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David L. Saunders Suwanna Chaorattanakawee Panita Gosi Charlotte Lanteri Sok Somethy Worachet Kuntawunginn Mali Ittiverakul Soklyda Chann Carrie Gregory Char Meng Chuor Satharath Prom Michele D. Spring Chanthap Lon 《Antimicrobial agents and chemotherapy》2016,60(3):1896-1898
Our recent report of dihydroartemisinin-piperaquine failure to treat Plasmodium falciparum infections in Cambodia adds new urgency to the search for alternative treatments. Despite dihydroartemisinin-piperaquine failure, and higher piperaquine 50% inhibitory concentrations (IC50s) following reanalysis than those previously reported, P. falciparum remained sensitive to atovaquone (ATQ) in vitro. There were no point mutations in the P. falciparum cytochrome b ATQ resistance gene. Mefloquine, artemisinin, chloroquine, and quinine IC50s remained comparable to those from other recent reports. Atovaquone-proguanil may be a useful stopgap but remains susceptible to developing resistance when used as blood-stage therapy. 相似文献
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Kamonporn Poramathikul Mariusz Wojnarski Somethy Sok Vannara Sokh Sivhour Chiek Heng Seng Sidonn Krang Sovann Ly Samon Nou Soklyda Chann Siriporn Sornsakrin Woradee Lurchachaiwong Worachet Kuntawunginn Paphavee Lertsethtakarn Aaron Farmer Brett Swierczewski Norman Waters Samandra Demons Brian Vesely Satharath Prom Chanthap Lon Ladaporn Bodhidatta 《Antimicrobial agents and chemotherapy》2021,65(11)
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Jessica Manning Pattaraporn Vanachayangkul Chanthap Lon Michele Spring Mary So Darapiseth Sea Youry Se Sok Somethy Sut-Thang Phann Soklyda Chann Sabaithip Sriwichai Nillawan Buathong Worachet Kuntawunginn Mashamon Mitprasat Raveewan Siripokasupkul Paktiya Teja-Isavadharm Eugene Soh Ans Timmermans Charlotte Lanteri Jaranit Kaewkungwal Montida Auayporn Douglas Tang Char Meng Chour Satharath Prom Mark Haigney Louis Cantilena David Saunders 《Antimicrobial agents and chemotherapy》2014,58(10):6056-6067
Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused by Plasmodium falciparum and Plasmodium vivax in Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericia''s formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (Cmax) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered at ClinicalTrials.gov under registration no. .) NCT01624337相似文献
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Suwanna Chaorattanakawee David L. Saunders Darapiseth Sea Nitima Chanarat Kritsanai Yingyuen Siratchana Sundrakes Piyaporn Saingam Nillawan Buathong Sabaithip Sriwichai Soklyda Chann Youry Se You Yom Thay Kheng Heng Nareth Kong Worachet Kuntawunginn Kuntida Tangthongchaiwiriya Christopher Jacob Shannon Takala-Harrison Christopher Plowe Jessica T. Lin Char Meng Chuor Satharath Prom Stuart D. Tyner Panita Gosi Paktiya Teja-Isavadharm Chanthap Lon Charlotte A. Lanteri 《Antimicrobial agents and chemotherapy》2015,59(8):4631-4643
Cambodia''s first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug-resistant Plasmodium falciparum malaria at some Thai-Cambodian border regions. We report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia by surveying for ex vivo drug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean 50% inhibitory concentration [IC50] increased from 12.8 to 29.6 nM), while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence of P. falciparum multidrug resistance 1 gene (Pfmdr1) multiple copy isolates and coincided with the timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as the first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of the P. falciparum chloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years had P. falciparum
kelch13 mutations, indicative of artemisinin resistance. Ex vivo bioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials, and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantial in vivo drug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of the P. falciparum
mdr1 copy number, as a stop-gap measure in areas of DHA-PPQ failure. 相似文献
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