Biological & pharmaceutical bulletin最新文献

Intravenous administration of branched-chain amino acid (BCAA)-enriched solution is contraindicated in patients with severe chronic kidney disease (CKD). However, there have been no reports on its risks in patients with mild-to-moderate CKD. In this study, we compared the incidence of acidosis between patients with mild-to-moderate CKD (estimated glomerular filtration rate [eGFR] ≥30 and <60 mL/min/1.73 m²) and patients without CKD (eGFR ≥60 mL/min/1.73 m²) who received intravenous BCAA-enriched solution after propensity score matching (PSM). A retrospective analysis of the medical records at Hiroshima University Hospital identified 608 patients who were treated with intravenous BCAA-enriched solutions between January 2005 and December 2010. The laboratory data for these patients were analyzed. After PSM, the incidence of acidosis was compared between 91 pairs of patients with mild-to-moderate CKD or no CKD using Fisher's exact test. The incidence of acidosis was significantly higher in the mild-to-moderate CKD group than in the non-CKD group (36.3 vs. 18.7%, p <0.05). The odds ratio for the incidence of acidosis in patients with mild-to-moderate CKD was 2.48 (95% confidence interval 1.26-4.88). Kaplan-Meier curves showed that the cumulative incidence of acidosis increased soon after initiation of intravenous BCAA-enriched solution in both groups. In conclusion, intravenous BCAA-enriched solution can cause acidosis even in patients without CKD, with an increased risk in patients with mild-to-moderate CKD, in whom this agent is not contraindicated. Therefore, intravenous BCAA-enriched solution should be administered with caution in patients with CKD, regardless of its severity.

Mineralocorticoid receptor (MR) blockers reduce cardiovascular complications as MRs play a crucial role in cardiovascular regulation. Diabetic cardiovascular complications are caused by vascular endothelial dysfunction. This study used a type 2 diabetic mouse model (DM) to investigate whether esaxerenone (ESAX), an MR blocker, ameliorates vascular endothelial dysfunction. ESAX (3 mg/kg/d) was administered via diet to KK-Ay mice or C57BL/6J mice, a nondiabetic control (Control), for 8 weeks, and metabolic parameters and blood pressure were measured. Vascular responses of the aortic segments were analyzed with acetylcholine, sodium nitroprusside, UK14304, or phenylephrine (PE). The other aortas were used for Western blot analysis. DM mice exhibited higher plasma glucose, insulin, metabolic parameters, and blood pressure levels than those of the Control mice. Parameters that did not include blood pressure were unaltered by DM or ESAX-administered DM (DM + ESAX). However, DM impaired UK14304-induced endothelial-dependent relaxation and nitric oxide production and elevated PE-induced contraction. ESAX administration ameliorated endothelial dysfunction and improved the protein kinase B (Akt) phosphorylation under α₂-agonist UK14304 stimulation in the aorta from DM mice compared with that of the Control mice. However, ESAX did not recover the increased G protein-coupled receptor kinase 2 (GRK2) expression and activity in the DM aorta. Furthermore, the DM-induced phosphorylation of serum and glucocorticoid-regulated kinase 1 (SGK1) was inhibited by ESAX. Overall, ESAX attenuates the development of DM-induced endothelial dysfunction by reducing SGK1 activity and enhancing Akt activity without affecting the GRK2 pathway. These results suggest that the vascular protective effects of ESAX could be employed for diabetic vascular complications.

The optimal pharmacokinetics (PK) of orally administered nanoparticles (NPs) varies depending on their application (e.g., drug delivery, adsorbent, and adjuvant). Therefore, engineering NPs to achieve optimal PK is essential for the development of drug designs. Some studies have demonstrated that individual NP factors change the intestinal absorption of NPs; however, no technology has been established to control the biodistribution of orally administered NPs. In this study, a database about the influence of NP characteristics on biodistribution after oral administration was provided. A library of N-isopropylacrylamide polymer NPs with various characteristics that could influence the biodistribution after oral administration, such as size, flexibility, hydrophobicity, surface charges, and surface chemistries, were prepared. NPs with various sizes were synthesized by tuning the surfactant concentration only during synthesis, whereas NPs with different flexibility, hydrophobicity, surface charge, and surface chemistry were synthesized by feeding the corresponding functional monomer. The total amount of NPs accumulated in the organs decreased with increasing NP size, rigidity, hydrophobicity, electric potential (whether positive or negative), and polyethylene glycol modification. The results indicated that the absorption of orally administered NPs can be controlled by optimizing the characteristics of NP such as size, flexibility, hydrophobicity, surface charge, and surface chemistry. The results of this study will provide useful information to design NP formulations.

Postmenopausal women are at a higher risk of developing dyslipidemia and osteoporosis due to estrogen deficiency, necessitating regular vitamin D supplementation and the use of cholesterol inhibitors, respectively, to prevent these conditions. Despite current treatments, alternatives are needed to address both conditions simultaneously. Ergosterol, a precursor of vitamin D₂, is a fungal sterol converted to brassicasterol by 7-dehydrocholesterol reductase, a cholesterol biosynthesis enzyme that converts 7-dehydrocholesterol (a precursor of vitamin D₃) into cholesterol. Our previous research demonstrated that ergosterol decreases cholesterol levels and increases 7-dehydrocholesterol levels in human HepG2 hepatoma cells. Furthermore, we reported that ergosterol increases vitamin D₂ levels, inhibits the cholesterol biosynthetic pathway, and potentially promotes vitamin D₃ biosynthesis in male rats fed a high-fat and high-sucrose diet. In this study, we investigated the effects of daily high ergosterol intake on cholesterol, vitamin D₂, and D₃ biosynthetic pathways in ovariectomized (OVX) rats using GC-MS and LC with tandem mass spectrometry. OVX rats treated with ergosterol for 14 weeks exhibited significantly decreased plasma cholesterol levels and markers of cholesterol absorption, such as the plant sterol sitosterol. Furthermore, 7-dehydrocholesterol levels increased in these rats compared to untreated OVX rats. We observed that 1α, 25-dihydroxyvitamin D₃ levels slightly increased in OVX rats treated with ergosterol. Additionally, ergosterol improved bone strength and increased OVX-induced bone resorption. These results indicate that daily ergosterol intake may aid in the simultaneous prevention of dyslipidemia and osteoporosis in postmenopausal women.

This study aimed to clarify the optimal value for the unbound cefmetazole concentration to remain above the minimum inhibitory concentration (MIC) (fT ≥ MIC) for efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing Escherichia coli. This double-center retrospective observational study was conducted at Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital from January 2012 to October 2022. Efficacy was determined via clinical evaluation (mortality rate, recurrence rate, vital changes) and bacteriological evaluation, and the optimal fT ≥ MIC was calculated via receiver operating characteristic curve analysis. As a result, the number of patients evaluated were 40 (35 and 5 in the treatment success and treatment failure groups, respectively). Univariate analysis showed that fT ≥ MIC, recurrence rate, and MIC for cefmetazole against bacteria were significantly different for the two groups (p < 0.05). Receiver operating characteristic curve analysis showed that the optimal fT ≥ MIC indicating efficacy was 57% (area under the curve: 0.94, 95% confidence interval: 0.86-1.00, p = 0.002). All patients with fT ≥ MIC ≥ 57% had successful treatment, whereas the frequency of treatment failure was high among those with fT ≥ MIC <57%. The optimal fT ≥ MIC for the clinical efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing E. coli was fT ≥ MIC ≥ 57%. This finding would be useful for optimal dosing of cefmetazole.

This study aimed to evaluate published population pharmacokinetic models of unbound cefazolin to assess their predictive performance using an independent dataset. A systematic literature search was conducted on PubMed to identify studies evaluating the population pharmacokinetics of unbound cefazolin in patients. Subsequently, the selected models were used for external validation. Predictive bias was visually assessed by plotting the prediction errors (PEs) and relative PEs. Predictive precision was evaluated by calculating the mean absolute error (MAE), root mean square error (RMSE), and mean relative error (MRE). The predictive performance of the 4 unbound population pharmacokinetic models was evaluated using clinical data from 64 patients and 218 unbound concentration samples. The PEs for unbound cefazolin concentrations in the Komatsu model indicated a positive bias, while the RPEs demonstrated similar predictive distributions along the y = 0 line, regardless of the predicted values. In contrast, the other 3 models showed a negative bias for both PE and RPE at unbound cefazolin concentrations. The best MAE, RMSE, and MRE (%) values were 4.71, 9.02, and 30.2 in Komatsu et al.'s model, while the next best values were 11.5, 16.1, and 107.2 in Chung et al.'s model. Both models, which performed best regarding bias and accuracy, were also utilized in studies on unbound concentrations and the correlation between total concentrations and protein-binding sites. This study identified these models as the most suitable for predicting unbound cefazolin concentration profiles in surgical patients.

As previously reported, vialinin A, inhibits tumor necrosis factor α (TNF-α) production and extracellular release from RBL-2H3 cells by targeting USP5. In this study, we examined its inhibitory effect and mechanism of action on immunoglobulin E (IgE)-mediated early-phase allergic reactions in RBL-2H3 cells. Vialinin A inhibited β-hexosaminidase release from RBL-2H3 cells and tended to suppress cytosolic calcium ion concentration elevations. Kinase analysis and results from immunoblotting showed that vialinin A inhibited Syk activation and its autophosphorylation. Consequently, the phosphorylation of Syk downstream signalling proteins, such as linker for activation of T cells family and phospholipase Cγ1/2, essential in calcium ion mobilization and cell activation were slightly inhibited. These results suggest that vialinin A affects degranulation of RBL-2H3 cells by inhibiting Syk.

Cannabinoid receptor type 1 (CB1R) plays a key role in neuronal homeostasis, synaptic plasticity, and neuroprotection. CB1R antagonists typically protect against CB1R agonists-induced neurotoxicity. However, we previously found that the CB1R antagonists rimonabant and its analog AM251 can also be neurotoxic: under serum-free conditions, these compounds induce apoptosis in human neuroblastoma SH-SY5Y cells through mitochondrial damage and endoplasmic reticulum (ER) stress. To elucidate the mechanisms of this neurotoxicity, we examined the effects of CB1R agonists. We co-treated SH-SY5Y cells with rimonabant or AM251 in combination with either the CB1R agonist arachidonyl 2-chloroethylamide (ACEA) or WIN 55212-2 mesylate (WIN). ACEA, but not WIN, protected cells from rimonabant- and AM251-induced apoptosis. While ACEA had only a limited effect on mitochondrial damage, it significantly reduced phosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α), a key marker of ER stress. Given that ACEA also functions as an agonist of transient receptor potential vanilloid 1 (TRPV1), we investigated its role in ACEA-mediated neuroprotection. The TRPV1 antagonist capsazepine blocked ACEA's protective effects, suggesting that ACEA acts through TRPV1 rather than CB1R. ACEA also prevented apoptosis induced by camptothecin, a well-established apoptosis inducer, through a similar capsazepine-sensitive mechanism, demonstrating its broader protective effects against apoptosis. These findings indicate that rimonabant and AM251 induce neurotoxicity independently of CB1R under serum-free conditions and that ER stress is likely to be a key target of CB1R-independent neuroprotection by ACEA. Our study highlights the complexity of CB1R ligand-associated neurotoxicity and neuroprotection.

In this study, we investigated guanidinylated chitosan (GCS), a chemically modified derivative of unmodified low-molecular-weight chitosan (CS), as a multifunctional excipient to enhance the solubility and absorption of poorly water-soluble drugs. Flurbiprofen (FP) was selected as a model drug to compare the performance of kneaded dispersions GCS-based (FP-GCS) and CS-based (FP-CS). Both GCS and CS increased the solubility of FP in a concentration-dependent manner, with no significant differences between them. However, dissolution testing showed that FP-GCS kneaded dispersion significantly enhanced the dissolution rate of FP alone in water and simulated gastric fluid (pH 1.2), but not under simulated intestinal conditions (pH 6.8). In vivo pharmacokinetic studies in rats demonstrated that FP-GCS kneaded dispersion achieved the highest plasma concentration of FP, suggesting enhanced gastrointestinal permeability. Moreover, FP-GCS kneaded dispersion markedly reduced gastric ulceration in a rat ulcer model. These results indicate that GCS is an effective oral drug delivery excipient capable of improving both the bioavailability and gastrointestinal safety of FP.

In recent years, radiotheranostics, a theranostic approach utilizing radioisotopes, has been gaining significant attention, primarily in the field of oncology. The success of this technology relies on the design of probes that specifically target desired sites, making the development of effective diagnostic and therapeutic agents a crucial area of research. This review provides an overview of the fundamental concepts and recent advancements in probe design for radiotheranostics, with a particular focus on pharmacokinetics and subcellular localization. Key topics discussed include: (1) multimerization, (2) introduction of the albumin-binding moiety, (3) charge modification, (4) glycosylation, (5) conjugation of cell-penetrating peptides, (6) introduction of the covalent binding moiety, (7) targeting the nucleus, and (8) utilizing drug release properties to control pharmacokinetics and intracellular localization. Through these strategies, we review the optimization and novel design possibilities for probes in radiotheranostics.