Jan Juřica

Background and purpose: The increasing prevalence of multidrug-resistant parasites, particularly Trypanosoma and Leishmania, together with the limited efficacy of current therapies, highlights the need for new antiprotozoal agents. Current therapeutic options remain limited by toxicity and insufficient efficacy. Building on our previous work on naphthalene and quinoline derivatives with antiparasitic activity, we report new derivatives with potent antiprotozoal activity against both Leishmania mexicana and Trypanosoma brucei. Experimental approach: The synthesized compounds were evaluated for their antiprotozoal activity against Leishmania mexicana and Trypanosoma brucei, cytotoxicity, and metabolic stability in rat and human liver microsomes. To investigate their possible mechanism of action, a comprehensive molecular modelling study was performed, including molecular docking, molecular dynamics simulations (per-residue analysis), and quantum theory of atoms in molecules (QTAIM) calculations. Key results: Some synthesized compounds exhibited inhibitory effects comparable to or greater than those of the reference compounds and showed no significant cytotoxicity. The most active molecules demonstrated high metabolic stability in both rat and human liver microsomes. Molecular modelling provided mechanistic insight into the observed antiparasitic activity and identified trypanothione reductase and arginase as possible molecular targets in Leishmania mexicana. For Trypanosoma brucei, our simulations suggest that trypanothione reductase is the most probable molecular target and that these compounds inhibit this enzyme. Conclusion: The synthesized hydroxynaphthalene and quinoline derivatives represent promising antiprotozoal compounds with favourable metabolic stability and low cytotoxicity. Molecular modelling provided a possible explanation for their biological activity and suggested potential molecular targets that may support their further optimization.

Introduction: Harmane (HAR) is a beta‐carboline alkaloid found in plants, heat‐processed foods, and tobacco. It is an active component of widely used antidepressant and anxiolytic herbs. In this study, we investigate the effects of HAR on rat CYP enzymes both in vivo and in vitro and examine the interactions between HAR and human CYP enzymes through in silico methods. Methods: The impact of subchronic premedication with HAR at doses of 25, 40, and 64 mg/kg on CYP enzyme activity was evaluated in rats using CYP‐specific probe substrates of CYP1A2, CYP2A, CYP2B, CYP2C6, CYP2C11, CYP2D1/2, and CYP3A1/2. In vitro inhibitory assays of HAR were conducted. Finally, HAR was docked in silico into human CYP enzyme active sites. Results and Discussion: HAR premedication significantly decreased the protein content and metabolic activity of rat CYP2B1, CYP2C11, CYP2D1/2, and CYP3A1/2. In vitro , HAR showed moderate inhibition of CYP2A1 and CYP3A1/2 (IC50 values of 14.0 and 1.2 µM, respectively) and no inhibition of the other enzymes tested. In silico docking studies with human CYP enzymes confirmed that HAR has the potential for CYP‐mediated drug–drug inhibitory interactions. In summary, HAR significantly inhibited the activities of several drug‐metabolizing CYP enzymes in the preclinical model. These findings suggest the need for further research into HAR’s pharmacokinetic interactions.

Salidroside (SAL) is the active ingredient of the traditional adaptogenic herb Rhodiola rosea. Cytochromes P450 (P450), crucial enzymes in drug metabolism, are central to understanding drug–herb interactions. This study investigates the impact of SAL on the metabolic activity of selected P450 in both rat and human systems. Wistar rats were administered intragastrically with SAL 5, 15, or 45 mg/kg/day for seven days. The metabolic activity of CYP1A2, CYP2C6, CYP2D, and CYP3A was measured in rat liver microsomes (RLMs). Amounts and gene expressions of CYP1A2 and CYP2C6 were assessed in RLMs using Western blot and two-step qRT-PCR. rPXR, hPXR, and CAR3 gene reporter assays were conducted. The in vitro inhibitory studies of SAL in both drug-naïve rat and human liver microsomes were performed. Interactions between SAL and human P450 were also studied by in silico methods. SAL at the dose of 5 mg/kg/day slightly increased the specific activity of the P450 studied. However, SAL did not change either the P450 protein levels or the expression of the corresponding genes in rat liver. It also did not cause direct inhibition of rat and human P450 in liver microsomes in vitro. Molecular docking with human P450 confirmed these findings. Moreover, SAL inhibited the agonist-mediated induction of both rat and human PXR. Based on our findings, SAL is unlikely to pose a significant risk of P450-mediated drug-herb interactions and rather preserves the constitutional CYP3A metabolic activity via interaction with PXR. Not applicable. The online version contains supplementary material available at 10.1007/s43440-026-00842-w.

The use of cannabinoids has a history spanning thousands of years, and their pharmacological and toxicological properties, particularly those of THC and CBD, are well-documented. However, their potential to induce drug-drug interactions remains underexplored. This review aims to provide a comprehensive perspective by contextualizing the historical and pharmacological significance of cannabinoids while focusing on their capacity to modulate the metabolic activity of cytochrome P450 isoforms relevant to drug metabolism. Additionally, we look at the impact of cannabinoids in neuronal circuits impacting the hypothalamic-pituitary hormonal axis, such as the locus coeruleus and raphe nuclei and their possible consequences on the cytochrome P450 system. Recognising potential interactions between cannabinoids and other drugs could enhance understanding of their pharmacological effects, improve the efficacy and safety profiles of cannabinoid-based therapies, and encourage further exploration into this under-researched area of psychopharmacology, with implications for both preclinical research and clinical practice.

Background and Objective: Achieving sufficient antibiotic concentration in the tissue is a key prerequisite for effective wound infection treatment. We evaluated clindamycin, ciprofloxacin, and co-trimoxazole penetration into exudate among patients treated with negative pressure wound therapy (NPWT). Methods: Ten consecutive patients receiving NPWT for deep sternal wound infection (DSWI) after open-heart surgery were enrolled in this prospective observational study. Serum and exudate samples were synchronously collected at 0 (pre-dose), 0.5, 1, 2, 3, and 5 h after clindamycin administration, and at 0, 0.5, 1, 2, 3, and 6 h after ciprofloxacin and co-trimoxazole administration. Wound penetration was assessed as the ratio of the average antibiotic concentration in the wound exudate to that found in serum. Results: The wound penetration ratio was significantly higher for free clindamycin concentrations (4.19 ± 1.43) than for total clindamycin concentrations (0.83 ± 0.23) (p = 0.007). Wound penetration was similar for both total and free ciprofloxacin concentrations (0.87 ± 0.35 vs. 0.81 ± 0.32; p = 0.777). The total and free exudate penetration ratios were about twofold higher for sulfamethoxazole (0.8 and 1.1, respectively) compared to trimethoprim (0.36 and 0.42, respectively). The hospital stay of open-heart surgery patients with DSWI was significantly longer (49 ± 20 days) than in those without infection (14 ± 12 days; p < 0.001). No 90-day mortality was observed. One patient experienced late DSWI recurrence. During the median follow-up of 2.3 years, all-cause mortality was 4.8%. Conclusion: Clindamycin, ciprofloxacin, and co-trimoxazole effectively penetrated wound exudate in patients on NPWT for post-sternotomy DSWI. The protocol for this study was retrospectively registered at ClinicalTrials.gov on July 16, 2024 (NCT06506032).