Pharmacology最新文献

Introduction: Muscular dystrophy (MD) refers to a group of genetic disorders leading to progressive weakness and degeneration of skeletal muscle. Among them, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the most common types. Histone deacetylase inhibitors (i.e., givinostat) is a recently approved therapy for DMD. In this systematic review, we aimed to evaluate givinostat in MD patients regarding safety and efficacy.

Methods: A systematic review was performed according to the PRISMA guidelines by searching through Medline, Embase, Cochrane Library, and Web of Science. Only randomized control trials comparing givinostat vs. placebo or other therapies are included. The primary outcomes were motor function alteration and histopathologic muscle changes and the secondary outcomes were the adverse reactions.

Results: A total of 188 records were identified, and after screening, two clinical trials met the inclusion criteria. In DMD patients, givinostat significantly slowed disease progression, improving four-stair climb times (p = 0.037) and reducing muscle fat infiltration. In BMD patients, fibrosis progression was not significantly different (p = 0.8282), but MRI showed reduced muscle fat replacement. Common adverse events included diarrhoea, thrombocytopenia, and hypertriglyceridemia, leading to dose reductions, though no new safety signals or treatment-related deaths were observed.

Conclusion: Givinostat seems to be effective in slowing disease progression in DMD but has little benefit in BMD. Its safety profile requires rigorous monitoring. Efficacy difference might be explained by the pathophysiology of the disease and the progression rate. Larger and longer follow-up trials are warranted to confirm longer term benefits and to optimize dosing strategies. Givinostat offers potential as a disease-modifying therapy for DMD but requires further investigation to establish its role in BMD.

Background: Sepsis, a severe infectious systemic syndrome with high morbidity and mortality, is pathologically characterized by multi-organ dysfunction, with pulmonary involvement predominating as acute lung injury (ALI) or its severe progression to acute respiratory distress syndrome. Contemporary therapeutic strategies exhibit limited efficacy, while traditional Chinese medicine (TCM) grounded in millennia of clinical empiricism demonstrates unique pharmacological advantages through multi-component and multi-target regulation.

Summary: The mechanism underlying sepsis-induced ALI centers on dysregulated inflammatory response, redox imbalance, and coagulopathy. This review systematically evaluates the effectiveness, mechanism, and clinical research progress of eight TCM formulas in the treatment of sepsis and ALI. Accumulating fundamental research and clinical trials demonstrate the potential of these TCM formulas in treating sepsis-induced ALI. The challenges and opportunities of TCM formulas in treating, including but not limited to, sepsis-induced ALI were emphasized.

Key message: This review bridges traditional therapeutic wisdom with modern pathogenesis understanding, offering novel combinatorial strategies for sepsis-induced ALI management.

Introduction: Considering the global burden of atherosclerosis-related cardiovascular mortality, this study investigates the anti-atherosclerotic potential of Actein, a 9,19-cyclobutane triterpenoid isolated from Cimicifuga spp.

Methods: The study employed both in vitro and in vivo experiments. In vitro, the effect of Actein on oxLDL-induced macrophage foam cells was examined. In vivo, ApoE-deficient mice were fed a high-fat diet to induce atherosclerosis and were then treated with actein (10 mg/kg) or atorvastatin for 8 weeks.

Results: Actein significantly reduced lipid accumulation in oxLDL-induced foam cells. In the in vivo model, actein treatment significantly lowered serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol. Furthermore, actein diminished the levels of inflammatory markers (interleukin [IL]-6, IL-1β, tumor necrosis factor-α, and matrix metalloproteinase-9 [MMP-9]) and upregulated the expression of ABCG1 and LXR proteins in liver tissue. The efficacy of actein was comparable to, and in some aspects superior to, that of atorvastatin.

Conclusion: These findings establish actein as a promising natural compound for the treatment of atherosclerosis, warranting further investigation into its therapeutic potential.

Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the loss of motor neurons, finally leading to death by respiratory failure. However, no effective drug is available for treating patients with ALS owing to the complex pathological mechanisms. Herbal medicines are globally known for the effects of their multiple bioactive components and lack of adverse effects. This study investigated the effects of a combined herbal medicine formulation containing Achyranthes bidentata Blume, Gastrodia elata Blume, and Chaenomeles sinensis Koehne extracts on motor function and to analyze the underlying biological mechanisms in the gastrocnemius and tibia anterior muscles and spinal cord of hSOD1G93A mice.

Methods: Rotarod and footprint analyses were performed to examine motor function. The biological mechanisms were examined using Western blot and immunohistochemistry analyses of the muscles and spinal cord in hSOD1G93A mice.

Results: Herbal medicine treatment improved motor function in hSOD1G93A mice by reducing the expression of inflammation-related proteins (glial fibrillary acidic protein and CD11b) and oxidative stress-related proteins (heme oxygenase 1 and ferritin) in the gastrocnemius and tibia anterior muscles and spinal cord. It also regulated autophagy in the muscles and spinal cord of hSOD1G93A mice.

Conclusion: Collectively, these findings suggest that the herbal medicine formulation reported herein may facilitate management of diseases with complex pathological mechanisms, such as ALS, or those with unclear pathological mechanisms.

Introduction: While the high morbidity of cancer continues to affect the global population, there are currently no effective and safe therapeutic options. Amphotericin-A21 (AmB-A21) is a derivative of amphotericin B (AmB). Its efficacy is similar to that of its precursor, but it has greater safety. AmB-A21 can induce apoptosis in neoplastic cells, meaning it could potentially be employed as a safe chemotherapeutic agent.

Methods: This study examined the antineoplastic effect of AmB-A21 on MCF-7, U-87MG, and A-549 cells by evaluating cytotoxicity, apoptosis, and protein expressions associated with cell death. MCF-7 cells were treated with AmB-A21 at 40 µm, U-87MG cells with AmB-A21 at 423 µm, and A-549 cells with AmB-A21 at 192 µm for all experiments. Non-treated cells were used as negative control. Comparative studies using AmB and cisplatin were also carried out.

Results: AmB-A21 reduced cell viability in a time-dependent manner. At 72 h, cell viability was reduced by 67% in MCF-7, 48% in U-87MG, and 47% in A-549 cells. AmB-A21 induced apoptosis by 50%, 58%, and 80% in MCF-7, U-87MG, and A-549 cells, respectively. A significant reduction in Bcl-2 expression and an important increase in Bax expression (55%/2.8-fold in MCF-7 cells, 40%/3.5 fold in U-87MG cells, and 45%/4.5-fold in A-549 cells) were also observed. AmB-A21 likewise increased caspase 9 activity 8.5-fold in MCF-7 cells, 4.1-fold in U-87MG cells, and 8-fold in A-549 cells.

Conclusion: Although comparatively AmB-A21 concentration for U-87MG cells was higher, it has potential for cancer therapy due to its safer profile.

Introduction: Exposure to potential drug-drug interactions (pDDIs) can be a notable source of avoidable drug-related harm that requires adequate management to prevent medical errors. We aimed to evaluate pDDIs and associated factors in hospitalized urological patients on admission, during hospitalization, and on discharge.

Methods: A retrospective cohort study was conducted at the Clinic of Urology of the University Clinical Centre Kragujevac, Serbia. To detect pDDIs, we used Lexicomp, which categorizes pDDIs as follows: X (avoid combination), D (consider therapy modification), C (monitor therapy), B (no action needed), and A (no known interaction). Multiple linear regression analysis was used to identify factors associated with the number of pDDIs.

Results: More than half of the 220 included patients had at least one pDDI on admission and discharge (57.3% and 63.6%, respectively), whereas 95.0% had at least one pDDI during hospitalization. The total number and number of X, D, C, and B categories of pDDIs were the highest during hospitalization and the lowest on admission. Duration of hospitalization, arrhythmias, dementia, renal failure, cancer, surgery during hospitalization, number of prescribed drugs, and various pharmacological drug classes were risk factors for a higher number of pDDIs, while age, ischemic heart disease, hypertension, and development of infection during hospitalization were protective factors in at least one of the stages. The impact of renal colic depended on the stage and category of pDDI.

Conclusion: More than half of the urological patients were exposed to at least one pDDIs at all stages. Medical professionals should regularly screen for pDDIs, particularly in patients with risk factors.

Introduction: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that affects various body systems, including the skin and facial features. Estrogen promotes lupus in human and mouse models of SLE. In this study, we conducted an in vivo study to investigate the relationship between two estrogen receptors (ER_α and ER_β) and platelet-activating factor acetylhydrolase (PAF-AH) on the symptoms of SLE.

Methods: Skin and facial features, serum PAF-AH activity, tumor-necrosis factor-alpha (TNF-α), and anti-double stranded DNA (anti-dsDNA) antibody titer, all of which are central to the classification and pathogenesis of SLE, were measured in SLE model mice injected with various ER antagonists.

Results: In SLE mice, the injection of an ER_β antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-α]pyrimidine-3-yl]-phenol induced the expression of facial erythema (especially around a cheek). The injection of an ER_α/β antagonist tamoxifen induced hair-loss on the head and the neck. The injection of an ER_α antagonist methylpiperidino pyrazole or tamoxifen increased PAF-AH activity and decreased TNF-α levels and anti-dsDNA antibody in mouse serum.

Conclusions: The activation of ER_α and inactivation of ER_β can cause inflammatory and cutaneous symptoms of SLE, respectively, implying that ER_α antagonists and/or ER_β agonists can be useful for the prevention and treatment of SLE.

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: Augmented renal clearance is a condition in which creatinine clearance exceeds 130 mL/min/1.73 m2. The present study aimed to identify drugs that increase creatinine clearance.

Methods: We initially investigated drugs associated with an upsurge in the reporting frequencies of "creatinine renal clearance increased" (CRCI) and "glomerular filtration rate increased" (GFRI) using the FDA Adverse Event Reporting System (FAERS) database. Effect of the drugs on renal clearance of creatinine and lithium was examined using rats.

Results: The database contained 625 reports on CRCI and GFRI. Among the primary suspect drugs identified, empagliflozin had the highest number of reports (29), followed by canagliflozin (27), emtricitabine/tenofovir (21), and sacubitril/valsartan (21). Dapagliflozin had 16 reports. Reporting odds ratios (95% confidence intervals) for empagliflozin, canagliflozin, and dapagliflozin were 29.7 (20.5-43.1), 28.6 (19.5-42.1), and 19.7 (12.0-32.3), respectively. In rats infused with phlorizin, a typical inhibitor of sodium-glucose cotransporters (SGLTs), increases were observed in fractional glucose excretion, creatinine clearance, and the renal clearance of lithium. The plasma concentration of creatinine remained unchanged, while that of lithium decreased. Renal glucose excretion in rats-administered phlorizin correlated with creatinine clearance (r = 0.859).

Conclusion: These results suggest that SGLT2 inhibitors may increase renal clearance of creatinine or drugs.