Arthrella Tablets

Clinical Study Study Clinical Ajay Chandanwale* VY Deshpande** Deepak Langade† Efficacy, Disease-Modifying Effect and Safety of Arthrella Tablets v/s Diclofenac in the Management of Rheumatoid Arthritis: A Randomized, Comparative, Double Blind Study Abstract Plant-based formulations provide a unique Rheumatoid arthritis (RA), an modality of treatment of rheumatoid arthritis as autoimmune disease of complex they are safe and have a disease-modifying action. etiology, is an ailment that Arthrella tablets can be used for reducing the pain inflicts considerable physical, and inflammation of rheumatoid arthritis. psychological and economic burden on the patients and care- they are safe and have a disease- Arthrella group, while it was providers. Progress of the disease, modifying action. The present 4.65 in patients in the diclofenac coupled with inadequate control study was conducted to evaluate group. Both the drugs were well- 37 through medications, leads to the efficacy of a multi-ingredient tolerated. It was concluded that irreversible joint damage. formulation “Arthrella” in Arthrella showed a comparable Although NSAIDs, corticosteroids comparison with diclofenac efficacy versus diclofenac, a and other DMARDs (disease- sodium in reducing the pain and standard, well-used NSAID. If modifying antirheumatic drugs) inflammation characteristics of the safety aspect is considered, have been used for treating RA, RA. Eighty patients were included Arthrella definitely has an edge they have their limitations in in the study. In the Arthrella while having an equivalent terms of tolerability, toxicity group, the pain score at rest efficacy. and disease-modifying effect. decreased from a mean of 61.8 at In this scenario, plant-based baseline to 40.27 at 8 weeks Introduction formulations provide a unique compared to a decrease from a Onset of RA can occur modality of treatment of RA as mean of 61.05 to 35.7 in the as early as 16 years of age; *HOD, MS (Ortho), Dept. of Orthopedics diclofenac group. The mean pain however, most patients are **MD Pharmacologists, Ex. Professor and index on joint movement afflicted in midlife 1-4. The main HOD, Dept. of Pharmacology declined from 61.38 to 38.88 in consequences that result from **MD Pharmacology, Dept. of Pharmacology the Arthrella group, while it the autoimmune process of the Address for correspondence: decreased from 59.1 to 31.84 in disease include synovial Department of Orthopedics and the diclofenac group. The mean inflammation and joint damage AUGUST 2006 Department of Pharmacology, Grant Medical College and Sir J.J. Group of reduction in the WOMAC score in the form of bone and cartilage Hospitals, Mumbai. was 4.80 for patients in the destruction 3,5 . Failure of medical INDIAN JOURNAL OF CLINICAL PRACTICE Vol. 17, No. 3

Clinical Study treatment to decrease joint administered tablet Arthrella in a feeling of well-being. For deterioration ultimately may lead dose of one tablet twice daily, assessing the tolerability of the to expensive procedures such as while Group B patients were medicine, epigastric burning/ total joint replacement 1,3. administered tablet diclofenac pain were recorded. Adverse The present study was 50 mg twice daily for a minimum effects were also recorded and conducted to evaluate the period of 12 weeks. Evaluation of monitored. efficacy of “Arthrella” in reducing patients was performed every the pain and inflammation 15 days. Patients who were on Results A total of 73 patients characteristics of RA. Arthrella other medications underwent a completed the trial. Table 1 is a multi-ingredient formulation washout period of 15 days, summarizes the baseline that is useful as a natural following which they were started characteristics of the patients in DMARD. In this study, the on one of the two drugs. The two the two groups. therapeutic benefits and the preparations were made to appear tolerability of Arthrella tablets identical and were blinded. Pain at rest have been compared with In the Arthrella group, the diclofenac sodium. Evaluation parameters pain at rest measured on a VAS, Following are the parameters decreased from an average of Materials and on which the efficacy of the drugs 61.8 at baseline to 40.27 at methods was evaluated: 8 weeks. In the diclofenac group, Patients diagnosed with RA Objective parameters: Joint the pain index decreased from having acute pain, swelling and an average of 61.05 to 35.7. The swelling, mobility of the joint inflammation, controlled results in the two groups were joint and Ritchie's index for joint with synthetic NSAIDs, and who comparable (p value not tenderness. The pain at rest and on required maintenance treatment significant) (Fig. 1). joint movement was evaluated to prevent recurrence and to on a visual analog scale (VAS). Pain on joint movement 38 minimize joint stiffness and swelling were included in the The WOMAC score was also used. The baseline average pain study. RA test was performed at Subjective parameters: index on VAS declined from 59.1 baseline for all patients enrolled These were pain, stiffness and a to 31.84 in the diclofenac group, in the study. However, RA- negative patients with clinical Table 1 features of RA were also enrolled. Age/sex and clinical parameters in Patients with acute flare, overt joint deformity, joint pain two groups following trauma, patients who Arthrella = 36 Diclofenac = 38 p value required surgical intervention and Male 17 18 — patients with history of gastritis, Female 19 20 — peptic ulcer and bleeding ulcers Age (yrs) 53.05 49.17 >0.05 were excluded from the study. Eighty patients diagnosed as Weight (kg) 64.05 63.97 >0.05 suffering from RA who needed Height (cm) 157.08 154.02 >0.05 drug therapy were enrolled in the Pulse rate (per minute) 81.97 78.97 >0.05 study. A written informed consent Systolic blood was obtained from all patients 125.88 124.89 >0.05 pressure (mmHg) before enrolling them in the AUGUST 2006 study. They were divided into Diastolic blood 82.11 80.31 >0.05 pressure (mmHg) two groups: Group A patients were INDIAN JOURNAL OF CLINICAL PRACTICE Vol. 17, No. 3

Clinical Study affects the synovial membranes of 65 Pain score on a 0-10 VAS 61.80 multiple joints in the body. Because 60 56.47 61.05 the disease is systemic, there are 55 51.52 55.92 50 47.91 many extra-articular features of 50.39 45 40.27 the disease as well. In most cases 40 42.36 of RA, the patient has remissions 35 35.70 and exacerbations of the 30 Arthrella (n = 36) 25 Diclofenac (n = 38) symptoms. It is important to 20 realize that there are very few Baseline 3 weeks 6 weeks 9 weeks 12 weeks patients that have complete Figure 1. Pain on a 0-10 VAS at rest in two treatment groups remission of the disease. at baseline and after 3, 6, 9 and 12 weeks of therapy. RA is an autoimmune disease that is acquired and in which while it decreased from 61.38 to three patients were rated to genetic factors appear to play an 38.88 in the Arthrella group. In show a very good response, while important role. The presence of this parameter also, the results 35 patients had good response. HLA-DR4 antibody in 70% of between the two groups were patients with RA lends support to Tolerability assessment by comparable (p value not the genetic predisposition to the physicians disease. Rheumatoid factor(s) are significant) (Fig. 2). Three patients in the antibodies to IgG, and are present Arthrella group were assessed to Fall in pain score in 60-80% of adults with the have very good tolerability to As is evident in Figure 3, the fall disease. the study drug, while 30 patients in pain score at rest and on joint The prevalence of the disease showed good tolerability and movement was initially equivalent is 1-2% of the general population three patients showed fair in the two groups. However, at the and is observed worldwide. tolerability. In the diclofenac end of the study, the patients in the diclofenac group had a marginally group, two patients showed Females with RA outnumber males by a ratio of 3:1. Onset of the 39 very good tolerability, 31 good higher fall in pain score. disease in adults is usually between tolerability and five fair the ages of 40-60 years, although it Reduction in WOMAC score: tolerability. can occur at any age. The mean reduction in the Discussion There are several different WOMAC score was 4.80 for RA is a chronic, systemic, classes of drugs utilized to treat patients in the Arthrella group, inflammatory disease that chiefly patients with the various types of while it was 4.65 in patients in the diclofenac group. Thus, there was no statistically 65 Pain score on a 0-10 VAS 61.38 significant difference between 60 56.11 55 59.10 the two study medicines in 49.58 50 53.71 reducing the WOMAC score 45 44.80 (p value not significant (Fig. 4). 40 46.31 39.86 38.88 35 Global efficacy by physicians 30 Arthrella (n = 36) 31.84 At the end of the study, four 25 Diclofenac (n = 38) patients in the Arthrella group 20 Baseline 3 Weeks 6 Weeks 9 Weeks 12 Weeks were rated as showing very good response, 31 patients were rated AUGUST 2006 Figure 2. Pain on a 0-10 VAS during joint use/mobility in two as good and one patient as fair. treatment groups at baseline and after 3, 6, 9 and 12 weeks For the diclofenac group, of therapy. INDIAN JOURNAL OF CLINICAL PRACTICE Vol. 17, No. 3

Clinical Study Fall in pain score at rest Fall in pain score on joint use/mobility comparable efficacy vis-a-vis 3 weeks 6 weeks 9 weeks 12 weeks 3 weeks 6 weeks 9 weeks 12 weeks diclofenac - a standard, well-used 0 NSAID. On all evaluation parameters, it was observed that Mean fall in Pain Score on VAS 5 5.33 5.13 5.27 5.39 Arthrella and diclofenac showed 10 similar results. In the reduction in 10.28 10.66 11.80 pain score, patients on diclofenac 15 13.89 12.79 showed a greater benefit. However, 16.58 20 if the safety aspect is considered, 18.69 19.27 21.53 the risk benefit ratio of both the 22.50 25 Arthrella (n = 36) study medicines will be equivalent, 25.35 Diclofenac (n = 38) 27.26 with Arthrella having a definite 30 edge on the safety parameter. Figure 3. Fall in pain score on 0-10 VAS in the two treatment B. serrata, a major ingredient groups at 3, 6, 9 and 12 weeks of study period. of Arthrella, is a moderate to large branching tree found in India, rheumatic disease. These classes treatment. The availability of a Northern Africa and the Middle include analgesics to control pain, natural, well tolerated and East. It yields a gummy oleo-resin corticosteroids, uric acid-lowering clinically effective medicine will which contains oils, terpenoids and drugs, immunosuppressive drugs, be of immense benefit to mitigate gum. Upto 16% of the resin is NSAIDs and DMARDs. NSAIDs are the pain, joint stiffness and essential oil, the majority being usually the first class of drugs inflammation in patients with alfa thujene and p-cymene. Studies prescribed and the most commonly longstanding RA. on experimental models in India used. One such product is Arthrella - have shown that ingestion of a Against this background, it is a herbomineral formulation, defatted alcoholic extract of 40 significant that the limitations of NSAID treatment are considered which contains Shallaki guggul (Boswellia serrata), Gold, Nirgundi Boswellia acts as a DMARD through a decrease in polymorphonuclear very carefully before instituting (Vitex negundo) and Ernad (Ricinus leukocyte infiltration and therapy. Many times, patients communis). In this randomized, migration, decrease in primary develop adverse effects to NSAIDs, comparative trial, it is noteworthy antibody synthesis6-8, and an almost given the necessity for prolonged that Arthrella has shown a total inhibition of the classical complement pathway. In vitro testing has revealed 3 weeks 6 weeks 9 weeks 12 weeks 0 that Boswellia specifically, and in a 0.05 dose-dependent manner, blocks Mean fall in WOMAC score 0.28 1 the synthesis of pro-inflammatory 5-lipoxygenase products, including 2 1.66 1.79 5-hydroxyeicosatetraenoic acid 3 2.77 2.49 and leukotriene B4. The other ingredients of 4 Arthrella are Nirgundi (V. negundo) and Erand (R. communis), which 4.65 5 4.83 have well known anti- Arthrella (n = 36) Diclofenac (n = 38) inflammatory action. Fresh 6 AUGUST 2006 leaves of V. negundo exert anti- Figure 4. Reduction in mean WOMAC score in the two inflammatory and pain-suppressing treatment groups at 3, 6, 9 and 12 weeks of study period. activities possibly mediated via INDIAN JOURNAL OF CLINICAL PRACTICE Vol. 17, No. 3

Clinical Study Conclusion improved immune function as From this trial, it can be concluded that the clinical efficacy of compared to auranofin. This is an Arthrella tablets is comparable to that of diclofenac sodium. Arthrella interesting observation and gives a tablets can be used for reducing the pain and inflammation of RA. The rational basis to the claims of efficacy of the drug in the management of RA can be attributed in part efficacy and safety of gold to its anti-inflammatory action as also to its disease-modifying activity. preparations 13 . In addition, No side-effects of Arthrella were reported by the patients in this trial. experimental models chronically treated with gold preparations have prostaglandin synthesis inhibition, months after treatment has been shown significantly increased antihistaminic activity, membrane discontinued. The most common superoxide dismutase and catalase stabilizing and antioxidant adverse reactions to auranofin are activity, two enzymes that reduce activities 9. diarrhea, skin rashes and itching. free radical concentrations in the Arthrella also contains gold, Auranofin can also cause metallic body14. which also acts as a DMARD. Gold taste and mouth sores. Since gold salts have been used since a long salts can cause serious kidney and References time in the treatment of bone marrow damage, all patients 1. Jacobson DL, et al. Clin. Immunol. Immunopathol. 1997;84:223-243. inflammatory arthritis. Although require regular blood and urine 2. Lawrence RC, et al.Arthritis Rheum. the exact mechanism of action of test monitoring. Rarely, patients 1998;41:778-799. gold is not well understood, in can have severe allergic reactions 3. American Society of Health-System Pharmacists Guidelines Committee. patients with inflammatory to auranofin resulting in shock. In Guidelines for the management of arthritis, such as adult and juvenile addition, detrimental effects of rheumatoid arthritis.Arthritis Rheum. 1996;39:713-722. RA, gold salts have been shown to auranofin on the levels of 4. Pucino F. Preventing radio-graphic decrease the inflammation of the antioxidant enzymes such as progression of joint damage in joint lining. This effect can prevent glutathione peroxidase have also rheumatoid arthritis. Program of The American Society of Health-System destruction of bone and cartilage. been reported12. Gold salts are often used as second- Ayurvedic gold preparations, in Pharmacists Midyear Clinical Meeting 2001; December 5, 2000; 41 New Orleans, Louisiana. line drugs when the arthritis comparison, have been used 5. Wernick R and Campbell SM. Ann. progresses in spite of the use of extensively for the treatment of RA Intern. Med. 2000;132:1564-1570. anti-inflammatory drugs (NSAIDs without such serious side effects. 6. Ammon HP. Wien. Med. Wochenschr. 2002;152(15-16): and corticosteroids). Recently, various studies have been 373-378. In a 5-year prospective conducted to provide insights about 7. Reddy GK, Chandrakasan G and controlled trial conducted on 137 the disease-modifying activity of Dhar SC. Biochem. Pharmacol. 1989;38(20):3527- 3534. patients with early RA (<2 years’ Ayurvedic gold formulations in RA. 8. Kimmatkar N, Thawani V, et al. duration) to test the benefit of early In one such study, the effects of an Phytomedicine 2003;10(1):3-7. therapy with a gold salt Ayurvedic gold preparation were 9. Dharmasiri MG, Jayakody JR, (auranofin)10, it was found that at evaluated on non-specific immunity et al. J. Ethnopharmacol. 2003; 87(2-3):199-206. 2 years, early gold therapy resulted in mice. Auranofin was studied for 10. Egsmose C, Lund B, et al. in significant benefits with respect comparison. Male mice were J. Rheumatol. 1 9 9 5 ; 2 2 ( 1 2 ) : to clinical and radiological administered with incremental doses 2208-2213. endpoints. A sample of 75 of these of these drugs orally for 10 days. 11. Borg G, Allander E, et al. J. Rheumatol. 1988;15:1747-1754. patients were followed-up for Parameters of study included body 12. Venardos K, Harrison G, et al. 5 years and these benefits of early weight, organ weight, peritoneal Clin. Exp. Pharmacol. Physiol. gold therapy were maintained11. exudate cell (PEC) counts and 2004;31(5-6):289-294. 13. Bajaj S, Ahmad I, et al. Indian J. However, treatment with phagocytic activity of PEC. The AUGUST 2006 Med. Res. 2001;113:192-196. auranofin can result in side effects results indicated that the Ayurvedic 14. Mitra A, et al. J. Ethnopharmacol. at any time during treatment or gold preparation significantly 2002 May;80(2-3):147-153. INDIAN JOURNAL OF CLINICAL PRACTICE Vol. 17, No. 3

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