Kshirsagar Na

The Use and Safety of Non-Allopathic Indian Medicines

Non-allopathic Indian medicines, referred to elsewhere in the world as complementary and alternative medicine have gathered increasing recognition in recent years with regard to both treatment options and health hazards. Ayurveda, Siddha, Unani and homeopathy are practiced in India as non-allopathic systems. These systems comprise a wide range of therapeutic approaches that include diet, herbs, metals, minerals, precious stones and their combinations as well as nondrug therapies. Ayurveda is the oldest system of medicine in the world and by far the most commonly practiced form of non-allopathic medicine in India, particularly in rural India, where 70% of the population lives.The difference between modern medicine and these systems stems from the fact that the knowledge base of many of the above systems, unlike Western medicine, is based on years of experience, observations, empiricism and intuition and has been handed down generations both through word of mouth and treatises. The focus on non-allopathic systems of medicine in India can be attributed to various causes including a need to revive a rich tradition, the dependency of 80% of the country’s population on these drugs, their easy availability, increasing worldwide use of these medicines, the lack of focused concerted scientific research and the abuse of these systems by quacks. Elsewhere, the increasing use of herbal products worldwide and the growth of the herbal product industry has led to increasing concern regarding their safety. The challenges in these non-allopathic systems relate to the patient, physician, regulatory authorities, the abuse/misuse of these medicines, quality and purity issues. Safety monitoring is mandated by a changing ecological environment, the use of insecticides, new manufacturing techniques, an as yet unregulated pharmaceutical industry, the availability of combinations of herbs over the counter and not mentioned in ancient Ayurvedic texts, and the need to look at the active principles of these medicines as potential chemotherapeutic agents.The Indian traditional medicine industry has come a long way from the times when it was considered unnecessary to test these formulations prior to use, to the introduction of Good Manufacturing Practice guidelines for the industry. However, we still have a long way to go. The conflict between the traditional practitioners and the purists demanding evidence of safety and efficacy needs to be addressed. There is an urgent need for the practitioners of the allopathic and non-allopathic systems to work together to optimise the risk-benefit profile of these medicines.

Anticonvulsant hypersensitivity syndrome: a review

Anticonvulsant hypersensitivity syndrome (AHS), characterised by fever, rash and internal organ involvement, is a rare, but potentially fatal adverse event that occurs most commonly with first-line aromatic anticonvulsants, but can also occur with non-aromatic anticonvulsants such as lamotrigine and valproic acid. AHS can begin anywhere from 1 to 12 weeks after commencement of therapy and has been estimated to occur at a frequency of 1/1000 to 1/ 10,000 exposures. Its true incidence, however, remains unknown due to under-reporting. The disease has protean manifestations mimicking several other conditions, and the diagnosis is thus difficult. Several hypotheses have been put forward to explain the pathogenesis of AHS. These include accumulation of toxic metabolites, graft versus host disease, antibody production and viral infections. The one based on toxic metabolites has found the greatest acceptance, perhaps due to the fact that it can be proven by an in vitro test; the lymphocyte toxicity assay. Discontinuation of the offending agent with supportive, symptomatic therapy forms the mainstay of management of AHS. In addition, counselling of both the patient and first degree relatives for susceptibility to AHS is an important aspect of management. In the last decade, several new anticonvulsants have been introduced for epilepsy. In addition, for resource-poor countries, inexpensive and effective first-line drugs such as phenytoin and phenobarbitone will continue to remain important treatment options. Thus, the problem of AHS will continue, and attempts should be made to further understand the molecular basis of and individual susceptibility to AHS. Adverse event monitoring programs must also actively seek AHS reports to estimate its true incidence.

Efficacies of 5- and 14-day primaquine regimens in the prevention of relapses in Plasmodium vivax infections.

Vivax malaria accounts for 80% of malaria cases in Mumbai (Bombay) and has high morbidity. In India, the standard treatment to prevent relapses of vivax malaria is a 5-day regimen of primaquine. However, between 1977 and 1997, the efficacy of this treatment declined from approximately 99% to 87%. The efficacy of the 5-day regimen was therefore compared with that of the 14-day regimen currently recommended by the World Health Organization, in Mumbai. The relapse rates observed, over a 6-month period of follow-up, were 0% with the 14-day regimen, 26.7% with the 5-day, and 11.7% when no primaquine treatment was given. The expenditure incurred on the door-to-door dispensing of the 5-day regimen appears to be without benefit. There is an urgent need to review the present strategy for controlling relapses in vivax malaria, at least for the city of Mumbai, and similar studies need to be carried out in other parts of India, to make all anti-relapse strategies more appropriate.

Dose-ranging studies on liposomal amphotericin B (L-AMP-LRC-1) in the treatment of visceral leishmaniasis

Efficacy and tolerability of liposomal amphotericin B (L-AMP-LRC-1; developed in India by the Liposome Clinical Pharmacology Centre, Mumbai, and the Liposome Research Centre, New Delhi) were assessed in 63 patients suffering from visceral leishmaniasis at centres in Mumbai and Patna. Patients were treated with different daily dose schedules ranging from 1 mg/kg for 21 days to 3.0 mg/kg for 7 days. L-AMP-LRC-1 was well tolerated by all 63 patients. Two patients on the 3.0 mg/kg dose developed bronchospasm on 4 occasions which reversed with standard treatment and could be prevented by increasing the duration of infusion to 3 h. Forty-three patients were freshly diagnosed cases while 20 were unresponsive to standard treatment. All 42 assessable freshly diagnosed cases responded completely to L-AMP-LRC-1 (1 patient died owing to pulmonary infection before completion of treatment), but 5 patients required additional doses for parasitological cure. All 20 patients unresponsive to standard therapy responded completely, but 3 patients required additional doses. The regimen of 2 mg/kg daily for 10 days was 100% effective; 3 mg/kg daily for 5 days was efficacious in 90.9% freshly diagnosed patients, and 3 mg/kg daily for 7 days was effective in 100% of the unresponsive cases of visceral leishmaniasis. L-AMP-LRC-1 is thus found to be safe and effective in freshly diagnosed as well as unresponsive cases of visceral leishmaniasis at dose schedules of shorter duration than used for conventional amphotericin B.

Safety, tolerability, efficacy and plasma concentrations of diethylcarbamazine and albendazole co-administration in a field study in an area endemic for lymphatic filariasis in India

Filariasis control programmes are moving towards a strategy of repeated single-dose mass treatment of endemic populations. Using a combination, such as albendazole (ALB) to diethylcarbamazine (DEC) gives both macrofilaricidal and anti-helmintic activity. However, the safety of the combination versus DEC alone should be established in field studies in large populations prior to incorporation into national programmes. The present study compared the safety, tolerability, and efficacy of single doses of DEC 6 mg/kg + ALB placebo with DEC 6 mg/kg + ALB 400 mg in populations living in two filariasis endemic villages in the district of Wardha in western India. The study was double blind, parallel group, and randomized. Safety and tolerability study were studied in males and females older than 5 years. Safety was assessed by monitoring if adverse events (AEs) over 5 days affected daily acivities. Subjects in the 2 treatment groups experienced insignificantly different effects on daily activities and the combination was shown to be safe. Efficacy was evaluated by microfilaraemia (Mf), immunochromatographic test (ICT) and ultrasonography (USG) at 0, 3, 6, and 12 months of follow up. The efficacy study enrolled 103 male patients (aged 18-50 years) in microfilariae positive, clinical disease and asymptomatic, amicrofilaremic groups. There was no significant difference in efficacy between groups at 12 months. Within the Mf positive group, significant differences were seen in microfilaraemia (P < 0.001) with both treatments, and in USG (P < 0.001 and P < 0.004 respectively), at 12 months. The present field study has shown the combination of DEC + ALB to be as safe as the single drug DEC and thus the combination can be put in use in the national filariasis control programmes. Both drugs were adequately absorbed. The study at present does not provide evidence for the greater efficacy of the combination at 12 months follow up. While the safety of the combination has been ascertained, the incorporation or otherwise of ALB into national programmes for greater efficacy must await results of studies with longer follow up.

Efficacy of a 14-day primaquine regimen in preventing relapses in patients with Plasmodium vivax malaria in Mumbai, India.

We studied the antirelapse efficacy of a supervised 14-d 15 mg/d regimen of primaquine therapy (n = 131) compared with no antirelapse therapy (n = 142) in 273 patients with confirmed Plasmodium vivax malaria in Mumbai, India, between July 1998 and April 2000. There were 6/131 (4.6%) recurrences in patients given primaquine compared with 13/142 (9.2%) in those not given antirelapse therapy. In the 14-d primaquine group, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) genotyping analysis of pre- and post-treatment blood samples was done for the 6 patients who had a recurrence of parasitaemia and the results gave a true relapse rate of 2.29% (3/131), 2 samples were classified as reinfections and 1 sample did not amplify. Our results indicate probable resistance to the 14-d regimen of primaquine for the first time in India and illustrate the need to (i) monitor patients given this regimen and (ii) carry out comparative studies between primaquine and new drugs such as tafenoquine and bulaquine for preventing relapses.

An unusual case of multidrug-resistant Plasmodium vivax malaria in Mumbai (Bombay), India

Drug-resistant strains of Plasmodium vivax are being reported from several parts of the world, including India (Garget al., 1995; Dua et al., 1996). Fortunately, most P. vivax infections are relatively mild and run a benign course (Wickramsinghe, 1981). An unusual case of infection with P. vivax (which was nonresponsive to chloroquine and mefloquine) and its implications are described below. A 13-year-old male patient, weighing 45 kg, was referred to the Department of Clinical Pharmacology at the King Edward VII Memorial Hospital (KEMH) in Mumbai (formerly Bombay) in November 1998. He had had intermittent fever, with chills, body ache, headache and malaise, since March 1997. At one stage he had been febrile (37.7-40.0°C) almost every day. His records, maintained meticulously by his educated parents, showed that no malarial parasites had been detected in smears of his peripheral blood prepared on several occasions in 1997. Despite this lack of confirmation that his fevers were caused by malaria, the patient had been treated, between March 1997 and December 1997, with full-dose chloroquine (25 mg/kg over 3 days), full-dose mefloquine (20 mg/kg, in two divided doses), 14 days of primaquine (15 mg/day) and an adult dose (three tablets, each containing 500 mg sulfadoxine and 25 mg pyrimethamine) of sulfadoxinepyrimethamine (SP). The records showed that the patient had provided a Plasmodium-positive blood sample for the first time on 4 July 1998, at a district malaria hospital; the parasite was identified as P. vivax. He apparently received incomplete and improper treatment with chloroquine, and was bloodsmear-positive when tested 25 days later. He then went to a second physician, who treated him, concurrently, with mefloquine (20 mg/kg, in divided doses) and two tablets of SP. The patient responded to this treatment and became afebrile within a few days. Two and a half months later, however, in October 1998, the patient became febrile again and P. vivax was again detected in a smear of peripheral blood at the district malaria hospital. At this time, a third doctor treated the boy, with injectable artemether (80 mg/ day for 6 days). Although the patient initially responded, he again became febrile and was smear-positive 20 days after the end of the artemether therapy, when he presented at the KEMH. Study of the boys medical history and records then revealed that, in OctoberNovember 1998, his initially irregular bouts of fever had begun to occur twice each week. Each episode lasted approximately 5 min, and took the form of fever (peaking at 37.740.00C) associated with chills, body ache, and headache. Between episodes, the patient appeared normal except for malaise. Treatment at the KEMH was begun, with supervised, full-dose chloroquine (25 mg/kg) on 24 November 1998 (day 1). Primaquine (15 mg/ day) was started on day 4, once the patients blood concentration of glucose-6-phosphatedehydrogenase was investigated and found to be normal, and the patient was asked to attend the hospital, for follow-up, on days 8, 15, 22 and 29. On day 14, however, the patient presented with fever and chills, and a few trophozoites and gametocytes of P. vivax were seen in a bloodsmear. A diagnosis of chloroquine-resistant vivax malaria was made and the patient was given supervised treatment with mefloquine (20 mg/kg, again in divided doses). Since the patient had then already completed 10 days of primaquine therapy, 15 mg primaquine/day for a further 21 days was advised. Thirteen days after the mefloquine treatment, however, the patient again had fever with chills, and a thick smear was found positive for P. vivax, although only

Safety and pharmacokinetics of a human monoclonal antibody to rabies virus: A randomized, dose-escalation phase 1 study in adults☆

BACKGROUND Rabies is an essentially fatal disease that is preventable with the timely administration of post-exposure prophylaxis (PEP). The high cost of PEP, which includes vaccine and hyperimmune globulin, is an impediment to the goal of preventing rabies in the developing world. Recently a recombinant human IgG(1) anti-rabies monoclonal antibody (SII RMab) has been developed in India to replace serum-derived rabies immunoglobulin. The present study was conducted to demonstrate the safety of SII RMab and to determine the dose resulting in neutralizing serum antibody titers comparable to human rabies immunoglobulin (HRIG) when administered in conjunction with rabies vaccine in a simulated PEP regimen. METHODS This randomized, open label, dose-escalation phase 1 study was conducted in healthy adults at a large tertiary care, referral, public hospital in India. Safety was assessed by active surveillance for adverse events along with standard laboratory evaluations and measurement of anti-drug antibodies (ADA). Anti-rabies antibody levels were measured by rapid fluorescent focus inhibition test (RFFIT) and ELISA. The study duration was 365 days. FINDINGS SII RMab was well tolerated with similar frequency of local injection site reactions to HRIG. The geometric mean concentrations of rabies neutralizing antibody in the vaccine plus SII RMab 10 IU/kg cohort were comparable to the vaccine plus HRIG 20 IU/kg cohort throughout the 365-day study period; day 14 geometric mean concentrations 23.4 IU/ml (95% CI 14.3, 38.2) vs. 15.3 IU/ml (95% CI 7.72, 30.3; p=NS), respectively. Future post-exposure prophylaxis studies of SII RMab at a dose of 10 IU/kg in conjunction with vaccine are planned.

Probable resistance to parenteral artemether in Plasmodium falciparum : case reports from Mumbai (Bombay), India

Malaria continues to kill approximately 0.5 million-2.5 million people each year in the tropics (Newton and White, 1999). Drug resistance among malarial parasites is rampant and is making treatment more and more difficult (White, 1998). Artemisinin (qinghaosu) and its derivatives, artemether and artesunate, arc currently the most rapidly acting antimalarial drugs, and are considered effective against all species and strains of the human parasites, including multidrug-resistant Plasmodium falciparum (De Vries and Dien, 1996). However, three cases of recrudescence among 37 patients who had each been given intramuscular artemether ( 480 mg, given over 5 days, as treatment for complicated malaria) raise the spectre of resistance even to this drug. These three cases, all seen at the Seth G.S. Medical College & K.E.M. Hospital, in Mumbai (Bombay), India, are described below. A 22-year-old male patient presented after having had fever, chills and rigors for 3 days. On examination, the patient was disoriented, semi-conscious and gave irrelevant answers to the questions asked. He had already been given chloroquine, though the dose could not be ascertained. Examination of smears of peripheral blood collected on the day of admission (day 1) revealed a parasitaemia of 5880 asexual parasites/ ftl, with 2.64% of the erythrocytes infected. Intramuscular artemethcr therapy was initiated (160 mg on day 1, and 80 mg on each of days 2, 3, 4, and 5) and the patient apparently responded rapidly, as no parasites could be detected on smears produced on days 2, 3 or 4. On day 5, however, just prior to the last dose of artemcther, the patient was found to be parasitaemic again (98 asexual parasites/ J.LI) although afebrile. On day 6 the patient had a similar parasitaemia and had become febrile. RII resistance was diagnosed and the patient was given sulfadoxine-pyrimethamine (three tablets, each containing 500 mg sulfadoxine and 25 mg pyrimethamine) and closely monitored. The patient responded, becoming afebrile and parasite-negative within 48 h, and remained aparasitaemic over the next 42 days of follow-up. Two other patients, both also adult males, who were found to have parasitaemias of 2.78% and 2.02% on presentation, were given the same treatment with artemether. Although both were smear-negative on days 5 and 6 (indicating parasitological cure), the patients subsequently returned, one on day 22 and the other on day 29, when they were smearpositive for the ring stages of P. falciparum and febrile. They were both diagnosed as cases of RI resistance and successfully treated, as the other case, with sulfadoxinepyrimethamine. Artemether has been in use in India for I year and the present reports are some of the results from one of the earliest clinical studies with the drug in India. All medication in the present study was supervised and documented. The two cases who were found to be parasitaemic again only after they had been discharged could both represent re-infections. However, the patient who became smearnegative and then smear-positive during his course of artemether probably represents a case of artemether resistance. The regimen of intramuscular artemether used in the present study has given cure rates of 100% (Bunang et al., 1991) or 90.3% (Bunang et al., 1993) against uncomplicated, falciparum malaria and of 65% against severe, falciparum malaria (Bunang et al., 1992). For India, a country that is presently witnessing dangerously escalating chloroquine resistance (Garg et al., 1999), the artemisinin derivatives represent valuable treatment options, particularly for complicated/ severe

Age-dependent sex bias in clinical malarial disease in hypoendemic regions.

Background and Objectives Experimental models show a male bias in murine malaria; however, extant literature on biases in human clinical malaria is inconclusive. Studies in hyperendemic areas document an absence of sexual dimorphism in clinical malaria. Data on sex bias in clinical malaria in hypoendemic areas is ambiguous—some reports note a male bias but do not investigate the role of differential mosquito exposure in that bias. Moreover, these studies do not examine whether the bias is age related. This study investigates whether clinical malaria in hypoendemic regions exhibits a sex bias and whether this bias is age-dependent. We also consider the role of vector exposure in this bias. Methods Retrospective passive clinical malaria datasets (2002–2007) and active surveillance datasets (2000–2009) were captured for the hypoendemic Mumbai region in Western India. To validate findings, passive retrospective data was captured from a primary malaria clinic (2006–2007) in hypoendemic Rourkela (Eastern India). Data was normalized by determining percent slide-positivity rates (SPRs) for males and females, and parasite-positivity distributions were established across age groups. The Mann–Whitney test, Wilcoxon Signed Rank test, and Chi-square analysis were used to determine statistical significances. Results In both the Mumbai and Rourkela regions, clinical malaria exhibited an adult male bias (p<0.01). A sex bias was not observed in children aged ≤10. Post-puberty, male SPRs were significantly greater than females SPRs (p<0.01). This adult male bias was observed for both vivax and falciparum clinical disease. Analysis of active surveillance data did not reveal an age or sex bias in the frequency of parasite positivity. Conclusion This study demonstrates an age-dependent sex bias in clinical malaria in hypoendemic regions and enhanced incidence of clinical malaria in males following puberty. Possible roles of sex hormones, vector exposure, co-infections, and other factors in this enhanced susceptibility are discussed.