摘要:

Abstract:An earlier study from this laboratory showed that the hepatic murine cytochrome P450 (P450) system was depressed by interferonin vivobut induced in cultured primary hepatocytes. The current investigation attempted to resolve this contradiction. The P450 content of the cells used in the earlier study fell precipitously during the first 24 hr of culture and remained at the same low level throughout another 48 hr of incubation. This failure to maintain the P450 level suggested that the cells may not have been sufficiently viable to support the mechanisms involved in the depressant activity of interferon. Accordingly, a chemically defined medium containing hydrocortisone was devised which supported an acceptable level and function of the P450 system throughout a 72 hr incubation period. Functionality of the P450 system was evaluated by measuring aminopyrine N‐demethylase and benzo[a]pyrene hydroxylase activities. When this steroid supplemented medium was used, interferon depressed both activities by about 25%; however, neither activity was affected significantly by poly IC. On the other hand, benzo[a]pyrene hydroxylase activity was depressed by both poly IC and interferon in hepatocytes induced with dexamethasone or with dexamethasone plus 3‐methylcholanthrene. These studies emphasize the necessity of maintaining an acceptable level of homeostasis in cultured hepatocytes if one is to derive meaningful interpretations of certain biological eve

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01636.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:The neurotoxicity of flucloxacillin, an isoxazolyl derivative of β‐lactamic antibiotics, was studied in rats by electroencephalographic recordings. The results show that intravenous flucloxacillin, (200 mg/kg) produced cortical activity modifications. The changes in electroencephalogram consist of irritative activity patterns and bursts of high voltage waves with spikes and polyspikes. The effects of other β‐lactamic drugs (cloxacillin, ampicillinsulbactam and penicillin G) on electroencephalography activity were also investigated after intravenous administration of equivalent doses. These drugs did not change the normal bioelectric cerebral activity of the

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01637.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Since guinea pig and rat atria have been used as models to study acute anthracycline‐induced cardiotoxicity, experiments were carried out in these preparations to evaluate possible acute cardiac effects mediated by mitoxantrone (MTX). After a latency period of approximately 90 min, MTX (10‐5—10‐4M) promoted a concentration‐related and time‐dependent decrease of spontaneous rate in guinea pig atria. A similar but less intense effect after a longer latency interval was observed in rat atria. In this preparation, MTX (10‐5—10‐4M) incubated up to 150 min., induced a gradual competitive β‐adrenergic blocking effect on the positive chronotropic action of isoproterenol. This was characterized by a progressive decline of pD2values without altering Emax. A similar and stronger effect was found in isolated guinea pig atria incubated under same conditions with MTX, except that 10‐4M exposed for 150 min. was able to depress the Emaxto isoproterenol by 21.2%. In addition, MTX (10‐4M) in this model promoted a non‐competitive antagonistic effect on the chonotropic action of histamine. These data are compatible with the idea that MTX could induce cardiac acute effects qualitatively similar to but of lower potency than those produced by doxorubicin in these two models. In addition, guinea pig atria seemed to display higher sensitivity to MTX compared

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01638.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Dopamine agonists and antagonists with different affinities for D1and D2receptors in the brain were assessed for their ability to affect clonic seizures in mice induced by chemoconvulsants. The dopamine D2antagonists remoxipride (5‐20 mg/kg) and raclopride (5‐20 mg/kg), haloperidol (2.5 and 5 mg/kg) and the D1antagonist SCH 23390 (0.3, 1.5 mg/kg) did not markedly modify seizures induced by pentylenetetrazole, picrotoxin or bicuculline. The dopamine D2agonist quinpirole only weakly blocked the action of pentylenetetrazole while the D1agonist SKF 38393 (1‐10 mg/kg subcutaneously) caused a dose‐dependent blockade of pentylenetetrazole‐induced seizures. The D1/D2agonist apomorphine given at “postsynaptic” doses (1 and 2 mg/kg) blocked pentylenetetrazole‐induced seizures. The protection afforded by apomorphine against pentylenetetrazole seizures appeared to be associated with its activation of both D1and D2receptors since both raclopride and SCH 23390 blocked the action of apomorphine. Reserpine and the two partial dopamine autoreceptor agonists, (—)3‐PPP and HW‐165, at high (non‐autoreceptor selective) doses induced seizures in animals treated with the subconvulsive dose of pentylenetetrazole. The overall results suggest that dopamine receptor blockade has a minor or limited effect on seizures caused by GABA inhibition. The anticonvulsant effect of dopamine agonists such as apomorphine appears to be mediated by postsynaptic dopamine D1and D2receptors. Stimulation of dopamine D1receptors can reduce seizure activity caused by GABA receptor blockade possibly by facilitation of GABA transmission in the striat

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01639.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Generation of reactive oxygen intermediates by activated polymorphonuclear neutrophil granulocytes plays an important role in development of microcirculatory injury. The effect of the β2‐adrenergic receptor agonists (β2‐agonists) isoprenaline and terbutaline on the chemiluminescence or oxygen consumption of human granulocytes in response to activation with n‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) and phorbol myristate acetate (PMA) was examined. The β2‐agonist effect on activated cell aggregation and volume change was examined as well. As E. Coli lipopolysaccharide and FMLP may prime granulocytes for enhanced generation of reactive oxygen intermediates in response to other activators, the effect of β2‐agonists on the priming effect of these agents was also investigated. Results: 1) Optimal concentrations of β2‐agonists decrease the human granulocyte generation of reactive oxygen intermediates in response to activation with FMLP by 40‐60%, without affecting the response to PMA. 2) β2‐Agonists modify the priming effect of FMLP on activation with PMA, but do not interfere with the priming effect of E. Coli lipopolysaccharide on activation with FMLP. 3) Isoprenaline have different effects on generation of reactive oxygen intermediates and cell aggregation in FMLP‐activated granulocytes. 4) High concentrations of isoprenaline and terbutaline have contrasting non‐specific effects on the chemiluminescence, but not on the oxygen consump

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01640.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:This study reports the effects of Ca2+channel blockers (Ca antagonists) on intraneuronal Ca2+([Ca2+]i) movements and on the disturbance of rotarod performance produced in rats by intracerebroventricular administration of paraquat. Paraquat (50 nmol) produced a decrement in rotarod performance which was present at 30 min. and maximal at 60 min. and was not associated with overt behavioural changes; larger doses of paraquat (100‐400 nmol intracerebroventricularly) produced paresis and convulsions which severely disrupted rotarod behaviour. The disruption of rotarod performance after paraquat (50 nmol intracerebroventricularly) was significantly reduced by giving Ca antagonists (flunarizine, verapamil and nicardipine) not only intraperitoneally 15 min. after paraquat but also intracerebroventricularly immediately before paraquat. The order of pharmacological potency was flunarizine ≥ verapamil>nicardipine. In contrast, intracerebroventricular administration of Bay K 8644, a Ca agonist, enhanced the disruption of rotarod performance caused by paraquat (50 nmol). Inin vitrostudies, paraquat markedly potentiated the rapid increase in [Ca2+]ilevels evoked by 50 mM KCl in rat brain synaptosomal fraction, although paraquat alone produced a small prolonged rise in [Ca2+]ilevels which had a slow onset. The above results suggest that paraquat induced neurotoxicity is associated with increased [Ca2+]ilevels in brain neuronal cells, and that paraquat might effect on membrane activity instabil

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01641.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Myelinated nerve fibres isolated from Wistar rats chronically exposed to 2,5‐hexanedione (0.8 ml/kg/day, intraperitoneally) over a period of 20 days, were stained with lectin‐horseradish peroxidase conjugates. The lectins with high affinity for terminal D‐galactopyranosyl residues, Bandeiraea simplicifolia‐B4(BSA I‐B4) and peanut agglutinin (PNA), showed glycoconjugates in the control nodes of Ranvier. In the treated animals, application of PNA‐HRP caused weak reactivity to the node of Ranvier; digestion with sialidase prior to the application of PNA‐HRP conjugate enhanced reactivity, thus revealing the presence of a sialoglycoprotein. The results indicate that glycoconjugates of the Ranvier node undergo a rearrangement during exposure to 2,5‐hexanedione. In particular, neutral glycoproteins with terminal galactose are replaced by sialoglycoproteins. These findings are consistent with the proposed role of polysialic acid as a regulator of axonal behaviour duri

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01642.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Calcipotriol is a novel vitamin D3analogue developed for topical treatment of psoriasis. Calcipotriol is believed to act via regulation of cell proliferation and differentiation. In this respect calcipotriol is as potent as 1α,25(OH)2D3, the physiologically active form of vitamin D3, but its calcaemic activityin vivois 100 to 200 times lower. In the present investigation, the effects of calcipotriol on cell growth regulationin vitroand on calcium metabolismin vivowere compared to those exerted by a number of metabolites and analogues of vitamin D3. Besides 1α,25(OH)2D3, these included the two physiologically occurring metabolites 25(OH)D3and 24,25(OH)2D3, and the two synthetic analogues 1α(OH)D3and 1α,24(OH)2D3. 25(OH)D3and 24,25(OH)2D3were shown to be inactive bothin vitroandin vivo.1α(OH)D3was found to have a low biological activityin vitro,but was highly calcaemicin vivoafter biotransformation to 1α,25(OH)2D3. Calcipotriol, 1α,24(OH)2D3and 1α,25(OH)2D3were all three potent regulators of cell proliferation and differentiationin vitro. In vivo,only calcipotriol showed a greatly reduced calcaemic activity after both oral and intravenous administration. It is concluded that calcipotriol, with a reduced risk of inducing calcaemic side‐effects upon absorption from the skin, possesses a favourable therapeutic profile for topical treatment of hyperproliferative

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01643.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:The pharmacokinetic parameters of digoxin given intravenously (0.075 mg/kg) alone and following treatment with oral cholestyramine (8 gm in 50 ml water) were studied in rabbits. Pretreatment with cholestyramine produced a significant decrease in the serum concentration of digoxin and significantly enhances its systemic clearance as indicated by a statistically significant decrease in the area under the concentration‐time curve (AUC), half time of elimination (t1/2), and mean residence time (MRT). These findings indicate that the idea of gastrointestinal dialysis, known with activated charcoal, could be extended to ion‐exchange resins that could be a potentially useful adjunctive measure in the management of drug overdose especially with commonly used drugs with a low therapeutic index like digo

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01644.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Abstract:Fenfluramine has been classified as a neurotoxin because animals treated with this anorectic lose 5‐HT uptake sites located on serotonergic nerve terminals. However, there are two possible bases for this finding:eitheruptake sites are lost because the terminals themselves have been destroyed (neurotoxicity);oruptake sites are lost from otherwise intact terminals. To distinguish between these possibilities, we established an animal model in which male Wistar rats were injected (intraperitoneally) with an irreversible 5‐HT uptake site antagonist (EEDQ). Since their 5‐HT sites were inhibited (blocked) non‐competitively, by this agent, such animals had effectively lost 5‐HT uptake sites from intact serotonergic terminals. Synaptosomes prepared from such animals showed the predicted reduction in theBmaxof [3H]paroxetine binding to the 5‐HT uptake site, and a reduction in the Vmaxof [14C]5‐HT uptake. However, they showed no significant reduction in maximal [14C]5‐HT loading (α) compared with synaptosome from sham‐injected controls. In contrast, fenfluramine‐treated animals showed reduced [3H]paroxetine binding, reduced maximal [14C]5‐HT uptake and significantly (P<0.02) reduced synaptosomal [14C]5‐HT loading. Therefore, the results suggest that fenfluramine does indeed cause the destruction of sero

ISSN:0901-9928    

DOI:10.1111/j.1600-0773.1993.tb01645.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY