Biology subjects

Wojnarski, M.

Publications and source records attributed to Wojnarski, M..

4 recordsLinked to original sources

bioRxiv2024

Safety, pharmacokinetics, and potential neurological interactions of ivermectin, tafenoquine and chloroquine in Rhesus Macaques

Ivermectin could be used for malaria control as treated persons are lethal to blood feeding Anopheles, resulting in reduced transmission. Tafenoquine could be used in combination with ivermectin to clear persons of liver stage Plasmodium vivax reservoir and as a prophylactic in high-risk populations. The safety of ivermectin and tafenoquine has not been evaluated. As earlier forms of 8-aminoquinolones were neurotoxic, and ivermectin is an inhibitor of the P-glycoprotein blood brain barrier transporter, there is concern that co-administration could be neurotoxic. The safety and pharmacokinetic interaction of tafenoquine, ivermectin, and chloroquine was evaluated in Rhesus macaques. No clinical, biochemistry, or hematological outcomes of concern were observed. The Cambridge Neuropsychological Test Automated Battery was employed to assess potential neurological deficits following drug administration. Some impairment was observed with tafenoquine alone and in the same monkeys with subsequent co-administrations. Co-administration of chloroquine and tafenoquine resulted in increased plasma exposure to tafenoquine. Urine concentrations of the 5,6 orthoquinone TQ metabolite were increased with co-administration of tafenoquine with ivermectin. There was an increase in ivermectin plasma exposure when co-administered with chloroquine. No interaction of tafenoquine on ivermectin was observed in vitro. Chloroquine and trace levels of ivermectin, but not tafenoquine, were observed in the cerebrospinal fluid. The 3"-O-demethyl ivermectin metabolite was observed in macaque plasma but not in urine or cerebrospinal fluid. Overall, the combination of ivermectin, tafenoquine, and chloroquine did not have clinical, neurological, or pharmacological interactions of concern in macaques, therefore this combination could be considered for evaluation in human trials.

pharmacology and toxicology↗

bioRxiv2023

Strong Positive Selection Biases Identity-By-Descent-Based Inferences of Recent Demography and Population Structure in Plasmodium falciparum

Malaria genomic surveillance often estimates parasite genetic relatedness using metrics such as Identity-By-Decent (IBD). Yet, strong positive selection stemming from antimalarial drug resistance or other interventions may bias IBD-based estimates. In this study, we utilized simulations, a true IBD inference algorithm, and empirical datasets from different malaria transmission settings to investigate the extent of such bias and explore potential correction strategies. We analyzed whole genome sequence data generated from 640 new and 4,026 publicly available Plasmodium falciparum clinical isolates. Our findings demonstrated that positive selection distorts IBD distributions, leading to underestimated effective population size and blurred population structure. Additionally, we discovered that the removal of IBD peak regions partially restored the accuracy of IBD-based inferences, with this effect contingent on the populations background genetic relatedness. Consequently, we advocate for selection correction for parasite populations undergoing strong, recent positive selection, particularly in high malaria transmission settings.

evolutionary biology↗

bioRxiv2022

The Parasite Intraerythrocytic Cycle and Human Circadian Cycle are Coupled During Malaria Infection

During infections with malaria parasites P. vivax, patients exhibit rhythmic fevers every 48 hours. These fever cycles correspond with the time parasites take to traverse the Intraerythrocytic Cycle (IEC) and may be guided by a parasite-intrinsic clock. Different species of Plasmodia have cycle times that are multiples of 24 hours, suggesting they may be coordinated with the host circadian clock. We utilized an ex vivo culture of whole blood from patients infected with P. vivax to examine the dynamics of the host circadian transcriptome and the parasite IEC transcriptome. Transcriptome dynamics revealed that the phases of the host circadian cycle and the parasite IEC were correlated across multiple patients, suggesting that the cycles are coupled. In mouse model systems, host-parasite cycle coupling appears to provide a selective advantage for the parasite. Thus, understanding how host and parasite cycles are coupled in humans could enable anti-malarial therapies that disrupt this coupling.

systems biology↗

bioRxiv2020

Safety, pharmacokinetics, and liver-stage Plasmodium cynomolgi effect of high-dose ivermectin and chloroquine in Rhesus Macaques

Previously, ivermectin (1-10 mg/kg) was shown to inhibit liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (IC50 = 10.42 M) and hypnozoites (IC50 = 29.24 M) in primary macaque hepatocytes when administered in high-dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for seven consecutive days was evaluated for prophylaxis or radical cure of Plasmodium cynomolgi liver-stages in Rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for seven days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in vitro. Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.

pharmacology and toxicology↗