Hepatocyte isolation from pig livers after warm ischaemic injury

Abstract Hepatocyte cultures have been used extensively for a wide variety of physiological, pharmacological and experimental studies. The warm ischaemic period before isolation is kept to a minimum to achieve a high yield of cells isolated and a good viability for culture. We have recently introduced a new concept of liver resuscitation after warm ischaemia that is based on a 3-h reperfusion period with an improved perfusate and simultaneous dialysis. In this study, we applied the new technique for hepatocyte isolation from livers subjected to 80 min of complete ischaemia at 37 °C. Cell yield was improved by a resuscitating perfusion from 58% to 73% and viability from 39% to 76%.     

Effects of Carbamazepine on Murine Humoral and Cellular Immune Responses

Summary: Oral administration of carbamazepine (CBZ)(15, 10, or 5 mg/kg) to mice significantly decreased both humoral and cellular immune responses evaluated by enumeration of direct and indirect plaque-forming spleen cells (PFC) and delayed–type hypersensitivity reaction (DTH) against sheep red blood cells (SRBC) as compared with those observed in normal control animals. Moreover, spleen T cells obtained from CBZ–treated donor mice were capable of decreasing both PFC and DTH responses of normal spleen cells transferred into lethally irradiated recipient animals. The immunodepressor effect of CBZ was observed even though administration of CBZ induced augmentation of spleen cellularity.     

Anticonvulsant Activities of 4–Bromobenzaldehyde Semicarbazone

Summary: Some of the properties of 4–bromobenzalde-hyde semicarbazone (compound IV), a prototype molecule of a new class of anticonvulsants, aryl semicarbazones, are described. Compound IV demonstrated activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ) tests in mice, with low neurotoxicity. When given orally to rats, it displayed high potency in the MES test and very low neurotoxicity, resulting in a high protective index (PI). Compound IV displayed no proconvulsant properties, and development of rapid tolerance was not noted. When administered intraperitoneally (i.p.) at doses of 100, 300, or 600 mg/kg to rats, compound IV had no effect on levels of γ-aminobu-tyric acid (GABA) or on GABA-T activity in whole brain. When tested in vitro, compound IV had no effect on rat brain GABA-T at a drug concentration of 100 μM. Although the activities of certain drug-metabolizing enzymes were increased after oral administration of compound IV to rats, these effects were less prominent than those of phenytoin (PHT) and carbamazepine (CBZ). The principal mode of action of compound IV does not appear to be an interaction with the GABA_A receptor complex, and other mechanisms, involving excitatory amino acid neurotransmission, will have to be considered in future investigations of the anticonvulsant activity of this compound.     

Model Features of a Cardiac lontophoretic Drug Delivery Implant

Pharmaceutical Research -     

Cyclic hormonal replacement therapy after the menopause: Transdermal versus oral treatment

Summary In an open, randomized, comparative, between-patient trial, 45 postmenopausal women were treated for 4 months with cyclical transdermal oestradiol 0.05 mg per day or oral conjugated equine oestrogens 0.625 mg per day, in both cases, plus, medroxyprogesterone acetate 10 mg per day on the last 8 days of each cycle. Similar relief from postmenopausal symptoms was obtained with both treatments. Post-treatment histological evaluation of the endometrium did not reveal neoplastic or hyperplastic change in any patient.Early follicular-phase plasma oestradiol levels were observed only after transdermal oestradiol. There was a significant reduction in serum total cholesterol and LDL cholesterol in both treatment groups, with no difference between treatments, whereas serum triglyceride levels were decreased only by transdermal oestradiol. Plasma calcium and phosphorus fell significantly and serum intact parathyroid hormone rose significantly, with no difference between the therapies. No significant changes were observed in clotting factors.Transdermal oestradiol appears to be an effective and safe hormonal replacement therapy, and this route of administration may be responsible for the more useful action of the drug on serum lipids and plasma oestradiol levels.     

When poor solubility becomes an issue: From early stage to proof of concept

Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8–12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.

The conference focused specifically on the impact of compounds with poor solubility on analytical evaluation, prediction of oral absorption, substance selection, material and formulation strategies and development. The existing tools and technologies, their potential utilization throughout the drug development process and the directions for further research to overcome existing gaps and influence these drug characteristics were discussed in detail.     

User satisfaction with a real-time automated feedback system for general practitioners: a quantitative and qualitative study.

OBJECTIVE: The GRIF automated feedback system produces real-time comments on the appropriateness of diagnostic tests ordered by general practitioners (GPs) based on recommendations from accepted national and regional practice guidelines. We investigated the experiences of GPs with this system and, more specifically, with the recommendations produced by the system as well as their views on using this system in daily practice. SETTING: We tested the GRIF system in an experiment in a laboratory setting and in a daily practice trial. STUDY PARTICIPANTS: General practitioners. INTERVENTION: In the laboratory experiment, GPs used the GRIF system to assess the appropriateness of 30 request forms. Each of the GPs was confronted with requests they had submitted to the diagnostic unit of the hospital in the past. In the field trial, the GRIF system was applied during patient consultations for 1 year. MAIN OUTCOME MEASURES: We measured GPs' satisfaction with the system using a questionnaire, and also conducted group discussions (in the laboratory experiment) and in-depth interviews (in the field trial) to elicit GPs' opinions of and experiences with the system. In addition, we explored GPs' reasons for not accepting the comments offered by the GRIF system. RESULTS: The results show that the GPs in the laboratory experiment had more positive attitudes towards the system compared with participants in the field trial. All discussion groups and most of the GPs in the field trial regarded receiving the immediate feedback during the test ordering process as an important advantage. The most frequently mentioned reason to reject the recommendation was disagreement with the content and/or the recommendations in the practice guidelines. CONCLUSION: Apart from securing agreement on guideline content, a prerequisite for using GRIF in daily practice on a large scale is that more attention is paid to promotion of the guidelines and their adoption, and stimulation of a positive attitude towards the practice guidelines among the users.     

东乡族及回族吸毒人群性激素水平的变化

本文测定了东乡族、回族吸毒者血清睾酮及促黄体生成素含量，发现血清睾酮含量吸毒组（ｎ＝４０，Ｘ＝３４０．１４±１０１．４９ｎｇ／ｄＬ）显著低于非吸毒组（ｎ＝４２，Ｘ＝４４４．５０±９８．８３ｎｇ／ｄＬ），Ｐ＜０．０１。未观察到ＬＨ含量的改变。戒毒期２０日以内组血清睾酮含量（ｎ＝１６，Ｘ＝２９７．９３±７８．２２ｎｇ／ｄＬ），低于戒毒期２０～６０日组（ｎ＝１７，Ｘ＝３８６．２９±８９．４５ｎｇ／ｄＬ），Ｐ＜０．０１。询问１０３名吸毒者，２月后性欲下降２５人（２４．２７％），增强２人（１．９４％），无变化１３人（１２．６２％），不愿回答者６３人（６１．１７％）。吸毒影响性功能，损害性健康。     

对曾氏推导的药物蛋白结合率公式的修正

对曾氏推导的药物蛋白结合率公式的修正娄建石（天津医科大学药理教研室，天津３０００７０）测定药物蛋白结合率是药物代谢动力学研究中的重要内容之一。曾衍霖教授根据国外文献推导出药物蛋白结合率公式（１），为这方面的研究提供了很好的计算依据。本文作者在计算药物...     

Oral self-administration of etonitazene in rhesus monkeys: Use of a fading procedure to establish etonitazene as a reinforcer

The establishment of orally delivered etonitazene (a potent opioid) as a reinforcer, was studied in eight rhesus monkeys. Initially, when given concurrent access to 2.5 μg/ml etonitazene and the water vehicle, five of the monkeys rejected the drug, whereas the other three monkeys consumed more drug solution than water. The five monkeys that rejected the drug solution underwent an acquisition phase to establish the drug as a reinforcer. A fading procedure was used to transfer control of responding from a 2% (wt/vol) ethanol solution to a 2.5 μg/ml etonitazene solution. Initially, responding was maintained by contingent deliveries of 2% ethanol. Next, across blocks of six or more sessions, increasing amounts of etonitazene were added in steps to the 2% ethanol solution. Subsequently, the 2% ethanol solution was decreased in steps to zero, leaving only the 2.5 μg/ml etonitazene present. When the fading procedure was completed, dose of etonitazene was varied by increasing the volume delivered, first under fixed ratio (FR 4) and then under an FR 8 reinforcement schedule. The same dose manipulations were made with the three monkeys who did not undergo the fading procedure because they preferred etonitazene over water when first tested. Etonitazene was established as a reinforcer for six of the eight monkeys because drug deliveries exceeded vehicle deliveries across a range of drug doses.