Pharmacology最新文献

Introduction: The purpose of our study was to evaluate the safety, tolerability, and pharmacokinetics of furaprevir, a new highly selective hepatitis C virus NS3/4A protease inhibitor.

Methods: The study was divided into 2 parts: Part A (single ascending-dose study, SAD) and Part B (multiple ascending-dose study, MAD). A total of 62 healthy subjects were enrolled in the studies. DNA samples were extracted from all subjects and genotypes of CYP3A5*3, CYP3A4*1G and POR*28 were analyzed by ligase detection reaction (LDR).

Results: We used nonlinear mixed effects model (NONMEM) to construct furaprevir population pharmacokinetics model. (1) In SAD, Cmax and AUC were greater than dose increased ratio in the dose rang of 100-400 mg; (2) In MAD, Cmax and AUC increased in an approximately dose-proportional manner in the dose range of 200-600 mg; (3) A one-compartment model with transit absorption described the plasma concentrations of furaprevir. The apparent clearance (CL) was estimated at 33.4 L/h. The distribution volume of compartment (V2) was 219.0 L. No serious adverse event occurred in the studies. But other screening gene mutations had no statistically significant effects on the pharmacokinetics of furaprevir.

Conclusion: Food significantly impacts the bioavailability of furaprevir. Furaprevir does not accumulate in vivo after multiple rising doses and has demonstrated safety and tolerability in healthy subjects, supporting its further investigation in patients with hepatitis C.

Introduction: This study aims to explore the reno-protective effect of Curcumin in focal and segmental glomerulosclerosis (FSGS) in Murine models, a common chronic glomerulopathy that leads to end stage renal disease.

Methods: Adult Wistar rats were used in this experiment. One group was treated with intravenous Adriamycin (ADR) injection to induce FSGS similar to that seen in humans and a second group was co-administered ADR and Curcumin (ADR-CUR). Saline treated rats served as controls. Renal injury was assessed by measuring the levels of serum creatinine, blood urea nitrogen (BUN), triglyceride and urinary protein. The homogenates of renal cortex were used to estimate the renal content of the inflammatory marker, tumor necrosis factor-a (TNF-a); oxidative stress marker, Malonaldehyde (MDA); and two anti-oxidants superoxide dismutase (SOD) and reduced glutathione (GSH). In addition, the rat kidneys were harvested by ends of week-8 and week-12 and examined for histological abnormalities.

Results: The ADR-treated rats showed biochemical and histological evidence of FSGS, in the form of proteinuria, elevated serum creatinine, BUN and triglycerides, elevated renal TNF-a and MDA, and segmental glomerulosclerosis. The ADR-CUR treated rats showed significant correction of all these variables. Co-administration with Curcumin resulted in improvement of the proteinuria, serum creatinine, BUN and triglyceride. The renal tissue levels of anti-oxidants SOD and GSH increased and that of TNF-a and MDA decreased and the histology revealed reduction in the extent of segmental glomerulosclerosis. The FSGS associated renal damage was notably antagonized by curcumin treatment.

Conclusion: Our findings confirm the reno-protective effects of Curcumin as a potential therapeutic agent in protection against the progression of FSGS and indicate that it is mitigated by inhibition of oxidant injury and inflammation and also by promotion of antioxidants. Curcumin ameliorated the ADR-induced FSGS in murine models. It may be a promising compound in the treatment of FSGS in human subjects. More human studies are needed to further elucidate its effects in FSGS.

Introduction: This meta-analysis aimed to assess the effectiveness and safety of combining anlotinib with chemotherapy in treating patients with small cell lung cancer (SCLC).

Methods: We systematically searched a range of databases, including PubMed, Embase, Cochrane Library, and Web of Science, up to July 28, 2023, complemented by searches in Chinese databases such as CNKI, Wanfang, and VIP, through July 4, 2023. The outcomes analyzed were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), median PFS (mPFS), overall survival (OS), vascular endothelial growth factor (VEGF) levels, and the adverse events.

Results: The analysis, which integrated data from 16 studies encompassing 1,083 patients, demonstrated that the combined treatment of anlotinib and chemotherapy significantly outperformed either anlotinib or chemotherapy alone in enhancing the ORR, DCR, and mPFS. Furthermore, this combination therapy also resulted in improved PFS, 1-year and 2-year overall OS, and reduced levels of VEGF) compared to chemotherapy alone, with all comparisons reaching statistical significance (p < 0.05). The combination of anlotinib with chemotherapy exhibited a considerably elevated risk of developing leukopenia (RR: 1.41, 95% CI: 1.09-1.82, p = 0.008). The subgroup analyses indicated the anlotinib plus etoposide group and anlotinib plus irinotecan were superior to the etoposide and the irinotecan groups, respectively, in terms of ORR outcome and DCR outcome. The subgroup analysis revealed that the combination of anlotinib and etoposide significantly increased the risk of thrombocytopenia and myelosuppression compared to etoposide alone. In patients with a history of one or an unspecified number of chemotherapy cycles, the integration of anlotinib into the chemotherapy regimen improved DCR. Conversely, in those who had undergone more than two prior treatment cycles, the risk of myelosuppression was heightened with the addition of anlotinib. Lastly, the risk of gastrointestinal adverse events was increased in patients receiving more than two treatment cycles of anlotinib plus chemotherapy compared to anlotinib monotherapy.

Conclusion: The findings of this investigation imply that the integration of anlotinib into chemotherapy regimens may enhance PFS, ORR, DCR, and OS in SCLC patients. This meta-analysis presents novel therapeutic prospects for SCLC, suggesting that the synergistic approach of anlotinib and chemotherapy could markedly enhance treatment outcomes for this patient population.

Introduction: The exosomes from adipose-derived mesenchymal stem cells (AMSCs) had therapeutic effects. However, whether the exosomes derived from hypoxia-treated AMSCs could improve renal functions in unilateral ureteral obstruction (UUO) mice remains unclear.

Methods: The exosomes were characterized using a transmission electron microscope and Western blot. Its size distribution was determined using the Zetasizer Nano ZS analysis system. The differentiation ability was assessed by alkaline phosphatase and oil red staining. Consequently, the function of exosomes in inhibiting inflammatory factors was evaluated using an enzyme-linked immunosorbent assay, and apoptosis inhibition was evaluated by Western blot. Finally, the function of exosomes to ameliorate kidney fibrosis was evaluated using quantitative reverse transcription polymerase chain reaction, Western blot, hematoxylin-eosin staining, and Masson staining.

Results: The cultured AMSCs could differentiate into osteoblast and adipocyte. Meanwhile, the cultured AMSCs could effectively secrete the exosomes, which were characterized by around 110 nm diameter and surface marker expression. Exosomes derived from hypoxia-treated AMSCs improved renal functions in UUO mice. The mechanism exploration revealed that exosomes could decrease the TNF-α and IL-6 and inhibit cell apoptosis. Finally, the fibrosis-associated protein was reversed, and the renal dysfunctions were ameliorated in UUO mice.

Conclusion: The exosomes derived from the hypoxia-treated AMSCs have a better effect than those from normal AMSCs in ameliorating renal dysfunctions in UUO mice.

Introduction: Eleclazine is a highly selective late sodium current inhibitor, possibly effective in reducing ventricular fibrillation (VF) in heart failure (HF) with ischemia-reperfusion (IR) injury. The electrophysiological effects of eleclazine at therapeutic hypothermia (TH) are unknown. We investigated the effects of eleclazine in suppressing VF in failing rabbit hearts with IR injury undergoing TH.

Method: HF was induced by right ventricular pacing. An IR model was created using coronary artery ligation for 60 min, followed by reperfusion for 30 min. Hearts were excised and Langendorff-perfused for optical mapping and electrophysiological studies. Electrophysiological studies were repeated after TH (33°C) for 30 min or eleclazine (1 μm) infusion for 20 min.

Results: In failing IR-injured hearts, eleclazine reduced action potential duration (APD) dispersion and accelerated intracellular Ca2+ uptake to suppress arrhythmogenic alternans but also exacerbated rate-dependent conduction slowing, resulting in neutral effects on VF inducibility at normothermia. TH increased VF severity. Eleclazine after TH ameliorated TH-induced APD dispersion and further depressed conduction to reduce VF inducibility and severity. TH after eleclazine also slowed conduction to a greater extent to reduce VF inducibility and severity by extrastimulus pacing. In control IR-injured hearts, eleclazine increased VF severity by dynamic pacing at normothermia, which was counteracted by TH.

Conclusions: Eleclazine does not prevent VF at normothermia but reduces VF inducibility and severity by extrastimulus pacing at TH in isolated failing hearts with regional IR injury.

Introduction: Diabetes mellitus is known to provoke devastating anomalies in myocardial structure and function, while effective therapeutic regimen is still lacking. The selective protease inhibitor UCF101 (5-[5-(2-nitrophenyl) furfuryl iodine]-1,3-diphenyl-2-thiobarbituric acid) has been shown to fend off ischemic heart injury, although its impact on diabetic cardiomyopathy remains elusive.

Methods: Our present work was conducted to examine the effect of UCF101 on experimental diabetes-evoked cardiac geometric and functional abnormalities as well as mechanisms involved. Adult mice were made diabetic using streptozotocin (STZ, 50 mg/kg, i.p., for 5 days) while receiving UCF101 (7.15 mg/kg, i.p.).

Results: STZ evoked cardiac hypertrophy, interstitial fibrosis, mitochondrial ultrastructural damage, oxidative stress, dampened autophagy (LC3B, Beclin 1, elevated p62), mitophagy (FUNDC1 and Parkin with upregulated TOM20), increased left ventricular end systolic diameter, reduced fractional shortening, ejection fraction, cardiomyocyte shortening capacity, velocities of shortening/re-lengthening, and rise in intracellular Ca2+ in conjunction with elongated diastole and intracellular Ca2+ removal, the responses were overtly reconciled by UCF101 with little effects from UCF101 itself. Levels of cell injury markers Omi/HtrA2, TNFα, and stress signaling (JNK, ERK, p38) were overtly enhanced along with compromised phosphorylation of cellular fuel AMP-activated protein kinase (AMPK) (Thr172) and cell survival molecule GSK3β, as well as downregulated SERCA2a and elevated phospholamban, the effect was reversed by UCF101 (except for SERCA2a). AMPK knockout, pharmacological inhibition, the mitophagy inhibitor liensinine, and parkin knockout nullified UCF101-offered cardioprotection in diabetes. UCF101 reversed STZ-induced upregulation in the AMPK degrading enzymes PP2A and PP2C.

Conclusion: These findings suggest that UCF101 rescues diabetes-mediated alterations in cardiac structure and function, likely through AMPK-mediated regulation of mitophagy.

Introduction: Melanocyte ferroptosis has been proven to contribute to the development of vitiligo. Tanshinone IIA (TSA), a Chinese herbal extract, has been shown to inhibit vitiligo progression. Whether TSA regulates ferroptosis in melanocytes remains unclear.

Methods: Hydrogen peroxide (H2O2) was used to induce melanocytes to stimulate vitiligo cell model in vitro. Cell proliferation was examined by 5-ethynyl-2'-deoxyuridine assay. The levels of malondialdehyde, reactive oxygen species, glutathione peroxidase, and iron were detected by corresponding commercial kit. The protein levels of ferroptosis-related markers and Nrf2 pathway-related markers were examined using western blot and immunofluorescence staining. Cell viability and cytotoxicity were analyzed using Cell Counting Kit-8 assay and lactate dehydrogenase detection. Mitochondrial morphology was examined using a transmission electron microscope.

Results: After H2O2 treatment, melanocyte proliferation was reduced, while oxidative stress and ferroptosis were enhanced. TSA treatment could inhibit ferroptosis in H2O2-induced melanocytes. Besides, TSA could activate Nrf2 pathway and promote Nrf2 nuclear translocation, and Nrf2-specific inhibitor (ML385) also reversed the inhibitory effect of TSA on H2O2-induced melanocyte ferroptosis.

Conclusion: Our data showed that TSA alleviated H2O2-induced melanocyte ferroptosis via activating Nrf2 pathway.

Introduction: Hypertension is prevalent in older women and men, but the impact of sex differences is unclear.

Methods: Blood pressure (BP) was evaluated weekly for 15 weeks using tail-cuff plethysmography in intact or gonadectomized female and male rats. Similarly, gonadectomized rats were subcutaneously treated daily for 15 weeks with estradiol in females or testosterone in males. Treatment with estrogen in males and androgen in females for BP was also examined. The non-genomic antihypertensive potency and efficacy of different sex steroids were determined; catheters were implanted in the carotid artery of hypertensive rats for BP recording with bolus injections in the jugular vein at cumulative doses (1 × 10-7-1 × 10-4M kg-1 min-1) of dehydroepiandrosterone (DHEA), estradiol, testosterone, or 5β-dihydrotestosterone (5β-DHT).

Results: Data showed a time-dependent increase in BP after gonadectomy in female and male rats until hypertension values were reached. Males are more sensitive to the development of hypertension than females. The increases in BP in females and males were completely prevented by estradiol or testosterone, respectively. Testosterone completely prevented hypertension in females, whereas estradiol only partially in males. Antihypertensive potencies in conscious hypertensive rats were DHEA = 5β-DHT = testosterone >> estradiol, in females and DHEA = 5β-DHT >> testosterone >> estradiol in males. The efficacy was DHEA = 5β-DHT = testosterone >> estradiol in females and 5β-DHT = DHEA >> testosterone >> estradiol in males.

Conclusion: Gonadectomized males developed hypertension faster than females, suggesting that androgen deficiency plays an important role in BP reduction. Antihypertensive responses of steroids are structure-dependent; estradiol demonstrated the lowest potency, whereas 5β-DHT was a potent antihypertensive without estrogenic and androgenic actions, suggesting it is as a therapeutic candidate for controlling hypertension in both sexes.