Current Issue : October-December Volume : 2026 Issue Number : 4 Articles : 5 Articles
Background/Objectives: In this study, we present an analysis of ayahuasca, a psychedelic preparation containing N,N-dimethyltryptamine (DMT) and β-carbolines, such as harmine (HRM), a reversible monoamine oxidase A (MAO-A) inhibitor that enables the oral bioavailability of DMT. CYP2D6 is a highly polymorphic enzyme associated with interindividual variability in drug exposure, but its influence on the pharmacokinetics of ayahuasca alkaloids remains poorly understood. Methods: Using physiologically based pharmacokinetic (PBPK) modeling, we simulated scenarios for poor (PM), normal (NM), and ultra-rapid (UM) metabolizers by adjusting CYP2D6 enzyme expression for each phenotype. Results: PMs showed increased systemic exposure to DMT (AUC +53.3%; Cmax +40.5%) and HRM (AUC +30.6%; Cmax +22.8%), while UMs exhibited reduced exposure to both compounds. Conclusions: These findings highlight the significant impact of CYP2D6 polymorphisms on the pharmacokinetics of DMT and HRM, reinforcing the value of PBPK modeling for predicting interindividual variability and potential clinical risks....
Background/Objectives: Oritavancin therapy for complex infections remains challenging due to the lack of well-established dosing regimens. The objective of this work was to apply PK/PD modeling and Monte Carlo simulation considering different PK/PD targets to identify multiple-dosing regimens that may ensure effective concentrations of oritavancin for the treatment of long-term infections. Methods: Plasma concentration– time profiles were simulated for different regimens (single dose of 1200 mg, 1200 mg followed by 800 mg every 7 days (q7d), 1200 mg followed by 800 mg q10d, 1200 mg q7d, 1200 mg q10d, 1200 mg q14d, 1200 mg q21d, and 1200 mg followed by 1200 mg on day 8, then 1200 mg q14d), and the probability of target attainment (PTA), indicative of treatment success, was estimated. Results: All dosing regimens provided probabilities of target attainment of 100% up to MICs of 0.5 mg/L when AUC0–24/MIC and Cmax/MIC were applied. Considering AUC0–72/MIC, the regimens would be adequate up to an MIC of 0.125 mg/L. For fCmin > MIC, all except 1200 mg q21d were adequate for an MIC of 0.125 mg/L, and 1200 mg day 1 + 800 mg q7d and 1200 mg q10d may be useful to treat infections due to bacteria with an MIC of 0.25 mg/L. Conclusions: More studies involving patients with complex infections are needed to better stablish the relationships among plasma concentrations, MIC values, and clinical outcomes. fCmin > MIC should be investigated as a potential PK/PD target for the treatment of these infections with oritavancin....
Background/Objectives: Combination of antiparasitic drugs with different mechanisms of action has been suggested as an effective strategy to delay the development of parasite resistance. Considering the need to understand the pharmacological basis of drug combinations, the current study evaluated the potential pharmacokinetic (PK) interactions and the clinical efficacy (pharmacodynamic response) occurring after the subcutaneous administration of ivermectin (IVM) and levamisole (LEV), administered either as single treatments or concurrently to different groups of parasitized calves on three commercial farms (A, B and C). Methods: Forty-five (45) male calves naturally infected with gastrointestinal nematodes were randomly allocated into three groups (n = 15): IVM, treated with IVM by subcutaneous injection (0.2 mg/kg); LEV, treated subcutaneously with LEV (8 mg/kg); IVM + LEV, simultaneously treated with IVM and LEV (two subcutaneous injections at the same dose rates). Seven animals from each treated group (farm C) were randomly selected to perform the PK study. Drug concentrations were measured by HPLC. The therapeutic response (efficacy) was determined at 14 days after treatment by the fecal egg reduction test. Results: The mean area under the concentration vs time curve (AUC) for IVM obtained after administration of IVM alone (274 ± 65.1 ng.d/mL) was similar to that obtained when IVM was co-administered with LEV (295 ± 111 ng.d/mL). Likewise, mean LEV AUC values were similar after LEV administration alone (8.90 ± 2.69 μg.h/mL) or combined with IVM (9.11 ± 1.82 μg.h/mL). No adverse PK interactions were observed after the combined treatment, with similar PK parameters (p > 0.05) obtained between the single-drug and the combination-based strategies. On farm A, the overall fecal egg reductions were 38% (IVM), 99% (LEV) and 100% (IVM + LEV). While Cooperia spp. and Haemonchus spp. showed reduced susceptibility to IVM treatment, LEV demonstrated high efficacy against both genera, with only a minimal proportion of Haemonchus spp. remaining after treatment. Similarly, total fecal egg reductions were 42% (IVM), 99% (LEV) and 100% (IVM + LEV) on farm B, and 54% (IVM), 99% (LEV) and 100% (IVM + LEV) on farm C. On those farms, IVM was ineffective against Cooperia spp. and/or Haemonchus spp., while LEV failed to control Ostertagia spp. Remarkably, the combination of both molecules was the only treatment that achieved 100% efficacy against all nematode genera (Cooperia, Ostertagia, Haemonchus and Oesophagostomum spp.). Conclusions: Based on the described PK and pharmacodynamic (PD) assessments, the IVM + LEV combination appears to be a promising pharmacological option for controlling resistant gastrointestinal nematodes in cattle, with the additional potential to delay the progression of nematode anthelmintic resistance. Overall, the study provides original and robust pharmacokinetic and efficacy data that contribute to the optimization of parasite control strategies in cattle. This drug combination strategy may enhance treatment efficacy and contribute to improved parasite control in cattle production systems....
Background/Objectives: Risperidone oral solution (RIS-OS) is an easy-to-administer treatment for schizophrenia designed to improve medication adherence and rapid onset of effect. Mixing RIS-OS with beverages such as black tea is prohibited due to reduced RIS concentrations observed in vitro, despite the absence of pharmacokinetic data. In this study, we evaluated the pharmacokinetics of RIS and its active metabolite 9-OH-RIS in rats following oral administration with black tea. Methods: Male Wistar rats received RIS-OS intravenously or orally as a water or Dimbula black tea mixture; serial tail-vein blood samples were collected as dried blood spots, RIS and 9-OH-RIS were quantified using HPLC/ESI-MS/MS, and pharmacokinetic parameters were calculated and compared using Welch’s t-test. Results: Compared with the water mixture, the black tea mixture significantly reduced RIS Cmax, while Tmax and AUC remained unchanged. Furthermore, AUMC and MRT were significantly higher. The results were similar for 9-OH-RIS. Despite reduced RIS content in vitro, no difference in absolute bioavailability was observed in vivo. Although only one black tea variety was tested, evaluating additional varieties may help identify the components responsible for reducing RIS content. Conclusions: Mixing RISOS with black tea may delay absorption without reducing overall exposure, providing evidence that may contribute to safer guidance regarding beverage coadministration....
Developing effective drugs for Alzheimer’s Disease (AD) is critically limited by insufficient brain exposure. To address this, structural optimization was employed to balance physicochemical properties and enhance blood-brain barrier (BBB) permeability, resulting in the development of ZJCK-6-72, a novel DYRK1A inhibitor. This study aims to comprehensively evaluate the drug-like properties and safety profile of ZJCK-6-72. Methods: A comprehensive in vitro and in vivo ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling of ZJCK-6-72 was conducted. Key assessments included pharmacokinetics, tissue distribution studies in rats, plasma protein binding assays, and metabolic stability testing. Additionally, acute toxicity was evaluated to determine the safety margin, and enzyme inhibition assays were performed to assess potential drug-drug interactions. Results: ZJCK-6-72 exhibited excellent oral bioavailability (78.03%) and extensive tissue distribution in rats. Notably, the compound demonstrated substantially enhanced brain penetration, with a brain-to-plasma ratio ranging from 1.92 to 4.63. The unbound brain-to-plasma partition coefficient (Kp, uu) was determined to be 3.50, significantly exceeding unity. Metabolic studies indicated a shift towards CYP1A2 and CYP2C19 mediated pathways, with concentrationdependent inhibition observed (IC50 ≈ 1.8 μM). The acute toxicity assessment revealed an LD50 of 233.9 mg/kg bodyweight. Discussion: The high Kp, uu value indicates that the efficient brain entry of ZJCK-6- 72 is likely driven by active uptake mechanisms rather than simple passive diffusion, confirming its ability to effectively evade efflux transporters. Although the inhibition of CYP1A2 and CYP2C19 suggests a potential for mechanism-based auto-inhibition, the acute toxicity profile demonstrates an acceptable safety margin for therapeutic development. Conclusion: ZJCK-6-72 displays an optimized pharmacokinetics profile characterized by superior unbound brain exposure. These findings support the potential of ZJCK-6-72 as a promising lead candidate for CNS-targeted AD therapy....
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