Efficacy of fabomotizole in counteracting the sequelae of prenatal peat smoke exposure in rats: Application of WOE/IV methodology

Introduction. Peat fire smoke poses a significant threat to public health by degrading ambient air quality. Pregnant women and the developing fetus represent the most vulnerable population subgroup due to heightened susceptibility to toxicants. The use of fabomotizole — a selective anxiolytic agent — is of particular interest for mitigating these pathological outcomes. Traditional preclinical statistical approaches often fail to provide a comprehensive quantitative benefit-risk assessment. The integration of advanced mathematical tools — specifically, the weight of evidence (WoE) and information value (IV) methodologies developed by the Scientific Centre for Expert Evaluation of Medicinal Products (SCEEMP), Russia — enables objective prediction of drug efficacy. This approach establishes a methodologically advanced framework for evidence-based decision-making in pharmaceutical R&D.

Objective. To assess the embryotoxicity and neurotoxic effects of peat smoke exposure in a rat model, and to evaluate the corrective efficacy of fabomotizole using WoE and IV methodologies.

Materials and methods. The study utilized outbred female Wistar rats (n = 10–14) weighing 240–270 g. To model smoke-induced teratogenesis, pregnant females were subjected to daily inhalational exposure of peat smoke from gestational day (GD) 1 to GD 20 (exposure duration: 44 min/day). Exposures were conducted during the critical window of organogenesis. Pharmacological correction was administered via oral gavage. Pregnant females received fabomotizole prenatally at doses of 1 and 10 mg/kg/day. Postnatal offspring were exposed to the compound through lactation at an estimated dose of 1–10 mg/kg/day. On postnatal day (PND) 21, direct administration was initiated at a dosage of 200 mg/kg/day. Embryotoxicity was assessed via gross necropsy and visceral examination. Postnatal development was evaluated using the following endpoints: sensorimotor reflex maturation (righting reflex), grip strength, locomotor activity, anxiety-like behavior, and cognitive function. Statistical analysis was performed using Statistica 10.0 and IBM SPSS Statistics 22.

Results. Prenatal exposure to peat smoke resulted in a significant increase in the incidence of developmental abnormalities. Specifically, hyperemia rates rose from 10.6% to 58.5%, petechiae increased from 7.1% to 43.1%, and intra-abdominal hemorrhage surged from 7.8% to 84.3%. Skeletal malformations included renal ectopia (rising from 12.5% to 27.1%) and delayed ossification: notably, retardation of the occipital bone was observed in 58.5% of specimens, with complete absence in 20.8%. In the offspring cohort, delayed acquisition of the cliff aversion reflex was observed in 65% of males and 59% of females, accompanied by increased anxiety-like behavior and cognitive impairment. Fabomotizole treatment (1 and 10 mg/kg) significantly reduced the incidence of developmental anomalies (p < 0.05), promoted skeletal ossification (most pronounced at 1 mg/kg), and normalized sensorimotor reflexes and behavioral performance. The calculated WoE index was 1.46 for the 1 mg/kg dose and 1.20 for the 10 mg/kg dose (p < 0.05), indicating strong predictive validity.

Conclusions. WoE and IV methodologies demonstrated a corrective effect of fabomotizole. The calculated WoE indices were 1.46 for the 1 mg/kg dose and 1.20 for the 10 mg/kg dose (p < 0.05). IV analysis identified hyperemia and hemorrhagic lesions as the primary predictors of embryotoxicity (IV = 0.34, p < 0.05). Skeletal malformations, including delayed ossification, also contributed significantly to the model (IV = 0.11). The consistency between WoE/IV metrics and classical statistical methods underscores the translational potential of this approach for preclinical drug safety assessment.

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