Comparing single and cumulative dosing procedures in human triazolam discriminators.
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This study evaluated a cumulative dosing procedure for drug discrimination with human participants. Four participants learned to discriminate triazolam (0.35 mg/70 kg) from placebo. A crossover design was used to compare the results under a single dosing procedure with results obtained under a cumulative dosing procedure. Under the single dosing procedure, a dose of triazolam (0, 0.05, 0.15, or 0.35 mg/70 kg) or secobarbital (0, 25, 75, or 175 mg/70 kg) was administered 45 min before assessment. Determining each dose-effect curve thus required four sessions. Under the cumulative dosing procedure, four doses of triazolam (0, 0.05, 0.10, and 0.20 mg/70 kg) or secobarbital (0, 25, 50, and 100 mg/70 kg) were administered approximately 55 min apart, producing a complete dose-effect curve in one four-trial session. Regardless of procedure, triazolam and secobarbital produced discriminative stimulus and self-reported effects similar to previous single dosing studies in humans. Shifts to the right in cumulative dose-effect curves compared to single dose-effect curves occurred on several self-report measures. When qualitative stimulus functions rather than quantitative functions are of interest, application of cumulative dosing may increase efficiency in human drug discrimination. (+info)
Dental anesthetic management of a patient with ventricular arrhythmias.
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During routine deep sedation for endodontic therapy, a dentist-anesthesiologist observed premature ventricular contractions (PVCs) on a 62-yr-old woman's electrocardiogram (EKG) tracing. The dentist was able to complete the root canal procedure under intravenous (i.v.) sedation without any problems. The dentist-anesthesiologist referred the patient for medical evaluation. She was found to be free from ischemic cardiac disease with normal ventricular function. The patient was cleared to continue her dental treatment with deep sedation. She subsequently continued to undergo dental treatment with deep intravenous sedation without incident, although her EKG exhibited frequent PVCs, up to 20 per minute, including couplets and episodes of trigeminy. This article will review indications for medical intervention, antiarrhythmic medications, and anesthetic interventions for perioperative PVCs. (+info)
Flumazenil discrimination by humans under a two-response and a novel-response procedure.
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In this study we assessed the discriminative stimulus, self-reported, and performance effects of flumazenil in humans. The first group (n = 6) was trained to discriminate flumazenil (0.56 mg/70 kg i.v.) from saline and tested with flumazenil (0.10, 0.32, 0.56, and 1.0 mg/70 kg) under a two-response drug discrimination procedure. The second group (n = 8) was trained to discriminate flumazenil (0.56 mg/70 kg i.v.) from saline and tested with flumazenil (0.32, 0.56, and 1.0 mg/70 kg), midazolam (0.10, 0.56, and 1.0 mg/70 kg), and caffeine (75 mg/70 kg) under a novel-response drug discrimination procedure. In both groups, flumazenil was acquired and maintained as a discriminative stimulus. Flumazenil dose-dependently increased flumazenil-appropriate responding and ratings of strength of drug effect and sedation, and decreased ratings of stimulant effects and psychomotor performance. Under the novel-response procedure, midazolam produced dose-dependent increases in flumazenil-appropriate responding. However, midazolam produced 43 and 25% novel responding at the intermediate and highest test doses, respectively. Midazolam dose-dependently increased ratings of strength of drug effect and sedation, and decreased ratings of stimulant effects and psychomotor performance. The magnitude of effects on ratings of strength of drug effect and sedation were comparable after flumazenil and midazolam, but psychomotor performance effects were greater after midazolam than after flumazenil. Caffeine produced mostly saline-appropriate responding. The results indicate that flumazenil has agonist effects similar to those of midazolam; however, novel responding after midazolam, and the greater performance decrement after midazolam, suggest that flumazenil does not act as a traditional benzodiazepine agonist. (+info)
Response-rate suppression in operant paradigm as predictor of soporific potency in rats and identification of three novel sedative-hypnotic neuroactive steroids.
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Novel neuroactive steroids were evaluated for their effects on operant responding, rotorod motor performance, and electroencephalogram recording in rats. Co 134444, Co 177843, and Co 127501 were compared with the prototypical gamma-aminobutyric acid(A)-positive allosteric modulators triazolam, zolpidem, pentobarbital, pregnanolone, and CCD 3693. Each of the compounds produced a dose-related decrease in response rates under a variable-interval 2-min schedule of positive reinforcement in an operant paradigm. In addition, all compounds produced a dose-related increase in ataxia and significant increases in nonrapid eye movement sleep in this experiment or have been previously reported to do so. Co 134444, Co 177843, and Co 127501 increased nonrapid eye movement sleep at doses that had no effect on rapid eye movement sleep. All of the compounds were more potent at decreasing operant responding than they were at increasing ataxia. Furthermore, the potency of compounds to produce response-rate suppression in an operant paradigm appeared to be a better predictor of soporific potency than did potency in the rotorod assay. The screening for sedative-hypnotic activity resulted in the identification of the novel orally active neuroactive steroids Co 134444, Co 177843, and Co 127501. (+info)
The hamster circadian rhythm system includes nuclei of the subcortical visual shell.
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The clock regulating mammalian circadian rhythmicity resides in the suprachiasmatic nucleus. The intergeniculate leaflet, a major component of the subcortical visual system, has been shown to be essential for certain aspects of circadian rhythm regulation. We now report that midbrain visual nuclei afferent to the intergeniculate leaflet are also components of the hamster circadian rhythm system. Loss of connections between the intergeniculate leaflet and visual midbrain or neurotoxic lesions of pretectum or deep superior colliculus (but not of the superficial superior colliculus) blocked phase shifts of the circadian activity rhythm in response to a benzodiazepine injection during the subjective day. Such damage did not disturb phase response to a novel wheel stimulus. The amount of wheel running or open field locomotion were equivalent in lesioned and control groups after benzodiazepine treatment. Electrical stimulation of the deep superior colliculus, without its own effect on circadian rhythm phase, greatly attenuated light-induced phase shifts. Such stimulation was associated with increased FOS protein immunoreactivity in the suprachiasmatic nucleus. The results show that the circadian rhythm system includes the visual midbrain and distinguishes between mechanisms necessary for phase response to benzodiazepine and those for phase response to locomotion in a novel wheel. The results also refute the idea that benzodiazepine-induced phase shifts are the consequence of induced locomotion. Finally, the data provide the first indication that the visual midbrain can modulate circadian rhythm response to light. A variety of environmental stimuli may gain access to the circadian clock mechanism through subcortical nuclei projecting to the intergeniculate leaflet and, via the final common path of the geniculohypothalamic tract, from the leaflet to the suprachiasmatic nucleus. (+info)
Midazolam and triazolam biotransformation in mouse and human liver microsomes: relative contribution of CYP3A and CYP2C isoforms.
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Midazolam (MDZ) and triazolam (TRZ) hydroxylation, reactions considered to be cytochrome P-4503A (CYP3A)-mediated in humans, were examined in mouse and human liver microsomes. In both species, alpha- and 4-hydroxy metabolites were the principal products. Western blotting with anti-CYP3A1 antibody detected a single band of immunoreactive protein in both human and mouse samples: 0.45 +/- 0. 12 and 2.02 +/- 0.24 pmol/mg protein (mean +/- S.E., n = 3), respectively. Ketoconazole potently inhibited MDZ and TRZ metabolite formation in human liver microsomes (IC(50) range, 0.038-0.049 microM). Ketoconazole also inhibited the formation of both TRZ metabolites and of 4-OH-MDZ formation in mouse liver microsomes (IC(50) range, 0.0076-0.025 microM). However, ketoconazole (10 microM) did not produce 50% inhibition of alpha-OH-MDZ formation in mouse liver microsomes. Anti-CYP3A1 antibodies produced concentration-dependent inhibition of MDZ and TRZ metabolite formation in human liver microsomes and of TRZ metabolite and 4-OH-MDZ formation in mouse liver microsomes to less than 20% of control values but reduced alpha-OH-MDZ formation to only 66% of control values in mouse liver microsomes. Anti-CYP2C11 antibodies inhibited alpha-OH-MDZ metabolite formation in a concentration-dependent manner to 58% of control values in mouse liver microsomes but did not inhibit 4-OH-MDZ formation. Thus, TRZ hydroxylation appears to be CYP3A specific in mice and humans. alpha-Hydroxylation of MDZ has a major CYP2C component in addition to CYP3A in mice, demonstrating that metabolic profiles of drugs in animals cannot be assumed to reflect human metabolic patterns, even with closely related substrates. (+info)
Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: evaluation of sex-dependent differences.
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Eighteen healthy volunteers (10 men and 8 women) participated in a single-dose, double-blind, three-way crossover pharmacokinetic and pharmacodynamic study. Treatment conditions were 0.25 mg of triazolam, a full-agonist benzodiazepine ligand; 10 mg of zolpidem, an imidazopyridine having relative selectivity for the type 1 benzodiazepine receptor subtype; and placebo. Weight-normalized clearance of triazolam was higher in women than in men (8.7 versus 5. 5 ml/min/kg), but the difference was not significant. In contrast, zolpidem clearance was lower in women than in men (3.5 versus 6.7 ml/min/kg, P <.06). Compared to placebo, both active medications produced significant benzodiazepine agonist-like pharmacodynamic effects: sedation, impaired psychomotor performance, impaired information recall, and increased electroencephalographic beta-amplitude. Effects of triazolam and zolpidem in general were comparable and less than 8 h in duration. There was no evidence of a substantial or consistent sex difference in pharmacodynamic effects or in the kinetic-dynamic relationship, although subtle differences could not be ruled out due to low statistical power. The complete dependence of triazolam clearance on CYP3A activity, as opposed to the mixed CYP participation in zolpidem clearance, may explain the differing sex effects on clearance of the two compounds. (+info)
Detection of triazolam and its hydroxy metabolites in rat hair by reversed-phase liquid chromatography with electrospray ionization mass spectrometry.
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A sensitive method using reversed-phase liquid chromatography coupled with electrospray ionization mass spectrometry (LC-ESI-MS) for simultaneous determination of triazolam (TZ) and its hydroxy metabolites in hair has been developed. After the addition of deuterium-labeled 1 -hydroxymethyltriazolam (1-HT-d4) as an internal standard, analytes in hair shaft and hair root samples were extracted with a basic medium, CH2Cl2/MeOH/28% NH4OH (20:80:2), at room temperature overnight. The chromatographic separation of the analytes was achieved using a 3-microm micro HPLC column (100 x 2.0-mm i.d.) with a gradient of acetonitrile in water containing 1% acetic acid as the mobile phase at a flow rate of 0.15 mL/min. The mass spectrometer was operated in selected-ion monitoring mode at quasi molecular ions [M+H]+ of TZ and its metabolites. Under the proposed conditions, the ranges of quantitation of TZ, 1-HT, and 4-HT were 0.1-10 ng/0.2 mL. The method has been applied to determine the hair shaft and hair root incorporation of TZ and its metabolites into Dark Agouti rats administered with 3 mg/kg or 6 mg/kg intraperitoneally twice a day for five days. Judging from the retention behavior by the chromatography and the mass spectra of the peaks detected, TZ, 1-HT, and 4-HT were incorporated in the hair shaft and the hair root. The concentration of 4-HT was the highest of all compounds detected. An unknown substance thought to be 1,4-diHT also appeared in both hair shaft and hair root samples. This substance was obtained from in vitro metabolic studies of TZ using rat liver microsome fraction and was accompanied by the other two metabolites, 1-HT and 4-HT. Structural elucidation was performed with online high-performance liquid chromatography-MS after acetylation of the substance with acetic anhydride and pyridine. This is the first report of the detection of the hydroxy metabolites of TZ in hair. The method has been found to be useful as a screening procedure of TZ intake in humans. (+info)