摘要:

Summary—The discovery of an inducible isoform of cyclooxygenase (COX‐2) requires a refinement of the theory that inhibition of cyclooxygenase activity explains both therapeutic and side effects of non‐steroidal anti‐inflammatory drugs (NSAIDs). Indeed, new pharmacological results suggest that COX‐2 inhibition provides the therapeutic (ie, anti‐inflammatory) activity of NSAIDs, whereas inhibition of constitutive COX‐1 is responsible for their gastric and renal side effects as well as for their antithrombotic activity. However, a role of COX‐1 in inflammation cannot be excluded. Furthermore, the functional relevance of COX‐2 expression and induction in various tissues warrants further investigation. These studies should help in predicting potential adverse effects as well as new indications for selective

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00144.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—Although a new generation of selective serotonin reuptake inhibitors (SSRIs) has been introduced in therapeutics as antidepressant drugs, a two to four week lag period still occurs between starting treatment with SSRIs and the onset of therapeutic effects in man. In vivo cerebral microdialysis can be used to measure extracellular concentrations of serotonin (5‐hydroxytryptamine, 5‐HT), which reflect intrasynaptic events. With the coupling of this new experimental method to very sensitive analytical assays such as liquid chromatography with electrochemical detection, it has recently been possible to obtain two major arguments supporting the hypothesis that somatodendritic 5‐HT1Aautoreceptors situated in the raphe nuclei play an important role in the mechanism of action of SSRIs. First, in the rat, single administration of SSRIs at low doses comparable to those used therapeutically increases extracellular 5‐HT concentrations in the vicinity of the cell body and the dendrites of serotoninergic neurones of the raphe nuclei. This effect is more marked than that observed in regions rich in nerve endings (frontal cortex). The magnitude of the activation of the serotoninergic neurotransmission depends on the brain area studied and the dose of the SSRIs administered to rats. This could be explained by simultaneous activation of somatodendritic 5‐HT1Aautoreceptors by endogenous 5‐HT in the raphe nuclei, thereby limiting the corticofrontal effects of the antidepressant. Second, SSRIs cause a larger increase in extracellular 5‐HT concentrations in the nerve endings when administered chronically: 5‐HT autoreceptors may have gradually desensitized during the 2–4 weeks of treatment with SSRIs. Preliminary studies of patients with depression appear to confirm these experimental results, as co‐administration of a 5‐HT1Aautoreceptor antagonist and a SSRI accelerated the onset of the antidepr

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00145.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—Endothelin‐1 (ET‐1) by itself was not an effective stimulus for inducing superoxide (O2*) generation in human resting or DMSO‐differentiated neutrophil‐like HL‐60 cells. ET‐1 (0.01 – 100 nM) was not able to modulate O2* generation stimulated by the chemotactic peptide N‐formyl‐L‐methionyl‐L‐leucyl‐L‐phenylalanine (fMLP, EC50= 4.24 ± 1.63 nM in the absence and 3.16 ± 1.95 nM in the presence of ET‐1). Neither did ET‐1 (0.01 – 100 nM) promote the mobilization of intracellular calcium ions or modulate fMLP‐induced [Ca2+]iincrease in this model of human neutrophils. Phosphoramidon, a neutral endopeptidase inhibitor, was not able to reveal any biological (O2*) or biochemical ([Ca2+]i) response to ET‐1 in the absence or in the presence of fMLP in these cells. These results indicate that DMSO‐differentiated neutrophil‐like HL‐60 cells are not sensitive to ET‐

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00146.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—Tracheal strips from normal and actively sensitized guinea pigs were studied to determine the responses to serotonin (5‐hydroxytryptamine, 5‐HT; 1 nM – 0.1 mM) and ouabain (0.1 μM – 0.1 mM), and the effects of increasing the extracellular calcium (Cao) concentration on tonic contractions elicited by 5‐HT. Sensitized trachea exhibited an increased responsiveness and sensitivity to 5‐HT and ouabain. Increases in Caoto achieve final concentrations of 5, 10 and 20 mM caused concentration‐related relaxations of normal and sensitized tissues contracted to a similar plateau level with 5‐HT. Inhibition of the Na+/K+‐ATPase by ouabain (10 μM) reversed the effects of Caofrom relaxation to contraction in normal and sensitized tissues contracted with 5HT. Sensitized preparations showed reduced relaxations in response to Cao(10–20 mM), and sensitized, ouabain‐treated, trachea showed augmented contractions to Cao(10–20 mM) when compared to normal tissues. These results demonstrate a decreased membrane‐stabilizing effect of Caoin sensitized trachea and the implication of the Na+/K+‐ATPase in the regulation of membrane stability by Cao, suggesting a possible relevance to those mechanisms un

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00147.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—The effects of ouabain and K+‐free solution were studied in estrogen‐primed rat uterine strips under resting tone or repeatedly stimulated with KCl, acetylcholine or oxytocin applied for 20 minutes at 60 minute intervals. These effects were compared with those of the K+channel opener cromakalim. In preparations under resting tone, ouabain (0.1 mM and 0.3 mM) induced rhythmic contractions which disappeared after 20–30 minutes whereas at a higher concentration (1 mM) it evoked a rapid, phasic response followed by a small tonic contraction. Exposure of the strip to a K+‐free solution induced either rhythmic waves, which ceased after 8–10 minutes, or a single phasic contraction which was followed by a small and slow increase in the resting tone (54 ± 10 mg after 180 min exposure). Nifedipine (0.3 μM) abolished the rhythmic or phasic component of these responses but failed to modify the late small tonic contraction induced by ouabain 1 mM or by K+‐free solution. Ouabain (0.1–1 mM) or K+‐free‐evoked responses disappeared after short (4 min) or prolonged (60 min) exposure to a Ca2+‐free, 3 mM EGTA‐containing solution. Cromakalim (10 nM −0.1 mM) did not induce any variation in the resting tone either in the presence or in the absence of Ca2+in the medium. In strips repeatedly stimulated with acetylcholine (0.1 mM) or oxytocin (1 μM), ouabain (0.3 mM), K+‐free‐solution and cromakalim (10 μM) reduced the amplitude of the initial, phasic response and progressively decreased the oscillatory component of the response to these agonists. Conversely, the successive responses evoked by KCl 60 mM in similar experimental conditions were not affected by ouabain or cromakalim. Ouabain (0.3 mM), K+‐free solution and cromakalim (10 μM) decreased the Ca2+‐independent, maintained contractions induced by acetylcholine or oxytocin after prolonged exposure to a Ca2+‐free, EGTA‐containing medium. These inhibitory effects were partially or completely reversed in the presence of the non‐selective potassium channel blocker tetraethylammonium (10 mM) or in a Ca2+‐free solution containing 60 mM K+. In conclusion, these results suggest that the response induced by ouabain or K+‐free solution in estrogen‐primed rat myometrium involves Ca2+influx through potential‐operated calcium channels but not Ca2+release from intracellular stores. In addition, our results show that prolonged exposure to ouabain or K+‐free medium decreases membrane receptor‐mediated responses in rat uterus. This inhibitory effect seems to be the result, at least in part, of a decrease in the cytosolic level

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00148.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—The effects of a new transdermal delivery system for clonidine (M‐5041T) on hypotensive effect, urine volume, plasma renin activity (PRA) and antidiuretic hormone (ADH) in spontaneously hypertensive rats (SHRs) were compared to the effects of the continuous infusion of clonidine. Both M‐5041T (1.5 and 4.5 mg/kg) and the continuous infusion of clonidine (250 μg/kg/24 h) elicited hypotensive effects persisting for 12 hours or more. These effects were based on consistent plasma concentrations of clonidine. These two treatments produced diuresis followed by antidiuresis, which was remarkably observed by continuous infusion of clonidine. Single subcutaneous injection of clonidine (50 μg/kg) produced diuresis accompanied by increases in electrolytes corresponding to plasma levels of clonidine. M‐5041T at 1.5 mg/kg did not affect PRA until 12 h, and produced an increase in PRA at 24 h. M‐5041T at 4.5 mg/kg and the continuous infusion of clonidine resulted in a decrease in PRA at 2 and 1 h followed by an increase at 12 and 24 h, respectively. M‐5041T at 1.5 mg/kg did not affect plasma levels of ADH. Plasma ADH did increase at 2 and 4 h accompanied by diuresis following M‐5041T at 4.5 mg/kg or the continuous infusion of clonidine, respectively. Clonidine‐induced diuresis was not at least due to the inhibition of ADH release. The decrease in urine volume observed by continuous infusion of clonidine may be due to decrease in renal blood flow based on stimulation of peripheral adorenoceptors of clonidine. These findings suggest that the increases in ADH and PRA are due to the compensatory effects related to both diuresis and the long‐lasting hypotensive effect induced by high plasma concentrations of clonidine. Thus, it can be expected that M‐5041T at 1.5 mg/kg showing the minimum effective plasma concentration of clonidine will not result in tolerance to the hypotensive effect of clonidine associated with the retent

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00149.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

Summary—In children, tiaprofenic acid (TA), a non steroidal antiinflammatory drug, propionic‐acid derivative, has been proven effective in the treatment of symptoms of tonsillitis and pharyngitis but not yet in the symptomatic treatment of fever. This doubleblind, parallel group, placebo (PI) controlled study was designed in order to demonstrate the antipyretic activity of TA. The coprescription of other antipyretic medications in children may therefore be avoided. Two groups of children, 29 (TA group) and 26 (PI group), were included and received either 4.2 ± 0.5 mg/kg of TA given orally in a single dose or a PI match. Rectal temperature was recorded just before and 1, 2, 4 and 6 hours after dosing. The maximum temperature decrease was significantly greater in the TA group (– 1.3 °C ± 0.7 °C) than in the PI group (– 0.4 °C ± 0.8 °C). The percentage of children who needed a rescue treatment during the study was 35% (10/29) and 62% (16/26) in the TA and PI group, respectively. The rescue treatment was composed of a single oral acetaminophen dose in case of fever above 39.5 °C or if the temperature decrease was not at least equal to 0.6 °C four hours after dosing. No major side effect was reported by the parents during the study period. In conclusion, TA at a single mean 4.2 mg/kg oral dose, is an effective antipyretic drug in febrile children. The duration of the antipyretic effect was estimated as at

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00150.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00151.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1996.tb00152.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY