BMC Pharmacology & Toxicology最新文献

This bioequivalence study was conducted to evaluate two oral formulations of cotrimoxazole tablets in healthy Chinese subjects. All 26 subjects recruited to this study were randomly and evenly classified into two groups and received a single dose (sulfamethoxazole: 400 mg and trimethoprim: 80 mg) of test cotrimoxazole tablets (generic drug) or reference cotrimoxazole tablets (branded drug). After a 7-day washout period, these subjects received one dose of reference drug or test drug. Blood samples were collected from participants before and up to 48 h after dosing to assess the concentration of sulfamethoxazole (SMX) and trimethoprim (TMP) in plasma and a plasma concentration-time curve was drawn. Then, the pharmacokinetics parameters were calculated accordingly. Our data revealed that there were no significant differences observed in the maximum plasma concentration (Cmax), area under the curve from time 0 to the last measurable concentration (AUC0-t), and area under the curve from time 0 to infinity (AUC0-∞) between the two formulations. For SMX, the 90% confidence intervals (CI) of the geometric mean ratio for Cmax, AUC0-t, and AUC0-∞ were 104.03-113.92%, 100.46-103.70%, and 100.41-103.81%, respectively. Similarly, for Trimethoprim (TMP), the 90% CI ranged from 98.54 to 106.95% for Cmax, from 99.31 to 107.68% for AUC0-t, and from 99.49 to 107.55% for AUC0-∞. Importantly, all these 90% CI values fell within the range of 80.00-125.00%, indicating that the test drug is bioequivalent to the reference drug. Furthermore, throughout the entire trial, no suspected serious adverse events were reported, indicating the safety profile of the newly developed generic cotrimoxazole. In summary, our study demonstrates that the newly developed generic formulation of cotrimoxazole is bioequivalent to the branded formulation under fasting conditions.

Background: Previous studies investigating the effect of oral supplementation of paricalcitol on reactive protein levels in chronic kidney disease (CKD) patients reported inconsistent findings. In this systematic review and meta-analysis, we have analyzed and interpreted the results obtained from previous randomized clinical trials on the effect of paricalcitol on C-reactive protein in CKD patients in the literature.

Methods: MEDLINE, SciVerse Scopus, and Clarivate Analytics Web of Science databases were searched until January 2023 and related articles were obtained through a careful screening process allowing extraction of required data from selected articles. The effect size was calculated using a random effect model and weighted mean differences (WMD) and 95% confidence intervals (CI). Heterogeneity among studies was evaluated using Cochran's Q test and I².

Results: Amongst the 182 articles obtained from the initial search, 4 studies (6 arms) were finally included in the meta-analysis. Pooled analysis shows that C-reactive protein levels significantly decrease after oral supplementation with paricalcitol (WMD: -2.55 mg/L, 95% CI (-4.99 to -0.11; P = 0.04). The studies used in this meta-analysis showed significant heterogeneity (I² = 66.3% and P = 0.01).

Conclusion: Oral paricalcitol supplementation in CKD patients can significantly reduce C-reactive protein levels, which may prevent CKD progression.

Background: With the increased use of BCR-ABL1 tyrosine kinase inhibitors (TKIs) in cancer patients, adverse events (AEs) have garnered considerable interest. We conducted this pharmacovigilance study to evaluate the AEs of BCR-ABL1 TKIs in cancer patients using the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods: To query AE reports from the FAERS database, we used OpenVigil 2.1. Descriptive analysis was then employed to describe the characteristics of TKIs-associated AE reports. We also utilized the disproportionality analysis to detect safety signals by calculating the proportional reporting ratio (PRR) and reporting odds ratios (ROR).

Results: From the FAERS database, a total of 85,989 AE reports were retrieved, with 3,080 significant AE signals identified. Specifically, imatinib, nilotinib, dasatinib, bosutinib, and ponatinib had significant AE signals of 1,058, 813, 232, 186, and 791, respectively. These significant signals were further categorized into 26 system organ classes (SOCs). The AE signals of imatinib and ponatinib were primarily associated with general disorders and administration site conditions. On the other hand, nilotinib, dasatinib, and bosutinib were mainly linked to investigations, respiratory, thoracic and mediastinal disorders, and gastrointestinal disorders, respectively. Notably, new signals of 245, 278, 47, 55, and 253 were observed in imatinib, nilotinib, dasatinib, bosutinib, and ponatinib, respectively.

Conclusions: The results of this study demonstrated that AE signals differ among the five BCR-ABL1 TKIs. Furthermore, each BCR-ABL1 TKI displayed several new signals. These findings provide valuable information for clinicians aiming to reduce the risk of AEs during BCR-ABL1 TKI treatment.

Background: Pulmonary fibrosis is a chronic progressive disease with complex pathogenesis, short median survival time, and high mortality. There are few effective drugs approved for pulmonary fibrosis treatment. This study aimed to evaluate the effect of praziquantel (PZQ) on bleomycin (BLM)-induced pulmonary fibrosis.

Methods: In this study, we investigated the role and mechanisms of PZQ in pulmonary fibrosis in a murine model induced by BLM. Parameters investigated included survival rate, lung histopathology, pulmonary collagen deposition, mRNA expression of key genes involved in pulmonary fibrosis pathogenesis, the activity of fibroblast, and M2/M1 macrophage ratio.

Results: We found that PZQ improved the survival rate of mice and reduced the body weight loss induced by BLM. Histological examination showed that PZQ significantly inhibited the infiltration of inflammatory cells, collagen deposition, and hydroxyproline content in BLM-induced mice. Besides, PZQ reduced the expression of TGF-β and MMP-12 in vivo and inhibited the proliferation of fibroblast induced by TGF-β in vitro. Furthermore, PZQ affected the balance of M2/M1 macrophages.

Conclusions: Our study demonstrated that PZQ could ameliorate BLM-induced pulmonary fibrosis in mice by affecting the balance of M2/M1 macrophages and suppressing the expression of TGF-β and MMP-12. These findings suggest that PZQ may act as an effective anti-fibrotic agent for preventing the progression of pulmonary fibrosis.

Background: Safinamide (SAF), an α-aminoamide derivative and a selective, reversible monoamine oxidase (MAO)-B inhibitor, has both dopaminergic and nondopaminergic (glutamatergic) properties. Several studies have explored the potential of SAF against various neurological disorders; however, to what extent SAF modulates the magnitude, gating, and voltage-dependent hysteresis [Hys_(V)] of ionic currents remains unknown.

Methods: With the aid of patch-clamp technology, we investigated the effects of SAF on voltage-gated sodium ion (Na_V) channels in pituitary GH3 cells.

Results: SAF concentration-dependently stimulated the transient (peak) and late (sustained) components of voltage-gated sodium ion current (I_Na) in pituitary GH₃ cells. The conductance-voltage relationship of transient I_Na [I_Na(T)] was shifted to more negative potentials with the SAF presence; however, the steady-state inactivation curve of I_Na(T) was shifted in a rightward direction in its existence. SAF increased the decaying time constant of I_Na(T) induced by a train of depolarizing stimuli. Notably, subsequent addition of ranolazine or mirogabalin reversed the SAF-induced increase in the decaying time constant. SAF also increased the magnitude of window I_Na induced by an ascending ramp voltage V_ramp. Furthermore, SAF enhanced the Hys_(V) behavior of persistent I_Na induced by an upright isosceles-triangular V_ramp. Single-channel cell-attached recordings indicated SAF effectively increased the open-state probability of Na_V channels. Molecular docking revealed SAF interacts with both MAO and Na_V channels.

Conclusion: SAF may interact directly with Na_V channels in pituitary neuroendocrine cells, modulating membrane excitability.

Purpose: Critically ill COVID-19 and non-COVID-19 patients receive thromboprophylaxis with the LMWH nadroparin. Whether a standard dosage is adequate in attaining the target anti-FXa levels (0.20-0.50 IU/ml) in these groups is unknown.

Methods: This study was a prospective, observational study in the ICU of a large general teaching hospital in the Netherlands. COVID-19 and non-COVID-19 patients admitted to the ICU who received LMWH in a prophylactic dosage of 2850 IU, 5700 IU or 11400 IU subcutaneously were eligible for the study. Anti-FXa levels were determined 4 h after administration. Relevant laboratory parameters, prespecified co-variates and clinical data were extracted from the electronic health record system. The primary goal was to evaluate anti-FXa levels in critically ill patients on a prophylactic dosage of nadroparin. The second goal was to investigate whether covariates had an influence on anti-FXa levels.

Results: A total of 62 patients were included in the analysis. In the COVID-19 group and non-COVID-19 group, 29 (96%) and 12 patients (38%) reached anti-FXa levels above 0.20 IU/ml, respectively. In the non-COVID-19 group, 63% of the patients had anti-FXA levels below the target range. When adjusted for nadroparin dosage a significant relation was found between body weight and the anti-FXa level (p = 0.013).

Conclusion: A standard nadroparin dosage of 2850 IU sc in the critically ill patient is not sufficient to attain target anti-FXa levels in the majority of the studied patient group. We suggest a standard higher dosage in combination with body-weight dependent dosing as it leads to better exposure to nadroparin.

Clinical trials registration: Retrospectively registered, ClinicalTrials.gov ID NTC 05926518 g, date of registration 06/01/23, unique ID 2020/1725.

Background: Cantharidin (CTD), the main toxic component of Mylabris, has been extensively used for tumor treatment in recent years. CTD-induced liver toxicity has attracted significant interest in clinic.

Methods: In this study, biochemical parameters and liver pathological changes were analyzed after CTD was administered to mice by gavage. Subsequently, a lipidomic approach was used to investigate serum lipid metabolism disorders, and the mechanism underlying CTD-induced liver injury in mice was explored.

Results: The results showed that the levels of TC and LDL-C were significantly increased after CTD intervention. Besides, pathological results showed inflammatory cell infiltration and hepatocyte necrosis in the liver. Furthermore, lipidomics found that a total of 18 lipid metabolites were increased and 40 were decreased, including LPC(20:4), LPC(20:3), PC(22:6e/2:0), PE(14:0e/21:2), PC(18:2e/22:6), glycerophospholipids, CE(16:0), CE(18:0) Cholesterol esters and TAG(12:0/12:0/22:3), TAG(16:1/16:2/20:4), TAG(18:1/18:1/20:0), TAG(16:2/18:2/18:2), TAG(18:0/18:0/20:0), TAG(13:1/19:0/19:0) glycerolipids. Metabolic pathway analysis found that glycerophospholipid, glycerol ester and glycosylphosphatidylinositol (GPI)-anchored biosynthetic metabolic pathways were dysregulated and the increase in PE caused by glycophoric metabololism and GPI may be the source of lipid metabolism disorders caused by CTD. Overall, the present study provided new insights into the mechanism of CTD-induced liver injury and increased drug safety during clinical application.

Introduction: The Gram-negative bacterium Helicobacter pylori, H. pylori, is associated with significant digestive disorders. However, the effectiveness of bacterial eradication is declining due to drug resistance. A potent anti-H. pylori activity is shown by the natural antimicrobial peptide pexiganan.

Objective: The current study aimed to evaluate the effectiveness of pexiganan and its lipid-liquid crystals (LLCs) in inducing Helicobacter pylori in mice.

Methods: In this experimental study, H. pylori infection was first induced in C57BL/6 mice. Secondly, the antibacterial efficacy of pexiganan and its LLCs formulations was investigated to eliminate H. pylori infection.

Results: The H. pylori infection could not be completely eradicated by pexiganan peptide alone. However, incorporating pexiganan within the LLC formulation resulted in an increased elimination of H. pylori. Under the H&E strain, the pexiganan-LLCs formulation revealed minimal mucosal alterations and a lower amount of inflammatory cell infiltration in the stomach compared to the placebo.

Conclusion: Clarithromycin was more effective than pexiganan at all tested concentrations. Furthermore, the pexiganan-loaded LLCs exhibited superior efficacy in curing H. pylori infection in a mouse model compared to pexiganan alone. This formulation can enhance H. pylori clearance while mitigating the adverse effects, typically associated with conventional drugs, leading to a viable alternative to current treatment options.

Background: To comprehend the influences of fenofibrate on hepatic lipid accumulation and mitochondrial function-related signaling pathways in mice with non-alcoholic fatty liver disease (NAFLD) secondary to high-fat diets together with free fatty acids-influenced HepG2 cells model.

Materials and methods: A random allocation of male 6-week C57BL/6J mice into three groups was done, including controls, model (14 weeks of a high-fat diet), and fenofibrate [similar to the model one with administered 0.04 g/(kg.d) fenofibrate by gavage at 11 weeks for 4 weeks] groups, which contained 10 mice each. This study verified NAFLD pathogenesis via mitochondrial functions in hepatic pathological abnormalities, liver index and weight, body weight, serum biochemical indexes, oxidative stress indicators, mitochondrial function indexes, and related signaling pathways. The effect of fenofibrate intervention was investigated in NAFLD model mice. In vitro, four groups based on HepG2 cells were generated, including controls, the FFA model (1.5 mmol/L FFA incubation for 24 h), LV-PGC-1α intervention (similar to the FFA model one after PPARGC1A lentivirus transfection), and LV control intervention (similar to the FFA model one after negative control lentivirus transfection) groups. The study investigated the mechanism of PGC-1α related to lipid decomposition and mitochondrial biosynthesis by Oil red O staining, colorimetry and western blot.

Results: In vivo experiments, a high-fat diet achieved remarkable changes regarding liver weight, liver index, serum biochemical indicators, oxidative stress indicators, liver pathological changes, mitochondrial function indicators, and body weight of the NAFLD model mice while fenofibrate improved the objective indicators. In the HepG2 cells model, the lipid accumulation increased significantly within the FFA model group, together with aggravated hepatocytic damage and boosted oxidative stress levels. Moreover, FFA induced excessive mitosis into fragmented in mitochondrial morphology, ATP content in cells decreased, mtDNA replication fold decreased, the expression of lipid decomposition protein PPARα reduced, mitochondrial biosynthesis related protein PGC-1α, NRF-1 and TFAM decreased. PGC-1α overexpression inhibited lipid deposition by improving mitochondrial biosynthesis and lipid decomposition.

Conclusion: Fenofibrate up-regulated PPARα/PGC-1α signaling pathway, promoted mitochondrial β-oxidation, reduced oxidative stress damage and lipid accumulation of liver. PGC-1α overexpression enhanced mitochondrial biosynthesis and ATP production, and reduced HepG2 intracellular accumulation of lipids and oxidative stress.

Background: Previously, observational studies showed that amlodipine can mitigate calcineurin inhibitor- and contrast-induced acute kidney injury (AKI). Herein, we aimed to measure the effect of amlodipine on renal ischemia/reperfusion (I/R) injury and find the underlying mechanisms.

Materials and methods: Bilateral renal I/R was induced by clamping the hilum of both kidneys for 30 min. The first dose of amlodipine 10 mg/kg was gavaged before anesthesia. The second dose of amlodipine was administered 24 h after the first dose. Forty-eight hours after I/R, rats were anesthetized, and their blood and tissue specimens were collected.

Results: Amlodipine significantly decreased the elevated serum levels of creatinine and blood urea nitrogen (BUN) and mitigated tissue damage in hematoxylin & eosin (H&E) staining. Amlodipine strongly reduced the tissue levels of malondialdehyde (MDA), interleukin 1β (IL1β), and tumor necrosis factor α (TNF-α). Amlodipine enhanced antioxidant defense by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2. Furthermore, amlodipine significantly improved mitochondrial biogenesis by promoting Sestrin2/peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α)/mitochondrial transcription factor A (TFAM) pathway. It also enhanced autophagy and attenuated apoptosis, evidenced by increased LC3-II/LC3-I and bcl2/bax ratios after renal I/R.

Conclusion: These findings suggest that amlodipine protects against renal I/R through Nrf2/Sestrin2/PGC-1α/TFAM Pathway.