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James K Rowlett - One of the best experts on this subject based on the ideXlab platform.
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anticonflict and reinforcing effects of Triazolam pregnanolone combinations in rhesus monkeys
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Bradford D Fischer, James K RowlettAbstract:Combinations of positive modulators of benzodiazepine and neuroactive steroid sites on GABAA receptors have been shown to act in an additive or supra-additive manner depending on the endpoint under study, but they have not been assessed on experimentally induced conflict or drug self-administration. The present study examined the interactive effects of the benzodiazepine Triazolam and the neuroactive steroid pregnanolone in a rhesus monkey conflict procedure (a model of anxiolysis) and on a progressive-ratio schedule of drug self-administration (a model of abuse potential). Both Triazolam and pregnanolone decreased rates of nonsuppressed responding, whereas only Triazolam consistently increased rates of suppressed responding (i.e., had an anticonflict effect). Fixed-ratio mixtures of Triazolam and pregnanolone also decreased rates of nonsuppressed responding and did so in an additive manner. In contrast, mixtures of Triazolam and pregnanolone produced either additive or supra-additive rate-increasing effects on suppressed responding, depending on the proportion of drugs in the mixture. Both Triazolam and pregnanolone were self-administered significantly, and Triazolam and pregnanolone mixtures had either proportion-dependent additive or infra-additive reinforcing effects. These results suggest that combinations of Triazolam and pregnanolone may have enhanced anxiolytic effects with reduced behavioral disruption and abuse potential compared with either drug alone.
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Anticonflict and reinforcing effects of Triazolam + pregnanolone combinations in rhesus monkeys.
Journal of Pharmacology and Experimental Therapeutics, 2011Co-Authors: Bradford D Fischer, James K RowlettAbstract:Combinations of positive modulators of benzodiazepine and neuroactive steroid sites on GABAA receptors have been shown to act in an additive or supra-additive manner depending on the endpoint under study, but they have not been assessed on experimentally induced conflict or drug self-administration. The present study examined the interactive effects of the benzodiazepine Triazolam and the neuroactive steroid pregnanolone in a rhesus monkey conflict procedure (a model of anxiolysis) and on a progressive-ratio schedule of drug self-administration (a model of abuse potential). Both Triazolam and pregnanolone decreased rates of nonsuppressed responding, whereas only Triazolam consistently increased rates of suppressed responding (i.e., had an anticonflict effect). Fixed-ratio mixtures of Triazolam and pregnanolone also decreased rates of nonsuppressed responding and did so in an additive manner. In contrast, mixtures of Triazolam and pregnanolone produced either additive or supra-additive rate-increasing effects on suppressed responding, depending on the proportion of drugs in the mixture. Both Triazolam and pregnanolone were self-administered significantly, and Triazolam and pregnanolone mixtures had either proportion-dependent additive or infra-additive reinforcing effects. These results suggest that combinations of Triazolam and pregnanolone may have enhanced anxiolytic effects with reduced behavioral disruption and abuse potential compared with either drug alone.
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role of gabaa benzodiazepine receptors containing alpha 1 and alpha 5 subunits in the discriminative stimulus effects of Triazolam in squirrel monkeys
Psychopharmacology, 2002Co-Authors: Snjezana Lelas, James K Rowlett, Roger D Spealman, James M Cook, Xiaoyan LiAbstract:Rationale: Conventional benzodiazepines (BZs), clinically used for treatment of anxiety and insomnia, bind to GABAA receptors containing α1, α2, α3, or α5 subunits. The role of these different GABAA receptor subtypes in mediating the subjective effects of BZs remains largely unknown. Objective: The purpose of the present study was to evaluate the role of GABAA receptors containing the α1 or α5 subunits in the discriminative stimulus (DS) effects of the conventional BZ agonist Triazolam. Methods: Squirrel monkeys were trained to discriminate Triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 schedule of food reinforcement. Results: The GABAA/α1-preferring agonists zolpidem and zaleplon engendered responses predominantly on the Triazolam lever (73–80% drug-lever responding), and the GABAA/α1 partial agonist CL 218,872 engendered an average maximum of less than 50% Triazolam-lever responding. The GABAA/α1-preferring antagonists β-carboline-3-carboxylate-t-butyl ester (βCCT) and 3-(propyloxy)-β-carboline (3-PBC) blocked the DS effects of Triazolam and zolpidem in a surmountable manner. Schild analyses for βCCT and 3-PBC in combination with Triazolam and zolpidem suggest that the interactions between these compounds were competitive in nature and mediated by a common population of receptors, presumably GABAA/α1 receptors. In contrast, the GABAA/α5-preferring agonist QH-ii-66 did not engender Triazolam-lever responding regardless of dose and did not alter the DS effects of Triazolam when administered in combination. Conclusions: The results are consistent with GABAA/α1 receptor involvement in mediating the DS effects of Triazolam. In contrast, binding to GABAA/α5 receptors may not play a critical role in mediating Triazolam's DS effects.
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isobolographic analysis of chlordiazepoxide and Triazolam combinations in squirrel monkeys discriminating Triazolam
Psychopharmacology, 2001Co-Authors: Snjezana Lelas, James K Rowlett, Roger D SpealmanAbstract:Rationale: The discriminative stimulus (DS) effects of chlordiazepoxide (CDP) differ from those of other typical benzodiazepine (BZ) agonists in that CDP does not always occasion full substitution for a BZ agonist DS. Objectives: The present study tested the hypothesis that the unusual DS effects of CDP may result from its relatively low intrinsic efficacy by examining the combinations of CDP and Triazolam using isobolographic analysis in squirrel monkeys discriminating Triazolam. Methods and results: Squirrel monkeys were previously trained to discriminate Triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. CDP occasioned partial substitution for Triazolam and did not alter the DS effects of Triazolam, whereas single doses of Triazolam enhanced the DS effects of Triazolam, and bretazenil antagonized the Triazolam DS. The isobolographic analysis showed that CDP and Triazolam combinations resulted in additive effects in animals in which CDP substituted for Triazolam, whereas infra-additive effects were obtained in animals in which CDP did not substitute for Triazolam. Conclusions: The partial substitution of CDP for Triazolam and the infra-additive effects obtained in animals in which CDP did not substitute for Triazolam suggest that CDP may have lower intrinsic efficacy than Triazolam. However, the lack of overall effect of CDP pretreatment and the lack of shift in animals in which CDP substituted for Triazolam suggest that other factors, such as differential activity at BZ receptor subtypes, may play a role in the effects of CDP.
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Triazolam discrimination in squirrel monkeys distinguishes high efficacy agonists from other benzodiazepines and non benzodiazepine drugs
Psychopharmacology, 2001Co-Authors: Snjezana Lelas, James K Rowlett, Roger D SpealmanAbstract:Rationale: Triazolam is a high-efficacy benzodiazepine (BZ) agonist, which might be hypothesized to engender highly pharmacologically specific discriminative stimulus (DS) effects and distinguish among BZ agonists with different intrinsic efficacy. Objectives: The pharmacological specificity of the Triazolam stimulus was determined by examining the effects of conventional and atypical BZ agonists, and other ligands active at the γ-aminobutyric acidA (GABAA) receptor complex. Receptor mechanisms underlying the DS effects of Triazolam were examined further using the BZ receptor antagonist flumazenil. Methods and results: Squirrel monkeys were trained to discriminate Triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. While the BZ agonists midazolam, diazepam, and lorazepam substituted fully for Triazolam, chlordiazepoxide, oxazepam and nordiazepam produced only partial substitution, suggesting these latter compounds may have reduced intrinsic efficacy. The BZ/α1-preferring agonist zolpidem substituted fully for Triazolam, and potencies for Triazolam-like effects of BZ agonists were significantly correlated with potencies for their zolpidem-like effects (Rowlett et al. 1999). Flumazenil antagonized the DS effects of Triazolam, but the slope of the Schild plot was significantly different from unity, suggesting multiple receptors may be involved in the DS effects of Triazolam. Conclusions: BZ agonists can be distinguished on the basis of substitution for Triazolam and, thus, the Triazolam discrimination may be a useful tool for identifying compounds of different efficacy at BZ receptors. BZ/α1 receptors appear to play a prominent role in the DS effects of Triazolam, but the contribution of other subtypes of BZ receptors cannot be ruled out.
Pertti J. Neuvonen - One of the best experts on this subject based on the ideXlab platform.
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Fluconazole, but not terbinafine, enhances the effects of Triazolam by inhibiting its metabolism
British Journal of Clinical Pharmacology, 2003Co-Authors: Anu Varhe, Klaus T Olkkola, Pertti J. NeuvonenAbstract:1 The interaction between Triazolam and two antifungal agents, fluconazole and terbinafine, was investigated in a double-blind, randomized crossover study of three phases. 2 Twelve healthy young volunteers received 100 mg fluconazole, 250 mg terbinafine or placebo orally once a day for 4 days. On day 4 they took a single 0.25 mg dose of Triazolam. Plasma samples were collected and pharmacodynamic effects were measured up to 17 h after the intake of Triazolam. 3 Fluconazole increased the area under the Triazolam concentration time-curve more than twofold (P
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fluconazole but not terbinafine enhances the effects of Triazolam by inhibiting its metabolism
British Journal of Clinical Pharmacology, 2003Co-Authors: Anu Varhe, Klaus T Olkkola, Pertti J. NeuvonenAbstract:1 The interaction between Triazolam and two antifungal agents, fluconazole and terbinafine, was investigated in a double-blind, randomized crossover study of three phases. 2 Twelve healthy young volunteers received 100 mg fluconazole, 250 mg terbinafine or placebo orally once a day for 4 days. On day 4 they took a single 0.25 mg dose of Triazolam. Plasma samples were collected and pharmacodynamic effects were measured up to 17 h after the intake of Triazolam. 3 Fluconazole increased the area under the Triazolam concentration time-curve more than twofold (P<0.001) and prolonged the elimination half-life of Triazolam nearly twofold (P<0.001). The peak concentration of Triazolam was also increased significantly (P<0.05) by fluconazole. 4 During the fluconazole phase pharmacodynamic effects of Triazolam (e.g. digit symbol substitution test, body sway and drowsiness) were enhanced significantly (P<0.05) when compared with the placebo phase. 5 Terbinafine did not change significantly the pharmacokinetics or pharmacodynamics of Triazolam. 6 Care should be taken when Triazolam is prescribed to patients using fluconazole. Although the interaction is not as strong as that of Triazolam with ketoconazole or itraconazole, it is clinically significant. Triazolam and probably other drugs metabolized by CYP3A4 can be used in normal doses with terbinafine.
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The Effect of Dexamethasone on the Pharmacokinetics of Triazolam
Pharmacology & Toxicology, 1998Co-Authors: Kirsti Villikka, Kari T. Kivistö, Pertti J. NeuvonenAbstract:: The effects of short-term use of a small dose of dexamethasone on the pharmacokinetics and pharmacodynamics of the CYP3A4 substrate, Triazolam, were examined. In a randomized, double-blind cross-over study with two phases, ten healthy volunteers were given either 1.5 mg dexamethasone or placebo once a day for 4 days. On the 5th day, 0.5 mg Triazolam was administered orally. Plasma Triazolam concentrations and effects of Triazolam were measured for 10 hr. Dexamethasone did not have statistically significant effects on the pharmacokinetics of Triazolam. The mean total area under the plasma Triazolam concentration-time curve was, however, 19% smaller during the dexamethasone phase than during the placebo phase (11.4 +/- 5.7 ng ml-1 hr versus 14.1 +/- 8.8 ng ml-1 hr (mean +/- S.D.); P = 0.09). The four psychomotor tests employed did not show significant differences in the effects of Triazolam between the phases. Although dexamethasone had only small effects on the pharmacokinetics and pharmacodynamics of Triazolam in the present study, higher doses or prolonged use of dexamethasone might cause a more pronounced induction of CYP3A4. Further studies on the effects of dexamethasone on the pharmacokinetics of CYP3A4 substrates in man are needed.
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Triazolam is ineffective in patients taking rifampin
Clinical Pharmacology & Therapeutics, 1997Co-Authors: Kirsti Villikka, Klaus T Olkkola, Kari T. Kivistö, J T Backman, Pertti J. NeuvonenAbstract:Background Triazolam is metabolized predominantly by cytochrome P450 3A4 (CYP3A4). Rifampin (rifampicin) is a potent inducer of CYP3A4 and it is known to markedly reduce plasma concentrations and effects of drugs such as midazolam. The possible interaction between rifampin and Triazolam was examined in this study. Methods The pharmacokinetics and pharmacodynamics of Triazolam were investigated in a randomized, double-blind crossover study with two phases. Ten young healthy volunteers took either 600 mg rifampin once daily or placebo for 5 days. On the sixth day, 0.5 mg Triazolam was administrered orally. Timed blood samples were collected and the effects of Triazolam were measured with five psychomotor tests for 10 hours. Results The area under the plasma Triazolam concentration-time curve in the rifampin phase was only 5.1% of that in the placebo phase (0.74 ± 0.14 versus 14.8 ± 1.0 ng · hr/ml [mean ± SEM; p < 0.001]). Rifampin pretreatment decreased the maximum plasma concentration of Triazolam to 12.4% of the control value (i.e., from 2.9 ± 0.2 to 0.36 ± 0.06 ng/ml [p < 0.001]) and the elimination half-life from 2.8 ± 0.1 to 1.3 ± 0.1 hours (p < 0.001). All psychomotor tests showed markedly reduced effects (p < 0.01) of Triazolam after rifampin pretreatment. Conclusions Triazolam is ineffective during rifampin treatment. This is most likely due to increased metabolism of Triazolam after induction of CYP3A4 in the gut wall and liver by rifampin. It is advisable to use hypnotic agents that are not metabolized by CYP3A4 during treatment with rifampin or other potent inducers of CYP3A4. Clinical Pharmacology & Therapeutics (1997) 61, 8–14; doi:
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effect of fluconazole dose on the extent of fluconazole Triazolam interaction
British Journal of Clinical Pharmacology, 1996Co-Authors: Anu Varhe, Klaus T Olkkola, Pertti J. NeuvonenAbstract:1Azole antimycotics interact with the short acting hypnotic Triazolam. The effect of fluconazole dose on the extent of fluconazole-Triazolam interaction was investigated in a double-blind, randomized cross-over study of four phases. 2Eight healthy volunteers received either 50 mg, 100 mg or 200 mg (400 mg on day 1) of fluconazole or placebo orally once a day for 4 days. On day 4, they took a 0.25 mg oral dose of Triazolam, after which plasma samples were collected and pharmacodynamic effects measured for 18 h. 3The mean area under the Triazolam concentration-time curve (AUC) was increased 1.6-, 2.1- and 4.4-fold (P<0.001) by fluconazole 50 mg, 100 mg and 200 mg, respectively. The increase in the elimination half-life of Triazolam (t½,z) varied from 1.3-fold (fluconazole 50 mg, P<0.05) to 2.3-fold (fluconazole 200 mg, P<0.001). The peak concentration of Triazolam was also increased significantly during all fluconazole phases; more than twofold by fluconazole 200 mg (P<0.001). 4The pharmacodynamic effects of Triazolam were increased significantly (P<0.05) by fluconazole 100 mg and 200 mg. 5Even a small 50 mg daily dose of fluconazole can interact with Triazolam and the extent of the interaction increases with increasing fluconazole dose. When Triazolam is used concomitantly with fluconazole 50–200 mg, the dose of Triazolam should be reduced, accordingly. Simultaneous use of Triazolam with higher fluconazole doses should be avoided.
Roland R. Griffiths - One of the best experts on this subject based on the ideXlab platform.
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relative abuse liability of indiplon and Triazolam in humans a comparison of psychomotor subjective and cognitive effects
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Lawrence P Carter, Roland R. Griffiths, Patricia E Suess, J H Casada, Christopher L Wallace, John D RoacheAbstract:Indiplon [ N -methyl- N -[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-α]pyrimidin-7-yl]phenyl]acetamide; NBI 34060] is a positive allosteric GABAA receptor modulator that is under development for the treatment of insomnia. This study compared the abuse potential of indiplon, a compound with preferential affinity for GABAA receptors containing an α1 subunit, with Triazolam in 21 volunteers with histories of drug abuse. Placebo, Triazolam (0.25, 0.5, and 0.75 mg), and indiplon (30, 50, and 80 mg) were studied in counterbalanced order under double-blind conditions at two different residential research facilities. Both drugs impaired psychomotor and cognitive performance and produced similar dose-related increases in participant and observer ratings of drug strength. The onset of action of both drugs was rapid (30 min); however, the duration of action of indiplon (3–4 h) was shorter than that of Triazolam (4–6 h). The profiles of subjective effects of Triazolam and indiplon were similar; however, a maximum of 52% of participants identified indiplon as a benzodiazepine or barbiturate, compared with 81% of participants after 0.75 mg of Triazolam. On participantrated subjective effects relevant to sedation, the slope of the Triazolam dose-effect curve was significantly steeper than that of indiplon. Neither the largest doses of indiplon and Triazolam nor the slope of the indiplon and Triazolam dose-effect curves were significantly different from each other on any of the same-day or next-day measures of positive drug effects or next-day measures of reinforcing effects. Together, these data suggest that although the abuse potential of indiplon is not different from that of Triazolam at these doses, psychomotor and cognitive impairment after large doses of indiplon might be less.
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Relative Abuse Liability of GHB in Humans: A Comparison of Psychomotor, Subjective, and Cognitive Effects of Supratherapeutic Doses of Triazolam, Pentobarbital, and GHB
Neuropsychopharmacology, 2006Co-Authors: Lawrence P Carter, Brian D Richards, Miriam Z Mintzer, Roland R. GriffithsAbstract:Although preclinical studies suggest that GHB has low likelihood for abuse, case reports indicate that GHB is abused. This study evaluated the relative abuse liability of GHB in 14 volunteers with histories of drug abuse. Psychomotor, subjective, and cognitive effects of a broad range of GHB doses (2–18?g/70?kg), up to a dose that produced severe behavioral impairment in each participant, were compared to placebo and two abused sedative/hypnotic drugs, Triazolam (0.5 and 1?mg/70?kg) and pentobarbital (200 and 400?mg/70?kg), under double-blind, double-dummy conditions at a residential research facility. In general, GHB produced effects similar to Triazolam and pentobarbital, although GHB was not identified as a benzodiazepine or barbiturate by participants that correctly identified Triazolam and pentobarbital as such. On most measures of likelihood of abuse (eg ratings of liking, reinforcing effects), effects of pentobarbital were significantly greater than those of Triazolam, with GHB being intermediate. GHB produced significantly greater negative subjective effects, including nausea, than the other drugs. Memory impairment after GHB was less than that after Triazolam and pentobarbital. Within participants, the dose–effect function for sedation was steeper for GHB than for Triazolam and pentobarbital. Also, at higher doses, GHB was associated with greater sedation and more variability across participants in sedation. Taken together, these data suggest that the profile of effects of GHB only partially overlaps with that of Triazolam and pentobarbital. Although the likelihood for GHB to be abused is intermediate to Triazolam and pentobarbital, the possibility of accidental overdose (ie greater sedation than intended) with GHB appears to be greater.
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zaleplon and Triazolam in humans acute behavioral effects and abuse potential
Psychopharmacology, 1999Co-Authors: Craig R Rush, Joseph M Frey, Roland R. GriffithsAbstract:Zaleplon, a pyrazolopyrimidine that is under development as a hypnotic, produces its pharmacological effects at the benzodiazepine-recognition site on the GABAA 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.
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Flunitrazepam and Triazolam: a comparison of behavioral effects and abuse liability.
Drug and Alcohol Dependence, 1998Co-Authors: Miriam Z Mintzer, Roland R. GriffithsAbstract:The performance, observer-rated, and participant-rated effects of orally administered placebo, and two benzodiazepines, flunitrazepam (2, 4 and 8 mg/70 kg) and Triazolam (0.25, 0.5 and 1 mg/70 kg), were compared in 14 sedative drug abusers using a double-blind crossover design. Both flunitrazepam and Triazolam produced dose-related decrements in memory and psychomotor/cognitive performance, and increases in many participant- and observer-rated measures. Effects of flunitrazepam had an earlier onset and a longer duration than those of Triazolam. Although there was evidence that the flunitrazepam doses selected for study were somewhat higher overall relative to the selected Triazolam doses, analysis of the participant-rated measures collected 24 h after drug administration (next-day) suggests that flunitrazepam may have a greater abuse liability than Triazolam when abuse liability is assessed 24 h after drug administration. The highest flunitrazepam dose produced effects that were significantly greater than those of the highest Triazolam dose on next-day ratings of good effects, take again, and worth; all tested flunitrazepam doses produced effects greater than any Triazolam dose on next-day ratings of liking and take again. The highest flunitrazepam dose, but no Triazolam dose, significantly increased the maximum dollar value at which participants chose drug over money in a Drug versus Money Choice Procedure.
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zolpidem and Triazolam in humans behavioral and subjective effects and abuse liability
Journal of Pharmacology and Experimental Therapeutics, 1990Co-Authors: Suzette M Evans, F R Funderburk, Roland R. GriffithsAbstract:Zolpidem, which is currently marketed in Europe as a hypnotic, is a short-duration imidazopyridine whose actions are mediated at the gamma-aminobutyric acid benzodiazepine receptor complex. However, zolpidem produces a variety of biochemical differences from classic benzodiazepine agonists including showing selectivity for the central BZ1 (omega 1) receptor subtype as well as showing a different pattern of distribution of binding sites. This study compared zolpidem to the benzodiazepine hypnotic Triazolam in 15 healthy male volunteers with histories of sedative drug abuse. Placebo, zolpidem (15, 30 and 45 mg) and Triazolam (0.25, 0.5 and 0.75 mg) were administered p.o. in a mixed sequence in a double-blind, cross-over design. The onset time with zolpidem was faster than with Triazolam, with peak effects of both drugs occurring at 1 to 2 hr after administration. Both zolpidem and Triazolam produced dose-related decrements in performance on various performance tasks including circular lights, reaction time, balance, number recall and the digit symbol substitution test. Both drugs also produced similar dose-related changes on various observer ratings including overall strength of drug effect. Triazolam, but not zolpidem, increased subject- and observer-rated sleepiness and produced greater impairment on a picture memory task. Zolpidem, but not Triazolam, produced increases in subject ratings of various somatic symptoms (e.g., dizzy, anxious and queasy) and there were 9 days on which subjects vomited after zolpidem, but none after Triazolam. Although the highest dose of both drugs was identified by subjects as being active, the highest dose of Triazolam was identified as being barbiturate, benzodiazepine or alcohol, almost twice as often as the highest dose of zolpidem. Overall, this study shows that although zolpidem produces many effects in common with Triazolam, it also has a unique profile of effects distinguishable from classic benzodiazepine agonists. The mechanism(s) underlying these differences is unclear, but may be related to the atypical biochemical profile of zolpidem.
Sadaki Inokuchi - One of the best experts on this subject based on the ideXlab platform.
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a case of torsades de pointes induced by severe qt prolongation after an overdose of eperisone and Triazolam in a patient receiving nifedipine
Clinical Toxicology, 2010Co-Authors: Takeshi Yamagiwa, Mari Amino, Seiji Morita, Rie Yamamoto, Takeshi Saito, Sadaki InokuchiAbstract:Introduction. Eperisone hydrochloride is a centrally acting muscle relaxant, and Triazolam is a short-acting benzodiazepine. Although commonly prescribed, cardiotoxicity induced by a single overdose of either drug is comparatively rare. A patient receiving nifedipine developed torsades de pointes (TdP) because of prolongation of the corrected QT (QTc) interval after an overdose of eperisone hydrochloride and Triazolam. Case report. A 60-year-old man receiving nifedipine was admitted in a comatose condition 3 h after ingesting 5,000 mg of eperisone and 2.5 mg of Triazolam. Electrocardiogram showed sinus rhythm with prolongation of the QTc interval (820 ms). The serum electrolyte levels were as follows: potassium, 3.8 mEq/L; magnesium, 2.4 mg/dL. The serum drug concentrations were high: eperisone, 15,360 ng/mL; Triazolam, 110.8 ng/mL. A temporary cardiac pacemaker was implanted immediately after the development of TdP, 11 h after the ingestion. The serum Triazolam concentration normalized on day 2. The QTc ...
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A case of torsades de pointes induced by severe QT prolongation after an overdose of eperisone and Triazolam in a patient receiving nifedipine.
Clinical toxicology (Philadelphia, Pa.), 2010Co-Authors: Takeshi Yamagiwa, Mari Amino, Seiji Morita, Rie Yamamoto, Takeshi Saito, Sadaki InokuchiAbstract:INTRODUCTION: Eperisone hydrochloride is a centrally acting muscle relaxant, and Triazolam is a short-acting benzodiazepine. Although commonly prescribed, cardiotoxicity induced by a single overdose of either drug is comparatively rare. A patient receiving nifedipine developed torsades de pointes (TdP) because of prolongation of the corrected QT (QTc) interval after an overdose of eperisone hydrochloride and Triazolam. CASE REPORT: A 60-year-old man receiving nifedipine was admitted in a comatose condition 3 h after ingesting 5,000 mg of eperisone and 2.5 mg of Triazolam. Electrocardiogram showed sinus rhythm with prolongation of the QTc interval (820 ms). The serum electrolyte levels were as follows: potassium, 3.8 mEq/L; magnesium, 2.4 mg/dL. The serum drug concentrations were high: eperisone, 15,360 ng/mL; Triazolam, 110.8 ng/mL. A temporary cardiac pacemaker was implanted immediately after the development of TdP, 11 h after the ingestion. The serum Triazolam concentration normalized on day 2. The QTc interval and eperisone concentration normalized on day 6. CONCLUSION: Eperisone and Triazolam overdose can cause life-threatening cardiotoxicity. Electrocardiographic monitoring and serial determination of QTc interval are likely the best way to observe these patients and evaluate the risk of cardiotoxicity.
Roger D Spealman - One of the best experts on this subject based on the ideXlab platform.
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role of gabaa benzodiazepine receptors containing alpha 1 and alpha 5 subunits in the discriminative stimulus effects of Triazolam in squirrel monkeys
Psychopharmacology, 2002Co-Authors: Snjezana Lelas, James K Rowlett, Roger D Spealman, James M Cook, Xiaoyan LiAbstract:Rationale: Conventional benzodiazepines (BZs), clinically used for treatment of anxiety and insomnia, bind to GABAA receptors containing α1, α2, α3, or α5 subunits. The role of these different GABAA receptor subtypes in mediating the subjective effects of BZs remains largely unknown. Objective: The purpose of the present study was to evaluate the role of GABAA receptors containing the α1 or α5 subunits in the discriminative stimulus (DS) effects of the conventional BZ agonist Triazolam. Methods: Squirrel monkeys were trained to discriminate Triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 schedule of food reinforcement. Results: The GABAA/α1-preferring agonists zolpidem and zaleplon engendered responses predominantly on the Triazolam lever (73–80% drug-lever responding), and the GABAA/α1 partial agonist CL 218,872 engendered an average maximum of less than 50% Triazolam-lever responding. The GABAA/α1-preferring antagonists β-carboline-3-carboxylate-t-butyl ester (βCCT) and 3-(propyloxy)-β-carboline (3-PBC) blocked the DS effects of Triazolam and zolpidem in a surmountable manner. Schild analyses for βCCT and 3-PBC in combination with Triazolam and zolpidem suggest that the interactions between these compounds were competitive in nature and mediated by a common population of receptors, presumably GABAA/α1 receptors. In contrast, the GABAA/α5-preferring agonist QH-ii-66 did not engender Triazolam-lever responding regardless of dose and did not alter the DS effects of Triazolam when administered in combination. Conclusions: The results are consistent with GABAA/α1 receptor involvement in mediating the DS effects of Triazolam. In contrast, binding to GABAA/α5 receptors may not play a critical role in mediating Triazolam's DS effects.
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isobolographic analysis of chlordiazepoxide and Triazolam combinations in squirrel monkeys discriminating Triazolam
Psychopharmacology, 2001Co-Authors: Snjezana Lelas, James K Rowlett, Roger D SpealmanAbstract:Rationale: The discriminative stimulus (DS) effects of chlordiazepoxide (CDP) differ from those of other typical benzodiazepine (BZ) agonists in that CDP does not always occasion full substitution for a BZ agonist DS. Objectives: The present study tested the hypothesis that the unusual DS effects of CDP may result from its relatively low intrinsic efficacy by examining the combinations of CDP and Triazolam using isobolographic analysis in squirrel monkeys discriminating Triazolam. Methods and results: Squirrel monkeys were previously trained to discriminate Triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. CDP occasioned partial substitution for Triazolam and did not alter the DS effects of Triazolam, whereas single doses of Triazolam enhanced the DS effects of Triazolam, and bretazenil antagonized the Triazolam DS. The isobolographic analysis showed that CDP and Triazolam combinations resulted in additive effects in animals in which CDP substituted for Triazolam, whereas infra-additive effects were obtained in animals in which CDP did not substitute for Triazolam. Conclusions: The partial substitution of CDP for Triazolam and the infra-additive effects obtained in animals in which CDP did not substitute for Triazolam suggest that CDP may have lower intrinsic efficacy than Triazolam. However, the lack of overall effect of CDP pretreatment and the lack of shift in animals in which CDP substituted for Triazolam suggest that other factors, such as differential activity at BZ receptor subtypes, may play a role in the effects of CDP.
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Triazolam discrimination in squirrel monkeys distinguishes high efficacy agonists from other benzodiazepines and non benzodiazepine drugs
Psychopharmacology, 2001Co-Authors: Snjezana Lelas, James K Rowlett, Roger D SpealmanAbstract:Rationale: Triazolam is a high-efficacy benzodiazepine (BZ) agonist, which might be hypothesized to engender highly pharmacologically specific discriminative stimulus (DS) effects and distinguish among BZ agonists with different intrinsic efficacy. Objectives: The pharmacological specificity of the Triazolam stimulus was determined by examining the effects of conventional and atypical BZ agonists, and other ligands active at the γ-aminobutyric acidA (GABAA) receptor complex. Receptor mechanisms underlying the DS effects of Triazolam were examined further using the BZ receptor antagonist flumazenil. Methods and results: Squirrel monkeys were trained to discriminate Triazolam (0.03 mg/kg, i.v.) from vehicle under a fixed-ratio 10 (FR 10) schedule of food reinforcement. While the BZ agonists midazolam, diazepam, and lorazepam substituted fully for Triazolam, chlordiazepoxide, oxazepam and nordiazepam produced only partial substitution, suggesting these latter compounds may have reduced intrinsic efficacy. The BZ/α1-preferring agonist zolpidem substituted fully for Triazolam, and potencies for Triazolam-like effects of BZ agonists were significantly correlated with potencies for their zolpidem-like effects (Rowlett et al. 1999). Flumazenil antagonized the DS effects of Triazolam, but the slope of the Schild plot was significantly different from unity, suggesting multiple receptors may be involved in the DS effects of Triazolam. Conclusions: BZ agonists can be distinguished on the basis of substitution for Triazolam and, thus, the Triazolam discrimination may be a useful tool for identifying compounds of different efficacy at BZ receptors. BZ/α1 receptors appear to play a prominent role in the DS effects of Triazolam, but the contribution of other subtypes of BZ receptors cannot be ruled out.
