摘要:

Abstract:Deprenyl (selegiline, jumex, eldepryl, movergan) which is closely related to phenylethylamine (PEA) is a drug with a unique pharmacological spectrum.Single dose effects: (a) It is a highly potent and selective inhibitor of B‐type monoamine oxidase (MAO), (b) In contrast to other MAO inhibitors it inhibits the noradrenaline releasing effect of tyramine, is therefore free of the ‘cheese effect’.Multiple dose effects unrelated to MAO inhibition: (a) It enhances superoxide dismutase and catalase activity in the striatum, (b) It facilitates the activity of the nigrostriatal dopaminergic neurones, (c) It prevents age‐related morphological changes in the neurocytes of the substantia nigra.Consequences of multiple dose effects: Compared to salt solution‐treated rats, male rats maintained on (–)deprenyl loose their capacity to ejaculate later on; retain for longer their learning ability; and live longer. Freshly diagnosed Parkinson's patients maintained on (–)deprenyl, require levodopa later than their placebo‐treated peers. Patients treated with levodopa plus (–)deprenyl live longer than those on levodopa alone. Chronic treatment with (–)deprenyl improves the performance of patients with

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00480.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Acetonitrile, a commonly used solvent is known to cause central nervous system dysfunctions. In order to gain an insight onto the mechanism of acetonitrile toxicity, we studied the kinetics of acetonitrile distribution in mice. Male ICR mice were given a tracer dose of 2–14C‐acetonitrile intravenously (60 μ mol/kg or 684 μCi/kg, spec. act. 11.4 mCi/ mmol). At various time intervals (5 min., 0.5, 1, 4, 8, 24 and 48 hr) after treatment, mice were anaesthetized and frozen by immersion in a dry ice/hexane mixture, or they were dissected for collection of organs and tissues. Frozen mice were processed for whole body autoradiography, which allows the detection of non‐volatile metabolites of acetonitrile at their sites of accumulation. Covalent binding of acetonitrile metabolites in tissues was determined using trichloroacetic acid followed by ethanol/ether extraction techniques. Whole body autoradiography revealed heavy localization of acetonitrile metabolites in the gastrointestinal tissues and bile. At 5 min., the highest levels of radioactivity occurred in the liver and kidney; levels declined over time. At 24 and 48 hr, acetonitrile derived radioactivity were detected in the gastrointestine, thymus, liver and male reproductive organs. Covalent binding studies at 24 and 48 hr after treatment indicated that 40–50% of the total radioactivity present in the liver was bound to the macromolecular fractions of the tissues. The radioactivity contents of other organs were, in large part (40–50% of total), present in the lipid fraction of the tissue. Our studies suggest that the irreversible association with tissues of radioactivity derived from 2–14C‐acetonitrile is due to the metabolic activation of acetonitrile and the covalent interaction of reactive metabolite(s) with lipid and macromolecular fracti

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00481.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The arrhythmogenic action of epinephrine was studied in 3 groups of rats: 10 rats with mild constriction of the abdominal aorta (group H1), 10 rats with severe constriction (group H2), 10 sham‐operated age‐matched rats (group C). Blood pressure and ECG were recorded before, during and after 5 min. perfusion of increasing doses of epinephrine (1, 5, 10 and 25 μ·g‐kg–1· min.–1). Ventricular arrhythmia was evaluated from the ECG using a modified Lown's grading system. The ventricular hypertrophy index was calculated from the heart/body weight ratio (mg/g). The mean arterial blood pressure was significantly higher in groups H1 and H2 than in the control group. The ventricular hypertrophy was significant in group H2, but not in group H1. There was no significant difference between the amplitudes of the epinephrine‐induced hypertensive responses in the 3 groups but the extent of arrhythmia was significantly lower in the animals with high hyp

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00482.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The relative activities of a series of nine monoalkyl esters ofmeso‐2, 3–dimercaptosuccinic acid have been examined as agents for the mobilization of cadmium from mice one week after intraperitoneal administration of cadmium chloride. Eight of these are newly synthetized; all are of the type ROOCCH(SH)CH(SH)COOH, were R=Me, MMDMS; R = C2H5, MEDMS; R = (CH2)2CH3, Mn‐PDMS; R = CHMe2) Mi‐PDMS; R = (CH2)3CH3, Mn‐BDMS; R = CH2CHMe2, Mi‐BDMS; R = (CH2)4CH3, Mn‐ADMS; R=(CH2)2CHMe2, Mi‐ADMS; and R = (CH2)5CH3, Mn‐HDMS. All are soluble in dilute sodium bicarbonate solutions and can be administered as aqueous solutions. Cadmium mobilization data were collected on each compound using mice previously loaded with cadmium; the monoesters were administered at a level of 0.40 mmol/kg intraperitoneally daily for five days. Data on whole body cadmium mobilization indicated that the monoester with the isoamyl group was the most effective under the conditions used. The relative whole body cadmium mobilization increased with the number of carbon atoms in the alkyl group of the monoester up to C5and then decreased for the C6compound. Cadmium removal from the kidneys and liver was also measured. It was found that the monoisoamyl ester was the most effective in removing cadmium from both the liver and the kidneys. The monoisoamyl ester also proved to be very effective in mobilizing cadmium from both the liver and the kidneys when given orally. This is the first compound which is reported capable of mobilizing cadmiumin vivofrom aged deposits after or

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00483.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The influence of surfactants on the changes in skin barrier properties was investigated in rats. Various ionic and non‐ionic surfactants were assessed using indomethacin as a model penetrant. The surfactants appeared to either increase or decrease the skin permeability, due to the properties of both compound and surfactant. Ionic surfactant sodium dodecylsulfate was the most powerful and exceeded controls by approximately 10 times measured by means of serum levels of indomethacin. Other surfactants caused concentration increase or decrease of indomethacin in seru

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00484.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:We studied the effects of dietary fat composition on the activities of the microsomal ethanol oxidizing system (MEOS), paranitrophenol hydroxylase (PH) activity and ethanol‐inducible cytochrome P450 isozymes (CYP2E1 and CYP2B1) in the liver of rats to determine the role of this ethanol metabolizing pathway in the pathogenesis of alcoholic liver disease (ALD). Wistar male rats were pair‐fed a liquid diet, containing either tallow (TF) or corn oil (CF) as the fat component, and ethanol or an isocaloric amount of dextrose, through an implanted intragastric cannula. Liver pathology of rats fed ethanol (CF‐ALC) and CF diet showed severe fatty change whereas the rats fed TF‐alcohol and the TF and CF controls did not. MEOS activity of the CF‐ALC group was 8 times of that in the CF‐CTL group (P<0.01). In TF‐ALC rats, MEOS activity was increased to 2.6 times compared to that of TF‐CTL (P<0.01). ApoCYP2E1 in CF‐ALC and TF‐ALC were 818 ± 63 and 433 ± 17 pmol/mg protein, respectively, and these values were significantly higher when compared with those of the pair‐fed controls (P<0.005). In contrast, apoCYP2B1 was increased to an equal degree in both CF‐ALC and TF‐ALC. When PH‐activity was measured, the level of activity on TF‐ALC rats did not differ from that of CF‐ALC rats. Thus, ethanol‐induction of apoCYP2Bl (2 x) and PH (6–8 x) were the same for CF and TF (2 x); but not for apoCYP2E1 (21 and 8 x, respectively) and MEOS activity (8 and 2.6 x, respectively). These results indicate that the dietary effect on the expression of CYP2E1 correlates with the induction of centrilobular liver damage seen in the corn oil fed rats. The centrilobular distribution of this isozyme also correlates with the site of liver cell injury further suggesting a pathogeni

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00485.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The effect of the dithiols British Anti‐Lewisite (BAL), dimercaptopropanesulfonic acid (DMPS), dimercaptosuc‐cinic acid (DMSA) and a new metal binding agent 2, 3–bis‐(acetylthio)‐propanesulfonamide (BAPSA) on the biliary excretion of arsenic in perfused livers of guinea pigs after acute experimental poisoning with As2O3was investigated. Guinea pigs received As2O3, 10.0 mg/kg subcutaneously at 9 a. m. as a single injection. One hour after the injection the livers were perfused (2.5 mix min.–1x g–1liver) with Krebs‐Henseleit buffer and glucose for 80 min. After 40 min. of saline perfusion (control) 0.1 or 0.7 mmol/1 BAL, DMSA, DMPS, or BAPSA were added to the perfusate and arsenic elimination in the bile and effluent perfusate was measured. The biliary excretion of arsenic in control livers between 40 and 80 min. was 0.7% of the total arsenic liver content before perfusion (= arsenic liver content after perfusion + portion excreted in the bile + perfusate). After antidote addition (0.1 mmol/l) the excretion was 0.2% for livers perfused with BAL, 6.8% for DMSA, 10.6% for DMPS, and 11.1% for BAPSA, respectively. After 0.7 mmol/l antidote the excretion of arsenic was 0.1% in livers perfused with BAL, 9.6% for DMSA, 12.3% for DMPS, and 13.3% for BAPSA, respectively. Except BAL, all compounds and most effectively BAPSA increased biliary excretion of arsenic. This indicates that excretion of arsenic which normally is mainly renal is shifted towards faecal excretion

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00486.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The effects of glimepiride and glibenclamide upon86Rb outflow,45Ca outflow and insulin release were examined in rat islets perifused at low (zero to 2.8 mM) or close‐to‐normal (8.3 mM) D‐glucose concentrations. At the low hexose concentrations, a marked and not reversible decrease in86Rb outflow contrasted with a rapid and reversible increase in45Ca outflow. The latter increase was abolished in the absence of extracellular Ca2+, and was not associated with any pronounced stimulation of insulin release. Inversely, in the presence of 8.3 mM D‐glucose, a comparable increase in45Ca efflux now coincided with an increase in86Rb efflux and a marked and not reversible stimulation of insulin release. Whether in terms of the time course or glucose dependency of the cationic and secretory responses, a coupled increase in both40Ca inflow and45Ca outflow thus coincided with either negative or positive changes in86Rb outflow and either minimal or marked changes in insulin output. Such dissociated behaviours suggest that the insulinotropic action of hypoglycemic sulfonylureas is not necessarily attributable solely to a primary decrease in K+cond

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00487.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Glutathione transferases (GST) are detoxifying enzymes who act with many endogenous and exogenous substances such as polycyclic aromatic hydrocarbons (PAH). The GST activity towardstrans‐stilbene oxide (GST‐tSBO) is inherited in an autosomal dominant fashion and can be separated in high (GST‐positive) and low (GST‐negative) phenotypes when measured in blood. Human fibroblast cultures were established from males matched for age, smoking habits and clinical manifestations of atherosclerosis. Matched pairs of GST‐negative and GST‐positive fibroblasts were studied. There was a very strong correlation between the levels of GST‐tSBO in peripheral blood and in cultured fibroblasts within the same individual. When fibroblasts were exposed to benzo(a)pyrene (BP) or dimethylbenzanthracene (DMBA) GST‐negative cells produced relatively more collagen than GST‐positive cells. GST‐negative fibroblasts showed a greater cell death than GST‐positive fibroblasts as well among controls as after exposure to PAH. It is concluded that lack of GST‐tSBO is easily discriminated in cultured skin fibroblasts. GST‐negative and GST‐positive fibroblasts showed different susceptibility towards some toxic stimuli that might be of

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00488.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The cardiac effects of increasing concentrations of isradipine (racemic) from 1.64 pM to 232 nM were studied in isolated spontaneously beating rabbit hearts. Inhibitory responses with regard to contraction amplitude, contraction velocity and oxygen consumption exhibited a biphasic progressive course at increasing drug exposure. Computer derived inhibitory Emax‐values of the second phase were 104, 103 and 87% (IC50: 7.1, 6.3 and 28.7 nM), respectively, whereas those of the initial phase were 24.7, 25.9 and 19.5% (IC50: 0.012, 0.038 and 0.026 nM). A progressive inhibition of frequency reached a maximum of only 21%. The ECG‐derived PQ‐interval showed a rapid increase (maximum 46%) at drug concentrations above 1 nM. Complete AV‐block and ventricular asystolia occurred in half of the hearts at the second highest (99 nM) and in all except one at the highest concentration. SA‐node activity was retained in 9 of 10 hearts at the second highest and in 3 at the highest drug exposure. The QRS‐ and the frequency‐corrected QT‐interval did not increase significantly. Coronary flow‐rate showed no initial increase, but a decrease to 70% of control at the highest concentration. Supplementaryin vitrostudies on rabbit coronary artery ring‐preparations contracted with 124 mM K+showed, however, an relaxant Emax‐value for isradipine of about 100% and an inhibitory EC50–value of 0.63 nM with a ‘Hill’ coefficient of 1.1. At toxic concentrations isradipine showed a kinetic monophasic accumulation in the rabbit heart of about 44‐fold with a half‐time of 10.6 min. The myocardial disposition of the drug was three‐phasic with half‐times of 4.3, 13.8 and 75 min., respectively. These findings seem compatible with a biphasic and only partial reversibility of the dynamic effects within 30 min.

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00489.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY