RESUMO
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 (omega1) 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.
Assuntos
Acetamidas/farmacocinética , Comportamento/efeitos dos fármacos , Hipnóticos e Sedativos/farmacocinética , Drogas Ilícitas/farmacocinética , Pirimidinas/farmacocinética , Triazolam/farmacocinética , Adolescente , Adulto , Comportamento Aditivo/psicologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Variações Dependentes do ObservadorRESUMO
The discriminative stimulus effects of the imidazopyridine hypnotic zolpidem and the classic benzodiazepine hypnotic triazolam were examined in seven healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 20 mg/70 kg zolpidem, and 0.5 mg/70 kg triazolam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made 3.75 h after drug administration. Five out of seven subjects acquired the three-response discrimination. Analyses of standardized and unstructured self-report questionnaires revealed that zolpidem and triazolam produced different profiles of effects; zolpidem was associated with a number of negative somatic symptoms including nausea, blurred vision, visual images/hallucinations, and heavy limbs, whereas triazolam was associated with greater sedative effects. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for zolpidem, relative to triazolam, which is consistent with its somewhat distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure for detecting between-drug differences.
Assuntos
Discriminação Psicológica/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Piridinas/farmacologia , Triazolam/farmacologia , Adulto , Cognição/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Inquéritos e Questionários , Fatores de Tempo , ZolpidemRESUMO
The discriminative stimulus effects of buspirone and diazepam were examined in 12 healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 15 mg/70 kg buspirone, and 10 mg/70 kg diazepam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made two hours after drug administration. Ten out of 12 subjects acquired the three-response discrimination. When lower doses of buspirone (3.75 and 7.5 mg/70 kg) and diazepam (2.5 and 5.0 mg/70 kg) were tested in a subsequent generalization testing phase, both buspirone and diazepam produced dose-related increases in appropriate drug identifications, without significant cross-generalization. Analyses of standardized and unstructured self report questionnaires revealed that buspirone and diazepam produced different profiles of effects, and that buspirone was associated with a number of "negative" subject-rated effects including tension, nausea, and dizziness. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for buspirone relative to diazepam which is consistent with its distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure.
Assuntos
Ansiolíticos/farmacologia , Buspirona/farmacologia , Diazepam/farmacologia , Discriminação Psicológica , Adulto , Afeto/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , MasculinoRESUMO
The psychomotor/cognitive performance, subject-rated, and observer-rated effects of single oral doses of the benzodiazepine hypnotic triazolam (0.125, 0.25, and 0.5 mg/70 kg) and the imidazopyridine hypnotic zolpidem (5, 10, and 20 mg/70 kg) were compared in 11 volunteers, in a double-blind, placebo-controlled, crossover design. Triazolam and zolpidem produced similar dose-related decrements on several performance measures, and similar dose-related increases on most observer-rated and several subject-rated measures. The drugs differed in the time course of their effects on these measures; the effects of zolpidem typically peaked 30 min earlier (1-1.5 h postdrug) than the effects of triazolam (1.5-2 h postdrug). Triazolam and zolpidem produced a different profile of effects on other performance measures which could not be attributed to time course differences. Triazolam produced significantly more impairment than zolpidem in time estimation. Triazolam, but not zolpidem, produced significant impairment on a short-term memory task. Zolpidem produced significantly more impairment than triazolam on several novel measures of performance on a computerized trail-making test. The observed differences between triazolam and zolpidem may be related to zolpidem's reported binding selectivity for the omega 1 receptor subtype.
Assuntos
Cognição/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Piridinas/farmacologia , Triazolam/farmacologia , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Rememoração Mental/efeitos dos fármacos , Percepção do Tempo/efeitos dos fármacos , ZolpidemRESUMO
The symptoms of poisoning by the pyrethroid and cyclodiene insecticides are characterized by hyperexcitation and convulsions followed by paralysis. The main target site of the pyrethroids has been identified to be the sodium channels which are kept open for unusually long periods of time, causing a prolonged sodium current to flow which, in turn, leads to hyperexcitation of the nervous system. We have now found large differential sensitivity to the pyrethroids in two types of sodium channels. The dorsal root ganglion neurons of the rat were endowed with two types of sodium channels, one sensitive to the blocking action of tetrodotoxin (TTX) and the other insensitive to TTX. The type I pyrethroid allethrin and the type II pyrethroid deltamethrin were both effective in prolonging the sodium current in the TXX-resistant sodium channel but had only a small effect on the TTX-sensitive sodium channel. These two types of sodium channels also exhibited marked differences in their physiological properties, including the time course of current, the activation voltage, and the steady-state inactivation. In contrast to the pyrethroids, lindane and the cyclodienes endrin, isobenzan, dieldrin and heptachlor-epoxide suppressed the GABA-induced chloride current. The initial transient component of the chloride current was blocked more than the late sustained component. The suppression of the GABA-mediated synaptic inhibition would cause hyperexcitation of the nervous system. The results are compatible with the convulsant action of these insecticides.
Assuntos
Dieldrin/toxicidade , Endrin/toxicidade , Proteínas de Membrana/efeitos dos fármacos , Piretrinas/toxicidade , Receptores de GABA-A/efeitos dos fármacos , Canais de Sódio/efeitos dos fármacos , Animais , Canais de Cloreto , Hexaclorocicloexano/toxicidade , Humanos , Tetrodotoxina/farmacologiaAssuntos
Planejamento de Dentadura , Prótese Total , Música , Adulto , Oclusão Dentária , Análise do Estresse Dentário , HumanosRESUMO
The effects of the microiontophoretic application of dynorphin A-(1-13) (DYN 13) and the benzomorphans ethylketocyclazocine (EKC), bremazocine and MRZ 2549, (kappa) opioid agonists, and of morphine and morphiceptin, (mu) opioid agonists, were compared on spontaneous or glutamate-evoked discharge of globus pallidus (GP) neurons in rat. Our results demonstrate that mu and kappa opioid agonists are able to depress the excitability of pallidal neurons, possibly by interacting with mu and kappa opioid receptor subtypes, respectively. In addition, the mu agonists and dynorphin A-(1-13), but not the benzomorphans, enhanced the excitability of a number of pallidal neurons. We have proposed a presynaptic site as the basis for this opioid-induced excitation, possibly also mediated by a mu opioid receptor. The selectivity of dynorphin A-(1-13) for benzomorphan kappa opioid receptors in the rat GP appears to be low and dynorphin A-(1-13) may elicit effects that are different from those produced by the benzomorphan kappa agonists by virtue of its ability to interact with other opioid receptor subtypes, for example mu opioid receptors.
Assuntos
Globo Pálido/fisiologia , Entorpecentes/farmacologia , Neurônios/efeitos dos fármacos , Receptores Opioides/fisiologia , Animais , Benzomorfanos/farmacologia , Dinorfinas/administração & dosagem , Dinorfinas/farmacologia , Globo Pálido/citologia , Globo Pálido/efeitos dos fármacos , Iontoforese , Masculino , Morfina/farmacologia , Naloxona/farmacologia , Entorpecentes/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Endogâmicos , Receptores Opioides kappa , Receptores Opioides muRESUMO
Experiments were conducted to assess the effects of chronic haloperidol (CHAL) administration on gamma-aminobutyric acid (GABA) receptor binding within the rat globus pallidus (GP) and on the responsiveness of individual pallidal neurons to microiontophoretically applied GABA and glycine. Rats were administered haloperidol in their food for 30 days in increasing concentrations and the experiments were conducted 2 days after termination of the haloperidol treatment. GABA receptor binding and neuronal responsiveness to GABA were significantly increased within the GP following CHAL treatment. The mean EC50 value for GABA was significantly decreased in the CHAL-treated rats, but there was no change in the EC50 for glycine. Scatchard analysis of [3H]muscimol binding demonstrated a single high-affinity binding site (Kd = 5 nM) within both control and CHAL-treated rats. The binding capacity (Bmax) of this high-affinity site was significantly increased in CHAL-treated rats without any change in the dissociation constant (Kd) for this site. These results suggest that CHAL administration may lead to a decrease in GABA release by striatopallidal efferents. The results of this study, combined with those of our previous study on SNR neurons, have demonstrated that blockade of striatally mediated dopamine (DA) neurotransmission leads to similar changes in GABAergic mechanisms at the level of the GP and SNR and suggest that DA regulation of the striatopallidal and striatonigral GABAergic pathways need not be differentially organized as has previously been postulated.
Assuntos
Globo Pálido/metabolismo , Haloperidol/farmacologia , Receptores de GABA-A/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Metabolismo Energético/efeitos dos fármacos , Globo Pálido/efeitos dos fármacos , Globo Pálido/fisiologia , Glucose/metabolismo , Glicina/farmacologia , Masculino , Muscimol/metabolismo , Ratos , Ratos Endogâmicos , Receptores de GABA-A/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologiaRESUMO
These studies were performed to evaluate the effects of chronic haloperidol administration on the responsiveness of the pars reticulata neurons of the substantia nigra (SNR) to microiontophoretically applied gamma-aminobutyric acid (GABA) and glycine. Rats were administered haloperidol in their feed (CHAL treatment) for 30 days in increasing concentrations. All experiments were conducted two days after termination of the CHAL treatment. GABA receptor binding and neuronal responsiveness to GABA were significantly increased within the SNR following CHAL treatment. The mean EC50 value for GABA was significantly decreased for SNR neurons in CHAL-treated rats, but there was no change in the EC50 for glycine. Specific [3H]GABA binding (4 nM) was elevated by more than 50% within the SNR. Scatchard analysis of [3H]muscimol binding data revealed that the binding capacities (Bmax) of both high and low affinity GABA binding sites within the SNR were significantly increased without a change in the apparent dissociation constants (Kd) of either site. Although no regional difference in responsiveness to GABA was detected within the SNR of CHAL-treated rats, the spontaneous activity of neurons located within the rostral two-thirds of the nucleus was reduced; however, there was no change in spontaneous activity of neurons located within the caudal one-third. These data provide direct physiological evidence to support the conclusion that the increase in GABA binding within the SNR following CHAL treatment reflects a neuronal supersensitivity to GABA.
Assuntos
Haloperidol/farmacologia , Substância Negra/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia , Animais , Glicina/farmacologia , Masculino , Muscimol/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Endogâmicos , Substância Negra/citologia , Substância Negra/metabolismo , Substância Negra/fisiologia , Fatores de Tempo , Ácido gama-Aminobutírico/metabolismoRESUMO
The induction of dopaminergic supersensitivity in rats by the administration of haloperidol in their diet for 30 days (CHAL) in three increasing concentrations (7-15 mg/kg/day) was compared to that induced by single daily subcutaneous injections (SCHAL, 0.7 mg/kg) on the basis of biochemical (radioimmunoassay of serum haloperidol levels, 3H-spiroperidol binding) or behavioral (apomorphine stereotypy, spontaneous locomotor activity) parameters. The two modes of administration produced equivalent blood levels of haloperidol by day 30. At 48 hours post treatment: spontaneous locomotor activity and stereotyped behavior were significantly increased in both groups of haloperidol-treated rats, stereotyped behavior was significantly greater in CHAL- vs. SCHAL-treated rats at 8 days post treatment and specific 3H-spiroperidol binding was increased 64% and 236% within the striatum and GP, respectively, of CHAL-treated vs. control rats. Scatchard analysis of 3H-spiroperidol binding isotherms revealed a significant increase in the Bmax of high affinity binding sites [KD approximately 55 pM] within the striatum of both CHAL- and SCHAL-treated rats at 48 hours post treatment. A second, lower affinity site was resolved within the SCHAL-treated group which was not detected within striatal homogenates of CHAL-treated or control rats.
Assuntos
Haloperidol/administração & dosagem , Receptores Dopaminérgicos/efeitos dos fármacos , Administração Oral , Animais , Apomorfina/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Resistência a Medicamentos , Haloperidol/sangue , Injeções Subcutâneas , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores Dopaminérgicos/fisiologia , Espiperona/metabolismo , Comportamento Estereotipado/efeitos dos fármacosRESUMO
This study was conducted in order to compare the effects of microiontophoretically-applied morphine and met-enkephalin (met-ENK) on spontaneous and/or glutamate-evoked activity of single globus pallidus (GP) neurons in locally anesthetized, paralyzed rats. The predominant effect of both morphine and met-ENK was a depression of pallidal neuronal activity. While very few GP neurons were excited by morphine (2/89), a small population of neurons was excited by met-ENK (16/89). Both the inhibitory and excitatory responses produced by morphine and met-ENK could be attenuated by the microiontophoretic application of naloxone. It was also found that morphine and met-ENK did not affect all GP neurons in a similar manner. When applied to the same neurons, morphine elicited depression in 11 of 16 GP neurons which were excited by the application of met-ENK. In contrast, neither of two GP neurons excited by morphine in this study displayed inhibition upon application of met-ENK. Thus the microiontophoresis of morphine and met-ENK to single GP neurons has demonstrated that these two substances can produce opposite effects when applied to the same neurons and suggests that two functionally distinct types of opiate receptor may exist within rat GP, one which mediates the inhibitory effects of morphine and met-ENK, possibly the classical mu (mu) receptor, and one that is preferentially selective to met-ENK and which mediates the excitatory effects of opiates within this region, possibly the classical delta (delta) receptor.
Assuntos
Encefalina Metionina/farmacologia , Globo Pálido/efeitos dos fármacos , Morfina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Interações Medicamentosas , Potenciais Evocados/efeitos dos fármacos , Glutamatos/farmacologia , Ácido Glutâmico , Masculino , Naloxona/farmacologia , Ratos , Ratos EndogâmicosRESUMO
The authors report two cases of cor triatriatum in a 54 year old woman undergoing open heart surgery with a preoperative diagnosis of mitral stenosis, and a 24 year old woman in whom the diagnosis had been made before surgery. Resection of the abnormal intra-left atrial fibrous membrane successfully restored normal haemodynamics in both cases. The main clinical and diagnostic features of the condition are described.