ISSN:1355-6215    

DOI:10.1080/1355621961000124646

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractRecent clinical and experimental studies have demonstrated that the habitual consumption of large amounts of ethanol has deleterious effects on the kidney. A variety of tubular defects have been described in patients with chronic alcoholism. Evidence is emerging that tubular dysfunction has an important pathophysiological role in a wide range of electrolyte and acid‐base disturbances commonly observed in these patients, and possibly in alcohol‐induced bone disease. These renal abnormalities are often reversible, disappearing with abstinence. However, since 1990 a few cases of a syndrome of acute tubular necrosis due to binge drinking of ethanol in the absence of other evident nephrotoxic mechanisms, or in association with the use of nonsteroidal anti‐inflammatory drugs, have been reported. A link between glomerulonephritis and alcoholism has become evident. IgA nephropathy has been demonstrated at autopsy in 64% of chronic alcoholics and, more recently, the association between alcoholism and postinfectious glomerulonephritis has been described. Structural and functional abnormalities of the kidney are reported with increasing frequency in the fetal alcohol syndrome seen in children who have been prenatally exposed to ethanol. In addition, over the last few years experimental studies in vitro or in animal models have provided information about the biochemical and molecular basis of alcohol‐induced injury to kidney. It is hoped that future experimental and clinical research will provide us with a more comprehensive knowledge of the mechanisms of renal damage in alcohol

ISSN:1355-6215    

DOI:10.1080/1355621961000124656

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractOpioids have been used and abused by humans for centuries. The μ opioid receptor represents the high affinity binding site for opioid narcotics with high abuse liability such as morphine, codeine and fentanyl. Heroin (diacetylmorphine), a semi‐synthetic derivative of morphine, crosses the blood‐brain barrier more readily than morphine due to its increased hydrophobicity. Once in the brain heroin is hydrolyzed to morphine, which acts at the μ opioid receptor and results in euphoria, thus conferring the reinforcing properties of heroin. Using molecular biology techniques, the μ opioid receptors from several species have been cloned. This article reviews recent progress in this area, with respect to the two major cellular functions of the μ opioid receptor: reduction of intracellular cAMP concentration by inhibiting adenylyl cyclase activity, and inhibition of neuronal firing by modulating membrane ion c

ISSN:1355-6215    

DOI:10.1080/1355621961000124666

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractOver the past 10 years a great deal has been learned about the cardiovascular effects of cocaine. In particular, the acute effects of cocaine have been studied extensively. Upon acute administration cocaine increases blood pressure and heart rate, primarily through an action on the sympathetic nervous system. Cocaine also suppresses the baroreflex response and vagal tone, further contributing to its effects on heart rate. At the same time cocaine is increasing the work‐load on the heart it induces coronary artery vasoconstriction, potentially leading to cardiac ischemia. At higher doses cocaine can depress ventricular function and slow electrical conduction in the heart. Both these effects appear to be mediated by cocaine's local anesthetic action. The effects of cocaine mediated by the sympathetic nervous system are greatly reduced in anesthetized animals. Further, when cocaine is administered repeatedly over a short period of time, acute tolerance can develop to the sympathomimetic effects of cocaine. In contrast, the effects of cocaine mediated by its local anesthetic action do not appear blunted by anesthesia or susceptible to acute tolerance. With chronic administration, higher doses appear to induce tolerance while lower doses may induce sensitization to cocaine's sympathomimetic effects. Cocaine also induces a variety of pathological changes in the heart, including myocardial contraction band necrosis and ventricular hypertrophy. These effects of cocaine on the heart can all contribute to potentially lethal cardiovascular events. In addition to the effects of cocaine alone, the metabolites of cocaine may also contribute to cocaine's cardiovascular toxicity, and both licit and illicit drugs used in combination with cocaine might potentially alter its cardiovascular effect

ISSN:1355-6215    

DOI:10.1080/1355621961000124676

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractA cloned μ opioid receptor was used to study its coupling to signal transduction pathways and its involvement in morphine‐induced opioid dependence in stably transfected Chinese hamster ovary (CHO) cells. Membrane binding assays with a μ‐selective agonist [3 H]DAMGO showed that one cell line expresses a high level of μ opioid receptors with a B max of ∼ 630 fmol/mg membrane protein and a K d of 0.47 nM for DAMGO. Stimulation of the transfected cells with DAMGO led to an increase in the low K m GTPase activity, indicative of activation of guanine nucleotide regulatory proteins (G proteins), and this effect was blocked by the opioid antagonist naloxone. In addition, binding of the μ opioid receptor to DAMGO was affected by GTP and nonhydrolizable GTP analogs, Gp(NH)pp and GTP‐γ‐S. These results suggest a functional coupling between the μ opioid receptor and G proteins. Furthermore, DAMGO treatment of the cells produced a dose‐dependent inhibition of the intracellular cyclic adenosine monophosphate (cAMP) level, with an EC 50 value of approximately 30 nM. Chronic treatment of the cells with morphine not only elevated the basal and forskolin‐stimulated cAMP levels after morphine withdrawal, but also increased the extent of the DAMGO‐induced reduction of intracellular cAMP levels. The whole cell binding assay with [3 H]DAMGO, on the other hand, did not detect receptor down‐regulation after chronic morphine treatment. These results suggest that chronic morphine treatment may trigger a compensatory mechanism in cellular signaling pathways to offset the inhibitory input from the μ receptor without down‐regulation of the surface receptor number, and that withdrawal of chronic inhibition leads to elevated activities of adenylyl cyclase to provide a basi

ISSN:1355-6215    

DOI:10.1080/1355621961000124686

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe role of σ receptors in the induction of heat shock protein (HSP)‐70 by non‐competitive N‐methyl‐Daspartate (NMDA) receptor antagonists (+)‐MK‐801 (dizocilpine) and phencyclidine (PCP) was studied. HSP‐70 is induced in the posterior cingulate and retrosplenial cortex of rat brain 24 hours after a single administration of dizocilpine (1 mg/kg) or PCP (50 mg/kg). The induction of heat shock protein HSP‐70 by dizocilpine or PCP was attenuated partially by pre‐treatment with the antipsychotic drug haloperidol (3 mg/kg, i.p., 15 minutes previously). However, pre‐treatment with high potent and selective σ receptor ligands, 4‐phenyl‐4‐(1‐phenylbutyl)piperidine (4‐PPBP, 3 mg/kg, i.p., 15 minutes previously) and N,N‐dipropyl‐2‐[4‐methoxy‐3‐(2‐phenylethoxy)phenyl]‐ethylamine monohydrochloride) (NE‐100, 3 mg/kg, i.p., 15 minutes previously) did not alter the induction of HSP‐70 by dizocilpine or PCP. These findings suggest that σ receptors may not play a significant role in the induction of HSP‐70 by non‐competitive NMDA receptor antagonists dizocilpine and PCP, and that protective effects of haloperidol on induction of HSP‐70 protein by dizocilpi

ISSN:1355-6215    

DOI:10.1080/1355621961000124696

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractEthanol is known to cause an acute and profound insulin resistance in man and the rat primarily via effects on glucose utilization. This paper examines the nature of these inhibitory effects on whole‐body glucose utilization using the euglycaemic hyperinsulinaemic clamp in the conscious unrestrained rat. We confirm that ethanol infusion causes an acute insulin resistance, the rate of glucose infusion required to maintain euglycaemia (GIR) being decreased markedly by ethanol. To ensure that the GIR is a measure of whole‐body glucose disposal, glucose turnover and hepatic glycogen levels were measured. These studies showed that ethanol totally suppressed hepatic glucose production. The reduction in GIR is associated with marked decreases in glucose uptake and glycogen synthesis in most skeletal muscles. In oxidative but not in non‐oxidative muscles, the activation of glycogen synthase in response to insulin was decreased by ethanol, suggesting that a defect in glycogen synthase activation may be responsible for the decrease in glycogen synthesis. The basis of the inhibitory effects of ethanol on insulin‐stimulated glucose metabolism in muscle is unknown, but may involve membrane‐associated impairments in insulin signalling and/or the glucose transpo

ISSN:1355-6215    

DOI:10.1080/1355621961000124706

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractAn investigation was made into the relative composition and synthesis rates of smooth muscle contractile proteins in vivo in different regions of the rat gastrointestinal tract. There was considerable homogeneity in the composition of sarcoplasmic proteins in the small bowel (i.e. 54‐58 mg/g) but considerable variability in the large bowel, i.e. highest in the caecum (97 mg/g) and lowest in the colon (21 mg/g). The myofibrillary protein concentration was constant throughout the gastrointestinal tract, i.e. 20‐34 mg/g. Stromal fractions varied from 6 to 39 mg/g and was highest in the cardiac region of the stomach and lowest in the duodenum. Fractional rates of protein synthesis were measured with a flooding dose of L‐[4‐3 H]phenylalanine. In control rats synthesis rates in sarcoplasmic protein fractions were relatively much higher (43‐107%/day) than myofibrillar (27‐52%/day) or stromal (6‐26%/day) proteins. Fractional rates of stromal protein synthesis showed the greatest variability while myofibrillar synthesis rates the least, throughout the alimentary tract. Jejunal seromuscular layer myofibrillar proteins had the highest synthesis rates (49%/day). In response to acute ethanol injection, protein synthesis in all jejunal fractions fell by 20‐30%. Contractile and non‐contractile proteins from the cardiac region of the stomach, duodenal seromuscular layer and large bowel seromuscular layer were insensitive to ethanol administration. Protein synthesis of sarcoplasmic proteins from the antrum, ileum seromuscular layer and myofibrillar proteins from the ileum seromuscular layer and caecum were also significantly depressed as a result of

ISSN:1355-6215    

DOI:10.1080/1355621961000124716

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractIn our society every second polytraumatized patient is a chronic alcoholic. A patient's alcohol‐related history is often unavailable and laboratory markers are not sensitive or specific enough to detect alcohol‐dependent patients who are at risk of developing alcohol withdrawal syndrome (AWS) during their post‐traumatic intensive care unit (ICU) stay. Previously, it has been found that plasma levels of norharman are elevated in chronic alcoholics. We investigated whether β‐carbolines, i.e. harman and norharman levels, could identify chronic alcoholics following trauma and whether possible changes during ICU stay could serve as a predictor of deterioration of clinical status. Sixty polytraumatized patients were transferred to the ICU following admission to the emergency room and subsequent surgery. Chronic alcoholics were included only if they met the DSM‐III‐R and ICD‐10 criteria for alcohol dependence or chronic alcohol abuse/harmful use and their daily ethanol intake was ≥ 60 g. Harman and norharman levels were assayed on admission and on days 2, 4, 7 and 14 in the ICU. Harman and norharman levels were determined by high pressure liquid chromatography. Elevated norharman levels were found in chronic alcoholics (n = 35) on admission to the hospital and remained significantly elevated during their ICU stay. The area under the curves (AUC) showed that norharman was comparable to carbohydrate‐deficient transferrin (CDT) and superior to conventional laboratory markers in detecting chronic alcoholics. Seventeen chronic alcoholics developed AWS; 16 of these patients experienced hallucinations or delirium. Norharman levels were significantly increased on days 2 and 4 in the ICU in patients who developed AWS compared with those who did not. An increase in norharman levels preceded hallucinations or delirium with a median period of approximately 3 days. The findings that elevated norharman levels are found in chronic alcoholics, that the AUC was in the range of CDT on admission and that norharman levels remained elevated during the ICU stay, support the view that norharman is a specific marker for alcoholism in traumatized patients. Since norharman levels increased prior to the onset of hallucinations and delirium it seems reasonable to investigate further the potential role of norharman as a possible substance

ISSN:1355-6215    

DOI:10.1080/1355621961000124726

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe plasma levels of 42 patients on a levomethadone maintenance treatment programme for intravenous heroin users were measured before and, respectively, 1, 2 or 4 hours after oral routine administration and related to the individual additional drug usage (detected by urine drug screening), liver function, side‐effects and withdrawal symptoms. In general, accelerated levomethadone metabolism induced by additional misuse of benzodiazepines, barbiturates and opiates resulted in significantly lower plasma levels of the substitute. In particular, high γ‐glutamyltransferase activity was related to benzodiazepine consumption. On the other hand, an impaired liver function reflected by increased β‐globulins resulted in an insufficient body clearance and drug accumulation. Major side effects, such as sweating, were not related to plasma levels whereas withdrawal symptoms like diarrhoea or “feeling cold” correlate with lower plasma concentrations. It is concluded that polydrug misuse in the methadone maintenance therapy creates a vicious circle of enzyme induction, thus increasing “instrumental drug utilization”. However, underestimated maintenance dosage may lead to additional drug consumption resulting, finally, in ther

ISSN:1355-6215    

DOI:10.1080/1355621961000124736

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY