Manjit Saluja

Chikungunya virus aches and pains: An emerging challenge

M, et al. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton Neurosci 2000;85:141–7. 7. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor 7 subunit is an essential regulator of inflammation. Nature 2003;421:384–8. 8. Badger AM, Griswold DE, Kapadia R, Blake S, Swift BA, Hoffman SJ, et al. Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvantinduced arthritis. Arthritis Rheum 2000;43:175–83. 9. Waldburger JM, Boyle DL, Edgar M, Pavlov VA, Tracey KJ, Firestein GS. Regulation of synoviocyte cytokine expression by acetylcholine and the 7 nicotinic receptor. Arthritis Rheum. In press.

Effectiveness of Chloroquine and Inflammatory Cytokine Response in Patients With Early Persistent Musculoskeletal Pain and Arthritis Following Chikungunya Virus Infection

To evaluate whether chloroquine (CQ) is more effective than meloxicam for treating early musculoskeletal pain and arthritis following acute chikungunya (CHIK) virus infection.

Ayurvedic medicine offers a good alternative to glucosamine and celecoxib in the treatment of symptomatic knee osteoarthritis: a randomized, double-blind, controlled equivalence drug trial

OBJECTIVE To demonstrate clinical equivalence between two standardized Ayurveda (India) formulations (SGCG and SGC), glucosamine and celecoxib (NSAID). METHODS Ayurvedic formulations (extracts of Tinospora cordifolia, Zingiber officinale, Emblica officinalis, Boswellia serrata), glucosamine sulphate (2 g daily) and celecoxib (200 mg daily) were evaluated in a randomized, double-blind, parallel-efficacy, four-arm, multicentre equivalence drug trial of 24 weeks duration. A total of 440 eligible patients suffering from symptomatic knee OA were enrolled and monitored as per protocol. Primary efficacy variables were active body weight-bearing pain (visual analogue scale) and modified WOMAC pain and functional difficulty Likert score (for knee and hip); the corresponding a priori equivalence ranges were ±1.5 cm, ±2.5 and ±8.5. RESULTS Differences between the intervention arms for mean changes in primary efficacy variables were within the equivalence range by intent-to-treat and per protocol analysis. Twenty-six patients showed asymptomatic increased serum glutamic pyruvic transaminase (SGPT) with otherwise normal liver function; seven patients (Ayurvedic intervention) were withdrawn and SGPT normalized after stopping the drug. Other adverse events were mild and did not differ by intervention. Overall, 28% of patients withdrew from the study. CONCLUSION In this 6-month controlled study of knee OA, Ayurvedic formulations (especially SGCG) significantly reduced knee pain and improved knee function and were equivalent to glucosamine and celecoxib. The unexpected SGPT rise requires further safety assessment. TRIAL REGISTRATION Clinical Drug Trial Registry-India, www.ctri.nic.in, CTRI/2008/091/000063.

Ayurveda-modern medicine interface: A critical appraisal of studies of Ayurvedic medicines to treat osteoarthritis and rheumatoid arthritis

The potential of Ayurvedic philosophy and medicines needs to be recognized and converted into real life treatment paradigm. This article describes a comprehensive therapeutic approach used in Ayurveda and modern medicine to treat arthritis. We present concise summary of various controlled drug trials carried out by us to validate standardized Ayurvedic drugs using modern medicine protocol to treat Rheumatoid Arthritis and Osteoarthritis knees. Several of the latter are published. The trials consistently demonstrate excellent safety of Ayurvedic medicines but often fail to unequivocally show superior efficacy. Some key findings of a recently unpublished trial in OA knees are also presented to show equivalence between Ayurvedic medicine and celecoxib and glucosamine, and we speculate that equivalence trials may be a way forward. The data from the trials also supports the Ayurvedic ‘Rasayana’ concept of immune-modulation and healing. We need to interpret logic of Ayurveda when, adopting modern science tools in drug development and validation and much research is required. Validation of Ayurvedic medicines using the latter approach may lead to an evidence based Ayurveda – Modern Medicine interface. Also, in pursuit of finding better treatment solutions, we ought to step beyond the realm of only drugs and attempt validation of comprehensive specific treatment package as per classical Ayurveda. Finally, validation of a combined (Ayurveda and modern medicine) therapeutic approach with superior efficacy and safety is likely to be a major leap in overcoming some of the current frustrations to treat difficult disorders like arthritis using only modern medicines.

A Randomized Controlled Exploratory Evaluation of Standardized Ayurvedic Formulations in Symptomatic Osteoarthritis Knees: A Government of India NMITLI Project

The multidisciplinary “New Millennium Indian Technology Leadership Initiative” Arthritis Project was undertaken to validate Ayurvedic medicines. Herbal formulations in popular use were selected by expert consensus and standardized using modern tools. Our clinical strategy evolved from simple exploratory evaluations to better powered statistically designed drug trials. The results of the first drug trial are presented here. Five oral formulations (coded A, B, C, D and E), with a common base of Zingiber officinale and Tinospora cordifolia with a maximum of four plant extracts, were evaluated; with placebo and glucosamine as controls. 245 patients suffering from symptomatic OA knees were randomized into seven arms (35 patients per arm) of a double blind, parallel efficacy, multicentric trial of sixteen weeks duration. The groups matched well at baseline. There were no differences for patient withdrawals (17.5%) or adverse events (AE) of mild nature. Intention-to-treat efficacy analysis, demonstrated no significant differences (P < .05) for pain (weight bearing) and WOMAC questionnaire (knee function); placebo response was high. Based on better pain relief, significant (P < .05) least analgesic consumption and improved knee status, “C” formulation was selected for further development. Controlled exploratory drug trials with multiple treatment arms may be used to economically evaluate several candidate standardized formulations.

Evaluating higher doses of Shunthi - Guduchi formulations for safety in treatment of osteoarthritis knees: A Government of India NMITLI arthritis project

Background: Results of an exploratory trial suggested activity trends of Zingiber officinale-Tinopsora cordifolia (platform combination)-based formulations in the treatment of Osteoarthritis (OA) Knees. These formulations were “platform combination+Withania somnifera+Tribulus terrestris” (formulation B) and “platform combination+Emblica officinale” (formulation C). This paper reports safety of these formulations when used in higher doses (1.5–2 times) along with Sallaki Guggul and Bhallataka Parpati (a Semecarpus anacardium preparation). Materials and Methods: Ninety-two patients with symptomatic OA knees were enrolled in a 6 weeks investigator blind, randomized parallel efficacy 4-arm multicenter drug trial. The 4 arms were (I) formulation B, 2 t.i.d.; (II) formulation B, 2 q.i.d.; (III) platform combination+Sallaki Guggul; (IV) Bhallataka Parpati+formulation C. A detailed enquiry was carried out for adverse events (AE) and drug toxicity as per a priori check list and volunteered information. Laboratory evaluation included detailed hematology and metabolic parameters. Patients were examined at baseline, first and fourth weeks, and on completion. Standard statistical program (SPSS version 12.5) was used for analysis. Results: None of the patients reported serious AE or withdrew due to any drug-related toxicity. Mild gut–related (mostly epigastric burning) AE was reported. A mild increase in liver enzymes [serum glutamic pyruvate transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT)] without any other hepatic abnormality was reported in 2 patients (group IV). Other laboratory parameters remained normal. The mean improvement in active pain visual analog scale (1.4, CI 0.5–2.22), WOMAC (functional activity questionnaire) pain score (1.37, CI 0.22–2.5), and urinary C-TAX (cartilage collagen breakdown product) assay was maximum (NS) in group IV. Lower dose group I showed numerically superior improvement compared with higher dose group II. Conclusion: The results suggested that despite higher doses, standardized Ayurvedic formulations demonstrated a good safety profile. An improved efficacy and likely chondroprotective effect was shown by group IV intervention. A confirmatory drug trial with adequate power and sample size was planned based on the learning from this trial.

Diet, Ayurveda and interface with biomedicine

We thank Dr Kontum for his interesting and useful comments to our paper[1] and further reference to the address by one of the authors (AC) to the recently concluded World Ayurveda Congress 2010 in Bangalore on the subject of ‘Ayurveda Biomedicine Interface’. Kontum has very rightly highlighted the ‘holistic approach’ as a contrast to just focusing on ‘drugs’. Also, he has described a relatively simple method of cooking rice practiced by his family that apparently enriches the health promotion and preventive value. Several such healthy practices advocated by Ayurveda could be included in the daily life style and living in modern times in addition to the one he suggested.

An open label, prospective, clinical study on a polyherbal formulation in osteoarthritis of knee.

Background: Currently, though pharmacological, mechanical, and surgical interventions are used, there is no known cure for osteoarthritis (OA). Objectives: The main aim of the study was to assess the efficacy and safety of “TLPL/AY/03/2008”, a polyherbal formulation on knee joint pain assessed on visual analogue scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Materials and Methods: It was an open label, single center, prospective, clinical study conducted in 36 patients of OA Knee. Two capsules of ‘TLPL/AY/03/2008’ were given to all patients twice daily orally after meals for 180 days. Results: Data describing quantitative measures are expressed as mean ± SD. Comparison of variables representing categorical data was performed using Chi-square test. The mean joint pain (as assessed on VAS) reduced significantly (59.85%; P < 0.05) and the mean WOMAC combined score, WOMAC pain sub-score, WOMAC stiffness sub-score, and WOMAC difficulty sub-score also reduced significantly at the end of the study. The mean time taken by the patients to walk 50 feet too, was reduced significantly (25.26%) at the end of the study. At the end of 4 months of the treatment, no patient needed paracetamol as rescue medicine to control pain. Most of the patients had shown good overall improvement assessed by the physician and by the patients. Majority of the patients showed excellent tolerability to the study drug. No significant change in most of the safety laboratory parameters was observed at the end of the study. Conclusion: The study provides good evidence in support of the efficacy and safety of the ‘TLPL/AY/03/2008’ in OA of knee.

Long term effectiveness of RA-1, a standardized Ayurvedic medicine as a monotherapy and in combination with disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis

Background: Data on long term use of Ayurvedic drugs is sparse. They may prove useful if combined with modern medicine in certain clinical situations (integrative medicine). We present the results of a long term observational study of RA-1 (Ayurvedic drug) used in the treatment of rheumatoid arthritis (RA). Objective The objective was to study safety of long term use of RA-1 for treatment of rheumatoid arthritis (RA). Materials and methods On completion of a 16 week randomized controlled study, 165 consenting volunteer patients were enrolled into a three year open label phase (OLP) study. Patients were symptomatic with persistent active disease and naïve for disease modifying anti-rheumatic drugs (DMARD). 57 patients were on fixed low dose prednisone. Patients were examined every 10–14 weeks in a routine rheumatology practice using standard care norms. They continued RA-1 (Artrex ™, 2 tablets twice daily) throughout the study period and were generally advised to lead a healthy life style. Based on clinical judgment, rheumatologist added DMARD and/or steroids (modified if already in use) to patients with inadequate response; chloroquine and/or methotrexate commonly used. Treatment response was assessed using American College of Rheumatology (ACR) efficacy measures and ACR 20% improvement index standard update statistical software (SAS and SPSS) were used; significant at p < 0.05. Results 158, 130 and 122 patients respectively completed evaluations at 1, 2 and 3 year primary end point. The ACR 20 response (range 34–40%) remained stable over three years (p = 0.33). Patients improved optimum for several measures by one year (p < 0.05) and this was sustained. The use of steroids varied from 42 to 49% patients at yearly end points (mean daily dose 5 mg prednisone); correspondingly the use of DMARD varied from 20 to 34% patients. 40% patients on RA-1 did not require DMARD/steroids for control of disease. 77% patients reported adverse events, albeit mild and mostly gut related, and not causing withdrawal. Several study limitations (especially self-selection) were reduced by the high patient retention and consistency in drug use. Conclusion RA-1 is safe and effective in the long term management of symptomatic active chronic RA. DMARDs and/or steroids can be used judiciously along with RA-1 to treat difficult disease/flares. Further studies are required to evaluate RA-1 in early RA. This paves way for research and application of integrative therapeutic approach in clinical medicine.

Evaluation of the joint distribution at disease presentation of patients with rheumatoid arthritis: a large study across continents

Background Genetic and environmental risk factors for rheumatoid arthritis (RA) are population dependent and may affect disease expression. Therefore, we studied tender and swollen joint involvement in patients newly diagnosed with RA in four countries and performed a subanalysis within countries to assess whether the influence of autoantibody positivity affected disease expression. Methods Patients with symptom duration <2 years fulfilling the American College of Rheumatology/European League Against Rheumatism 2010 RA classification criteria were selected from METEOR (Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology), an international observational database, and the Dutch Leiden Early Arthritis Clinic. Indian (n=947), Mexican (n=141), South African (n=164) and Dutch (n=947) autoantibody-positive and negative patients with RA, matched by symptom duration, were studied for swollen and tender joint distribution. Results Between countries, the reported distribution of swollen joint distribution differed, with more knee synovitis in Mexico, South Africa and India compared with the Netherlands (37%, 36%, 30% and 13%) and more elbow (29%, 23%, 7%, 7%) and shoulder synovitis (21%, 11%, 0%, 1%) in Mexico and South Africa compared with India and the Netherlands. Since the number of autoantibody-negative patients in Mexico and South Africa was limited, Indian and Dutch autoantibody-positive and negative patients with RA were compared. The number of swollen and tender joints was higher in autoantibody-negative patients, but the overall distribution of involved joints was similar. Conclusion Joint involvement at diagnosis does not differ between autoantibody-positive and negative patients with RA in India and the Netherlands. However, joint involvement is reported differently across countries. More research is needed whether these differences are cultural and/or pathogenetic.