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At least 19 recordsLinked to original sources
PubMed2001

Isobolographic analysis of chlordiazepoxide and triazolam combinations in squirrel monkeys discriminating triazolam.

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.

Animals↗
PubMed2000

Effect of grapefruit juice dose on grapefruit juice-triazolam interaction: repeated consumption prolongs triazolam half-life.

OBJECTIVE: Grapefruit juice inhibits CYP3A4-mediated metabolism of several drugs during first pass. In this study, the effect of grapefruit juice dose on the extent of grapefruit juice-triazolam interaction was investigated. METHODS: In a randomised, four-phase, crossover study, 12 healthy volunteers received 0.25 mg triazolam with water, with 200 ml normal-strength or double-strength grapefruit juice or, on the third day of multiple-dose [three times daily (t.i.d.)] administration of double-strength grapefruit juice. Timed blood samples were collected up to 23 h after dosing, and the effects of triazolam were measured with four psychomotor tests up to 10 h after dosing. RESULTS: The area under the plasma triazolam concentration time curve (AUC(0-infinity)) was increased by 53% (P < 0.01), 49% (P < 0.01) and 143% (P < 0.001) by a single dose of normal-strength, a single dose of double-strength and multiple-dose administration of double-strength grapefruit juice, respectively. The peak plasma concentration (Cmax) of triazolam was increased by about 40% by a single dose of normal-strength grapefruit juice (P < 0.01) and multiple-dose grapefruit juice (P < 0.01) and by 25% by a single dose of double-strength grapefruit juice (P < 0.05). The elimination half-life (t(1/2)) of triazolam was prolonged by 54% during the multiple-dose grapefruit juice phase (P < 0.001). A significant increase in the pharmacodynamic effects of triazolam was seen during the multiple-dose grapefruit juice phase in the digit symbol substitution test (DSST, P < 0.05), in subjective overall drug effect (P < 0.05) and in subjective drowsiness (P < 0.05). CONCLUSIONS: Even one glass of grapefruit juice increases plasma triazolam concentrations, but repeated consumption of grapefruit juice produces a significantly greater increase in triazolam concentrations than one glass of juice. The t(1/2) of triazolam is prolonged by repeated consumption of grapefruit juice, probably due to inhibition of hepatic CYP3A4 activity.

Adult↗
PubMed1985

Triazolam, an anomalous benzodiazepine receptor ligand: in vitro characterization of alprazolam and triazolam binding.

Both alprazolam and triazolam displaced clonazepam (but not Ro 5-4864) from rat brain membranes with high affinity, showing them to act at central but not peripheral benzodiazepine receptors. At 0 degrees C, 10 microM gamma-aminobutyric acid (GABA) increased the ability of alprazolam, but not of triazolam, to displace ethyl-beta-carboline-3-carboxylate (beta-CCE) and Ro 15-1788 from these receptors. At 37 degrees C, GABA increased the affinity of the receptors for both drugs, with a +GABA/-GABA ratio of 1.5 for each in promoting Ro 15-1788 binding displacement. As both triazolam and alprazolam act as anxiolytics in vivo, the results at 37 degrees C would be compatible with the hypothesis that GABA causes an increase in affinity of drugs that act in this way, but the results at 0 degrees C would not be compatible. At 37 degrees C, alprazolam had a higher IC50 for the benzodiazepine receptor than at 0 degrees C, whereas triazolam showed the reverse effect. The relative IC50 values in vitro at 37 degrees C correlated better with the potency in vivo than those obtained at 0 degrees C. At 0 degrees C, both drugs showed Hill plots with slopes of 0.9-1 with beta-CCE and Ro 15-1788. At 37 degrees C, the slopes with triazolam were much reduced, indicating that the drug may have a selective action on a subclass of central benzodiazepine receptors. In the studies reported here, alprazolam behaved like other benzodiazepines, whereas triazolam showed several anomalous properties. It would be of interest if these properties could be related either to the drug's use as a hypnotic or to the side effects it sometimes induces.

Alprazolam↗
PubMed1983

Triazolam as a hypnotic for geriatric patients. A double-blind cross-over comparison of nitrazepam and triazolam regarding effects on sleep and psychomotor performance.

Triazolam 0.25 mg was compared with nitrazepam 5 mg as a hypnotic for 26 geriatric inpatients in a double-blind cross-over study. Sleep quantity and quality and psychomotor performance were studied. The sleep quantity and quality were similar for both drugs. There were no statistically significant differences between the two drugs in the psychomotor tests. The results are in contrast to results from other studies and might be explained by the composition of the patient material in the present study.

Aged↗
PubMed1995

Coadministration of nefazodone and benzodiazepines: II. A pharmacokinetic interaction study with triazolam.

This study was conducted to determine the potential for an interaction between nefazodone, a new antidepressant, and triazolam after a single dose of triazolam and multiple doses of nefazodone in a randomized, double-blind, placebo-controlled study in healthy male volunteers. The metabolism of triazolam is dependent on cytochrome P450 3A4, and because nefazodone has been shown in vitro to be an inhibitor of this isoenzyme, this study was conducted to assess the potential for an interaction between the two drugs. Twelve subjects were assigned to one of two groups and received an oral dose of either placebo or 0.25 mg of triazolam on days 1 and 2. Nefazodone (200 mg) was administered twice daily from the evening of day 2 to the morning of day 9. Subjects received either 0.25 mg of triazolam or placebo with the nefazodone dose on the mornings of days 8 and 9. Serial blood samples were collected on the mornings of days 1, 2, 8, and 9 for the analysis of triazolam by a validated gas chromatography/electron capture detection method and on days 8 and 9 for the analysis of nefazodone and its metabolites, hydroxynefazodone (HO-nefazodone) and m-chlorophenylpiperazine (mCPP), by a validated high-performance liquid chromatography/ultraviolet method. Noncompartmental pharmacokinetic analysis showed that there was no effect of triazolam on the pharmacokinetics of nefazodone, HO-nefazodone, or mCPP after the coadministration of triazolam and nefazodone. There was a significant effect of 200 mg of nefazodone twice daily on the pharmacokinetics of triazolam. Mean triazolam peak concentration values increased (p = 0.003) from 2.33 to 3.88 ng/ml when triazolam was administered alone and in combination with nefazodone, respectively. Corresponding mean triazolam area under the curve values increased (p < 0.001) from 8.14 to 31.74 ng.h/ml. The plasma protein binding of triazolam was approximately 85% when triazolam was given alone and when given concurrently with nefazodone. The increase in triazolam concentrations in plasma appears to be attributable to the inhibition of cytochrome P450 3A4 metabolism by nefazodone. If triazolam is coadministered with nefazodone, a reduction in the triazolam dosage is recommended; no dosage adjustment is required for nefazodone.

Adult↗
PubMed1988

Triazolam kinetics: interaction with cimetidine, propranolol, and the combination.

Nineteen healthy volunteers received a single 0.5-mg oral dose of triazolam on four occasions under the following conditions: (1) triazolam alone; (2) triazolam with cimetidine, 300 mg four times daily; (3) triazolam with propranolol, 40 mg four times daily; (4) triazolam with both cimetidine and propranolol. Triazolam kinetics were determined from multiple plasma concentrations measured during 24 hours after each dose. Compared with control, peak plasma triazolam concentration (Cmax) was significantly increased by cimetidine (5.4 versus 3.9 ng/mL), total area under the plasma concentration curve (AUC) increased (21.3 versus 16.1 ng/mL X hr), and oral clearance decreased (485 versus 668 mL/min). However triazolam half-life was not increased. During propranolol alone, triazolam Cmax (4.1 ng/mL), AUC (14.3 ng/mL X hr), and clearance (759 mL/min) did not differ significantly from control, whereas kinetic variables for triazolam with cimetidine plus propranolol were similar to those with cimetidine alone. Plasma free fraction for triazolam (17 to 18% unbound) did not differ significantly among the four treatment conditions. Mean steady-state plasma cimetidine concentrations during trials 2 and 4 were similar (1.04 versus .98 micrograms/mL), whereas plasma propranolol was significantly higher during cimetidine plus propranolol than with propranolol alone (47 versus 29 ng/ml, P less than .001). Thus cimetidine coadministration significantly inhibits triazolam clearance, causing increased triazolam AUC and Cmax, but without a prolongation in half-life. Propranolol itself does not impair triazolam clearance, nor does propranolol potentiate the inhibitory effect of cimetidine alone.

Adult↗
PubMed1994

Effects of chronic treatment with triazolam on operant responding in rats.

The aims of the present study were to investigate the effect of the benzodiazepine antagonist, flumazenil, on operant responding in rats treated chronically with the short-acting hypnotic triazolam and to study the consequence of chronic triazolam treatment on the time course of effects of triazolam and zolpidem. Zolpidem is an imidazopyridine with a pharmacological and behavioral profile that differs from that of the benzodiazepine hypnotics. Rats were treated with saline or triazolam (1 or 3 mg/kg) twice daily for 5 days and were tested daily 1, 3, 5.5 or 7.5 h after injection. In addition, on the 5th day of chronic treatment all rats were injected with flumazenil (10 mg/kg) 10 min before session. The time course of effects of triazolam and zolpidem was determined after cessation of repeated saline or triazolam treatment. Tolerance to the depressant effect of 1 mg/kg of triazolam developed during long-term administration. Flumazenil decreased operant responding in rats pretreated with triazolam. The effect was statistically significant when rats had received 1 mg/kg of triazolam 3 h before the session or 3 mg/kg of triazolam 3, 5.5 or 7.5 h before the session. After cessation of chronic treatment, rats pretreated chronically with 3 mg/kg of triazolam displayed decreased sensitivity to triazolam and to 10 mg/kg but not 3 mg/kg of zolpidem. The present results indicate that chronic treatment with triazolam induces tolerance to the rate-decreasing effect of the drug and dependence as measured by flumazenil-induced disruption of operant responding. The limited degree of cross-tolerance between zolpidem and triazolam may suggest that their pharmacological mechanisms of action are distinct.

Animals↗
PubMed2001

Determination of triazolam involving its hydroxy metabolites in hair shaft and hair root by reversed-phase liquid chromatography with electrospray ionization mass spectrometry and application to human hair analysis.

A sensitive method using reversed-phase liquid chromatography coupled with electrospray ionization mass spectrometry has been developed for simultaneous determination of triazolam and its hydroxy metabolites in hair. After the addition of deuterium-labeled 1-hydroxymethyltriazolam as an internal standard, the analytes in hair shaft and hair root samples were extracted with a basic medium, CH(2)Cl(2):MeOH:28% NH(4)OH (20:80:2) at room temperature overnight. The chromatographic separation of the analytes was achieved using a semimicro HPLC column (3-microm particle size; 100 x 2.0-mm i.d.) by gradient elution with acetonitrile in water containing 1% acetic acid as eluent. The mass spectrometer was operated in selected-ion monitoring mode at quasi-molecular ions [M+H](+) of triazolam and its metabolites. The method has been applied to determine the incorporation of triazolam and its metabolites into the hair shafts and hair roots of Dark Agouti rats administered 3 or 6 mg/kg triazolam intraperitoneally twice a day for 5 days. Triazolam, 1-hydroxymethyltriazolam, and 4-hydroxytriazolam were incorporated into the hair shafts and the hair roots. The concentration of 4-hydroxytriazolam was the highest of all compounds detected. An unknown substance considered to be 1,4-dihydroxytriazolam also appeared in the hair samples. The structural elucidation was performed with online HPLC-MS after acetylation of the substance with acetic anhydride and pyridine. The time course studies of triazolam and the metabolites in both rat hair roots and plasma were carried out after single intraperitoneal administration of triazolam. The concentrations of triazolam and the metabolites in the hair roots reflected those in the plasma. The proposed method using selected-reaction monitoring was applied to the determination of triazolam and the metabolites in human hairs of a triazolam addict. Triazolam, 1-hydroxymethyltriazolam, and 4-hydroxytriazolam were identified in the black hair shafts, whereas only triazolam was detected in the hair roots and the white hair shafts. This is the first report on the detection of triazolam and its metabolites in human hairs.

Aged↗
PubMed1997

Enhanced effect of triazolam with diltiazem.

AIMS: Triazolam, a triazolobenzodiazepine hypnotic agent, is metabolized by CYP3A4. Diltiazem is an inhibitor of this isozyme. The aim of this study was to determine if diltiazem affects plasma concentrations of triazolam in humans. METHODS: We investigated the interaction between triazolam and diltiazem in a randomized, three-phase crossover study. Seven healthy male volunteers received orally either a single 0.25 mg dose of triazolam, a 0.25 mg dose of triazolam after a 3-day treatment of diltiazem (180 mg day-1), or a placebo. Plasma samples were collected to determine triazolam concentration over a 24 h period. The pharmacodynamic effects of triazolam were investigated using the peak saccadic velocity of eye movements (PSV), electroencephalogram (EEG), and visual analogue scale (VAS) through 8 h. RESULTS: Diltiazem pretreatment significantly increased the area under the triazolam concentration-time curve (8.0 +/- 2.4 to 18.2 +/- 3.1 ng ml-1 h; P < 0.001; mean +/- s.d.). Peak triazolam concentration was increased (2.1 +/- 0.7 to 3.6 +/- 1.0 ng ml-1, P < 0.05) and the elimination half-life prolonged (4.1 +/- 2.1 to 7.6 +/- 1.9 h; P < 0.01). The PSV, EEG, and VAS of the triazolam plus diltiazem group revealed significant differences from the triazolam alone group or the control placebo group. CONCLUSIONS: Diltiazem markedly affects the pharmacokinetics of triazolam and increases the intensity of its sedative effects. Inhibition of CYP3A isozyme by diltiazem may explain the observed pharmacokinetic interaction. Therefore, triazolam should be avoided when patients are using diltiazem.

Administration, Oral↗
PubMed1991

Effect of ranitidine on the disposition of orally and intravenously administered triazolam.

The effect of orally administered ranitidine on the pharmacokinetic properties of orally and intravenously administered triazolam was determined. Twelve healthy males with a mean age of 35 years were enrolled in this four-way, randomized, crossover study. Each subject received a total of four treatments, each separated by one week. The treatments consisted of (1) one orally administered 0.25-mg triazolam tablet after treatment with ranitidine; (2) one orally administered 0.25-mg triazolam tablet, with no ranitidine pretreatment; (3) a 0.25-mg intravenous dose of triazolam after treatment with ranitidine; and (4) a 0.25-mg intravenous dose of triazolam, with no ranitidine pretreatment. Ranitidine pretreatment consisted of five 150-mg oral doses (as the hydrochloride salt) given every 12 hours; the last dose was given two hours before triazolam was administered. Blood samples were taken at intervals up to 12 hours after triazolam treatment. Serum triazolam concentrations were measured by modified high-performance liquid chromatography, and pharmacokinetic values were calculated. Pretreatment with ranitidine had no effect on the disposition of intravenously administered triazolam but significantly increased the area under the serum drug concentration-time curve of oral triazolam. Ranitidine pretreatment had no effect on triazolam's terminal elimination rate constant or on the time to reach maximum serum triazolam concentration. Ranitidine pretreatment increased the systemic availability of triazolam by increasing its absorption.

Administration, Oral↗
PubMed2001

Triazolam discrimination in squirrel monkeys distinguishes high-efficacy agonists from other benzodiazepines and non-benzodiazepine drugs.

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 gamma-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/alpha1-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/alpha1 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.

Animals↗
PubMed1996

The effect of ingestion time interval on the interaction between itraconazole and triazolam.

BACKGROUND: The plasma concentrations and effects of triazolam are markedly increased when it is ingested with itraconazole. The dependence of this interaction on the time interval of their ingestion and the possibility of avoiding the interaction by a correct daily dosing was studied. METHODS: Ten healthy volunteers took part in this randomized crossover study of five phases, each separated by 4 weeks. The subjects received a single 0.25 mg oral dose of triazolam either without itraconazole or with a single 200 mg dose of itraconazole that was ingested either simultaneously with triazolam or 3, 12, or 24 hours before triazolam. Plasma concentrations of triazolam and itraconazole were determined and pharmacodynamic effects were measured up to 17 hours. RESULTS: Itraconazole ingested simultaneously or 3, 12, or 24 hours before triazolam increased the mean area under the triazolam concentration-time curve 3.1-, 4.8-, 4.6-, and 3.8-fold (p < 0.001), respectively. The mean increase in the peak concentration of triazolam ranged from 1.4-fold (taken simultaneously, p < 0.05) to 1.8-fold (3 or 12 hours after itraconazole, p < 0.001). The elimination half-life of triazolam was increased about threefold (p < 0.001) during all itraconazole phases. Pharmacodynamic effects of triazolam were increased along with increased plasma concentrations of triazolam. CONCLUSIONS: Even a single 200 mg dose of itraconazole interacts considerably with triazolam when this hypnotic agent is ingested within 24 hours after itraconazole. Thus during the daily itraconazole use this interaction cannot be avoided by increasing the time interval between their intake. Furthermore, the risk of interaction is obvious for several days after the cessation of itraconazole therapy.

Adult↗
PubMed2000

Dose-response effects of zaleplon as compared with triazolam (0.25 mg) and placebo in chronic primary insomnia.

The effects of two nights of treatment with the short-acting benzodiazepine receptor agonist zaleplon, triazolam, or placebo was assessed in chronic primary insomniacs using two concurrent, multi-center, randomized, double-blind, Latin Square crossover studies. Study 1 (n = 47) compared zaleplon (10 and 40 mg) to triazolam (0.25 mg) and placebo. Study 2 (n = 36) compared zaleplon (20 and 60 mg) to triazolam (0.25 mg) and placebo. For each study, polysomnographically recorded sleep parameters and patient reports of sleep quality were collected during baseline and two consecutive nights during the four treatment phases in each study. All doses of zaleplon produced significant decreases in latency to persistent sleep. Although no minimally effective dose could be determined, dose-response effects were apparent. Triazolam 0.25 mg produced a decrease in latency to persistent sleep that was comparable to that of zaleplon 10 mg. Only the triazolam dose and the 60 mg dose of zaleplon produced significant increases in total sleep time over placebo. Zaleplon 40 and 60 mg and triazolam produced decreases in the percentage of REM sleep compared to placebo. Patient reports of efficacy were consistent with objective findings. In addition, all doses of zaleplon tended to increase while triazolam decreased the percentage of stage 3/4 sleep. There was no evidence of residual daytime impairment for any of the zaleplon doses, however, triazolam administration produced significant impairment in performance on a digit copying test. A higher number of adverse events were seen with the 40 and 60 mg doses of zaleplon compared to triazolam (0.25) and placebo. At higher doses, zaleplon is more effective than triazolam at reducing latency to persistent sleep in chronic insomnia and is not associated with the decrease in slow-wave sleep or residual impairment observed with triazolam. However, increases in total sleep time were apparent only at doses which produced concomitant increases in the number of adverse events. In contrast, triazolam (0.25 mg) produced increases in total sleep time (;25 min) and decreases in latency to persistent sleep at a dose of 0.25 mg. Copyright 2000 John Wiley & Sons, Ltd.

Journal Article↗
PubMed1996

Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism.

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.

Administration, Oral↗
PubMed1996

Effect of fluconazole dose on the extent of fluconazole-triazolam interaction.

1. Azole 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. 2. Eight 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. 3. The 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 (t1/2,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). 4. The pharmacodynamic effects of triazolam were increased significantly (P < 0.05) by fluconazole 100 mg and 200 mg. 5. Even 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.

Adult↗
PubMed1994

In vivo high intrinsic efficacy of triazolam: a positron emission tomography study in nonhuman primates.

The triazolobenzodiazepine triazolam is a central-type benzodiazepine receptor (BZR) ligand that is widely prescribed as a hypnotic agent. Triazolam produces its effects through potentiation of gamma-aminobutyric acid-mediated neurotransmission. Findings reported from in vitro binding studies showed some discrepancies concerning the pharmacological characteristics of triazolam. The present study aims to characterize in vivo the biochemical properties of triazolam, i.e., cerebral pharmacokinetics, interaction with BZR, potency, and intrinsic efficacy. Triazolam was studied in living nonhuman primates using positron emission tomography. Two different studies were carried out: (a) a direct study using [11C]triazolam and (b) an indirect competition study using the radiolabeled BZR antagonist 1C]flumazenil. Results showed that, in the brain in vivo, triazolam binds specifically and competitively to the BZR. Its rapid cerebral kinetics is consistent with a hypnotic profile (maximal binding after 23 min, elimination half-life of 202 min). Triazolam is very potent in displacing [11C]flumazenil (ID50 = 28 +/- 6 micrograms/kg). Hill analysis of the displacement curve does not show obvious binding-site heterogeneity. Triazolam is 20 times more potent in displacing [11C]flumazenil and 50 times more potent in inhibiting pentylenetetrazol-induced paroxysmal activity than the full benzodiazepine agonist diazepam. Interestingly, the simultaneous use of positron emission tomography and EEG recording allowed us to show that triazolam-positive intrinsic efficacy is slightly higher (20%) than that of diazepam. An attractive hypothesis proposes that the severity of side effects of BZR ligands is proportional to their intrinsic efficacy. Therefore, our study shows that triazolam side effects, as for other benzodiazepines, may be related to its high intrinsic efficacy in vivo.

Animals↗
PubMed1995

Effects of triazolam on drinking in baboons with and without an oral self-administration history: a reinstatement phenomenon.

In a test of the reinforcing efficacy of triazolam under an oral drug self-administration procedure, three baboons consumed higher volumes of triazolam than of vehicle. Although these results suggested that triazolam was serving as a reinforcer, the unconditioned effect of triazolam itself on drinking remained unclear. Therefore, the effect of pretreatment with triazolam on consumption of a nondrug fluid was assessed in sessions that were otherwise identical to oral drug self-administration sessions. Following oral pretreatment with triazolam (0.6-19.2 mg total dose), there was a dose-dependent increase in drinking, suggesting that triazolam increased fluid consumption per se. However, subsequent manipulations showed that following pretreatment with triazolam, there was no systematic change in tap water consumption from the regular drinking spout and that the dipsogenic effect of pretreatment with triazolam was not specific to a particular fluid; however, the effect was specific to prior experience with the oral self-administration procedure. Thus, the dose-related increase in consumption from the drinkometer spout following triazolam pretreatment most likely is explained as the "priming" or "reinstatement" of an operant that previously had produced drug reinforcement, even though extinction (i.e., substitution of the drug vehicle) was in effect.

Administration, Oral↗