Effects of zaleplon or triazolam with or without ethanol on human performance.

Objectives and background: Given that non-selective gamma-aminobutyric acid (GABA) agonist hypnotics impair performance and potentiate the disruptive effects of ethanol, this study was done to determine the performance-impairing and ethanol-potentiating effects of zaleplon, a new selective GABA agonist hypnotic.Methods: Eighteen healthy men (12) and women (six), 31.5+/-5.6 years old, were studied. Each underwent six treatments of 2 days in duration, presented in a Latin square design with 2-12 recovery days between. The treatments were: placebo-placebo; placebo-ethanol; triazolam-placebo; triazolam-ethanol; zaleplon-placebo; and zaleplon-ethanol; with triazolam (0.25 mg) or placebo administered at 08:30 h, zaleplon (10 mg) or placebo at 09:00 h, and ethanol (0.75 g/kg) or placebo consumed from 09:30 h. Performance tests were completed each day at 10:30, 12:00 and 14:30 h.Results: Breath ethanol concentration (BrEC), tested 0.5, 2.0, 4.5 and 6 h post consumption, did not differ among treatments and peaked at 0.052%, declining to 0.037, 0.009 and 0.001%. Triazolam with and without ethanol impaired digit symbol substitution, symbol copying, simple and complex reaction times and divided attention performance relative to placebo-placebo treatment. It did so consistently at 10:30 and 12:00 h, and less consistently at 14:30 h. Zaleplon without ethanol impaired only digit symbol substitution and divided attention tracking, and only at 10:30 h. Zaleplon with ethanol impaired most measures at 10:30 and 12:00 h, but not at 14:30 h. Zaleplon without ethanol consistently differed from triazolam without ethanol in the extent of performance impairment. Zaleplon with ethanol began to differ from triazolam with ethanol in performance impairment on the 12:00 and 14:30 h test sessions. Ethanol itself impaired most measures at 10:30 h, fewer at 12:00 h and none at 14:30 h. All active drug treatments increased self-rated sleepiness compared with placebo-placebo. Triazolam without ethanol produced greater self-rated sleepiness than zaleplon without ethanol. The addition of ethanol to both drugs generally produced comparable levels of self-rated sleepiness.Conclusions: In an absolute sense, zaleplon produced less performance impairment and a shorter period of ethanol potentiation than triazolam.

Efficacy and safety of zaleplon at peak plasma levels.

Zaleplon is a non-benzodiazepine sleep medication that shows efficacy as a sleep inducer comparable to that of other hypnotics but with significantly fewer residual effects. In addition, evaluations of psychomotor or memory function at zaleplon peak plasma levels show much less impairment than noted with other hypnotics, suggesting an improved benefit-to-risk profile for zaleplon compared with older available agents. Thus, zaleplon can be used to treat symptoms of insomnia when they occur without the concern of next-day psychomotor or memory impairment, whether administered at bedtime or later during the night. Such an approach permits physicians to reformulate their strategies for safe and effective management of sleeplessness.

The synthesis and biochemical pharmacology of enantiomerically pure methylated oxotremorine derivatives.

Previous pharmacological studies of methylated oxotremorine derivatives bearing substituents at the 3-, 4-, and 5-positions of the pyrrolidinone ring have been conducted using racemic mixtures, and not with optically active compounds. The synthesis and radioligand binding data of optically active, methylated oxotremorine derivatives at the 3- and 4-positions are described. There are significant pharmacological differences between the 3- and 4-position derivatives. The 4-position enantiomers have weak, approximately equal affinity and antagonist-like profiles, whereas the 3-position enantiomers have significantly different affinities and partial agonist-like profiles.

Interleukin-1 beta decreases acetylcholine measured by microdialysis in the hippocampus of freely moving rats.

Interleukin (IL-1) is a cytokine which plays an important role in the modulation of the acute response in host defense. This cytokine is also increased in patients with Alzheimer's disease. In the present experiment systemic injection of IL-1 beta (7.5-50 micrograms/kg) decreased extracellular acetylcholine in the hippocampus. This effect could not be attributed entirely to general malaise since lithium chloride (130 mg/kg) had the opposite effect. Heat-inactivation of the cytokine eliminated the reduction of extracellular ACh. The results give further evidence of a relationship between the immune system and the central nervous system and suggest a possible relationship between IL-1 and cholinergic function or dysfunction in the hippocampus.

Chemical and biochemical studies of 2-propynylpyrrolidine derivatives. Restricted-rotation analogues of N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM-5).

A series of optically pure 2-[substituted-3-aminopropynyl]pyrrolidine derivatives, which are restricted-rotation analogues of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM-5, compound 1), have been prepared from d- and l-proline. The compounds when tested in a series of in vitro muscarinic assays [[3H]CD (cortex), [3H]QNB (cortex), [3H]PZ (cortex), [3H]QNB (heart), [3H]QNB + GppNHp (heart)] were found to have weaker muscarinic properties than compound 1. The decrease in affinity was attributed to the increased size of the molecule resulting from the addition of a methylene group to form the pyrrolidine ring. The use of optically active compounds provided a more detailed examination of the complex pharmacological effects of the flexible muscarinic agent 1. The R enantiomers in the acetamide derivatives 12b, 12d, and 12f had a 5-10-fold greater affinity for the muscarinic receptor than the corresponding S enantiomers. A 5-fold difference or less found in the (R)- and (S)-carbamate derivatives 9, 15, and 16 suggested close overlap of the two enantiomers in the receptor binding domain. The affinity differences found in the enantiomeric acetamido derivatives when compared to those of the carbamate analogues may be the result of limited rotation of the acetamido group.

Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain.

A current hypothesis links the neuroexcitatory properties of certain acidic amino acids to their ability to cause selective neuronal lesions. Intracerebral injection of the neuroexcitatory tryptophan metabolite, quinolinic acid, has behavioral, neurochemical, and neuropathological consequences reminiscent of those of exogenous excitotoxins, such as kainic and ibotenic acids. Its qualities as a neurotoxic agent suggest that quinolinic acid should be considered as a possible pathogenic factor in neurodegenerative disorders.

Chronic infusion of endogenous excitatory amino acids into rat striatum and hippocampus.

The effects of chronic intrastriatal and intrahippocampal infusions of endogenous excitatory amino acids were examined on the light microscopic level. Repeated manual injections of either glutamate or aspartate (1.8 mumoles/0.5 mu 1 every 12 hours for 14 days), but not of equimolar GABA, caused neuronal degeneration proximal to the tip of the injection cannula. Nerve cell death was limited to a spherical area with a radius of approximately 0.5 mm. Continuous infusion of these amino acids via osmotic minipumps, at total daily doses identical to those used in the experiments employing manual injections, did not result in lesions in striatum or hippocampus. Attempts using minipump administration of cysteine sulfinate or combinations of glutamate with aspartate, cysteine sulfinate or DL-threo-beta-hydroxyaspartate were equally unsuccessful in producing neuronal cell loss. The efficient re-uptake systems for the endogenous amino acids may suffice to continuously remove large quantities of the infused compounds from vulnerable neuronal sites. It appears, however, that these protective mechanisms can be overcome by extremely high local concentrations of glutamate or aspartate. Possible implications for the pathogenesis of human neurodegenerative disorders are discussed.

Huntington's disease. Glutamate and aspartate metabolism in blood platelets.

The metabolism of two excitatory amino acids, glutamate and aspartate, was determined in human blood platelets because of their hypothetical involvement in the etiology of the heritable neurodegenerative disorder, Huntington's disease (HD). The specific activities of the two acids and their amides, glutamine and asparagine, constitute markers for the efficiency of the enzymatic cascades originating from [3H]acetate and [14C]glucose, respectively. Results demonstrate that both precursors are converted by temperature-dependent processes, thus indicating the presence, in platelets, of all glycolytic and tricarboxylic acid cycle enzymes necessary for the biosynthesis of glutamate and aspartate. No differences between normal and HD platelets were found in any of the specific activities investigated. A genetic defect in any of these enzymes is therefore not likely to underlie HD neuropathology.

Platelet glutamate and aspartate uptake in Huntington's disease.

A possible involvement of amino acid uptake mechanisms in the etiology of the human neurodegenerative disease, Huntington's disease (HD), was investigated. Measurement of glutamate (Glu) and aspartate (Asp) uptake was performed in blood platelets, which have previously been shown to constitute a peripheral model system for central amino acid uptake processes. Analyses of Glu and Asp accumulation at 10(-7) M and kinetic examination of the high affinity site for Glu indicate no significant differences between control and HD platelets. A genetically determined defect in amino acid uptake therefore does not seem to underlie the nerve cell loss observed in HD patients.

The human platelet as a model for the glutamatergic neuron: platelet uptake of L-glutamate.

L-Glutamate uptake into human platelets revealed two components: a high-affinity system (KmH = 3.1 microM), which was sodium-dependent, and a low-affinity site (Km = 88 microM) displaying temperature rather than sodium dependency. These kinetic properties were similar to those found in crude synaptosomal preparations and brain slices. However, Vmax values were far higher in brain (VmaxH = 325 +/- 96, VmaxL = 3759 +/- 1116 pmol/mg wet weight per min) than in platelets (VmaxH = 14 +/- 6, VmaxL = 313 +/- 63 pmol/mg platelet protein per 10 min), indicating a denser population in brain than in platelets of qualitatively similar sites. Pharmacological analysis substantiated the resemblance of nerve endings and platelets: the specific uptake inhibitors threo-3-hydroxy-DL-aspartate and DL-aspartate-beta-hydroxamate as well as D- and L-glutamate and L-aspartate showed similar--though not identical-- IC50 values in both preparations; a spectrum of compounds devoid of inhibitory effects in synaptosomes also did not interfere with glutamate uptake in platelets. Uptake parameters were studied in a population of human volunteers to determine the variability of platelet glutamate uptake. Whole blood could be stored up to 6 h after venipuncture without any appreciable change in experimental values. Percentage of variation between 0.09 and 0.28 for three repetitive (weekly) assays in single subjects indicated that glutamate uptake measurements in human platelets are sufficiently suited for future clinical studies.