Pharmacology Research & Perspectives最新文献

A duplication/triplication copy number variant in the 9p24.1 chromosomal region with the additional gene copies being located on a small supernumerary marker chromosome has been identified in patients with psychosis. Mice genetically engineered to harbor 9p24.1 duplications or triplications have been shown to display schizophrenia-like phenotypes, including deficits in startle habituation, latent inhibition, working memory, and social interaction and a reduction in the dendritic spine density. Genetic fine-mapping traced these phenotypes to a duplication or triplication of the Gldc gene, that is, to the presence of three or four functional copies of the Gldc gene. The enzyme glycine decarboxylase (GLDC) degrades glycine, which is a co-agonist at the NMDA receptor. In mice with 4 copies of Gldc, extracellular glycine concentrations have been reported to be reduced, while total glycine concentrations were unaltered. Here, we tested the hypothesis that chronically administered glycine could revert phenotypic changes observed in mice with 4 copies of Gldc. We found that 1.3 g/kg glycine administered in the drinking water reversed the startle habituation deficit, the spatial working memory deficit in Y-maze, the sociability deficit and the latent inhibition deficit, while it had a minimal effect on the density of dendritic spines. We conclude that oral administration of glycine is sufficient to reverse some of the behavioral deficits in mice with 4 copies of Gldc but has a very limited effect on dendritic spine density.

Budesonide is a first-line inhaled glucocorticoid (ICS) for asthma treatment in adults and children. The purpose of this study was to compare the pharmacokinetics and assess the bioequivalence between two budesonide pressurized metered-dose inhalers (pMDIs, 200 μg/actuation × 1 actuation) in healthy Chinese subjects. The study was conducted in 32 healthy Chinese subjects using a single-center, randomized, open-label, four-period and crossover design with a 3-day washout between periods. Blood samples were collected up to 16 h post-dose. Plasma concentrations of budesonide were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Reference-scaled average bioequivalence (RSABE) or average bioequivalence (ABE) method was applied to evaluate the bioequivalence, on the basis of the within-subject standard deviation (S_WR) of the reference product (Budiair), and the safety was also assessed. Eventually, 31 subjects completed this study. For the maximum concentration (C_max) (within-subject standard deviation, S_WR ≥ 0.294), the RSABE method showed a geometric mean ratio (GMR) of 97.13% with a 95% upper confidence bound of < 0. For the area under plasma concentration-time curve from time zero to the last measurable concentration (AUC_0-t) and the area under plasma concentration-time curve extrapolated to infinity (AUC_0-∞) (S_WR < 0.294), ABE yielded GMRs of 104.81% and 104.61%, with 90% confidence intervals (CIs) of 99.98%-109.86% and 99.81%-109.63%, respectively. All adverse events (AEs) were mild to moderate and transient, with no serious adverse events (SAEs) reported. The two budesonide pMDIs (200 μg) were bioequivalent and well tolerated in healthy Chinese subjects. Trial Registration: Chinese Clinical Trial Registry, Registration No. CTR20244600; ClinicalTrials.gov identifier: NCT06924190.

Nalfurafine is the only clinically approved kappa opioid receptor (KOPr) agonist that can cross the blood-brain barrier and exert CNS effects. Because its clinical use is not associated with dysphoria, it is widely believed to have an atypical pharmacological profile. Nalfurafine's atypical properties are proposed to result from its G-protein-biased KOPr agonist property, leading to the widespread use of nalfurafine as a nonaversive KOPr agonist in preclinical research. The validity of nonaversive claims for nalfurafine was investigated in mice by comparing its antinociceptive and aversive effects with those of the typical, nonbiased KOPr agonist U50,488 in tail withdrawal and conditioned place aversion (CPA) tests. Dose responses for tail withdrawal with nalfurafine and U50,488 were determined in warm (52°C) water in adult male and female C57BL/6J mice. Doses of U50,488 produced antinociception from 5 mg/kg, and doses of nalfurafine from 0.06 mg/kg. Four-fold lower doses of either KOPr agonist (U50,488: 1.25 mg/kg; nalfurafine: 0.015 mg/kg) were subthreshold for antinociception. No sex differences were seen. Antinociceptive effects were fully blocked by the KOPr antagonist norBNI (10 mg/kg). Antinociceptive doses of nalfurafine (0.06 mg/kg) and U50,488 (5.0 mg/kg) both induced CPA. Subantinociceptive doses of nalfurafine (0.015 mg/kg) and U50,488 (1.25 mg/kg) were nonaversive in CPA. Thus, in mice, at doses that are antinociceptive, CPA was evident for both KOPr agonists. Neither nalfurafine nor U50,488 showed a separation between their antinociceptive and aversive effects, contradicting the hypothesis that nalfurafine is a nonaversive analgesic in mice. The findings caution against assuming nalfurafine is a nonaversive KOPr agonist for use in preclinical research.

The recommended therapeutic target for vancomycin for serious methicillin-resistant S. aureus infections is an area under the concentration-time curve (AUC) over 24 h to a minimum inhibitory concentration (MIC) ratio of ≥ 400. Its applicability to coagulase-negative staphylococcal (CoNS) bloodstream infections is unclear. Our review aims to determine the pharmacodynamic target of vancomycin for CoNS bloodstream infections. In January 2025, MEDLINE, Embase, and PubMed were searched to identify manuscripts reporting the relationship between vancomycin drug exposure (AUC) and bactericidal activity or clinical response for CoNS. Studies of alternative drug delivery systems/formulations, combination therapy, prophylaxis, other infections, and static in vitro studies were excluded. Overall, six articles were included. One in vivo study in young infants found that an AUC_0-24 ≥ 300 mg/L·h and AUC₂₄ ≥ 424 mg/L·h were associated with a 7.8-fold and 7.3-fold increased likelihood of bacteriological cure, respectively. Two studies in adults showed that an AUC₂₄/MIC ratio ≥ 373 resulted in improved treatment success and microbiological eradication. An in vitro model demonstrated that a vancomycin AUC₂₄/MIC ratio ≥ 665 achieved maximal bacterial killing, while a rabbit model linked an AUC₂₄/MIC ≥ 520 to an 80% reduction in C-reactive protein. Early treatment within 24 h was associated with the greatest chance of bacteriological cure. Two studies of biofilm-embedded CoNS demonstrated inadequate bacterial killing at AUC₂₄/MIC ratios of 260 and 354. Overall, or CoNS bloodstream infections, an AUC₂₄ ≥ 424 mg/L·h (median MIC 1 mg/L) or AUC₂₄/MIC ≥ 373 improves clinical outcomes. This review highlights the need for early effective vancomycin treatment. Alternative antibiotic therapy should be considered for biofilm-embedded CoNS infections.

The objectives of this study were to compare the pharmacokinetics and safety profiles of the test (T) preparation (Ferric carboxymaltose injection, BrightGene Bio-Medical Technology Co. Ltd.) and reference (R) preparation (Ferinject, Vifor France) after intravenous injection in Chinese adult subjects with iron deficiency anemia (IDA) under fasting conditions. Conducted as a single-center, randomized, open-label, parallel-group trial, the study enrolled 96 IDA patients who were randomly allocated (1:1) to receive a 500 mg intravenous dose of either the T or R preparation. Post-dose blood samples for pharmacokinetic analysis were collected at multiple time points, while any adverse events were documented. The pharmacokinetic results showed comparable serum concentration-time curves between the two groups. The 90% confidence intervals for the geometric mean ratios of C_max, AUC_0-t, and AUC_0-∞ of total serum iron and C_max, AUC_0-t of serum transferrin-bound iron were within the predefined bioequivalence criterion of 80%-125%, indicating bioequivalence between the T and R preparations under fasting conditions. There were no significant differences in the safety profile between the two groups. This study confirmed the bioequivalence of the T and R preparations under fasting conditions, along with good safety.

The use of proton pump inhibitors (PPIs) has increased in Western countries over several decades, and there is concern about unsubstantiated indications and effects of long-term use. The study aimed to describe the prevalence, incidence, indications, and prescription pattern for PPIs over the past decade in an entire national cohort. This nationwide drug utilization study used data from the Norwegian Prescription Database and Norwegian Patient Registry. Patterns of PPI use were investigated from 2009 to 2022. Prevalent, long-term, and incident PPI use were calculated. The indication for PPI was defined by the diagnosis code linked to each prescription. Upper endoscopies during the study period were assessed for incident PPI users. PPI prescription increased from 58.1 mill DDD in 2009 to 166.9 mill DDD in 2022, that is, 43 and 106 DDD/1000 inhabitants/day. Prevalent PPI use increased from 3.5% to 9.9%, paralleling an increased incidence from 2.9% to 5.4%. The dominant indications in 2009 and 2022 were esophageal disease in primary care (72.5% and 57.6% of total DDDs) and GERD in specialist care (10.7% and 4.7% of total DDDs). Musculoskeletal disorders, pain, and ulcer prophylaxis all increased during the period. Upper endoscopy around incident PPI use decreased from 25.3% to 11.1%. In conclusion, the 2.46-fold increase in prevalent PPI use was caused by an absolute increase in PPI prescribed against esophageal disease and GERD, and prophylaxis in patients using ulcerogenic comedication, mainly prescribed in primary care. The findings may help inform strategies to reduce a probable overuse of PPIs.

Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are first-line antiviral agents for chronic hepatitis B (CHB), yet comparative real-world data in Southeast Asian populations remain limited. This retrospective cohort study aimed to compare the efficacy, biochemical response, antifibrotic effect, and renal safety of TDF versus ETV in treatment-naïve Vietnamese patients with CHB over a 48-week period. A total of 348 patients (TDF: 181; ETV: 167) were included and evaluated at baseline, Weeks 12, 24, and 48. Both groups demonstrated comparable virologic suppression at Week 48 (TDF: 58.0%, ETV: 52.1%, p > 0.05). TDF achieved significantly higher ALT normalization at Week 24 (72.9% vs. 59.9%, p = 0.01) and Week 48 (84.0% vs. 69.5%, p = 0.001). In contrast, ETV led to faster AST normalization and greater early reductions in APRI and FIB-4 at Week 12. Renal function mildly declined in the TDF group (mean eGFR change: -3.84 ± 11.98, p < 0.001) but improved in the ETV group (+3.02 ± 12.34, p = 0.002). Both treatments were well tolerated with no virologic breakthrough or serious adverse events. In conclusion, both TDF and ETV offer effective antiviral therapy for Vietnamese CHB patients. TDF may be preferable in patients with active hepatic inflammation, whereas ETV may benefit those with baseline renal concerns or early fibrotic progression. These findings support a tailored approach to HBV management based on individual patient profiles.

The current treatments for advanced prostate adenocarcinoma (PAC) include the androgen receptor antagonist enzalutamide and docetaxel-based chemotherapy. Elevated monoamine oxidase-A (MAO-A) mRNA expression and activity in tumorous prostate positively correlate with disease progression and therapy resistance. While MAO-B mRNA expression was also demonstrated in PAC cell lines, its role remained unclear. Therefore, this study evaluates the effects of the irreversible MAO-B inhibitor selegiline and rasagiline and their combinations with conventional therapies on androgen-insensitive (PC-3, DU145) and androgen-sensitive (22Rv1, LNCaP, VCaP) PAC cell lines. MAO activity was determined by the MAO-Glo luminescence assay, viability by the ATP-based chemiluminescence method, proliferation by the Luna-II automated cell counter, and mRNA expressions by RT-qPCR. MAO-B mRNA was stably expressed by all PAC cell lines, with the highest expression in 22Rv1 and LNCaP cells. Selegiline reduced MAO-B activity by 75%-80% and decreased cell counts by 40%-50% at 100 μM in PC-3 and 22Rv1 cells. Selegiline concentration-dependently inhibited cell proliferation (100 μM-10 mM) and reduced viability (1-10 mM) similar to rasagiline in all cell lines. Combination with enzalutamide in 22Rv1, and with docetaxel in PC-3 demonstrated potentiating and additive effects, respectively. Selegiline reduced FOXA1 and GLUT1 mRNA expressions related to cancer progression and metabolism in both cell lines, increased the apoptosis-related BAX in PC-3, and decreased AR, EGFR, and SNAI2 in 22Rv1 linked to proliferation and metastasis. These findings suggest potential for selegiline repurposing in both androgen-sensitive and -insensitive PAC therapy by promoting apoptosis and inhibiting cancer growth and survival signals, respectively.

This study aimed to evaluate the safety of colistin therapy by monitoring renal function and electrolyte levels in critically ill neonates with late-onset sepsis (LOS) hospitalized in the neonatal intensive care unit (NICU) between 2015 and 2021. This retrospective case-control study included 58 critically ill neonates treated with colistin for late-onset sepsis and 22 control neonates with late-onset sepsis who did not receive colistin. Data were analyzed to compare patient outcomes, microbiological profiles, and side effects of treatment. Statistical analyses were performed using repeated-measures ANOVA and Bayesian calculations to evaluate serum creatinine levels and biochemical parameters over time. Serum creatinine levels showed similar alterations within the first 7 days of colistin treatment with moderate evidence. However, serum magnesium and sodium levels were lower on the 7th day in the colistin-treated group compared with the control group. Colistin therapy in critically ill neonates with late-onset sepsis appears to be a viable treatment option with an acceptable short-term safety profile. These findings emphasize the importance of routine monitoring of renal function and electrolyte levels during colistin use in neonatal intensive care to minimize potential complications.

Baxdrostat is a novel, highly potent, selective, competitive inhibitor of human aldosterone synthase currently under development for the treatment of uncontrolled and resistant hypertension and chronic kidney disease. We assessed the risk of QTc-interval prolongation with baxdrostat using concentration-QTc (C-QTc) modeling in healthy adult participants using data from two placebo-controlled Phase 1 studies: a multiple-ascending dose (MAD) study of baxdrostat 0.5-5 mg (N = 56; NCT05500820) and a Phase 1 four-way crossover thorough QT/QTc (TQT) study assessing the pharmacokinetics, pharmacodynamics, safety and tolerability of baxdrostat at supratherapeutic doses of 16 and 32 mg (N = 28; NCT06194032). In the TQT study, 28 participants were randomized to one of four treatment sequences (each n = 7) of baxdrostat 16 mg, baxdrostat 32 mg, placebo and open-label moxifloxacin 400 mg. Digital electrocardiogram and pharmacokinetic data were collected at baseline and up to 48 h post dose. Dependent and independent variables of the pre-specified linear mixed-effect model were placebo-corrected baseline-adjusted ΔΔQTcF and baxdrostat plasma concentrations, respectively. Results were consistent between the two C-QTc modeling analyses. Baxdrostat treatment did not produce QT-interval prolongation, both at concentrations of interest and geometric mean of the maximum observed plasma concentration. Upper bounds of the two-sided 90% confidence interval for the ΔΔQTcF mean estimates were < 10 ms. Pharmacokinetic data for the 16 and 32 mg doses in the TQT study were as expected, and both doses were well tolerated. These data illustrate that baxdrostat is not associated with the risk of QT-interval prolongation at therapeutic and supra-therapeutic concentrations.