建立啮齿类酒精饮用动物模型的影响因素及研究进展

酒精使用障碍(AUD)是威胁人类健康乃至生命的重要因素之一。世界卫生组织数据显示,全球每年因AUD而死亡的人数约330万。AUD已成为一个全球性公共卫生和社会性问题,但其神经行为学机制并未完全阐明。因此,建立有效和可靠的酒精饮用动物模型对AUD机制的探讨非常重要。本文从动物品系和造模方法等方面进行综述,探讨可能对造模结果造成偏差的相关影响因素,以期对AUD的动物行为学研究有所裨益。     

Factors affecting the bioavailability of phenytoin

The bioavailability of seven phenytoin (DPH) formulations, five brands of tablets and two suspensions, was measured in a cross-over study with six healthy volunteers. Single doses of 600 mg of DPH were used and the bioavailability was determined as the area under the serum DPH concentration-time curve (AUC). Highly significant differences between the bioavailability of various products were found. The highest bioavailability was obtained with suspension prepared from the micronized raw material of DPH and the lowest bioavailability (26% of that of the former suspension) with the tablets having the largest particle size of DPH. The in vitro dissolution rate of the products in borate buffer at pH 9 showed a significant (p less than 0.01; r=0.93) correlation with the in vivo bioavailability of the DPH products. In addition to the particle size, several other formulation factors are important for dissolution rate and absorption characteristics of DPH products. The properly performed measurement of the in vitro dissolution rate can be used as a preliminary screening test in predicting the bioavailability of DPH products.     

Factors affecting the pharmacokinetics of nifedipine

Summary The plasma pharmacokinetics of nifedipine and the formation of its metabolites have been studied in volunteers under conditions which would affect the activity of the cytochrome P-450 system.The pharmacokinetics of a 10-mg capsule of nifedipine were not significantly different between smokers and non-smokers of similar age.After pretreatment with cimetidine, which inhibits the activity of cytochrome P-450, the peak plasma concentration and area under the plasma-time concentration curve for nifedipine were increased by a mean 84%. In contrast, pre-treatment with ranitidine which has little effect on cytochrome P-450, did not significantly alter nifedipine pharmacokinetics.Smoking does not contribute significantly to the variability in nifedipine pharmacokinetics. However, the interaction between nifedipine and cimetidine, but not ranitidine, may be of clinical importance.     

Factors affecting the outcome of assisted conception

In order to assess the major biological and clinical factors which influence the outcome of both IVF and GIFT, the results of a large GIFT series performed in this unit have been analysed over a time interval when two different policies have been in force as to the number of oocytes that should be transferred. The reason for using GIFT data, as opposed to IVF, is simply because it is more difficult to adversely affect the outcome of GIFT treatment, as opposed to IVF, and hence this allows more critical appraisal and interpretation of results. The GIFT series to be described was conducted between March 1986 and October 1987, when a flexible policy on the number of oocytes for transfer was in operation. Since then a fixed policy has been in force at the request of the Hospital's Ethics Committee and the Voluntary Licensing Authority (now the Interim Licensing Authority), whereby three, or exceptionally four, oocytes are transferred irrespective of individual patient's circumstances because of concern about the relative risk and sequelae of multiple pregnancy and selective reduction of pregnancy. I still believe, however, that some infertile couples have a lower chance of pregnancy with assisted, or natural conception and also a lower risk of multiple pregnancy and that it is therefore important to assess the biological and clinical factors influencing fecundity in order to formulate appropriate treatment policies.     

Factors affecting grip strength testing

The rodent grip strength test was developed decades ago and is a putative measure of muscular strength. This test has been included in the functional observational battery (FOB) to screen for neurobehavioral toxicity, and changes in grip strength have been interpreted as evidence of motor neurotoxicity. Despite its widespread use, questions remain about what the grip strength test actually measures. In this study, potential confounders of the grip strength test were identified and tested, including operational parameters, disruption of peripheral sensory function and changes in body weight. Operational parameters (sampling rate, system type and trial angle but not trial speed) had dramatic effects on grip strength data. Doxorubicin (DX, 10 mg/kg iv) was used to cause sensory impairment. It decreased forelimb and hindlimb grip strength (by 27% and 32%, respectively, compared with controls), an effect that was correlated with degeneration of peripheral and central sensory components (distal tibial and sural nerves, dorsal funiculus of the spinal cord and dorsal, but not ventral, spinal roots). Feed restriction-induced loss of body weight (26% compared with controls) and muscle mass (20% compared with controls) reversibly decreased both forelimb and hindlimb grip strength (18% and 17%, respectively, compared with controls). Ignoring these confounding factors could potentially lead to increased data variability and inconsistency within single studies, across studies and in historical control data sets. To assist in data interpretation and evaluation of grip strength results, it is suggested that exact conditions of application of the test be reported in greater detail. Furthermore, given that the grip strength test can be influenced by factors other than true muscular strength, use of the term grip performance is proposed to better reflect the apical nature of this test.     

Factors affecting the absolute bioavailability of nifedipine.

1. Nifedipine was administered to eight volunteers (seven Caucasian, one East Asian of Chinese origin) as a single 10 mg capsule orally and as 2.5 mg intravenously. The pharmacokinetics were determined under fasting conditions and following 200 ml double strength grapefruit juice taken orally both 2 h before and at the time of dosing. 2. In a separate study, the pharmacokinetics of nifedipine were defined in eight South Asian volunteers (with both parents originating from the Indian subcontinent) following 10 mg nifedipine orally and 2.5 mg intravenously. 3. The administration of grapefruit juice did not alter the pharmacokinetics of intravenous nifedipine, but resulted in a significantly increased area under the plasma concentration-time curve (AUC) (191 +/- 59 c.f. 301 +/- 95 ng ml-1 h, P < 0.05) and bioavailability (0.63 +/- 0.18 c.f. 0.86 +/- 0.15, P < 0.05) following oral nifedipine. The elimination half-life was unchanged by administration of grapefruit juice and there was no evidence of decreased formation of the nitropyridine first-pass metabolite. 4. The AUC of nifedipine after intravenous administration was significantly higher in South Asian subjects than in Caucasians (146 +/- 39 c.f. 74 +/- 18 ng ml-1 h, P < 0.002). This was due to a lower systemic clearance in the South Asians which was 50% of that in the Caucasians. The half-life was markedly prolonged in South Asians (4.1 +/- 1.9 c.f. 1.7 +/- 0.5 h, P < 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)     

Factors in cobra venoms affecting the complement system

Three constituents of cobra venoms are known to interact with complement: the “cobra venom factor” (CVF), a high-molecular-weight factor (H-CoF), and the “cobra inhibitor” (CI). CVF and CI act by forming complexes with certain complement components. In doing so, CVF replaces an endogenous component, C3b, and hence activates the alternative pathway and leads to C3 (and C5) consumption. In contrast, CI competes with essential complex formations of endogenous components and thus inhibits various reactions. Both, CVF and CI, are useful tools to study the biochemistry of complement and its pathophysiological involvements. The effect of H-CoF on complement has not yet been studied in detail.     

Factors affecting microcin E492 production

The production of the antibiotic polypeptide microcin E492 by Klebsiella pneumoniae RYC492 has been studied in respect to the composition of the culture medium. The nature of both the carbon and nitrogen sources had a dramatic effect on the levels of the microcin detected in the supernants of the liquid cultures. Gluconeogenic precursors such as lactate or citrate led to microcin titers 10 to 100 fold higher than those obtained with glucose. However, neither glycerol nor cAMP stimulated the production, ruling out a typical type of catabolic repression by glucose. Limitation of growth by phosphate or nitrogen led to a marked decrease in production. Treatment with mitomycin C did not result in an enhancement of microcin levels.     

Factors affecting drug administration in hospital

Summary Factors affecting drug administration to 500 consecutive patients in a gynaecological ward have been investigated. Females undergoing surgery received more drugs per patient than non-operated subjects. The numbers of concurrent diseases, the ages of the patients and the lengtht of stay in hospital were associated with increased administration of drugs. The majority of drugs in regular use were administered for infections, whereas analgesics, laxatives and tranquillizers were most often given for occasional use. The majority of patients received several drugs simultaneously. The results have demonstrated that concurrent administration of many drugs is an essential part of the hospital care of patients, rendered necessary by the genuine requirements of treatment.     

Factors affecting solubilized dopamine-sensitive adenylate cyclase

Bovine striatal adenylate cyclase was solubilized with sodium cholate and assayed for its responsiveness to a variety of agents. Magnesium ions (0–20 mM), guanylyl-imidodiphosphate (10–50 μM), and striatal lipids were effective in increasing enzyme activity. The adenylate cyclase could be stimulated by dopamine, and neuroleptic drugs inhibited the effect of dopamine (50 μM) with potencies that paralleled their clinical potencies. The ic₅₀ values for spiroperidol, haloperidol and chlorpromazine were 0.2, 3 and 500 nM respectively.     

Factors affecting tryptophan-induced hypoglycaemia in rats

The mechanisms whereby tryptophan administration leads to hypoglycaemia in some groups of rats but not others have been investigated. Animals insensitive to tryptophan are rendered responsive by adrenalectomy. This effect is reversed by steroid replacement. Turnover studies with [2-³H]glucose show that hypoglycaemia in sensitive animals is associated with a decrease in glucose synthesis. Tryptophan administration causes a marked and sustained increase in plasma glucagon concentrations in all animals. The locus of the inhibition of gluconeogenesis in tryptophan-sensitive animals is the reaction catalysed by phosphoenolpyruvate carboxykinase. The sensitivities to tryptophan of gluconeogenesis in isolated hepatocytes from normal and adrenalectomized animals were similar. Cells from chronically streptoxotocin-diabetic animals required higher concentrations of the amino acid for the same effect. These results are discussed in relation to previous discrepancies in the literature, and a unifying hypothesis for tryptophan-induced hypoglycaemia is proposed.