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Artesunate is the key antimalarial drug in the treatment of multidrug-resistant Plasmodium falciparum malaria in mainland southeast Asia. In China, Burma (Myanmar), Laos, Cambodia, and Vietnam it is widely available through the private sector. Widespread criminal production and distribution of counterfeit artesunate tablets in this region has resulted in the deaths of many people who would otherwise have survived their malaria infection. The spurious artesunate tablets contain no active drug. They are labelled to resemble a product, manufactured by Guilin Pharmaceutical Company, Guilin, People's Republic of China, that is the most commonly available brand of artesunate.1Rozendaal J Fake antimalarials circulating in Cambodia.Bull Mekong Malaria Forum. 2000; 7: 62-68Google Scholar, 2Newton PN Proux S Green M et al.Fake artesunate in southeast Asia.Lancet. 2001; 357: 1948-1950Summary Full Text Full Text PDF PubMed Scopus (195) Google Scholar In 2000–01, 38% of shop-bought oral artesunate sampled in Vietnam, Cambodia, Laos, and Burma, did not contain the active drug. However, the appearance of the packaging allowed detection of counterfeit tablets, which could be confirmed by the Fast-Red dye test.3Green MD Mount DL Wirtz RA Authentication of artemether, artesunate and dihydroartemisin in antimalarial tablets using a simple colorimetric method.Trop Med Int Health. 2001; 6: 980-982Crossref PubMed Scopus (64) Google Scholar Some blisterpacks containing the fake tablets bore a poor, easily recognisable, copy of the genuine hologram. During a more recent larger survey of fake antimalarials in this region, we noticed two new sophisticated fake hologram styles on artesunate blisterpacks in southern Laos and northern Cambodia (see www.shoklo-unit.com/fakeas2.pdf for photographs). High-performance liquid chromatography confirmed the absence of artesunate. The main distinguishing features of the first new counterfeit, from the genuine product are a different mountain silhouette and the absence of the legend Guilin Pharma written on the hologram. This can just be seen with the naked eye as a pale strip. The printing on the counterfeit blisterpack is less clear than that on the genuine product and all four samples collected were printed with the code 00902 and manufacture and expiry dates of 09/00 and 09/03. Blisterpacks with a second fake hologram style, bought in southern Laos in 2003, are indistinguishable from the genuine hologram, apart from the absence of the microscopic legend Guilin Pharma. The samples collected have the code 010901 with manufacture and expiry dates of 09/01 and 09/04. Artesunate was collected from 22 pharmacies in southern Laos, of which 19 offered only counterfeit drug, all of which were labelled as made by Guilin Pharma. Since these new counterfeits are so convincing, they are probably escaping detection elsewhere in Asia and could be disseminated to other continents. In Cambodia, a poster and television campaign warning the public of the existence of fake artesunate and informing them how to identify such tablets seems to have driven the trade in counterfeit artesunate underground.1Rozendaal J Fake antimalarials circulating in Cambodia.Bull Mekong Malaria Forum. 2000; 7: 62-68Google Scholar Health personnel will find the latest counterfeits much more difficult to identify, because they differ from the genuine product only in subtle characteristics. Earlier reports1Rozendaal J Fake antimalarials circulating in Cambodia.Bull Mekong Malaria Forum. 2000; 7: 62-68Google Scholar, 2Newton PN Proux S Green M et al.Fake artesunate in southeast Asia.Lancet. 2001; 357: 1948-1950Summary Full Text Full Text PDF PubMed Scopus (195) Google Scholar of the scale of the problem seem to have had little effect and research on fake drugs seems to be an example of applied health research with minimum effect on health policy. International organisations, including WHO, have done little to counter this lethal trade. This inaction is partly because of the lack of resources available for the regulation and policing of the drug supply in tropical countries, the secrecy of the pharmaceutical industry, possible links between the counterfeiters and officials in the producing countries, and because the effects of fake antimalarials are disguised in the unrecognised deaths of the rural poor.4R Cockburn, Crime, fear and silence: making public the fake pharmaceutical drug racket. Proceedings of the First Global Forum on Pharmaceutical Anti-Counterfeiting. Geneva, Switzerland, Sept, 2002.Google Scholar, 5Newton PN Rozendaal J Green M White NJ Murder by fake drugs—time for international action.BMJ. 2002; 324: 800-801Crossref PubMed Google Scholar Such failure to act contrasts with the recent rapid mobilisation of public-health resources to counter severe acute respiratory syndrome in the same region. We believe that urgent action is needed to find, prosecute, and close down the factories, collect and incinerate all suspect artesunate, prosecute the shops selling it, warn the public, and ensure that inexpensive quality-assured antimalarial drugs are made readily available. We gratefully acknowledge all who have helped with collecting drug samples and for the help of Shunmay Yeung. This work was part of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme funded by the Wellcome Trust, UK.

Journal Article The pharmacokinetic properties of intramuscular quinine in Gambian children with severe falciparum malaria Get access D. Waller, D. Waller 1Nuffield Department of Clinical Medicine, University of Oxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar S. Krishna, S. Krishna 1Nuffield Department of Clinical Medicine, University of Oxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar C. Craddock, C. Craddock 2Department of Haematology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar D. Brewster, D. Brewster 3Royal Victoria Hospital, Banjul, The Gambia Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Jammeh, A. Jammeh 4Medical Research Council Laboratories, Fajara, The Gambia Search for other works by this author on: Oxford Academic PubMed Google Scholar D. Kwiatkowski, D. Kwiatkowski 4Medical Research Council Laboratories, Fajara, The Gambia Search for other works by this author on: Oxford Academic PubMed Google Scholar J. Karbwang, J. Karbwang 5Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar P. Molunto, P. Molunto 5Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic PubMed Google Scholar N.J. White N.J. White ∗ 1Nuffield Department of Clinical Medicine, University of Oxford, UK4Medical Research Council Laboratories, Fajara, The Gambia ∗Address reprint requests to Dr N. J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 84, Issue 4, July-August 1990, Pages 488–491, https://doi.org/10.1016/0035-9203(90)90009-4 Published: 01 August 1990 Article history Received: 27 September 1989 Accepted: 17 October 1989 Published: 01 August 1990

<ns4:p>Background Even on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission (&lt;24hours). Lactic acidosis, largely due to impairment of the microcirculatory flow due to parasite sequestration, is a main risk factor for poor outcome. There are no adjuvant treatments for severe malaria that target this complication. Sevuparin, a heparin-like drug, binds to <ns4:italic>Plasmodium falciparum</ns4:italic> erythrocyte membrane protein blocking merozoite invasion, preventing cytoadherence and transiently de-sequestering infected erythrocytes. Leading to improved microcirculatory flow by reversing/preventing parasite sequestration. If given early during admission this could result in improvements in outcomes . Sevuparin has been shown to be safe and well tolerated in adults with only some mild transient effects on activated partial thromboplastin time (APTT) were reported, without clinical consequences. Methods A Phase I trial designed to provide data on safety, dosing, feasibility of sevuparin as an adjuvant therapy in Kenya and Zambian children with severe malaria complicated by lactic acidosis (&gt; 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient’s APTT results using standard methods. Conclusions The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes. Registration PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021)</ns4:p>

No abstract is provided for this article.

Tradeoffs between reproduction and somatic maintenance are a frequently cited explanation for reproductive senescence in long‐lived vertebrates. Between‐individual variation in quality makes such tradeoffs difficult to detect and evidence for their presence from wild populations remains scarce. Here, we examine the factors affecting rates of senescence in maternal breeding performance in a natural population of red deer ( Cervus elaphus ), using a mixed model framework to control for between‐individual variance. Senescence began at 9 years of age in two maternal performance traits. In both traits, females that produced more offspring in early life had faster rates of senescence. This tradeoff is evident alongside significant effects of individual quality on late life breeding performance. These results present rare evidence in support of the disposable soma and antagonistic pleiotropy theories of senescence from a wild vertebrate population and highlight the utility of mixed models for testing theories of ageing.

Background The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known. Methods The relation between polymorphisms in the P falciparum multidrug resistant gene 1 (pfmdr1) and the in-vitro and in-vivo responses to mefloquine were assessed in 618 samples from patients with falciparum malaria studied prospectively over 12 years. pfmdr1 copy number was assessed by a robust real-time PCR assay. Single nucleotide polymorphisms of pfmdr1, P falciparum chloroquine resistance transporter gene (P falciparum) and P falciparum Ca2 ATPase gene (pfATP6) were assessed by PCR-restriction fragment length polymorphism. Findings Increased copy number of pfmdr1 was the most important determinant of in-vitro and in-vivo resistance to mefloquine, and also to reduced artesunate sensitivity in vitro. In a Cox regression model with control for known confounders, increased pfmdr1 copy number was associated with an attributable hazard ratio (AHR) for treatment failure of 6·3 (95% CI 2·9–13·8, p<0·001) after mefloquine monotherapy and 5·4 (2·0–14·6, p=0·001) after artesunate-mefloquine therapy. Single nucleotide polymorphisms in pfmdr1 were associated with increased mefloquine susceptibility in vitro, but not in vivo. Interpretation Amplification in pfmdr1 is the main cause of resistance to mefloquine in falciparum malaria. Relevance to practice Multidrug resistant P falciparum malaria is common in southeast Asia, but difficult to identify and treat. Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance. In this study we show that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with mefloquine. Increase in pfmdr1 copy number predicts failure even after chemotherapy with the highly effective combination of mefloquine and 3 days' artesunate. Monitoring of pfmdr1 copy number will be useful in epidemiological surveys of drug resistance in P falciparum, and potentially for predicting treatment failure in individual patients.

In some areas clinicians have combined parenteral artesunate and quinine in the belief that the 2 drugs would be additive or synergistic in severe malaria. A randomized comparison of the effectiveness of intravenous (i.v.) artesunate versus i.v. artesunate and i.v. quinine together on parasite clearance was conducted in 1998/99 amongst 69 patients with uncomplicated and severe Plasmodium falciparum malaria in western Thailand. The parasite clearance time did not differ significantly between the 2 treatment groups (P = 0.12), but adverse events were significantly more frequent in the artesunate plus quinine group (P = 0.05). Quinine did not have a significant antipyretic effect and artesunate did not affect the electrocardiographic QTc interval. There is no benefit evident from combining parenteral administration of these 2 antimalarial drugs in the acute phase of treatment.

Objective Antimalarial chemoprophylaxis for high risk groups in endemic areas of Southeast Asia has the potential to reduce malaria transmission and accelerate elimination. However, the optimal choice of medication and dosing for many potential candidates is not clear. For a planned randomised controlled trial of prophylaxis for forest goers in Cambodia, artemether-lumefantrine (AL) was selected because of its ongoing efficacy and excellent tolerability and safety. As AL had not been used before for this purpose, a previously published pooled pharmacometric meta-model was used to determine the optimal dosing schedule. Results A full 3 day AL treatment course given twice a month, and twice daily treatment given once a week, resulted in trough concentrations consistently above the therapeutic threshold of 200 ng/mL. However, the most favourable exposure profile, and arguably most practical dosing scenario, was an initial 3 day full AL treatment course followed by twice daily dosing given once a week for the duration of chemoprevention. The latter was adopted as the dosing schedule for the trial.

Artesunate is the most widely used of the artemisinin derivatives. These drugs are being used increasingly throughout the tropical world, and are an essential component of the treatment of multi-drug resistant malaria. The recent and widespread appearance of counterfeit artesunate tablets in several countries in Southeast Asia poses a serious threat to health in this region. We have developed a simple, inexpensive colorimetric test to determine artesunate authenticity in tablets. The test is based on a reaction between an alkali decomposition product of artesunate and a diazonium salt, fast red TR (FRTR). The appearance of a yellow color indicates the presence of artesunate. The specificity of the test is dependent on the pH of the reaction. Among other antimalarials tested, (i.e. artemisinin, artemether, chloroquine, quinine, primaquine, sulfadoxine, and pyrimethamine) only artesunate produced a positive color reaction at pH 4. The assay requires only 1% of the total weight of a standard tablet containing 50 mg of artesunate and can be completed within 10 min. The method was tested on six genuine artesunate tablets and six counterfeit artesunate tablets obtained in Southeast Asia. The average amount of artesunate in the genuine tablets was determined to be 50.8±2.9 mg while the counterfeit tablets were found to contain no artesunate.

<title>Abstract</title> <bold>Background</bold> Artemisinin resistance in <italic>Plasmodium falciparum</italic> threatens global malaria elimination efforts. To contain and then eliminate artemisinin resistance in Eastern Myanmar a network of community-based malaria posts was instituted and targeted mass drug administration (MDA) with dihydroartemisinin-piperaquine (three rounds at monthly intervals) was conducted. The prevalence of artemisinin resistance during the elimination campaign (2013-2019) was characterized. <bold>Methods</bold> Throughout the six-year campaign<italic> Plasmodium falciparum</italic> positive blood samples from symptomatic patients and from cross-sectional surveys were genotyped for mutations in kelch-13 – a molecular marker of artemisinin resistance. <bold>Result</bold> The program resulted in near elimination of falciparum malaria. Of 5,162 <italic>P. falciparum</italic> positive blood samples genotyped, 3,281 (63.6%) had K13 mutations. The prevalence of K13 mutations was 73.9% in 2013 and 64.4% in 2019. Overall, there was a small but significant decline in the proportion of K13 mutants (p&lt;0.001). In the MDA villages there was no significant change in the K13 proportions before and after MDA. The distribution of different K13 mutations changed substantially; F446I and P441L mutations increased in both MDA and non-MDA villages, while most other K13 mutations decreased. The proportion of C580Y mutations fell from 9.2% (43/467) before MDA to 2.3% (19/813) after MDA (p&lt;0.001). Similar changes occurred in the 487 villages where MDA was not conducted. <bold>Conclusion</bold> The malaria elimination program in Kayin state, eastern Myanmar, led to a substantial reduction in falciparum malaria. Despite the intense use of artemisinin-based combination therapies, both in treatment and MDA, this did not select for artemisinin resistance.

Eusocial societies are characterized by a clear division of labour between non-breeding workers and breeding queens, and queens often do not contribute to foraging, defence and other maintenance tasks. It has been suggested that the structure and organization of social mole-rat groups resembles that of eusocial insect societies. However, the division of labour has rarely been investigated in wild mole-rats, and it is unknown whether breeders show decreased foraging activity compared with non-breeding helpers in natural groups. Here, we show that, in wild Damaraland mole-rats (Fukomys damarensis) , breeders show lower activity in foraging areas than non-breeding group members. Both breeders and non-breeders displayed variation in activity across the different seasons. Our results suggest that group living allows social mole-rat breeders to reduce their investment in energetically costly behaviour, or alternatively, that the high cost of reproduction in this species forces a behavioural trade-off against foraging investment.

The API 20NE kit and a simple screening system involving Gram9s stain, the oxidase reaction, colistin and gentamicin resistance, and colonial characteristics on a differential agar medium, were used to test 400 strains of Pseudomonas pseudomallei. The API kit identified 390 (97.5%) strains correctly on first testing and all but one of the remainder on second testing. Only one strain was initially misidentified (as Ps cepacia). The screening system was 100% accurate in identifying Ps pseudomallei. In non-endemic areas the API 20NE kit may be used to identify sporadic imported strains of Ps pseudomallei. Such kits may also help to delineate the geographical distribution of melioidosis. In endemic areas the screening tests described offer a cheap, simple, and accurate means of presumptively identifying Ps pseudomallei from clinical specimens.