Treatment Of Plasmodium Falciparum Malaria Research Articles

Formulation development and evaluation of the anti-malaria properties of sustained release artesunate-loaded solid lipid microparticles based on phytolipids

Contexts: Artemisinins and its derivatives are considered the basis in the treatment of Plasmodium falciparum malaria due to their high potency and rapid action. However, they have short half life, low solubility, and poor oral bioavailability, hence the need to formulate sustained release lipid particulate dosage form of these drugs.Objectives: To formulate and evaluate artesunate-loaded solid lipid microparticles (SLMs) based on structured lipid matrices consisting of soybean oil and dika wax.Materials and methods: The lipid matrices were characterized by differential scanning calorimetry (DSC), small-angle X-ray diffraction (SAXD), and wide-angle X-ray diffraction (WAXD). The SLMs were prepared by hot melt-homogenization. Time-dependent particle size analysis, time-dependent pH stability studies, encapsulation efficiency (EE%), and in vitro drug release were carried out on the SLMs. In vivo anti-malarial studies were performed using a modified Peter’s 4-day suppressive protocol using Plasmodium berghei infected mice.Results and discussion: Thermograms of the lipid matrices showed modifications in the microstructure of dika wax as a result of inclusion of soybean oil. SAXD and WAXD diffractograms showed that the lipid matrices were found to be non-lamellar. Particle size of SLM increased with time, while the pH was almost constant. The SLMs had maximum EE% of 80.6% and sustained the release of artesunate more than the reference tablet. In vivo pharmacodynamic studies showed that the SLMs had significant (p < 0.05) reduction in parasitaemia compared with reference tablet.Conclusion: Artesunate-loaded SLMs could be used once daily in the treatment of malaria.

Evaluation of parasite subpopulations and genetic diversity of the msp1, msp2 and glurp genes during and following artesunate monotherapy treatment of Plasmodium falciparum malaria in Western Cambodia

BackgroundDespite widespread coverage of the emergence of artemisinin resistance, relatively little is known about the parasite populations responsible. The use of PCR genotyping around the highly polymorphic Plasmodium falciparum msp1, msp2 and glurp genes has become well established both to describe variability in alleles within a population of parasites, as well as classify treatment outcome in cases of recurrent disease. The primary objective was to assess the emergence of minority parasite clones during seven days of artesunate (AS) treatment in a location with established artemisinin resistance. An additional objective was to investigate whether the classification of clinical outcomes remained valid when additional genotyping was performed.MethodsBlood for parasite genotyping was collected from 143 adult patients presenting with uncomplicated falciparum malaria during a clinical trial of AS monotherapy in Western Cambodia. Nested allelic type-specific amplification of the genes encoding the merozoite surface proteins 1 and 2 (msp1 and msp2) and the glutamate-rich protein (glurp) was performed at baseline, daily during seven days of treatment, and again at failure. Allelic variants were analysed with respect to the size of polymorphisms using Quantity One software to enable identification of polyclonal infections.ResultsConsiderable variation of msp2 alleles but well-conserved msp1 and glurp were identified. At baseline, 31% of infections were polyclonal for one or more genes. Patients with recurrent malaria were significantly more likely to have polyclonal infections than patients without recurrence (seven of nine versus 36 of 127, p = 0.004). Emergence of minority alleles during treatment was detected in only one of twenty-three cases defined as being artemisinin resistant. Moreover, daily genotyping did not alter the final outcome classification in any recurrent cases.ConclusionsThe parasites responsible for artemisinin-resistant malaria in a clinical trial in Western Cambodia comprise the dominant clones of acute malaria infections rather than minority clones emerging during treatment. Additional genotyping during therapy was not beneficial. Disproportionately high rates of polyclonal infections in cases of recurrence suggest complex infections lead to poor treatment outcomes. Current research objectives should be broadened to include identification and follow-up of recurrent polyclonal infections so as to define their role as potential agents of emerging resistance.

Prevalence of Polymorphisms in Antifolate Drug Resistance Molecular Marker Genes pvdhfr and pvdhps in Clinical Isolates of Plasmodium vivax from Kolkata, India

Sulfadoxine-pyrimethamine has never been recommended for the treatment of Plasmodium vivax malaria as the parasite is intrinsically resistant to pyrimethamine. The combination was introduced as a promising agent to treat Plasmodium falciparum malaria in many countries but was withdrawn after a few years due to development and spread of resistant strains. Presently, sulfadoxine-pyrimethamine is used as a partner drug of artemisinin-based combination therapy to treat uncomplicated falciparum malaria, and a combination of artesunate-sulfadoxine-pyrimethamine is currently in use in India. In countries like India, where both P. vivax and P. falciparum are equally prevalent, some proportion of P. vivax bacteria is exposed to sulfadoxine-pyrimethamine due to misdiagnosis and mixed infections. As reports on the in vivo therapeutic efficacy of sulfadoxine-pyrimethamine in P. vivax are rare, the study of mutations in the marker genes P. vivax dhfr (pvdhfr) and pvdhps is important for predicting drug selection pressure and sulfadoxine-pyrimethamine resistance monitoring. We studied the prevalence of point mutations and haplotypes of both the genes in 80 P. vivax isolates collected from urban Kolkata, India, by the DNA sequencing method. Point mutation rates in both the genes were low. The double mutant pvdhfr A15N50R58N117I173 (mutations are in boldface) and the single mutant pvdhps genotype S382G383K512A553V585 were more prevalent, while 35% of the isolates harbored the wild-type genotype. The triple mutant ANRNI-SGKAV was found in 29.9% isolates. No quintuple mutant genotype was recorded. The P. vivax parasites in urban Kolkata may still be susceptible to sulfadoxine-pyrimethamine. Hence, a combination of antimalarial drugs like artesunate-sulfadoxine-pyrimethamine introduced for P. falciparum infection might be effective in P. vivax infection also. Study of the therapeutic efficacy of this combination in P. vivax is thus strongly suggested. (The study protocol was registered in the Clinical Trial Registry-India [CTRI] of the Indian Council of Medical Research under registration number CTRI/2011/09/002031.).

Efficacy of Chloroquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Honduras

Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization-World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras.

In vitro interaction of artemisinin derivatives or the fully synthetic peroxidic anti-malarial OZ277 with thapsigargin in Plasmodium falciparum strains

BackgroundSemi-synthetic artemisinin derivatives are powerful peroxidic drugs in artemisinin-based combination therapy (ACT) recommended as first-line treatment of Plasmodium falciparum malaria in disease-endemic countries. Studies by Eckstein-Ludwig and co-workers showed both thapsigargin and artemisinin specifically inhibit the sarcoplasmic reticulum Ca2+−ATPase of Plasmodium falciparum (PfATP6). In the present study the type of interaction between thapsigargin and artemisinin derivatives as well as the ozonide OZ277 (RBx11160 or arterolane) was evaluated in parasite cultures. The latter compound is an adamantane-based peroxide and the first fully synthetic clinical candidate recently registered in India by Ranbaxy Laboratories Ltd. for anti-malarial combination therapy.MethodsDrug interaction studies were performed using a previously described fixed ratio method and anti-malarial activity measured using the [3H] hypoxanthine incorporation assay.ResultsThe sum 50% and 90% fractional inhibitory concentration (∑FIC50, 90) of the interaction of thapsigargin with OZ277, artemether or artesunate, against NF54 and K1 strains of P. falciparum ranged from 0.9 to 1.4.ConclusionThe interaction of thapsigargin with OZ277, artesunate or artemether was additive, data consistent with previous observations indicating that activity of anti-malarial peroxides does not derive from reversible interactions with parasite targets.

Pharmacokinetic Profile of Artemisinin Derivatives and Companion Drugs Used in Artemisinin-Based Combination Therapies for the Treatment of Plasmodium falciparum Malaria in Children

Malaria is one of the most common parasitic infections worldwide. Plasmodium falciparum is the most prevalent strain in Africa and also the most fatal. The disease especially affects children, with those under age 5 years accounting for approximately 86 % of malaria deaths in 2010. The objectives of this review are to summarize and evaluate published literature reporting the pharmacokinetic parameters of artemisinin-based combinations used to treat P. falciparum in paediatric populations and to identify and discuss controversies regarding pharmacokinetics of these agents in children. A search of MEDLINE (1948-September 2012), EMBASE (1980-September 2012), International Pharmaceutical Abstracts (1970-September 2012), Google and Google Scholar was conducted for articles describing pharmacokinetics of antimalarials in children. Our search produced 30 articles, of which 23 were included in the review: artemisinin compounds, 12 articles; lumefantrine, four articles; amodiaquine, five articles; sulfadoxine, six articles; pyrimethamine, one article; mefloquine, three articles; and piperaquine, two articles. Studies were summarized based on comparison groups and major findings. Many controversies were identified, including pharmacokinetic equivalence of novel dosage forms, altered pharmacokinetic parameters in children versus adults, effect of drug interactions, and association of pharmacokinetic changes with clinical outcomes. A large variation in pharmacokinetic parameters of many antimalarial agents was shown, which may be a consequence of the wide range of ages and/or bodyweights of each paediatric cohort. These studies may mask important associations with age and bodyweight and produce mean data that do not adequately represent the paediatric population as a whole. In order to properly assess the clinical implications of such pharmacokinetic changes and recommend safe and effective dosage regimens, there is an urgent need for dose-optimization studies for all recommended first- and second-line agents, along with the different drug formulations, used in paediatric populations with P. falciparum.

Molecular assessment of atpase6 mutations associated with artemisinin resistance among unexposed and exposed Plasmodium falciparum clinical isolates to artemisinin-based combination therapy

BackgroundArtemisinin-based combination therapy (ACT) is the mainstay of global efforts for treatment of Plasmodium falciparum malaria, but decline in its efficacy is the most important obstacle towards malaria control and elimination. Therefore, the present molecular analysis provides information on putative mutations associated with artemisinin resistance in P. falciparum clinical population unexposed and exposed to artesunate 4 years after adoption of ACT as the first-line anti-malarial therapy in Iran.MethodsIn this study, blood samples (n = 226) were collected from uncomplicated P. falciparum-infected patients from different health centers of Chabahar district in Sistan and Baluchistan province in the south-eastern part of Iran, during 2003 to 2010. All collected isolates were analysed for putative candidate mutations (TTA) L263E (GAA), (GAA) E431K (AAA), (GCA) A623E (GAA) and (AGT) S769N (AAT) of pfatpase6 gene using nested PCR/RFLP, followed by sequencing. Furthermore, the gene copy number was assessed by real-time quantitative PCR (RT-qPCR) in the presence of SYBR green.ResultsNeither the pfatpase6 L263E nor the A623E mutation was detected among all examined isolates. The E431K mutation was found in 23% of the analysed samples unexposed to ACT; however, it was detected in 17.8% (34/191) of P. falciparum isolates exposed to artesunate after 2007. High frequency of this single nucleotide polymorphisms (SNP) (overall 18.6%) among both examined groups (X2 test, P>0.05) indicated that this SNP should be considered as an unrelated mutation to artemisinin resistance. In contrast, S769N mutation was not detected in unexposed isolates; however, it was found in 2.6% (5/191), four years after introduction of ACT in this malaria setting. Also, detected SNPs were not significantly frequent in both unexposed and exposed examined isolates (X2 test, P> 0.05). Investigation in the copy number of pfatpase6 gene revealed a similar number of copy (n = 1) as in an isolate sensitive to artemisinin.ConclusionTaken together, the results suggest, in particular, that pfatpase6 S769N gene needs more consideration for its possible association with artesunate resistance among P. falciparum isolates.

Surveillance of molecular markers of Plasmodium falciparum resistance to sulphadoxine-pyrimethamine 5 years after the change of malaria treatment policy in Ghana.

In 2005, sulphadoxine-pyrimethamine (SP) became the drug of choice for intermittent preventive treatment of Plasmodium falciparum malaria in pregnancy (IPTp) in Ghana. Reports suggest the use of SP by others to treat uncomplicated malaria. Because of the increased use of SP, the prevalence of mutations in the genes, dihydrofolate reductase (dhfr), and dihydropteroate synthetase (dhps), linked to SP resistance in P. falciparum were determined. Blood samples from 945 children with uncomplicated malaria collected at nine sites from 2003 to 2010 were analyzed using polymerase chain reaction and restriction fragment length polymorphism. Prevalence of the dhfr triple and dhfr plus dhps quadruple mutations showed significant increase in trend from 2003 to 2010 (χ(2) = 18.78, P < 0.001, χ(2) = 15.11, P < 0.001, respectively). For dhps double mutant G437 + E540 the prevalence was low (1.12%) caused by the very low prevalence of E540. Our findings show the wide use of SP in Ghana and therefore its use for IPTp needs to be closely monitored.

New drugs from ancient texts

Professor Karl Wah-Keung Tsim, a neurobiologist who heads a research team in the Life Science Division of the Hong Kong Special Administrative Region University of Science and Technology, believes that, for all the challenges it may face, traditional Chinese medicine is potentially a pharmacological gold mine. There are around 100 000 formulas going back 2000 years, drugs that can be used to treat a range of illnesses from depression and insomnia, to osteoporosis, he says, pointing out that researchers have already found at least one gem in the form of artemisinin, which is known as qinghaosu in Mandarin. The therapeutic value of artemisinin m the treatment of Plasmodium falciparum malaria was discovered in 1972 by Professor Tu Youyou, a member of the China Academy of Chinese Medical Sciences in Beijing, who researched traditional medicine texts as well as folk remedies. But artemisinin is one of only a few derivatives of traditional drugs to make the jump from ancient texts to contemporary science-based medicine, and it is certainly the only example so far of a drug that could be described as a gem. Chinese medicine, in this context, is distinct from other forms of traditional medicine, such as Ayurvedic medicine, or other forms of traditional medicine. medicine, primarily the use of a combination of herbs prescribed in compounds, is hugely important in China, where it represents around 40% of the Chinese pharmaceutical market, with annual sales of US$ 21 billion. A popular choice among patients in China, it is also a choice that the government increasingly supports. According to Vice Health Minister, Wang Guoqiang, in 2011 the Chinese government invested roughly US$1 billion (RMB 6 billion) in traditional medicine research and projects, nearly tripling the amount invested in 2010. More than RMB 4 billion of that was used to support services in Chinas 1814 traditional medicine hospitals while another 1 billion went into building 70 county-level traditional medicine hospitals. Traditional hospitals constitute around 15% of the total hospital system, explains Dr Zhang Qi, coordinator of the traditional medicine team at the World Health Organization (WHO), who notes that traditional Chinese medicine is also offered in the country's so-called 'western medical hospital'. Chinese medicine is big in China and other Asian countries, where, according to WHO, up to 80% of some populations use it for health care. However, it is less accepted elsewhere, partly because of the lack of an evidence base as well as concerns about quality. Such doubts are typified by the reports produced on a regular basis by the Medicines Healthcare Products Regulatory Agency in the United Kingdom of Great Britain and Northern Ireland, which recently said that there is a substantial global trade in Chinese remedies of questionable quality. In an attempt to prevent the sale of poor-quality products, in May 2011 the European Union made it illegal to sell any traditional Chinese herbal treatments not registered under the European Union Herbal Medicines Registration Scheme. Improving drug quality standards is at the top of Chinas agenda and is the focus of the work being done by Professor Liu Liang, director of the State Key Laboratory for Quality Research in Chinese Medicines, in Macau, China, where he and his team of researchers are working on quality control of traditional Chinese medicines, using contemporary technology. Our main focus is how to arrive at some standards in order to achieve consistency in production, including in the manufacturing process, Liang says. Convincing the global research and development community of the evidence basis for traditional Chinese medicine is proving even more challenging than establishing quality standards. However, here too Chinese researchers in state and academic institutions are pushing forward. They are trying to isolate the active ingredients of traditional medicines, a task made difficult because most Chinese medicines contain multiple components. …

Artemisinin-Resistant Malaria: Research Challenges, Opportunities, and Public Health Implications

Artemisinin-based combination therapies are the most effective drugs to treat Plasmodium falciparum malaria. Reduced sensitivity to artemisinin monotherapy, coupled with the emergence of parasite resistance to all partner drugs, threaten to place millions of patients at risk of inadequate treatment of malaria. Recognizing the significance and immediacy of this possibility, the Fogarty International Center and the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health convened a conference in November 2010 to bring together the diverse array of stakeholders responding to the growing threat of artemisinin resistance, including scientists from malarious countries in peril. This conference encouraged and enabled experts to share their recent unpublished data from studies that may improve our understanding of artemisinin resistance. Conference sessions addressed research priorities to forestall artemisinin resistance and fostered collaborations between field- and laboratory-based researchers and international programs, with the aim of translating new scientific evidence into public health solutions. Inspired by this conference, this review summarizes novel findings and perspectives on artemisinin resistance, approaches for translating research data into relevant public health information, and opportunities for interdisciplinary collaboration to combat artemisinin resistance.

No Evidence of Decreased Artemisinin Efficacy in a High-Transmission Malaria Setting in Mali

No Evidence of Decreased Artemisinin Efficacy in a High-Transmission Malaria Setting in Mali

Operational research in non-governmental organisations: necessity or luxury?

We are in a hospital out-patient clinic in a sub-Saharan African country, where doctors are busy treating malaria cases. A prescription for chloroquine is given to a patient who complains that he has already taken the drug several times and it does not work. He asks for an alternative, but the doctor says that chloroquine is what is recommended and that it is the only medicine available. When research was initially proposed to assess the situation, there was strong resistance by the implementers: ‘We are too busy and have no time for research.’ Several months later, operational research (OR) conducted by a non-governmental organisation (NGO) proved that the patient was correct—chloroquine treatment had a 91% failure rate, and the drug was not effective for treating Plasmodium falciparum malaria.1,2 The lesson learnt was that the clinicians were busy with consultations, but actually giving useless medicine. In that context, OR helped us to be accountable to ourselves, our patients and our donors. This example does not lay blame on the clinicians in this setting, who often do the best they can with very limited resources. It illustrates why, about a decade ago, Medecins Sans Frontieres (MSF–Brussels), an international NGO, began to realise—late as this may have been—that during the implementation of programmes, a culture of inquiry is essential to show what works and what does not, and to find practical solutions.3,4 Since then, some important indicators of institutional involvement in research include: allocation of dedicated human resources; a 10-fold increase in output of publications; establishment of an MSF ethics review board;5 an innovation fund; and an on-line repository allowing open access to all publications written by MSF staff.3 We ask, what is the definition of OR in an NGO, why is it essential, and what are some of the key elements in building it? From an NGO perspective, a pragmatic definition is ‘the search for knowledge on interventions, strategies and tools that can enhance the quality or performance of programs’.3 Broadly speaking, OR is thus the ‘science of doing better’. Why is it relevant for implementing NGOs? The key reasons include 1) improving programme performance, 2) assessing the feasibility of new strategies and/or interventions, and 3) to advocate for policy change. Additional positive spin-offs include improved medical visibility and credibility, better knowledge of the scientific literature among field staff, facilitation of networking and partnerships and improvements in data collection, monitoring and feedback. What are the key elements to building OR within an NGO? Our experience has been described elsewhere;2,3 these include: establishing a ‘critical mass’ of dedicated human resources; developing an OR policy guideline (a road-map); defining a mechanism for generating programme-relevant research questions and integrating them into annual plans; establishing a research registry to avoid duplication of studies; and strong dissemination, including publishing in peer-reviewed journals.6 These aspects need to be accompanied by capacity building approaches that are practical and output based.7 Despite a plethora of over 37 000 NGOs globally involved with activities at various levels of society,4 the complimentary role OR can play in making their actions more effective is poorly understood and utilised. Implementing NGOs have a vital role to play in changing society for the better. Integrating OR into that vision will not only help to know objectively what is happening on the ground, it will also make them more effective advocates to demand improvements and accountability from policy makers and governments. Operational research is not a luxury; it should be an integral part of all NGOs’ programmes.

Early treatment failure during treatment of Plasmodium falciparum malaria with atovaquone-proguanil in the Republic of Ivory Coast

The increased spread of drug-resistant malaria highlights the need for alternative drugs for treatment and chemoprophylaxis. The combination of atovaquone‐proguanil (Malarone®) has shown high efficacy against Plasmodium falciparum with only mild side-effects. Treatment failures have been attributed to suboptimal dosages or to parasite resistance resulting from a point mutation in the cytochrome b gene. In this paper, a case of early treatment failure was reported in a patient treated with atovaquone-proguanil; this failure was not associated with a mutation in the parasite cytochrome b gene, with impaired drug bioavailability, or with re-infection.

Artemether-Lumefantrine: An Option for Malaria

To review the pharmacology, pharmacokinetics, safety, and efficacy of artemether-lumefantrine for the treatment of Plasmodium falciparum malaria. English-language articles indexed in PubMed (1947-November 2011) were identified, using the search terms artemether-lumefantrine, artemether-lumefantrine AND malaria, Coartem, and Coartem AND malaria. Available English-language articles were reviewed. In addition, the malaria treatment regimens recommended by region as provided by the World Health Organization and the treatment guidelines from the Centers for Disease Control and Prevention were reviewed. Artemether-lumefantrine is an artemisinin-derived combination antimalarial approved by the Food and Drug Administration in 2009 for the treatment of P. falciparum malaria. The dual mechanisms of action of artemether-lumefantrine provide rapid and sustained parasite clearance. In the reviewed studies, the polymerase chain reaction (PCR)-corrected 28-day cure rates of artemether-lumefantrine were noninferior to the most common comparators, including chloroquine, dapsone, and other artemisinin derivatives (86-100% vs 51-100%, respectively). PCR-corrected day-42 cure rates were 92-99.3% for artemether-lumefantrine versus 62-100% for the comparator groups. The major adverse effects (gastrointestinal and central nervous system) were mild to moderate in severity and did not require a change in therapy. Although adherence to artemether-lumefantrine has been described as a potential problem due to the complicated dosing schedule, studies have described clinical cure rates similar to those of other antimalarials. Artemether-lumefantrine is a safe and effective treatment for children and adults with P. falciparum malaria.

Can we teach an old drug new tricks?

Although resistance to chloroquine (CQ) has relegated it from modern chemotherapeutic strategies to treat Plasmodium falciparum malaria, new evidence suggests that higher doses of the drug may exert a different killing mechanism and offers this drug a new lease of life. Whereas the established antimalarial mechanisms of CQ are usually associated with nanomolar levels of the drug, micromolar levels of CQ trigger a distinct cell death pathway involving the permeabilization of the digestive vacuole of the parasite and a release of hydrolytic enzymes. In this paper, we propose that this pathway is a promising antimalarial strategy and suggest that revising the CQ treatment regimen may elevate blood drug levels to trigger this pathway without increasing the incidence of adverse reactions.

Why do Plasmodium malariae infections sometimes occur in spite of previous antimalarial medication?

Quartan malaria due to Plasmodium malariae is commonly regarded as being preventable by current antimalarials. A case of P. malariae infection occurred in spite of previous treatment of Plasmodium falciparum malaria 4 months earlier with a full therapy course of intravenous quinine hydrochloride and oral doxycycline followed by artemether + lumefantrine. Since the patient was not anymore exposed to agents of malaria in the meantime, a new infection by P. malariae after therapy is unlikely. The present observation is difficult to explain by the current view on the origin of latent P. malariae infections and recurrences which are thought to arise from intra-erythrocytic development stages susceptible to common antimalarials. The most likely explanation of our observation is a delayed pre-erythrocytic development. The latency between infection by P. malariae and the quartan malaria fever attack might have been extended further by an initial subclinical circulation of a low number of intra-erythrocytic asexual parasites in the blood stream preceeding the clinical quartan malaria breakthrough.

In vivo efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria in Central Ethiopia

BackgroundIn vivo efficacy assessments of the first-line treatments for Plasmodium falciparum malaria are essential for ensuring effective case management. In Ethiopia, artemether-lumefantrine (AL) has been the first-line treatment for uncomplicated P. falciparum malaria since 2004.MethodsBetween October and November 2009, we conducted a 42-day, single arm, open label study of AL for P. falciparum in individuals >6 months of age at two sites in Oromia State, Ethiopia. Eligible patients who had documented P. falciparum mono-infection were enrolled and followed according to the standard 2009 World Health Organization in vivo drug efficacy monitoring protocol. The primary and secondary endpoints were PCR uncorrected and corrected cure rates, as measured by adequate clinical and parasitological response on days 28 and 42, respectively.ResultsOf 4426 patients tested, 120 with confirmed falciparum malaria were enrolled and treated with AL. Follow-up was completed for 112 patients at day 28 and 104 patients at day 42. There was one late parasitological failure, which was classified as undetermined after genotyping. Uncorrected cure rates at both day 28 and 42 for the per protocol analysis were 99.1% (95% CI 95.1-100.0); corrected cure rates at both day 28 and 42 were 100.0%. Uncorrected cure rates at day 28 and 42 for the intention to treat analysis were 93.3% (95% CI 87.2-97.1) and 86.6% (95% CI 79.1-92.1), respectively, while the corrected cure rates at day 28 and 42 were 94.1% (95% CI 88.2-97.6) and 87.3% (95% CI 79.9-92.7), respectively. Using survival analysis, the unadjusted cure rate was 99.1% and 100.0% adjusted by genotyping for day 28 and 42, respectively. Eight P. falciparum patients (6.7%) presented with Plasmodium vivax infection during follow-up and were excluded from the per protocol analysis. Only one patient had persistent parasitaemia at day 3. No serious adverse events were reported, with cough and nausea/vomiting being the most common adverse events.ConclusionsAL remains a highly effective and well-tolerated treatment for uncomplicated falciparum malaria in the study setting after several years of universal access to AL. A high rate of parasitaemia with P. vivax possibly from relapse or new infection was observed.Trial RegistrationNCT01052584

Chloroquine resistance status a decade after: Re-emergence of sensitive Plasmodium falciparum strains in malaria endemic and epidemic areas in Kenya

Development and spread of chloroquine (CQ) resistance led to its withdrawal in most malaria endemic countries. In Kenya, this occurred in 1998 when clinical efficacy dropped below 50%. Less than a decade after CQ was removed from routine use in Malawi, the drug has reversed to activity and is again effective for first-line treatment of uncomplicated malaria. There is a probability of a similar reversed activity in Kenya for more 10 years of its absence in uncomplicated Plasmodium falciparum malaria treatment. The present study was aimed at establishing the CQ resistance status in the country, 10 years after its withdrawal, by looking at high malaria transmission zone, Mbita, a malaria endemic area and some malaria epidemic areas of the Kenyan highlands. The prevalence of T76 and Y86 P. falciparum molecular markers for CQ resistance in Pfcrt and Pfmdr1 genes were investigated by PCR-RFLP and dot blot analysis in 64 samples collected in March to May 2007 in the endemic area and 38 samples collected in April to July the same year in the epidemics. The study shows that 67.3% of field isolates from the endemic site still harbor Y86 mutation in Pfmdr1 while 32.7% have the wild type allele N86 compared to the 94% and 6 % prevalence observed in Mwea, an endemic area, in 2004 (χ 2 =10.08, P=0.00015, 95% CI=2.085-27.8). In the epidemics 75% of field isolates from the epidemic sites still harbor Y86 mutation in Pfmdr1 while 25% have the wild type allele N86 compared to the 91.6% and 8.4% prevalence observed in an epidemic area in 1997 (χ 2 =1.585, P=0.208, 95% CI=0.701-19.176). From the study there is a significant change in the proportions of the resistant genotypes in the endemic areas while in the epidemics, there was also a noticeable shift though not significant. This therefore indicates a slow but steady re-emergence of P. falciparum CQ sensitive strains in the country. Though does not warrant the reintroduction of CQ for malaria treatment.

Widespread Availability of Artemisinin Monotherapy in the United States

To the Editor: Artemisinin-based combination therapies are recommended as first line treatments for Plasmodium falciparum malaria in most areas of the world. The article by Shahinas et al. (1) describes a patient who had P. falciparum malaria after returning from Nigeria. Her isolate had an elevated 50% inhibitory concentration to artemisinin derivatives. She had obtained artesunate in Nigeria and took it weekly for malaria prophylaxis, which might have contributed to the relative resistance found.

Resistance to Artemisinin-based Combination Therapies in Uganda: An Impending Threat

Plasmodium falciparum malaria is one of the most significant causes of morbidity and mortality in tropical Africa. Chloroquine phosphate emerged as the revolutionary drug of choice for the prevention and treatment of malaria, pushing the previously administered quinine to the sidelines. However, since the 1970s, sensitivity to chloroquine has been on the decline. In response to this, health professionals began to turn to a different drug: artemisinin-based combination therapies (ACT). ACT is now accepted by the World Health Organisation (WHO) as the most effective strategy to treat Plasmodium falciparum malaria, despite some initial misgivings (their long-term usefulness has yet to be determined). In this light, based on a few tentative studies conducted since 2003, the WHO has established an emerging, yet noticeable, trend in growing resistance to ACT drugs. Although, at this moment, there is no hard evidence of any ACT resistance within the Ugandan population, this paper will explore, through published and unpublished sources, and a baseline survey conducted in July 2008 by AMREF (African Medical and Research Foundation, an international medical organisation based in Kenya), how this resistance will soon emerge in Uganda, what the precipitating factors are, and through a careful evaluation of these causes, offer courses of action so as avoid the devastating consequences of ACT resistance. Author’s Note Elana Siegel graduated from Brown University as a pre-medical candidate with a major in Slavic Studies (with admission to the National Slavic Honor Society). In July and August of 2008 she worked as a research assistant for Col. (ret) Robert Leitch, M.B.E., in Uganda, for the African Medical Research Foundation (AMREF), in a project regarding a baseline study of the malaria, AIDS and TB (MAT) Integrated Model. She is a native of London, UK.