Artificial intelligence uncovers carcinogenic human metabolites.

The genome of a eukaryotic cell is often vulnerable to both intrinsic and extrinsic threats owing to its constant exposure to a myriad of heterogeneous compounds. Despite the availability of innate DNA damage responses, some genomic lesions trigger malignant transformation of cells. Accurate prediction of carcinogens is an ever-challenging task owing to the limited information about bona fide (non-)carcinogens. We developed Metabokiller, an ensemble classifier that accurately recognizes carcinogens by quantitatively assessing their electrophilicity, their potential to induce proliferation, oxidative stress, genomic instability, epigenome alterations, and anti-apoptotic response. Concomitant with the carcinogenicity prediction, Metabokiller is fully interpretable and outperforms existing best-practice methods for carcinogenicity prediction. Metabokiller unraveled potential carcinogenic human metabolites. To cross-validate Metabokiller predictions, we performed multiple functional assays using Saccharomyces cerevisiae and human cells with two Metabokiller-flagged human metabolites, namely 4-nitrocatechol and 3,4-dihydroxyphenylacetic acid, and observed high synergy between Metabokiller predictions and experimental validations.

Bioequivalence of a biosimilar enoxaparin (Cloti-Xa™) and its innovator (Clexane® ): A single-dose, randomized, double-blind, two-period, two-treatment, two-sequence, crossover, balanced study in healthy human subjects.

Currently, several biosimilars of low-molecular-weight heparins (LMWHs) with differing potencies are being developed and marketed globally. Thus, it is important that the potency of each biosimilar LMWH be compared with its innovator's molecule. The present study aimed to determine the bioequivalence of biosimilar (Cloti-Xa™) and innovator (Clexane® ) formulations of enoxaparin sodium (40 mg/0.4 ml) in healthy human volunteers. It was conducted as a single-dose, randomized, double-blind, two-period, two-treatment, two-sequence, crossover, balanced, pharmacodynamic study (NCT05265676). The participants were sequentially and randomly administered subcutaneous injections of Cloti-Xa™ (test) and Clexane® (reference), separated by a one-week washout period. To assess the Anti-Xa & Anti-IIa activities, tissue factor pathway inhibitor (TFPI) release and activated partial thromboplastin time (aPTT), blood samples were obtained at various timepoints upto 24 h after the drug administration. Bioequivalence was concluded if the two-sided 90% CI for the test to reference ratio of the population is within 80%-125% for each of the Ln-transformed values of Amax and AUECt for Anti-Xa and Anti-IIa. TFPI and aPTT data were submitted as supportive evidence. The study sample consisted of twenty-four male participants. The 90% CIs of Amax and AUECt for Anti-Xa activity were 105.50%-113.90% and 103.97%-112.08%, and for Anti-IIa activity were 106.56%-117.90% and 107.35%-124.86%, respectively. In addition, the 90% CI of the ratio of Anti-Xa/Anti-IIa activity falls within the acceptance criteria. TFPI and aPTT profiles were similar for both products. No serious adverse events were observed during the study. Conclusively, the results showed that Cloti-Xa™ and Clexane® are bioequivalent and well-tolerated.

Polymyxin B-Induced Kidney Injury Assessment of a Novel Formulation of Polymyxin B (VRP-034) in Rats.

Despite the crucial role of Polymyxin-B in treating life-threatening gram-negative infections, its clinical utility is limited due to the risk of acute kidney injury. In response, a novel formulation of polymyxin-B is being developed to mitigate drug-induced kidney injury. In this study, we have assessed the toxicity of four variants of that novel formulation (VRP034_F21-F24) in comparison with standard polymyxin-B using kidney injury biomarkers in rats. Sprague-Dawley rats were subcutaneously administered either polymyxin-B (control) or one of the four polymyxin-B formulations at a dose of 25 mg/kg/day (HED: 4 mg/kg/day) in four divided doses for two days. Serum samples were collected at baseline and at the end of day 2 for the determination of serum biomarkers. Necropsy was done on day 2 and kidney was collected for histopathological evaluation. In the control group, statistically significant increase (p < 0.0001) in all biomarkers was observed on day 2 as compared to baseline values [urea: 311%; creatinine: 700%; KIM-1: 180%; cystatin-C: 66%] and 50% of the animals died (one after the 7th dose and two after the 8th dose) before scheduled necropsy. In contrast, animals treated with novel formulations did not show a significant increase across any of the biomarkers and no mortality was observed. Histopathology of the control group kidney confirmed necrotic changes in tissues with congestion and vacuolization, whereas only minor tubular damage was noted in two formulation groups (VRP034_F21, F24) and no appreciable damage was detected in the other two groups (VRP034_F22-23). The novel formulation of polymyxin-B tested in this study significantly reduced the risk of polymyxin-induced kidney injury in rats.