Antirelapse Efficacy of Various Primaquine Regimens for Plasmodium vivax.

Background. Efficacy of standard dose of primaquine (PQ) as antirelapse for P. vivax has decreased. We aimed to assess efficacy of different PQ regimens. Methods. It was an open label, randomized, controlled, parallel group, assessor blind study comparing antirelapse efficacy of 3 PQ regimens (B = 15 mg/day × 14 days, C = 30 mg/day × 7 days, and D = 30 mg/day × 14 days) with no PQ group (A) in P. vivax patients. Paired primary and recurrence samples were subjected to 3 methods: (i) month of recurrence and genotyping, (ii) by PCR-RFLP, and (iii) PCR sequencing, to differentiate relapse and reinfection. The rates of recurrence relapse and reinfection were compared. Methods were compared for concordance between them. Results. The recurrence rate was 16.39%, 8.07%, 10.07%, and 6.62% in groups A, B, C, and D, respectively (P = 0.004). The relapse rate was 6.89%, 1.55%, 4%, and 3.85% as per the month of recurrence; 8.2%, 2%, 4.58%, and 3.68% (P = 0.007) as per PCR-RFLP; and 2.73%, 1.47%, 1.55%, and 1.53% as per PCR sequencing for groups A, B, C, and D, respectively. The concordance between methods was low, 45%. Conclusion. The higher recurrence rate in no PQ as compared to PQ groups documents PQ antirelapse activity. Regimens tested were safe. However, probable resistance to PQ warrants continuous monitoring and low concordance and limitations in the methods warrant caution in interpreting.

A randomized, parallel study of the safety and efficacy of 45 mg primaquine versus 75 mg bulaquine as gametocytocidal agents in adults with blood schizonticide-responsive uncomplicated falciparum malaria [ISCRTN50134587].

BACKGROUND: The WHO recommends that adults with uncomplicated P. falciparum successfully treated with a blood schizonticide receive a single dose of primaquine (PQ) 45 mg as a gametocytocidal agent. An earlier pilot study suggested that 75 mg of bulaquine (BQ), of which PQ is a major metabolite, may be a useful alternate to PQ. METHODS: In a randomized, partial blind study, 90 hospitalized adults with Plasmodium falciparum malaria that was blood schizonticide-responsive and a gametocytemia of > 55/microl within 3 days of diagnosis were randomized to receive single doses of either PQ 45 mg or BQ 75 mg on day 4. We assessed gametocytemia on days 8, 15, 22 and 29 and gametocyte viability as determined by exflagellation (2 degrees end point) on day 8. RESULTS: On day 8, 20/31 (65%) primaquine recipients versus 19/59 (32%) bulaquine recipients showed persistence of gametocytes (P = 0.002). At day 15 and beyond, all patients were gametocyte free. On day 8, 16/31 PQ and 7/59 BQ volunteers showed gametocyte viability (p = 0.000065). CONCLUSION: BQ is a safe, useful alternate to PQ as a Plasmodium falciparum gametocytocidal agent and may clear gametocytemia faster than PQ.

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.

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/microl 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.

Diagnostic and prognostic utility of rapid strip (OptiMal and Paracheck) versus conventional smear microscopy in adult patients of acute, uncomplicated P. falciparum malaria in Mumbai, India.

OBJECTIVES: The present study compared the diagnostic and prognostic utility of two rapid tests the (Paracheck and OptiMal) versus conventional smear microscopy. METHODS: Using two independent microscopists we carried out the three tests in 31 adult cases of smear positive, acute, uncomplicated Plasmodium falciparum malaria. All three tests were done pretreatment, and on Days 8, 15 and 29. RESULTS: Compared to microscopy, the Paracheck had a sensitivity of 100%, while the OptiMal had a sensitivity of 83.7%. The lower sensitivity of OptiMal resulted from misidentification by both microscopists of 6/31 cases as Plasmodium vivax. As a follow up tool, the OptiMal was better than Paracheck, due to the earlier disappearance of the parasite LDH. Also in the Paracheck, between microscopists, there was a significant difference in reading the tests, on Days 8 and 15. CONCLUSION: Our study reiterates, the continued utility of conventional smear microscopy.

A randomized, crossover, assessor-blind study of the bioequivalence of a single oral dose of 200 mg of four formulations of phenytoin sodium in healthy, normal Indian volunteers.

The objective of the study was to compare the bioavailability of a single oral 200-mg dose of four brands of phenytoin sodium available in the Indian market. Dilantin, Epsolin, and M-toin were compared with Eptoin, which was taken as the reference standard. A randomized, assessor-blind, four-way crossover study was done in 12 healthy Indian volunteers. The study was conducted at a clinical pharmacology ward at King Edward VII Memorial Hospital, a tertiary referral center in Mumbai (Bombay). All 12 subjects received a single oral 200-mg dose of all the formulations with a 2-week washout period between the formulations. Blood samples for plasma phenytoin levels were collected at 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours. Safety was measured by pretreatment and posttreatment biochemical investigations, physical examination, and ECG. The pharmacokinetics of the four brands of phenytoin were calculated by maximum plasma concentration (C(max)), time to reach C(max) (t(max)), area under the concentration versus time curve for time 0 to 72 hours (AUC(0-72)), and from time 0 to infinity (AUC(0- infinity)). For all brands, 90% CI of all untransformed and log transformed pharmacokinetic parameters failed to remain within prescribed limits of 80% to 120% for untransformed data and 80% to 125% for log transformed data. Since phenytoin obeys Micheles Mentens kinetics, the AUC methodology used for comparison would give only an approximate indication of relative bioavailability. M-toin was shown to be bioinequivalent to Eptoin. The other comparisons indicate but do not prove bioinequivalence of the other brands. The results of the study show that in India switching phenytoin brands could have significant implications and is not advisable once a patient is carefully titrated on one formulation.

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.

A cost-effectiveness analysis of three antimalarial treatments for acute, uncomplicated Plasmodium falciparum malaria in Mumbai, India.

BACKGROUND: Malaria is a major public health problem representing 2.3% of the overall global disease burden. The cost of treatment of malaria continues to rise as older drugs and insecticides become less effective and are replaced by more effective, but also more expensive products. METHODS: A post-hoc pharmacoeconomic analysis (direct and indirect costs only) of three antimalarials, chloroquine, mefloquine and co-artemether, was carried out to address the problem of switch to a more expensive first-line antimalarial in the face of growing chloroquine resistance. RESULTS: From the perspective of a large public hospital, it was seen that in an area of high grade chloroquine resistance, the total expenditure on patients who fail chloroquine would exceed the excess expenditure on mefloquine when the RII + RIII resistance exceeded 9%. CONCLUSIONS: Switch to a more expensive drug like mefloquine as a first-line option would be cost-effective when the moderate-severe chloroquine resistance exceeded 9%.

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 non-drug 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.

Therapeutic drug monitoring in a developing country: an overview.

Therapeutic Drug Monitoring (TDM) was introduced in India in the mid and late 1980s and the last 10 years have seen it grow, together with the growth of separate Clinical Pharmacology departments. The TDM service in the country is broadly of two types: in large teaching hospitals where the service is available through departments of Clinical Pharmacology, and in the private sector, where drug estimations are done by clinical biochemistry departments with minimal interpretation. This article is based on literature review and our own experiences over a 10 year period in a department of Clinical Pharmacology. It focuses on the evolution of TDM, its problems such as lack of funding, special aspects such as the impact of ethnic differences, nutritional deficiencies, quality of medicines and availability of generic products; its utility as a research tool and its future.

A pharmacoeconomic analysis of the impact of therapeutic drug monitoring in adult patients with generalized tonic-clonic epilepsy.

AIMS: To carry out a retrospective pharmacoeconomic analysis of the impact of therapeutic drug monitoring (TDM) in adult patients with generalized tonic-clonic epilepsy in an academic, non profit making organization. METHODS: Twenty-five patients who had undergone TDM were compared with 25 age, disease and duration of drug therapy matched controls who had not undergone TDM. Only direct costs were calculated. These included cost to the hospital of providing the TDM service, cost to the hospital per seizure saved, and cost to the patient per seizure saved. RESULTS: Patients undergoing TDM had much more effective seizure control (P = 0.00032, OR 4.846, 95% confidence interval 1.29,18.3), fewer adverse events, better earning and were more likely to be married than the control group. CONCLUSIONS: In patients with adult onset epilepsy, a minimum of two drug estimations per year offers significant benefit in terms of better seizure control, fewer adverse events and greater chances of remission.

A randomized, double-blind, parallel-group, comparative safety, and efficacy trial of oral co-artemether versus oral chloroquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in adults in India.

In India, treatment of acute, uncomplicated Plasmodium falciparum malaria is becoming increasingly difficult due to resistance to chloroquine, thus there is a need for new antimalarial drugs. CGP 56697 (co-artemether), a new drug, is a combination of artemether and lumefantrine in a single oral formulation (one tablet = 20 mg of artemether plus 120 mg of lumefantrine). In a double-blind study, 179 patients with acute uncomplicated P. falciparum malaria were randomly assigned to receive either CGP (n = 89) given as a short course of 4 x 4 tablets over a 48-hr period or chloroquine (n = 90) given as four tablets (one tablet = 150 mg of chloroquine base) initially, followed by two tablets each at 6-8, 24, and 48 hr. Due to a death in the chloroquine group and a decrease in the chloroquine cure rate to < 50% (based on the blinded overall cure rate at that time), recruitment was terminated prematurely. CGP 56697 showed a superior 28-day cure rate (95.4% versus 19.7%; P < 0.001), time to parasite clearance (median = 36 versus 60 hr; P < 0.001), and resolution of fever (median = 18 versus 27 hr; P = 0.0456). This drug provides a safe, effective, and rapid therapy for the treatment of acute uncomplicated P. falciparum malaria.

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.

Relapse pattern of Plasmodium vivax in Mumbai: a study of 283 cases of vivax malaria.

OBJECTIVES: To analyze the relapse pattern of Plasmodium vivax in the city of Mumbai. METHODS: 283 cases of smear positive vivax malaria were treated with full dose (25 mg/kg) chloroquine and were asked to follow up for at least one year. None of the patients received primaquine. RESULTS: Of the 150 cases who followed up for at least one year, 19 relapsed, 17/19 relapsed within the first 6 months; indicating that the relapse pattern in the city is predominantly of the tropical or Chesson strain type. CONCLUSIONS: Vivax malaria patients should be monitored for at least six months. Those who do relapse should receive treatment with full dose chloroquine and 14 days of primaquine treatment.

Therapeutic drug monitoring in a developing country: an overview.

Therapeutic Drug Monitoring (TDM) was introduced in India in the mid and late 1980s and the last 10 years have seen it grow, together with the growth of separate Clinical Pharmacology departments. The TDM service in the country is broadly of two types: in large teaching hospitals where the service is available through departments of Clinical Pharmacology, and in the private sector, where drug estimations are done by clinical biochemistry departments with minimal interpretation. This article is based on literature review and our own experiences over a 10 year period in a department of Clinical Pharmacology. It focuses on the evolution of TDM, its problems such as lack of funding, special aspects such as the impact of ethnic differences, nutritional deficiencies, quality of medicines and availability of generic products; its utility as a research tool and its future.