The aim of the present study was to investigate changes in plasma concentrations and tissue distribution of endogenous substrates of organic anion transporting polypeptide (OATP) 1B, hexadecanedioate (HDA), octadecanedioate (ODA), tetradecanedioate (TDA), and coproporphyrin-III, induced by its weak inhibitor, probenecid (PBD), in rats. PBD increased the plasma concentrations of these four compounds regardless of bile duct cannulation, whereas liver-to-plasma (Kp,liver) and kidney-to-plasma concentration ratios of HDA and TDA were reduced. Similar effects of PBD on plasma concentrations and Kp,liver of HDA, ODA, and TDA were observed in kidney-ligated rats, suggesting a minor contribution of renal disposition to the overall distribution of these three compounds. Tissue uptake clearance of deuterium-labeled HDA (d-HDA) in liver was 16-fold higher than that in kidney, and was reduced by 80% by PBD. This was compatible with inhibition by PBD of d-HDA uptake in isolated rat hepatocytes. Such inhibitory effects of PBD were also observed in the human OATP1B1-mediated uptake of d-HDA. Overall, the disposition of HDA is mainly determined by hepatic OATP-mediated uptake, which is inhibited by PBD. HDA might, thus, be a biomarker for OATPs minimally affected by urinary and biliary elimination in rats. 相似文献
Treatment with vitamin K antagonists (VKA) reduces fibrinolytic resistance through the inhibition of thrombin-mediated activation of thrombin activatable fibrinolysis inhibitor (TAFI). Because low-molecular weight heparin (LMWH) is co-administered with VKA during initiation of anticoagulant treatment, we evaluated the effect of dual anticoagulation on fibrinolytic resistance.
Patients and Methods
Two groups of patients were studied: 1) patients on stable warfarin; 2) patients starting oral anticoagulant therapy, who were evaluated during dual anticoagulation and after enoxaparin withdrawal. Only samples with an INR between 2 and 3 were compared. The resistance of clots to t-PA-induced fibrinolysis was evaluated in blood and plasma by thromboelastography (TEG) and turbidimetry, respectively.
Results
In patients on dual anticoagulation, blood fibrinolysis time (TEG) was significantly shorter than in patients on warfarin alone and significantly correlated with LMWH level. The profibrinolytic effect was partly ascribable to a reduction of thrombin-dependent TAFI activation: 1) thrombin and TAFIa generation were significantly reduced by dual anticoagulation; 2) the addition of enoxaparin to warfarin-blood reduced TAFI-mediated fibrinolysis inhibition. Patients on dual anticoagulation also displayed a reduction in clot strength, a phenomenon known to reduce fibrinolytic resistance. The profibrinolytic effect of LMWH co-administration was not seen in plasma, likely because TAFIa generation was below the threshold required to inhibit fibrinolysis.
Conclusions
Co-administration of LMWH in patients under VKA reduces the fibrinolytic resistance of blood clots via TAFI-dependent and TAFI-independent mechanisms. Further studies are warranted to assess the clinical implications of these findings. 相似文献
Significant number of studies has been performed to find alternatives or treatments for diseases of the nervous forum by identifying structures with activity at the central nervous system (CNS). However most of the screenings are usually conducted on an ad hoc basis and not systematically. 相似文献
A balanced translocation t(Y;16)(q11.21;q24) is described ina male with severe oligoasthenoteratozoospermia (OAT). Beforehaving a chromosome investigation, the patient and his partnerhad undergone intracytoplasmic sperm injection (ICSI) treatmentresulting in the birth of a healthy 46,XX child. After detectionof the t(Y;16) translocation, the couple opted for further ICSItreatment, although they were extensively counselled on therisk of having chromosomally unbalanced offspring. This treatmentresulted in a twin pregnancy, one with a 46,XX karyotype andthe other a 46,X,t(Y;16) (q11.21;q24) karyotype, the same asthe father. After an uncomplicated pregnancy two healthy childrenwere born. We conclude that patients with a Y/autosome translocationas a cause of OAT can have chromosomally normal children afterICSI treatment. 相似文献
Drug-induced hyperuricemia and gout present an increasingly prevalent problem in clinical practice. Herein, we review the urate-lowering or urate-raising effects of commonly used agents. We performed a PubMed search using the terms gout, urate, and medication, along with the specific agents/classes described herein. Reports were reviewed until 2022, and original studies were considered if they primarily or secondarily reported the effects of 1 or more drugs on serum urate level. Previous reviews were assessed for references to additional studies that described urate-altering effects of medications. Urate-changing drugs are summarized regarding their magnitude of effect, mechanism of action, and clinical significance. Potentially urate-lowering drugs include angiotensin II receptor blockers, calcium channel blockers, high-dose aspirin and salicylates, some nonsalicylate nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, sodium-glucose cotransporter 2 inhibitors, statins, and fenofibrate. Potentially urate-increasing drugs discussed include diuretics, β-blockers, insulin, pyrazinamide, ethambutol, calcineurin inhibitors, low-dose aspirin, testosterone, and lactate. In patients who have or are at risk for hyperuricemia or gout, an increased awareness of drugs that affect serum urate level may allow for prescribing that effectively treats the indicated problem while minimizing adverse effects on hyperuricemia and gout. 相似文献
Introduction: The unmet need and the growing prevalence of hyperuricemia and its complications worldwide have pushed investigators to identify new agents to manage hyperuricemia.
Areas covered: This review discusses the drugs in preclinical and early clinical trials for hyperuricemia, their mechanisms of action and available results. This article reviews a total of 10 novel agents: i) drugs in Phase II/III trials – arhalofenate (MBX201), AC201, RDEA group of drugs (including lesinurad), tranilast, ulodesine (BCX4208); and ii) drugs in Phase I trials, including levotofisopam, UR1102, KX1151, LC350189 and Marine Active.
Expert opinion: The goal of emerging therapies is to address the unsatisfactory control of serum uric acid in patients with symptomatic hyperuricemia such as those with gout, to provide better tolerability compared to traditional agents and minimize the risk of adverse events, especially in patients with comorbidities and the elderly. Some drugs like arhalofenate, ulodesine (BCX-4208) and lesinurad are in or have completed Phase II and Phase III trials. The growing knowledge about the urate transporters in the kidney have advanced our knowledge of pathophysiology of hyperuricemia and have led to the development of several new potential treatment options. Availability of new drugs will lead to better management and address the unmet need in patients with symptomatic hyperuricemia in the coming years. 相似文献
The aim of this systematic review was to identify high quality randomised controlled trials (RCTs) and to provide an update on the most appropriate surgical treatments for knee cartilage defects.
Methods
Two reviewers independently searched three databases for RCTs comparing at least two different treatment techniques for knee cartilage defects. The search strategy used terms mapped to relevant subject headings of MeSH terms. Strict inclusion and exclusion criteria were used to identify studies with patients aged between 18 and 55 years with articular cartilage defects sized between one and 15 cm2. Risk of bias was performed using a Coleman Methodology Score. Data extracted included patient demographics, defect characteristics, clinical outcomes, and failure rates.
Results
Ten articles were included (861 patients). Eight studies compared microfracture to other treatment; four to autologous chondrocyte implantation (ACI) or matrix-induced ACI (MACI); three to osteochondral autologous transplantation (OAT); and one to BST-Cargel. Two studies reported better results with OAT than with microfracture and one reported similar results. Two studies reported superior results with cartilage regenerative techniques than with microfracture, and two reported similar results. At 10 years significantly more failures occurred with microfracture compared to OAT and with OAT compared to ACI. Larger lesions (> 4.5 cm2) treated with cartilage regenerative techniques (ACI/MACI) had better outcomes than with microfracture.
Conclusions
Based on the evidence from this systematic review no single treatment can be recommended for the treatment of knee cartilage defects. This highlights the need for further RCTs, preferably patient-blinded, using an appropriate reference treatment or a placebo procedure. 相似文献
It is well established that the expression and function of drug transporters at the blood-brain barrier are altered in Alzheimer's disease (AD). However, we recently demonstrated in a mouse model of AD that the expression of key drug transporters and metabolizing enzymes was modified in peripheral organs, such as the small intestine and liver, suggesting that systemic drug absorption may be altered in AD. The purpose of this study was to determine whether the expression of drug transporters in the kidneys differed between 8- to 9-month-old wild-type mice and APPswe/PSEN1dE9 (APP/PS1) transgenic mice, a mouse model of familial AD, using a quantitative targeted absolute proteomics approach. The protein expression of the drug transporters—multidrug resistance-associated protein 2, organic anion transporter 3, and organic cation transporter 2—was upregulated 1.6-, 1.3-, and 1.4-fold, respectively, in kidneys from APP/PS1 mice relative to wild-type mice. These results suggest that in addition to modified oral absorption of certain drugs, it is possible that the renal excretion of drugs that are multidrug resistance-associated protein 2, organic anion transporter 3, and organic cation transporter 2 substrates could be altered in AD. These changes could affect the interpretation of studies conducted during drug development using this mouse model of AD and potentially impact dosage regimens of such drugs prescribed in this patient population. 相似文献