The little we know about the pharmacokinetics and pharmacodynamics of praziquantel (racemate and R-enantiomer)

Praziquantel has been the mainstay of schistosomiasis control since 1984 and widely distributed since 2006 through ‘preventive chemotherapy' programmes to school-aged children or at-risk populations. In addition, preschool-aged children are now recognized as a vulnerable population and a group for targeted treatment, but they may be difficult to dose correctly with the available product—a racemate, based on the biologically active enantiomer (R-praziquantel) and the inactive distomer (S-praziquantel), which contributes the bitter taste and doubles the size of the tablets. Hence, a paediatric formulation is required, possibly enantiomerically pure. Developing such a product and extending its use to younger children should be pharmacologically guided, but limited data exist on pharmacokinetics and pharmacokinetic/pharmacodynamic correlations for praziquantel. This article presents available data on the chemistry, pharmacokinetics and pharmacodynamics of praziquantel, as well as R-praziquantel, and points to gaps in our knowledg

Aminosidine plus sodium stibogluconate for the treatment of Indian kala-azar: a randomized dose-finding clinical trial

This randomized, open sequential design trial was set up to assess the efficacy, tolerability and toxicity of 20 d courses of combined intramuscular aminosidine and sodium stibogluconate at various dosages in patients with newly-diagnosed kala-azar in Bihar, India. Three successive studies of 96 patients each were originally planned with aminosidine administered at 12, 6 and 3 mg/kg/d, respectively. For each aminosidine dosage, patients were randomly assigned to receive sodium stibogluconate at 20, 10 or 5 mg/kg/d of antimony. Ninety-six patients were enrolled and assigned aminosidine 12 mg/kg/d as scheduled. In the subsequent study with aminosidine at 6 mg/kg/d, the trial was interrupted after 40 patients had entered owing to inadequacy of the treatment. With aminosidine 12 mg/kg/d the success rates with sodium stibogluconate at 20, 10 and 5 mg/kg/d were 88%, 71% and 72%, respectively and did not differ significantly. With aminosidine 6 mg/kg/d, 69%, 50% and 46% of patients were cured with the same sodium stibogluconate doses, respectively; again, there was no significant difference between the subgroups. The overall success rate with aminosidine at 12 mg/kg/d (76%) was significantly higher than that with 6 mg/kg/d (55%) (odds ratio = 2·69; 95% confidence interval, 1·11-6·4). Patients improved clinically and the treatments were equally well tolerated. The combination of aminosidine 12 mg/kg/d and sodium stibogluconate 20 mg/kg/d for 20 d appears to be an effective and safe replacement in Bihar for sodium stibogluconate alone for ⩾40

Treatment of urinary schistosomiasis: methodological issues and research needs identified through a Cochrane systematic review

SUMMARY Guidelines recommend praziquantel (PZQ) for the treatment and control of schistosomiasis, with no real alternative. Metrifonate was still widely used against Schistosoma haematobium in the 1990s, and then withdrawn. Experimental studies and clinical trials suggest that artemisinin compounds are active against S. haematobium. In a Cochrane systematic review assessing the efficacy and safety of drugs for treating urinary schistosomiasis, 24 randomized controlled trials (n=6315 individuals) met our inclusion criteria. These trials compared a variety of single agent and combination regimens with PZQ, metrifonate or artemisinin derivatives. The review confirmed that both the standard recommended doses of PZQ (single 40 mg/kg oral dose) and metrifonate (3×7·5-10 mg/kg oral doses administered fortnightly) are efficacious and safe in treating urinary schistosomiasis, but there is no study comparing these two regimens head-to-head. There is currently not enough evidence to evaluate artemisinin compounds. Most of the studies included in the Cochrane systematic review were insufficiently powered, lacked standardization in assessing and reporting outcomes, and had a number of methodological limitations. In this paper we discuss the implications of these findings with respect to public health and research methodology and propose priority research needs

Out of (West) Africa-Who Lost in the End?

On October 29, 2014, 4 days before the annual meeting of the American Society of Tropical Medicine and Hygiene (ASTMH) to be held in New Orleans, LA, meeting registrants received an e-mail letter from the Louisiana Department of Health and Hospitals stating "we have requested that any individuals that will be traveling to Louisiana following a trip to the West African countries of Guinea, Liberia, and Sierra Leone or have had contact with an Ebola-infected individual remain in a self-quarantine for the 21 days following their relevant travel history…we see no use in you traveling to New Orleans to simply be confined to your room." This communication made it clear that those recently in countries experiencing the 2014 Ebola epidemic would not be able to participate in the meeting. The ASTMH sent their own communication stating that the Society did not agree with the State's policy, but had no choice but to abide. However inconvenient and upsetting this decision might have been, what really matters transcends the mere disturbance of long-planned schedules. More broadly, we lost on five levels

Risk factors for in-hospital mortality of visceral leishmaniasis patients in eastern Uganda.

OBJECTIVE: To identify risk factors for in-hospital mortality in patients treated for visceral leishmaniasis (VL) in Uganda. METHODS: Retrospective analysis of VL patients' clinical data collected for project monitoring by Médecins Sans Frontières in Amudat, eastern Uganda. RESULTS: Between 2000 and 2005, of 3483 clinically suspect patients, 53% were confirmed with primary VL. Sixty-two per cent were children <16 years of age with a male/female ratio of 2.2. The overall case-fatality rate during pentavalent antimonial (n = 1641) or conventional amphotericin B treatment (n = 217) was 3.7%. There was no difference in the case-fatality rate between treatment groups (P > 0.20). The main risk factors for in-hospital death identified by a multivariate analysis were age <6 years and >15 years, concomitant tuberculosis or hepatopathy, and drug-related adverse events. The case-fatality rate among patients >45 years of age was strikingly high (29.0%). CONCLUSION: Subgroups of VL patients at higher risk of death during treatment with drugs currently available in Uganda were identified. Less toxic drugs should be evaluated and used in these patients

In vivo assessment of drug efficacy against Plasmodium falciparum malaria: duration of follow-up.

To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r(2) = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up

Treatment of urinary schistosomiasis: methodological issues and research needs identified through a Cochrane systematic review

Guidelines recommend praziquantel (PZQ) for the treatment and control of schistosomiasis, with no real alternative. Metrifonate was still widely used against Schistosoma haematobium in the 1990s, and then withdrawn. Experimental studies and clinical trials suggest that artemisinin compounds are active against S. haematobium. In a Cochrane systematic review assessing the efficacy and safety of drugs for treating urinary schistosomiasis, 24 randomized controlled trials (n=6315 individuals) met our inclusion criteria. These trials compared a variety of single agent and combination regimens with PZQ, metrifonate or artemisinin derivatives. The review confirmed that both the standard recommended doses of PZQ (single 40 mg/kg oral dose) and metrifonate (3×7·5-10 mg/kg oral doses administered fortnightly) are efficacious and safe in treating urinary schistosomiasis, but there is no study comparing these two regimens head-to-head. There is currently not enough evidence to evaluate artemisinin compounds. Most of the studies included in the Cochrane systematic review were insufficiently powered, lacked standardization in assessing and reporting outcomes, and had a number of methodological limitations. In this paper we discuss the implications of these findings with respect to public health and research methodology and propose priority research need

Population pharmacokinetics of orally administered mefloquine in healthy volunteers and patients with uncomplicated Plasmodium falciparum malaria

Background The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic/pharmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate. Patients and methods Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM. Results A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration-time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life (407 versus 566 h) and T>MIC (766 versus 893 h). Conclusions This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy individuals and patients. As VC/F is related to the earlier portion of the concentration-time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/

New Treatment Approach in Indian Visceral Leishmaniasis: Single-Dose Liposomal Amphotericin B Followed by Short-Course Oral Miltefosine

Background. In Bihar, India, home to nearly one-half of the world's burden of visceral leishmaniasis, drug resistance has ended the usefulness of pentavalent antimony, which is the traditional first-line treatment. Although monotherapy with other agents is available, the use of 2 drugs with different modes of action might increase efficacy, shorten treatment duration, enhance compliance, and/or reduce the risk of parasite resistance. To test the feasibility of a new approach to combination therapy in visceral leishmaniasis (also known a kala-azar), we treated Indian patients with a single infusion of liposomal amphotericin B (L-AmB), followed 1 day later by short-course oral miltefosine. Methods. We used a randomized, noncomparative, group-sequential, triangular design and assigned 181 subjects to treatment with 5 mg/kg of L-AmB alone (group A; 45 subjects), 5 mg/kg of L-AmB followed by miltefosine for 10 days (group B; 46 subjects) or 14 days (group C; 45 subjects), or 3.75 mg/kg of L-AmB followed by miltefosine for 14 days (group D; 45 subjects). When it became apparent that all regimens were effective, 45 additional, nonrandomized patients were assigned to receive 5 mg/kg of L-AmB followed by miltefosine for 7 days (group E). Results. Each regimen was satisfactorily tolerated, and all 226 subjects showed initial apparent cure responses. Nine months after treatment, final cure rates were similar: group A, 91% (95% confidence interval [CI], 78%-97%]; group B, 98% (95% CI, 87%-100%); group C, 96% (95% CI, 84%-99%]; group D, 96% (95% CI, 84%-99%); and group E, 98% (95% CI, 87%-100%). Conclusions. These results suggest that treatment with single-dose L-AmB followed by 7-14 days of miltefosine is active against Indian kala-azar. This short-course, sequential regimen warrants additional testing in India and in those regions of endemicity where visceral leishmaniasis may be more difficult to treat. Trial registration. ClinicalTrials.gov identifier: NCT0037082