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British Journal of Clinical Pharmacology 1983The effect of the new, short-acting benzodiazepine, midazolam as well as that of triazolam and flunitrazepam on the sleep of rabbits was recorded for 6 h. Midazolam at 1...
The effect of the new, short-acting benzodiazepine, midazolam as well as that of triazolam and flunitrazepam on the sleep of rabbits was recorded for 6 h. Midazolam at 1 mg kg-1 i.v. augmented both rapid eye movement sleep (REMS) and non-REM sleep (NREMS) only in the first half of the observation period. At 10 mg kg-1 i.v., NREMS was further increased in the first and, to a lesser degree, in the second 3-h period, while REMS was suppressed. Both doses were less effective orally than intravenously. Qualitatively, the effect of triazolam 0.01 and 0.1 mg kg-1 i.v. was very similar to that of the corresponding low and high intravenous doses of midazolam, except that the high dose of triazolam had a prolonged effect on total sleep time. Like midazolam, triazolam was substantially less effective orally than intravenously. Flunitrazepam at 0.1 and 1 mg kg-1 i.v. produced almost the same effects as midazolam and triazolam at the respective low and high intravenous doses, but had a longer duration of action. In contrast to midazolam and triazolam, flunitrazepam was almost as active orally as intravenously.
Topics: Administration, Oral; Animals; Anti-Anxiety Agents; Benzodiazepines; Electroencephalography; Electromyography; Flunitrazepam; Injections, Intravenous; Male; Midazolam; Rabbits; Sleep; Sleep, REM; Triazolam; Wakefulness
PubMed: 6138078
DOI: 10.1111/j.1365-2125.1983.tb02268.x -
JAMA Network Open Apr 2024Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear. (Observational Study)
Observational Study
IMPORTANCE
Although insomnia guidelines recommend the use of several individual hypnotics, the most useful hypnotic for treating insomnia in a clinical setting remains unclear.
OBJECTIVE
To determine which guideline-recommended hypnotics have lower risks of monotherapy failure and which hypnotics have a higher risk of long-term prescription for insomnia treatment.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective observational cohort study used data from the Japan Medical Data Center Claims Database from April 1, 2005, to March 31, 2021. Participants included adults whose first prescribed pharmaceutical treatment for insomnia was guideline-recommended hypnotic monotherapy. Data were analyzed from December 24, 2022, to September 26, 2023.
EXPOSURES
Suvorexant, ramelteon, eszopiclone, zolpidem, and triazolam monotherapy.
MAIN OUTCOMES AND MEASURES
The primary outcome was monotherapy failure, defined as a change in hypnotic or having an additional hypnotic prescribed for insomnia within 6 months of the first prescription of a guideline-recommended hypnotic monotherapy. The secondary outcome was monotherapy discontinuation, defined as no prescription of any hypnotic for 2 consecutive months within 6 months after prescribing a guideline-recommended hypnotic in patients for whom monotherapy did not fail. Monotherapy failure and discontinuation were compared using Cox proportional hazards and logistic regression models, respectively.
RESULTS
The study included 239 568 adults (median age, 45 [IQR, 34-55] years; 50.2% women) whose first prescription for insomnia was guideline-recommended hypnotic monotherapy. During the 6-month follow-up period, 24 778 patients (10.3%) experienced failure of monotherapy with a guideline-recommended hypnotic. In comparison with eszopiclone, there were more cases of monotherapy failure for ramelteon (adjusted hazard ratio [AHR], 1.23 [95% CI], 1.17-1.30; P < .001), fewer cases for zolpidem (AHR, 0.84 [95% CI, 0.81-0.87]; P < .001) and triazolam (AHR, 0.82 [95% CI, 0.78-0.87]; P < .001), and no significant difference between suvorexant and eszopiclone. Among those without monotherapy failure, monotherapy was discontinued in 84.6% of patients, with more discontinuations for ramelteon (adjusted odds ratio [AOR], 1.31 [95% CI, 1.24-1.40]; P < .001) and suvorexant (AOR, 1.20 [95% CI, 1.15-1.26]; P < .001) than for eszopiclone and no significant difference between zolpidem or triazolam and eszopiclone.
CONCLUSIONS AND RELEVANCE
Due to uncontrolled confounding factors in this cohort study, no conclusions regarding the pharmacologic properties of guideline-recommended hypnotics can be drawn based on these results. Further studies accounting for confounding factors, including diagnoses of chronic vs acute insomnia disorder, insomnia and psychiatric symptom severity, and physician attitudes toward hypnotic prescription, are needed.
Topics: Adult; Female; Humans; Male; Middle Aged; Cohort Studies; Eszopiclone; Hypnotics and Sedatives; Indenes; Japan; Retrospective Studies; Sleep Initiation and Maintenance Disorders; Treatment Failure; Triazolam; Zolpidem
PubMed: 38630476
DOI: 10.1001/jamanetworkopen.2024.6865 -
Basic & Clinical Pharmacology &... Mar 2012This MiniReview is a personal recollection of selected research topics, which the author in collaboration with colleagues has studied, aiming to improve the... (Review)
Review
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.
Topics: Age Factors; Cell Membrane; Drug Interactions; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Pharmacogenetics; Pharmacokinetics
PubMed: 22348413
DOI: 10.1111/j.1742-7843.2012.00858.x -
Journal of Psychiatric Research Jul 2022Benzodiazepine receptor agonists and related medications, such as Z-drugs and dual orexin receptor antagonists (BZDs), have been associated with unintentional traumatic...
Benzodiazepine receptor agonists and related medications, such as Z-drugs and dual orexin receptor antagonists (BZDs), have been associated with unintentional traumatic injury due to their central nervous system (CNS)-depressant effects. Drug-drug interactions (DDIs) may contribute to the known relationship between BZD use and unintentional traumatic injury, yet evidence is still lacking. We conducted high-throughput pharmacoepidemiologic screening using the self-controlled case series design in a large US commercial health insurance database to identify potentially clinically relevant DDI signals among new users of BZDs. We used conditional Poisson regression to estimate rate ratios (RRs) between each co-exposure (vs. not) and unintentional traumatic injury (primary outcome), typical hip fracture (secondary outcome), and motor vehicle crash (secondary outcome). We identified 48 potential DDI signals (1.1%, involving 39 unique co-dispensed drugs), i.e., with statistically significant elevated adjusted RRs for injury. Signals were strongest for DDI pairs involving zolpidem, lorazepam, temazepam, alprazolam, eszopiclone, triazolam, and clonazepam. We also identified four potential DDI signals for typical hip fracture, but none for motor vehicle crash. Many signals have biologically plausible explanations through additive or synergistic pharmacodynamic effects of co-dispensed antidepressants, opioids, or muscle relaxants on CNS depression, impaired psychomotor and cognitive function, and/or somnolence. While other signals that lack an obvious mechanism may represent true associations that place patients at risk of injury, it is also prudent to consider the roles of chance, reverse causation, and/or confounding by indication, which merit further exploration. Given the high-throughput nature of our investigation, findings should be interpreted as hypothesis generating.
Topics: Antidepressive Agents; Benzodiazepines; Databases, Factual; Drug Interactions; Humans
PubMed: 35526445
DOI: 10.1016/j.jpsychires.2022.04.033 -
Drug and Alcohol Dependence Dec 2000Zaleplon is a chemically novel hypnotic that preferentially binds alpha(1)-subunit containing subtypes of the alphabetagamma configuration of the gamma-aminobutyric acid...
Zaleplon is a chemically novel hypnotic that preferentially binds alpha(1)-subunit containing subtypes of the alphabetagamma configuration of the gamma-aminobutyric acid (GABA)(A) receptor. Zaleplon and the non-subtype-selective hypnotic triazolam occasioned 100% drug-appropriate responding in baboons trained to discriminate lorazepam or pentobarbital from vehicle. Flumazenil shifted the zaleplon generalization gradient at least five-fold to the right. A plasma elimination half-life of 6-8 h for oral 10 mg/kg zaleplon and 0.32 mg/kg triazolam was paralleled by discriminative control for 7 h. Zaleplon maintained self-injection greater than vehicle, as did comparison doses of the similarly selective hypnotic zolpidem and triazolam. Concurrent food-maintained responding increased during self-injection of all three drugs. Preferential binding at this alpha(1)-containing GABA(A) subtype did not diminish the benzodiazepine (Bzs)-like behavioral effects of zaleplon.
Topics: Acetamides; Animals; Behavior, Animal; Discrimination Learning; Dose-Response Relationship, Drug; GABA Modulators; Hypnotics and Sedatives; Male; Papio; Pyrimidines; Self Administration; Triazolam
PubMed: 11064184
DOI: 10.1016/s0376-8716(00)00123-x -
Canadian Medical Association Journal Apr 1982
Topics: Anti-Anxiety Agents; Confusion; Humans; Male; Middle Aged; Triazolam
PubMed: 6122497
DOI: No ID Found -
The Journal of Pharmacology and... Jun 2011Combinations of positive modulators of benzodiazepine and neuroactive steroid sites on GABA(A) receptors have been shown to act in an additive or supra-additive manner...
Combinations of positive modulators of benzodiazepine and neuroactive steroid sites on GABA(A) receptors have been shown to act in an additive or supra-additive manner depending on the endpoint under study, but they have not been assessed on experimentally induced conflict or drug self-administration. The present study examined the interactive effects of the benzodiazepine triazolam and the neuroactive steroid pregnanolone in a rhesus monkey conflict procedure (a model of anxiolysis) and on a progressive-ratio schedule of drug self-administration (a model of abuse potential). Both triazolam and pregnanolone decreased rates of nonsuppressed responding, whereas only triazolam consistently increased rates of suppressed responding (i.e., had an anticonflict effect). Fixed-ratio mixtures of triazolam and pregnanolone also decreased rates of nonsuppressed responding and did so in an additive manner. In contrast, mixtures of triazolam and pregnanolone produced either additive or supra-additive rate-increasing effects on suppressed responding, depending on the proportion of drugs in the mixture. Both triazolam and pregnanolone were self-administered significantly, and triazolam and pregnanolone mixtures had either proportion-dependent additive or infra-additive reinforcing effects. These results suggest that combinations of triazolam and pregnanolone may have enhanced anxiolytic effects with reduced behavioral disruption and abuse potential compared with either drug alone.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Conflict, Psychological; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Macaca mulatta; Pregnanolone; Reinforcement, Psychology; Self Administration; Triazolam
PubMed: 21411495
DOI: 10.1124/jpet.111.180422 -
Anesthesia Progress 2014
Topics: Adjuvants, Anesthesia; Age Factors; Anesthetics, Local; Conscious Sedation; Dose-Response Relationship, Drug; Drug Interactions; Drug Labeling; Drug Overdose; Female; Humans; Hypnotics and Sedatives; Lidocaine; Male; Risk Assessment; Sex Factors; Sleep Apnea, Obstructive; Triazolam; United States; United States Food and Drug Administration
PubMed: 24932976
DOI: 10.2344/0003-3006-61.2.45 -
Psychopharmacology Sep 2012Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM. (Comparative Study)
Comparative Study
RATIONALE
Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM.
OBJECTIVE
This study in humans evaluated the effects of supratherapeutic doses of DXM and triazolam.
METHODS
Single, acute oral doses of DXM (100, 200, 300, 400, 500, 600, 700, and 800 mg/70 kg), triazolam (0.25 and 0.5 mg/70 kg), and placebo were administered to 12 healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Subjective, behavioral, and physiological effects were assessed repeatedly after drug administration for 6 h.
RESULTS
Triazolam produced dose-related increases in subject-rated sedation, observer-rated sedation, and behavioral impairment. DXM produced a profile of dose-related physiological and subjective effects differing from triazolam. DXM effects included increases in blood pressure, heart rate, and emesis; increases in observer-rated effects typical of classic hallucinogens (e.g., distance from reality, visual effects with eyes open and closed, joy, anxiety); and participant ratings of stimulation (e.g., jittery, nervous), somatic effects (e.g., tingling, headache), perceptual changes, end-of-session drug liking, and mystical-type experience. After 400 mg/70 kg DXM, 11 of 12 participants indicated on a pharmacological class questionnaire that they thought they had received a classic hallucinogen (e.g., psilocybin). Drug effects resolved without significant adverse effects by the end of the session. In a 1-month follow-up, volunteers attributed increased spirituality and positive changes in attitudes, moods, and behavior to the session experiences.
CONCLUSIONS
High doses of DXM produced effects distinct from triazolam and had characteristics that were similar to the classic hallucinogen psilocybin.
Topics: Adult; Affect; Attitude; Dextromethorphan; Dose-Response Relationship, Drug; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Follow-Up Studies; GABA Modulators; Hallucinogens; Humans; Male; Psilocybin; Surveys and Questionnaires; Triazolam; Young Adult
PubMed: 22526529
DOI: 10.1007/s00213-012-2680-6 -
Pharmacology, Biochemistry, and Behavior Oct 2015Benzodiazepines are positive allosteric modulators of the GABAA receptor and are prescribed as anxiolytics, hypnotics, and anticonvulsants. While these drugs clearly...
Benzodiazepines are positive allosteric modulators of the GABAA receptor and are prescribed as anxiolytics, hypnotics, and anticonvulsants. While these drugs clearly have clinical value, their use is associated with unwanted side effects such as sedation and motor impairment. Neuroactive steroids are endogenous modulators of GABAA receptors and recent evidence has shown that combinations of the triazolo-benzodiazepine triazolam and the endogenous neuroactive steroid pregnanolone can produce both supra-additive anxiolytic effects and infra-additive reinforcing effects. In the present study, we investigated these same combinations as well as combinations of two clinically-relevant drugs from different chemical classes, the 1, 4 substituted (7-nitro) benzodiazepine clonazepam and the synthetic neuroactive steroid ganaxolone, in rats trained under a 10-response, fixed ratio (FR) schedule of food reinforcement. All four drugs induced a significant and dose-dependent suppression of food-maintained responding. From the dose-response functions, ED50s (i.e., the doses that engendered 50% of the maximum rate-decreasing effect) were generated for each drug. Dose-response functions for combinations of triazolam/pregnanolone, clonazepam/ganaxolone, triazolam/ganaxolone, and clonazepam/pregnanolone were then determined. Isobolographic analysis of the rate-decreasing effects of these combinations revealed that the potencies of the triazolam/pregnanolone combinations were supra-additive while the clonazepam/ganaxolone combinations were additive or infra-additive in relation to predicted values based on dose-additive effects. Furthermore, mixtures of clonazepam/pregnanolone were supra-additive while triazolam/ganaxolone combinations were additive, infra-additive and supra-additive. These results suggest that the ability of benzodiazepine and neuroactive steroid combinations to attenuate rates of food-maintained responding depends critically on both the constituent drugs and the dose of drug in the mixtures.
Topics: Animals; Benzodiazepines; Dose-Response Relationship, Drug; Drug Combinations; GABA Modulators; Male; Pregnanolone; Rats; Rats, Sprague-Dawley; Reaction Time; Reinforcement Schedule; Steroids; Triazolam
PubMed: 26255153
DOI: 10.1016/j.pbb.2015.08.003