Pharmacology Research & Perspectives最新文献

The dose-response relationship between metformin and change in hemoglobin A1c (HbA1c) shows a maximum at 1500-2000 mg/day in patients with type 2 diabetes (T2D) in the U.S. In Japan, there is little evidence on the HbA1c-lowering effect of high-dose metformin because the maintenance and maximum doses of metformin were raised in 2010. The aim of this study was to investigate whether there is saturation of the dose-response relationship for metformin in Japanese T2D patients. Longitudinal clinical information of T2D patients was extracted from electronic medical records. Supervised machine learning models with random effect were constructed to predict change in HbA1c: generalized linear mixed-effects models (GLMM) with/without a feature selection and combining tree-boosting with Gaussian process and mixed-effects models (GPBoost). GPBoost was interpreted by SHapley Additive exPlanations (SHAP) and partial dependence. GPBoost had better predictive performance than GLMM with/without feature selection: root mean square error was 0.602 (95%CI 0.523-0.684), 0.698 (0.629-0.774) and 0.678 (0.609-0.753), respectively. Interpretation of GPBoost by SHAP and partial dependence suggested that the relationship between the daily dose of metformin and change in HbA1c is non-linear rather than linear, and the HbA1c-lowering effect of metformin reaches a maximum at 1500 mg/day. Interpretation of GPBoost, a non-linear supervised machine-learning algorithm, suggests that there is saturation of the dose-response relationship of metformin in Japanese patients with T2D. This finding may be useful for decision-making in pharmacotherapy for T2D.

Data addressing safety concerns related to potential drug interactions between cannabis-derived products and pharmaceutical medications in the pediatric population are lacking. In this study, we retrieved case reports through a published literature search using PubMed and spontaneous reporting data using the Food and Drug Administration's Adverse Event Reporting System (FAERS) to identify potential cannabis- and cannabinoid-drug interactions in individuals younger than 18 years old. To evaluate the published case reports, we used the Drug Interaction Probability Scale (DIPS), a 10-item questionnaire designed to discern the causal relationship between a potential drug interaction and adverse drug reactions (ADRs). FAERS reports were deduplicated and analyzed to gather information regarding patient demographics, associated drugs, nature of the ADRs, outcomes, professions of the reporters, and reporting timelines. Seven published case reports and 9142 FAERS ADRs reports were included in the final analysis. Based on the findings, caution is warranted when cannabis or cannabinoids are used in combination with prescribed medications, including methadone, everolimus, fluoxetine, and paroxetine. Cannabinoids may inhibit drug-metabolizing enzymes, including several cytochrome P450s, leading to increased drug exposure and potentially, an increased risk for ADRs.

of the key disciplines that equip next-generation researchers engaged in ethnopharmacology research with the necessary knowledge and skills to navigate the transition from traditional ethnopharmacology to modern drug discovery.

New onset insomnia is often experienced by patients during hospitalization due to environmental disruptions, pain and increased patient care activities. Patient distress arising from poor sleep quality and quantity often results in the prescribing of hypnotics. Melatonin use in hospital settings is common and is increasingly used for off label indications including primary insomnia in those aged < 55 years, prevention of delirium and to facilitate benzodiazepine discontinuation. A literature review was conducted to evaluate the efficacy, effectiveness, safety, tolerability, and cost-effectiveness of melatonin for various off-label indications in inpatient hospital settings. The review found limited high quality evidence demonstrating a clinically meaningful benefit from melatonin in improving sleep, delirium, or facilitating benzodiazepine discontinuation in the inpatient setting. Study findings were inconsistent, and those that did show statistical improvement were of uncertain clinical benefit. The review also found a paucity of data on the safety of melatonin when used in hospitalized patients, and no evidence to support cost-effectiveness. Non-pharmacological interventions are recommended as first-line treatment of insomnia and for the prevention of delirium in inpatient settings. The use of interventions without evidence for efficacy or effectiveness is contrary to the quality use of medicines principles in Australia's National Medicines Policy. Context-specific evidence on the efficacy and effectiveness of a medicine should guide clinician decision-making and prescribing, to improve the quality use of medicines.

Doxorubicin (DOXO) has long been used clinically and remains a key drug in cancer therapy. DOXO-induced cardiomyopathy (DICM) is a chronic and fatal complication that severely limits the use of DOXO. However, there are very few therapeutic agents for DICM, and there is an urgent need to identify those that can be used for a larger number of patients. The most likely pathogenic mechanism of DICM is the involvement of reactive oxygen species (ROS) and promotion of cell death. In this study, we investigated the efficacy and mechanism of action of edaravone (EDA), a known radical scavenger in DICM. Two methods of EDA administration were employed: daily and weekly. Our results showed that the daily administration group had prolonged survival periods and preserved the left ventricular ejection fraction in DICM mice. In contrast, in the weekly treatment group, slight improvements were observed in these indicators compared with those in DICM mice; however, none of them were statistically significant. These results show that the daily administration group had a higher efficacy than the weekly administration group. Gene-expression results showed that Nrf2 and its related genes were upregulated in the daily group but not in the weekly group. Based on these results, we hypothesized that the Sirt1/Nrf2/HO-1 and ABCB4 pathways were involved in EDA. However, there is limited evidence that EDA is effective against DICM. The findings obtained herein bolster the evidence in DICM by demonstrating prolonged survival and continued preservation of cardiac function and proposing a possible mechanism.

The aim of this study was to evaluate safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of a novel inhaled formulation of voriconazole (ZP-059). In the single ascending dose part, 4 cohorts of 6 healthy subjects received one dose of inhaled voriconazole (5-40 mg). In the multiple ascending dose part, 3 cohorts of 6 subjects with mild asthma received voriconazole 10 mg twice daily [BID], 20 mg BID or 40 mg once daily. In the 2-period crossover part, 16 subjects with mild to moderate asthma each received one dose of inhaled voriconazole 20 mg and one dose of oral voriconazole 200 mg. A bioanalytical method was developed and validated to simultaneously determine concentrations of voriconazole and its metabolite N-oxide voriconazole in serum and sputum. Inhaled voriconazole was well tolerated with no treatment emergent adverse events (TEAEs) leading to treatment discontinuation. The PK profile of inhaled voriconazole showed rapid absorption, apparent greater than proportional increase in exposure with increasing dose, a consistent half-life across dosing, and large clearance and volume of distribution. Following repeat administration limited accumulation was observed. Systemic exposure following inhaled voriconazole was much lower than following oral voriconazole. Serum data confirmed that voriconazole was extensively metabolized also when administered by inhalation. Sputum data following inhaled voriconazole were limited but demonstrated increasing exposure with increasing dose. The current study shows the newly developed dry powder inhaled formulation of voriconazole to be safe and well tolerated, providing a possible improved treatment approach for patients affected by allergic bronchopulmonary aspergillosis. Trial Registration: ClinicalTrials.gov ID: NCT04229303.

Pharmacogenomics is a field of personalized medicine that aims to tailor drug dosing based on the genetics of an individual. The polymorphic and complex CYP2D6 gene is important to analyze because of its role in the metabolism of approximately a quarter of all drugs. Several bioinformatic tools have been developed to genotype CYP2D6 from short-read sequencing data. Among these, Cyrius, a tool specifically designed for CYP2D6 genotyping, has demonstrated high performance across various datasets. However, Cyrius has not been updated in the past 3 years, during which dozens of new star alleles have been identified and some previously defined ones revised. In this work, we simulated all known CYP2D6 haplotypes to assess the ability of Cyrius to identify them. In that dataset, Cyrius was unable to call or misidentified 50 of 360 samples. Given the importance of providing an up-to-date tool, particularly in clinical settings, we present an upgraded version of the tool, named BCyrius, which includes all the missing star alleles as well as revisions to the previously listed ones. BCyrius successfully identified 100% of the currently defined minor star alleles, higher than Cyrius (85.6%) and the two other tested tools, Aldy and StellarPGx, which identified 92.2% and 87.8%, respectively. BCyrius also demonstrated slightly improved performance on a dataset of real biological samples, resulting in a higher call rate while maintaining similar accuracy with Cyrius. In addition to providing genotyping results, BCyrius also reports the predicted phenotype, along with information for each detected haplotype, including population frequencies.

In this study, the structure of a new boron compound obtained using 3-methoxy catechol and 4-methoxy phenyl boronic acid was characterized by ¹H, ¹³C NMR, LC-MS-IT-TOF, UV-Vis and FTIR spectroscopy. The antioxidant activities of the newly synthesized compound were evaluated by DPPH free radical scavenging, ABTS quation radical scavenging and CUPRAC copper reducing capacity methods. Anticholinesterase activities were determined by acetylcholinesterase and butyrylcholinesterase enzyme inhibitor assays. Antiurease and antithyrosinase enzyme inhibition activities were also examined. Cytotoxic effects were evaluated on healthy cell lines and breast and colon cancer cell lines using MTT method. The results showed that the synthesized compound has high antioxidant activity. Especially the average antioxidant activity values obtained at 10 μg/mL concentration were found to be statistically significantly (p < 0.05) higher than the reference values of α-TOC and BHT. When the antioxidant activity data (IC₅₀) were compared separately with α-TOC and BHT reference values, the new compound was found to be more effective. In acetylcholinesterase enzyme inhibition, the average activity values were found to be statistically significantly (p < 0.05) higher than the galantamine reference value. However, no statistically significant difference was observed at BChE (% inhibition) level with galantamine reference value. In terms of urease and tyrosinase enzyme inhibition activities, the urease activity of the synthesized compound was statistically significantly (p < 0.05) lower than the thiurea reference value. Tyrosinase activity was statistically significantly (p < 0.05) lower than kojic acid reference values. The synthesized and characterized compound was found to have no toxic effect on healthy cell lines and did not show any cytotoxic effect on breast cancer (MCF-7) and colon cancer (HT-29) cell lines.

Interindividual variation in pharmacokinetics can occur due to diet, environmental or lifestyle factors, underlying pathology, and gene variants, typically single nucleotide polymorphisms (SNPs). Genetic mechanisms have received the most attention in research and education about ethnic differences in pharmacokinetics. Making this connection between genetics and ethnicity is problematic because it could reinforce the erroneous idea that there is a biological basis to ethnicity. The aim of this work was to design an educational intervention about interindividual variation in pharmacokinetics, explore how students perceive ethnicity and genetic differences prior to the educational intervention, and then assess the impact of the intervention and whether it could influence any misconceptions students might have about ethnicity and genetic similarity. Through the use of questionnaires and focus groups, we found that students typically refer to ethnicity to mean culture and place of origin, whereas in the pharmacological literature, ethnicity is synonymous with racial groups, that is, Black, White, and Asian. Prior to the educational intervention, students tended to expect a genetic mechanism for ethnic differences in drug metabolism and this was reduced after the intervention when a range of other nongenetic mechanisms were presented for interindividual variation. However, students' views about possible underlying mechanisms for ethnic differences in hypertension and about ethnicity more generally were unaffected by the intervention. This highlights the importance of reevaluating the way ethnicity is presented across the medical and medical sciences curriculums to be clear that ethnicity is socially constructed and avoid implying a biological basis.