Piperaquine Pharmacokinetic and Pharmacodynamic Profiles in Healthy Volunteers of Papua New Guinea after Administration of Three-Monthly Doses of Dihydroartemisinin–Piperaquine

Mass drug administration (MDA) with monthly dihydroartemisinin-piperaquine (DHA-PQP) appears useful in malaria control and elimination strategies. Determining the relationship between consecutive piperaquine phosphate (PQP) exposure and its impact on QT interval prolongation is a key safety consideration for MDA campaigns

The Artemiside-Artemisox-Artemisone-M1 Tetrad: Efficacies against Blood Stage P. falciparum Parasites, DMPK Properties, and the Case for Artemiside

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5–2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies

The artemiside-artemisox-artemisone-m1 tetrad : efficacies against blood stage p. falciparum parasites, dmpk properties, and the case for artemiside

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf ) blood stage parasites (IC50 1.5–2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.Supplementary Material 1: S1 Efficacy of artemisox, dose response curves against asexual, and gametocyte blood stage parasites: Figure S1a–e; S2 Efficacy of M1, dose response curves against asexual, and gametocyte blood stage parasites: Figure S2a–d; S3 Pharmacokinetics and metabolism, circulating concentrations of artemiside, artemisox, and artemisone: Table S3a–f, LC-MS/MS chromatograms of M1 Figure S3a–c; S4 In vitro efficacy data— previously published data for artemiside, artemisone, M1: Table S4a–c; S5 In vivo efficacy data— previously published data for artemiside, artemisone: Table S5; S6 Neurotoxicity data–previously published neurotoxicity data for DHA, artesunate, artemiside, artemisone: Table S6.Supplementary Material 2: PDF copy of reference [37].The South African Medical Research Council (MRC) Flagship Project MALTB-Redox with funds from the National Treasury under its Economic Competitiveness and Support Package, a South African National Research Foundation (SA NRF) grant, and by a South African MRC Strategic Health Innovation Partnership (SHIP) grant, a South African MRC Collaborative Centre for Malaria Research grant and the Department of Science and Innovation and SA NRF South African Research Chairs Initiative (SARChI) Grant.https://www.mdpi.com/journal/pharmaceuticsam2022BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC

Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome after renal transplantation in the United States

BACKGROUND: The incidence and risk factors for diabetic ketoacidosis (diabetic ketoacidosis) and hyperglycemic hyperosmolar syndrome (hyperglycemic hyperosmolar syndrome, previously called non-ketotic hyperosmolar coma) have not been reported in a national population of renal transplant (renal transplantation) recipients. METHODS: We performed a historical cohort study of 39,628 renal transplantation recipients in the United States Renal Data System between 1 July 1994 and 30 June 1998, followed until 31 Dec 1999. Outcomes were hospitalizations for a primary diagnosis of diabetic ketoacidosis (ICD-9 code 250.1x) and hyperglycemic hyperosmolar syndrome (code 250.2x). Cox Regression analysis was used to calculate adjusted hazard ratios for time to hospitalization for diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome. RESULTS: The incidence of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome were 33.2/1000 person years (PY) and 2.7/1000 PY respectively for recipients with a prior diagnosis of diabetes mellitus (DM), and 2.0/1000 PY and 1.1/1000 PY in patients without DM. In Cox Regression analysis, African Americans (AHR, 2.71, 95 %CI, 1.96–3.75), females, recipients of cadaver kidneys, patients age 33–44 (vs. >55), more recent year of transplant, and patients with maintenance TAC (tacrolimus, vs. cyclosporine) had significantly higher risk of diabetic ketoacidosis. However, the rate of diabetic ketoacidosis decreased more over time in TAC users than overall. Risk factors for hyperglycemic hyperosmolar syndrome were similar except for the significance of positive recipient hepatitis C serology and non-significance of female gender. Both diabetic ketoacidosis (AHR, 2.44, 95% CI, 2.10–2.85, p < 0.0001) and hyperglycemic hyperosmolar syndrome (AHR 1.87, 95% CI, 1.22–2.88, p = 0.004) were independently associated with increased mortality. CONCLUSIONS: We conclude that diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome were associated with increased risk of mortality and were not uncommon after renal transplantation. High-risk groups were identified

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

BioRXiv version. Please see https://rubenarslan.github.io/generation_scotland_pedigree_gcta/ to access this website in a browsable form

Stability of Pentoxifylline Injection: Application to Neonatal/Pediatric Care Setting

Pentoxifylline (PTX) is administered as 6- or 12-hour intravenous infusions in the treatment of sepsis or necrotizing enterocolitis in neonates; however, there is a paucity of formal stability data for PTX in the end-use solution. We investigated PTX stability in the simulated clinical conditions of neonatal intensive care, where PTX injection is diluted to 5 mg/mL and administered via syringe pump. A stability-indicating high performance liquid chromatography (HPLC) assay was established for PTX. The clinical simulation stability study comprised PTX 5 mg/mL in 20 mL syringes and was conducted at three temperatures, all protected from light: refrigerator (4°C); room temperature (22°C) and incubator/humidicrib (35°C). PTX stability also was evaluated at room temperature and exposed to light. Samples were drawn at pre-determined times over a 10 day period and stored frozen (-80°C) until assayed by HPLC. A single exponential equation was fitted to the concentration-time data to determine PTX stability. Forced degradation studies confirmed that PTX was stable at elevated temperature (up to 45°C), exposed to light and under acidic stress for up to 10 days, but subject to degradation under alkali and oxidative stress. PTX injection 5 mg/mL in 0.9% w/v sodium chloride or 5% w/v glucose was found to be stable when protected from light at 22°C and 35°C, and exposed to light at 22°C for at least 7 days. These data provide clinically relevant evidence that PTX injection is stable in the end-use, ICU/incubator clinical conditions for at least 24 hours

Physical compatibility of pentoxifylline and intravenous medications.

OBJECTIVE: To investigate the physical and chemical compatibility of pentoxifylline (PTX) with a wide range of parenteral medications used in the neonatal intensive care setting. DESIGN: PTX and drug solutions were combined in glass phials and inspected visually for physical incompatibility. The chemical compatibility was evaluated on the basis of PTX concentrations. RESULTS: Precipitation, colour change or turbidity was not visible in any of the test mixtures, indicating no observed physical incompatibility or apparent risk of blockage in narrow-bore intravenous tubing. The PTX concentration was approximately 2.5% and 4.5% lower when combined with dopamine and amoxicillin, respectively. The PTX concentration ratios for all other combinations were in the range of 99%-102%. CONCLUSION: In simulated Y-site conditions, physical compatibility testing of PTX and 30 parenteral medications revealed no evidence of precipitation. Based on PTX concentration tests, it could be prudent to avoid mixing PTX with dopamine or amoxicillin

Simultaneous determination of primaquine and carboxyprimaquine in plasma using solid phase extraction and LC-MS assay

Sensitive bioanalytical methods are required for pharmacokinetic studies in children, due to the small volume and modest number of samples that can be obtained. We sought to develop a LC–MS assay for primaquine and its active metabolite, carboxyprimaquine, following simultaneous, solid phase extraction of both analytes from human plasma. The analysis was conducted on a single-quad LC–MS system (Shimadzu Model 2020) in ESI+ mode, with quantitation by selected ion monitoring. Primaquine, carboxyprimaquine and 8-aminoquinoline (internal standard) were separated using a mobile phase of 80:20 methanol:water with 0.1% (v/v) formic acid and a Luna C18 HPLC column, at ambient temperature. Solid phase extraction of the analytes from plasma (0.5 mL) was achieved with Oasis® HLB cartridges. The retention times for primaquine, 8-aminoquinoline and carboxyprimaquine were 3.3, 5.7 and 8.5 min, respectively. The calibration curve range (2–1500 μg/L) was appropriate for the limits of quantification and detection for primaquine (2 μg/L and 1 μg/L, respectively) and carboxyprimaquine (2.5 μg/L and 1 μg/L) and the anticipated plasma concentrations of the analytes. Intra- and inter-day precision for both primaquine and carboxyprimaquine was 85% and sensitivity of 1–2 μg/L