摘要:

Abstract:The dependence creating properties of drugs are mediated by structures in the brain. The mesolimbic system seems to play a crucial role in the behaviourally reinforcing effects of opiates and other drugs of abuse. The significance of dopamine in opiate reinforcement is still a matter of debate, in spite of the large number of studies on this subject. Dopamine appears to be involved in conditioning processes and in drug self‐administration behaviour only once it has been established. Neuropeptides, centrally active fragments of hormones, may play a role in the individual vulnerability for the development of drug dependence. Administration of a number of wellknown neuropeptides attenuates the acquisition of drug self‐administration behaviour. The virtues and flaws of some widely used animal models for drug dependence are discus

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00525.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The amiloride derivatives, 2′,3′‐benzobenzamil (BB), 3′,4′‐dichlorobenzamil (DCB), and 5‐(N‐4‐chlorobenzyl)‐2′,4′‐dimethylbenzamil (CBDB) are known as inhibitors of the Na+/Ca2+exchange. This kind of drug action was recently suggested to be a new inotropic mechanism. In guinea‐pig myocardium, we have studied the inotropic and the accompanying electrophysiological effects of the three compounds in order to assess their selectivity of action. In left atria and in papillary muscle, force of contraction increased with DCB and CBDB (atria only) at a high concentration (5 × 10‐5− 10‐4mol/l) and after long exposure time, whereas BB produced a negative inotropic effect. In the isolated perfused Langendorff heart, the amiloride derivatives tested decreased spontaneous heart rate and force of contraction and prolonged the duration of contraction. In isolated cardiac myocytes, sodium current, calcium current and the delayed rectifier were reduced by concentrations of BB, DCB and CBDB similar to the IC50values reported for the inhibition of the Na+/Ca2+exchange. Our results demonstrate that the amiloride derivatives have multiple sites of action. It is concluded that more specific modulators of the Na+/Ca2+exchange are required in order to define their contribution to the regulation of c

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00526.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Fifteen children (3‐12 years) with peritonitis were given imipenem/cilastatin intravenously (15 or 25 mg/kg) every six hours for 3‐14 days. One day during treatment days 2‐8, multiple blood and urine samples were collected from each individual over a six hour dosing interval. Twelve children completed the study. The urinary recovery of imipenem and cilastatin averaged 50‐70% of the administered dose. The plasma t1/2for imipenem averaged 55 min. while that for cilastatin was even more rapid (~ 38 min.). Little or no accumulation of either imipenem or cilastatin was observed for this regimen in this age group of paediatric patients. Steady state conditions prevailed within 2 days of initiation of therapy. The pharmacokinetics of imipenem and cilastatin in paediatric patients 3‐12 years of age appear similar to those observed f

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00527.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:GEA 857 [2‐(4‐chlorophenyl)‐1,1‐dimethylethyl 2‐amino‐3‐methylbutanoate], a structural analogue of the serotonin (5‐HT) uptake inhibitor alaproclate but without effects on the 5‐HT uptake, was shown to potentiate muscarinic cholinergic responses in N1E‐115 neuroblastoma cells. In intracellular recording experiments, GEA 857 (1 μM) increased the cell input resistance and prolonged the action potential. It also prolonged the cellular response to carbachol acting on muscarinic receptors in a manner mimicked by potassium channel blockers such as 4‐aminopyridine and TEA. GEA 857 did not affect the carbachol stimulated uptake of45Ca, but depressed the carbachol activated outflow of86Rb from neuroblastoma cells. The conclusion drawn from these results is that GEA 857 reduces potassium conductances in the membrane in N1E‐115 neuroblastoma cells and, thereby, prolongs muscarinic a

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00528.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:GEA 857 [2‐(4‐chlorophenyl)‐1,1‐dimethylethyl 2‐amino‐3‐methylbutanoate], a structural analogue of the 5‐HT uptake blocker alaproclate, was tested for its ability to modify tremor and salivation induced by muscarinic agonists (oxotremorine, arecoline) and acetylcholinesterase inhibitors (physostigmine, THA) in the male rat. These agents were employed at submaximal doses. GEA 857, similarly to alaproclate (Ögrenet al.1985a&b), produced a dose‐dependent, statistically significant (in the 5‐20 mg/kg dose range) enhancement of the tremor response induced by all four cholinergic stimulants. However, unlike alaproclate, GEA 857 failed to enhance salivation in a consistent manner. GEA 857 itself did not produce tremor in the absence of the muscarinic agonists or the acetylcholinesterase inhibitors. The potentiation of oxotremorine tremor by GEA 857 could be fully blocked by atropine (1 mg/kg intraperitoneally). Unlike alaproclate, GEA 857 failed to affect 5‐HT uptake or 5‐HT metabolism in the 10‐20 mg/kg dose range. However, similarly to the action of alaproclate, the potentiating effect of GEA 857 on muscarinic responses could be explained neither by actions on serotonergic mechanisms nor by actions on muscarinic receptor mechanisms in the striatum. Evidence is presented suggesting that the ability of GEA 857 to enhance responses evoked by muscarinic agonists involves inhibitory properties of GEA 857 at certain membranal Ca2+‐dependent K+channels, the blockade of which can potentiate or prolong mu

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00529.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:Kava, an intoxicating beverage prepared from the pepper plantPiper methysticum, is widely consumed by the indigenous peoples in the islands of the South Pacific. As the first of a series of studies on the neuropharmacological interactions of kava with CNS receptors we tested purified pyrones and kava resin for activity on GABA and benzodiazepine binding sites in rat and mouse brain membranes. Only weak activity was observed on GABAAbinding sites in washed synaptosomal membranes prepared from rat brain and this was abolished by extraction of the membranes with Triton X‐100, suggesting that lipid soluble components were involved. No effects were observed on GABAabinding sites in rat brain membranesin vitro.Kava resin and pyrones exerted some weak effects on benzodiazepine bindingin vitrobut this did not correlate with pharmacological activity. In addition, inex vivostudies, no effects were observed on [3H]diazepam binding to brain membranes prepared from mice in which selected kava constituents were injected intraperitoneally, whereas similarly administered diazepam (5 mg/kg) inhibited [3H]diazepam binding by>95%. Similar lack of activity was observed inin vivobinding studies; injection of kava resin failed to influence the CNS binding of the benzodiazepine‐receptor ligand [3H]Ro15‐1788 injected into mice prior to sacrifice. The pharmacological activities of kava resin and pyrones do not appear to be explained by any significant interaction with GABA or benzodiazepine binding

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00530.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The present study was designed to determine modulation of the direct inotropic effect of an anticholinesterase organophosphorus compound, phosphamidon, by the reactivator obidoxime. We investigated the effects of phosphamidon (n = 9), obidoxime (n = 5), and their combination (n = 5) on the mechanical and energetic indices of left ventricular function, in the isolated working rat heart model. Phosphamidon at a concentration range of 10‐6‐10‐3M had a positive inotropic effect. Obidoxime at a concentration range of 10‐6‐10‐3M had no significant effect on heart rate, but did have a statistically significant positive inotropic effect on end‐systolic pressure, cardiac output, mean left ventricular pressure, and maximal time derivative of left ventricular pressure (dP/dtmax) (P<0.01). Perfusion with 10‐3M obidoxime caused a 19% increase in left ventricular stroke work and a 31% increase in total pressure‐volume area. Perfusion with phosphamidon and obidoxime at concentrations ranging from 10‐6to 10‐3M resulted in a more intense inotropic response than the separate drug effects. At the highest combined concentrations tested, cardiac output increased by 60%, left ventricular stroke work increased by 100%, and left ventricular total pressure volume area increased by 111% of their control values (P<0.001). We conclude that obidoxime augments the positive inotropic effect of phosphamidon on the isola

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00531.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:An atypical antipsychotic drug clozapine and a selective sigma antagonist BMY 14802 were significantly less effective in the behavioural experiments (against apomorphine, d‐amphetamine and MK‐801), as well in the radioligand binding studies against3H‐spiperone (dopamine2‐receptors) and3H‐haloperidol (sigma receptors) in the rat brain, as compared to a typical antipsychotic compound haloperidol. Contrary to haloperidol and BMY 14802, clozapine was a relatively selective antagonist of MK‐801‐induced motor excitation in the mouse. A nearly 3‐fold lower dose of clozapine was needed to block the effect of MK‐801 (6.4 μmol/kg) as compared to the action of amphetamine (17 μmol/kg). Haloperidol and clozapine, but not BMY 14802, antagonized apomorphine‐induced aggressiveness in the rat. After long‐term treatment (for 15 days) with BMY 14802 (10 mg/kg daily), haloperidol (0.5 mg/kg daily) and clozapine (10 mg/kg daily) the motor depressant effect of apomorphine (0.15 mg/kg) was reversed. Chronic haloperidol treatment, but not administration of BMY 14802 and clozapine, increased the number of dopamine2‐receptors in the rat brain. BMY 14802 caused upregulation of sigma receptors in frontal cortex, whereas haloperidol induced the opposite change in cerebellum. Repeated treatment with clozapine significantly augmented the motor stimulating effect of MK‐801 in rats. Simultaneously with a behavioural change the density of3H‐TCP binding sites in the rat forebrain was elevated after long‐term treatment with clozapine, probably indicating the involvement of PCP binding sites at NMDA cha

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00532.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:A single dose of 100 mg per kg body weight of a commercial mixture of polychlorinated biphenyls (PCB), Fenclor 64 was given intraperitoneally to pregnant rabbits. The distribution in dams and foetuses and excretion in milk was investigated for six of the congeners by quantifying them in fat from maternal adipose tissue, from whole foetuses and newborn bodies and from newborn gastric contents. The cytochrome‐P‐450 induction after Fenclor 64 in foetuses and suckling off‐spring was followed by measuring the following hepatic mixed function oxidase (MFO) activities: p‐nitroanisole‐demethylase, ethoxyresorufin‐deethylase, ethoxycoumarin‐deethylase and NADPH cytochrome‐C reductase. At the 28th day of pregnancy PCB fat concentrations in foetuses were similar to those in mothers (126.4 ± 7.1 and 152.6 ± 28.1 μg/g of fat, respectively). By the 5th day of life fat concentrations in the youngs were double those of foetuses (216.81 ± 8.12 μg/g) and remained high until weaning (142.2 ± 15.5 μg/g at the 20th day). PCB concentrations in mothers'fat decreased during lactation (104.1 μg/g at the 20th day) but at the end of the experiment they were still high (95.5 μg/g). The cytochrome‐P‐450 concentration and MFO activities in young rabbits'livers from treated dams were significantly higher than controls from the 5th (P<0.01) to the 10th (P<0.01) day of life, with the exception of NADPH‐cyt‐C‐reductase (P<0.05). By the 20th day the differences between control and treated animals were smaller but significant (P<0.05), except for ethoxycoumarin deethylase; by the 40th day all the MFOs and the cytochrome‐P‐450 concentration

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00533.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Abstract:The toxicokinetic properties of C6 to C10 n‐alkanes, aromates and naphthenes have been investigated in rats during inhalation of 100 p.p.m. of the single hydrocarbons for 3 days, 12 hr/day. The concentration of hydrocarbon was measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat at days 1, 2 and 3, immediately after termination of exposure and 12 hr after exposure on day 3. The main conclusions drawn from the study were: a) Aromatic hydrocarbons show high concentrations in blood and low concentrations in organs. b) Naphthenic hydrocarbons show low concentrations in blood and high concentrations in organs. c) n‐Alkanes show very low concentrations in blood, relatively high concentrations in brain and a high potential for accumulation in fat with repeated exposures. d) Biological concentrations of hydrocarbons within one class increase in general with increasing molecular weight, though with specific exceptions. e) Accumulation is obviously influenced by differences in metabolism and enzyme induction potential. f) Lipid solubility is not the only parameter relevant for the evaluation of hydrocarbon accumulat

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1992.tb00534.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY