapies were withdrawn. The patients were evaluated on weekly basis using clinical parameters which included severity of pain (score), morning stiffness, Ritchie articular index, joint score (As described by the American Rheumat$TZAssociation), disability score and grip strength. Erythrocyte sedimentation rate, rheumatoid arthritis factor and radiological examination14 were performed every month. Side effects volunteered by the patients were recorded at each visit and the patients compliance was assessed by asking the patient to return the capsule container and counting the remaining capsules. At the end of the study period, the patients were asked to express their preference for one of the two treatments given. The study protocol was approved by the Ethical Committee of the Sassoon General Hospital and the patients were free to withdraw from the study if they so desired. Additional prescription of NSAlDs were allowed in case of severe pain. Treatment The indigenous formulation based on Ayurvedic medicine was prepared from herbal and mineral materials, composition of which is given in Table 1. Botanical identification and Ayurvedic criteria for desired quality were in accordance with the guidelines of pharmacopoeia1 standards15 and were carried out by a qualified chemist approved by Food and Drug Administration. The mineral origin ingredient Jasad Bhasma was prepared by the traditional method as described in Sharangdhar Samhita by using zinc-ore. The total zinc contents in Jasad-Bhasma were estimated17 before processing it for formulation. All the herbal and mineral ingredients were powdered finely and mixed into desired quantities and hard capsules were prepared in accordance with standard guidelines. Statistical Analysis Analysis was restricted to patients who completed the study. The data obtained was processed on a computer with the help of mini- tab software package of statistical analysis (Minitab Inc, University Park, PA 16802, USA). Differences between treatment groups were compared by Wilcoxon and Students ttest. Data are expressed as Mean SEM

RESULTS Treatment with the indigenous formulation altered clinical and biochemical parameters significantly as compared with placebo (P< 0.01) and produced greater pain relief. A significant reduction in time
Table 1. Composition of Ayurvedic formulation Local name Ashwagandha Sallai Guggul Turmeric Jasad Bhasma Scientific name Withania somnifera Boswellia serrta Curcuma longa Zinc complex Plant part Root Oleo-gum resin Rhizome (Mineral) Weight / Capsule(mg) 450 100 50 50

duration of morning stiffness, joint score, Ritchie articular index, disability score and the erythrocyte sedimentation rate was observed, however the grip strength was significantly increased [Table 2). Onset of significant therapeutic effect started from the end of second week and remained till the end of the
Table 2. Effect of therapy at the end of 3 months Description Severity of pain (score) Morning (minutes) Joint score Ritche articular index Grip strength (mm Hg) Disability score E r y t h r o c y t e sedimentation rate (mm/hr)_ ------------------Mean SEM, P < 0.01
l

Placebo
2.760.09

A y u r v e d i c formulation 1.060.12* 17.572.55* 1.930.28* 4.960.49* 57.593.43* 0.760.16* 20.67 1.64

stiffness

34.20k3.69 4.170.35 8.860.56 33.072.70 2.130.19 35.131.98

therapy. Treatment with indigenous formulation produced seroconversion of rheumatoid arthritis factor in 9 patients at the end of three months period compared to none in the placebo group. The seroconversion achieved during therapy with indigenous

AYURVEDIC FORMULATION IN RHEUMATOID ARTHRITIS 100

formulation did not revert during the placebo period. Radiological assessment did not show any significant change either due to drug or placebo therapy. The drug treatment group had one patient complaining nausea, one had dermatitis and four with pain in abdomen, however, these side effects did not necessitate discontinuation of drug therapy. Patients compliance was satisfactory in both the groups. Out of 20 patients, 18 preferred the indigenous preparation and 2 placebo (P < 0.05). Analysis of data indicated that the residual effect outlasting the drug administration in case of indigenous formulation group did not remain more than two weeks. The drug treatment group had three patients and the placebo group had 18 patients who required NSAlDs to control their pain (P < 0.05). DISCUSSION The present study indicates the clinical and biochemical efficacy of the indigenous formulation in thetreatment of rheumatoid arthritis. This formulation was designed after scrutiny of the evidences given in texts of A rvedic medicine and available research data 5,9, 10,16 Among the contents of this formulation Withania somnifera commonly known as Ashwagandha is considered to be most efficacious.g This agent has anti-inflammatory and analgesic properties contributing to pain relief and decrease in in addition, it is cllrn-n~ inflammatory process; to possess anabolic adoptogenic which could contribute to its beneficial effect. Its immunomodulatory activity could alter the immunopathological processes rapidly and probably this may account for the seroconversion observed in our patients. Roots of this plant has a number of chemical components like steroidal lactones, glycosides and alkaloids, however the component responsible for the pharmacological actions has been claimed to be withanolides. Curcuma longa, commonly known as Turmeric has antiseptic and anti-inflammatory properties. Curcumin, an alkaloid isolated from this plant has

anti-inflammatory, anti-arthritic and anti- rheumatic properties. It also has beneficial effects on platelet aggregation and vascular prostaglandin synthesis. The activation of adrenohypophysial axis may be responsible for inhibition of late arthritic changes. Activated proteases which are responsible for acute inflammatory process are inhibited by the volatile oil of the lant which could add to its anti-arthritic activity. 2830 Boswellia serrata, commonly known as Sallai Guggul contains beta boswellic acid, a pentacyclic triterpene, present in oleo gum-resin of the plant exudate has anti- inflammatory and analgesic activity. Zinc deficiency has been shown to be a consistent finding in rheumatic disorders and its supplementation is claimed to be useful.33334 Jasad Bhasma, a traditional Ayurvedic preparation used in this formulation had about 60% of elemental zinc however data on its bioavailability has yet to be generated. It is possible that a combined action of these ingredients may be producing a synergistic action. The exact mechanism of action can not be commented at this stage, however the present study can be considered as an important step to enter into further research in order to understand more about the pathophysiology and treatment of rheumatoid arthritis. Although, there are no earlier experimental evidences of such seroconversion; Levamisol has been reported to reduce rheumatoid arthritis factor titers.35 Further studies particularly to observe quantitative effect of this drug in the process of seroconversion and also on other parameters like C-Reactive Proteins are required to be carried out. This formulation appears to be quite effective and safe, however, its effect on long term administration, remains to be evaluated in a larger sample group. ACKNOWLEDGEMENTS We thank Dean, BJ Medical College and Sassoon General Hospitals for facilities and to Eisen Pharmaceutical Co. Pvt: Ltd. for the supply of test preparations. Statistical assistance by Dr. M. Rajarshi, Department of Statistics, University of Poona, IS also gratefully acknowledged.

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101 R.R. KULKARNI et al.

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