Translational and Clinical Pharmacology最新文献

Large language models (LLMs) have emerged as a powerful tool for biomedical researchers, demonstrating remarkable capabilities in understanding and generating human-like text. ChatGPT with its Code Interpreter functionality, an LLM connected with the ability to write and execute code, streamlines data analysis workflows by enabling natural language interactions. Using materials from a previously published tutorial, similar analyses can be performed through conversational interactions with the chatbot, covering data loading and exploration, model development and comparison, permutation feature importance, partial dependence plots, and additional analyses and recommendations. The findings highlight the significant potential of LLMs in assisting researchers with data analysis tasks, allowing them to focus on higher-level aspects of their work. However, there are limitations and potential concerns associated with the use of LLMs, such as the importance of critical thinking, privacy, security, and equitable access to these tools. As LLMs continue to improve and integrate with available tools, data science may experience a transformation similar to the shift from manual to automatic transmission in driving. The advancements in LLMs call for considering the future directions of data science and its education, ensuring that the benefits of these powerful tools are utilized with proper human supervision and responsibility.

Safety pharmacology examines the potential for new drugs to have unusual, rare side effects such as torsade de pointes (TdP). Recently, as a part of the Comprehensive in vitro Proarrhythmia Assay (CiPA) project, techniques for predicting the development of drug-induced TdP through computer simulations have been proposed and verified. However, CiPA assessment generally does not consider the effect of cardiac cell inter-individual variability, especially related to metabolic status. The study aimed to explore whether rare proarrhythmic effects may be linked to the inter-individual variability of cardiac cells and whether incorporating this variability into computational models could alter the prediction of drugs' TdP risks. This study evaluated the contribution of two biological characteristics to the proarrhythmic effects. The first was spermine concentration, which varies with metabolic status; the second was L-type calcium permeability that could occur due to mutations. Twenty-eight drugs were examined throughout this study, and qNet was analyzed as an essential feature. Even though there were some discrepancies of TdP risk predictions from the baseline model, we found that considering the inter-individual variability might change the TdP risk of drugs. Several drugs in the high-risk drugs group were predicted to affect as intermediate and low-risk drugs in some individuals and vice versa. Also, most intermediate-risk drugs were expected to act as low-risk drugs. When compared, the effects of inter-individual variability of L-type calcium were more significant than spermine in altering the TdP risk of compounds. These results emphasize the importance of considering inter-individual variability to assess drugs.

Candesartan is an antihypertensive agent that acts on an angiotensin II receptor. Candesartan cilexetil is a prodrug that is converted into the active form of candesartan during intestinal absorption. This study aimed to assess the pharmacokinetics and bioequivalence of a reference and a test formulation of candesartan cilexetil tablets in healthy Chinese volunteers. A randomized, open-label, single-dose, crossover study was conducted with two treatment periods. Forty-eight healthy Chinese volunteers participated under fasted conditions. Qualified subjects were randomly divided into two groups (1:1 ratio) to receive either the test or reference formulation first. A washout period of 14 days separated the administration of the two formulations. Blood samples were collected at specific time points and analyzed for candesartan concentration using Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). The maximum concentration (C_max), the AUC from time zero to the last measured time point (AUC_0-t) and the AUC from time zero to infinity (AUC_0-∞) fell within the bioequivalence range of 80% to 125%. These results suggest that the test and reference formulations of candesartan cilexetil tablets are bioequivalent, meaning they have similar rates and extents of absorption in healthy Chinese volunteers. No serious adverse events or side effects were reported throughout the study.

Tegoprazan orally disintegrating tablet (ODT) formulation is a novel formulation to improve a convenience in comparison to taking the conventional tablet of tegoprazan, a potassium-competitive acid blocker. The purpose of this study was to evaluate the pharmacokinetic and safety profiles of tegoprazan ODT when administered via two routes: nasogastric tube or oral dosing. This study is expected to expand the administration route of tegoprazan ODT. The study was conducted in an open-label, randomized, single-dose, two-way crossover design with a 1-week washout period. Healthy subjects aged 19 to 45 years were administered 50 mg of tegoprazan ODT orally or dissolved in water via nasogastric tube. Tegoprazan, the active ingredient, was quantified using a ultra-high performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS), and pharmacokinetic parameters were determined through non-compartmental analysis. Safety was monitored throughout the study. A total of 48 subjects, successfully completed the trial. The geometric mean ratios for log-transformed C_max and AUC_t, representing the ratio of nasogastric tube group to oral dosing group, along with 90% confidence intervals, were 1.1087 (1.0243-1.2000) and 1.0023 (0.9620-1.0442), respectively. All adverse events were unrelated to tegoprazan and mild in intensity. The pharmacokinetic profiles of tegoprazan ODT were equivalent between the nasogastric tube and oral administration. Considering the demonstrated linear pharmacokinetics and concentration-dependent pharmacodynamics of tegoprazan, the administration via nasogastric tube is expected to yield effects equivalent to those of oral administration. This approach offers a viable alternative, especially beneficial for patients with oral intake difficulties.

Megestrol is commonly used to address appetite loss, cachexia, and significant weight loss in cancer or acquired immune deficiency syndrome patients. This study aimed to assess the pharmacokinetics and determine the bioequivalence of two orally administered megestrol acetate suspensions (625 mg/5 mL) in healthy Korean male subjects. A randomized, open-label, single-dose crossover study was conducted involving fifty-four healthy male subjects who were randomized into two sequence groups. Each subject received either a test or reference drug formulation of 625 mg/5 mL megestrol acetate with a two-week washout period between treatments. Plasma samples were collected before and up to 120 hours after administration, and their plasma drug concentrations were analyzed using validated liquid chromatography-mass spectrometry/mass spectrometry. The pharmacokinetic parameters were calculated, and bioequivalence was confirmed if the 90% confidence intervals of the geometric mean ratios were within the specified bounds of 80.00% to 125.00%. In total, fifty-two subjects completed the study, contributing to the pharmacokinetic analysis. The 90% confidence intervals for the geometric mean ratios of the test formulation compared to the reference formulation were 93.85% to 108.90% for maximum plasma concentration and 91.60% to 101.78% for area under the concentration-time curve from the point of administration to last time point of blood sampling. Throughout the study, no serious or unexpected adverse events were observed. The pharmacokinetic profiles of both formulations of megestrol acetate (625 mg) were comparable and well tolerated in healthy Korean male adult subjects. The test formulation met regulatory criteria for bioequivalence.

Trial registration: ClinicalTrials.gov Identifier: NCT06147908.

Decentralized clinical trials (DCTs) consist of off-site trial-related procedures referred to as decentralized elements. We aimed to provide an overview of the landscape of DCTs by comparing regulatory guidance reports and analyzing decentralized elements from clinical trial registries. Two guidance reports on DCTs published by the U.S. Food and Drug Administration and the European Medicines Agencies were summarized and analyzed. Both guidance publications commonly emphasized an assessment of the appropriateness of decentralized elements along 2 axes: patient safety and data integrity. DCT cases were identified from ClinicalTrials.gov by searching with 6 keywords: decentralized, remote, mobile, digital, virtual, and hybrid. Cases where the keyword was used in a non-DCT context, such as digital flexor tendon, were excluded by means of natural language processing. A total of 4,874 trials were identified as DCT cases, with annual increases, especially after 2020. The most common keywords were 'mobile' and 'digital' (36.2% and 24.8%, respectively). Interventions in the DCT cases were analyzed by means of a network analysis. Behavioral and technological tokens were frequently combined, such as 'rehabilitation' and 'app.' Drugs were used in only 1.8% of the DCT cases. Of these, most drugs had been approved previously (96.8%) and were in oral formulation (67.2%). Most of the DCT cases identified in this study involved simple interventions and low-risk drugs. These characteristics were in accordance with the common recommendations in the DCT guidance publications.

Insomnia, commonly treated with benzodiazepine (BZD) receptor agonists, presents challenges due to associated serious side effects such as abuse and dependence. To address these concerns, many researches have been conducted to develop and advance both pharmacological and non-pharmacological interventions. Dual orexin receptor antagonists (DORAs), which include suvorexant, daridorexant and lemborexant, have recently been approved by United States Food and Drug Administration (US FDA) as a novel pharmacotherapeutic alternative. Unlike BZD receptor agonists that act as positive allosteric modulators of the gamma-aminobutyric acid type A subunit alpha 1 receptor, DORAs function by binding to both orexin receptor types 1 and 2, and inhibiting the action of the wake-promoting orexin neuropeptide. These drugs induce normal sleep without sleep stage change, do not impair attention and memory performance, and facilitate easier awakening. However, more real-world safety information is needed. Selective orexin-2 receptor antagonists (2-SORAs) is under clinical developments. This review provides an overview of the mechanism of action in relation to insomnia, pharmacokinetics, efficacy and safety information of DORAs and SORA. According to insomnia management guidelines, the first-line treatment for chronic insomnia is cognitive behavioral therapy for insomnia (CBT-I). Although it has proven effective in improving sleep-related quality of life, it has several restrictions limitations due to a face-to-face format. Recently, prescription digital therapy such as Somryst^® was approved by US FDA. Somryst^®, a smartphone app-based CBT-I, demonstrated meaningful responses in patients. However, digital limitations may impact scalability. Overall, these developments offer promising alternatives for insomnia treatment, emphasizing safety, efficacy, and accessibility.

Clinical trials have evolved with digital technologies and tend towards patient-centricity. A multi-stakeholder approach is needed to address the emerging complexities in clinical trials. In particular, the introduction of digital technologies and an emphasis on patient-centricity are the major trends in clinical trials. In response, we established a public-private partnership-based organization named Advanced Regulatory Innovation for Clinical Trials Transformation (ARICTT). Eleven organizations in total, from academia, industry, and regulatory agencies, participate in ARICTT. Based on multi-stakeholder collaboration from academia, industry, and government/regulatory bodies, we collected and prioritized current topics in clinical trials based on an internal survey. We established a three-year roadmap with axes that were termed trend, goal, structure, theme, topic, and method. In addition, we planned the development of recommendations based on real-world cases with feasibility studies. We developed appropriate organizational structure to fulfill the roadmap of ARICTT. The selected topics were decentralized clinical trials during the first year, followed by the three topics that were awarded the highest priority according to the internal survey: advances in the informed consent process, supporting sites using digital technology, and an effective recruitment strategy. We developed a case-based recommendation paper presenting an overview of the regulatory landscape and practical considerations with explanatory cases. We also designed and conducted fully decentralized trials to evaluate considerations in real-world settings for the selected topics. Overall engagement and communication were supported by the online platform and annual symposiums. In conclusion, we established a multi-stakeholder, public-private partnership-based organization to accelerate the transformation of clinical trials.

Intraventricular hemorrhage (IVH) is a cause of morbidity and mortality in preterm infants and is strongly associated with adverse neurological outcomes. The incidence of severe IVH (grade 3 or 4) has persisted despite the overall decline in IVH. IVH has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. The cascade of adverse events following IVH includes inflammation, white matter injury, and delayed oligodendrial maturation. In this study, we aimed to identify long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) expression in the peripheral blood of preterm infants with IVH compared to normal controls, resulting in the finding of novel biomarkers for IVH. We conducted transcriptome sequencing and small RNA sequencing for identifying differential expression of RNA in preterm infants with IVH. We identified differentially expressed 47 lncRNAs, 95 miRNAs, and 1,370 mRNAs in preterm infants with IVH compared to normal control. Particularly, lncRNA H19 exhibited significantly high expression in preterm infants with IVH. The functional analysis revealed that differentially expressed RNAs in preterm infants with IVH were associated with ferroptosis, heme metabolism, and immune response such as lymphocyte activation and interferon response. In conclusion, these results demonstrate the potential of lncRNA, miRNA, mRNA as possible diagnostic and prognostic biomarkers for IVH.

There are few theories and little empirical evidence about the bilateral impact of substance use and coronavirus disease 2019 (COVID-19), so a logical and accurate picture of this area is required. We investigated the effects of opium use on severity of disease on hospitalized COVID-19 patients in east of Iran. Demographic and clinical characteristics, vital signs, laboratory tests, mortality rate, type and duration of opium consumption in hospitalized patients who recovered from COVID-19 in the follow-up after 3 months were evaluated. In this study, 60 (20%) participants were the opium user and 251 (80%) were the non-user patients. Based on clinical symptoms, hypertension and systolic blood pressure in opium user were significantly higher than non-user patients (p < 0.05). In the laboratory tests, only the level of urea was higher in the opium positive group (37 [26.5-48.5] vs. 32 [23-43], respectively) and the percent of lymphocytes were lower in the opium positive (17 [8.2-25.8] vs. 18.7 [13.85-26.35], respectively). The initial therapies of both opium positive and negative infected patients showed not any significant changes (p > 0.05). Among the studied groups, one deceased case with COVID-19 was related to a drug user patient. Although, uses of opium reduced the levels of some risk factors, vital signs at admission and initial therapies during hospitalization in COVID-19 patients but it increased lung and heart diseases. Also, the severity of COVID-19 including hospitalization and mortality were associated with opium consumption.