Publications by authors named "Nada Abla"

Article Synopsis
  • * The World Health Organization's updated guidelines in October 2023 limit primaquine use in breastfeeding women, assuming it could harm infants with G6PD deficiency, although there's ongoing anticipation for tafenoquine recommendations.
  • * Recent studies argue for lifting primaquine restrictions due to findings showing very low infant exposure to the drug in breastfeeding scenarios, suggesting minimal risk to infants while highlighting the public health benefits of preventing malaria relapses in mothers.
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The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID-19) prompted a global effort to evaluate drug repurposing opportunities. Pyronaridine and amodiaquine are both components of approved antimalarials with in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro activity does not always translate to clinical efficacy across a therapeutic dose range.

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Drug resistance to sulfadoxine-pyrimethamine and amodiaquine threatens the efficacy of malaria chemoprevention interventions in children and pregnant women. Combining pyronaridine (PYR) and piperaquine (PQP), both components of approved antimalarial therapies, has the potential to protect vulnerable populations from severe malaria. This randomized, double-blind, placebo-controlled (double-dummy), parallel-group, single site phase I study in healthy adult males or females of Black sub-Saharan African ancestry investigated the safety, tolerability, and pharmacokinetics of PYR + PQP (n = 15), PYR + placebo (n = 8), PQP + placebo (n = 8), and double placebo (n = 6) administered orally once daily for 3 days at the registered dose for the treatment of uncomplicated malaria.

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As part of a collaboration between Medicines for Malaria Venture (MMV), Certara UK and Monash University, physiologically-based pharmacokinetic (PBPK) models were developed for 20 antimalarials, using data obtained from standardized in vitro assays and clinical studies within the literature. The models have been applied within antimalarial drug development at MMV for more than 5 years. During this time, a strategy for their impactful use has evolved.

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Background: This exploratory study investigated four repurposed anti-infective drug regimens in outpatients with COVID-19.

Methods: This phase 2, single centre, randomised, open-label, clinical trial was conducted in South Africa between 3rd September 2020 and 23rd August 2021. Symptomatic outpatients aged 18-65 years, with RT-PCR confirmed SARS-CoV-2 infection were computer randomised (1:1:1:1:1) to standard-of-care (SOC) with paracetamol, or SOC plus artesunate-amodiaquine (ASAQ), pyronaridine-artesunate (PA), favipiravir plus nitazoxanide (FPV + NTZ), or sofosbuvir-daclatasvir (SOF-DCV).

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Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection.

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Article Synopsis
  • M5717 is a new drug that fights malaria by blocking a protein (PeEF2) in malaria-causing germs called Plasmodium.
  • Researchers found it tricky to figure out safe doses for people because the drug stays in the body longer than expected, causing it to build up.
  • They created a new way to test the drug that helps reduce side effects while ensuring it still works effectively in animals, which could also help develop other similar drugs in the future.
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Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This randomized, single-blind, placebo-controlled, single-center phase 1 trial investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination.

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Atovaquone-proguanil (ATV-PG) plus amodiaquine (AQ) has been considered as a potential replacement for sulfadoxine-pyrimethamine plus AQ for seasonal malaria chemoprevention in African children. This randomized, double-blind, placebo-controlled, parallel group study assessed the safety, tolerability, and pharmacokinetics (PKs) of ATV-PG plus AQ in healthy adult males and females of Black sub-Saharan African origin. Participants were randomized to four treatment groups: ATV-PG/AQ (n = 8), ATV-PG/placebo (n = 12), AQ/placebo (n = 12), and placebo/placebo (n = 12).

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OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from -oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring.

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The active enantiomer R-Praziquantel (PZQ) shows a clinically lower relative exposure when administered enantiomerically pure compared with a racemic form. We investigated the hypothesis that enantiomer-enantiomer interactions on cytochrome P450 (P450) enzymes could explain this observation and aimed to further deepen the understanding of PZQ metabolism. First, in an in vitro metabolite profiling study, the formation of multiple metabolites per P450, together with an observed interconversion of cis-4'-OH-PZQ to trans-4'-OH-PZQ in human hepatocytes, pointed out the inadequacy of measuring metabolite formation in kinetic studies.

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Background: Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles.

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Purpose: To examine the utility of human plasma as an assay medium in Caco-2 permeability studies to overcome poor mass balance and inadequate sink conditions frequently encountered with lipophilic compounds.

Methods: Caco-2 permeability was assessed for reference compounds with known transport mechanisms using either pH 7.4 buffer or human plasma as the assay medium in both the apical and basolateral chambers.

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L-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the noncompartmental estimates of the pharmacokinetic profiles in both studies. Dose, food, and formulation were found to significantly affect L-PZQ exposure in both studies.

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With ∼429,000 deaths in 2016, malaria remains a major infectious disease where the need to treat the fever symptoms, but also to provide relevant post-treatment prophylaxis, is of major importance. An azepanylcarbazole amino alcohol is disclosed with a long- and fast-acting in vivo antiplasmodial efficacy and meets numerous attributes of a desired post-treatment chemoprophylactic antimalarial agent. The synthesis, the parasitological characterization, and the animal pharmacokinetics and pharmacodynamics of this compound are presented along with a proposed target.

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After more than 40 years of use, Praziquantel (PZQ) still remains the drug of choice for the treatment of intestinal and urogenital schistosomiasis. Its anti-parasitic activity resides primarily in the (R)-enantiomer. Hitherto neither the molecular target nor the pharmacokinetic-pharmacodynamic relationship have been fully elucidated.

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Article Synopsis
  • - The lack of collaboration between academia and the pharmaceutical industry limits new drug discovery, but open source drug initiatives, like sharing physical compounds, could help bridge this gap and accelerate research.
  • - The Medicines for Malaria Venture created the Malaria Box, a collection of over 400 compounds tested against malaria, which has been shared with almost 200 research groups, encouraging public data sharing on screening results.
  • - Recent findings from the Malaria Box screenings revealed mechanisms of action for many compounds against various life stages of the malaria parasite, and some showed effectiveness against other pathogens and cancer cell lines, providing valuable data for further drug development.
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SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human.

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Article Synopsis
  • Recent findings show that artemisinin-resistant parasites are emerging, creating a demand for new antimalarial drugs.
  • A high-throughput screening (HTS) campaign resulted in discovering potent carbazole analogues effective against the Plasmodium falciparum K1 strain.
  • Follow-up studies on structure-activity relationship (SAR) and improving drug properties led to a promising compound that works well when given orally in a mouse model of malaria.
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Antagonism of the CRTH2 receptor represents a very attractive target for a variety of allergic diseases. Most CRTH2 antagonists known to date possess a carboxylic acid moiety, which is essential for binding. However, potential acid metabolites O-acyl glucuronides might be linked to idiosynchratic toxicity in humans.

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New phenoxyacetic acid antagonists of CRTH2 are described. Following the discovery of a hit compound by a focused screening, high protein binding was identified as its main weakness. Optimization aimed at reducing serum protein binding led to the identification of several compounds that showed not only excellent affinities for the receptor (41 compounds with K(i) < 10 nM) but also excellent potencies in a human whole blood assay (IC(50) < 100 nM; PGD2-induced eosinophil shape change).

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Capillary zone electrophoresis (CZE) is a convenient experimental tool for mimicking the low-throughput in vitro skin model used to optimize the delivery of peptides by transdermal iontophoresis. This paper is devoted to the extraction of pertinent molecular parameters from CZE experiments at different pH values, the optimization of CZE experimental conditions, and the development of an in silico filter useful for drug design and development. The effective mobility (mu(eff)) of ten model dipeptides was measured by CZE at different pH values, enabling to determine their pK(a) values, charge and mu(eff) at any pH.

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ABCC4 encodes multidrug resistance protein 4 (MRP4), a member of the ATP-binding cassette family of membrane transporters involved in the efflux of endogenous and xenobiotic molecules. The aims of this study were to identify single nucleotide polymorphisms of ABCC4 and to functionally characterize selected nonsynonymous variants. Resequencing was performed in a large ethnically diverse population.

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Purpose: To investigate the topical iontophoresis of valaciclovir (VCV) as a means to improve cutaneous aciclovir (ACV) delivery.

Methods: ACV and VCV electrotransport experiments were conducted using excised porcine skin in vitro.

Results: While the charged nature of the prodrug, VCV, enabled it to be more efficiently iontophoresed into the skin than the parent molecule, ACV, only the latter was detectable in the receptor chamber, suggesting that VCV was enzymatically cleaved into the active metabolite during skin transit.

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The objective of the study was to investigate the relationship between transdermal iontophoretic flux--specifically, the electromigratory component--and electrophoretic mobility as determined by capillary zone electrophoresis (CZE). First, the steady-state iontophoretic transport rates of a series of dipeptides across porcine skin were determined in vitro. Co-iontophoresis of acetaminophen was used to quantify the respective contributions of electroosmosis (EO) and electromigration (EM).

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