Pharmazie最新文献

This study aimed to evaluate the temporal effect of a serum creatinine (SCr) correction intervention in critically ill patients with daily muscle wasting. A total of 5,355 critical care days in 574 patients with creatinine clearance (Clcr) and glomerular filtration rate (GFR) measured and estimated simultaneously were included. The primary endpoint was the difference in accuracy over time of the estimated Clcr/GFR relative to the measured Clcr. The CG equation was used to estimate Clcr, and the MDRD and CKD-EPI-equations were used to estimate GFR. Estimated Clcr(round-up)/GFR(round-up) indicates the estimated Clcr/GFR calculated using the rounded up value if SCr was <0.6 mg/dL. Bias was analyzed using Bland-Altman analysis, correlation using Spearman's rank correlation coefficient, and accuracy using percentage within 30% of the measured Clcr (P30). The CKD-EPI equation showed a large underestimation bias in the early period, whereas the CG and MDRD equations indicated large overestimation biases in the later period. Round-up correction increased the underestimation bias in the early period of the CG(round-up) and MDRD(round-up) equations, but decreased the overestimation bias in the later period. The limits of agreements for the CG(round-up) and MDRD(round-up) equations were narrower, although not consistently acceptable. The correlations were stronger for the CG(round-up) and MDRD(round-up) equations. Accuracy did not improve with the corrective intervention. Conclusion: SCr round-up correction increased the underestimation of kidney function in the early phase, but mitigated overestimation in the later phase. The limits of agreement remained unacceptable, and the accuracy did not improve.

Cabazitaxel is a highly protein-bound drug that has been associated with the development of severe neutropenia, and decreased albumin (Alb) levels may contribute to this phenomenon. For some highly protein-bound drugs, adjustment of drug concentration according to Alb levels is performed in clinical practice. On the other hand, in the case of cabazitaxel, a decrease in Alb levels may lead to an increased proportion of unbound drug at the same dose, which could potentially raise the risk of developing severe neutropenia. Therefore, in this study, we investigated the usefulness of a novel index, the cabazitaxel dose divided by the Alb level (Dose/Alb), as a more accurate predictor of severe neutropenia in patients with metastatic castration-resistant prostate cancer receiving cabazitaxel. Thirty-nine patients were divided into two groups: 14 patients with grade 3-4 neutropenia and 25 with grade 0-2 neutropenia. Dose/Alb at the initiation of cabazitaxel was significantly higher in the grade 3-4 neutropenia group than in the grade 0-2 group (P = 0.013). Logistic regression analysis revealed that Dose/Alb was associated with the development of grade 3-4 neutropenia (odds ratio = 1.70, P = 0.021). Receiver operating characteristic analysis identified a cutoff value of 10.5 mg/g/dL; 75.0% of patients with Dose/Alb > 10.5 mg/g/dL developed grade 3-4 neutropenia, versus 18.5% with Dose/Alb ≤ 10.5 mg/g/dL (P < 0.01). The present study shows that a Dose/Alb-based prediction method may be able to predict the risk of developing grade 3-4 neutropenia at the time of the first dose of cabazitaxel.

Introduction: Carnitine is essential for mitochondrial fatty acid transport and energy production. Tube-fed patients with severe motor and intellectual disabilities (SMID) receiving carnitine-free enteral nutrition are at increased risk of carnitine deficiency. Famotidine, used to treat gastroesophageal reflux disease (GERD), inhibits carnitine transport in vitro, but its clinical impact remains unclear. This study investigated the effect of famotidine on blood carnitine concentrations and L-carnitine supplementation requirements in tube-fed patients with SMID. Methods: A retrospective observational study including patients receiving exclusive enteral nutrition and L-carnitine supplementation was conducted at the Tokyo Metropolitan Tobu Medical Center. Blood carnitine level and L-carnitine dose were compared between famotidine users and non-users. Results: Among 25 subjects (45 data points), famotidine users required significantly higher L-carnitine doses to maintain normal free carnitine levels than did non-users (22.0 ± 4.0 mg/kg/day vs. 13.0 ± 2.8 mg/kg/day, respectively [p = 0.024]). A correlation between L-carnitine dose and free carnitine level was observed only among non-users of famotidine (correlation coefficient: 0.352). Additionally, 36.8% of famotidine users exhibited persistently low free carnitine levels despite supplementation, compared to 3.9% of non-users. Conclusion: Famotidine use was associated with increased L-carnitine supplementation requirements, likely due to impaired renal carnitine reabsorption. Routine monitoring of famotidine-treated patients may help prevent L-carnitine deficiency. Further studies should assess possible long-term effects and explore alternative GERD treatments that have minimal impact on carnitine metabolism. Expanding insurance coverage for carnitine testing could improve early detection and intervention.

Patients with neurological disease are at high risk of polypharmacy. We previously reported that a countermeasure against polypharmacy which combined a pharmacist check followed by a multidisciplinary team review was useful for diabetes patients with polypharmacy. We evaluated this polypharmacy countermeasure in neurology patients with polypharmacy admitted to our neurological ward. A single-center, retrospective observational study was conducted at Gifu University Hospital. Study participants included neurology patients taking six or more drugs on admission to the neurology ward between June 2021 and April 2023. Of 435 patients admitted to the neurology ward, 24.4% (106/435) [≥65 years old, 28.3% (79/276) patients; < 65 years old, 16.7% (27/159) patients] were taking six or more drugs at admission. Prescription content was optimized in 62 patients, and a total of 212 drugs were discontinued. The median number of medications significantly decreased from 9.0 (interquartile range, 7-10) at admission to 8.0 (interquartile range, 6.25-10) at discharge (p < 0.001). On multivariate analysis, the number of drugs taken on admission and length of hospital stay were significant factors which contributed to drug reduction, while concomitant use of immunosuppressive drugs was a significant factor in increasing the number of drugs. This countermeasure for polypharmacy, which combined a pharmacist check followed by a multidisciplinary team review, was useful in older and non-older patients with polypharmacy on a neurology ward.

Metformin, a well-established antidiabetic drug, has recently gained attention in geroscience for its potential to modulate key aging-related pathways. This review aims to summarize current knowledge regarding metformin's mechanisms of action beyond glycemic control, with emphasis on its influence on molecular hallmarks of aging and its potential as a geroprotective agent. A comprehensive literature review was conducted using scientific databases to synthesize findings from in vitro, in vivo, and clinical studies investigating the effects of metformin on aging-related processes. Particular attention was given to studies elucidating the drug's biochemical pathways and its role in age-associated diseases. Evidence indicates that metformin affects several hallmarks of aging, including mitochondrial dysfunction, oxidative stress, chronic inflammation, and cellular senescence. Mechanistically, activation of adenosine monophosphate-activated protein kinase (AMPK) and inhibition of mitochondrial Complex I are central to its systemic actions. These effects contribute to improved metabolic regulation, reduced production of reactive oxygen species, and enhanced autophagy. Additionally, metformin has shown protective effects in age-related disorders such as cardiovascular disease, neurodegeneration, and cancer. Its long-standing clinical use, low toxicity, and cost-effectiveness further support its relevance in aging research.

Objective: We conducted a pharmacovigilance analysis of mesalazine-related adverse events (AEs) in the realworld using the America's FAERS and Japan's JADER databases. Methods: We extracted reports of mesalazine-associated AEs from FAERS and JADER spanning the first quarter of 2004 to the third quarter of 2024. In the disproportionality analysis, we applied the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma-Poisson shrinker (MGPS) algorithms for signal detection. The time to onset of AEs was assessed using Kaplan-Meier curves and the Weibull distribution test. Results: The analysis encompassed 40,265 AEs reports from FAERS and 4,330 from JADER. Mesalazine-related preferred terms (PTs) mapped to 27 System Organ Classes (SOCs) in FAERS and 25 SOCs in JADER. Gastrointestinal disorders emerged as the most frequently reported SOC in both databases. Three SOCs demonstrated significant signal strength across both datasets: (1) gastrointestinal disorders, (2) general disorders and administration site conditions, and (3) respiratory, thoracic, and mediastinal disorders. Common AEs including diarrhœa, pancreatitis, gastroenteritis, asmyopericarditis, proctitis ulcerative, and glutamate dehydrogenase level abnormal aligned with established drug labeling. Notably, novel pharmacovigilance signals were detected for organizing pneumonia (FAERS: n = 113, ROR = 35.21, 95%CI 29.21-42.46; JADER: n = 32, ROR = 7.90, 5.56-11.22) and eosinophilic pneumonia (FAERS: n = 77, ROR = 41.25, 32.87-51.76; JADER: n = 179, ROR = 57.69, 49.26-67.56), both requiring urgent clinical attention. AEs mainly occurred within 30 days (58.36%) with a median onset of 17 days, and the median onset time of female patients (12 days) was shorter than male patients (25 days). Conclusion: This pharmacovigilance study provides clinically significant evidence regarding safety-associated adverse events (AEs) of mesalazine in real-world settings. The detection of novel safety signals, particularly organizing pneumonia and eosinophilic pneumonia, highlights the necessity for enhanced post-marketing surveillance through longitudinal AE monitoring. Our findings contribute to the evolving safety profile of mesalazine and warrant further clinical investigations to validate their clinical relevance and establish causal relationships.

Poor aqueous solubility may decrease the absorption and oral bioavailability of lipophilic drugs. In the current study, artemether (ART) and lumefantrine (LMF) o/w self-nano emulsifying drug delivery system (SNEDDS) formulations were prepared. Equilibrium solubility studies were conducted and pseudo-ternary phase diagrams were constructed to identify excipients with the best solubilizing capacity for ART and LMF. They were subsequently used to manufacture and optimize SNEDDS using experimental designs, which were then characterized. Solubility and emulsification studies revealed that ART and LMF are highly soluble in oleic acid (OA). Cremophor^® EL (CEL) and Transcutol^® HP (THP) were selected as surfactant and co-surfactant. The addition of Capryol™ 90 (C90) increased the region of nano-emulsion formation without evidence of precipitation of ART and LMF. Compatibility studies revealed no prominent or significant incompatibilities between the drugs and selected excipients. The optimized formulation was stable as dispersions with nano-sized droplets and a loading capacity >99 % for both ART and LMF and a release >95% within 15 min for both drugs, reflecting a significant increase in the rate and extent of dissolution compared to that of the pure drug.

Activation of microglia plays a pivotal role in the pathogenesis of neuroinflammation-mediated neurodegenerative diseases. Glycyrrhizic acid (GA), a principal triterpenoid saponin in Glycyrrhiza glabra, has been reported to exhibit a range of biological activities. Nevertheless, the function of GA in microglia activation remains unclear. In this study, the effects and mechanisms of GA on the inflammatory response were investigated in the lipopolysaccharides (LPS)-stimulated microglial BV2 cells. BV2 cells were treated with GA (0, 20 and 50 μM), followed by stimulation with LPS (1 μg/mL). The results demonstrated that GA significantly inhibited the expression of tumor necrosis factor-α (TNF-α ) and interleukin-1β (IL-1β) at the mRNA and protein levels induced by LPS. Furthermore, the release of reactive oxygen species (ROS) and the migration of microglia were suppressed by GA in LPS-stimulated BV2 cells. In addition, GA reduced the activation of mitogen-activated protein kinases (MAPKs) and the phosphorylation of Akt. GA also inhibited the phosphorylation of Iκ Bα kinase (IKK) and p65, and blocked the nuclear translocation of p65 protein. The findings indicate that GA inhibited the inflammatory response in LPS-stimulated microglial BV2 cells through the suppression of MAPK, Akt, and nuclear factor-κ B (NF-κ B) signaling pathways, suggesting that GA may serve as a potential therapeutic approach for the treatment of neuroinflammation-associated neurodegenerative diseases.

Midazolam is a short-acting benzodiazepine widely used for sedation; however, its duration of action can be prolonged by various factors including hypoalbuminemia. Previous behavioral studies in rats with low albumin levels reported reduced muscle strength and spontaneous locomotion, but the relationship between hypoalbuminemia and midazolam pharmacokinetics remains unclear. This study investigated whether prolonged midazolam sedation in hypoalbuminemia correlates with unbound and brain midazolam concentrations. Low-albumin rats were generated using protein-controlled diets for 30 days. Midazolam (5 mg/kg, i. p.) was administered and total blood and brain concentrations were determined by high-performance liquid chromatography 10 and 60 minutes after administration. Compared to controls, low albumin rats showed significantly higher total blood concentrations at 60 minutes (0.27 ± 0.02 vs 0.12 ± 0.02 μg/mL) and brain concentrations (0.21 ± 0.02 vs 0.10 ± 0.03 μg/mL). Unbound concentrations remained below quantification limits due to ultrafiltration adsorption. Pharmacokinetic analysis revealed prolonged half-life and decreased clearance in low-albumin rats. These findings suggest that hypoalbuminemia prolonged midazolam actions through sustained blood and brain concentrations, likely due to increased initial unbound drug levels that rapidly distribute to the brain before accumulating in peripheral tissues. Clinicians should exercise caution when administering midazolam to patients with hypoalbuminemia.