Pharmacology Research & Perspectives最新文献

Vornorexant is a novel dual orexin receptor antagonist (DORA) for the treatment of insomnia with a short elimination half-life. Estimation of the human orexin receptor occupancy can provide insight into the duration of the sleep-promoting effect of DORAs. Herein, we developed a pharmacokinetic-receptor occupancy (PK/RO) model for OX₁ and OX₂ receptors in rats and estimated their receptor occupancy in humans based on the human plasma concentrations after oral administration of vornorexant. The estimated occupancy of the human OX₂ receptor, which is primarily involved in sleep induction, exceeded 70% at 30 min after dosing of therapeutic doses of 5 and 10 mg. The human OX₂ receptor occupancy at 6 h post-dose of 5 and 10 mg was estimated to be approximately 50% and 60%, respectively, comparable to the occupancy necessary to exert sleep-promoting effects in rats. Occupancy of the human OX₁ receptor by vornorexant was higher than that of the OX₂ receptor. The estimated human OX₁ and OX₂ receptor occupancy decreased with short half-lives depending on the plasma concentration. These results suggest that vornorexant exerts rapid sleep-promoting effects and maintains sleep for at least 6 h, and these estimations of the OX₂ receptor occupancy could support the clinical results. Vornorexant may have a favorable PK/RO profile for rapid sleep onset and sufficient sleep maintenance with minimal next-day residual effects in humans.

Drug-food interactions may compromise therapeutic efficacy, particularly for life-saving medications such as anticoagulants. Changes in gastric fluid properties, including pH modification and surface film formation, can alter drug dissolution and release. This study evaluated a potential interaction between clopidogrel and spinach and explored the underlying mechanisms. In vitro disintegration and dissolution studies were conducted using HCl and phosphate buffers with and without 5% and 7.5% spinach extract. Drug release was quantified by high-performance liquid chromatography (HPLC), with six media conditions analyzed in triplicate. Disintegration testing was performed in simulated gastric and intestinal fluids and in the presence of spinach leaves to assess the effect of film formation on tablet wetting and disintegration. In vitro-in vivo extrapolation (IVIVE) was assessed using GastroPlus software. Clopidogrel dissolution decreased with increasing spinach concentration in both media. In HCl buffer, dissolution declined from 99% to 94% and 89%, while in phosphate buffer it decreased from 71% to 66% and 56%. These effects were associated with increased pH (HCl: 1.91, 2.83, 2.98; phosphate: 6.81, 8.83, 6.84), increased solution viscosity, 17.63 to 17.67 and 17.70 in HCl buffer, and from 17.44 to 17.50 and 17.54 in phosphate buffer. Moreover, reduced fluid penetration was due to spinach leaves coverage. IVIVE analysis showed weak correlations (R² = 0.74 in HCl and 0.69 in phosphate buffer). Spinach reduced clopidogrel dissolution in vitro, with statistically significant effects at 5% spinach in HCl buffer (ANOVA test, p-value 0.019) and 7.5% in phosphate buffer (ANOVA test, p-value < 0.001). This interaction appears to be mediated by pH alteration, physical film formation, and potentially metal-drug complexation. Confirmation through in vivo studies is warranted.

Vancomycin (VAN) remains the first-line treatment for methicillin-resistant, multidrug-resistant gram-positive bacterial infections, even among cancer patients. Patients with hematological malignancies (HMs) represent a unique population, whose physiological and pathological changes often differ from those of the general population. These variations may cause significant alterations in the in vivo pharmacokinetics (PK) of VAN, causing unpredictable changes in the safety, efficacy, and bacterial resistance. Customized dosing of VAN (CD_van) offers potential solutions to these challenges. However, there is currently a lack of guideline-based, consensus-driven references, and limited research on the implementation of CD_van in HM patients, particularly in adults. This review concentrates on adult HM patients and reviews studies on VAN PK in them (including population PK and its models), focusing on current mainstream and novel CD_van technologies, including therapeutic drug monitoring-guided, model-guided, closed-loop control systems, and artificial intelligence-guided CD_van technologies. The challenges faced in the broader implementation of these technologies and the promising solutions exploited, such as blockchain technology-driven clinical decision support systems, are also discussed. Understanding the multifaceted aspects of PK research and personalized dosing of VAN in HM patients will help facilitate the rational treatment of VAN, in-depth PK research, and the development of CD_van techniques in HM patients.

We developed a computational model, called "Unbiased microRNA-disease association predictor (UBMDA)," to predict microRNA-disease associations. UBMDA has two major differences from those reported previously. First, we did not apply a similarity-based feature extraction method, which is the main basis of previous studies. Instead, we used International Classification of Diseases 11th Revision disease codes and microRNA nucleotide sequences as input features. Thus, UBMDA can be applied to newly discovered or poorly studied microRNAs and diseases. Second, we constructed an appropriate negative sample dataset. A positive sample dataset consisting of microRNAs and diseases pairs with proven associations between microRNAs and diseases is publicly available. However, datasets reporting no associations between microRNAs and diseases are rare. Therefore, a negative sample dataset was created by combining microRNAs and diseases. Because more commonly studied microRNAs and diseases are more likely to be included in the positive sample dataset, creating a negative sample dataset without taking this bias into consideration could cause an imbalance in disease and microRNA frequencies between positive and negative sample datasets, leading to biased prediction. To prevent such an imbalance, we created a negative sample dataset considering the frequency of each microRNA and disease in the positive sample dataset, such that these frequencies were similar between the negative and positive sample datasets. We successfully developed a computational model with a simple and intuitive structure. UBMDA will contribute to accelerating the development of microRNA-related biomarkers and therapeutics.

Immunomodulatory drugs (IMIDs) and proteasome inhibitors (PIs) are part of the frontline treatment landscape for multiple myeloma (MM). Despite their effectiveness, these drugs are associated with adverse effects, particularly clinically significant drug-induced peripheral neuropathy. The aim of this study was to evaluate the association between peripheral neuropathy and IMIDs and PIs used in MM, stratified by type of nerve dysfunction. VigiBase, the World Health Organization's global database of individual case safety reports (ICSRs), was analyzed. All ICSRs reported from 1 December 2001 to 31 May 2023 were extracted. Peripheral neuropathy cases were identified using MedDRA-preferred terms (neuropathy peripheral, autonomic neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy) and standardized MedDRA queries (SMQ: peripheral neuropathy). Disproportionality signals were assessed using the reporting odds ratio (ROR) and information component (IC). Associations with peripheral neuropathy were found for all IMIDs and PIs. Both IMIDs and PIs were associated with peripheral sensory neuropathy. Associations with autonomic neuropathy were observed for bortezomib (ROR 12.90; 95% CI: 9.01-18.47), ixazomib (ROR 19.01; 95% CI: 7.89-45.80), carfilzomib (ROR 9.35; 95% CI: 3.01-29.10) thalidomide (ROR 8.86; 95% CI: 4.21-18.70). Associations with peripheral motor neuropathy were detected for bortezomib (ROR 63.87; 95% CI: 51.78-78.80), thalidomide (ROR 30.62; 95% CI: 22.67-41.40), lenalidomide (ROR 2.95; 95% CI: 2.11-4.14), pomalidomide (ROR 5.03; 95% CI: 2.91-8.69). Signals of autonomic neuropathy were identified for bortezomib, carfilzomib, ixazomib, and thalidomide, while signals of peripheral motor neuropathy were observed for bortezomib, thalidomide, lenalidomide, and pomalidomide. Associations with peripheral sensory neuropathy were detected for all IMIDs and PIs analyzed.

Environmental stressors, such as ionizing radiation, accelerate aging by causing DNA damage and triggering pathways that lead to cell cycle arrest, apoptosis, and subsequent inflammation. The thrombopoietin receptor agonist romiplostim (RP), which is used as a clinical treatment for chronic idiopathic thrombocytopenic purpura and aplastic anemia, is known to be promising in reducing radiation-induced tissue damage. In this study, we established a mouse model of radiation-induced premature aging to evaluate the potential of RP in ameliorating this process. Female C57BL/6JJcl mice were subjected to total body irradiation with various irradiation schedules. Mice irradiated with 5 Gy every 4 weeks (total dose of 10 Gy over 2 months) showed a significant aging phenotype, including graying hair and elevated serum aging markers (CDKN2A/p16^INK4a, tumor necrosis factor-α (TNF-α), and C-reactive protein), compared with sham-irradiated controls. RP was intraperitoneally administered to the mouse model (10 μg/kg weekly or 50 μg/kg every 4 weeks). Treatment significantly reduced TNF-α levels by 15% and the area of graying body hair by 70%. Although bone marrow cell recovery was incomplete, spleen cell counts were significantly restored (2-fold) by 50 μg/kg RP, and SA-β-gal activity, a marker of cellular senescence, was also significantly suppressed by approximately 15%. These findings suggest that RP may partially ameliorate radiation-induced premature aging, providing a basis for future research addressing health issues associated with aging and radiation exposure.

Efavirenz (EFV) is the first-line treatment for acquired immunodeficiency syndrome. However, capsaicin may affect its properties, although the underlying mechanisms remain unknown. This study aimed to investigate the effects of dihydrocapsaicin (DHC) on the pharmacokinetics of EFV both in vivo and in vitro. Twelve Sprague-Dawley rats were divided into two groups including experimental and control. The experimental group was pretreated with DHC (10 mg/kg/day) for two weeks with 5% sodium carboxymethyl cellulose prior to receiving EFV. After a single-dose oral administration of 56 mg/kg EFV, blood samples (50 μL) were collected from the caudal vein and analyzed. The effects of DHC on EFV in vitro were further studied in rat liver microsomes (RLMs). The area under the plasma concentration-time curve for EFV increased from 8821.45 ± 2877.31 to 22347.15 ± 7579.96 μg/mL/h (p < 0.05); the maximum plasma time increased from 2.50 ± 0.84 to 3.50 ± 0.55 h (p < 0.05) and elimination half-life increased from 3.13 ± 0.87 to 3.51 ± 0.79 h (p < 0.05). In contrast, the plasma clearance rate decreased from 6.71 ± 2.48 to 2.65 ± 0.98 L/h/kg (p < 0.05) in the experimental group compared to that in the control group. Additionally, the results showed that DHC significantly inhibited the metabolism of EFV in RLMs. Drug-drug interactions were observed between DHC and EFV, altering the pharmacokinetics of EFV both in vivo and in vitro. The dosage of capsaicin should be monitored and adjusted in patients receiving EFV maintenance therapy.