Measurement of initial N-acetyl aspartate concentration by magnetic resonance spectroscopy and initial infarct volume by MRI predicts outcome in patients with middle cerebral artery territory infarction.

BACKGROUND AND PURPOSE: (1)H MR spectroscopy can be used to study biochemical changes occurring in the brain in stroke. We used it to examine the relationship between metabolite concentration (N-acetyl aspartate [NAA], lactate, cholines and creatines), size of infarct, clinical deficit, and 3-month clinical outcome in patients with middle cerebral artery (MCA) territory infarction. METHODS: Thirty-one patients with acute MCA territory infarction were recruited within 72 hours of the onset of symptoms. Single-voxel short echo time stimulated echo acquistion mode spectroscopy was used to obtain metabolite data from the infarct core. Metabolite concentrations were determined with use of variable projection time domain-fitting analysis. Infarct size was determined with T2-weighted images. Patient outcome groups at 3 months were "independent," "dependent," or "dead." RESULTS: All patients (100%; 95% CI 75% to 100%) who had an infarct >70 mL did poorly. Eighteen of 20 patients (90%; 95% CI 68% to 99%) with a core NAA concentration <7 mmol/L did poorly at 3 months, whereas 7 of 11 patients (64%; 95% CI 31% to 89%) with an initial NAA concentration >7 mmol/L did well. Combining these results showed that all patients who had an initial infarct volume >70 mL did poorly, irrespective of the NAA concentration. Of those patients with infarcts <70 mL, those who had a core NAA concentration >7 mmol/L did well (88%; 95% CI 47% to 100%), whereas those with a lower NAA concentration did poorly (80%; 95% CI 44% to 97%). There was no association between other metabolite concentrations and outcome. CONCLUSIONS: Infarct volume and NAA concentration can together predict clinical outcome in MCA infarction in humans.     

The epidemiology of acute hepatitis A in north Queensland, 1996-1997.

Details on all cases of hepatitis A notified in North Queensland in 1996 and 1997 were prospectively collected. There were two substantial outbreaks and a total of 225 cases during this period. The total incidence rate (per 100,000) was 11.0 in 1996 and 27.0 in 1997. Aborigines and Torres Strait Islanders constituted 29% of cases and had incidence rates of 75.2 and 62.7 per 100,000 for 1996 and 1997 respectively. Thirty-nine cases (17.3%) were admitted to hospital for a total of 202 bed-days and a 4 year old died with fulminating hepatitis. A probable source of infection was identified for 69% of cases. The common risk categories for infection were: living in or visiting a rural Aboriginal or Torres Strait Islander community, injecting drug use, contact with a known case of hepatitis A, and travel to countries with endemic hepatitis A.     

Quinuclidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase: optimization from lipid profiles

Novel 3-substituted quinuclidine inhibitors of cholesterol biosynthesis are reported. Compounds were optimized against oxidosqualene cyclase-lanosterol synthase (OSC) inhibition in vivo, rather than by the conventional optimization of structure-activity relationship information based on in vitro OSC inhibition. Thus, examination of HPLC lipid profiles from orally dosed rats showed cholesterol biosynthetic intermediates and whether cholesterol levels were reduced. A new substituted quinuclidine pharmacophore 18a-c was rapidly found for the inhibition of OSC, and the most promising inhibitors were validated by the confirmation of potent OSC inhibition. Compound 16 gave an IC50 value of 83 +/- 11 nM for human and an IC50 value of 124 +/- 14 nM, for rat, coupled with oral and selective inhibition of cholesterol biosynthesis derived from OSC inhibition (rat, ED50 = 1.3 +/- 0.7 mg/kg, n = 5; marmoset, 15 mg/kg dose, n = 3, caused complete inhibition). These 3-substituted quinuclidines, which were derived from a quinuclidine series previously known to inhibit cholesterol biosynthesis at the squalene synthase step, may afford a novel series of hypocholesterolemic agents acting by the inhibition of OSC.     

Zaleplon and triazolam in humans: acute behavioral effects and abuse potential

Zaleplon, a pyrazolopyrimidine that is under development as a hypnotic, produces its pharmacological effects at the benzodiazepine-recognition site on the GABA_A benzodiazepine-receptor complex. Unlike most benzodiazepines, zaleplon binds selectively to the BZ₁ (ω₁) subtype of the benzodiazepine receptor. The present study compared the acute subject-rated effects, performance-impairing effects, and abuse potential of zaleplon and triazolam, a triazolobenzodiazepine hypnotic, in 14 healthy volunteers with histories of drug abuse. Zaleplon (25, 50, and 75 mg), triazolam (0.25, 0.5, and 0.75 mg) and placebo were administered orally in this double-blind, crossover study. Zaleplon and triazolam produced comparable dose-related effects on several subject-rated drug-effect questionnaires. Zaleplon and triazolam also produced comparable dose-dependent decrements on several performance tasks including balance, circular lights, digit-enter and recall, DSST, picture recall/recognition and repeated acquisition. Same-day and next-day subject-rated measures reflecting abuse potential (e.g., drug liking, good effects, and monetary street value) also suggest that zaleplon and triazolam were comparable. The only notable between-drug difference observed in the present study was that the time-action function of zaleplon differed from that of triazolam. The onset time, time to maximum drug effect, and duration of action were shorter with zaleplon than triazolam. Thus, despite its non-benzodiazepine structure and unique benzodiazepine-receptor binding profile, the behavioral pharmacological profile of zaleplon is similar to that of triazolam. Received: 14 April 1998/Final version: 13 January 1999     

Neurotoxicity of 1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol (TMIQ) and effects on catecholamine homeostasis in SH-SY5Y cells

We have investigated the potential neurotoxicity of the catecholamine depleting agent 1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol (TMIQ) in SH-SY5Y neuroblastoma cells. TMIQ induced a time and dose related inhibition of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; thiazoyl blue (MTT) reduction and an increase in lactate dehydrogenase release. After 72 h TMIQ (30 μM) significantly (P < 0.05) inhibited MTT reduction, and significantly increased LDH release. TMIQ cytotoxicity was not prevented by the inclusion of monoamine oxidase inhibitors (clorgyline or deprenyl), antioxidants (α-tocopherol or Trolox C) or the uptake(1) inhibitor imipramine. TMIQ also induced a dose dependent stimulation of [(3)H]noradrenaline (NA) uptake, with maximum at 100 μM and EC(50) of 8 μM. This stimulation of [(3)H]NA uptake was not prevented by the inhibition of protein kinase C, or activation of adenylate or guanylate cyclases. In addition, TMIQ significantly (P < 0.05) displaced [(3)H]nisoxetine binding from the uptake(1) recognition site with a K(i) of 71 ± 8 μM. However, as this interaction occurs at concentrations of TMIQ well above the EC(50) for [(3)H]NA uptake, it is unlikely to explain TMIQ stimulated NA uptake. Furthermore, TMIQ inhibited potassium evoked [(3)H]NA release from SH-SY5Y cells, with an IC(50) of 490 μM. Thus, TMIQ is cytotoxic to SH-SY5Y cells. However, the exact mechanism of toxicity requires further investigation, since it appears not to involve monoamine oxidase bioactivation, and is not mediated through membrane based free radical damage. Furthermore, although TMIQ inhibits mitochondrial Complex I (IC(50) = 1.5 mM) with potency apparently greater than MPTP (2.7 mM), mitochondrial respiration was unaffected. The present studies suggest that the mechanism of toxicity differs from that causing depletion of catecholamines and inhibition of tyrosine hydroxylase by TMIQ described in previous studies.     

Progressive-ratio performance maintained by drug infusions: Comparison of cocaine,diethylpropion, chlorphentermine,and fenfluramine

Cocaine, diethylpropion, chlorphentermine, and fenfluramine were compared on a drug-maintained progressive-ratio procedure in baboons. Intravenous infusions of drug were contingent on completion of a fixed-ratio response requirement (fixed number of lever-press responses) with a 3-h time-out period following each infusion. Prior to testing each dose of drug, stable self-infusion performance was first established with 0.4 mg/kg cocaine when the fixed-ratio requirement was 160. Subsequently, a test dose of drug was substituted for the standard dose of cocaine. If the dose of drug maintained a criterion level of self-infusion performance (six or more infusions per day for 2 days), the ratio requirement was systematically increased every day until the breaking point at which the self-infusion performance fell below a criterion level (one or zero infusionsper day). Fenfluramine did not maintain criterion self-infusion performance at any dose tested (0.02–5.0 mg/kg). The dose ranges of the other drugs that maintained maximum breaking points were 1.0–5.6 mg/kg for chlorphentermine, 1.0–3.0 mg/kg for diethylpropion, and 0.1–0.4 mg/kg for cocaine. Within-animal comparison of the maximum breaking points indicated that cocaine maintained the highest breaking points, followed in order by diethylpropion, chlorphentermine, and fenfluramine. The rank ordering of these drugs with the breaking point measure corresponds well with both the results of other animal experiments on measurement of reinforcing efficacy of these drugs and with the clinical information about the human subjective effects and abuse of these drugs.     

Local cerebral blood flow following transient cerebral ischemia. II. Effect of arterial PCO2 on reperfusion following global ischemia

Following 5 minutes of global ischemia, local cerebral blood flow (LCBF) was shown to have an initial reactive hyperemia that was followed, within the first hour, by persistent hypoperfusion (Part I). Intracranial pressure (ICP) was never elevated during the period of poor reperfusion. These experiments attempted to reverse the state of subnormal LCBF by inducing hypercarbia or hyocarbia or maintaining normocarbia. Although hypocarbia did increase LCBF at several electrode sites, neither the intracerebral steal syndrome nor the "squeeze" syndrome are a dominant consequence of hypercarbia in this model of global ischemia. Hypercarbia was consistently more effective in elevating LCBFs and in recovery of the electrocorticogram. It appears that, in the absence of raised ICP, hypercarbia may be preferred to normal or low PACO2,. Even though hypercarbia was superior to normocarbia or hypocarbia, hypercarbia was not a completely satisfactory regimen for reversing the state of poor reperfusion.