Pharmacology Research & Perspectives最新文献

Ropeginterferon alfa-2b (ropeg) represents a new-generation interferon-based therapy approved for polycythaemia vera (PV) treatment. This study aimed to elucidate its population pharmacokinetics-pharmacodynamics (PopPK-PD) and exposure-response (E-R) relationships. A PopPK model was developed using pooled data from four clinical studies, including two Phase I studies in healthy volunteers (n = 48) and two Phase II studies in Chinese or Japanese patients with PV (n = 78). Sequential modeling was used to analyze pharmacokinetics-pharmacodynamics (PK-PD) regarding hematological parameters, including hematocrit, platelet, and white blood cell counts. Hematological changes were simulated using fast- and slow-dose titration regimens. Individual exposure values were used to analyze the E-R relationships regarding complete hematologic response (CHR), driver mutation, JAK2V617F allele burden, and safety. In this study, we developed a target-mediated drug disposition model. Sigmoid indirect effects elucidated the PK-PD in terms of hematological changes. Simulations showed that the fast-titration regimen significantly accelerated hematocrit reduction. Logistic regression models showed that the probability of achieving CHR increased with exposure at Week 24 but not at Week 52. In contrast, JAK2V617F allele reductions correlated with exposure at both Weeks 24 and 52. Exposure-safety analysis revealed a manageable risk of adverse events associated with transaminase increases. This study established a robust framework for ropeg PK-PD, providing insights into its E-R relationships and disease-modifying action. Trial Registration: A17-102, A19-201, and A20-202 are registered at ClinicalTrials.gov. The registration numbers are as follows: A17-102, NCT03546465; A19-201, NCT04182100; and A20-202, NCT05485948. A17-101 is registered at www.chinadrugtrials.org.cn. The registration number is CTR20190451.

In Peru, 33 113 individuals were diagnosed with tuberculosis (TB) in 2023. While TB treatments are generally effective, 3.4% to 13% of cases are associated with significant adverse drug reactions, with drug-induced liver injury (DILI) being the most prevalent. Limited data exist on genetic risk factors for DILI in Latin America; even less is known about these factors in native Peruvian populations. This study aimed to determine the prevalence of TB drug-metabolizing genotypes in these populations. A cross-sectional analysis was conducted using genetic data from 254 participants from the Peruvian Genome Project (PGP) representing three subpopulations: Coast, Andes, and Amazon. Twenty-three genes associated with TB treatment, include isoniazid, rifampin, ethambutol, and pyrazinamide, as identified in the PharmGKB database, were analyzed. Significant differences were observed in genotype frequencies among subpopulations for AGBL4, NAT2, GSTP1, SLCO1B1, NOS, and CYP2B6 genes. The Amazonian population demonstrated a higher risk of DILI due to the increased prevalence of hepatotoxic alleles in AGBL4, GSTP1, and SLCO1B1. In contrast, alleles in the NOS gene indicated a lower risk of hepatotoxicity in the Andean population. However, the high-risk genotypes identified in the study's native Peruvian populations exhibit distinct prevalence patterns compared to those reported in the 1000 Genomes Project. These findings can inform the development of personalized therapeutic strategies to improve TB treatment outcomes among Peru's diverse subpopulations.

It is common for patients with mental illnesses to be prescribed multiple psychotropic medications to effectively manage their conditions. Psychotropic polypharmacy has been shown to potentiate and increase the risks of several adverse effects, including QT prolongation. This study aimed to investigate the prescribing trends of and differences in prescribing of QT-prolonging medications (QTPMs) at admission and discharge in hospitalized patients. This retrospective observational study utilized inpatient data from three public hospitals between January and December 2019. QTPMs were classified according to the AZCERT classification. QTPMs doses were evaluated by calculating the ratio of prescribed daily dose (PDD) to the defined daily dose (DDD). Subgroup analyses showed significant differences between patient groups on admission and discharge (all p < 0.001). Mean QTPMs decreased significantly between the two time points only in patients admitted to acute medical and geriatric units (p < 0.001). PDD/DDD ratio for conditional risk QTPMs in acute mental health unit (AMHU) patients was increased at discharge (p = 0.038). Patients admitted to acute medical and geriatric units were four and eight times more likely to be discharged with one QTPM with known risk in combination with more QTPMs with conditional risk. Logistic regression showed significant relationships with age and total number of regular medicines at admission for those prescribed high-dose QTPMs at discharge. The findings underscore the necessity for enhanced monitoring of QTPMs in hospitalized patients, particularly for those at higher risk.

Delivery of bioactive agents to achieve tissue regeneration at targeted sites with minimal side effects requires the use of biodegradable carriers and sustained release of the therapeutic at appropriate concentrations. We developed a copper-free polyethylene glycol-based click hydrogel to deliver bone morphogenetic protein-2 (BMP2), a potent regulator for bone regeneration that is currently delivered to orthotopic sites using an absorbable collagen sponge, leading to a burst release of BMP2, potentially causing ectopic bone formation. In contrast, the hydrogel is delivered as a liquid, conforming to the contours of treatment sites, polymerizing rapidly at body temperature without generating heat, exhibiting minimal swelling after gelation, and releasing its payload as it degrades. We assessed the safety and effectiveness of BMP2 delivery in vitro and in mouse cranial defects in vivo, comparing it to BMP2 delivered via a collagen sponge. No toxicity was observed in vitro or systemically, nor was there allergic sensitization caused by the hydrogel in rabbits. Released BMP2 increased the production of osteogenic markers in vitro. Hydrogel + BMP2 caused equivalent defect closure and total bone growth compared to collagen + BMP2; however, there was more vascularization within the defect but less bone growth outside of the defect on the calvaria for hydrogel + BMP2 compared to collagen + BMP2. In conclusion, the click hydrogels used in this study are safe and effective for administering BMP2 with fewer undesired off-target effects and high potential to be used with BMP2 for bone regeneration, supporting the use of click chemistry hydrogels to deliver bioactive agents to treatment sites safely and effectively.

In Japan, biopharmaceutical startups have not been sufficiently nurtured, leading to weak international competitiveness in new drug development. This is partly due to low levels of entrepreneurship in the private sector and limited investment in startups. Therefore, it is crucial for the Japanese government to provide financial support for biopharmaceutical startups. This study aims to offer a comprehensive overview of the current state of government grants and investments for biopharmaceutical startups in Japan, as well as to discuss the associated challenges and future directions. Both grant programs specifically focused on drug discovery and development and those supporting a broader range of industries, including drug discovery and development, were identified through literature reviews and web searches. Advisory programs affiliated with government agencies that assist biopharmaceutical startups were also identified. Additionally, the government has established national university funds at four universities, which have made investments in biopharmaceutical startups. While the government offers various grant programs to support biopharmaceutical startups at different stages of research and development, the relatively small scale of these grants and limited support for seed-stage projects pose significant challenges. Consulting services provided by the government, which offer advice on drug development strategies and processes, have been particularly beneficial for university researchers in Japan who lack expertise in drug discovery and development. However, some initiatives spread across different ministries, highlighting the need for a more unified national approach.

The co-expression of different types of G protein-coupled receptors (GPCRs) in the same cells can have implications for receptor signaling and receptor cross-talk, potentially altering the apparent potency or efficacy of ligands targeting each receptor. The endocannabinoid and orexinergic systems, consisting of class A GPCRs and their endogenous ligands, are highly complex and regulate processes such as appetite, sleep, nociception, and energy homeostasis. The shared anatomical distribution of cannabinoid and orexin receptors in various regions of the central nervous system (CNS), coupled with data from previous studies exploring physical and functional interactions between these receptors, suggests that the endocannabinoid and orexinergic systems engage in crosstalk. In this study, we explored how orexin receptors (OX₁, OX₂) altered the in vitro signaling of cannabinoid receptors (CB₁, CB₂) in Chinese hamster ovary (CHO)-K1 cells by quantifying cyclic adenosine monophosphate (cAMP) inhibition and βarrestin2 recruitment. Our results suggest that orexin receptors alter agonist-dependent signaling at the cannabinoid receptors by enhancing cannabinoid receptor-mediated cAMP inhibition while increasing or decreasing cannabinoid receptor-mediated βarrestin2 recruitment. These initial results are important for understanding the effects associated with cannabinoid ligands and may provide novel insights for therapeutics targeting physiological processes modulated by both systems.

To examine various medications and substances, in vivo models such as rats and mice are routinely used. However, it is utterly desirable to reduce extensive amounts of animals for these experimental models, which are costly and time-consuming. Animals are frequently put through a variety of procedures that could cause them pain, distress, or even harm; therefore, it is important to think about the ethical ramifications of using them in research. Thus, by following the three R's of animal research: reduction, replacement, and refinement, living animals used in studies should be minimized. The embryo of Gallus gallus, the domestic chicken, is a great model to research many different diseases and conditions. Its efficient blood supply from the chorioallantoic membrane gives us a unique possibility to administer chemicals or cells to the embryo in a noninvasive manner. In this review, we evaluate some advantages and disadvantages of using the developing chicken as an alternative in vivo model for development, disease, and pharmacological treatment. We focus on the top two leading causes of death: neurological disorders and cancer. We present a number of studies that describe the use of the chicken embryo in neuroscience and neurodevelopment research, in cancer research, and pharmacodynamic and pharmacokinetic studies. These studies show that the chicken embryo is an inexpensive, readily available, self-sufficient model with a short incubation period, high accessibility, and ideal for drug screening, making it an appealing model that can provide insightful biological and pharmacological information.

β-adrenergic blockers (β-blockers) are extensively used to inhibit β-adrenoceptor activation and subsequent cAMP production in many cell types. In this study, we characterized the effects of β-blockers on mouse pancreatic β-cells. Unexpectedly, high concentrations (100 μM) of β-blockers (propranolol and bisoprolol) paradoxically increased cAMP levels 5-10 fold, enhanced Ca²⁺ influx, and stimulated a 2-4 fold increase in glucose- and glimepiride-induced insulin secretion in MIN6-K8 clonal β-cells and isolated mouse pancreatic islets. These effects were observed despite minimal expression of β-adrenoceptors in these cells. Mechanistically, the cAMP increase led to ryanodine receptor 2 (RYR2) phosphorylation via protein kinase A (PKA), triggering Ca²⁺-induced Ca²⁺ release (CICR). CICR then activates transient receptor potential cation channel subfamily M member 5 (TRPM5), resulting in increased Ca²⁺ influx via voltage-dependent Ca²⁺ channels. These effects contradict the conventional understanding of the pharmacology of β-blockers, highlighting the variability in β-blocker actions depending on the experimental context.

Anxiety disorder is a persistent, widespread, and intractable mood disorder, and the available pharmacotherapies have limited efficacy with significant side effects. Trace amine-associated receptor 1 (TAAR1) is an emerging drug target for neuropsychiatric disorders. This study examined the effects and underlying mechanisms of a novel TAAR1 agonist, PCC0105004, in a rat model of CUMS-induced anxiety-like behavior. The elevated zero maze and open field tests test were employed to evaluate the anti-anxiety-like activity of PCC0105004. PCC0105004 dose-dependently attenuated anxiety-like behaviors in rats without affecting spontaneous activity. Morphologically, PCC0104005 decreased the density of dendritic spines in the amygdala. For the mechanistic studies, whole-genome transcriptomic analysis revealed significant differences in the patterns of amygdala gene expression in the CUMS-induced anxiety rat model. These transcriptomic data were further confirmed by using RT-qPCR and western blotting, further revealing alterations associated with genes (Col1a1, DCN, Ewsr1) known to regulate synaptic plasticity, and PCC0105004 was able to reverse these changes. These results suggest that PCC0105004 is a promising anxiolytic candidate for pharmacotherapy of anxiety and warrants further examination and development.

Huntington's disease (HD) is a challenging neurodegenerative disorder linked to Huntingtin (HTT) gene mutation, lacking an effective cure despite numerous therapeutic attempts. Cordyceps sinensis, recognized for its health benefits, particularly its constituent cordycepin, exhibits neuroprotective effects in various neurodegenerative diseases. However, the neuroprotective potential of cordycepin in HD remains insufficiently explored. In this study, in vitro experiments using HD cell models demonstrate that cordycepin treatment enhances cell survival, slightly diminishes mutant HTT aggregates, and improves neuronal formation. In vivo investigations on R6/2 HD transgenic mice reveal a modest increase in body weight and a slight amelioration in pathological aggregates following cordycepin administration, although behavioral changes are not significant. While the underlying mechanisms remain unexplored, the findings suggest cordycepin's promise as a supplementary therapeutic for HD, providing neuroprotective effects and reducing mutant protein aggregates.