Artemisinin Combination Treatment Research Articles

Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects

The aim of this study was to investigate which principal human cytochrome P450 (CYP450) enzymes are affected by artemisinin and to what degree the artemisinin derivatives differ with respect to their respective induction and inhibition capacity. Seventy-five healthy adults were randomized to receive therapeutic oral doses of artemisinin, dihydroartemisinin, arteether, artemether or artesunate for 5 days (days 1-5). A six-drug cocktail consisting of caffeine, coumarin, mephenytoin, metoprolol, chlorzoxazone and midazolam was administered orally on days -6, 1, 5 and 10 to assess the activities of CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Four-hour plasma concentrations of parent drugs and corresponding metabolites and 7-hydroxycoumarin urine concentrations were quantified by liquid chromatography-tandem mass spectrometry. The 1-hydroxymidazolam/midazolam 4-h plasma concentration ratio (CYP3A) was increased on day 5 by artemisinin [2.66-fold (98.75% CI: 2.10-3.36)], artemether [1.54 (1.14-2.09)] and dihydroartemisinin [1.25 (1.06-1.47)] compared with day -6. The S-4'-hydroxymephenytoin/S-mephenytoin ratio (CYP2C19) was increased on day 5 by artemisinin [1.69 (1.47-1.94)] and arteether [1.33 (1.15-1.55)] compared with day -6. The paraxanthine/caffeine ratio (CYP1A2) was decreased on day 1 after administration of artemisinin [0.27 (0.18-0.39)], arteether [0.70 (0.55-0.89)] and dihydroartemisinin [0.73 (0.59-0.90)] compared with day -6. The alpha-hydroxymetoprolol/metoprolol ratio (CYP2D6) was lower on day 1 compared with day -6 in the artemisinin [0.82 (0.70-0.96)] and dihydroartemisinin [0.83 (0.71-0.96)] groups, respectively. In the artemisinin-treated subjects this decrease was followed by a 1.34-fold (1.14-1.58) increase from day 1 to day 5. These results show that intake of artemisinin antimalarials affect the activities of several principal human drug metabolizing CYP450 enzymes. Even though not significant in all treatment groups, changes in the individual metrics were of the same direction for all the artemisinin drugs, suggesting a class effect that needs to be considered in the development of new artemisinin derivatives and combination treatments of malaria.

In vitro assessment of artesunate, artemether and amodiaquine susceptibility and molecular analysis of putative resistance‐associated mutations of Plasmodium falciparum from São Tomé and Príncipe

To evaluate the basal in vitro responses of Plasmodium falciparum isolates collected in The Democratic Republic of São Tomé and Príncipe to artemether (ATH), artesunate (ATN) and amodiaquine (AMQ). The prevalence of given single nucleotide polymorphisms in the pfmdr1, pfcrt, pftctp and pfATPase6 genes was assessed by PCR-RFLP or DNA sequencing, and gene copy numbers were estimated by real-time PCR. Mean IC50s to ATH and ATN were relatively low (1.12 nm and 0.58 nm, respectively). However, 10% of parasites displayed AMQ IC50 values above the accepted resistance threshold of 60 nm and there was a positive association between susceptibility to all three drugs (ATH vs. ATN: R = 0.84; ATH vs. AMQ: R = 0.68; ATN vs. AMQ: R = 0.72). Mutations in the pfcrt and pfmdr1 genes were highly prevalent, while only one synonymous polymorphism was detected in the pfATPase6 gene and no mutations were found in pftctp. All isolates harboured a single copy of the genes studied. Artemisinin combination treatment in the São Tomé and Príncipe should be efficacious, although a significant number of AMQ-resistant parasites were detected and the susceptibility to each drug was positively associated with that of the other two. Mutations in the pfcrt and pfmdr1 genes are near fixation, most likely because of high levels of chloroquine resistance, whereas only one protein type of the artemisinin resistance candidate, PfATPase6, was identified.

Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial

Objective To compare rapid diagnostic tests (RDTs) for malaria with routine microscopy in guiding treatment decisions for febrile patients.Design Randomised trial.Setting Outpatient departments in northeast Tanzania at varying levels of...

Should New Antimalarial Drugs Be Subsidized?

We use analytical and numerical models to explain and quantify the welfare effects of subsidies for artemisinin combination treatments (ACTs), a valuable new class of antimalarial drugs. There are two (second-best) efficiency rationales for such subsidies: by expanding drug use, they reduce infection transmission from one individual to another, and they slow the evolution of drug resistance by deterring use of substitute monotherapy drugs for which resistance emerges more rapidly than for ACTs. Our analysis merges epidemiological models of malaria transmission among individuals and mosquitoes, evolution of drug resistance, and economic models of the demand for alternative drugs; parameter values for the simulations are representative of malaria prevalence in sub-Saharan Africa. We find that large subsidies for ACT are welfare improving across many plausible scenarios for malaria transmission, drug-demand elasticities, and evolution of drug resistance; the benefits of the policy are often several times larger than the costs.

Mechanisms of Drug Resistance in Malaria: Current and New Challenges

Anti-malarial chemotherapy based on a limited number of drugs has been the mainstay of malaria control for many decades. However, the lack of new effective and affordable drugs and the emergence and spread of drug resistant parasites is seriously hindering treatment strategies, and is contributing to the resurgence of malaria, especially that caused by Plasmodium falciparum. Present knowledge indicates that drug resistance in malaria emerges through selection of parasites harbouring genetic mutations that confer a selective advantage over sensitive parasites in the presence of drug pressure. Resistance to antifolates such as Fansidar®, (pyrimethamine in combination with sulphadoxine), is known to be caused by mutations in the genes encoding the drugs therapeutic targets, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). In the case of quinoline-based compounds, such as chloroquine and mefloquine, resistance is thought to be dependent on the exclusion of the drug from the site of action. This has been shown to be mediated by mutations in two genes denoted pfmdr1 and pfcrt, which encode proteins localized on the membrane of the parasitophorous food vacuole where these drugs are thought to act. In recent years, heath authorities have been increasingly recommending the use of Artemisinin Combination Treatment (ACT) in an effort to halt the spread of antimalarial drug resistance. Resistance to artemisinin derivatives has not yet been reported in natural human parasite populations, but it has already been achieved in rodent malaria models suggesting it may arise also in P. falciparum. Major focus should now be aimed at understanding the mechanisms of resistance to artemisinin derivatives before it becomes a serious public health problem. The post-genomic era of malaria has opened unprecedented opportunities for a better understanding of drug resistance mechanisms and consequently, for rational design of novel compounds less prone to resistance. Keywords: Malaria, drug resistance, mechanisms, genomics, proteomics

Cultivation and genetics ofArtemisia annuaL. for increased production of the antimalarial artemisinin

Malaria has been treated for over 350 years with quinine and quinine-derived drugs. However, in several areas of the world, some strains of the malarial parasitePlasmodium falciparumhave developed resistance against these drugs. Recently, the World Health Organization (WHO) recommended the use of artemisinin-combination treatments (ACT) as the first-line treatment for multidrug-resistant falciparum malaria. The WHO estimates that current supplies of artemisinin are sufficient for only 30 million ACT, and is foreseeing the need for 130–220 million ACT in 2005 (WHO, 2004). Current research on the production of synthetic artemisinin-like compounds by the Roll Back Malaria project, pharmaceutical companies and academia resulted in a promising synthetic artemisinin-like compound (OZ277) which is currently undergoing phase I clinical trials. In about 5 years this drug is expected to be approved and made available to the public, however, meeting current global demands for ACT depends on the immediate availability of affordable artemisinin-derived drugs. This will involve expansion of the area under cultivation ofArtemisia annuaand improved methods of cultivation and processing of raw material, associated with more efficient methods for extraction and purification of artemisinin from plant material. This review addresses the agricultural, environmental and genetic aspects that may be useful in the successful large-scale cultivation ofA. annuaand for producing the antimalarial artemisinin in areas where it is urgently needed today. It also includes geographic aspects (latitude and altitude), which will help make decisions about crop establishment in tropical countries, and includes a list of Good Agricultural and Collection Practices forA. annua.

The Benefits of Artemisinin Combination Therapy for Malaria Extend Beyond the Individual Patient

Garner and Graves discuss the implications of a new study in PLoS Medicine that found that artemisinin combination treatment reduces infectiousness.

Economic Access to Effective Drugs for Falciparum Malaria

The increasing death toll from drug-resistant falciparum malaria is cause for international concern. In 2002, the US Agency for International Development commissioned the Institute of Medicine (IOM) to recommend global actions to ensure the broadest possible access to new, effective antimalarial treatments. In a report issued in 2004, the IOM Committee on Economics of Antimalarial Drugs recommended a global subsidy of 300 million dollars to 500 million dollars per year to replace increasingly ineffective drugs with coformulated artemisinin combination treatments to be distributed through public and private channels in affected areas. This approach allows the existing market to support the switch to new drugs and keeps treatment costs for consumers at levels similar to the current price of chloroquine. The leverage of an international subsidy of combination therapy can also discourage the distribution of monotherapies (such as solo artemisinins), the use of which might foster increasing resistance to antimalarial drugs in the future.

COMPARISON OF THE PARASITOLOGIC EFFICACY OF AMODIAQUINE AND SULFADOXINE-PYRIMETHAMINE IN THE TREATMENT OF PLASMODIUM FALCIPARUM MALARIA IN THE BUNGOMA DISTRICT OF WESTERN KENYA

The efficacy of amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP) was assessed in 310 symptomatic children from western Kenya with uncomplicated Plasmodium falciparum malaria. A non-blinded, randomized, 14-day study was performed and parasitologic criteria were used. Of 310 patients included, 238 (77%) completed the study: 120 received AQ and 118 received SP. In those treated with AQ, there were sensitive (S) infections in 107 patients (89.2%, 95% confidence interval [CI] = 82.2, 94.1%), RI resistance in 10 (8.3%, 95% CI = 4.1, 14.8%), RII resistance in 1 (0.8%, 95% CI = 0, 4.6%), and RIII resistance in 2 (1.7%, 95% CI = 0.2, 5.9%). In those treated with SP, there were S infections in 74 patients (62.7%, 95% CI = 53.3, 71.4%), RI resistance in 21 (17.8%, 95% CI = 11.4, 25.9%), RII resistance in 11 (9.3%, 95% CI = 4.7, 16.1%), and RIII resistance in 12 (10.2%, 95% CI = 5.4, 17.1%). Resistance rates were consistently higher in the SP-treated patients (P < 0.001). Resistance to SP in this area has reached such levels that it should no longer be the first-line treatment. Alternative treatment, such as SP plus AQ combination treatment or artemisinin combination treatment, is urgently needed.