Quantification of the antimalarial drug pyronaridine in whole blood using LC–MS/MS — increased sensitivity resulting from reduced non-specific binding

Malaria is one of the most important parasitic diseases of man. The development of drug resistance in malaria parasites is an inevitable consequence of their widespread and often unregulated use. There is an urgent need for new and effective drugs. Pyronaridine is a known antimalarial drug that has received renewed interest as a partner drug in artemisinin-based combination therapy. To study its pharmacokinetic properties, particularly in field settings, it is necessary to develop and validate a robust, highly sensitive and accurate bioanalytical method for drug measurements in biological samples. We have developed a sensitive quantification method that covers a wide range of clinically relevant concentrations (1.5 ng/mL to 882 ng/mL) using a relatively low volume sample of 100 μL of whole blood. Total run time is 5 min and precision is within ±15% at all concentration levels. Pyronaridine was extracted on a weak cation exchange solid-phase column (SPE) and separated on a HALO RP amide fused-core column using a gradient mobile phase of acetonitrile–ammonium formate and acetonitrile-methanol. Detection was performed using electrospray ionization and tandem mass spectrometry (positive ion mode with selected reaction monitoring). The developed method is suitable for implementation in high-throughput routine drug analysis, and was used to quantify pyronaridine accurately for up to 42 days after a single oral dose in a drug-drug interaction study in healthy volunteers

A Comparison of Two Short-Course Primaquine Regimens for the Treatment and Radical Cure of Plasmodium vivax Malaria in Thailand

Thai adult males (N = 85) with acute Plasmodium vivax malaria and normal glucose-6-phosphate dehydrogenase screening were randomized to receive 30 mg or 60 mg primaquine daily for 7 days (N = 43 and 42, respectively). The regimens were well tolerated and all patients recovered fully. Median fever clearance (47 hours; range 4 to 130 hours), mean ± SD parasite clearance times (87.7 ± 25.3 hours), gametocyte clearance, and adverse effects were similar in the 2 groups. Two patients, 1 from each group, had a 30% reduction in hematocrit. The cumulative 28 day relapse rate (95% confidence interval) by Kaplan Meier survival analysis was 29% (16–49%) in the 30 mg group compared with 7% (2–24%) in the 60 mg group; P = 0.027. Comparison with previous data obtained at this same site suggests that the recurrences comprised approximately 17% recrudescences and 12% relapses in the 30 mg/day group compared with 3% recrudescences and 4% relapses in the 60 mg/day group. These data suggest that the dose-response relationships for primaquine's asexual stage and hypnozoitocidal activities in-vivo are different. A 1 week course of primaquine 60 mg daily is an effective treatment of vivax malaria in this region

Community engagement and population coverage in mass anti-malarial administrations: a systematic literature review

BACKGROUND: Mass anti-malarial administration has been proposed as a key component of the malaria elimination strategy in South East Asia. The success of this approach depends on the local malaria epidemiology, nature of the anti-malarial regimen and population coverage. Community engagement is used to promote population coverage but little research has systematically analysed its impact. This systematic review examines population coverage and community engagement in programmes of mass anti-malarial drug administration. METHODS: This review builds on a previous review that identified 3049 articles describing mass anti-malarial administrations published between 1913 and 2011. Further search and application of a set of criteria conducted in the current review resulted in 51 articles that were retained for analysis. These 51 papers described the population coverage and/or community engagement in mass anti-malarial administrations. Population coverage was quantitatively assessed and a thematic analysis was conducted on the community engagement activities. RESULTS: The studies were conducted in 26 countries: in diverse healthcare and social contexts where various anti-malarial regimens under varied study designs were administered. Twenty-eight articles reported only population coverage; 12 described only community engagement activities; and 11 community engagement and population coverage. Average population coverage was 83% but methods of calculating coverage were frequently unclear or inconsistent. Community engagement activities included providing health education and incentives, using community structures (e.g. existing hierarchies or health infrastructure), mobilizing human resources, and collaborating with government at some level (e.g. ministries of health). Community engagement was often a process involving various activities throughout the duration of the intervention. CONCLUSION: The mean population coverage was over 80% but incomplete reporting of calculation methods limits conclusions and comparisons between studies. Various community engagement activities and approaches were described, but many articles contained limited or no details. Other factors relevant to population coverage, such as the social, cultural and study context were scarcely reported. Further research is needed to understand the factors that influence population coverage and adherence in mass anti-malarial administrations and the role community engagement activities and approaches play in satisfactory participation

In vivo parasitological measures of artemisinin susceptibility

Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24

Constraints on Axion-like Particles from X-Ray Observations of NGC1275

Axion-like particles (ALPs) can induce localized oscillatory modulations in the spectra of photon sources passing through astrophysical magnetic fields. Ultra-deep Chandra observations of the Perseus cluster contain over $5\times {10}^{5}$ counts from the active galactic nucleus (AGN) of the central cluster galaxy NGC1275 and represent a data set of extraordinary quality for ALP searches. We use this data set to search for X-ray spectral irregularities from the AGN. The absence of irregularities at the ${ \mathcal O }(30 \% )$ level allows us to place leading constraints on the ALP-photon mixing parameter {g}_{a\gamma \gamma }\lesssim 1.4\mbox{--}4.0\times {10}^{-12}\,{\mathrm{GeV}}^{-1} for ${m}_{a}\lesssim {10}^{-12}\,\mathrm{eV}$, depending on assumptions on the magnetic field realization along the line of sight.European Research Counci

Safety and pharmacokinetic properties of a new formulation of parenteral artesunate in healthy Thai volunteers

Background: Parenteral artesunate is the first-line therapy for severe malaria. Artesunate, in its current formulation, must be prepared immediately before administration by first dissolving in sodium bicarbonate solution and then diluting in saline. A novel solvent for rapid and stable single step reconstitution of artesunate was recently developed showing improved solubility and stability. This study aimed to compare the safety and pharmacokinetic properties of the currently available and newly developed parenteral formulation of artesunate in healthy Thai volunteers. Methods: This was an open-label, randomized, 4 periods, 4-treatments, 24-sequence, single-dose, cross-over study in 72 male and female healthy Thai volunteers. Frequent pharmacokinetic samples were collected in all volunteers at each dose occasion. Observed concentration–time profiles were analysed with a non-compartmental approach followed by a bioequivalence evaluation. Results: Both intramuscular and intravenous administrations of the new parenteral formulation of artesunate were safe and well-tolerated, with no additional safety signals compared to the currently used formulation. The pharmacokinetic properties of artesunate and its active metabolite, dihydroartemisinin, were well-characterized, and showed rapid conversion of artesunate into dihydroartemisinin. Intramuscular administration of the newly formulated artesunate resulted in almost complete bioavailability of dihydroartemisinin. The pharmacokinetic properties were similar between the old and new formulation. Conclusions: The new and more easily prepared formulation of artesunate was safe and well-tolerated, with similar pharmacokinetic properties compared to the currently used formulation. Dihydroartemisinin, the active metabolite responsible for the majority of the anti-malarial effect, showed equivalent exposure after both intravenous and intramuscular administration of artesunate, suggesting that both routes of administration should generate comparable therapeutic effects. Trial registration: The study was registered to clinicaltrials.gov (#TCTR20170907002)

Clinical Epidemiology of 7126 Melioidosis Patients in Thailand and the Implications for a National Notifiable Diseases Surveillance System.

Background:National notifiable diseases surveillance system (NNDSS) data in developing countries are usually incomplete, yet the total number of fatal cases reported is commonly used in national priority-setting. Melioidosis, an infectious disease caused by Burkholderia pseudomallei, is largely underrecognized by policy-makers due to the underreporting of fatal cases via the NNDSS. Methods:Collaborating with the Epidemiology Division (ED), Ministry of Public Health (MoPH), we conducted a retrospective study to determine the incidence and mortality of melioidosis cases already identified by clinical microbiology laboratories nationwide. A case of melioidosis was defined as a patient with any clinical specimen culture positive for B. pseudomallei. Routinely available microbiology and hospital databases of secondary care and tertiary care hospitals, the national death registry, and NNDSS data were obtained for analysis. Results:A total of 7126 culture-confirmed melioidosis patients were identified from 2012 to 2015 in 60 hospitals countrywide. The total number of cases diagnosed in Northeast, Central, South, East, North, and West Thailand were 5475, 536, 374, 364, 358, and 19 cases, respectively. The overall 30-day mortality was 39% (2805/7126). Only 126 (4%) deaths were reported to the NNDSS. Age, presentation with bacteremia and pneumonia, prevalence of diabetes, and 30-day mortality differed by geographical region (all P < .001). The ED at MoPH has agreed to include the findings of our study in the next annual report of the NNDSS. Conclusions:Melioidosis is an important cause of death in Thailand nationwide, and its clinical epidemiology may be different by region. In developing countries, NNDSS data can be supplemented by integrating information from readily available routine data sets