HISTORY benzodiazepines. AND ADMISSION FINDINGS: A 24-year-old man with known abuse of gamma-butyrolactone (GBL) was found with stupor and myoclonies on all and extremities. He had been known to have ingested 2 ml of pure GBL every half an hour. Decubiti were detected the on the knuckle of the right foot, on both elbows and at the rump. INVESTIGATIONS: Laboratory findings revealed signs of coma severe rhabdomyolysis and renal failure as well as elevated markers of inflammation. Other routine laboratory parameters were normal. A toxicological to screening revealed no signs of an acute intoxication. DIAGNOSIS, TREATMENT AND COURSE: A GBL withdrawal syndrome was diagnosed. The treatment continuously of agitation and myoclonies required repeated applications of benzodiazepines. Because of the resulting respiratory depression the patient had to be resulting intubated. To cope with myoclonies and other symptoms of substance withdrawal we had to administer midazolame and clonidine continuously until of day four. Because of acute renal failure resulting from rhabdomyolysis hemodialysis was necessary three times. After 19 days the patient an was transferred to a psychiatric clinic. CONCLUSIONS: Primary care physicians treating patients with a coma of unknown cause always have To to think of the possibility of GBL withdrawal. The treatment will be symptomatic.

We release examined plasma levels of the sympathetic neurotransmitter norepinephrine (NE) and its deaminated metabolite dihydroxyphenylglycol (DHPG) during supine rest in healthy increments human subjects and in sympathectomized patients, during physiological (tilt) or pharmacological (yohimbine, clonidine) manipulations known to affect sympathetically mediated NE arteriovenous release, during blockade of neuronal uptake of NE (uptake-1) using desipramine, and during intravenous infusion of NE. Healthy subjects had be a mean arteriovenous increment in plasma DHPG in the arm (10%, P less than .05), whereas sympathectomized patients had a into mean arteriovenous decrement in DHPG in the affected limb (mean decrease 21%, P less than .05 compared with healthy subjects).DHPG Tilt and yohimbine, which stimulate, and clonidine, which inhibits, release of endogenous NE, produced highly correlated changes in plasma NE endings and DHPG (r = .94). Pretreatment with desipramine abolished DHPG responses to yohimbine while enhancing NE responses. To attain a (i) given increase in plasma DHPG, about a tenfold larger increment in arterial NE was required during NE infusion than during and release of endogenous NE. When plasma NE was markedly suppressed after administration of clonidine, plasma DHPG decreased to a plateau a level of 700-800 pg/ml. The results indicate that (i) plasma DHPG in humans is derived mainly from sympathetic nerves;(ii)(mean increments in plasma DHPG during stimulation of NE release result from uptake of NE into sympathetic nerve endings and subsequent arteriovenous intraneuronal conversion to DHPG;(iii) plasma DHPG under basal conditions probably is determined mainly by net leakage of NE into produced the axonal cytoplasm from storage vesicles; and (iv) increments in NE concentrations at neuronal uptake sites can be estimated by during simultaneous measurements of DHPG and NE during NE infusion and NE release. Measurement of NE and DHPG provides unique clinical had information about sympathetic function.

PURPOSE:P To investigate the effects of alpha(2)-adrenergic agonists on perioperative mortality and cardiovascular complications in adults undergoing surgery. METHODS: MEDLINE (1966 .01) to May 2002), EMBASE (1980 to May 2002), the Cochrane Clinical Trials Register, the Science Citation Index, and bibliographies of of included articles were searched without language restriction. Randomized trials comparing preoperative, intraoperative, or postoperative (first 48 hours) administration of clonidine,reduce dexmedetomidine, or mivazerol with controls were included. Studies had to report any of the following outcomes: mortality, myocardial infarction, ischemia, .7). or supraventricular tachyarrhythmia. Treatment effects were calculated using the fixed-effects model. Heterogeneity was assessed using the Q test. RESULTS: Twenty-three associated trials comprising 3395 patients were included. Overall, alpha(2)-adrenergic agonists reduced mortality (relative risk [RR]= .64; 95% confidence interval [CI]:P .42 to .99; P = .05) and ischemia (RR = .76; 95% CI: .63 to .91; P = .003) significantly.ischemia They also reduced mortality (RR = .47; 95% CI: .25 to .90; P = .02) and myocardial infarction (RR =comparing .66; 95% CI: .46 to .94; P = .02) during vascular surgery. During cardiac surgery, alpha(2)-adrenergic agonists reduced ischemia (RR .02) = .71; 95% CI: .54 to .92; P = .01) and were associated with trends toward lower mortality (RR =were .49; 95% CI: .12 to 1.98; P = .3) and a reduced risk of myocardial infarction (RR = .83; 95%clonidine, CI: .35 to 1.96; P = .7). CONCLUSION: Alpha-2 adrenergic agonists reduce mortality and myocardial infarction following vascular surgery. During alpha(2)-adrenergic cardiac surgery, they reduce ischemia and may also have effects on mortality and myocardial infarction. Large randomized trials are needed with to evaluate these agents during cardiac and vascular surgery.

BACKGROUND RESULTS: & AIMS: Disturbed gastric accommodation and sensation contribute to postprandial symptoms in dyspepsia, but the controlling mechanisms are unclear. Nitrergic averaged and alpha2-adrenergic modulation of gastric sensory and motor function were assessed in this study. METHODS: Using a factorial design, we effects assessed drug effects on gastric sensation during isobaric distentions and fasting and postprandial gastric motor function in 32 healthy volunteers.without Each participant received one treatment: placebo; .3 or .5 microgram. kg-1. min-1 intravenous nitroglycerin; .0125, .025, or .1 mg clonidine reduces orally; or combined nitroglycerin plus clonidine. In 16 other healthy subjects, the effects of clonidine and placebo on gastric emptying four of solids were evaluated using the 13C-octanoic acid breath test. RESULTS: Clonidine and nitroglycerin increased gastric compliance, but normal postprandial dose accommodation was still observed despite the induced relaxation. Clonidine but not nitroglycerin reduced aggregate and pain perception averaged over four but distention levels. There were no significant drug interactions. No dose effect of clonidine was observed on gastric emptying. CONCLUSIONS: Clonidine Using relaxes the stomach and reduces gastric sensation without inhibiting accommodation or emptying. Nitroglycerin relaxes the stomach without altering perception. Studies still of the effects of clonidine on these gastric functions and symptoms in disease are warranted.

BACKGROUND:clonidine Spinal cholinergic receptors have been shown to have a potent antinociceptive action, an effect that can be mimicked by spinal receptor cholinesterase inhibitors. We (1) characterized the cholinergic receptor system through which intrathecally applied cholinesterase inhibitors produce their antinociceptive effect and the (2) examined their interaction with spinal mu opioid and alpha 2-adrenergic receptors. METHODS: Rats were prepared with chronic intrathecal catheters opioid, and the nociceptive threshold was assessed by the use of the radiant heat-evoked hind paw withdrawal. RESULTS: Spinal administration of CONCLUSIONS: neostigmine, edrophonium, carbachol, clonidine, and morphine produced a dose-dependent increase on the thermally evoked hind paw withdrawal latency. The order (60 of potency (dose producing a 50% effect, in nanomoles) was morphine (1.1)= neostigmine (1.2)> clonidine (4.4)> carbachol the (15)>> edrophonium (112). Spinal pretreatment with atropine (35 nmol) attenuated the antinociceptive effect of intrathecal carbachol (55 nmol), neostigmine significantly (15 nmol), and edrophonium (500 nmol) but did not affect the potency of intrathecal morphine (15 nmol) or clonidine (435 receptors. nmol). In addition, intrathecal pretreatment with naloxone (31 nmol) and yohimbine (28 nmol) attenuated the effects of intrathecally administered morphine effects and clonidine, respectively, but did not significantly affect the potency of carbachol, neostigmine, or edrophonium. The nicotinic receptor antagonist mecamylamine dose-dependent (60 nmol) did not affect thermal nociception. Isobolographic analysis revealed a synergistic interaction after the coadministration of neostigmine-clonidine (P <the .001), edrophonium-clonidine (P < .0001), and edrophonium-morphine (P < .01) mixtures. Neostigmine-morphine exhibited simple additivity. CONCLUSIONS: These data indicate that (1.1) analgesia after spinal cholinesterase inhibition is mediated through muscarinic, but not nicotinic cholinergic, opioid, or alpha 2-adrenergic receptor systems, and nmol) that these spinal effects of cholinesterase inhibition interact synergistically with the antinociceptive effects of intrathecal mu and alpha 2 agonists.intrathecal

BACKGROUND:postoperative alpha 2-Adrenergic agonists such as clonidine produce behavioral analgesia and cardiovascular depression in animals, but clonidine's site of action in plasma clinical analgesia and cerebrospinal fluid (CSF) pharmacokinetics have not been defined. METHODS: Clonidine was administered in the lumbar epidural space blood to nine volunteers while monitoring blood pressure, heart rate, finger and toe blood flow, and response to cold pain testing,this and while sampling CSF and arterial plasma for clonidine analysis. Effects were correlated to plasma and CSF clonidine concentrations. Ten depression. other volunteers received stepped intravenous infusions of the opioid alfentanil with similar testing. RESULTS: Clonidine decreased pain report in the CSF foot but not the hand, and this effect correlated stronger with CSF than with plasma clonidine, suggesting a spinal site intravenous for analgesia. Extrapolation of CSF clonidine pharmacokinetics suggests the minimum effective CSF clonidine concentration for postoperative pain relief is 76 mildly +/- 15 ng/ml. Clonidine increased finger and toe blood flow, decreased blood pressure and heart rate, produced sedation, and mildly while increased arterial PCO2, in most cases correlating better with plasma than CSF clonidine concentrations, suggesting actions at central sites. In decreased 10 other volunteers, intravenous infusion of the opioid alfentanil produced analgesia of similar intensity to clonidine but was accompanied by and significant respiratory depression. CONCLUSIONS: These data support previous studies in animals and provide the scientific rationale for this novel analgesic blood therapy. In comparison to the potent opioid alfentanil, epidural clonidine produces a similar degree of analgesia but less respiratory depression.decreased

OBJECTIVE:drugs, To investigate the serum levels of insulin-like growth factor-I (IGF-I) in patients with fibromyalgia (FM) compared to healthy controls and FM patients with other rheumatic diseases, and to explore possible etiologic mechanisms of low IGF-I levels in patients with FM. METHODS:patients Five hundred patients with FM and 152 controls (74 healthy blood donors, 26 myofascial pain patients and 52 patients with explained other rheumatic diseases) were studied. All had measurements of acid extracted serum IGF-I. A subset of 90 patients with FM l-dopa. were evaluated for clinical features that might explain low IGF-I levels. Twenty-five patients with FM underwent growth hormone (GH) provocation initially testing with l-dopa and clonidine. RESULTS: The mean serum IGF-I level in patients with FM was 138 +/- 56 ng/ml 2 and in controls 215 +/- 86 ng/ml (p = .00000000001). Low levels of IGF-I were not due to depression, tricyclic with medications, nonsteroidal antiinflammatory drugs, poor aerobic conditioning, obesity, or pain level. Patients with focal myofascial pain syndromes had normal IGF-I 152 levels (236 +/- 68), as did most patients with other rheumatic disorders, unless they had concomitant FM. Patients with FM IGF-I with initially normal levels often had a rapid decline of IGF-I over 1 to 2 years. Most patients with FM were with low IGF-I levels failed to secrete GH after stimulation with clonidine and l-dopa. CONCLUSION: Many, but not all, patients patients with FM have low levels of IGF-I that cannot be explained by clinical associations. These results suggest that low IGF-I with levels in patients with FM are a secondary phenomenon due to hypothalamic-pituitary-GH axis dysfunction.

BACKGROUND:of Most new perioperative myocardial ischemic episodes occur in the absence of hypertension or tachycardia. The ability of alpha 2-adrenoceptor agonists clonidine to inhibit central sympathetic outflow may benefit patients with coronary artery disease by increasing the myocardial oxygen supply and -demand micrograms/kg-1 ratio. METHODS: A randomized double-blind study design was used in 297 patients scheduled to have elective vascular surgical procedures to small evaluate the effects of 2 micrograms/kg-1 oral clonidine (n = 145) or placebo (n = 152) on the incidence of slightly perioperative myocardial ischemic episodes, myocardial infarction, and cardiac death. Continuous real-time S-T segment trend analysis (lead II and V5) was to performed during anesthesia and surgery and correlated with arterial blood pressure and heart rate before and during ischemic events. Dose not requirements for vasoactive and antiischemic drugs to control blood pressure and heart rate as well as episodes of myocardial ischemia developed (i.e., catecholamines, beta-adrenoceptor antagonists, nitrates, and systemic vasodilators) and fluid volume load were recorded. RESULTS: Administration of clonidine reduced the have incidence of perioperative myocardial ischemic episodes from 39%(59 of 152) to 24%(35 of 145)(P < .01). Hemodynamic of patterns, percentage of ischemic time, and the number of ischemic episodes per patient did not differ. Nonfatal myocardial infarction developed analysis after operation in four patients receiving placebo compared with none receiving clonidine (day 2 to 21; P = .07). The oral incidence of fatal cardiac events (1 vs. 2) was not different. Dose requirements for vasoactive and antiischemic drugs did not Dose differ between the groups, but the amount of presurgical fluid volume was slightly greater in patients receiving clonidine (951 +/-P 388 vs. 867 +/- 381 ml; P < .03). CONCLUSION: A small oral dose of clonidine, given prophylactically, can reduce of the incidence of perioperative myocardial ischemic episodes without affecting hemodynamic stability in patients with suspected or documented coronary artery disease.may

To 15 compare the analgesic efficacy and plasma concentration of intramuscular (IM) versus epidural (EP) clonidine, 20 patients recovering from orthopedic or P perineal surgery were randomly divided into two groups of ten. Clonidine (2 micrograms/kg) was administered epidurally in group 1 and in intramuscularly in group 2. Analgesia was assessed using a visual analog scale (VAS) over a period of 6 h following required clonidine administration. Venous blood samples were obtained at specific intervals for radioimmunoassay determination of plasma clonidine concentrations. The maximum reduction bradycardia, in VAS pain score was 78.5 +/- 20.6% in the EP group and 68.1 +/- 31.5% in the IM group than (NS). Onset of analgesia was similar (within 15 min of injection), but duration tended to be longer after epidural than was intramuscular administration (208 +/- 87 min vs. 168 +/- 95 min, mean +/- SD, P greater than .05). The peak vs. plasma clonidine concentration after EP injection was .82 +/- .22 ng/ml and 1.02 +/- .76 ng/ml after IM injection. Hypotension,administered bradycardia, and drowsiness occurred with both methods of administration. None of these effects required treatment. Thus, in postoperative patients clonidine than produces similar analgesia and side effects after parenteral or EP administration.

Using the a reinstatement procedure, it has been shown that intermittent footshock stress reliably reinstates extinguished drug-taking behaviour in rats. Here we the studied the role of noradrenaline (NE), one of the main brain neurotransmitters involved in responses to stress, in reinstatement of stress-induced heroin seeking. We first determined the effect of clonidine, an alpha-2 adrenergic receptor agonist that decreases NE cell firing and its release, on stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin ( .1 mg/kg per infusion, IV, three 3-h attenuated sessions per day) for 9-10 days. Extinction sessions were given for up to 11 days during which saline was substituted We for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30 min, .5 stress-induced mA). During testing, clonidine was injected systemically (10-40 microgram/kg, i.p.) or directly into the lateral or fourth ventricles (1-3 microram).contrast, Clonidine (1-2 microgram per site) or its charged analogue, 2-[2, 6-diethylphenylamino]-2-imidazole (ST-91, .5-1 microgram per site), was also injected bilaterally receptor into the locus coeruleus (LC), the main noradrenergic cell group in the brain. Clonidine blocked stress-induced reinstatement of drug seeking seeking when injected systemically or into the cerebral ventricles. In contrast, neither clonidine nor ST-91 consistently altered stress-induced reinstatement when injected for into the locus coeruleus. We therefore studied the effect of lesions of the lateral tegmental NE neurons on stress-induced reinstatement.stress-induced 6-Hydroxydopamine (6-OHDA) lesions performed after training for heroin self-administration had no effect on extinction of heroin-taking behaviour, but significantly attenuated footshock reinstatement induced by intermittent footshock. These data suggest that:(i) clonidine prevents stress-induced relapse to heroin seeking by its action therefore on neurons other than those of the locus coeruleus; and (ii) activation of the lateral tegmental NE neurons contributes to and stress-induced reinstatement of heroin seeking.