Disposition of a silicon-containing amide, an inhibitor of acyl-CoA: cholesterol acyltransferase, in dog and rat

The pharmacokinetics of 3-(decyldimethylsilyl)-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide (DMPP), an inhibitor of acyl-CoA:cholesterol acyltransferase, have been studied in the dog and the rat using 14C and 3H dual-labelled drug. In both species, gastrointestinal absorption of DMPP was slow and incomplete, amounting to approximately 20 per cent of the oral dose given in corn oil. In the rat, use of PEG-400, Tween 80, ethanol, and aqueous CMC as vehicles resulted in similar or lower absorption than corn oil. Absorbed DMPP was rapidly and extensively distributed to body tissues. Data from the rat showed highest concentrations of radioactivity in the liver and spleen, while concentrations in the adrenals and lung also markedly exceeded circulating radioactivity levels. In both dog and rat. DMPP was completely metabolized prior to excretion. The routes of biotransformation involved hydrolysis of the amide bond, oxidation of the phenyl ring, and degradation of the decyldimethylsilyl propanoyl moiety. The metabolites of DMPP were excreted slowly, predominantly in the faeces. The elimination half-life of 14C was 105 h in the dog and 83 h in the rat, while that of 3H was approximately 32 h in both species.     

妇幼保健院医疗设备配置的思考和探讨

妇幼保健院运营的模式,服务的对象都有别于综合性医院。通过对设备使用效益的调查、分析,提出妇幼保健院医疗设备的配置,应符合本院的特点。配置应遵循:适用性、特色性、经济性、先进性,不可盲目求新、求全,避免设备使用的低效益。     

Human dolasetron pharmacokinetics: II Absorption and disposition following single-dose oral administration to normal male subjects

Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapyinduced nausea and vomiting. A previous study demonstrated that following intravenous administration to healthy male subjects, dolasetron disappeared extremely rapidly from plasma, and less than 1 per cent of the dose appeared in the urine. A major plasma metabolite, reduced dolasetron, peaked rapidly in the plasma. In this study, dolasetron was administered orally to healthy male subjects at doses ranging from 50 to 400 mg (mesylate monohydrate). Plasma concentrations of dolasetron were low and sporadic, and there was little excreted in urine; this prevented dolasetron pharmacokinetic analysis. Reduced metabolite concentrations peaked rapidly, with a median value of 1.00 h. The median terminal disposition half-life was 7.80 h. Median values for fraction of dose excreted in urine and renal clearance were 22.2 per cent and 2.56 ml min^?1 kg^?1. Whereas areas under the plasma concentration—time curves were proportional to dose, renal clearance increased with dose (p < 0.05). However, given dose proportionality to AUC, this is probably of little therapeutic consequence. Since reduced dolasetron has significant anti-emetic activity in the ferret model, it appears that this metabolite may play a significant role in pharmacodynamic activity.     

高三学生时间管理倾向、自尊与成就动机的关系研究

目的探讨时间管理倾向、自尊与成就动机的关系。方法以青少年时间管理倾向量表（ATMD）、成就动机测量表（AMS）和自尊量表（SES）对高三151名文、理和艺术学生进行了研究。结果①高三学生在自尊上有显著性别差异（P〈0.05）;②高三文、理科和艺术学生在时间价值感（0.020）、自尊水平（0.017）上差异显著（P〈0.05）;③时间管理倾向各因子与自尊、自尊与成就动机两因子、时间管理倾向各因子与成就动机因子（时间价值感与避免失败动机除外）均有显著性相关（P〈0.05）。4时间管理总分和自尊对成就动机有显著的预测。结论高三学生时间管理倾向、自尊与成就动机三者密切相关。     

Disposition in mice of 7-hydroxystaurosporine,a protein kinase inhibitor with antitumor activity

UCN-01, a hydroxylated derivative of staurosporine, was selected for study because of its promising antitumor activity. For mice dosed intravenously, subcutaneously, or by oral gavage with this compound, the maximum tolerated doses (MTD) were 20, 10, and >100 mg/kg, respectively. UCN-01 was stable in mouse and dog plasma, but in human plasma it was converted to a metabolite in a process not inhibited by standard protease and esterase inhibitors. Following n intravenous dose of 10 mg/kg UCN-01, the half-lives for the initial (t _1/2) and terminal (t _1/2) exponential phases of elimination were 10 and 85 min, respectively; the area under the plasma concentration-time curve (AUC value) was 117 g min ml^–1. In mice dosed by oral gavage with 10 mg/kg, the calculated value for the half-life of the elimination phase was 150 min. The AUC value was 15 g min ml^–1, giving a value for bioavailability of 13%. After subcutaneous dosing with 10 mg/kg, the calculated values for half-lives for the distribution and elimination phases were 23 and 130 min, respectively; the AUC value was 113 g min ml^–1. Since this value is equivalent to that obtained for intravenous dosing, administration of UCN-01 by the subcutaneous route may be an alternative to intravenous dosing in preclinical and clinical trials.This work was supported by contract NO1-CM-27710 (National Cancer Institute, National Institutes of Health, Department of Health and Human Services)     

Epidemiologie, Risikofaktoren und Pathologie des Rektumkarzinoms

Zusammenfassung Das Rektum ist nach dem Kolon die zweithäufigste Lokalisation eines Karzinoms im Gastrointestinaltrakt. Männer sind etwa 1,5-mal häufiger betroffen als Frauen. Das mediane Erkrankungsalter liegt bei 60–65 Jahren. Umweltfaktoren und genetische Faktoren beeinflussen das Risiko für die Entstehung von Rektumkarzinomen. Zu den wichtigsten Risikofaktoren gehören der Konsum von Alkohol und Tabak sowie eine fleischreiche, balaststoff-, gemüse- und obstarme Ernährung. Weitere Risikofaktoren sind ein Diabetes mellitus und eine vorangegangene Cholezystektomie oder eine Strahlentherapie des Beckens. Protektiv können regelmäßige körperliche Betätigung, die Einnahme nichtsteroidaler Antirheumatika und bei postmenopausalen Frauen eine Hormonersatztherapie wirken.Die histopathologische Aufarbeitung von operativ entfernten Rektumkarzinomen umfasst die Evaluierung der Infiltrationstiefe (pT-Kategorie), des Nodalstatus (pN-Kategorie), der Tumordifferenzierung (Grading) und der Resektionsränder. Dabei ist nicht nur der orale und aborale Absetzungsrand, sondern auch der zirkumferenzielle Absetzungsrand zu beurteilen. Bei neoadjuvant therapierten Karzinomen ist die standardisierte Evaluation der therapiebedingten Tumorregression vorzunehmen. Bei histologischem Karzinomnachweis in endoskopisch resezierten Polypen ist die Beurteilung prognoserelevanter histologischer Faktoren notwendig, um zu klären, ob eine chirurgische Resektion notwendig ist.     

Body mass index is a predictor of discharge to a postacute care facility following total shoulder arthroplasty

BackgroundThe purpose of this study is to evaluate the effect of body mass index (BMI) on discharge to a postacute care (PAC) facility following elective total shoulder arthroplasty (TSA).MethodsThe National Surgical Quality Improvement Program database was queried to identify adult patients (>18 years old) who underwent inpatient TSA for primary osteoarthritis between 2005 and 2018. Hemiarthroplasty, revision TSA, trauma indications, and outpatient procedures were excluded. Patient and perioperative data were identified. Univariate analysis and multivariate logistic regression were used to assess the relationship between BMI and discharge to PAC facilities.ResultsA total of 10,198 patients with a primary TSA were identified. The majority (93%) of patients were discharged home vs. 7% to PAC facilities. Patients discharged to PAC had significantly higher mean BMI (P = .006). After controlling for demographic and comorbid factors, BMI was the only modifiable risk factor that was independently associated with an increased risk of discharge to a PAC. For every increase in BMI point, there was an increased risk of discharge to a PAC by 2.9% (odds ratio [OR] 1.029, confidence interval [CI] 1.016-1.041, P < .001). Additional covariates associated with PAC discharge were older age (OR 1.113, CI 1.099-1.127, P < .001), female gender (OR 3.037, CI 2.489-3.705, P < .001), and dependent functional status (OR 8.322, CI 5.544-12.492, P < .001).ConclusionMost patients undergoing TSA were discharged home following surgery. While age, sex, and functional status also affect disposition, elevated BMI is the only modifiable risk factor that independently predicts PAC discharge. Consideration of patient BMI prior to elective TSA may greatly improve discharge planning and management of patient expectations.     

Pharmacokinetics of 4′-cyano-2′-deoxyguanosine,a novel nucleoside analog inhibitor of the resistant hepatitis B virus,in a rat model of chronic kidney disease

IntroductionThe novel nucleoside analog, 4′-cyano-2′-deoxyguanosine (CdG), possesses inhibitory activity against both the wild-type and resistant hepatitis B virus. Since the dosage of the currently available nucleoside analog preparations needs to be adjusted, depending on renal function, we investigated the effect of renal dysfunction on the pharmacokinetics of CdG in a rat model of chronic kidney disease (CKD).MethodsCKD model rats were either intravenously or orally administered CdG at a dose of 1 mg/kg. The concentration of CdG in plasma, organs (liver and kidney) and urine samples were determined by means of a UPLC system interfaced with a TOF-MS system.ResultsFollowing intravenous administration, the plasma retention of CdG was prolonged in CKD model rats compared to healthy rats. In addition, the clearance of CdG was well correlated with plasma creatinine levels in CKD model rats. Similar to the results for intravenous administration, the plasma concentration profiles of CdG after oral administration were also found to be much higher in CKD model rats than in healthy rats. However, the results for the organ distribution and urinary excretion of CdG, the profiles of which were similar to that of healthy rats, indicated that CdG did not accumulate to a significant extent in the body.ConclusionThe extent of renal dysfunction has a direct influence on the pharmacokinetics (plasma retention) of CdG without a significant accumulation, indicating that the dosage of CdG will be dependent on the extent of renal function. .     

The metrics of MWCNT-induced pulmonary inflammation are dependent on the selected testing regimen

Convincing evidence suggests that high-surface-activity nano-materials, such as MWCNT, exert two modes of action (MoA), in which one appears to be related to surface activity/area and occurs concurrent with deposition, and the other is related to cumulative lung burden. Pulmonary inflammation induced by the latter mode appears to be dependent on cumulative volumetric lung burden and on whether the accumulated particle displacement volume within the pool of alveolar macrophages is above or below the kinetic lung overload threshold. However, the relative importance and effect of each MoA are still controversial. In addition, the test protocol variables, which may predetermine the leading MoA, have not yet received increased attention. This study compares the respective outcome of previously published repeated-exposure inhalation studies with MWCNT (Nanocyl and Baytube) in rats. Modeling procedures were performed to compare post hoc the equivalence of empirical and modeled outcomes, including critical protocol variables. This comparison provided compelling evidence that the accumulated retained particle displacement volume was the most prominent unifying denominator linking the pulmonary retained volumetric particle dose to inflammogenicity and toxicity. However, conventional study designs may not always be appropriate to unequivocally dissociate the surface area/activity-related acute adversity from the cumulative retention volume-related adversity. Thus, in the absence of adequately designed studies, it may become increasingly challenging to differentiate substance-specific deposition-related acute effects from the more chronic retained cumulative dose-related effects. In summary, this analysis of existing data supports the conclusion that both the deposition and retention-related effects need to be judiciously dissociated to better understand the MoA of heightened concern. This exercise supports the conclusion that hypothesis-based computational study design delivers the highest degree of scientifically important information and may further reduce the number of experimental animals in repeated-exposure inhalation studies with low-toxicity, biopersistent, poorly soluble granular particles.