Comparative in vitro assessment of the antiplasmodial activity of quinine – zinc complex and quinine sulphate

Incessant malaria endemicity in the tropics and subtropical regions and the recent work done on the synthesis of metal drug complexes of antimalarial drugs and the evaluation of their antimalarial activities in vitro, has led to the development of this study. Quinine-Zinc complex (QZ) was synthesized using a modification of Singla and Wadhwa method. Melting point determination, TLC analysis, infra red, ultra violet, atomic absorption spectroscopy and mole ratio determination were all carried out on the complex synthesized. Direct measurement of the antimalarial activity of the potential new drug (QZ) against parasite growth in vitro was used to comparatively ascertain the antimalarial activity of QZ relative to Quinine sulphate (QS). Measurement of antimalarial activity was carried out based on the inhibition of parasite growth with respect to inhibition of schizont formation in freshly collected infected blood samples from patients. The results showed that QZ complex was formed and its antimalarial activity was three times that of QS alone. This study suggests that the quinine-zinc complex could have a better therapeutic activity than quinine

Tackling resistance: Emerging antimalarials and new parasite targets in the era of elimination [version 1; referees: 2 approved]

Malaria remains a significant contributor to global human mortality, and roughly half the world’s population is at risk for infection with Plasmodium spp. parasites. Aggressive control measures have reduced the global prevalence of malaria significantly over the past decade. However, resistance to available antimalarials continues to spread, including resistance to the widely used artemisinin-based combination therapies. Novel antimalarial compounds and therapeutic targets are greatly needed. This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine. In addition, we describe recent large-scale genetic and resistance screens that have been instrumental in target discovery. Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination

Knowledge among Drug Dispensers and Antimalarial Drug Prescribing Practices in Public Health Facilities in Dar es Salaam.

Irrational prescribing and dispensing of antimalarials has been identified as a contributing factor in the emergence of malaria parasites resistant to existing antimalarial drugs. Factors that contribute to such irrational prescribing and dispensing should therefore be identified to address this problem. The aim of this study was to assess irrational antimalarial drug dispensing and prescribing practices in public health facilities. A descriptive-retrospective cross-sectional study was conducted between January and June 2011 in order to assess prescribing and dispensing practices for antimalarial drugs in three public hospitals and nine health centers in Dar es Salaam, Tanzania. Thirty-two drug dispensers were interviewed using a structured questionnaire. A total of 4,320 prescriptions for the period January to December 2010 were collected and assessed for antimalarial drug prescribing patterns. The majority (84.6%) of drug dispensers had poor knowledge regarding the basic information required from patients before dispensing artemether-lumefantrine. Seventeen of 32 drug dispensers did not know the basic information that should be given to patients in order to increase absorption of artemether-lumefantrine after oral intake. Most drug dispensers also showed limited knowledge about the dosage and contraindications for artemether-lumefantrine. Eighty-seven percent of all prescriptions contained artemether-lumefantrine as the only antimalarial drug, 77.1% contained at least one analgesic, and 26.9% contained at least one antibiotic, indicating unnecessary use of analgesics and antibiotics with antimalarial drugs. A substantial number of prescriptions contained antimalarial drugs that have already been declared ineffective for the treatment of malaria in Tanzania, providing additional evidence of inadequate knowledge among health care workers concerning treatment policy. Despite the government's efforts to increase public awareness regarding use of artemether-lumefantrine as first-line treatment for uncomplicated malaria, there is still irrational prescribing, dispensing, and use of this combination. Based on the results of this study, it is proposed that regular on-the-job training and continuing education be provided to drug dispensers and prescribers in public health facilities

Treatment of malaria restricted to laboratory-confirmed cases: a prospective cohort study in Ugandan children.

BACKGROUND: Presumptive treatment of malaria in febrile children is widely advocated in Africa. This may occur in the absence of diagnostic testing or even when diagnostic testing is performed but fails to detect malaria parasites. Such over-treatment of malaria has been tolerated in the era of inexpensive and safe monotherapy. However, with the introduction of new artemisinin-based combination therapy (ACT), presumptive treatment becomes economically and clinically less acceptable. METHODS: The risks and benefits of only treating children with microscopy confirmed malaria using a prospective cohort design were investigated. A representative sample of 601 children between one and 10 years of age were recruited from a census population in Kampala, Uganda and were followed for all of their health care needs in a study clinic. Standard microscopy was performed each time a child presented with a new episode of fever and antimalarial therapy given only if the blood smear was positive. RESULTS: Of 5,895 visits for new medical problems 40% were for febrile illnesses. Of the 2,359 episodes of new febrile illnesses, blood smears were initially reported as negative in 1,608 (68%) and no antimalarial therapy was given. Six of these initially negative smears were reported to be positive following quality control reading of all blood smears: four of these patients were subsequently diagnosed with uncomplicated malaria and two cleared their parasites without antimalarial treatment. Of the 1,602 new febrile illnesses in which the final blood smear reading was classified as negative, only 13 episodes (0.8%) were diagnosed with malaria in the subsequent 7 days. All 13 of these episodes of malaria were uncomplicated and were successfully treated. CONCLUSION: In this urban setting, malaria was responsible for only 32% of febrile episodes. Withholding antimalarial therapy in febrile children with negative blood smears was safe and saved over 1,600 antimalarial treatments in 601 children over an 18-month period. In the era of expensive ACT, directing resources towards improving diagnostic and treatment practices may provide a cost-effective measure for promoting rational use of antimalarial therapy

MEPicides: Potent antimalarial prodrugs targeting isoprenoid biosynthesis

AbstractThe emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme. In addition, parasites that produced higher levels of the Dxr substrate were resistant to RCB-185. Notably, environmental isolates resistant to current therapies remained sensitive to RCB-185, the compound effectively treated sexually-committed parasites, and was both safe and efficacious in malaria-infected mice. Collectively, our data demonstrate that RCB-185 potently and selectively inhibits Dxr in P. falciparum, and represents a promising lead compound for further drug development.</jats:p

The spread of antimalarial drug resistance: A mathematical model with practical implications for ACT drug policies

Most malaria-endemic countries are implementing a change in antimalarial drug policy to artemisinin combination therapy (ACT). The impact of different drug choices and implementation strategies is uncertain. A comprehensive model was constructed incorporating important epidemiological and biological factors and used to illustrate the spread of resistance in low and high transmission settings. The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and that in low transmission areas ACTs slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. A major obstacle to achieving the benefits of high coverage is the current cost of the drugs. This argues strongly for a global subsidy to make ACTs generally available and affordable in endemic areas

Comparative analysis of two methods for measuring sales volumes during malaria medicine outlet surveys.

BACKGROUND: There is increased interest in using commercial providers for improving access to quality malaria treatment. Understanding their current role is an essential first step, notably in terms of the volume of diagnostics and anti-malarials they sell. Sales volume data can be used to measure the importance of different provider and product types, frequency of parasitological diagnosis and impact of interventions. Several methods for measuring sales volumes are available, yet all have methodological challenges and evidence is lacking on the comparability of different methods. METHODS: Using sales volume data on anti-malarials and rapid diagnostic tests (RDTs) for malaria collected through provider recall (RC) and retail audits (RA), this study measures the degree of agreement between the two methods at wholesale and retail commercial providers in Cambodia following the Bland-Altman approach. Relative strengths and weaknesses of the methods were also investigated through qualitative research with fieldworkers. RESULTS: A total of 67 wholesalers and 107 retailers were sampled. Wholesale sales volumes were estimated through both methods for 62 anti-malarials and 23 RDTs and retail volumes for 113 anti-malarials and 33 RDTs. At wholesale outlets, RA estimates for anti-malarial sales were on average higher than RC estimates (mean difference of four adult equivalent treatment doses (95% CI 0.6-7.2)), equivalent to 30% of mean sales volumes. For RDTs at wholesalers, the between-method mean difference was not statistically significant (one test, 95% CI -6.0-4.0). At retail outlets, between-method differences for both anti-malarials and RDTs increased with larger volumes being measured, so mean differences were not a meaningful measure of agreement between the methods. Qualitative research revealed that in Cambodia where sales volumes are small, RC had key advantages: providers were perceived to remember more easily their sales volumes and find RC less invasive; fieldworkers found it more convenient; and it was cheaper to implement than RA. DISCUSSION/CONCLUSIONS: Both RA and RC had implementation challenges and were prone to data collection errors. Choice of empirical methods is likely to have important implications for data quality depending on the study context