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The excessive prescription of benzodiazepines is putting more people at risk of dependence on these drugs and is exacerbating the fatal overdose toll of opioids. A rapid and sensitive SERS method has been developed for trace detection of select benzodiazepines in low-dosage suspect counterfeit tablets, capsules, and injectable solutions using two different portable handheld Raman spectrometers equipped with either a 785-nm laser or a 1064-nm laser. A total of 169 samples and blanks were examined using five handheld Raman spectrometers, which provided data set of 729 examinations. The extraction/SERS procedures yielded true positive rates above 90% for alprazolam, diazepam, and midazolam using the 1064-nm device and yielded true positive rates above 95% for alprazolam, clonazepam, diazepam, estazolam, midazolam, and temazepam using the 785-nm device; however, the extraction/SERS procedures yielded true positive rates below 60% for lorazepam and triazolam. The minimum concentration (Cmin ) of the benzodiazepine standards that reproducibly yielded a positive match ranged from 1 to 10 μg/ml using the 1064-nm laser device and from 0.5 to 50 μg/ml using the 785-nm laser device. For the analysis of authentic and suspect counterfeit tablets containing these benzodiazepines, the measured Cmin ranged between 10 and 15 µg per tablet or capsule for 1064-nm laser device and 1-100 µg per tablet or capsule for 785-nm laser device. The developed methods are simple, rapid, and ideal for screening suspect benzodiazepine-containing pharmaceutical products at satellite laboratories located within or near international mail facilities and express courier hubs.

Background Previous studies have investigated α1GABAA and α5GABAA receptor mechanisms in the behavioral effects of ethanol (EtOH) in monkeys. However, genetic studies in humans and preclinical studies with mutant mice suggest a role for α2GABAA and/or α3GABAA receptors in the effects of EtOH. The development of novel positive allosteric modulators (PAMs) with functional selectivity (i.e., selective efficacy) at α2GABAA and α3GABAA receptors allows for probing of these subtypes in preclinical models of the discriminative stimulus and reinforcing effects of EtOH in rhesus macaques. Methods In discrimination studies, subjects were trained to discriminate EtOH (2 g/kg, intragastrically) from water under a fixed-ratio (FR) schedule of food delivery. In oral self-administration studies, subjects were trained to self-administer EtOH (2% w/v) or sucrose (0.3 to 1% w/v) under an FR schedule of solution availability. Results In discrimination studies, functionally selective PAMs at α2GABAA and α3GABAA (HZ-166) or α3GABAA (YT-III-31) receptors substituted fully (maximum percentage of EtOH-lever responding ≥80%) for the discriminative stimulus effects of EtOH without altering response rates. Full substitution for EtOH also was engendered by a nonselective PAM (triazolam), an α5GABAA -preferring PAM (QH-ii-066) and a PAM at α2GABAA , α3GABAA , and α5GABAA receptors (L-838417). A partial (MRK-696) or an α1GABAA -preferring (zolpidem) PAM only engendered partial substitution (i.e., ~50 to 60% EtOH-lever responding). In self-administration studies, pretreatments with the functionally selective PAMs at α2GABAA and α3GABAA (XHe-II-053 and HZ-166) or α3GABAA (YT-III-31 and YT-III-271) receptors increased EtOH, but not sucrose, drinking at doses that had few, or no, observable sedative-motor effects. Conclusions Our results confirm prior findings regarding the respective roles of α1GABAA and α5GABAA receptors in the discriminative stimulus effects of EtOH and, further, suggest a key facilitatory role for α3GABAA and potentially α2GABAA receptors in several abuse-related effects of EtOH in monkeys. Moreover, they reveal a potential role for these latter subtypes in EtOH's sedative effects.

In this study, an alternative method for synthesizing magnetic cobalt adeninate metal-organic frameworks was developed, and the synthesized materials were examined for their potential application for separating and enriching benzodiazepines from complex samples. Benzodiazepines, widely used as hypnotics, muscle relaxants, sedatives, and anxiolytics, are a class of drugs that require accurate detection and monitoring. Results showed that Fe3 O4 nanoparticles could be well anchored onto the external surface of cobalt adeninate metal-organic frameworks by using amino-silane as a linkage. Their adsorption of benzodiazepines was mainly promoted by intermolecular hydrogen binding, π-π interactions and electrostatic attraction. Their potential application was evaluated by extraction of benzodiazepines in urine and wastewater samples prior to liquid chromatography with mass spectrometry. Under optimum conditions, the calibration curves were linear with a correlation coefficient of ≥0.9928 in the concentration range of 10-5000 ng/L for lorazepam and 5-5000 ng/L for estazolam, chlordiazepoxide, alprazolam, midazolam and triazolam. The limits of detection were in the range of 0.71-2.49 ng/L. The percent of extraction recoveries were 80.2-94.5% for urine and 84.1-94.4% for wastewater, respectively. Results suggested that magnetic cobalt adeninate metal-organic frameworks could potentially be a promising material for enriching benzodiazepines from urine and wastewater with high accuracy and precision.

The potential consequences of drug-drug interaction on the strategies adopted by anti-doping laboratories to report an adverse analytical finding for morphine were investigated. We evaluated in vitro the effects of 14 drugs on the principal metabolic pathways of morphine. The selected drugs are among those most commonly used by the athletes, none of them presently included in the World Anti-Doping Agency (WADA) Prohibited List. The non-prohibited drugs included 4 antifungals (fluconazole, itraconazole, ketoconazole, and miconazole), 6 benzodiazepines (alprazolam, bromazepam, clonazepam, lorazepam, lormetazepam, and triazolam), and 4 non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen, ketoprofen, and nimesulide). The in vitro assays were based on the use of either human liver microsomes or uridine 5'-diphospho-glucuronosyl-transferases. Morphine and its glucuronides were determined by developed liquid chromatography-mass spectrometry procedure after dilution with an aqueous solution containing their deuterated isotopologues as internal standards. Morphine is mainly excreted as phase II metabolites: about 70% of the parent compound is found to be biotransformed by UGT2B7 to morphine-3-glucuronide (6065%) and morphine-6-glucuronide (5-10%). A reduction of the enzymatic activity of the UGT2B7 was recorded in the presence of 9 of the 14 drugs under investigation (ketoconazole, miconazole, itraconazole, diclofenac, ibuprofen, clonazepam, lorazepam, lormetazepam, and triazolam), with a consequent significant reduction of the levels of the glucuronide metabolites. This phenomenon in vivo may affect the rate of the urinary excretion of morphine with the risk of reporting "false negative" results, especially in case of results close to the decision limit value set by WADA.

Objective Next-day residual effects of a nighttime dose of gabapentin 250 mg were evaluated on simulated driving performance in healthy participants in a randomized, placebo-controlled, double-blind, multicenter, four-period crossover study that included diphenhydramine citrate 76 mg and triazolam 0.5 mg. Methods At treatment visits, participants (n = 59) were dosed at ~23:30, went to bed immediately, and awakened 6.5 h postdose for evaluation. The primary endpoint was the standard deviation of lateral position for the 100-km driving scenario. Additional measures of driving, sleepiness, and cognition were included. Results Study sensitivity was established with triazolam, which demonstrated significant next-day impairment on all driving endpoints, relative to placebo (p

We have studied whether the phase II metabolism of 19-norandrosterone, the most representative metabolite of 19-nortestosterone (nandrolone), can be altered in the presence of other drugs that are not presently included on the Prohibited List of the World Anti-Doping Agency. In detail, we have evaluated the effect of non-prohibited drugs belonging to the classes of anti-fungals, benzodiazepines, and non-steroidal anti-inflammatory drugs on the glucuronidation of 19-norandrosterone. In vitro assays based on the use of either pooled human liver microsomes or specific recombinant isoforms of uridine diphosphoglucuronosyl-transferase were designed and performed to monitor the formation of 19-norandrosterone glucuronide from 19-norandrosterone. Determination of 19-norandrosterone (free and conjugated fraction) was performed by gas chromatography - mass spectrometry after sample pretreatment consisting of an enzymatic hydrolysis (performed only for the conjugated fraction), liquid/liquid extraction with tert-butylmethyl ether, and derivatization to form the trimethylsilyl derivative. In parallel, a method based on reversed-phase liquid chromatography coupled to tandem mass spectrometry in positive electrospray ionization with acquisition in selected reaction monitoring mode was also developed to identify the non-prohibited drugs considered in this study. Incubation experiments have preliminarily shown that the glucuronidation of 19-norandrosterone is principally carried out by UGT2B7 (39%) and UGT2B17 (31%). Inhibition studies have shown that the yield of the glucuronidation reaction is reduced in the presence of the anti-fungals itraconazole, ketoconazole, and miconazole, of the benzodiazepine triazolam and of the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen, while no alteration was recorded in the presence of all other compounds considered in this study. Copyright © 2015 John Wiley & Sons, Ltd.

Objective Older people are more likely to have insomnia. One of the most prescribed hypnotics in Japan is triazolam. Although some studies showed the possibility of adverse effects of triazolam in older people, there have been few studies investigating these effects in a clinical setting. The aim of this study was to determine whether patients who used triazolam regularly had increased risks of pneumonia, trauma, and pressure ulcers. Methods The research design was a retrospective cohort study using claim data. The subjects of the study were patients who were insured by Fukuoka Late Stage Elderly Healthcare Insurance. We defined patients who had received triazolam for 180 days or longer during fiscal year 2011 as the triazolam group, and those who had not received any hypnotics during the period as the non-triazolam group. Each patient in the triazolam group was then matched with a unique control from the non-triazolam group according to propensity score. Multivariate conditional logistic regression analyses were used to obtain adjusted odds ratios for pneumonia, trauma, and pressure ulcer in the triazolam group compared with the non-triazolam group. Results The number of patients in the triazolam and non-triazolam groups in the unmatched cohort was 13,015 and 411,610, respectively. Adjusted odds ratios show that the risks for pneumonia, trauma, and pressure ulcer in the matched cohort increased by approximately 40%, 30%, and slightly less than 30%, respectively (all statistically significant). Conclusions Regular use of triazolam is a risk factor for pneumonia, trauma, and pressure ulcer in older people. Copyright © 2015 John Wiley & Sons, Ltd.

AIM: Short term administration of benzodiazepines (BZD) was found to prolong reaction time (RT) in experimental studies. However, studies on long term BZD use did not always adjust for important confounders and showed inconsistent results. We aimed to identify a possible relationship between long term BZD use and RT in BZD users in this large cross-sectional, observational study.METHODS: The RTs of non-users (n = 2404) were compared with low (n = 288), intermediate (n = 74), and high dose BZD users (n = 57) in the Netherlands Study of Depression and Anxiety (NESDA). RTs were obtained from the Implicit Association Test. Analyses were adjusted for sociodemographic characteristics, health indicators, severity of psychopathology and antidepressant use.RESULTS: Of the NESDA participants, 419 subjects (14.8%) used BZDs. A higher dose of BZDs was associated with prolonged RTs (P = 0.01). When comparing the different dose groups, the high dose group, but not the low and medium dose groups, had significantly longer RTs than the non-users.CONCLUSIONS: Tolerance for the RT prolonging effect of relatively high doses of BZDs does not seem to develop. As prolonged RTs can have adverse consequences in daily life, BZDs should be prescribed conservatively at the lowest possible dose.

Aim Short term administration of benzodiazepines (BZD) was found to prolong reaction time (RT) in experimental studies. However, studies on long term BZD use did not always adjust for important confounders and showed inconsistent results. We aimed to identify a possible relationship between long term BZD use and RT in BZD users in this large cross-sectional, observational study. Methods The RTs of non-users (n = 2404) were compared with low (n = 288), intermediate (n = 74), and high dose BZD users (n = 57) in the Netherlands Study of Depression and Anxiety (NESDA). RTs were obtained from the Implicit Association Test. Analyses were adjusted for sociodemographic characteristics, health indicators, severity of psychopathology and antidepressant use. Results Of the NESDA participants, 419 subjects (14.8%) used BZDs. A higher dose of BZDs was associated with prolonged RTs (P = 0.01). When comparing the different dose groups, the high dose group, but not the low and medium dose groups, had significantly longer RTs than the non-users. Conclusions Tolerance for the RT prolonging effect of relatively high doses of BZDs does not seem to develop. As prolonged RTs can have adverse consequences in daily life, BZDs should be prescribed conservatively at the lowest possible dose.

Objective: To assess the effects of hypnotics on prefrontal cortex activity in healthy subjects using near‐infrared spectroscopy (NIRS) in a double‐blind, placebo‐controlled crossover trial. Methods: Eighteen healthy males received acute doses of ramelteon (8 mg), triazolam (0.125 mg), or placebo in a predetermined randomization schedule, with a washout period of more than 1 week. All subjects performed a verbal fluency task during NIRS assessments at baseline and at 1 and 4 hr post‐dose. The number of words correctly generated during the task (behavioral performance) and scores on the Stanford Sleepiness Scale (SSS) were also recorded at each test time. Results: Compared with the placebo, triazolam (0.125 mg) significantly decreased oxyhemoglobin (oxy‐Hb) concentration change in NIRS during the posttask period and significantly increased behavioral performance, whereas triazolam (0.125 mg) and ramelteon (8 mg) significantly increased SSS scores. Conclusions: The differential effects of two types of hypnotics on oxy‐Hb change measured by NIRS were observed in acute dosing, suggesting that when assessing brain activity of patients with psychiatric disorders, researchers should consider how certain types of hypnotics can influence brain function. This would also provide useful information to clinicians when prescribing hypnotics suitable for their patients' conditions., ファイル公開：2019-11-01

Drug-induced akinesia is a potential cause of pressure ulcers. However, pressure ulcers that are caused by drug-induced akinesia are not considered an adverse drug reaction (ADR). We propose that drug-induced pressure ulcers (DIPU) are pressure ulcers that are caused by an external force that is experienced after drug administration, and we considered resolution of these ulcers after drug discontinuation to be a supportive finding. In this report, we reviewed the medical records of pressure ulcer cases from a 300-bed hospital. Among 148 patients, four patients with pressure ulcers met the criterion for DIPU. In these cases, the suspected DIPU were related to treatment with olanzapine, fluvoxamine, valproic acid, clotiazepam, triazolam and rilmazafone. These drugs were administrated to manage the patients' behavioral and psychological symptoms that accompanied dementia. The DIPU in these patients were categorized as stage IV according to the National Pressure Ulcer Advisory Panel criteria. Discontinuation of the causal drugs led to significant improvements or complete healing of the pressure ulcers, and the patients subsequently recovered their mobility. Therefore, we propose that DIPU are potential ADR that have been overlooked in clinical practice. Thus, recognition of DIPU as an ADR may be important in preventing and appropriately managing pressure ulcers among elderly patients.

Aim The present study evaluated the possibility of drug interactions involving blueberry juice (BBJ) and substrate drugs whose clearance is dependent on cytochromes P4503A (CYP3A) and P4502C9 (CYP2C9). Methods A 50:50 mixture of lowbush and highbush BBJ was evaluated in vitro as an inhibitor of CYP3A activity (hydroxylation of triazolam and dealkylation of buspirone) and of CYP2C9 activity (flurbiprofen hydroxylation) using human liver microsomes. In clinical studies, clearance of oral buspirone and oral flurbiprofen was studied in healthy volunteers with and without co-treatment with BBJ. Results BBJ inhibited CYP3A and CYP2C9 activity in vitro, with 50% inhibitory concentrations (IC50) of less than 2%, but without evidence of mechanism-based (irreversible) inhibition. Grapefruit juice (GFJ) also inhibited CYP3A activity, but inhibitory potency was increased by pre-incubation, consistent with mechanism-based inhibition. In clinical studies, GFJ significantly increased area under the plasma concentration−time curve (AUC) for the CYP3A substrate buspirone. The geometric mean ratio (GMR = AUC with GFJ divided by AUC with water) was 2.12. In contrast, the effect of BBJ (GMR = 1.39) was not significant. In the study of flurbiprofen (CYP2C9 substrate), the positive control inhibitor fluconazole significantly increased flurbiprofen AUC (GMR = 1.71), but BBJ had no significant effect (GMR = 1.03). Conclusion The increased buspirone AUC associated with BBJ is quantitatively small and could have occurred by chance. BBJ has no effect on flurbiprofen AUC. The studies provide no evidence for concern about clinically important pharmacokinetic drug interactions of BBJ with substrate drugs metabolized by CYP3A or CYP2C9.

This MiniReview is a personal recollection of selected research topics, which the author in collaboration with colleagues has studied, aiming to improve the predictability of drug therapy. In early studies, we found bi- and trivalent cations to reduce the absorption of various tetracyclines and fluoroquinolones. Certain antacids elevated the bioavailability of some non-steroidal anti-inflammatory drugs and sulphonylureas. Various brands of phenytoin tablets revealed great differences in their bioavailability, causing clinical consequences. Numerous factors affecting the antidotal effect of activated charcoal were also studied, with charcoal compared to other gastrointestinal decontamination methods, including ipecac and gastric lavage. Effect of age and diseases on the pharmacokinetics of drugs was a research topic. Acute sotalol intoxications revealed its QT-prolonging properties, and even small mixed overdoses of moclobemide with serotonergic drugs proved fatal. Itraconazole and other potent inhibitors of CYP3A4 could drastically increase exposure to drugs like midazolam, triazolam, buspirone, lovastatin, simvastatin and oxycodone, whereas rifampicin greatly reduced their plasma concentrations. A change from potent inhibition to induction caused a 400-fold change in the exposure to oral midazolam. CYP2C8 was revealed to be crucial in the metabolism and interactions of several drugs. Many interactions affecting statins are CYP3A4-mediated, but transporters are important in certain interactions. Tizanidine is very susceptible to CYP1A2 inhibition. Fruit juices such as grapefruit juice can raise or lower exposure to different drugs. Both drug interactions and pharmacogenetics can modify the activity of cell membrane transporters and cause variability in the pharmacokinetics of and response to their substrate drugs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The prediction of drug–drug interactions (DDIs) from in vitro data usually utilizes an average dosing interval estimate of inhibitor concentration in an equation-based static model. • Simcyp®, a population-based ADME simulator, is becoming widely used for the prediction of DDIs and has the ability to incorporate the time-course of inhibitor concentration and hence generate a temporal profile of the inhibition process within a dynamic model. WHAT THIS PAPER ADDS • Prediction of DDIs for 35 clinical studies incorporating a representative range of drug–drug interactions, with multiple studies across different inhibitors and victim drugs. • Assessment of whether the inclusion of the time course of inhibition in the dynamic model improves prediction in comparison with the static model. • Investigation of the impact of different inhibitor and victim drug parameters on DDI prediction accuracy including dosing time and the inclusion of active metabolites. Assessment of ability of the dynamic model to predict inter-individual variability in the DDI magnitude. AIMS Static and dynamic models (incorporating the time course of the inhibitor) were assessed for their ability to predict drug–drug interactions (DDIs) using a population-based ADME simulator (Simcyp®V8). The impact of active metabolites, dosing time and the ability to predict inter-individual variability in DDI magnitude were investigated using the dynamic model. METHODS Thirty-five in vivo DDIs involving azole inhibitors and benzodiazepines were predicted using the static and dynamic model; both models were employed within Simcyp for consistency in parameters. Simulations comprised of 10 trials with matching population demographics and dosage regimen to the in vivo studies. Predictive utility of the static and dynamic model was assessed relative to the inhibitor or victim drug investigated. RESULTS Use of the dynamic and static models resulted in comparable prediction success, with 71 and 77% of DDIs predicted within two-fold, respectively. Over 40% of strong DDIs (>five-fold AUC increase) were under-predicted by both models. Incorporation of the itraconazole metabolite into the dynamic model resulted in increased prediction accuracy of strong DDIs (80% within two-fold). Bias and imprecision in prediction of triazolam DDIs were higher in comparison with midazolam and alprazolam; >50% of triazolam DDIs were under-predicted regardless of the model used. Predicted inter-individual variability in the AUC ratio (coefficient of variation of 45%) was consistent with the observed variability (50%). CONCLUSIONS High prediction accuracy was observed using both the Simcyp dynamic and static models. The differences observed with the dose staggering and the incorporation of active metabolite highlight the importance of these variables in DDI prediction.

The hydrolytic reaction of Triazolam in acidic solution at room temperature was studied spectrophotometrically. The reversible azomethine bond cleavage reaction of Triazolam took place and an open-ring compound was in equilibrium with a closed-ring compound. Kinetic studies indicate that the hydrolysis reaction is first order with respect to proton concentration. The indirect determination of acid-dissociation constant was carried out from the kinetic data. The pKa value (2.19) is similar to the one obtained (2.26) from spectrophotometric acid-base studies. The shift of peak potential of the Triazolam obtained by differential pulse polarography also showed the acid hydrolysis of the compound.

The proton NMR and the high-resolution electron impact mass spectra of alprazolam and triazolam, two new triazolo [4,3-a]-[1,4]-benzodiazepines were studied.

Drugs that act as allosteric activators at the benzodiazepine site of the gamma-aminobutyric acid (GABA(A)) receptor complex are used commonly to treat insomnia but relatively little is known of how such use affects learning and memory. Although anterograde effects on memory acquisition have been shown, possible retrograde effects on consolidation are more relevant when such agents are administered at bedtime. We tested the effects of two GABA(A) allosteric activators on sleep-dependent motor skill memory consolidation in 12 healthy male subjects. Subjects slept in a sleep laboratory for four consecutive nights (one accommodation night followed by three experimental nights). Placebo, triazolam 0.375 mg, and zolpidem 10 mg were given to each subject in counterbalanced order on the experimental nights. Polysomnographic (PSG) sleep measurement and sleep-dependent motor learning were assessed at each condition. Triazolam was associated with longer total sleep time and increased Stage 2 sleep. Both zolpidem and triazolam were associated with increased latency to rapid eye movement (REM) sleep. Overnight motor learning correlated with total sleep time in the placebo condition but not in the triazolam or zolpidem conditions. A statistically significant impairment in motor performance occurred overnight in the triazolam condition only. Triazolam, given in sufficient doses to prolong sleep in healthy people, affected overnight motor learning adversely. Zolpidem, in a dose sufficient to prolong REM onset latency but without other effects on PSG-measured sleep, degraded the relationship between total sleep time and overnight motor learning. These data indicate that non-selective or alpha1-preferring benzodiazepine site allosteric activators can interfere with sleep-dependent memory consolidation.

Eighteen healthy volunteers of both sexes, aged 20-34, were tested in the morning while undertaking real car driving avoidance manoeuvres and during monotonous simulated driving after 1 and 3 nights of medication with triazolam 0.25 mg, nitrazepam 5 mg or placebo. The study was a double-blind, randomized, cross-over study, where a minimum of 7 days wash-out separated the 3 treatment periods. Nitrazepam was found to impair performance in the simulated task after 1 but not after 3 nights of medication. Performance in the triazolam condition was not significantly different from the other conditions on this task on either day. However, after one night of medication triazolam tended to score worse than placebo but better than nitrazepam. In real car driving a tendency was noted for nitrazepam to score worst, whereas the difference between placebo and triazolam was hardly noticeable. The same tendency appeared on both days. Language: en

Background and purpose: Heterologous expression of a1, b2 and g2S(g1) subunits produces a mixed population of GABAA receptors containing a1b 2o ra1b2g2S(g1) subunits. GABA sensitivity (lower in receptors containing g 1o rg2S subunits) and the potentiation of GABA-activated chloride currents (IGABA) by benzodiazepines (BZDs) are dependent on g2S(g1) incorporation. A variable g subunit incorporation may affect the estimation of IGABA potentiation by BZDs. We propose an approach for estimation of BZD efficiency that accounts for mixed population of a1b2 and a1b2g2S(g1) receptors. Experimental approach: We investigated the relation between GABA sensitivity (EC50) and BZD modulation by analysing triazolam-, clotiazepam- and midazolam-induced potentiation of IGABA in Xenopus oocytes under two-microelectrode voltage clamp.

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.

The effect of pomegranate juice (PJ) or grapefruit juice (GFJ) on CYP3A activity was studied in vitro and in healthy human volunteers. In human liver microsomes, the mean 50% inhibitory concentrations (IC(50)) for PJ and GFJ versus CYP3A (triazolam alpha-hydroxylation) were 0.61% and 0.55%, (v/v) respectively, without preincubation of inhibitor with microsomes. After preincubation, the IC(50) for PJ increased to 0.97% (P < .05), whereas the IC(50) for GFJ decreased to 0.41% (P < .05), suggesting mechanism-based inhibition by GFJ but not PJ. Pretreatment of volunteer subjects (n = 13) with PJ (8 oz) did not alter the elimination half-life, volume of distribution, or clearance of intravenous midazolam (2 mg). Administration of PJ also did not affect C(max), total area under the curve (AUC), or clearance of oral midazolam (6 mg). However, GFJ (8 oz) increased midazolam C(max) and AUC by a factor of 1.3 and 1.5, respectively, and reduced oral clearance to 72% of control values. Thus, PJ does not alter clearance of intravenous or oral midazolam, whereas GFJ impairs clearance and elevates plasma levels of oral midazolam.

In the last few decades, the chemistry of 1,2,4-triazoles and their fused heterocyclic derivatives has received considerable attention owing to their synthetic and effective biological activities such as antinflammatory, CNS stimulants sedatives, antianxiety, antimicrobial agents and antimycotic activity such as fluconazole, intraconazole, voriconazole. Also, there are known drugs in market containing the 1,2,4-triazole group e.g. Triazolam, Alprazolam, Etizolam and Furacylin. Present antitubercular drugs are more toxic and multiple drug therapy is required. So it is important to find out the analogues with good antitubercular activity. Microwave heating has attracted the attention of investigators in synthesis of drugs to shorten the length of reactions significantly, to increase their selectivity, and to increase the product yields, which is particularly important in the case of high-temperature processes that take a long time. This review includes the Microwave synthesis of 1,2,4- triazoles and its reported derivatives.

Decreasing Pain and Anxiety Associated with Atrial Shock. introduction: Implantable atrial defibrillators (IADs) have proved to be safe and effective in the management of atrial fibrillation. A potential limitation of self-activated IAD therapy is patient-reported pain and anxiety. The main objective of the present study was to determine whether triazolam improved patient perception of the shock experience or altered patient memory of shock discomfort relative to placebo. Methods and Results: A total of 15 men and women (mean age: 59 ± 6 years) were enrolled in this double-blind, placebo-controlled, crossover study of triazolam. Randomized study medication was administered orally 75 minutes prior to scheduled atrial shock delivery. Patient perception of the shock experience was assessed along with sedation, memory, anxiety, and mood. Triazolam reduced mean pre-shock anxiety (t = 2.98, df = 14, P = 0.01) and shock-related pain (t = 2.74, df = 13, P = 0.01) and intensity (t = 2.64, df = 13, P = 0.018) relative to placebo. Similarly, participants recalled less discomfort the morning after shock with triazolam than with placebo (t = 2.82, df = 11, P = 0.017). Conclusions: This study was the first to investigate the use of an oral benzodiazepine administered prior to patient-activated shock delivery with an IAD. Our data indicate that oral triazolam is beneficial in decreasing pain and anxiety associated with self-activated atrial defibrillation. If triazolam provides a similar benefit in the community to that which has been reported here, this medication could be offered to patients as an adjunct to intermittent IAD therapy.

Aims To investigate whether the electroencephalogram (EEG) directly reflects the CNS effects of benzodiazepines by evaluating the relation of the EEG to plasma drug concentrations and to Digit-Symbol Substitution Test (DSST) scores after a single dose of triazolam, a representative benzodiazepine agonist. Methods Thirteen healthy male subjects were given 0.375 mg triazolam or placebo in a double-blind crossover study. Plasma samples were collected during 8 h after dosage. Pharmacodynamic effects were measured by DSST and EEG at corresponding times. Results Pharmacokinetic parameters for triazolam were consistent with established values. Compared with placebo, triazolam significantly impaired psychomotor performance on the DSST (P

A capillary electrochromatographic (CEC) method was applied to the simultaneous separation of barbiturates (barbital, phenobarbital, secobarbital and thiopental) and benzodiazepines (nitrazepam, diazepam and triazolam). The separation was performed in a 75 microm i.d. capillary, packed with 3-(1,8-naphthalimido)propyl-modified silyl silica gel (NAIP), studying the effects of buffer pH and mobile phase composition. Using an applied voltage of 20 kV and the short-end injection method (9 cm capillary effective length), the mobile phase of 1.0 mM citrate buffer (pH 5.0) containing 45% methanol provided the baseline separation of seven toxic drugs in less than 9 min. In CEC with NAIP, the benzodiazepines were separated by the combination of hydrophobic and pi-pi interactions, whereas the separation of the barbiturates was based on the hydrophobic interaction.

The aim of the present study was to compare the hangover effects of night-time administration of triazolam (0.25 mg), flunitrazepam (1 mg) and quazepam (15 mg) in healthy subjects. Daytime sleepiness and performance level following the night-time administration of the drugs were assessed using Standford Sleepiness Scale (SSS), Sleep Evaluation Questionnaire (SEQ), Multiple Sleep Latency Test (MSLT), actigraphy recordings and Continuous Performance Test (CPT). Fifteen healthy volunteers were given one of the three hypnotics at each drug session, which lasted for 1 week, in a single-blind cross-over fashion. No significant between-drug difference was observed for the psychomotor performance assessed by CPT. Subjective hangover effects assessed by SSS and SEQ in the morning were prominent for flunitrazepam and quazepam relative to triazolam, whereas objective indices such as MSLT or activity counts obtained in actigraphy indicated a marked hangover effect of quazepam compared with the other two compounds restrictively in the afternoon, which were nearly in accordance with their pharmacokinetic profiles.

Background: The results of previous laboratory experiments with humans suggest that light and moderate drinkers respond differentially to the effects of benzodiazepines. The aim of this study was to further assess the behavioral effects of a benzodiazepine in light and moderate drinkers. Methods: To accomplish this aim, 12 volunteers (6 light drinkers and 6 moderate drinkers) learned to discriminate 0.375 mg of triazolam, a triazolobenzodiazepine hypnotic. After they learned this discrimination, a test-of-novel-doses phase was conducted in which a range of doses of triazolam (0, 0.06, 0.125, 0.25, and 0.375 mg) was tested in both groups of volunteers. The subject-rated and performance-impairing effects of triazolam were assessed concurrently. Results: There was not a significant difference between the groups in terms of the number of trials needed to learn the discrimination, nor did the proportion of light and moderate drinkers who learned to accurately discriminate 0.375 mg of triazolam differ significantly. The discriminative-stimulus, subject-rated, and performance-impairing effects of triazolam were an orderly function of dose but did not differ across the light and moderate drinkers. Conclusions: Future studies should examine the discriminative-stimulus effects of a lower dose of triazolam (e.g., 0.25 mg) in light and moderate drinks or use a fading procedure to determine differences in terms of the lowest discriminable dose.

Objectives: To assess the cognitive and psychomotor effects of single oral doses of valerian in healthy volunteers in comparison with a placebo and the hypnotic agent triazolam. Methods: In a double-blind, placebo-controlled, four-way crossover study nine healthy subjects (5 males, 4 females) received in random order valerian 500 mg, valerian 1000 mg, triazolam 0.25 mg and placebo. Doses were separated by a wash-out period of at least 1 week. Subjects were tested before each dose and at 2, 4 and 8 h after the dose of each compound using the critical flicker fusion (CFF), choice reaction time (CRT), digit symbol substitution test (DSST), symbol search test (SST), digit span test (DST) and visual analogue scales of mood. Results: Repeated measures ANOVA was used to examine the changes in performance on tests over time and significant effects were further analysed using simple main effects analysis with least significant difference corrections. Statistically significant differences were only noted for the cognitive tests: SST (F(3, 8)¼3.182, p

The effect of platelet-activating factor (PAF) on neurotransmitter release from rat brain slices prelabeled with [3H]acetylcholine ([3H]ACh), [3H]norepinephrine ([3H]NE), or [3H]serotonin ([3H]5-HT) was studied. PAF inhibited K+ depolarization-induced [3H]ACh release in slices of brain cortex and hippocampus by up to 59% at 10 nM but did not inhibit [3H]ACh release in striatal slices. PAF did not affect 5-HT or NE release from cortical brain slices. The inhibition of K(+)-evoked [3H]ACh release induced by PAF was prevented by pretreating tissues with several structurally different PAF receptor antagonists. The effect of PAF was reversible and was not affected by pretreating brain slices with tetrodotoxin. PAF-induced inhibition of [3H]ACh release was blocked 90 +/- 3 and 86 +/- 2% by pertussis toxin and by anti-G alpha i1/2 antiserum incorporated into cortical synaptosomes, respectively. The results suggest that PAF inhibits depolarization-induced ACh release in brain slices via a G alpha i1/2 protein-mediated action and that PAF may serve as a neuromodulator of brain cholinergic system.

Rifabutin is effective in the treatment and prevention of Mycobacterium avium infection in people with HIV infection. Rifabutin is structurally related to another rifamycin, rifampin, a well-known inducer of the human P-450 isoform 3A. The rabbit isoform CYP3A6 and the human isoform CYP3A4 have similar P-450 predominance and substrate specificity and are both induced by rifampin. Our goal was to predict the CYP3A induction capacity of rifabutin and to determine if ex vivo CYP3A induction potential of rifamycins is predictive of that obtained in vivo. We determined the in vivo and ex vivo CYP3A6 induction by 4 days of treatment with rifabutin (100 mg/kg), rifampin (100 mg/kg), or vehicle (DMSO) in the rabbit. The ex vivo measures were CYP3A6 activity (N-demethylation of erythromycin and hydroxylation of triazolam) and CYP3A content in rabbit hepatic microsomes preparations. The in vivo measures were oral clearance of triazolam and its formation clearance to its hydroxylated metabolites, α-hydroxytriazolam and 4-hydroxytriazolam. Rifampin increased CYP3A6 activity by 2- to 3-fold in hepatic microsomes compared to vehicle. Rifabutin increased CYP3A content 1.7-fold, but did not significantly increase microsomal CYP3A6 activity. Oral triazolam clearance and formation clearances to the two hydroxylated metabolites were 2- to 3-fold greater in rabbits treated with rifampin. These clearances were unaffected by rifabutin administration. Ex vivo enzyme activities correlated with in vivo changes in clearance of triazolam and the formation clearance to its hydroxylated metabolites. Rifabutin is a weaker inducer of CYP3A6 than rifampin. These data suggest that ex vivo enzyme activity is a viable approach to predict in vivo inductive potential of CYP3A inducers. Copyright © 2001 John Wiley & Sons, Ltd.

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.

Study Objectives. To determine the effect of the selective serotonin reuptake inhibitor citalopram on plasma levels of triazolam, and to determine the effect of a single dose of triazolam on steady-state levels of citalopram and its major metabolites. Design. Open-label, multidose study. Setting. Clinical Studies, Ltd., Fort Lauderdale, Florida. Participants. Eighteen healthy male and female volunteers. Interventions. Subjects received triazolam 0.25 mg alone and another 0.25mg dose after 4 weeks of citalopram 20 mg/day for 1 week, followed by 3 weeks of citalopram 40 mg/day. Measurements and Main Results. Pharmacokinetic parameters were determined after single-dose administration of triazolam alone, after administration of citalopram alone at steady state, and after coadministration of the drugs. The pharmacokinetics of triazolam and its metabolite α-hydroxytriazolam were unchanged by citalopram coadministration. Triazolam appeared to be absorbed slightly more quickly during coadministration. Citalopram kinetics were unaffected by coadministration. Conclusion. No pharmacokinetic interaction between the drugs was observed, suggesting that triazolam and other cytochrome P450 3A4 substrates can be coadministered safely with citalopram. (Pharmacotherapy 2000; 20(7):750–755)

A report is given on a 59-year-old female who acquired a wet maculopathy in her only seeing eye during amiodarone therapy given for a cardiac disorder. After withdrawal of the drug and subsequent central retinal laser therapy her visual acuity stabilized at 0.7 (follow-up time 6 years). With no similar reports in literature, it is suggested that the association between amiodarone therapy and the central retinopathy was accidental only.

1. The mPer1 and mPer2 genes are putative mouse clock genes that regulate circadian oscillator present in the suprachiasmatic nucleus (SCN) neuron. While they are also expressed in the granular cell layer in the cerebellum, their function is unknown. In a first step to verify the physiological roles of mPer1 and mPer2 genes in the cerebellum, we examined the effects of benzodiazepines on the expression of the mPer1 and mPer2 genes. 2. mPer2 mRNA expression was higher at ZT16 than ZT4 in the mouse cerebellum. 3. High-dose administration of diazepam (10 mg kg-1) or triazolam (1 mg kg-1) reduced mPer1 mRNA level 1 h after treatment in the cerebellum. 4. Reduced expression of mPer1 by diazepam treatment was transient. No difference of mPer1 mRNA level between diazepam (10 mg kg-1)- and vehicle-treated group was observed 6 h after treatment. 5. Administration of high doses of tandospirone (30 mg kg-1), a non-benzodiazepine anxiolytic also reduced mPer1 mRNA expression 1 h after treatment. 6. Administration of high doses of clozapine (5 mg kg-1) or haloperidol (1 mg kg-1) impaired the rota-rod performance without affecting on mPer1 mRNA level. 7. Diazepam and tandospirone inhibited the expression of mPer1 mRNA in the primary cultured cerebellum granule cells. 8. Transient reductions of mPer1 mRNA levels by various benzodiazepines and tandospirone is associated with impairment of coordinated movement, such as rota-rod performance and equilibrium.

This review was conducted to identify the current data on drug interactions with alprazolam, midazolam, and triazolam to guide practitioners in the use of these drugs. The Medline electronic database from 1966 through 1998 was used to identify clinical studies of the pharmacokinetic effect of drugs on these three benzodiazepines. Of a total of 491 literature reports identified, 59 prospective studies met our selection criteria. The pharmacokinetic parameters of AUC, Cmax, t1/2, and tmax were evaluated for changes following an interaction. To allow comparison between studies, changes in the parameters were normalized relative to the control values. Pharmacodynamic effects and measures, when reported in the original studies as statistically significant, were classified as a strong interaction, and when the interaction was present but not statistically significant, they were classified as mild in this review. As a result, clinically significant drug interactions were noted for all three benzodiazepines, although it is clear that statistically significant pharmacokinetic changes do not always translate into clinically significant pharmacodynamic consequences. All three benzodiazepines were susceptible to drug interactions, but oral dosing of midazolam and triazolam resulted in greater alterations in the pharmacokinetic parameters than alprazolam due to their larger presystemic extraction. Ketoconazole and itraconazole were found to be the most potent metabolic inhibitors that prolonged the duration of or intensified the magnitude of the dynamic response produced by the three benzodiazepines. Rifampin, carbamazepine, and phenytoin were noted to be potent metabolic inducers, and their treatments result in loss of benzodiazepine therapeutic efficacy. In conclusion, potent metabolic inhibitors and inducers can either significantly prolong or diminish the dynamic effects of benzodiazepines via their influence on the pharmacokinetics of benzodiazepines.

A retrospective survey of 669 cases of acute benzodiazepine poisoning admitted between January and December 1996 to 59 critical care departments was carried out. A review and retrospective analysis of the records of 95 deceased persons who had ingested benzodiazepines in 27 police prefectural jurisdictions in Japan during the same period, was performed to compare these cases and postmortem medicolegal cases of acute benzodiazepine poisoning. The majority of cases in both groups were deliberate self-poisoning (82.7% and 83.2%, respectively). Efforts to decrease morbidity and mortality from acute drug poisoning should target drugs taken frequently in serious and lethal overdoses. This study confirmed that flunitrazepam, triazolam, etizolam, and nitrazepam were the main agents ingested in cases of acute benzodiazepine poisoning in both the critical care and postmortem groups. More specifically flunitrazepam was the derivative most commonly used in the postmortem group. The statistically significant difference was thought to be attributable to the characteristics of the pharmacokinetic parameters of flunitrazepam, which has a short time to peak interval and a relatively long elimination half-life. In other words, rapid onset and prolonged coma contribute to successful suicide. The majority of patients in the critical care group (82.8%) and in the postmortem group (76.8%) had not undergone plasma or urinary drug screening tests. The lack of drug identification may result in serious diagnostic errors or wrong estimates of severity as well as interfere with scientific progress in the study of acute drug poisoning. Six deaths (0.9% of total) were recorded in the critical care departments as a result of poisoning following ingestion of benzodiazepines in combination with other drugs. Five of them were cases of cardiopulmonary arrest on arrival at the hospital. Therefore, most deaths related to benzodiazepines have occurred outside the hospital as a result of prolonged comatose periods in persons who were not discovered. The fact that acute benzodiazepine poisoning is a kind of the iatrogenic disease in Japan should be taken into consideration, since in most of the cases of poisoning the benzodiazepines were prescribed by a physician and given to the patient by a pharmacist. We regard careless prescriptions and routine dispensation of benzodiazepines as being among the reasons why the number of cases of acute poisoning fails to decrease. Accordingly, to prevent acute benzodiazepine poisoning, it is important to control the clinical use of benzodiazepines (especially flunitrazepam, triazolam, etizolam, nitrazepam) more appropriately by monitoring medication use and carefully counseling patients.

The antagonistic effects of zolpidem 10 mg on withdrawal symptoms caused by abrupt or gradual discontinuation (half-dose over 4 nights) of triazolam 0·25 mg in patients with chronic insomnia, who had been receiving regular treatment for over one month, were assessed in a randomized, double-blind, placebo-controlled clinical trial in general practice. Eighty-four patients were enrolled, mostly women (67·9%), with a mean age of 54·3±11·0 years. Twenty-one different general practitioners were solicitated for the recruitment. The subjects were randomized into four groups, and all received triazolam 0·25 mg during the run-in phase from day 1 (D1) to day 3 (D3). The following treatments were given from D4 to D7: triazolam 0·125 mg+zolpidem 10 mg (Group 1); zolpidem 10 mg (Group 2); placebo (Group 3); or triazolam 0·125 mg+placebo (Group 4). Groups 1 and 2 received zolpidem 10 mg from D7 to D24, while Groups 3 and 4 received placebo. Finally, all four groups received placebo (blind withdrawal phase) from D25 to D28. The following assessment criteria were used: clinical global impression (CGI) scale completed by the practitioner; patient questionnaire based on routine sleep criteria, wakefulness and daytime alertness. Secondary criteria were sleep diaries and visual analogue scales. Study drop-outs were reported and explained. The effectiveness/tolerance ratio was found to be statistically significant using the CGI (p

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.

In order to examine the effects of temazepam on memory, a battery of cognitive tests and analogue mood ratings were given to healthy volunteers after oral administration of 5, 10 and 30 mg. The lowest dose had no effect and 10 mg only significantly increased self-ratings of well-being. Temazepam (30 mg) significantly improved recall of items learned prior to drug administration, but impaired recall and recognition of word lists acquired after drug administration. However, when retrieval was assessed indirectly using a backwards reading task there was no impairment, indicating that automatic information processing was unaffected. Temazepam (30 mg) significantly reduced self-ratings of anxiety and increased those of sedation. It also significantly impaired performance in symbol copying, digit-symbol substitution and number cancellation tasks. It is striking that, at a dose that was sedative and impaired many aspects of performance, temazepam nonetheless improved retrieval of items learned prior to drug administration. (C) 1998 John Wiley & Sons, Ltd.

SUMMARY Zaleplon (N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-7-y l)phenyl)]-N-ethylacetamide) is a non-benzodiazepine sedative-hypnotic with benzodiazepine-like sedative effects, but with less apparent liability for accompanying undesirable side effects. Zaleplon displaces [3H]flunitrazepam from rat cortical membranes with an IC50 value of 200 nM and enhances t-butylbicyclophosphorothionate [35S]TBPS binding by 73%, suggesting pharmacological activity mediated by the GABAA benzodiazepine receptor complex. In various preclinical procedures such as motor activity, muscle relaxation, EEG, anticonvulsant activity, and vigilance, zaleplon produced effects similar to those of other sedative-hypnotic compounds such as triazolam and flurazepam; furthermore, these effects, when evaluated, were reversed by the benzodiazepine receptor antagonist flumazenil. Zaleplon increased punished (conflict) responding in squirrel monkeys and rats and these effects were also antagonized by flumazenil. When established as a discriminative stimulus in rats at 3.0mg/kg i.p., zaleplon showed a dose-related increase in drug-appropriate responding up to the training dose and a correlated decrease in response rate. Triazolam (0.1 to 1.0 mg/kg), the benzodiazepine partial agonist Ro 17-1812 (0.3 to 3.0mg/kg), and the triazolopyridine CL 218,872 (1.0 to 3.0 mg/kg) substituted consistently for zaleplon in all rats, whereas the imidazo-pyridines zolpidem (3.0 to 10 mg/kg) and alpidem (10 to 30 mg/kg), the benzodiazepine partial agonist bretazenil (0.03 to 10 mg/kg) and the novel putative anxio-lytic CL 273,547 (10 to 56 mg/kg) did not result in consistent drug-appropriate responding in all rats. These results suggest that the effects of zaleplon are similar in many respects to other compounds acting at the benzodiazepine receptor complex but differ as well from both benzodiazepine and non- benzodiazepine drugs. This profile of activity, coupled with additional information in ancillary procedures, yields a pre-clinical profile of a short-acting sedative-hypnotic non-benzodiazepine that is currently in Phase III development for the treatment of sleep disturbances.

Sleep disturbances and need for hypnotics are disproportionately greater in the elderly compared to younger adults. The present study provides a placebo-controlled subjective hypnotic efficacy of zolpidem, triazolam, and temazepam in elderly insomniacs. After a single-blind placebo screening week (DSM-III-R criteria), 335 elderly insomniacs (ages 60 to 85) were randomized to 28 days of double-blind treatment with zolpidem 5 mg, triazolam 0.125 mg, temazepam 15 mg, or placebo, followed by a 4-day single-blind, placebo withdrawal period. The primary efficacy parameters were self-reported sleep latency (SSL) and self-reported total sleep duration (SSD); they were measured by responses on daily Morning Questionnaires. SSL values were compared by Cox proportional hazards regression technique. SSD values were compared by ANOVA. Compared to placebo, zolpidem and temazepam produced significantly shorter SSL over the 4 treatment weeks, but triazolam did not. In the zolpidem group, SSL was significantly shorter than in the placebo group at all four treatment weeks; in the temazepam group, SSL was significantly shorter than in the placebo group at weeks 1, 3, and 4. SSD was increased above baseline levels in all groups. No tolerance to the subjective effects or rebound above baseline levels occurred in any of the treatment groups. Overall, the drugs were well tolerated. No difference was found among the placebo and treatment groups in overall adverse event incidence rates. However, compared with zolpidem and placebo, temazepam produced significantly higher incidences of drowsiness and fatigue, and triazolam produced a significantly higher incidence of nervousness than zolpidem. Drug Dev. Res. 40:230–238, 1997. © 1997 Wiley-Liss, Inc.

OBJECTIVE: Although it has been stated frequently that older people are more sensitive to benzodiazepines, the relative roles of impaired baseline performance, impaired elimination, and altered responsiveness have not been defined. We evaluated postural sway and plasma triazolam concentrations after administration of placebo and triazolam 0.375 mg in both young and older healthy subjects. DESIGN: Double-blind placebo-controlled trial. PARTICIPANTS: Nine young and nine older healthy men. INTERVENTION: All subjects received triazolam 0.375 mg or placebo on different study days, which were separated by at least 48 hours. MEASUREMENTS: Postural sway, visual analog scale of drowsiness, and plasma triazolam levels. RESULTS: The older subjects swayed more during triazolam than did the younger subjects, and this resulted in an increased number of losses of balance. This difference appeared to be caused by greater baseline sway in the older subjects rather than higher concentrations or increased responsiveness. A subset of older people had a much greater number of losses of balance during triazolam than did the rest of the subjects, and these individuals could be identified from their baseline sway. CONCLUSIONS: In this study, the increase in drug effect seen in the older subjects was of similar magnitude to that of the young, but it resulted in greater postural sway after drug administration than was seen in the young. The higher postural sway and the corresponding increased instability seen in the older subjects may put these older persons at increased risk of drug-related falls. This study also suggests that it should be possible to develop techniques that will identify individuals at particular risk of drug-induced postural instability. J Am Geriatr Soc 44:300–304, 1996.

The quinolizinones Ro 19-5663, Ro 19-5686 and Ro 41-3696 bind with high affinity to the benzodiazepine receptor (BZR) in vitro in the rat brain. These compounds exhibit anxiolytic-like effects in an operant punishment task in mice and rats and anticonvulsant effects by fully protecting against pentylenetetrazol-induced tonic seizures in mice and rats and fully protecting against audiogenic seizures in genetically susceptible mice. However, they produced at most only minimal motor impairment in the rotarod task in rodents. These compounds attenuated flunitrazepaminduced sleep in squirrel monkeys, thus antagonizing the effects of a BZR full agonist. In a precipitated withdrawal paradigm, chronic oral treatment in seizure-prone young DBA/2J mice or adult squirrel monkeys was followed by iv challenge with the BZR antagonist sarmazenil. Following the completion of a chronic treatment regiment with high doses of these quinolizinones, no signs of precipitated withdrawal were observed in mice and only weak signs of sarmazenil-induced withdrawal were observed in monkeys. In contrast, sarmazenil challenge after chronic treatment with the BZR full agonists triazolam and alprazolam elicited marked withdrawal reactions in mice and monkeys, respectively. In sum, these quinolizinones are BZR partial agonists which offer potential anxiolytic and anticonvulsant efficacy concomitant to reduced adverse effects, including a clear reduction of dependence liability, in comparison to BZR full agonists. © 1995 Wiley-Liss, Inc.

The product licences for triazolam in Britain were suspended in October 1991. We aimed to determine whether the sudden withdrawal of a benzodiazepine from the market constitutes a major impetus for patients to reduce or stop their benzodiazepine consumption. Patients in 10 London general practices who were prescribed triazolam in the 12 months prior to the withdrawal of its licence were interviewed. Data from written and computerized general practice records were also studied. One hundred and forty-seven patients were identified, of whom 107 (73%) were interviewed; 38 were chronic users; 68 patients had a history of serious physical illness while 33 had a history of psychiatric problems; 45% of chronic and 66% of intermittent triazolam users had stopped receiving prescriptions for benzodiazepines from 6 months after the withdrawal of triazolam's licence up to 18 months later. Only 12 (11%) recalled suffering significant withdrawal effects. We conclude that official action to curb prescribing of a benzodiazepine acts as an important stimulus for patients to reduce or stop their use of all psychotropic medication without increasing psychological morbidity or leading to unacceptable side effects.

Much controversy has surrounded triazolam since it was marketed in the late 1970s. In spite of ongoing debate no major pharmacoepidiomological study has been published, comparing triazolam to other benzodiazepines (BZD). The present study examines the occurrence of medical events after a prescription for one of five BZD. Data was obtained from the Saskatchewan Health Data Bases on all persons who received a prescription for one of triazolam, flurazepam, oxazepam, lorazepam or diazepam, not having had a prescription for any of these in the previous six months. These persons were monitored for eight types of medical events. (1. suicides and attempts, 2. depression, 3. other psychiatric condition, 4. traffic accident injury, 5. injury due to falls, 6. injury due to poisoning, 7. seizures, 8. allergic reactions) for three weeks after their prescription for the BZD. Rates for medical events were compared to those in an unexposed population sample. It was concluded that, on the whole, triazolam does not appear to show a record of hospitalization worse than the other five BZD tested. In general, BZD should be used cautiously, judiciously and at the lowest possible dose.

Twelve healthy male subjects were divided into 2 groups–the triazolam and placebo groups. The first three days were designated the baseline days. On the last three days, the bedtime and rising time were advanced 3 hours compared with the baseline days, and 0.5 mg of triazolam or a placebo was orally administered at bedtime. Their sleep was monitored polygraphically. Rectal temperature was measured for 6 days. There were no marked changes in the sleep pattern except that the sleep onset time was advanced by 3 hours. On the other hand, the nadir and acrophase of the body temperature were significantly advanced in the triazolam group. These findings suggest triazolam changes the phase of the human body temperature rhythm.

CL 284,846, N-[3-3-cyanopyrazolo[1,5-a]pyrimidin-7-yl(phenyl)]-N-ethylacetamide, is a novel non-benzodiazepine sedative-hypnotic with benzodiazepine-like sedative effects, but with less apparent liability for accompanying undesired side effects. Three metabolites of the parent sedative-hypnotic have been isolated and identified, a desethyl metabolite, CL 284,859, a desethyl-5-keto metabolite, CL 345,644, and a 5-keto metabolite, CL 345,905. In experiments to determine the ability of these compounds to displace [3H]-flunitrazepam from rat cortical benzodiazepine receptors, the IC50 values were 205 nM for CL 284,846 compared to 4.5 nM for diazepam as a positive control, and 11 μM for CL 284,859. The other two metabolite, CL 345,644 and CL 345,905, failed to displace [3H]-flunitrazepam. In a second experiment designed to evaluate in vivo receptor-mediated activity, CL 284,846 (3.0 mg/kg; 9.836 μmol/kg) was established as a discriminative stimulus (DS) in rats. While CL 284,846 (0.03ndash;3.0 mg/kg; 0.098–9.836 μmol/kg) showed a doserelated increase in drug-appropriate responding and one dose of triazolam (0.3 mg/kg; 0.875 μmol/kg) substituted as a positive control, all three metabolites (3.0–100.0 mg/kg; 10.3–341.3 μmol/kg for CL 284,859; 6.0–201.2 μmol/kg for CL 345,644; 9.3–311.5 μmol/kg for CL 345,905) failed to substitute for the DS effects of CL 284,846. These results suggest that CL 284,859, CL 345,644, and CL 345,905, the metabolites of the sedative-hypnotic CL 284,846, have no significant neuropharmacological effects at central benzodiazepine receptors and, thus, do not contribute to the activity of the parent compound. © 1994 Wiley-Liss, Inc.

Therapeutic trials for sleep-wake schedule disorders have been described, but a long-term follow-up of adolescents with such disorders have not previously been reported. We investigated 10 adolescents with sleep-wake schedule disorders who had formerly received intensive treatment. The investigation was carried out with detailed questionnaires about current sleep conditions and social state. The follow-ups were obtained from 1.2 to 11.2 years after the initial treatment. Three cases have remitted, and six have improved in illness severity. All patients showed improvement in social adaptation. Improvement in the social adaptation level was greater than improvement in the illness severity level. More cases should be studied to learn what factors influence the prognosis of these disorders.