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STUDY OBJECTIVES: Prescription use and misuse of opioids are linked to greater sleep disturbance. However, there are limited data on the prevalence of sedative-hypnotic medication use among persons who use opioids. Therefore, this study examined whether past-year sedative-hypnotic use among persons who used/misused opioids was higher than among individuals who did not use opioids. METHODS: Data were acquired from the US National Survey on Drug Use and Health for 2015–2018. Use of a sedative benzodiazepine (temazepam, flurazepam, triazolam) or a Z-drug (eszopiclone, zaleplon, zolpidem) was examined in relation to use/misuse of an opioid within the past year. Logistic regression models estimated the associations between opioids and sedative-hypnotics using inverse probability of treatment weighting. A secondary machine learning analysis tested 6 binary classifiers to predict sedative-hypnotic use based on opioid use/misuse and other covariates. RESULTS: Of 171,766 respondents, 24% used a prescription opioid whereas 3.6% misused an opioid in the past year. Among those who used a prescription opioid, 1.9% received a sedative benzodiazepine and 9% received a Z-drug during the same time frame. Use of an opioid was associated with greater odds of sedative benzodiazepine use (odds ratio, 4.4; 95% confidence interval, 3.61–5.4) and Z-drug use (odds ratio, 3.8; 95% confidence interval, 3.51–4.09), and stronger associations were noted for misuse of an opioid. Machine learning models accurately classified sedative-hypnotic medication use for > 70% of respondents based on opioid use/misuse. CONCLUSIONS: Sedative-hypnotic use is common among persons who use opioids, which is of concern given the elevated mortality risk with concurrent use of these substances. CITATION: Tubbs AS, Ghani SB, Naps M, Grandner MA, Stein MD, Chakravorty S. Past-year use or misuse of an opiod is associated with use of a sedative-hypnotic medication: a US National Survey on Drug Use and Health (NSDUH) study. J Clin Sleep Med. 2022;18(3):809–816.

Isoniazid (INH) is prescribed both for the prophylaxis as well as the treatment of tuberculosis. It is primarily metabolized through acetylation by a highly polymorphic enzyme, N-acetyl transferase 2 (NAT2), owing to which significant variable systemic drug levels have been reported among slow and rapid acetylators. Furthermore, many drugs, like phenytoin, diazepam, triazolam, etc., are known to show toxic manifestation when co-administered with INH and it happens prominently among slow acetylators. Additionally, it is revealed in in vitro inhibition studies that INH carries noteworthy potential to inhibit CYP2C19 and CYP3A4 enzymes. However, CYP inhibitory effect of INH gets masked by opposite enzyme-inducing effect of rifampicin, when used in combination. Thus, distinct objective of this study was to fill the knowledge gaps related to gene-drug-drug interactions (DDI) potential of INH when given alone for prophylactic purpose. Whole body-PBPK models of INH were developed and verified for both slow and fast acetylators. The same were then utilized to carry out prospective DDI studies with CYP2C19 and CYP3A4 substrates in both acetylator types. The results highlighted likelihood of significant higher blood levels of CYP2C19 and CYP3A4 substrate drugs in subjects receiving INH pre-treatment. It was also re-established that interaction was more likely in slow acetylators, as compared to rapid acetylators. The novel outcome of the present study is the indication that prescribers should give careful consideration while advising CYP2C19 and CYP3A4 substrate drugs to subjects who are on prophylaxis INH therapy, and are slow to metabolic acetylation.

Introduction Benzodiazepines contribute to substance use disorder and are often part of polydrug abuse, most frequently with opioids. Although dental opioid prescribing differs significantly between countries, little is known about the patterns of dental benzodiazepine prescribing. The aim of this study is to compare dental prescribing of benzodiazepines among the U.S., England, and Australia in 2013–2018. Methods Population-level data were accessed from national data sets for each country for dental benzodiazepine prescriptions. Outcome measures of dental benzodiazepine prescribing included: (1) prescribing rates by population for each year and (2) the quantity and relative proportion of benzodiazepines by type for each country. The analysis was conducted in 2020. Results Between 2013 and 2018, U.S. dentists prescribed 23 times more than English dentists and 7 times more than Australian dentists by population. During the study period, the rate of dental benzodiazepine prescribing decreased in England and the U.S. but increased in Australia. Despite these trends, U.S. dental prescribing rates remained 28 times more than English dentists and 6 times more than Australian dentists in 2018 (U.S., 3.10 prescriptions/1,000 population; England, 0.11 prescriptions/1,000 population; Australia, 0.50 prescriptions/1,000 population). U.S. dentists prescribed a wider variety of benzodiazepines than English and Australian dentists. Diazepam was most commonly prescribed in all countries. In the U.S., triazolam, lorazepam, and alprazolam were next most commonly prescribed. Temazepam was next most frequent in England and Australia. Conclusions Significant variation in benzodiazepine prescribing rates and types were seen among the countries. To improve patient safety, further investigation into the appropriate use and choices of benzodiazepines in dentistry is needed.

Anxiety disorders have high prevalence and generate major disability. But they have poor treatment targeting because psychiatry lacks diagnostic biomarkers. Right frontal goal-conflict-specific-rhythmicity (GCSR) in the simple stop signal task appears homologous to hippocampal "theta" as an anxiety-process biomarker but is weak and transient. An anticipatory response inhibition task (ARIT) elicits strong subjective conflict and so might generate stronger GCSR. Healthy participants provided EEG during an ARIT, which allowed direct comparison of selective (left, SG; right, GS), and nonselective (both, SS) handed stopping. We assessed GCSR as intermediate versus the average of short and long delay stop-specific power. SG produced right frontal 5-12 Hz GCSR that, as in the SST: significantly correlated with trait anxiety and neuroticism; and was sensitive to pregabalin (75 mg), buspirone (10 mg), and perhaps triazolam (0.25 mg). GS and SS produced faster stopping and only 9-10Hz GCSR, which did not correlate significantly with trait anxiety or neuroticism and was sensitive to pregabalin and buspirone but not triazolam. Source localization suggested that GCSR, like stopping, involves multiple right frontal circuits that depend on response speed. Anxiolytic-sensitive GCSR generalizes from the speeded stop signal task to fixed-time anticipatory response inhibition tasks. GCSR, and the circuits engaged, vary with stop signal RTs conditions. Tasks with longer stop times may be optimal to generate GCSR homologous with rodent hippocampal theta as (a) the first direct anchor of a specific neural form of trait anxiety; (b) a single-dose screen in normal humans for novel anxiolytics; and (c) a potential clinical anxiety biomarker. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background Researchers have long been interested in the potential drug–drug interactions (DDIs) between opioids and benzodiazepines. However, much remains unknown concerning the interactions between these two drug classes. The objective of this work is to study the mechanism underlying the DDIs between opioids and benzodiazepines from the perspective of their pharmacokinetic (PK) interactions. A PK interaction occurs when two drugs are metabolized by the same cytochrome P450 enzymes and is one of the most common reasons for DDIs. Methods We quantitatively predicted the DDIs between three opioids (fentanyl, oxycodone and buprenorphine) and four benzodiazepines (alprazolam, diazepam, midazolam and triazolam) using a physiologically based pharmacokinetic (PBPK) modeling approach. A set of PBPK models was first constructed for these common opioids and benzodiazepines using SimCYP software, and the DDIs between them were then explored at various dosages. Results Our simulation results suggested there were no PK interactions between normal doses of opioids and benzodiazepines; but weak interactions can be expected with the combination of opioids and overdosed benzodiazepines. Particular attention should be given to the combination of fentanyl and overdosed alprazolam since a PK interaction can be observed between them. Conclusion Our results appear to indicate that pharmacodynamics may play a more important role than PKs in causing DDIs between opioids and benzodiazepines. This study also demonstrated that molecular modeling can be a very useful tool to mitigate the problem of “missing metabolic reaction parameters” in PK modeling and simulation. Electronic supplementary material The online version of this article (10.1007/s40268-019-00282-3) contains supplementary material, which is available to authorized users.

Background: Hypnotics, such as benzodiazepines and nonbenzodiazepines, have been used to aid sleep and treat insomnia in older adults. However, there is limited information for the comparative efficacy and safety of different hypnotics for insomnia in older adults. Methods: EMBASE, PubMed, ClinicalTrials.gov, and ProQuest Dissertations and Theses A&I databases were searched. We included randomised controlled trials comparing hypnotics with either another hypnotic or placebo for insomnia treatment in elderly people. A multivariate random effect network meta-analysis in a frequentist framework was used for estimations of treatment effects and safety. Findings: Twenty-two articles with 5172 older adults were included. Eszopiclone was ranked as the best therapy for prolonging objective total sleep time (28·60 mins), and low-dose doxepin appeared to be the optimal treatment for increasing subjective total sleep time (28·19 mins) and objective sleep efficiency (6.8%) compared with control. Zaleplon was the most effective therapy in reducing objective and subjective sleep onset latency (-21·63 mins and -15·92 mins) compared with control. The risk of overall adverse events was highest with triazolam use (odd ratio, 1·89, 95% confidence interval 1·10 to 3·25) compared to placebo. Interpretation: Considering unclear risk of bias and the potential adverse effects of benzodiazepines and nonbenzodiazepines, we suggest that low-dose doxepin can be the optimal pharmacotherapy for the improvements of sleep duration and sleep efficiency. Future RCTs investigating the treatment effects of hypnotics, particularly low-dose doxepin, on insomnia in older adults are warranted. Funding Statement: HYC acknowledges the support of the Taiwan Ministry of Science and Technology (MOST 106-2314-B-038 -058 -MY3). YKT was supported by the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-002 -098 -MY3). Declaration of Interests: All authors declared no conflicts of interest in this work. Ethics Approval Statement: The study is registered with PROSPERO, number CRD42016046301.

Study Objectives This study investigated the association between ambient nighttime temperature and sleep problems assessed by the prescription dose of sleeping pills in South Korean adults. Methods We used the 2002–2015 National Health Insurance Service-National Sample Cohort. A total of 711,079 adults who were 20 years old or older were included, wherein 42,858 adults (~6%) had been prescribed hypnotic medications including zolpidem (N05CF02) and triazolam (N05CD05). Ambient temperature data was calculated as the mean highest temperature of nighttime (23:00–07:00) for every month from January to December. We combined the drug-prescribed date with the administrative districts-level daily nighttime temperature between 2002 and 2015. Results We found that a non-linear, U-shaped relationship between nighttime temperature and hypnotic medication prescription. With an increase per 1°C temperature or an increase in a square per 1°C, the prescription dose of sleeping pills was significantly increased (both p < 0.05). At each 5°C nighttime temperature, subjects belonging to low (≤0°C and 0–5°C) or high (20–25°C and ≥25°C) temperature categories had significantly higher doses of sleeping pills than those at the reference temperature (10–15°C). Changes in nighttime temperature had a significant non-linear effect on the prescribed dosage of hypnotic medications for both adults (p < 0.0001) and the elderly (p = 0.0006). Conclusion We found that either a high or low nighttime temperature was significantly associated with a high daily dose of hypnotic medications in the Korean population.

Flualprazolam is a novel designer benzodiazepine, structurally related to alprazolam, flubromazolam and triazolam. In the last couple of years, it has been frequently detected in seizures and in forensic cases in Sweden and Finland. However, there is a lack of published blood concentrations for the drug, which presents difficulties when assessing its relevance for the cause of death. A quantitative method for the determination of flualprazolam in post-mortem blood was developed and validated, and subsequently used to analyse samples from 33 deaths previously screened as testing positive for flualprazolam in Sweden and Finland. Most of the cases in the study were accidental deaths (61 %) or suicides (18 %). The median (range) flualprazolam concentration was 18.0 (3.0-68) ng/g. The majority of the deceased were male (82 %) and the median age was 30 years. The median age in the Swedish cases was significantly higher (35 years) than in the Finnish cases (23 years) (p

Objectives: This study aimed to compare the risk of fractures, acute myocardial infarction, atrial fibrillation, and ventricular arrhythmia among Danish citizens aged ≥ 65 which were new users of promethazine or domperidone, triazolam, loratadine, and betahistine. Secondly, the study aimed to perform a risk stratification to identify the most relevant predictors for the study outcomes. Methods: The study period was 01/01/2015 to 31/12/2016. The data sources were the Danish registers. Each patient was followed for 90 days. A logistic regression model was used to compute the unadjusted and adjusted odds ratios (OR), and a conditional inference tree was used to identify the most relevant predictors for the study outcomes. Results: Promethazine had a higher risk of hospitalization for atrial fibrillation than loratadine and betahistine (OR 1.58; 95% CI 1.07–2.63 and OR 3.22; 95% CI 1.69–7.14, respectively). For fractures, acute myocardial infarction, and ventricular arrhythmia hospitalizations, no statistically significant differences were found among drugs under investigation. The medical history of cardiac arrhythmia (OR 4.14; 95% CI 2.94–5.78, p < 0.0001) was the most relevant predictor for atrial fibrillation hospitalizations. Conclusion: This study found an increased risk of atrial fibrillation hospitalization among promethazine users, and the risk was higher among patients with prior cardiac arrhythmia.

Flualprazolam is a nonregistered drug in the benzodiazepine family and constitutes a new psychoactive substance (NPS). Since 2014, a growing number of designer benzodiazepines have become available over the Internet and on the counterfeit drug market. In June 2019, a cluster of patients intoxicated with flualprazolam was identified by the Oregon Poison Center. As an emerging drug of abuse, the clinical characteristics of flualprazolam have been poorly characterized thus far. Over a one-week period, 6 teenagers presented to local emergency departments after ingesting illegally obtained counterfeit alprazolam, which led to sedation. Other symptoms included slurred speech, confusion, and mild respiratory depression. All 6 patients had resolution of their symptoms within 6 hours of ingestion. Blood and urine samples, as well as a tablet fragment, were obtained from 3 patients. The tablet and biological samples were analyzed by using liquid chromatography–quadrupole time-of-flight mass spectrometry and were found to contain the NPS flualprazolam without other drugs or intoxicants. With this case series, we add to the medical literature a clinical description of an emerging drug of abuse. Flualprazolam appears to share the clinical properties of other benzodiazepines. As flualprazolam and other NPSs become more common, physicians must be aware of their availability and characteristics. Sedation lasting

BACKGROUND Benzodiazepines have been used preoperatively as part of an anesthesia regimen to attenuate the anxiety of patients. In this study, we aimed to examine the effect of oral triazolam, a short-acting benzodiazepine, on anxiety, sedation, and amnesia. METHODS Ninety patients, aged 20-55 years, were randomly assigned to receive no premedication, or to receive triazolam 0.25 mg or 0.375 mg 1 h before anesthesia. Anxiety score, sedation score, blood pressure, heart rate and psychomotor performance were measured on the evening before surgery and on the day of surgery. Additional tests of psychomotor performance were performed in the postanesthesia care unit and on the next day of surgery. The occurrence of amnesia, bispectral index (BIS), recovery profiles and patient satisfaction with overall anesthesia care were also evaluated. RESULTS Changes in the anxiety and sedation scores on the day of surgery were not significantly different among groups, whereas the increases in systolic blood pressure and heart rate were significantly less in both triazolam groups. The triazolam groups both showed a higher incidence of high satisfaction scores (≥ 2). The two triazolam groups also showed similar outcomes, except for a dose-dependent increase in the number of patients with amnesia and BIS values < 90. Delayed recovery from general anesthesia and psychomotor impairment were not observed in the triazolam groups. CONCLUSIONS Triazolam 0.25 mg or 0.375 mg reduced the hemodynamic changes associated with anxiety, produced potent amnesia, and improved patient satisfaction. We suggest that triazolam can be used effectively as anesthetic premedication in adults.

Purpose Insomnia is problematic for older adults. After behavioral modifications fail to show adequate response, pharmacologic options are used. The pharmacokinetics of agents used to treat insomnia may be altered. This review focuses on the safety and efficacy of medications used to treat insomnia. Methods A literature search of Medline, PubMed, and Embase was conducted (January 1966–June 2016). It included systematic reviews, randomized controlled trials, observational studies, and case series that had an emphasis on insomnia in an older population. Search terms included medications approved by the US Food and Drug Administration for insomnia: benzodiazepines (triazolam, estazolam, temazepam, flurazepam, and quazepam), nonbenzodiazepine receptor agonists (non-BzRAs; zaleplon, zolpidem, and eszopiclone), suvorexant, ramelteon, doxepin and trazodone. Off-label drugs such as other antidepressants, antihistamines, antipsychotics, gabapentin, pramipexole, tiagabine, valerian, and melatonin were also included. Findings Cognitive behavioral therapy and sleep hygiene are considered initial therapy for insomnia. Benzodiazepines are discouraged in the geriatric population, especially for long-term use. Although non-BzRAs have improved safety profiles compared with benzodiazepines, their side effects include dementia, serious injury, and fractures, which should limit their use. Ramelteon has a minimal adverse effect profile and is effective for sleep-onset latency and increased total sleep time, making it a valuable first-line option. Although the data on suvorexant are limited, this drug improves sleep maintenance and has mild adverse effects, including somnolence; residual daytime sedation has been reported, however. Sedating low-dose antidepressants should only be used for insomnia when the patient has comorbid depression. Antipsychotic agents, pramipexole, and tiagabine have all been used for insomnia, but none has been extensively studied in an older population, and all have considerable adverse effects. Gabapentin may be useful in patients with restless leg syndrome or chronic neuropathic pain and insomnia. Diphenhydramine should be avoided in the elderly. Valerian and melatonin are unregulated products that have a small impact on sleep latency and can produce residual sedation. Implications An ideal treatment for insomnia should help to improve sleep latency and sleep duration with limited awakenings and be without significant adverse effects such as daytime somnolence or decreased alertness. Cognitive behavioral therapy should always be first line treatment. Clinical inertia regarding previous prominent use of benzodiazepines and non-BzRAs will be a significant challenge for patients accustomed to their issuance. The future direction of insomnia treatment should have an emphasis on nonpharmacologic interventions, treating comorbid conditions, and focusing therapy on using benzodiazepines and non-BzRAs as last resorts.

Retention of the ability to wake from sleep in response to dangerous situations is an ideal characteristic of safe hypnotics. We studied the effects of a dual orexin receptor antagonist-22 (DORA-22) and the GABA-A receptor modulator, triazolam, on the ability to wake in response to aversive stimuli. We examined four modalities of sensory inputs, namely, auditory (ultrasonic sound), vestibular (trembling), olfactory (predator odor), and autonomic (hypoxia) stimuli. When the mice fell asleep, one of the four stimuli was applied for 30 s. In the case of auditory stimulation, latency to arousal following vehicle, DORA-22, and triazolam administration was 3.0 (2.0–3.8), 3.5 (2.0–6.5), and 161 (117–267) s (median and 25–75 percentile in the parentheses, n = 8), respectively. Latency to return to sleep after arousal was 148 (95–183), 70 (43–98), and 60 (52–69) s, respectively. Similar results were obtained for vestibular and olfactory stimulation. During the hypoxic stimulation, latencies for arousal and returning to sleep were not significantly different among the groups. The findings of this study are consistent with the distinct mechanisms of these sleep promoting therapies; GABA-A receptor activation by triazolam is thought to induce widespread central nervous system (CNS) suppression while DORA-22 more specifically targets sleep/wake pathways through orexin receptor antagonism. These data support the notion that DORA-22 preserves the ability to wake in response to aversive and consciousness-inducing sensory stimuli, regardless of modality, while remaining effective in the absence of threat. This study provides a unique and important safety evaluation of the potential for certain hypnotics.

Background Progesterone-derived neuroactive steroids have shown promise clinically (e.g., anti-seizure medications) but, as with other GABAA receptor modulators (e.g., benzodiazepines), may have the potential for abuse. Methods We evaluated the reinforcing effects of progesterone, a steroid precursor of endogenous neuroactive steroids, with and without pretreatments with the neuroactive steroid synthesis inhibitor, finasteride, in rhesus monkeys trained under a progressive-ratio (PR) schedule of i.v. midazolam injection. We also assessed reinforcing effects of the short-acting neuroactive steroid alphaxolone and the long-acting neuroactive steroid ganaxolone in comparison with the short-acting benzodiazepine triazolam and the long-acting benzodiazepine clonazepam. Results At least one dose of progesterone, alphaxolone, and ganaxolone was self-administered significantly above vehicle levels in all monkeys tested (n = 4 for progesterone, n = 3 for alphaxolone and ganaxolone). The 5α-reductase inhibitor finasteride attenuated progesterone self-administration, consistent with the reinforcing effects of progesterone being mediated by the in vivo synthesis of neuroactive steroids. The comparison drugs, triazolam and clonazepam, were self-administered significantly above vehicle by all monkeys. Although the maximum number of injections/session maintained by the neuroactive steroids was below that maintained by the midazolam training dose, analysis of break points (i.e., highest response requirement achieved) suggested modest differences in relative reinforcing effectiveness for neuroactive steroids compared with benzodiazepines. Conclusions Our results are consistent with endogenous and synthetic neuroactive steroids having reinforcing effects similar to that of benzodiazepines, with reinforcing effectiveness possibly lower for the neuroactive steroids compared with benzodiazepines based on some measures.

In recent years, the intake of functional foods containing high-doses of green tea polyphenols (GP) has been increasing. In this study, the long-term safety of high-dose GP was assessed from a pharmacokinetic point of view by focusing on the drug-metabolizing enzyme, cytochrome P450 (CYP). Mice were fed a diet containing 3% GP for 4weeks, and the CYP expression levels and activity were determined. The GP-treated group showed a significant decrease in the hepatic CYP3A and an increase in the hepatic CYP2C expression compared with the control group. CYP1A, CYP2D, and CYP2E expression were not different between the GP-treated and the control groups. In the small intestine, there were no differences in the CYP3A protein levels between the groups. The increase in the plasma triazolam concentration in the GP-treated group was observed. Although no changes were found in the hepatic CYP3A levels in mice receiving a diet containing 0.1% GP for 4weeks, a significant decrease was seen in the hepatic CYP3A level in mice receiving a diet containing 3% GP for only 1week. This study revealed that the intake of a high-dose GP results in a liver-specific decrease in the CYP3A expression level. The results also indicated that the effects of GP on CYP3A were not observed following the intake of a low-dose GP. In the future, caution should be taken in cases when functional foods containing a high-dose GP are concomitantly consumed with a CYP3A substrate drug.

IntroductionPharmaceutical research and development of drugs is well-known for its high uncertainty (Kuwashima, 2006; Pisano, 2006a, 2006b). The theoretical total of chemical compounds that may become potential new drugs is estimated to be 1060 (Okuno, 2014). Discovering new drugs from such an enormous number of potential alternatives is an important issue for researchers in pharmaceutical companies (Becker & Lillemark, 2006; Garnier, 2008; Kuwashima, 2015; Pisano, 1997).1In this study, the process leading to the discovery of a new drug is explored, focusing on Rozerem (generic name: ramelteon), a therapeutic agent for insomnia released by Takeda Pharmaceutical Company Limited (hereinafter, Takeda) in 2010 (Japan) as an example. In the Japanese pharmaceutical industry, when Rozerem was introduced into the market, the mean number of chemical compounds explored to discover a single new drug was approximately 25,000 (Japan Pharmaceutical Manufacturers Association, 2010). On the other hand, Rozerem was discovered through the exploration of only approximately 300 alternatives.Discovery Process of Rozerem2(1) Trigger for researchResearch and development of Rozerem was initiated under the direction of Katsura Morita, the president of Takeda. At the end of 1991, Morita learned from the press about a variety of social problems because of memory impairment caused by Halcion (generic name: triazolam), a sleep-inducing agent from Upjohn (US) that was dominant in the market. Therefore, he instructed the drug research division to develop a sleep-inducing agent with fewer side effects.(2) Determining the drug targetIn April 1992, the sleep-inducing drug research team was formed in the drug research division and the project started. Initially, the team had five members, including two chemists and three biologists. In this project, Takeda aimed to develop a safer sleep-inducing agent, instead of a drug that has a potent therapeutic effect but also strong side effects, like Halcion. Therefore, the team decided to choose a target different from the GABA receptor, which is the target of Halcion.The first drug target chosen was camphor, which is a drug used as an anti-inflammatory analgesic. Camphor was considered suitable as a sleep-inducing agent because its chemical structure is partly similar to that of prostaglandins. The hypnotic effect of prostaglandins had just been discovered in the early 1990s. However, when the pharmacological effect was investigated further, it became clear that developing camphor as a sleep-inducing agent was not desirable. The biggest problem was that prostaglandin receptors were distributed throughout the body. The candidate drug must act selectively in the brain to safely serve as a sleep-inducing agent, but this was difficult to achieve with prostaglandins, which have receptors throughout the body.The next drug target chosen was melatonin, which is a type of hormone. At that time, several studies showed that melatonin may have a coordination effect on the circadian rhythm.3 However, most of these studies used animal models, and only a very weak sleep-inducing effect was observed in humans.After analyzing information on melatonin collected from all over the world, the Takeda research team hypothesized that if a substance with more potent activity than melatonin is synthesized, it may exert a strong sleep-inducing effect on humans. Based on this hypothesis, a study was initiated on determining a melatonin receptor agonist4 as a new drug target.(3) Determining the target compoundIn this project, the following two criteria were set as requirements for the target compound.1) The compound should have a more potent pharmacological effect than melatonin and also have a long duration.2) The compound should not bind to receptors or enzymes other than those in the brain.In December 1993, research was initiated with the aim of discovering chemical compounds satisfying these two criteria. …

Mental retardation is one of the major disorders covered in special care dentistry. Patients show poor oral health and are a challenge for the dentist due to lack of cooperation. Triazolam is a short-acting benzodiazepine and has been used in the dental office for many years because of its favorable properties. In this study, five patients with mental retardation were sedated with triazolam on a dental out-patient setting. Patients were administrated with 0.25 mg or 0.5 mg of triazolam on the first dose according to the patient's cooperation. Twenty minutes after the initial dose, patients received 0.25 mg of triazolam. Triazolam was administrated sublingually to one patient and orally to four patients. Hydroxyzine was also administrated to three patients in order to prevent nausea and vomiting. All patients were inhaled with 50% nitrous oxide during the sedation. Treatment time ranged from 20 minutes to 55 minutes. Two patients showed paradoxical reactions and were administrated with intramuscular injections of flumazenil. In result, depending on the range of dental treatment and level of intellectual disability, we can assume that triazolam may be beneficial for sedation in disabled patients.

Summary Postmortem drug redistribution (PMR) is a well-recognized phenomenon which affects the concentration of drugs inside the various body tissues and organs, possibly determining misled interpretation of postmortem drug concentrations. In contrast, drug levels in peripheral blood are commonly considered to be comparable with antemortem concentrations. The difference between central and peripheral blood concentrations is known as the “central to peripheral ratio” (C/P). Drugs with high C/P ratios are associated with potential for PMR. In several forensic cases, PMR should be taken into account for the correct estimation of drug blood levels at the moment of death, especially when multiple psychotropic drugs have been co-ingested. In the case reported hereby, the PMR of several benzodiazepines including triazolam, alprazolam, and delorazepam (chlordesmethyldiazepam) plus zolpidem was evaluated in a fatal multidrug suicide case. A 38-year-old man was found dead in his apartment. On the scene, many packaging of pharmaceutical drugs were found. During the autopsy, no evidence of natural disease nor trauma was found to account for his death. Heart (central) and femoral (peripheral) blood, urine and vitreous humor were collected and submitted to toxicological analysis. Delorazepam, triazolam and zolpidem were detected at therapeutic levels in peripheral blood while alprazolam and ethanol were found at toxic levels. The potential synergistic sedative effect of multiple benzodiazepines intake, combined to high ethanol concentration, produced a condition compatible with fatal intoxication. C/P ratio for the tested compounds ranged from 1.22 (alprazolam) to 1.47 (delorazepam) demonstrating moderate PMR for these drugs. This is the first report in which the PMR of delorazepam is discussed.

Background Opioid-use disorder is associated with a high degree of co-abuse with benzodiazepines. While the mechanisms underlying the co-abuse of opioids and benzodiazepines remain unknown, α1 subunit-containing GABAA receptors may play a critical role in the reinforcing effects of benzodiazepine-type compounds, depending on whether the monkeys have a history of benzodiazepine or stimulant self-administration. The present study extended our prior research by comparing the reinforcing effects of a compound lacking activity at α1 subunit-containing GABAA receptors with the reinforcing effects of non-selective GABAA receptor positive allosteric modulators in monkeys with a history of opioid self-administration. Methods The reinforcing effects of L-838,417 (partial intrinsic efficacy at α2, α3, and α5 subunit-containing GABAA receptors, but no efficacy at α1 subunit-containing GABAA receptors, i.e., “α1-sparing compound”) were compared with those of the non-selective GABAA receptor partial modulator MRK-696, and non-selective GABAA receptor full modulators, triazolam and lorazepam, in rhesus monkeys (n = 3) experienced in remifentanil self-administration under a progressive-ratio schedule of intravenous drug injection. Results Neither the partial modulator nor the α1-sparing compound were self-administered above vehicle levels. The full modulators triazolam and lorazepam were self-administered significantly above vehicle levels, albeit at lower levels than remifentanil. Conclusions Our findings suggest that relatively high efficacy at one or more GABAA receptor subtypes is required for a compound to have reinforcing effects in monkeys with a history of remifentanil self-administration, in contrast to monkeys with benzodiazepine or stimulant self-administration histories.

The most widely used animal models to develop sleep-disorder drugs are rodents, particularly rats and mice. However, unlike humans, these rodents are nocturnal. Thus, diurnal non-human primates represent a valuable and more translational animal model to study sleep. Although sleep-disorder drugs have been screened in non-human primates, the use of a telemetry system is not a desirable method for a rapid drug efficacy assessment system because of the need for expensive equipment, complicated surgery, and the long time before results can be obtained from analysis by inspection. Locomotor activity has traditionally been used as an indicator of the effects of drugs, genes, and disease models. The Nano-Tag, a new device for analyzing activity after an easy implantation surgery, measures locomotor activity without expensive equipment and the need for inspection for data processing, and the overall cost is much lower than that of a telemetry system. In this study, we compared the data obtained from polysomnography and on locomotor activity in telemetry transmitter-embedded cynomolgus monkeys by implanting the Nano-Tag subcutaneously in the forehead and administering sleep-disorder drugs to confirm if sleep–wake states could be measured using the Nano-Tag. When we compared the changes in awake time per unit time measured using polysomnography and locomotor activity counts per unit time measured using the Nano-Tag, cynomolgus monkeys exhibited a diurnal preference, and the correlation coefficients were positive during the 24-h period. Additionally, the correlation coefficients during the 12-h dark period were positive when the hypersomnia treatment drug modafinil was administered. The correlation coefficients during the 12-h light period were also positive when the insomnia treatment drug triazolam was administered. These results suggest that measuring locomotor activity is an effective tool for identifying sleep–wake states and screening sleep-disorder drugs at low cost and with less burden to animal subjects., Neuroscience; Physiology; Zoology; Animal physiology; Veterinary medicine; Animal behaviour; Cynomolgus monkey; Nano-Tag; Screening; Sleep disorder drug; Telemetry

CYP3A probe drugs such as midazolam and endogenous markers, and plasma 4β-hydroxycholesterol (4β-OHC) and urinary 6β-hydroxycortisol-to-cortisol ratios (6β-OHC/C) have been used as markers of CYP3A induction in cynomolgus monkeys, as with humans. However, there is limited information on their sensitivity and ability to detect CYP3A induction, as most studies were evaluated only at a high dose of the inducer, rifampicin (RIF; 20 mg/kg). In the present study, the CYP3A induction by RIF over a range doses of 0.2, 2 and 20 mg/kg (n = 4) was examined using CYP3A probe drugs (midazolam, triazolam and alprazolam) and the plasma and urinary endogenous CYP3A markers (4β-OHC and 6β-OHC/C). The sensitivity and relationship for detecting CYP3A induction was compared among the markers. Four days repeated oral administration of rifampicin to cynomolgus monkeys reduced the area under the plasma concentration-time curve of all CYP3A probe drugs in a rifampicin dose-dependent manner. Although the endogenous CYP3A markers (4β-OHC and 6β-OHC/C) were also changed for the middle (2 mg/kg) and high (20 mg/kg) doses of rifampicin, the fold-changes were relatively small, and CYP3A induction could not be detected at the lowest dose of rifampicin (0.2 mg/kg). In conclusion, CYP3A probe drugs are more sensitive for detecting CYP3A induction than endogenous CYP3A markers in cynomolgus monkeys, even for a short experimental period.

Background: Anecdotal evidence suggests that there may be sex differences in Drug-drug Interactions (DDI) involving specific drugs. Regulators have provided general guidance for the inclusion of females in clinical studies. Some clinical studies have reported sex differences in the Pharmacokinetics (PK) of CYP3A4 substrates, suggesting that DDI involving CYP3A4 substrates could potentially show sex differences. Objective: The aim of this review was to investigate whether recent prospective DDI studies have included both sexes and whether there was evidence for the presence or absence of sex differences with the DDIs. Methods: The relevant details from 156 drug interaction studies within 124 papers were extracted and evaluated. Results: Only eight studies (five papers) compared the outcome of the DDI between males and females. The majority of the studies had only male volunteers. Five studies had females only while 60 had males only, with 7.7% of the studies having an equal proportion of both sexes. Surprisingly, four studies did not specify the sex of the subjects. : Based on the limited number of studies comparing males and females, no specific trends or conclusions were evident. Sex differences in the interaction were reported between ketoconazole and midazolam as well as clarithromycin and midazolam. However, no sex difference was observed with the interaction between clarithromycin and triazolam or erythromycin and triazolam. No sex-related PK differences were observed with the interaction between ketoconazole and domperidone, although sex-related differences in QT prolongation were observed. Conclusion: This review has shown that only limited progress had been made with the inclusion of both sexes in DDI studies.

Outdoor artificial nighttime light is increasingly recognized as a form of environmental pollution. Excessive nighttime light exposure, whether from indoor or outdoor sources, has been associated with a number of deleterious effects on human health. We performed a population-based cohort study in South Korea to assess the possible association between outdoor nocturnal lighting and insomnia in older adults, as measured by prescriptions for hypnotic drugs.This study used data from the 2002-2013 National Health Insurance Service-National Sample Cohort (NHIS-NSC), and a total of 52,027 adults who were age 60 years or older were included in the study. Light data were based on satellite mapping of artificial light. The usage data of two hypnotic drugs, zolpidem (N05CF02) and triazolam (N05CD05), were extracted from the NHIS-NSC records.Of the 52,027 patients in this cohort, 11,738 (22%) had prescriptions for hypnotic drugs. Increasing outdoor artificial nighttime light exposure (stratified by quartile) was associated with an increased prevalence of hypnotic prescriptions and daily dose intake. Compared with individuals in the lowest quartile 1, the regression coefficients for prescription days and daily defined doses of all hypnotic drugs and certain hypotonic drugs were significantly higher among those living in areas with higher outdoor artificial nighttime light (quartiles 2 through 4).Outdoor artificial nighttime light exposure was significantly associated with prescription of hypnotic drugs in older adults. These findings are consistent with the hypothesis that outdoor artificial nighttime light may cause sleep disturbances.

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.

To investigate the relationship between benzodiazepine and risk of developing pneumonia in patients with schizophrenia, whose benzodiazepine dosage and usage frequency was higher than that of the general population. We conducted a nested case–control study to assess the association between benzodiazepine use and pneumonia among patients with schizophrenia. By using the Taiwan National Health Insurance Research Database, we identified a schizophrenia cohort comprising 34,929 patients during 2000–2010. Within the schizophrenia cohort, 2501 cases of pneumonia and 9961 matched control patients (1:4 ratio) were identified. Benzodiazepine exposure was categorized by drug, treatment duration, and daily dose. Conditional logistic regression models were used to examine the association between benzodiazepine exposure and the risk of pneumonia. The current use (within 30 days) of midazolam led to the highest pneumonia risk (adjusted risk ratio = 6.56, P

Stupor is a diagnostic challenge at emergency department. Differential diagnosis includes idiopathic recurrent stupor, formerly attributed to “endozepine-4” accumulation. This condition has been recently questioned because many suspected cases resulted in exogenous benzodiazepine intake that eludes the conventional toxicological assay. In case of unexplained recurrent stupor, to extend the benzodiazepine search in nonconventional matrices can allow unmasking of hidden toxic behavior.

BACKGROUND: Triazolam has similar pharmacological properties as other benzodiazepines and is generally used as a sedative to treat insomnia. Alprazolam represents a possible alternative to midazolam for the premedication of surgical patients. The purpose of this study was to evaluate the anxiolytic, sedative, and amnestic properties of triazolam and alprazolam as pre-anesthetic medications. METHODS: Sixty adult patients were randomly allocated to receive oral triazolam 0.25 mg or alprazolam 0.5 mg one hour prior to surgery. A structured assessment interview was performed in the operating room (OR), the recovery room, and the ward. The levels of anxiety and sedation were assessed on a 7-point scale (0 = relaxation to 6 = very severe anxiety) and a 5-point scale (0 = alert to 4 = lack of responsiveness), respectively. The psychomotor performance was estimated using a digit symbol substitution test. As a memory test, we asked the patients the day after the surgery if they remembered being moved from the ward to the OR, and what object we had shown them in the OR. RESULTS: There were no significant differences between the groups with respect to anxiety and sedation. The postoperative interviews showed that 22.2% of the triazolam-treated patients experienced a loss of memory in the OR, against a 0% memory loss in the alprazolam-treated patients. In comparison with alprazolam 0.5 mg, triazolam 0.25 mg produced a higher incidence of amnesia without causing respiratory depression. CONCLUSIONS: Oral triazolam 0.25 mg can be an effective preanesthetic medication for psychomotor performance.

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.

We have previously shown that menthol attenuates the anticoagulant effect of warfarin by increasing the expression levels of CYP3A and CYP2C in the liver. This study evaluated the effects of menthol on the pharmacokinetics of the CYP3A substrate triazolam and the CYP2C substrate phenytoin. Menthol was orally administered to mice for 7 d. Twenty-four hours after the administration of menthol, triazolam was orally administered, and the plasma concentration was measured. In addition, the CYP3A metabolic activity for triazolam and the CYP3A expression level in the liver were determined. The effects of menthol on the pharmacokinetics of phenytoin were assessed in the same manner. In the menthol-treated group, the area under the blood concentration-time curve (AUC) of triazolam was lower and its clearance was higher compared with the control group. The CYP3A metabolic activity and CYP3A expression level in the liver were significantly increased in the menthol-treated group compared with the control group. Similarly, the AUC of phenytoin was lower and the hepatic CYP2C expression level was higher in the menthol-treated group. Thus, menthol lowered the plasma concentrations of triazolam and phenytoin when concurrently administered. These effects may be attributed to an increased metabolic activity for these drugs due to the increased expression of CYP3A and CYP2C in the liver.

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.

Continuing our studies for the analyses of drugs of abuse in municipal wastewater, a method was developed for the analysis of benzodiazepines in wastewater samples using liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). Ten benzodiazepines and metabolites were analyzed (structures were found), including alprazolam, α-OH-alprazolam (the primary urinary metabolite of alprazolam), chlordiazepoxide, flurazepam, 2-OH-ethylflurazepam (the primary urinary metabolite of flurazepam), 7-NH2-flunitrazepam, nordiazepam, oxazepam, temazepam and α-OH-triazolam (the primary urinary metabolite of triazolam) (representative chromatograms were found). These drugs were chosen because of their widespread abuse. Wastewater samples were collected at both the Oxford Wastewater Treatment Plant (WWTP) in Oxford, Mississippi (MS) and the University WWTP in University, MS. These wastewater samples were collected on weekends in which the Ole Miss Rebel football team held home games at the Vaught-Hemingway Stadium, University, and one weekend on which there was no game. The collected samples were analyzed using a validated method and found to contain alprazolam, α-OH-alprazolam, nordiazepam, oxazepam and temazepam. None of the samples contained chlordiazepoxide, flurazepam, 2-hydroxyethyl-flurazepam, 7-NH2-flunitrazepam and α-OH-triazolam.

Objective The most common mental diseases in pregnant women are depression and anxiety disorders (estimated prevalence 6.5–12.9% and 15.6%, respectively [1] , [2] ). The drugs used in their treatment (antidepressants and benzodiazepines) can produce serious obstetric complications, as well as deleterious effects in fetal development and later in life [1] . The aim of this study was to compare maternal hair and meconium for detecting in utero drug exposure to benzodiazepines and antidepressants. Methods Maternal hair and meconium samples were collected after delivery from 145 mother–newborn dyads. Samples were analyzed for the determination of benzodiazepines (alprazolam, clonazepam, bromazepam, diazepam, nordiazepam, lorazepam, lormetazepam, oxazepam, flunitrazepam, 7-aminoflunitrazepam, triazolam, and zolpidem), antidepressants (amitriptyline, clomipramine, fluoxetine, paroxetine, venlafaxine, citalopram), and 6 metabolites by LC-MS/MS. Hair samples were segmented in 3 segments corresponding with the 3 trimesters (n = 99), but if the amount of hair was not enough a 8-cm segment was employed (n = 46). Maternal hair results (LOQ = 5–20 pg/mg) and meconium Results (LOQ = 5–20 ng/g) were compared. Results Forty-nine hair samples (33.8%) tested positive, 23 (15.9%) for benzodiazepines (19 segmented and 4 non-segmented) and 33 (22.8%) for antidepressants (23 segmented and 10 non-segmented). Specifically, the most frequently detected compounds in hair were nordiazepam (n = 13, > LOD-224.6 pg/mg), citalopram (n = 11, 30.2–7166.1 pg/mg), diazepam (n = 10, 6.6–879.5 pg/mg), amitriptyline (n = 8, 11.3–556.5 pg/mg), and venlafaxine (n = 8, 14.4–659.1 pg/mg). Twenty-eight meconium samples (19.3%) tested positive, 24 (16.6%) for benzodiazepines and 8 (5.5%) for antidepressants. The most frequently detect compounds in meconium were nordiazepam (n = 16, > LOD-125.1 ng/g), diazepam (n = 12, > LOD-68.6 ng/g), citalopram (n = 5, > LOD-2729.5 ng/g) and its metabolite desmethylcitalopram (n = 4, > LOD-1286.1 ng/g), and alprazolam (n = 3, 5.7–42.2 ng/g). The overall agreement between maternal hair and meconium results was 66.9%, but this value increased to 70.2% when only the hair results corresponding with the third trimester were compared with meconium. This good agreement was due to the high percentage of negative results (n = 84), but if only positive results were analyzed the percentage decreased to 19.7% and 42.6%, respectively. A better correlation was found between positive results in both specimens for benzodiazepines (39.1%) than antidepressants (18.2%). Moreover, when hair samples were positive in the three trimesters (n = 15), meconium was positive in 7 cases, and in the remaining cases the concentration in hair was decreasing along pregnancy, except in one case. Surprisingly, when benzodiazepines were administrated during delivery (n = 15), in 6 cases meconium tested positive at low concentrations (1.1–8.6 ng/g). Conclusion Maternal hair was more sensitive than meconium to detect consumption during pregnancy, while meconium was able to detect consumption during the third trimester and also during delivery.

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.

The area of fruit juice-drug interaction has received wide attention with numerous scientific and clinical investigations performed and reported for scores of drugs metabolized by CYP3A4/CYP2C9. While grapefruit juice has been extensively studied with respect to its drug-drug interaction potential, numerous other fruit juices such as cranberry juice, orange juice, grape juice, pineapple juice and pomegranate juice have also been investigated for its potential to show drug-drug interaction of any clinical relevance. This review focuses on establishing any relevance for clinical drug-drug interaction potential with pomegranate juice, which has been shown to produce therapeutic benefits over a wide range of disease areas. The review collates and evaluates relevant published in vitro, preclinical and clinical evidence of the potential of pomegranate juice to be a perpetrator in drug-drug interactions mediated by CYP3A4 and CYP2C9. In vitro and animal pharmacokinetic data support the possibility of CYP3A4/CYP2C9 inhibition by pomegranate juice; however, the human relevance for drug-drug interaction was not established based on the limited case studies.

A 68-year-old woman presented with a sudden severe headache, vomiting, and disturbed consciousness. She was admitted to the emergency room. Computed tomography (CT) revealed a hemorrhage in the right temporal lobe. Angiography demonstrated a ruptured aneurysm in the right middle cerebral artery (MCA) and an unruptured aneurysm in the left MCA. The subarachnoid hemorrhage was grade 3 (Hunt and Kosnik classification). Emergency craniotomy, clipping of the ruptured aneurysm and removal of the hematoma were performed. The left hemiparesis improved, and the patient was able to walk. We prescribed triazolam (0.25 mg/day) to treat the patient's insomnia. The unruptured aneurysm was additionally clipped on the 15th hospital day. After the second operation, the patient complained of delirium with restlessness, excitement, disorganized behavior, and sleep disturbance. Treatment with thiapride (150 mg/day) did not improve the delirium. We additionally administered Yi-gan san (7.5 g/day) and switched the triazolam to ramelteon (8 mg/day). The Memorial Delirium Assessment Scale score improved dramatically (from 16 at onset to 5 on day 7 and 1 at two months). Yi-gan san is reported to be effective for the treatment of behavioral and psychological symptoms of dementia. Ramelteon, a melatonin receptor agonist, is implicated in the regulation of the sleep-wake cycle. Ramelteon, unlike other hypnotic drugs, does not cause oversedation, rebound insomnia, withdrawal symptoms or dependence. In addition, we have noted no adverse effects, including oversedation or clinically significant changes in laboratory data, during combination therapy. A combination of ramelteon and Yi-gan san may therefore be beneficial in elderly patients with delirium, especially when there is a risk of oversedation.

Eszopiclone is the active S-enantiomer of R,S-zopiclone, and is a cyclopyrrolone hypnotic acting via the GABA-benzodiazepine receptor system. Nearly 6 million prescriptions for eszopiclone are written yearly in the United States.This paper addresses the pharmacokinetic properties of eszopiclone and the extent to which the longer half-life of eszopiclone compared to other commonly used hypnotics (immediate-release zolpidem, modified-release zolpidem, triazolam, zaleplon) may translate into either improved efficacy in enhancing sleep maintenance, or increased probability of residual sedative or performance-impairing effects.Eszopiclone is metabolized mainly by Cytochrome P450-3A (CYP3A) isoforms. The mean half-life in healthy nonelderly individuals (6.1 h) is prolonged in the elderly, in patients with hepatic insufficiency, and by coadministration of CYP3A inhibitors. In clinical trials, eszopiclone consistently improves sleep maintenance relative to placebo, based on measures of shortened wake time after sleep onset, and prolonged total sleep time. However eszopiclone may also produce residual sedation and impairment of driving performance in the initial morning waking hours. A bitter or metallic taste is a common though non-serious adverse effect of eszopiclone. Overall, eszopiclone provides a therapeutic option for patients with sleep maintenance problems, though with accompanying potential for residual morning sedation, as well as a relatively high dollar cost of treatment.

Objective Cocaine users display deficits in inhibitory control and make impulsive choices that may increase risky behavior. Buspirone is an anxiolytic that activates dopaminergic and serotonergic systems and improves impulsive choice (i.e., reduces sexual risk-taking intent) in cocaine users when administered chronically. We evaluated the effects of acutely administered buspirone on inhibitory control and impulsive choice. Methods Eleven subjects with a recent history of cocaine use completed this within-subject, placebo-controlled study. Subjects performed two cued go/no-go and a sexual risk delay-discounting task following oral administration of buspirone (10 and 30 mg), triazolam (0.375 mg; positive control), and placebo (negative control). Physiological and psychomotor performance and subject-rated data were also collected. Results Buspirone failed to change inhibitory control or impulsive choice; however, slower reaction times were observed at the highest dose tested. Buspirone did not produce subject-rated drug effects but dose-dependently decreased diastolic blood pressure. Triazolam impaired psychomotor performance and increased ratings of positive subject-rated effects (e.g., Like Drug). Conclusions These findings indicate that acutely administered buspirone has little impact on behavioral measures of inhibitory control and impulsive sexual decision-making. Considering previous findings with chronic dosing, these findings highlight that the behavioral effects of buspirone differ as a function of dosing conditions.

Benzodiazepines are effective anxiolytics, hypnotics, and anticonvulsants but unwanted side effects, including abuse potential, limit their use. A possible strategy to increase the therapeutic index of this drug class is to combine benzodiazepines with neuroactive steroids. The present study evaluated the extent to which combinations of benzodiazepines (triazolam, clonazepam) and neuroactive steroids (pregnanolone, ganaxolone) induced additive, supra-additive, or infra-additive effects in an elevated zero maze and a drug discrimination procedure in rats. Male Sprague-Dawley rats (N = 7/group) were placed into an elevated zero maze apparatus following injections of multiple doses of triazolam and pregnanolone, alone and combined, or clonazepam and ganaxolone, alone and combined. These drugs/drug combinations also were evaluated in rats (N = 8) trained to discriminate triazolam (0.1 mg/kg, i.p.) from vehicle. Drug interactions were evaluated using isobolographic and dose-addition analysis. In the elevated zero maze, all drugs engendered dose-dependent increases in time spent in the open quadrant when administered alone. Triazolam and pregnanolone, as well as clonazepam and ganaxolone combinations produced additive or supra-additive effects depending on the fixed-proportion that was tested. In triazolam discrimination, all drugs engendered dose-dependent increases in triazolam-lever responding. In combination, triazolam and pregnanolone and clonazepam and ganaxolone produced predominantly additive discriminative stimulus effects, except for one fixed proportion of clonazepam and ganaxolone which had supra-additive effects. Although drug interactions depended on the constituent drugs, the combination tested, and the behavioral endpoint; a combination was identified that would be predicted to result in supra-additive anxiolytic-like effects with predominantly additive discriminative stimulus effects.

Oral sedation with benzodiazepines and anxiolysis with nitrous oxide are 2 effective methods to help alleviate anxiety and fear of dental procedures. Many patients would prefer to have their dentistry performed with sedation if it were offered to them. This article presents a detailed discussion on minimal sedation that should give the reader a good understanding of this valuable aspect of clinical care.

In recent years, there has been heightened awareness regarding the use of drugs to modify a person's behavior to facilitate crime. A drug rape case involving the potent, short-acting sedative triazolam will be presented. On three occasions, the victim consumed green tea and chocolate before being massaged and ultimately sexually abused. Screening for alcohol, commonly used drugs and illicit substances in blood and urine sampled during the forensic examination 20 h after the last incident, was negative. Consequently, hair samples for chemical analysis were taken from the assaulted individual 34 days after the last incidents. The hair was cut into three 2-cm segments (0-6 cm) that were washed, dissolved in extraction solvent and screened and verified by ultra performance liquid chromatography coupled with time of flight mass spectrometry (UPLC-TOF-MS) and with tandem mass spectrometry (UPLC-MS/MS), respectively. In the 2-cm hair segment corresponding to the period of the alleged assaults, the presence of the sedative triazolam was revealed at a concentration of 1.0 pg/mg hair. The preserved urine sample, taken 20 h after the last incident, was reanalyzed by UPLC-MS/MS for metabolites of triazolam, and 39 μg/l α-hydroxytriazolam was detected in the hydrolyzed urine. This case illustrates that hair is a valuable forensic specimen in situations where natural processes have eliminated the drug from typical biological specimens due to delays in the crime being reported. Furthermore, it was possible to verify the hair finding with a urine sample by detection of a metabolite of triazolam.

Objective To investigate whether gender is associated with use of hypnotics or sedatives and with different types of hypnotics or sedatives in older people after adjustment for age, socioeconomic status (i.e., education) and co-morbidity (i.e., number of other drugs). Setting Sweden Method We conducted a register-based analysis of data on gender, age, dispensed drugs, and education from people aged 75-89 years registered in the Swedish Prescribed Drug Register between July and October 2005 (n = 645,429). Main outcome measure The hypnotic or sedative drug classes were benzodiazepines, benzodiazepine related drugs (i.e., Z-drugs) and other types of hypnotics or sedatives. The individual hypnotics or sedatives were nitrazepam, flunitrazepam, triazolam, zopiclone, zolpidem, clomethiazole and propiomazine. Results In the total study population, 27.1% of the women and 18.1% of the men were dispensed at least one hypnotic or sedative drug. The logistic regression analyses of those who used hypnotics or sedatives (n = 151,700) revealed that women were more likely than men to use benzodiazepines (adjusted OR = 1.11; 95% CI 1.07–1.14) and benzodiazepine related drugs (adjusted OR = 1.14; 95% CI 1.12–1.17), whereas men were more likely to use other types of hypnotics or sedatives (adjusted OR = 0.69; 95% CI 0.67–0.71). Among the individual hypnotics or sedatives, the strongest associations with gender was found for nitrazepam (adjusted OR = 1.19; 95% CI 1.14–1.25 for women compared with men), zolpidem (adjusted OR = 1.18; 95% CI 1.16–1.21), clomethiazole (adjusted OR = 0.48; 95% CI 0.46–0.51) and propiomazine (adjusted OR = 0.77; 95% CI 0.75–0.79). Conclusion Use of hypnotics or sedatives in old age seems to be related to female gender. Also, among elderly users of hypnotics or sedatives, women appear to be more likely to use benzodiazepines and benzodiazepine related drugs than men. The explanation to these gender differences merits further investigation.

Objective:Family caregivers of cancer patients suffer from physical, psychological, and social distress and therefore are often referred to as second order patients. Akathisia is a common side effect of antipsychotics and antidepressants that causes great discomfort and even agitation and is often described by patients administered these drugs as the most distressing side effect of their treatment. Several studies of akathisia as a cause of distress in cancer patients have been reported. However, akathisia has not been reported as a cause of distress in family caregivers of cancer patients.Method/Case report:A 74-year-old spouse caregiver who was under treatment for major depressive disorder was not able to visit the hospital where her husband, a terminally ill cancer patient, was being treated. Initially, the spouse caregiver thought that she could not visit the hospital because of the symptoms of her depression and her grief about losing her husband. However, careful clinical examination revealed that she was suffering from akathisia in addition to her grief.Results:Discontinuation of her sulpiride treatment resulted in the disappearance of her akathisia symptoms, and therefore she became able to visit the hospital and care for her terminally ill husband.Significance of results:Drug induced akathisia is a cause of distress in spouse caregivers taking certain drugs. It is important for clinicians to realize that family caregivers might suffer from not only socioeconomic, physical, and psychological problems but also side effects of medication.

It is well known that psychotropic drugs,such as hypnotics and anxiolytics,increase the risk of falls for patients (includingfalls from high places).The present study was undertaken to evaluate the risk of falls following the taking of suchdrugs,with the focus on the benzodiazepine (BZ) family of hypnotics and anti-anxiety drugs previously reported to have ahigh risk of causing falls.When drugs of the BZ family were classified according to tmax,the mean frequency of falls differedbetween short tmax drugs and the long tmax drugs (P

Summary Background Disturbed body balance and standing steadiness are problematic for those who wake up at night or in the morning after using hypnotic drugs. As a result, falls and hip fractures are frequently reported in patients using sleep medication. Methods A literature search was performed to identify double blind, placebo-controlled clinical trials that examined body balance and standing steadiness. Drugs that were searched were nitrazepam, triazolam, lorazepam, temazepam, loprazolam, flunitrazepam, flurazepam, and the Z-drugs zopiclone, zolpidem and zaleplon. Results A total of 57 studies were eligible for inclusion. Results showed that both benzodiazepine hypnotics and the Z-drugs significantly impair body balance and standing steadiness after single dose administration. Impairments correlate significantly with blood plasma levels and are greatest at peak plasma concentrations, but are sometimes still present upon awakening. Balance problems were dose-related and most pronounced in elderly. Co-administration of alcohol aggravated the impairment. After repeated daily use of hypnotic drugs partial tolerance develops to the impairing effects on standing steadiness. Conclusion Single dose administration of benzodiazepine hypnotics and Z-drugs significantly impair body balance in a dose-dependent manner. Zolpidem and zopiclone produced similar significant impairment as benzodiazepine hypnotics. Zaleplon significantly impaired balance up to 2 h after intake. Partial tolerance develops after repeated daily use. In conclusion, patients should be warned about the possible risk of imbalance and falls due to the use of sleep medication.

Eperisone hydrochloride is a centrally acting muscle relaxant, and triazolam is a short-acting benzodiazepine. Although commonly prescribed, cardiotoxicity induced by a single overdose of either drug is comparatively rare. A patient receiving nifedipine developed torsades de pointes (TdP) because of prolongation of the corrected QT (QTc) interval after an overdose of eperisone hydrochloride and triazolam.A 60-year-old man receiving nifedipine was admitted in a comatose condition 3 h after ingesting 5,000 mg of eperisone and 2.5 mg of triazolam. Electrocardiogram showed sinus rhythm with prolongation of the QTc interval (820 ms). The serum electrolyte levels were as follows: potassium, 3.8 mEq/L; magnesium, 2.4 mg/dL. The serum drug concentrations were high: eperisone, 15,360 ng/mL; triazolam, 110.8 ng/mL. A temporary cardiac pacemaker was implanted immediately after the development of TdP, 11 h after the ingestion. The serum triazolam concentration normalized on day 2. The QTc interval and eperisone concentration normalized on day 6.Eperisone and triazolam overdose can cause life-threatening cardiotoxicity. Electrocardiographic monitoring and serial determination of QTc interval are likely the best way to observe these patients and evaluate the risk of cardiotoxicity.

Background When performing dental treatment under general anesthesia in adult patients who have difficulty cooperating due to intellectual disabilities, anesthesia induction may be difficult as well. In particular, patients who refuse to come into the dental office or sit in the dental chair may have to be forced to do so. However, for adult patients with a large physique, physical restraint may be difficult, while oral sedatives as premedication may be helpful. Here, a retrospective analysis was performed to investigate the effect of oral sedatives. Methods A hospital-based medical information database was searched for patients who were prescribed oral midazolam or triazolam between January 2009 and December 2017. Pre-anesthesia evaluation, anesthesia, and anesthesia recovery records of all patients were analyzed, and information on disability type, reason for prescribing oral sedatives, prescribed medication and dose, cooperation level during anesthesia induction, anesthesia duration, length of recovery room stay, and complications was retrieved. Results A total of 97 patients were identified, of whom 50 and 47 received midazolam and triazolam, respectively. The major types of disability were intellectual disabilities, autism, Down syndrome, blindness, cerebral palsy, and epilepsy. Analyses of changes in cooperation levels after drug administration showed that anesthesia induction without physical restraint was possible in 56.0% of patients in the midazolam group and in 46.8% of patients in the triazolam group (P = 0.312). Conclusions With administration of oral midazolam or triazolam, general anesthesia induction without any physical restraint was possible in approximately 50% of patients, with no difference between the drugs.

Pharmacokinetic analyses of three kinds of benzodiazepines--midazolam (MDZ), triazolam (TRZ) and alprezolam (APZ)--were performed in rats with cannulated portal and jugular veins. Each drug was administered to the double-cannulated rats, and pharmacokinetic data for the parent drugs and their 1'- and 4-hydroxylated metabolites were compared with those obtained in non-cannulated mice. In bioavailability, the drugs ranked APZTRZ = MDZ in rats, and APZTRZMDZ in mice, with the values for MDZ remarkably different between rats and mice (19% in rats versus 2.3% in mice). In contrast, hepatic availability (Fh) was similar (APZTRZMDZ) in both species. Highly significant relationships were found between the ratio of the area under the plasma concentration-time curve (AUC) for the parent drugs in portal blood (AUC(por)) to that in systemic blood (AUC(sys)) and Fh in rats and mice. The double-cannulated rat is useful for estimating the hepatic availability of drug candidates by determining the AUC values for the parent drugs in portal and systemic blood samples.