ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00828.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00829.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

Polymorphic oxidation of the sparteine/debrisoquine‐type has been shown to account for much of the interindividual variation in the metabolism, pharmacokinetics and pharmacodynamics of an increasing number of drugs, including some antiarrhythmic, antidepressant and beta‐adrenoceptor antagonist agents. Impaired hydroxylation of these drugs results from the absence of the enzyme cytochrome P450IID6 in the livers of poor metabolisers, who constitute 6% to 10% of Caucasian populations. The clinical importance of the phenomenon has to be explored further and for most sparteine/debrisoquine‐related substrates there is a need for controlled prospective studies to define the consequences to the patient of impaired or enhanced drug oxid

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00830.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

In a dynamic inhalation system, mice, rats and rabbits were exposed to bromobenzene vapour (250–3400 p.p.m.) for 4 hr. Blood concentrations of bromobenzene were determined by head‐space gas chromatography. After inhalation of 1000 p.p.m. for 4 hr, concentrations of 153, 102 and 47 μg bromobenzene/ml blood were found in mice, rats and rabbits, respectively.In vitroexperiments showed a blood/air partition coefficient at 37° of approximately 200, which was reflected by a linear uptake of bromobenzene up to an air concentration of 2500 p.p.m. Compared with results obtained previously by intraperitoneal bromobenzene administration inhalation resulted in higher blood concentra

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00831.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The stimulation‐evoked3H‐overflow from rabbit isolated ear arteries preincubated with3H‐noradrenaline was studied. Three strips were derived from each central artery. The strips were incubated (30 min.) with3H‐noradrenaline (10‐7M) and the spontaneous3H‐outflow and stimulation‐evoked3H‐overflow were followed by fractional collection. After a wash‐out period (75 min.), the strips were stimulated (225 mA; 150 monophasic pulses; 3 Hz; 0.5 msec.) several times. The initial stimulation‐evoked3H‐overflow (S1) was about 5‐fold higher than the subsequent five3H‐overflows (S2‐S6) which remained almost constant. Bretylium (10‐5M), tetrodotoxin (10‐6M), and omission of Ca2+from the physiological salt solution reduced the stimulation‐evoked3H‐overflow by maximally 52%, 77% and 62%, respectively. An increase in stimulation current from 50 to 225 mA caused a continuous rise in stimulation‐evoked3H‐overflow, which tended to be Ca2+‐sensitive. The stimulation‐evoked3H‐overflow was frequency‐dependent: at 1–4 Hz, the3H‐overflows were the same; at 8 and 16 Hz, they increased. Cocaine (3 × 10‐5M) plus corticosterone (4 ×10‐5M) enhanced the stimulation‐evoked3H‐overflow at 1–8 Hz, while it had no effect at 16 Hz. Propranolol (3 × 10‐7M) did not antagonize this enhancement. An increase in number of pulses from 10 to 1000 in the stimulus caused a corresponding rise in the evoked3H‐overflow. This was also the case when cocaine plus corticosterone were present. Cocaine at low concentrations increased the stimulation‐evoked3H‐overflow at two frequencies (3 and 16 Hz), while a high concentration of cocaine decreased the3H‐overflow at 16 Hz. The results suggest that the strip preparation of rabbit central ear artery is suitable for studying the release of3H‐noradrenaline evoked by electrical

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00832.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

Three experiments were performed to study the subchronic effects of treatment with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP, 2 × 40 mg/kg subcutaneously two weeks before testing) in C57 BL/6 mice upon spontaneous motor activity and the reversal of the long‐term behavioural changes by acute treatment with L‐Dopa. Mice treated with MPTP showed a drastic reduction of striatal dopamine levels (‐88%) associated with reductions of all three parameters of spontaneous motor activity, i.e. locomotion, rearing and total activity, during both the initial, exploratory, stage (first 90 min), and later stages of the 3‐ or 4‐hr test periods. L‐Dopa (5–80 mg/kg subcutaneously) injected 60 min. after the start of testing dose‐dependently improved all three parameters studied in MPTP treated mice with 10 mg/kg being the lowest dose causing a significant effect, while doses above 20 mg/kg caused hyperactivity. During the initial period, rearing activity in MPTP mice was to a variable degree suppressed by the L‐Dopa treatment (20–80 mg/kg); these reductions were followed by enormous increases in motor activity by the 40 mg/kg (locomotion) and 80 mg/kg (total activity) L‐Dopa groups. Both the degree and duration of the L‐Dopa‐induced hypoactivity for locomotor behaviour increased dose‐dependently in control mice. No suppressive effects of L‐Dopa were obtained for total activity in control mice, although the 80 mg/kg L‐Dopa doses evoked hyperactivity for up to 90 min. following treatment for both locomotion and total activity. At the 20–80 mg/kg doses, significant reductions were even obtained in MPTP mice during the initial period after administration, for locomotor activity; In saline‐treated control mice, the higher doses of L‐Dopa (20–80 mg/kg) by which caused considerable reductions in locomotor activity followed again by large increases in activity may have been caused an initial dopamine autoreceptor action, which appears also for the MPTP treated mice as reflected by the locomotion data of the 20–80 mg/kg L‐Dopa groups. The results indicate that the MPTP‐treated mouse model may provide an important drug screen of compounds of potential therapeutic impo

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00833.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The effect of toluene on the preference of ethanol was studied in rats. Toluene was administered orally by stomac tube in doses of 200, 400 or 800 mg/kg daily for 5 weeks or by inhalation at a concentration of 2000 p.p.m. 6 or 8 hr daily for 5 or 6 days per week for 2 weeks in rats of different age. During toluene inhalation exposure the rats had access to either tap water or ethanol‐containing water (6 or 10%). After the exposure and during oral administration the rats had access to both ethanol‐free and ethanol‐containing water. Toluene inhibited the body weight gain in the highest oral dose group and in rats exposed to toluene and forced to drink ethanol in the inhalation experiments. In these experiments, the intake of fluid was reduced in the exposure period in rats forced to drink ethanol‐containing water and further reduced in rats exposed to both ethanol and toluene. Exposure to toluene alone increased the fluid consumption. The preference of ethanol defined as consumed ethanol‐containing water in per cent of the total water intake was not influenced by oral administration of toluene. It was, however, reduced by toluene given by inhalation to rats forced to drink ethanol‐containing water during the exposure period. Toluene exposure alone or forced ethanol intake alone caused in these experiments a short‐lasting reduction of the ethanol preference. It is concluded that toluene decreases the preference of ethanol in rats forced to drink ethanol during exposu

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00834.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The disposition of tritium‐labelled ivermectin (22, 23 di‐3H‐avermectin, B1a) in Atlantic salmon was studied by whole‐body autoradiography, liquid scintillation counting, and thin‐layer chromatography. Ivermectin was slowly absorbed, the highest concentrations being found in lipid‐containing organs. High concentrations were also found in the central nervous system, indicating that the blood‐brain barrier in salmon is poorly developed compared to mammals. The excretion of the drug was very slow. The total amount of radioactivity in blood, muscle, liver and kidney diminished by only 35% from day 4 to day 28 after administration. Excretion was mainly by the biliary route, and enterohepatic circulation of the drug was apparent. The drug was mainly excreted in the unchanged form. Distribution to the central nervous system, and the prolonged excretion period, makes the drug unsuitable for the control of parasitic infestati

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00835.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

A sensitive radioreceptor assay for the determination of glycopyrrolate concentrations in human plasma, urine and cerebrospinal fluid (CSF) is described. The applicability of the assay for kinetic studies in humans was studied by determining the plasma concentrations and the renal excretion in three gynaecological surgical patients, who received 8 μg/kg of glycopyrrolate as a premedication intramuscularly. Tritiated N‐methyl scopolamine was used to label the muscarinic cholinergic receptors in the membrane preparation obtained from the rat brain. The limit of detection of the assay was 70 ng/1 in plasma, 2 μg/1 in urine and 140 ng/1 in CSF. There was no evidence of cross‐reactivity of glycopyrrolate derivatives in clinical concentrations. A very rapid absorption was found with a mean maximum plasma concentration (Cmax) of 14.26 (range 12.02–16.97) μg/1 and mean Tmax(time to Cmax) of 13.3 (range 10–15) min. and almost 50% of the dose administered was excreted into the urine within 3 hr. The CSF levels of glycopyrrolate were under detection limit. It is concluded that the sensitivity of the method is sufficient for pharmacokinetic studies of glycopyrrolate after therapeu

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00836.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

The hexamethonium derivative W84 (hexamethylene‐bis‐[dimethyl‐(3‐phthalimidopropyl)‐ammonium bromide]) combined with atropine has an overadditive protective action against organophosphorus intoxications. It affects allosterically the binding of (—)[3H]N‐methylscopolamine ([3H]NMS) to muscarinic cholinoceptors. Because nicotinic receptors are involved in organophosphorus intoxications, the interaction of W84 with nicotinic cholinoceptors was investigated. (—)[3H]nicotine (2.5 nM) was used to label nicotinic binding sites in rat brain membranes in 50 mM Tris, pH 7.3, at 23°. Under control conditions, (—)[3H]nicotine‐binding revealed a KDof 4×10‐9M and a Bmaxof 53 fmol/mg membrane protein. W84 inhibited (—)[3H]nicotine‐binding with an IC50 of 3 × 10‐5M by reducing the binding affinity. The IC50 of hexamethonium was 20 × 10‐5M. At 10‐4M, W84 did not affect the dissociation rate of (—)[3H]nicotine, suggesting a lack of allosteric activity. For sake of comparison, the action of W84 was checked on [3H]NMS‐binding (control: KD∼ 1 × 10‐9M, Bmax∼ 500 fmol/mg prot.). W84 inhibited the binding of [3H]NMS (0.5 nM) with an IC50 of 1.5 × 10‐5M. At 10‐4M, W84 prevented [3H]NMS‐dissociation almost completely, thus displaying the allosteric action at muscarinic cholinoceptors. In conclusion, the results of the (—)[3H]nicotine‐binding experiments point to a pure competitive action of W84 at nicotine cholinoceptors, lacking any allosteric effect. This competitive action may contribute to t

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1990.tb00837.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY