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glutamic pyruvic transaminase (SGPT) with otherwise normal liver function; seven patients (Ayurvedic intervention) were withdrawn and SGPT normalized after stopping the drug.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.

Comparative study of amrutbhallataka and glucosamine sulphate in osteoarthritis: Six months open label randomized controlled clinical trial.

BACKGROUND: AmrutBhallatak (ABFN02), a 'rasayana' drug from Ayurveda is indicated in degenerative diseases and arthritis. OBJECTIVE: To evaluate safety and efficacy of ABFN02 in osteoarthritis (OA) and compare it with Glucosamine sulphate (GS). MATERIALS AND METHODS: This was a randomized open comparative study. Ambulant OPD patients of OA knees (n = 112) were enrolled for 24 weeks. Tablets (750mg each) of GS and ABFN02 were matched. Three groups of patients: (A) GS, one tablet × twice/day × 24 weeks. (B) ABFN02, incremental pulse dosage (one tablet x twice/day × two weeks, two tablets × twice/day × two weeks, three tablets × twice/day × two weeks), two such cycles of drug and non-drug phases alternately for six weeks each (C) ABFN02 continuous dosage akin to GS. Pain visual analogue score (Pain-VAS) and Western Ontario and Mc-Master University Osteoarthritis Index (WOMAC) were the primary outcome measures. Secondary outcome measures were Health assessment questionnaire (HAQ), paracetamol consumption, 50 feet walking, physician and patient global assessment, knee stiffness, knee status, urinary CTX II, serum TNFa-SRI, SRII and MRI knee in randomly selected patients. RESULTS: ABFNO2 and GS demonstrated, adherence to treatment 87.75% and 74.3%, reduction in Pain-VAS at rest 61.05% and 57.1%, reduction in pain-VAS on activity 57.4% and 59.8%, WOMAC score drop 62.8% and 59.1% respectively. Secondary outcome measures were comparable in all groups. Safety measures were also comparable. No serious adverse events reported. However, asymptomatic reversible rise in liver enzymes was noted in the ABFNO2 group. CONCLUSIONS: ABFN02 has significant activity in OA; the formulation needs further investigation.

Comparable efficacy of standardized Ayurveda formulation and hydroxychloroquine sulfate (HCQS) in the treatment of rheumatoid arthritis (RA): a randomized investigator-blind controlled study.

Hydroxychloroquine sulfate (HCQS) is a popular disease-modifying antirheumatic drug (DMARD) despite modest efficacy and toxicity. Ayurveda (ancient India medicinal system) physicians treat rheumatoid arthritis (RA) with allegedly safer herbal formulations. We report a head-to-head comparison in an exploratory drug trial. The objective is to compare standardized Ayurvedic formulations and HCQS in the treatment of RA. One hundred twenty-one patients with active moderately severe RA (ACR 1988 classified) were randomized into a 24-week investigator-blind, parallel efficacy, three-arm (two Ayurvedic and HCQS) multicenter drug trial study; polyherb (Tinospora cordifolia and Zingiber officinale based) and monoherb (Semecarpus anacardium). Study measures included joint counts (pain/tenderness and swelling), pain visual analogue scale, global disease assessments, and health assessment questionnaire. Oral meloxicam (fixed-dosage schedule) was prescribed to all patients during the initial 16 weeks. Patients on prednisolone could continue a fixed stable dose (<7.5 mg daily). Rescue oral use of paracetamol was permitted and monitored. All groups matched well at baseline. An intent-to-treat analysis (ANOVA, significance P < 0.05) did not show significant differences by treatment groups. In the polyherb, monoherb, and HCQS arms, 44%, 36%, and 51%, respectively, showed ACR 20 index improvement. Several efficacy measures improved significantly in the HCQS and polyherb groups with no difference between the groups (corrected P). However, the latter was individually superior to monoherb. Only mild adverse events (gut and skin, and none withdrew) were reported with no differences between the groups. Forty-two patients dropped out. This preliminary drug trial controlled for HCQS demonstrated a standardized Ayurvedic polyherb drug to be effective and safe in controlling active RA. A better-designed study with a longer evaluation period is recommended.

Potential of (18)F-FDG-PET as a valuable adjunct to clinical and response assessment in rheumatoid arthritis and seronegative spondyloarthropathies.

AIM: To evaluate the role of fluorine-18-labeled fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in various rheumatic diseases and its potential in the early assessment of treatment response in a limited number of patients. METHODS: This study involved 28 newly diagnosed patients, of these 17 had rheumatoid arthritis (RA) and 11 had seronegative spondyloarthropathy (SSA). In the SSA group, 7 patients had ankylosing spondylitis, 3 had psoriatic arthritis, and one had non-specific SSA. Patients with RA were selected as per the American College of Rheumatology criteria. One hour after FDG injection, a whole body PET scan was performed from the skull vertex to below the knee joints using a GE Advance dedicated PET scanner. Separate scans were acquired for both upper and lower limbs. Post-treatment scans were performed in 9 patients in the RA group (at 6-9 wk from baseline) and in 1 patient with psoriatic arthropathy. The pattern of FDG uptake was analysed visually and quantified as maximum standardized uptake value (SUVmax) in a standard region of interest. Metabolic response on the scan was assessed qualitatively and quantitatively and was correlated with clinical assessment. RESULTS: The qualitative FDG uptake was in agreement with the clinically involved joints, erythrocyte sedimentation rate, C-reactive protein values and the clinical assessment by the rheumatologist. All 17 patients in the RA group showed the highest FDG avidity in painful/swollen/tender joints. The uptake pattern was homogeneous, intense and poly-articular in distribution. Hypermetabolism in the regional nodes (axillary nodes in the case of upper limb joint involvement and inguinal nodes in lower limb joints) was a constant feature in patients with RA. Multiple other extra-articular lesions were also observed including thyroid glands (in associated thyroiditis) and in the subcutaneous nodules. Treatment response was better appreciated using SUVmax values than visual interpretation, when compared with clinical evaluation. Four patients showed a favourable response, while 3 had stable disease and 2 showed disease progression. The resolution of regional nodal uptake (axillary or inguinal nodes based on site of joint involvement) in RA following disease modifying anti-rheumatoid drugs was noteworthy, which could be regarded as an additional parameter for identifying responding patients. In the SSA group, uptake in the affected joint was heterogeneous, low grade and non-symmetrical. In particular, there was intense tendon and muscular uptake corresponding to symptomatic joints. The patients with psoriatic arthritis showed intense FDG uptake in the joints and soft tissue. CONCLUSION: (18)F-FDG PET accurately delineates the ongoing inflammatory activity in various rheumatic diseases (both at articular and extra-articular sites) and relates well to clinical symptoms. Different metabolic patterns on FDG-PET scanning in RA and SSA can have important implications for their diagnosis and management in the future with the support of larger studies. FDG-PET molecular imaging is also a sensitive tool in the early assessment of treatment response, especially when using quantitative information. With these benefits, FDG-PET could play a pivotal clinical role in the management of inflammatory joint disorders in the future.

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.

Hypersensitivity to intravenous ondansetron: a case report.

INTRODUCTION: Ondansetron, a 5-hydroxytryptamine3 receptor antagonist widely used in the prevention and treatment of chemotherapy-induced nausea and vomiting, is associated with various unusual adverse drug reactions. In this paper, we describe a hypersensitivity reaction to a single intravenous dose of ondansetron. CASE PRESENTATION: A 19-year-old woman presented to the emergency department of our institute with 3-4 episodes of nausea, vomiting and epigastric distress. She had a diagnosis of polycystic ovarian disease and had been on treatment with cyproterone acetate 2 mg, ethinyl estradiol 0.035 mg, finasteride 5 mg and metformin 500 mg for a month. She had been taking oral roxithromycin 500 mg per day for the past 3 days for treatment of a mild upper respiratory tract infection. She also occasionally took rabeprazole 10 mg for gastritis which had worsened after treatment with roxithromycin. She was treated with a single 4 mg dose of ondansetron intravenously. She immediately developed urticaria, which was treated with intravenous dexamethasone 4 mg and chlorpheniramine maleate 20 mg. The reaction abated within a few minutes and she was discharged within an hour. She was asymptomatic at 72 hours of follow-up.She had no history of ondansetron exposure, or drug or food allergies. On the Naranjo's causality assessment scale, the adverse event was 6 indicating a "probable" reaction to ondansetron. CONCLUSION: 5-hydroxytryptamine3 receptor antagonists have been associated with life-threatening adverse reactions such as hypotension, seizures and anaphylaxis. The wide availability of these drugs in India has promoted their off label use in the treatment of gastritis, migraine and so on. Our case represents an off label use in a patient who could have been treated with a safer drug.Some authors have suggested that anaphylaxis may be a class effect while others think it may be drug specific. In our case, the reaction could be either anaphylaxis or anaphylactoid, but the latter seems more likely given the history of absence of prior sensitization. Other components of the drug, such as solvent, also need to be considered as a cause of this reaction. Considering all of the existing evidence, we need to be more cautious while using ondansetron and also to be aware of the various unusual side effects, especially when used in an out-of-hospital set-up.Our case report underscores the importance of physicians judiciously using the drug, particularly in the outpatient setting so as to reduce the incidence of avoidable adverse drug reactions.

Tropical infections in the ICU.

Certain arthropod-borne infections are common in tropical regions because of favorable climatic conditions. Water-borne infections like leptospirosis are common due to contamination of water especially during the monsoon floods. Infections like malaria, leptospirosis, dengue fever and typhus sometimes cause life threatening organ dysfunction and have several overlapping features. Most patients present with classicial clinical syndromes: fever and thrombocytopenia are common in dengue, malaria and leptospirosis; coagulopathy is frequent in leptospirosis and viral hepatitis. Hepatorenal syndrome is seen in leptospirosis, falciparum malaria and scrub typhus. The pulmonary renal syndrome is caused by falciparium malaria, leptospirosis, Hantavirus infection and scrub typhus. Fever with altered mental status is produced by bacterial meningitis, Japanese B encephalitis, cerebral malarial, typhoid encephalopathy and fulminant hepatic failure due to viral hepatitis. Subtle differences in features of the organ failure exist among these infections. The diagnosis in some of these diseases is made by demonstration of antibodies in serum, and these may be negative in the first week of the illness. Hence empiric therapy for more than one disorder may be justified in a small proportion of cases. In addition to specific anti-infective therapy, management of organ dysfunction includes use of mechanical ventilation, vasopressor drugs, continuous renal replacement therapy and blood products. Timely transfer of these patients to well-equipped ICUs with experience in managing these cases can considerably decrease mortality and morbidity.

Utility of the polymerase chain reaction in the diagnosis of tuberculous meningitis.

Due to inconsistent clinical presentations and the lack of a rapid, sensitive and specific test, tuberculous meningitis (TBM) is particularly difficult to diagnose. The present study was carried out to determine the utility of the polymerase chain reaction (PCR) using INS primers in the diagnosis of TBM and to compare the efficacy of two different DNA extraction protocols. Fifty-seven cerebrospinal fluid (CSF) samples from suspected cases of meningitis -- 30 definitive/possible TBM and 27 non-TBM -- were processed for microscopy, culture and PCR. Results of computer tomographic (CT) scan findings were noted. The results of smear, culture and PCR were compared using culture and/or clinical response to treatment as the gold standard. The sensitivity of microscopy, culture, CT scan and PCR was 3.3%, 26.7%, 60.0% and 66.7%, respectively. PCR following QIAmp DNA extraction had a sensitivity of 66.7% compared to PCR following a DNA extraction protocol based on the use of cetyl trimethyl ammonium bromide (CTAB) (50%). PCR was positive in all culture-positive CSF samples using either extraction method. PCR is a rapid and sensitive technique; above all, it can diagnose tuberculous meningitis at a very early stage.

Leprosy & gangrene: a rare association; role of anti phospholipid antibodies.

BACKGROUND: Leprosy still remains an important public health problem for many parts of the world. An association of gangrene with leprosy is a rare one & can have a number of causative mechanisms. We present a case with Leprosy & gangrene with positive anti phopholipid antibody titers. CASE PRESENTATION: A 50-year-old non-diabetic, non-hypertensive lady presented with 2 months history of progressive gangrene of bilateral toes. She was found to have madarosis & hypopigmented, hypoaesthetic macular lesions on the upper limb & thighs. Bilateral ulnar & popliteal nerves were thickened. A skin biopsy of the lesions revealed borderline tuberculoid leprosy, slit skin smears revealed a bacteriological index of 1+. She did not have any evidence of thromboembolic episode or atherosclerosis. ACLA was positive at presentation & also on another occasion 6 weeks later. ACLAs were of the IgM type on both occasions. Lupus Anticoagulant & beta2 GPI antibody were negative. DOPPLER of the lower limb arteries did not reveal any abnormality. Patient was successfully treated with multi-drug antileprotics & anticoagulants. CONCLUSION: Infectious APLAs should be recognized as a cause of thrombosis in Leprosy. Appropriate anticoagulation can salvage limb function.

Anti-neutrophil cytoplasmic antibodies (ANCA) in systemic lupus erythematosus: prevalence, clinical associations and correlation with other autoantibodies.

AIM: This study was undertaken to clarify the nature of anti-neutrophil cytoplasmic antibodies (ANCA) along with other autoantibodies in lupus nephritis (LN) patients and in systemic lupus erythematosus (SLE) patients without nephritis and to know their correlation with clinical manifestations and presence of other autoantibodies. MATERIAL AND METHODS: Fourty one LN patients and 18 SLE patients without nephritis were studied. LN patients were subdivided into diffuse proliferative glomerulonephritis (DPGN), focal proliferative glomerulonephritis (FPGN), rapidly progressive glomerulonephritis (RPGN) and membranoproliferative glomerulonephritis (MPGN). Anti-neutrophil cytoplasmic antibodies (ANCA) were detected by indirect immunofluorescence and confocal laser scanning microscope using PMN and HL60 cells. ANCA specificities like anti-myeloperoxidase (anti-MPO), anti-proteinase 3 (anti-PR3), anti-lactoferrin (anti-LF) and anti-cathepsin G (anti-CG) were detected by ELISA. Other autoantibodies like anti-nuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), anti-single stranded DNA(anti-ssDNA), anti-ribonucleoproteins (anti-nRNP), anti-Smith antibodies (anti-Sm) and rheumatoid factor (RF) were also tested. RESULTS: ANCA was detected in 37.3% patients. The predominant ANCA pattern was perinuclear (p-ANCA). ANCA positivity was higher in LN patients and when confirmed by ELISA, 54.5% ANCA positives had anti-myeloperoxidase (anti-MPO). The cytoplasmic ANCA (c-ANCA) pattern was not seen in any patient. Two patients having FPGN with crescents showed atypical 'X-ANCA' pattern with dual specificity to anti-MPO and anti-PR3 by ELISA. The titers of ANCA were more in LN as compared to SLE without nephritis. LN cases having DPGN, FPGN, RPGN with crescents had higher titer p-ANCA positivity with corresponding anti-MPO antibodies, along with ANA, anti-dsDNA, anti-ssDNA and anti-Sm + anti-nRNP and also high SLEDAI scores. CONCLUSION: ANCA in SLE may be used as a serological marker along with clinical and histopathological assessment to differentiate vasculitides in LN cases from SLE without nephritis.

Antibodies to Ro/SS-A and La/SS-B in systemic lupus erythematosus and other autoimmune disorders.

AIM: 1. To study the presence of anti-Ro/SS-A, anti-La/SS-B, anti-Sm and anti-nRNP in diagnosed antinuclear factor (ANF) positive systemic lupus erythematosus (SLE) cases and their association with various organ involvement. 2. To study autoantibodies in other autoimmune disorders. MATERIAL AND METHODS: A total of 4050 suspected cases of autoimmune disorders referred for serological work up were evaluated for ANF by indirect immunofluorescence technique, anti-dsDNA by PHA, autoantibodies to Ro-SS-A and La/SS-B by ELISA and rheumatoid factor was tested by latex agglutination using commercial kits. RESULTS: Out of 4050 patients 19.5% were ANF positive and 5% were anti-dsDNA positive. Out of these 50 diagnosed ANF positive cases of SLE, an incidence of anti-dsDNA 54%, anti-Sm 25.9%, anti-nRNP 29.6%, anti-Ro/SS-A 10% and anti-La/SS-B was 22% was observed. In rheumatoid arthritis, 17.4% positivity of anti-Ro/SS-A and 39.1% positivity for anti-La/SS-B was observed. In SLE with renal involvement, joint complaints and skin or malar rash were seen in 66%, 56% and 46%, respectively. CONCLUSION: Determining anti-Ro/SS-A and anti-La/SS-B antibody could be important in evaluating patients with suspected connective tissue disorders, who usually show diverse clinical presentations like skin, kidney and joint manifestations. The most prominent feature in anti-Ro/SS-A and anti-La/SS-B positive patients was skin involvement and sicca complex in 60% of SLE patients.