{ "items": [ "\n\n
<jats:title>ABSTRACT</jats:title>\n<jats:p>The 2-aminopyridine MMV048 was the first drug candidate inhibiting <jats:named-content content-type=\"genus-species\">Plasmodium</jats:named-content> phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant <jats:named-content content-type=\"genus-species\">Plasmodium falciparum</jats:named-content> and <jats:named-content content-type=\"genus-species\">Plasmodium vivax</jats:named-content> clinical isolates. Excellent <jats:italic>in vitro</jats:italic> antiplasmodial activity translated into high efficacy in <jats:named-content content-type=\"genus-species\">Plasmodium berghei</jats:named-content> and humanized <jats:named-content content-type=\"genus-species\">P. falciparum</jats:named-content> NOD-<jats:italic>scid IL-2R</jats:italic>\u03b3<jats:sup><jats:italic>null</jats:italic></jats:sup> mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate <jats:italic>in vivo</jats:italic> intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation <jats:named-content content-type=\"genus-species\">Plasmodium</jats:named-content> PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.</jats:p>
\n \n\n \n \n<jats:sec><jats:title>Introduction</jats:title><jats:p>Antibiotic use in low-income and middle-income countries continues to rise despite the knowledge that antibiotic overuse can lead to antimicrobial resistance. There is a paucity of detailed data on the use of antibiotics in primary care in low-resource settings.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To describe the presentation of acute infections and the indications for antibiotic prescription.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>A 2-year retrospective review of routinely collected data.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>All 32 primary care units in one district in northern Thailand.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>Patients attending primary care with a history of fever, documented temperature, International Statistical Classification of Diseases 10 code for infection or prescribed a systemic antibiotic. Patients attending after the initiation of a study on C-reactive protein testing in four centres were excluded.</jats:p></jats:sec><jats:sec><jats:title>Outcome measures</jats:title><jats:p>The proportion of patients prescribed an antibiotic and the frequency of clinical presentations.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>762\u2009868 patients attended the health centres, of whom 103\u2009196 met the inclusion criteria, 5966 were excluded resulting in 97\u2009230 attendances consisting of 83\u2009661 illness episodes.</jats:p><jats:p>46.9% (39 242) of the patients were prescribed an antibiotic during their illness. Indications for antibiotic prescription in the multivariable logistic regression analysis included male sex (adjusted OR (aOR) 1.21 (95% CI 1.16 to 1.28), p<0.001), adults (aOR 1.77 (95% CI 1.57 to 2), p<0.001) and a temperature >37.5\u00b0C (aOR 1.24 (95% CI 1.03 to 1.48), p=0.020). 77.9% of the presentations were for respiratory-related problems, of which 98.6% were upper respiratory tract infections. The leading infection diagnoses were common cold (50%), acute pharyngitis (18.9%) and acute tonsillitis (5%) which were prescribed antibiotics in 10.5%, 88.7% and 87.1% of cases, respectively. Amoxicillin was the most commonly prescribed antibiotic.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Nearly half of the patients received an antibiotic, the majority of whom had a respiratory infection. The results can be used to plan interventions to improve the rational use of antibiotics. Further studies in private facilities, pharmacies and dental clinics are required.</jats:p></jats:sec>
\n \n\n \n \n<jats:p>On the western border of Thailand, <jats:italic>Plasmodium falciparum</jats:italic> has become resistant to almost all antimalarial agents. The molecular basis of resistance in these parasite populations has not been well characterized. This study assessed genetic polymorphisms in the <jats:italic>pfmdr1</jats:italic> gene in 54 parasites collected from the western border of Thailand to determine the relationship of<jats:italic>pfmdr1</jats:italic> copy number and codon mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine, quinine, and artesunate assessed in vitro. A point mutation at codon 86 (resulting in a change of Asn to Tyr) was associated with a significantly lower 50% inhibitory concentration (IC<jats:sub>50</jats:sub>) of mefloquine (median, 9 ng/ml versus 52.4 ng/ml; <jats:italic>P</jats:italic> = 0.003). Overall 35% of the isolates (19 of 54) had an increase in <jats:italic>pfmdr1</jats:italic> copy number, and all 19 carried the wild-type allele at codon 86. Increased<jats:italic>pfmdr1</jats:italic> copy number was associated with higher IC<jats:sub>50</jats:sub>s of mefloquine (<jats:italic>P</jats:italic> = 0.04) and artesunate (<jats:italic>P</jats:italic> = 0.005), independent of polymorphism at codon 86. The relationship between <jats:italic>pfmdr1</jats:italic> and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype.</jats:p>
\n \n\n \n \n<jats:p>Combining artemisinin or a derivative with mefloquine increases cure rates in falciparum malaria patients, reduces transmission, and may slow the development of resistance. The combination of artesunate, given for 3 days, and mefloquine is now the treatment of choice for uncomplicated multidrug-resistant falciparum malaria acquired on the western or eastern borders of Thailand. To optimize mefloquine administration in this combination, a prospective study of mefloquine pharmacokinetics was conducted with 120 children (4 to 15 years old) with acute uncomplicated falciparum malaria, who were divided into four age- and sex-matched groups. The patients all received artesunate (4 mg/kg of body weight/day orally for 3 days and mefloquine as either (i) a single dose (25 mg/kg) on day 2 with food, (ii) a split dose (15 mg/kg on day 2 and 10 mg/kg on day 3) with food, (iii) a single dose (25 mg/kg) on day 0 without food, or (iv) a single dose (25 mg/kg) on day 2 without food. Delaying administration of mefloquine until day 2 was associated with a mean (95% confidence interval) increase in estimated oral bioavailability of 72% (36 to 109%). On day 2 coadministration with food did not increase mefloquine absorption significantly, and there were no significant differences between patients receiving split- and single-dose administration. In combination with artesunate, mefloquine administration should be delayed until the second or third day after presentation.</jats:p>
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