摘要:

Summary—The main clinical features, pathophysiology and underlying mechanisms of drug‐induced parkinsonism are reviewed. The clinical manifestations of drug‐induced parkinsonism are often indistinguishable from idiopathic Parkinson's disease. However, some subtle differences may exist: for example drug‐induced parkinsonism is often associated with tardive dyskinesias, bilateral symptoms and the absence of resting tremor, etc. Besides toxins (egmanganese, carbon monoxide or MPTP), many drugs are known to produce parkinsonism: dopamine blocking drugs (true neuroleptics used as antipsychotics: phenothiazines, butyrophenones, thioxanthenes but also sulpiride, “hidden” neuroleptics prescribed as anti‐nausea or anti‐vomiting drugs (such as metoclopramide and other benzamide derivatives), dopamine depleting drugs (reserpine, tetrabenazine), alpha‐methyldopa, calcium channel blockers (flunarizine, cinnari‐zine, etc). The putative role of other drugs (egfluoxetine, lithium, amiodarone) as well as the therapeutic management of this side

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00808.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—Several neuropeptides play a key role in the transfer (substance P, calcitonin gene‐related peptide, etc) and control (enkephalins, cholecystokinin, etc) of nociceptive messages from primary afferent fibres to spino‐thalamic neurones in the dorsal horn of the spinal cord. This first relay in nociceptive pathways has been shown to be a major target for opioids such as analgesic drugs, and the effects of exogenous (mainly morphine) and endogenous opioids on the release of neuropeptides within the dorsal horn are reviewed here for a better understanding of the cellular mechanisms responsible for their antinociceptive action. Complex modulations of thein vitro(from tissue slices) andin vivo(in halothane‐anaesthetized rats whose intrathecal space was perfused with an artificial cerebrospinal fluid) release of substance P and calcitonin gene‐related peptide by opioids have been reported, depending on the opioid receptor (mu, delta, kappa, and their subtypes) stimulated by these compounds. In particular, the inhibition by delta agonists of substance P release from primary afferent fibres, and that by the concomitant stimulation of mu and kappa receptors of the release of calcitonin gene‐related peptide are very probably involved in the analgesic action of specific opioids and morphine at the level of the spinal cord. Furthermore, the negative modulation (through presynaptic opioid autoreceptors) by delta and mu agonists of the spinal release of met‐enkephalin, and the complex inhibitory/excitatory influence of delta, mu and kappa receptor ligands on the release of cholecystokinin within the dorsal horn very likely also contribute to the antinociceptive action of these drugs and morphine. The reviewed data strongly support the existence of functional interactions between mu and kappa receptors within the spinal cord, and their key role in the analgesic action of non specific opiates (acting on mu, delta and kappa receptors) suc

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00809.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—Research into the biological basis of lens transparency has demonstrated the implication of lens sugar stress in the diabetic cataract whereas senile cataract is the result of natural degeneration which is enhanced by various external factors such as cosmic and ionizing rays, or oxidative processes. Drugs have been developed which are aimed at being effective on lens pathological physiology and metabolism, concurrently. Such molecules: aldose reductase inhibitors (ARIs: sorbinil, AD‐5467, CT‐112 and imirestat), acetyl salicylic acid (ASA), salicylate (SA) and sodium monomethyl trisilanol orthohydroxybenzoate (SMB, a prodrug for salicylate) have undergone pharmacodynamic, pharmacokinetic and/or clinical studies which are presented here. ARIs have shown efficacy in slowing down and preventing the progression of experimental sugar cataracts; sorbinil can partially reverse the very early morphological signs of sugar cataract. Sorbinil and imirestat have also demonstrated anti‐oxidant properties. ARIs administration (per os or by topical instillation) generally results in lens levels compatible with concentrations that are efficient on biochemical mechanisms of cataract formation. However, at the present time, clinical evaluations are in progress and as yet, there is no confirmation of their efficacy in man. ASA and SA can prevent various mechanisms of lens protein denaturation; they inhibit AR and prevent,in vitro, the formation of some pigments found in the aged cataractous lens. Extrapolation of the ASA ocular pharmacokinetics results in animal to man, suggest that ASA administration per os could result in efficacious levels in the lens. This is also sustained by the observation of a reduced frequency of cataracts in ASA treated diabetic rhumatoid arthritis patients. SMB pharmacokinetic studies have shown small but persistent levels of the active principle in the lens. They suggest that the capsule slows down SA diffusion into the lens and that, on the contrary, lens epithelium facilitates its penetration. Preliminary results of pharmacodynamic studies ar

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00810.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—The vasopressor responses of three natural endothelins (ET‐1, ET‐2, ET‐3) and their precursors, pro‐ETs, were studied in a pithed rat preparation, which allows the profile and the potency of vasoconstrictor agents to be determined in the absence of central control of the cardiovascular system. ET‐1 was found to be 4‐ and 8‐fold more potent in raising blood pressure than ET‐2 and ET‐3, respectively. The immediate precursors of these isopeptides, h‐pro‐ET‐1 (human), p‐pro‐ET‐1 (porcine), pro‐ET‐2 and proET‐3, produced significantly smaller pressor responses than their respective ETs, when measured either as peaks or as areas under the time‐effect curve. Hence, the bioavailability of h‐pro‐ET‐1, p‐pro‐ET‐1 and pro‐ET‐2, assessed on the basis of these two parameters, was approximately 50% of that of their corresponding ET, whereas the bioavailability of pro‐ET‐3 was only 25% that of ET‐3. Phosphoramidon inhibits metallopeptidases, the enzymes that convert pro‐ETs to ETs. The approximate iv doses of phosphoramidon reducing by 50% the pressor effects of the pro‐ETs were 2.5, 0.625, less than 2.5 (this dose produced 75% inhibition) and 5 mg/kg iv for h‐pro‐ET‐1, p‐pro‐ET‐1, pro‐ET‐2 and pro‐ET‐3, respectively. In conclusion, these results indicate that the rat may have more than one pro‐ET converting enzyme, each specific for one of the natural pro‐ETs studied, although the alternative explanation, that there is

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00811.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—Changes in neurobiological parameters were examined from early life (10 days post‐natal) until late adulthood (8 months post‐natal) in three successive generations of alcoholized rats. The mean daily consumption of alcohol by the 2nd and 3rd generation rats (7.40 ± 0.22 and 7.70 ± 0.20 g ethanol/kg body weight, respectively) was significantly greater than that of the 1st generation alcoholized group (4.26 ± 0.33 g/kg). Brain/body weight ratios of alcoholized rats, 10 days post‐natal, were significantly greater than controls, with 1st generation alcoholized rats presenting significantly greater brain/body weight ratios than those of the 2nd or 3rd generation, which tended toward control weights and ratios. This difference between alcoholized rats and controls persisted, although to a lesser extent, at 8 months post‐natal. Glycogen content in the brains of rats of all alcoholized generations was significantly lower than in controls at 10 days post‐natal, with a reversal of this situation in later life for 2nd and 3rd generation rats, which presented significantly greater cerebral glycogen levels than control or 1st generation alcoholized rats (which had an equivalent cerebral glycogen content). In 10‐day‐old rat pups, monoamine oxidase (MAO) activity in brain tissues had a tendency (mostly non‐significant) to be greater in alcoholized rats than in controls, with a reversal of this situation,iea statistically significant decrease in MAO activity in the 2nd and 3rd alcoholized generations with respect to controls, in 8‐month‐old rats. MAO activity in adrenal glands of alcoholized rats was greater than in controls at 10 days post‐natal, and this differ

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00812.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—The effects on renal function of quinapril, an angiotensin I converting enzyme (ACE) inhibitor, and of nifedipine, a dihy‐dropyridine calcium antagonist, were studied in the early stages of diabetes in rats. Wistar rats received one injection of streptozotocin (STZ) to induce diabetes; the hyperglycaemia was then controlled with daily insulin therapy (2–3 units NPH insulin/rat). One week after STZ injection, rats were treated orally with quinapril (0.3 or 3 mg/kg/d) or nifedipine (30 mg/kg/day) for 1 week, after which renal functions were compared with those of untreated diabetic rats or non‐diabetic control rats. At the end of these two weeks, diabetic rats had gained less weight and had developed renal hypertrophy and glomerular hyperfiltration (3.21 ± 0.23vs2.36 ± 0.09 ml/min for non‐diabetic rats, mean ± SEM,P<0.01). Their urinary albumin excretion was higher, as was the urinary excretion of water, sodium, potassium, urea and glucose. One week treatment with quinapril or nifedipine had no significant effect on the increase in the glomerular filtration rate (respectively 2.97 ± 0.18 and 2.99 ± 0.15 ml/min). Quinapril and nifedipine differed with regard to their effects on urinary albumin excretion. Albuminuria was increased by nifedipine but not by quinapril (respectively 0.554 ± 0.158 and 0.149 ± 0.046 mg/day/100 g BW,P<0.05). This difference between the effects of the dihydropyridine and the ACE inhibitor on albuminuria may be linked to different effects on the glom

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00813.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—In order to identify tissue specific regulation of angiotensin converting enzyme (ACE), the effects of dexamethasone (0.04 mg sc per day for 7 days) and triiodothyronine (T3) (0.5 mg/kg sc per day for 10 days) on ACE activity were investigated in different tissues in male Wistar rats. ACE activity was measured by fluorimetry in the plasma, heart, lung and kidney. In the kidney, ACE activity was measured in the medulla, cortex and brush border of proximal tubular cells and3H‐ramiprilat binding was used to characterise the changes in brush border ACE activity. Dexamethasone elicited a significant increase in lung ACE activity and a significant decrease in plasma ACE activity, but did not alter enzyme activity in the other tissues studied. T3 produced a significant decrease in lung ACE activity and an increase in ACE activity in the plasma and heart. In the kidney, ACE activity was not modified in the medulla whereas in the cortex and brush border ACE activity was doubled. This increase in ACE activity corresponded to a similar increase in the maximum number of binding sites of3H‐ramiprilat, suggesting that the increase in activity corresponded to an increase in the ACE level. The increased heart and kidney ACE activity in response to T3 may contribute to the cardiovascular effects of thyroid hormones through increased local angiotensin II generation. These results show that under dexamethasone or T3, ACE activity can vary from one tissue to another, suggesting that the ACE regulatory mechanism acts differently in each t

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00814.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—The influence of the dihydropyridine calcium entry blockers nicardipine, amlodipine, nifedipine, isradipine and of the dihydropyridine calcium entry promotor BAY K 8644 on the disappearance rate of propranolol by isolated rat hepatocytes was compared to the effect of diltiazem and verapamil, two non‐dihydropyridine calcium channel blockers and known inhibitors of hepatic cytochrome P450 mixed function oxidases. All compounds dose‐dependently inhibited the disappearance rate of propranolol. Nicardipine and isradipine were more potent in inhibiting the disappearance rate of propranolol than the other dihydropyridines and than diltiazem and verapamil. The inhibitory effect of nicardipine on the disappearance rate of propranolol was not stereoselective and was not influenced b

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00815.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY

摘要:

Summary—Effects of repeated intravenous (iv) administration of diazepam on food intake were investigated in freely moving rats implanted with a chronic iv cannula. Diazepam (0.2 and 2 mg/kg) was automatically injected iv at 3‐h intervals for 3 consecutive days. Food intake was measured twice daily,iefor the light phase (7 00–19 00) and dark phase (19 00–7 00). Food intake during the light phase was increased in a dose‐dependent manner following diazepam. Each injection of diazepam provoked hyperphagia, followed by a compensatory hypophagia until the next diazepam injection. Body weight, however, was increased significantly in rats treated with diazepam. When diazepam (2 mg/kg) was automatically injected at 3‐h intervals for 10 consecutive days, tolerance did not develop to the hyperphagia and body weight was increased significantly following diazepam injection. After cessation of diazepam injection, both food intake and body weight decreased. These findings suggest that such excessive iv treatment with diazepam induces hyperphagia showing no tolerance accompanied by an increase in body weight, thus resulting in a trend toward obes

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1994.tb00816.x

出版商:Blackwell Publishing Ltd    

年代:1994

数据来源: WILEY