Pharmacologic Advances in the Global Control and Treatment of Malaria: Combination Therapy and Resistance

Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 12/2007; 82(5):601-5. DOI: 10.1038/sj.clpt.6100361
Source: PubMed


Combination drug therapy for malaria is recommended both to prevent and to overcome drug resistance. Drug combinations developed for use in Asia are being deployed in Africa, where higher rates of malaria affect the therapeutic and public health objectives of malaria chemotherapy as well as drug safety. Rational consideration of drug mechanisms, pharmacokinetics (PK), pharmacodynamics (PD), and malaria epidemiology should result in more effective combination regimens that retain therapeutic and prophylactic efficacy in the face of resistance.

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    • "Artemisinin combination therapy (ACT) is now the treatment of choice for uncomplicated Plasmodium falciparum malaria [1,2]. These combinations involve a rapidly eliminated and fast-acting artemisinin derivative, responsible for a rapid decline in the parasite biomass, together with a much slower eliminated drug that kills the remaining parasites. "
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    ABSTRACT: Background: Fixed-dose combinations of artemisinin combination therapy are strongly recommended to facilitate drug administration and compliance. New fixed-dose combinations must nevertheless be evaluated in relevant populations in terms of efficacy and pharmacokinetics. Methods: A single-arm, open-label, clinical trial was performed in Indian patients with acute uncomplicated Plasmodium falciparum malaria to investigate the efficacy and the pharmacokinetics of mefloquine when combined with artesunate in a fixed-dose combination (400/200 mg of mefloquine base/artesunate). The pharmacokinetic analysis was performed using a population approach. Results: Seventy-seven patients were included in the study. Mefloquine pharmacokinetics obeys a two-compartment model with first-order absorption and elimination. Mean parameter estimates (% inter-individual variability) were as follows: 0.16 h(-1) (75%) for the absorption rate constant, 1.13 L/h (30%) for the apparent plasma clearance, 271 L (21%) for the apparent central distribution volume, 344 L (54%) for the apparent peripheral distribution volume, and 1.43 L/h for the apparent distribution clearance. These values were consistent with the pharmacokinetic results described in Thai patients. No significant covariate was found for clearance. Body weight explained the inter-individual variability of the apparent central and peripheral distribution volumes. The PCR-adjusted efficacy of the treatment was 100%. Conclusions: The lack of significant covariate explaining the inter-individual variability of mefloquine clearance, combined with the excellent efficacy, supports the use of the standard 200/400 mg of artesunate-mefloquine fixed-dose combination in Indian patients with uncomplicated P. falciparum malaria.
    Malaria Journal 05/2014; 13(1):187. DOI:10.1186/1475-2875-13-187 · 3.11 Impact Factor
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    • "Prompt recognition and timely treatment with efficacious drugs remains a primary control strategy for malaria [11]. Artemisinin-based combination therapy (ACT) has been recommended as the drug of choice for the treatment of uncomplicated malaria and have widely been adopted as first line treatment in sub-Saharan Africa [12]. Early diagnosis and treatment are crucial in achieving the drug’s intended benefits. "
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    ABSTRACT: Background Artemisinin-based combination treatment (ACT) has been widely adopted as one of the main malaria control strategies. However, its promise to save thousands of lives in sub-Saharan Africa depends on how effective the use of ACT is within the routine health system. The INESS platform evaluated effective coverage of ACT in several African countries. Timely access within 24 hours to an authorized ACT outlet is one of the determinants of effective coverage and was assessed for artemether-lumefantrine (Alu), in two district health systems in rural Tanzania. Methods From October 2009 to June 2011we conducted continuous rolling household surveys in the Kilombero-Ulanga and the Rufiji Health and Demographic Surveillance Sites (HDSS). Surveys were linked to the routine HDSS update rounds. Members of randomly pre-selected households that had experienced a fever episode in the previous two weeks were eligible for a structured interview. Data on individual treatment seeking, access to treatment, timing, source of treatment and household costs per episode were collected. Data are presented on timely access from a total of 2,112 interviews in relation to demographics, seasonality, and socio economic status. Results In Kilombero-Ulanga, 41.8% (CI: 36.6–45.1) and in Rufiji 36.8% (33.7–40.1) of fever cases had access to an authorized ACT provider within 24 hours of fever onset. In neither of the HDSS site was age, sex, socio-economic status or seasonality of malaria found to be significantly correlated with timely access. Conclusion Timely access to authorized ACT providers is below 50% despite interventions intended to improve access such as social marketing and accreditation of private dispensing outlets. To improve prompt diagnosis and treatment, access remains a major bottle neck and new more innovative interventions are needed to raise effective coverage of malaria treatment in Tanzania.
    Malaria Journal 05/2013; 12(1):155. DOI:10.1186/1475-2875-12-155 · 3.11 Impact Factor
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    • "Malaria remains endemic in most tropical countries, especially those in sub-Saharan Africa (Snow et al., 2005; Alonso et al., 2011). The emergence of Plasmodium falciparum parasites with reduced susceptibility to artemisinins and partner drugs (e.g., mefloquine, lumefantrine and piperaquine) that comprise artemisinin-based combination therapies (ACTs) are worrisome and challenge existing efforts to control, treat and eliminate Plasmodium falciparum malaria (Nyunt and Plowe, 2007, Fairhurst et al., 2012). The discovery and development of new antimalarial drugs thus remains a priority. "
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    ABSTRACT: Ethnopharmacological relevance: Aqueous preparations of Vernonia guineensis Benth. (Asteraceae) are used in Cameroonian folk medicine as a general stimulant and to treat various illnesses and conditions including malaria, bacterial infections and helminthic infestations. Materials and methods: Ten gram samples of the leaf and tuber powders of Vernonia guineensis were extracted separately using dichloromethane, methanol and distilled water. The extracts were dried in vacuo and used in bioassays. These extracts and three compounds previously isolated from Vernonia guineensis [vernopicrin (1), vernomelitensin (2) and pentaisovalerylsucrose (3)] were screened for antiplasmodial activity against chloroquine (CQ)-sensitive (Hb3) and CQ-resistant (Dd2) Plasmodium falciparum lines. Results: Crude extracts and pure compounds from Vernonia guineensis showed antiplasmodial activity against both Hb3 and Dd2. The IC50 values of extracts ranged from 1.64 to 27.2 µg/ml for Hb3 and 1.82-30.0 µg/ml for Dd2; those for compounds 1, 2 and 3 ranged from 0.47 to 1.62 µg/ml (1364-1774 nM) for Hb3 and 0.57-1.50 µg/ml (1644-2332nM) for Dd2. None of the crude extracts or pure compounds was observed to exert toxic effects on the erythrocytes used to cultivate the Plasmodium falciparum lines. Conclusion: In Cameroonian folk medicine, Vernonia guineensis may be used to treat malaria in part due to the antiplasmodial activity of sesquiterpene lactones (1, 2), a sucrose ester (3) and perhaps other compounds present in crude plant extracts. Exploring the safety and antiplasmodial efficacy of these compounds in vivo requires further study.
    Journal of ethnopharmacology 03/2013; 147(3). DOI:10.1016/j.jep.2013.03.051 · 3.00 Impact Factor
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