1. The present study evaluates which factors should be incorporated into a simplified approach to reasonably predict CYP3A-mediated drug–drug interaction (DDI) at an early drug discovery stage.
1 The effect of 100 μm (20 μg ml−1) of D,L-carnitine was studied on the isolated heart of the rat subjected to 30 min of low flow ischaemia followed by reperfusion. 2 In untreated hearts (n = 30) ischaemia produced an almost total loss of contractility (P < 0.05 compared with non-ischaemic time control) which was accompanied by an increase in resting tension of approximately 235% (P < 0.05). Ventricular arrhythmias developed during ischaemia in 100% (P < 0.05) of untreated hearts studied. Following reperfusion, untreated hearts recovered 16.3% of contractile function and demonstrated a 60% elevation in resting tension. The incidence of reperfusion-associated ventricular fibrillation was 60%. 3 Carnitine treatment produced no effect on either the contractile depression or the elevation in resting tension during ischaemia but did significantly decrease the incidence of arrythmias at the termination of ischaemia to 63.3% (n = 30, P > 0.05). In the presence of carnitine, contractile recovery at the end of reperfusion was significantly increased to 30.2% (n = 10, P < 0.05) and the elevation in resting tension was decreased to 30% (n = 10, P > 0.05). The incidence of ventricular arrhythmias during reperfusion was significantly reduced by carnitine. 4 Two populations of mitochondria, subsarcolemmal (SLM) and interfibrillar (IFM) isolated at the end of the ischaemic period exhibited an overall increase in oxidative phosphorylation rates as well as uncoupled oxygen consumption; both phenomena were more pronounced with IFM. Carnitine generally potentiated this response. A 29% and 38% inhibition in atractyloside-sensitive ADP uptake was observed in SLM and IFM, respectively, following ischaemia, which was partially prevented by carnitine. 5 After 10 min of reperfusion, adenosine diphosphate (ADP) uptake in SLM was further reduced to 55% of control whereas with IFM, uptake was not different from that seen at the end of ischaemia. Mitochondria isolated from hearts after 30 min of reperfusion revealed a significantly depressed oxidative phosphorylation as well as ADP/ATP translocase activity. These defects were partially reversed in hearts perfused with carnitine. 6 Our study demonstrates that D,L-carnitine protects the rat isolated heart against injury associated with ischaemia and reperfusion through a mechanism associated with improved mitochondrial function.
Recent studies have demonstrated that the negative chronotropic and inotropic responses of the heart to cholinergic muscarinic receptor stimulation are strikingly enhanced with aging in the rat model. The present study investigated the electrophysiological basis of this phenomenon by determining the effects of a muscarinic receptor agonist, carbachol, on transmembrane action potential parameters in right atrial tissue and right ventricular free wall preparations from adult (6–8 months old) and aged (26–28 months old) Fischer 344 rats. In addition, the effect of carbachol on atrioventricular conduction time (AVT) was determined in isolated perfused beating hearts. The results showed the following. The baseline maximum diastolic potential (MDP: adult, −76.4 ± 1.8 mV; aged, −66.8 ± 1.5 mV; p < 0.05; n = 5) but not the action potential duration measured at 95% repolarization (APD 95 : adult, 40.0 ± 5.0 ms; aged, 47.4 ± 6.7 ms; n = 5) differed significantly in aged compared with adult atrium. No significant age-related difference was evident in baseline MDP measured in ventricular epicardium (adult, −69.8 ± 0.5 mV; aged, −69.0 ± 1.1 mV; n = 6) or endocardium (adult, −72.5 ± 1.4 mV; aged, −73.0 ± 1.2 mV; n = 6). The baseline action potential duration measured at 50% repolarization (APD 50 ) differed significantly with age in ventricular endocardium (adult, 11.6 ± 2.2 ms; aged, 23.0 ± 4.6 ms; p < 0.05; n = 6) but not in epicardium (APD 50 : adult, 8.1 ± 0.4 ms; aged, 13.0 ± 2.3 ms; n = 6). Superfusion with carbachol (0.1 nM – 10 μM) resulted in concentration-dependent hyperpolarization of MDP in atrium; the magnitude of hyperpolarization differed significantly with age (2.5-fold higher in the aged; p < 0.05; n = 5). Carbachol caused concentration-dependent shortening of APD 50 ; this effect differed significantly with age in the ventricle (2-fold greater in the aged; p < 0.05; n = 6) but not in the atrium. Carbachol prolonged the AVT in atrial-paced (240 beats/min) hearts; the magnitude of carbachol-induced increase in AVT did not differ significantly with age. These results are consistent with the possibility that in the aging heart, greater hyperpolarization at the level of the right atrium (likely involving pacemaker cells) and greater shortening of APD 50 at the level of ventricular myocytes may contribute to the enhanced cholinergic-triggered bradycardia and negative inotropic response, respectively.Key words: aging heart, action potential, cholinergic responses, carbachol.
Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV.
Abstract Background Few large-sample studies in China have focused on the early survival of dental implants. The present study aimed to report the early survival rates of implants and determine the related influencing factors. Methods All patients receiving dental implants at our institution between 2006 and 2017 were included. The endpoint of the study was early survival rates of implants, according to gender, age, maxilla/mandible, dental position, bone augmentation, bone augmentation category, immediate implant, submerged implant category, implant diameter, implant length, implant torque, and other related factors. Initially, SPSS22.0 was used for statistical analysis. The Chi-square test was used to screen all factors, and those with p < 0.05 were further introduced into a multiple logistic regression model to illustrate the risk factors for early survival rates of implants. Results In this study, we included 1078 cases (601 males and 477 females) with 2053 implants. After implantation, 1974 implants were retained, and the early survival rate was 96.15%. Patients aged 30–60 years (OR 2.392), with Class I bone quality (OR 3.689), bone augmentation (OR 1.742), immediate implantation (OR 3.509), and implant length < 10 mm (OR 2.972), were said to possess risk factors conducive to early survival rates. Conclusions The early survival rate of implants in our cohort exceeded 96%, with risk factors including age, tooth position, bone quality, implant length, bone augmentation surgery, and immediate implantation. When the above factors coexist, implant placement should be treated carefully.
Anagrelide (ANA) is a phosphodiesterase 3A (PDE3A) inhibitor, commonly prescribed for essential thrombocythemia. It also functions as a molecular glue, inducing complex formation between PDE3A and Schlafen 12. This association either triggers apoptosis or inhibits proliferation in tumor cells, supporting its use in cancer therapy. Conventionally administered orally, ANA undergoes rapid metabolism and elimination, resulting in a short drug exposure time at the site of action. Here, we explored the pharmacokinetic profile of a subcutaneously (SC) injected ANA formulation in Sprague-Dawley rats by quantifying plasma ANA and metabolite concentrations using liquid-chromatography–tandem mass spectrometry. We further evaluated the in vivo tumor regression efficacy of orally and SC administered ANA in a patient-derived gastrointestinal stromal xenograft mouse model – UZLX-GIST2B – characterized by a KIT exon 9 driver mutation. The SC ANA exhibited extended-release plasma concentration–time profiles compared to intravenous and oral administrations. After a single administration in rats, plasma concentrations of ANA were detected up to 56 days later, and ANA metabolites up to 30 days later. The SC formulation also significantly reduced tumor volumes and demonstrated dose-dependent histological responses, nearly eradicating tumor tissue in 11 days with the highest dose. These findings suggest that the SC slow-release formulation maintains stable drug concentrations during treatment, potentially improving therapeutic efficacy at the target site.
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