Cassius M. Phogole

Pre‐eclampsia is a hypertensive disorder of pregnancy affecting 3–8% of pregnancies worldwide, with no disease‐modifying therapy currently available. Drug repurposing offers a promising strategy, yet no candidate has been validated to date. Pregnancy‐associated physiological changes alter drug pharmacokinetics (PK), and pre‐eclampsia itself may further modify drug disposition, complicating dose selection and contributing to inconclusive clinical trial outcomes. A structured literature search identified six prospective or randomized controlled trials of repurposed drugs for established pre‐eclampsia: esomeprazole, omeprazole, sulfasalazine, pravastatin, recombinant antithrombin, and metformin. All drugs were well tolerated, with metformin the one to show promising clinical benefit by prolonging gestation; the remaining five drugs yielded inconclusive or null efficacy outcomes. Critically, PK sampling was conducted in only three trials, and none systematically characterized exposure–response relationships using key pre‐eclampsia biomarkers, including soluble fms‐like tyrosine kinase‐1, soluble endoglin, and placental growth factor. Further common methodological limitations included small sample sizes (12–120 participants), heterogeneous gestational age eligibility criteria, and dosing regimens extrapolated from non‐pregnant populations without pregnancy‐specific optimization. These shortcomings likely contributed to the translational gap between promising preclinical findings and positive clinical trial outcomes. Model‐informed drug development (MIDD) approaches, including physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) modeling, optimal sampling strategies, and simulation‐based dose selection, offer a framework to improve pre‐eclampsia trial design. Future studies should integrate these approaches with biomarker‐guided exposure–response analyses and prediction of fetal exposure throughout pregnancy to enhance therapeutic development, optimize maternal–fetal safety, and accelerate the identification of effective disease‐modifying therapies for pre‐eclampsia.

Background: Sertraline (SER) is a selective serotonin reuptake inhibitor (SSRI) prescribed for depression, including during pregnancy. Existing literature suggests a potential association between gestational SER use and cardiac and neurodevelopmental anomalies in exposed offspring. This study evaluated the relative impacts of SER and its metabolite desmethylsertraline (DES) on the proteome during early development. Methods: Zebrafish embryos and larvae were exposed to individual treatments of translated umbilical cord-blood equivalent concentrations of SER or DES during early developmental stages. Quantified activity tracking and protein expression levels of serotonin transporter (SERT) were used to confirm a significant SSRI effect in exposed larvae. A whole-larvae proteomic analysis was conducted using a label-free quantitative liquid chromatography-mass spectrometry approach. Protein identification was performed using zebrafish and human protein databases. Results: Apparent therapeutic SSRI effect of exposure doses of SER and DES was confirmed in zebrafish larvae, by reduced activity levels, as well as decreased SERT. DES, but not SER, resulted in several differentially regulated proteins, identified in both the zebrafish and human databases. The results from the two databases correlated and aligned with an increased risk for cardiovascular and neurodevelopmental dysregulation. Conclusion: Proteomic data suggest that DES, rather than SER, at physiologically relevant doses, may be responsible for adverse clinical outcomes reported after gestational SSRI use. Current data positions larval zebrafish as a possible tool for assessment of long-term risk after gestational SER use, as well as a drug development tool in this context. Clinical trial number: N/A.

In low-resource settings, access to intravenous formulations of antituberculosis drugs is lacking or absent. Thus, critically ill patients with tuberculosis (TB) are often treated with readily available tablets which are crushed, mixed with water, and administered via a nasogastric tube (NGT). This has been associated with plasma concentrations below the recommended target, particularly of rifampicin (RIF) and isoniazid (INH), leading to clinical failure and development of drug resistance. We aimed to identify physiochemical factors contributing to lower plasma concentrations of antituberculosis drugs when administered in this manner using laboratory-based techniques, including the addition of ascorbic acid (AA) for optimum administration. Aqueous solubility of crushed medication using the inversion mixing method was evaluated against easily implementable mixing methods (sonication/vortexing) with or without AA. Stability of crushed medication in simulated-gastrointestinal fluids was evaluated with or without AA. Drug loss via NGT surface adsorption was quantitatively determined. RIF demonstrated poor aqueous solubility of 5.2%. Incorporation of AA improved the solubility to 29.7%, and with the addition of mixing techniques, solubility improved to 86.3%. Mixing methods with AA further improved the solubilities of both INH (80%) and pyrazinamide (PZA, 64%) to over 90%. AA also showed protective effects against unstable RIF in simulated-gastric fluid. Conventional flushing of NGT after drug administration with 10 mL of water resulted in drug losses of 1.5%, 0.13%, and 1.4% for RIF, INH, and PZA, respectively. An additional flushing step halved this amount. These interventions may improve the poor plasma concentrations of crushed antituberculosis drugs in critically ill patients. IMPORTANCE: The incidence of tuberculosis (TB) in intensive care units (ICUs) can be as high as 3% in high-burden settings, translating to more than 7,500 patients admitted to the ICU annually. In resource-limited settings, the lack or absence of intravenous formulations of drug-sensitive antituberculosis medications necessitates healthcare practitioners to crush, dissolve, and administer the drugs to critically ill patients via a nasogastric tube (NGT). This off-label practice has been linked to plasma concentrations below the recommended target concentrations, particularly of rifampicin and isoniazid, leading to clinical failure and the development of drug resistance. Optimizing the delivery of crushed drug-sensitive antituberculosis medication via the NGT to critically ill patients is of utmost importance.