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Introduction: This study aimed to investigate the effect of mirabegron, a β3‐adrenoceptor agonist with widespread clinical use for treating overactive bladder disease, on isolated healthy human ureter strips. Materials and Methods: This was a prospective study employing a series of in vitro organ bath experiments using ureteral tissues of kidney grafts from 10 healthy donors. The ureteral strips were subjected to cumulative mirabegron concentrations (10−9–10−4.5 M). Effects on frequency or amplitude of spontaneous, 10 mM KCl‐ or EFS‐induced contractions were evaluated. Results: Mirabegron decreased the frequency of spontaneous ureteric contraction in a concentration‐dependent manner. Statistically significant decrease in the frequency of spontaneous contraction was observed at 10−8–10−4.5 M. In 10 mM KCl medium, statistically significant change in frequency was observed at 10−9–10−4.5 M. Statistically significant decrease in the amplitudes of spontaneous contraction was observed at 10−7–10−4.5 M. In a 10 mM KCl medium, statistically significant change in amplitudes was observed at 10−8–10−4.5 M. Conclusions: Mirabegron reduced the amplitude and frequency of human ureter activity in in vitro organ bath studies. This effect was achieved in a dose‐dependent manner on isolated tissue strips. Although monotherapy with mirabegron remains uncertain, this study has the potential to elucidate the mechanism underlying the effectiveness of mirabegron, particularly in combination therapy for ureteral stones. [ABSTRACT FROM AUTHOR]

Introduction Despite improvements in the treatment strategies to manage sepsis, it is still a major cause of mortality and morbidity, especially in the intensive care units with very high cost [...], Tumor necrosis factor-alpha (TNF-[alpha]) is a pivotal mediator that triggers inflammatory process, oxidative stress, and multiple organ injury in sepsis. We investigated the effects of infliximab on survival, mesenteric artery blood flow (MBF), vascular reactivity, and oxidative and inflammatory injuries in cecal ligation and puncture (CLP)-induced sepsis. Wistar rats were divided into Sham, CLP, Sham+infliximab, and CLP+infliximab subgroups. Twenty-four hours before the operations, rats were injected intraperitoneally with infliximab (7 mg/kg) or vehicle (saline; 1 mL/kg). Twenty hours after the operations, MBF and phenylephrine responses of isolated aortic rings were measured. Tissue damages were examined biochemically and histopathologically. Furthermore, survival rates were monitored throughout 96 h. Infliximab improved survival, mesenteric perfusion, and aortic function after CLP. Increases of serum AST, ALT, LDH, BUN, Cr, and inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6) induced by CLP were blocked by infliximab. Infliximab prevented malondialdehyde elevations in septic liver, lung, spleen, and kidney tissues, as well as glutathione reductions in septic liver, spleen, and kidney tissues. Protective effects of infliximab on multiple organ damage were also observed histopathologically. Infliximab showed protective effects in sepsis due to its improvement effects on mesenteric perfusion, aortic function, and its anti-inflammatory and antioxidative effects. Key words: infliximab, sepsis, survival, multiple organ dysfunction, vascular reactivity, mesenteric arterial blood flow. Le facteur de necrose tumorale alpha (TNF-[alpha]) constitue dans la septicemie un mediateur pivot du declenchement du processus inflammatoire, du stress oxydatif et provoquant des lesions dans des organes multiples. Nous avons etudie les effets de l&apos;infliximab sur le taux de survie, le flux sanguin arteriel mesenterique (FSM), la reactivite vasculaire ainsi que les lesions oxydatives et inflammatoires dans un modele de septicemie provoquee par l&apos;occlusion et la perforation du cscum (OPC). Nous avons reparti des rats Wistar dans les sous-groupes suivants : << sham >> (intervention factice), OPC, sham+infliximab et OPC+infliximab. Vingt-quatre heures avant l&apos;intervention chirurgicale, nous avons injecte aux rats de l&apos;infliximab (a 7 mg/kg) ou le vehicule (solution saline; 1 mL/kg) par voie intraperitoneale. Vingt heures apres l&apos;intervention chirurgicale, nous avons mesure le FSM et la reaction a la phenylephrine dans des anneaux aortiques isoles. Nous avons etudie les dommages tissulaires a l&apos;aide d&apos;analyses biochimiques et histopathologiques. En outre, nous avons surveille le taux de survie des rats surune periode de 96 heures. Nous avons observe que l&apos;infliximab permettait d&apos;ameliorer le taux de survie, la perfusion mesenterique et le fonctionnement de l&apos;aorte apres l&apos;OPC. L&apos;infliximab permettait d&apos;inhiber l&apos;augmentation des taux d&apos;AST, d&apos;ALT, de LDH, d&apos;azote ureique (BUN), de Cr et de cytokines inflammatoires (TNF-[alpha], interleukine 1-beta et interleukine 6) que provoquait l&apos;OPC. L&apos;infliximab permettait d&apos;empecher la hausse des taux de malondialdehyde dans les tissus hepatique, pulmonaire, splenique et renal septiques, ainsi que la diminution des taux de glutathion dans les tissus hepatique, splenique et renal septiques. Nous avons aussi observe les effets protecteurs de l&apos;infliximab contre des dommages histopathologiques a des organes multiples. Nous avons observe que l&apos;infliximab avait des effets protecteurs contre la septicemie en raison des ameliorations qu&apos;il permettait d&apos;obtenir en matiere de perfusion mesenterique, de fonction aortique ainsi que de ses effets anti-inflammatoires et antioxydants. [Traduit par la Redaction] Mots-cles : infliximab, septicemie, survie, dysfonctionnement d&apos;organes multiples, reactivite vasculaire, flux sanguin arteriel mesenterique.

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BACKGROUND: 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors have several pleiotropic effects, including anti-inflammatory properties, and are reported to improve endothelial functions. Pathophysiologically, acute lung injury (ALI) is caused by a severe inflammatory response and endothelial dysfunction. OBJECTIVE: To investigate the effects of simvastatin (an HMG-CoA reductase inhibitor) on oxidative stress and lung histopathology in 2 murine models of ALI, induced by oleic acid and endotoxin. METHODS: The mice were randomly divided into 2 groups: one received 2 mg/kg/d intraperitoneal simvastatin for 15 days. Then the groups were further divided into 3, which received saline, oleic acid, or endotoxin. Four hours after inducing ALI we obtained lung samples for histopathology analysis, myeloperoxidase, glutathione, and malondialdehyde measurement, and blood samples for malondialdehyde measurement. RESULTS: Endotoxin and oleic acid lung injury increased tissue myeloperoxidase (P .009 for both), decreased tissue glutathione (P = .02 and P = .009, respectively), and increased tissue malondialdehyde (P = .009 for both), compared to the control group. Simvastatin decreased myeloperoxidase only in the oleic acid group (P = .01). Simvastatin increased glutathione (P = .005 and P = .003, respectively) and lowered malondialdehyde in both the endotoxin and oleic acid groups (P = .003 for both). Histopathology revealed that simvastatin protected the lung tissue in both ALI models, but the protection was greater in the endotoxin group. CONCLUSIONS: Pretreatment with simvastatin decreased the severity of ALI in oleic acid and endotoxin ALI models, by decreasing inflammation and oxidative stress. [ABSTRACT FROM AUTHOR]

Aim: The assessment of efficacy should be paralleled with extensive pharmacokinetic parameters, and a valid bioanalytical method is a pre-condition for accurate plasma concentration. Materials & methods: A simple, specific, rapid and sensitive LC-MS/MS method has been developed for quantitative analysis of aprepitant in rat plasma. A C18 column was used as stationary phase and the mobile phase consisted of a mixture of formic acid in water and formic acid in acetonitrile. Quantification was performed using multiple reaction monitoring mode. Results: The selectivity, linearity, accuracy, precision, robustness and ruggedness of the method were evaluated in accordance with bioanalytical method validation guideline of ICH and all results were within the acceptable range. Conclusion: The validated LC-MS/MS method was found to be useful for the quantitative analysis of aprepitant in rat plasma samples.

Objective: To report a case of severe rhabdomyolysis that developed after administration of atorvastatin to a patient receiving regular colchicine treatment., Case Summary: A 45-year-old man with nephrotic syndrome and amyloidosis presented with dyspnea, altered mentation, and severe fatigue. He had been taking colchicine 1.5 mg/day for amyloidosis for 3 years without adverse effects. Atorvastatin 10 mg/day was prescribed for hypercholesterolemia one month prior to admission. After 2 weeks of atorvastatin treatment, he began to experience myalgia and reduced muscle strength. The creatinine and creatine kinase concentrations on admission were 8.1 mg/dL and 9035 U/L, respectively. The patient was diagnosed with rhabdomyolysis with the findings of myoglobinuric, oliguric acute renal failure, and more than 50-fold elevated creatine kinase concentration. His muscle strength improved after withdrawal of atorvastatin and colchicine. However, he died because of nosocomial pneumonia that developed during his hospital stay. The Naranjo probability scale indicated that atorvastatin and colchicine were probable causes of rhabdomyolysis., Discussion: Atorvastatin and colchicine have well-known myotoxic adverse effects. Despite atorvastatin's proven safety, its use with certain drugs, such as colchicine, makes it a potential myotoxic drug. This might be because concomitant administration of P-glycoprotein substrates, such as statins, and colchicine, which is a P-glycoprotein inhibitor, modifies pharmacokinetics by increasing bioavailability and organ uptake of the substrates, leading to more adverse reactions and toxicities., Conclusions: We recommend checking the creatine kinase level one week after prescribing 2 or more potentially myotoxic drugs concomitantly, after dose increase of a myotoxic drug, or after prescribing a new drug to a patient already using other myotoxic agents.