S.S. Dalvi

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.

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.

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

Preliminary report of the evaluation of the gametocytocidal action of bulaquine, in adult patients with acute, Plasmodium falciparum malaria.

In the treatment of human malaria, the 8-aminoquinolines, such as primaquine (PQ), are unique because they exhibit activity against several stages in the life-cycle of the parasites causing the disease (WHO, 1990). The World Health Organization (1990) recommends that PQ is used as a gametocytocide against Plasmodium falciparum (in a single, 45-mg dose) and as a tissue schizonticide against P. vivax (at a dose of 15 mg/day for 14 days). The clinical utility of PQ is limited by its haematological toxicity, however, particularly in individuals who have glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. There is also some evidence, that, at least in India, the efficacy of a single dose of PQ in the treatment of chloroquine-sensitive P. falciparum malaria is declining (Gogtay et al., 1999). During the last decade, attempts have been made to synthesise newer 8-aminoquinolines or modify the basic structure of PQ to produce derivatives which have the antiparasitic activity of PQ but lower toxicity. Bulaquine (formerly called CDRI 80/53) is one such compound. It differs from PQ only in having a 2,4 dihydrofuran group in the basic side chain that is anchored to the quinoline nucleus in the 8 position. In a preclinical study using Rhesus monkeys with sporozoite-induced P. cynomolgi B malaria, bulaquine was found to be almost as effective as PQ, 100% radical cure been achieved using 7 days of treatment with either bulaquine at 1.25 mg base/kg.day or PQ at 1 mg base/kg.day (Dutta et al., 1989). In a subsequent 3-day test (Puri and Dutta, 1990), again using Rhesus moneys with P. cynomolgi B malaria, the doses of bulaquine needed to give causal prophylaxis (3.16 mg/ kg.day for 3 days) were similar to those of PQ (1.78 mg/kg.day for 3 days). Bulaquine has been licensed for use in India — for use, at 25 mg base/day for 5 days, to prevent relapses of P. vivax malaria — since 2001. In the present study, as there have been no published studies on the use of this drug as a gametocytocidal agent, the gametocytaemias in adult patients suffering from acute, uncomplicated, P. falciparum malaria were followed after they had been treated with quinine and either bulaquine or PQ. The study protocol was approved both by the Drugs Controller General of India and the ethics committees of the K.E.M. Hospital and Kasturba Hospital for Infectious Diseases — the institutions in Mumbai, India, where the patients were examined and treated. Written informed consent was obtained from all participating subjects. To be enrolled, a patient had to be aged >18 years, have at least 55 P. falciparum gametocytes/μl blood (and therefore be infective to mosquitoes; Fleck et al., 1996) in the first 72 h of admission, and have normal G6PDH status. Patients with symptoms and signs indicative of complicated malaria and those unwilling to comply with the protocol instructions (including attending for all scheduled follow-up examinations) were excluded. On the day of admission (‘day 1’) each patient received the first of seven daily doses of quinine (30 mg/kg.day) in combination with doxycycline (100 mg/day; Na-Bangchang and Karbwang, 1993). On day 4, each patient was also given a single S C

A prospective study evaluating the efficacy of a single, 45-mg dose of primaquine, as a gametocytocidal agent, in patients with Plasmodium falciparum malaria in Mumbai, India

Abstract The efficacy of a single dose of 45 mg primaquine, as a gametocytocidal agent, was assessed in Mumbai, India, among adults with uncomplicated or severe Plasmodium falciparum malaria. All the patients investigated had been found gametocytaemic, with at least 56 gametocytes/μl blood, within the first 72 h of their illness. Those with uncomplicated malaria, like those with severe malaria, were randomized to receive or not receive primaquine. All the patients were followed up for 29 days post-admission, for gametocytaemia and gametocyte viability (as determined by exflagellation). Among those with uncomplicated malaria, six (27.3%) of the 22 who did not receive primaquine but only one (4.2%) of the 24 who did receive the drug, on day 4, remained gametocytaemic on day 29 (P < 0.05). Similarly, seven (31.8%) of the 22 severe cases who did not receive primaquine but only two (9.5%) of the 21 severe cases who received the drug, on day 8, were found gametocytaemic on day 15 (P < 0.05). While the single, 45-mg dose of primaquine recommended by the World Health Organization was effective in clearing gametocytes from the blood of > 90% of the present cases of malaria, > 4% of the patients with uncomplicated malaria and > 9% of those with the severe disease continued to harbour gametocytes in their peripheral blood 29 and 15 days after taking the primaquine, respectively.

A randomized, parallel-group study in Mumbai (Bombay), comparing chloroquine with chloroquine plus sulfadoxine-pyrimethamine in the treatment of adults with acute, uncomplicated, Plasmodium falciparum malaria.

A major problem in the control of malaria is the development of resistance, of the parasites to the existing drugs and of the vectors to insecticides. With few new drugs in the pipeline, in an era of declining resources, it is imperative to make judicious use of the existing antimalarials. In the city of Mumbai, resistance exists to chloroquine (CQ) and to sulfadoxine-pyrimethamine (SP). Use of a combination of CQ with SP would theoretically slow down the development of resistance to each of the drugs and increase their useful lives. The effectiveness of this combination in the treatment of adults from Mumbai, who had acute, uncomplicated Plasmodium falciparum malaria, was compared with that of CQ alone. The combination was found to be significantly more effective, in terms of 28- or 42-day cure rates, and to be more cost-effective.

Adverse drug reactions to Indian traditional remedies: past, present and future

Ayurveda is the traditional system of medicine of India more than 3000 years old and still practised extensively in India and neighbouring countries. There is little systematic information on adverse effects. The medicines themselves, based on plants and minerals, can cause serious adverse effects in some patients if used inappropriately, or can interact with conventional (allopathic) medicines to cause harm. There is also the possibility of misuse and mislabelling of Ayurvedic medicines, with consequent harm to patients. Better surveillance and more ready access to information on these drugs would help both traditional and conventional practitioners and their patients.