GABAA/Benzodiazepine Receptor Complex in the Dorsal Hippocampus Mediates the Effects of Chrysin on Anxiety-Like Behaviour in Female Rats

Systemic injections of the flavonoid chrysin (5,7-dihydroxyflavone) exert anxiolytic-like effects in ovariectomised and cycling female rats through actions on gamma-aminobutyric acid-A (GABAA) receptors; however, it is unknown if chrysin directly acts on brain structures that are involved in regulating emotional processes, such as the hippocampus. The present study evaluated the effects of intrahippocampal microinjections of 0.25, 0.5, and 1 μg of chrysin on anxiety-like behaviour in the elevated plus maze (EPM) and locomotor activity test (LAT) in female rats in proestrus and dioestrus. Similar doses of the neurosteroid allopregnanolone were used as a reference GABAergic anxiolytic drug. The participation of the GABAA/benzodiazepine receptor complex was evaluated by administering the antagonists picrotoxin, bicuculline and flumazenil. In proestrus, 0.5 and 1 μg of chrysin and allopregnanolone induced anxiogenic-like behaviour. In dioestrus, chrysin, and allopregnanolone (0.5 μg) induced anxiolytic-like effects. Picrotoxin, bicuculline and flumazenil prevented the effects of chrysin and allopregnanolone in both proestrus and dioestrus. None of the treatments significantly affected locomotor activity. These results indicate that the GABAA/benzodiazepine receptor complex in the dorsal hippocampus regulates the effects of chrysin on anxiety-like behaviour, similar to the actions of allopregnanolone. The divergent effects of treatments across the oestrous cycle phases suggest complex interactions between GABAA receptors and compounds with an anxiolytic potential.

Trends in the Prescription of Benzodiazepine Receptor Agonists from 2009 to 2020: A Retrospective Study Using Electronic Healthcare Record Data of a University Hospital in Japan

In recent years, the prescription trends of benzodiazepine receptor agonists (BZRAs) have not been investigated in Japan despite the publication of guidelines that promote cautious use of BZRAs. The prescription trend of BZRAs was assessed using the electronic healthcare records data of a University Hospital in Japan. The data from April 2009 to March 2021 were used. The following three types of outcomes were set: the proportion of patients who were prescribed with BZRAs within those prescribed hypnotics or anxiolytics; the mean number of the types of prescribed BZRAs, and the mean average daily doses of BZRAs. The same analysis was conducted for benzodiazepines (BZDs) and non-benzodiazepines (Z-drugs). As a result, we found that the proportions of patients prescribed BZRAs within those prescribed hypnotics or anxiolytics began to decrease, particularly from 2015 for patients aged <75 years and those aged ≥75 years. Further, the degree of decrease was larger in patients aged ≥75 years. The proportion for BZDs decreased particularly in the study period, and the proportion for Z-drugs also began to decrease approximately from 2016 in patients aged ≥75 years. The results suggest a possibility that guidelines affected the decreased prescriptions of BZRAs.

Use of Benzodiazepines and Z-Drugs in Nursing Home Residents with Dementia: Prevalence and Appropriateness

Background: Guidelines worldwide recommend restricted prescription of benzodiazepine receptor agonists (BZRAs), i.e., benzodiazepines and Z-drugs, for the treatment of dementia-associated behavioral and psychological symptoms and insomnia. Objective: To assess the prevalence and appropriateness of BZRA use among nursing home residents with dementia. Methods: This is a post-hoc analysis of BZRA prescriptions from two intervention studies on psychotropic drug use, conducted from 2016 to 2018. It includes 1,111 residents of dementia special care units from 24 Dutch long-term care organizations. We assessed the prevalence of use of continuous and as-needed BZRA prescriptions and their association with registered symptoms. Continuous BZRA prescriptions were evaluated for appropriateness, i.e., whether indication, dosage, duration, and evaluation accorded with guidelines for the treatment of challenging behavior in dementia and sleep disorders. Results: The prevalence of BZRA use is 39.2%(95%CI: 36.3%–42.0%): continuous 22.9%; only as-needed 16.3%. Combinations of preferred BZRAs and appropriate indications occur in 19.0%of continuous anxiolytic prescriptions and 44.8%of hypnotic prescriptions. Frequently registered inappropriate indications are aggression/agitation for anxiolytics (continuous: 75.7%; as-needed: 75.2%) and nighttime agitation for hypnotics (continuous: 40.3%; as-needed: 26.7%). None of the continuous prescriptions with appropriate indications were appropriate for all other items. For most of the prescriptions, duration and time to evaluation exceeded 4 weeks. Conclusion: BZRA use in nursing home residents with dementia is highly frequent. A large proportion of prescriptions do not follow the guidelines with regard to indication, exceed the recommended duration and are not evaluated in a timely manner. The discrepancy between evidence-based guidelines and daily practice calls for an exploration of factors maintaining inappropriate use.

Development of a 3D-Printed Dosing Platform to Aid in Zolpidem Withdrawal Therapy

The long-term use of benzodiazepine receptor agonists (BZRAs) is associated with multiple side effects, such as increased sedation, hangover or an elevated risk of dependency and abuse. Unfortunately, the long-term use of BZRAs is reaching worrying intake rates, and therefore, the need for action is high. It was demonstrated already that the overall willingness of patients for deprescription increased when a slow dose reduction scheme with the possibility for dose increase, if needed, is employed. The current study aims to develop a flexible dosing platform of zolpidem hemitartrate (ZHT) to facilitate such withdrawal therapy. As this is the first report on the extrusion and 3D printing of ZHT, its thermal behaviour and sensitivity towards photolytic degradation was characterised. It was shown that ZHT possesses multiple polymorphs and was especially prone to oxidative photolysis. Next, a variety of immediate release polymers (Eudragit EPO, Kollidon VA64, Kollidon 12PF and Soluplus) were blended and extruded with Polyox WSR N10 to investigate their feedability and printability by mechanical and rheological analysis. The addition of PEO was shown to enable printing of these brittle pharmaceutical polymers, although the processing temperature was deemed critical to avoid surface defects on the resulting filaments. An EPO(70)PEO(30) system was selected based on its suitable mechanical properties and low hygroscopicity favoring ZHT stability. The matrix was blended with 1% or 10% API. The effect of certain printing parameters (caplet size, nozzle diameter, % overlap) on dissolution behaviour and caplet weight/dimensions/quality was assessed. A flexible dosing platform capable of delivering <1 mg and up to 10 mg of ZHT was created. Either caplet modification (incorporation of channels) or disintegrant addition (Primojel, Explotab, Ac-Di-Sol, Primellose and Polyplasdone-XL) failed to achieve an immediate release profile. This study provides the first report of a 3D-printed flexible dosing platform containing ZHT to aid in withdrawal therapy.

Effect of adjuvant drugs on the analgesic activity of opioid morphine analgesics and compound RU-1205

Introduction: Adjuvant medications can be used to increase the analgesic effect of opioid analgesics, reduce the manifestation of side effects, and also for premedication. This paper provides information on the effect of clonidine, haloperidol, metocloparmide, diazepam, midazolam on opioid analgesics: - morphine and the selective kappa-opioid agonist compound RU-1205. Materials and methods: A probable interaction between RU-1205, morphine and adjuvant drugs in pain behaviors was carried out on the model of somatogenic pain. 95 male mice received either RU-1205 (5 mg/kg, i.p.) and morphine (1 mg/kg, i.p.) separately or in combination with haloperidol (0.45 mg/kg, i.p.); midazolam (0.3 mg/kg, i.p.); diazepam (1 mg/kg, i.p.); metoclopramide (5 mg/kg, i.p.), and clonidine (1 mg/kg, i.p.). The analgesic effect was assessed by tail flick test. Registration of the latent period of the reaction was carried out 30, 60 and 90 minutes after the adjuvant drug administration. Results: When studying the interaction with morphine, it was found that clonidine, haloperidol and metoclopramide enhanced the effects; diazepam offset them, and midazolam had no affect on the analgesic properties. In the course of the studies, RU-1205 showed an increase in analgesic activity when combined with clonidine, a slight increase with midazolam, and a decrease when co-administered with diazepam. Haloperidol had no influence on the effect of RU-1205, while metoclopramide both potentiated and reduced the analgesic effect. Discussion: Pharmacodynamic and pharmacokinetic interactions of RU-1205 with an α2AR agonist, benzodiazepine receptor agonists, D2P antagonist, and σ-receptor blocker were established. Conclusion: The presented data make it possible to more accurately formulate ideas about the localization and action mechanism of the kappa-agonist of opioid receptors, the compound RU-1205.

The Association between Use of Benzodiazepine Receptor Agonists and the Risk of Obstructive Sleep Apnea: A Nationwide Population-Based Nested Case-Control Study

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway collapse. Benzodiazepine receptor agonists (BZRAs) are associated with pharyngeal muscle relaxation, increased apnea duration, and hypoxia, which might worsen OSA. This study aimed to examine the association between the use of BZRAs and the risk of OSA. The study was conducted using data from the National Health Insurance Database of Taiwan between 2002 and 2011. We only included new users who were never exposed to any BZRAs and identified 1848 participants with OSA, and 1848 matched controls. A logistic regression model was used to determine the association between the use of BZRAs and the development of OSA. BZRA exposure was divided into usage patterns, dosage, duration, and pharmacokinetic class. We found an increased risk of OSA in current users and recent past users compared with distant past users. Patients with a higher cumulative dose of BZRAs were more likely to develop OSA compared to those with a lower cumulative dose. We found an increased risk of OSA in patients treated with BZRAs, especially for current users and those with higher cumulative doses. A reduced risk of OSA was found in Z-drug users compared with benzodiazepine users.

Association of Benzodiazepine Receptor Agonist Use With Changes in Psoriasis Severity in Adult Population: A Population-Based Study

To date, it remains uncertain whether benzodiazepine receptor agonists (BZRAs) are aggravating factors even though these drugs can elevate the levels of biomarkers associated with the development of psoriasis. Therefore, this study aimed to investigate the association of BZRA use with changes in psoriasis severity. All data were sourced from the National Health Insurance system in Taiwan. We conducted a population-based retrospective cross-sectional study of 15,727 psoriasis patients who received BZRAs (BZRA users), and 18,856 psoriasis patients who did not receive BZRAs (nonusers). At least a 1-year washout period without any BZRA prescriptions was required. The main outcome was the change in psoriasis severity between before and after BZRA exposure. This study detected the exacerbation of psoriasis severity in mild psoriasis population by using a logistic model. Then, this study carried another logistic model among those patients who had severe psoriasis to calculate the odds ratios (ORs) for the improvement of the psoriasis severity. Among patients with mild psoriasis, BZRA users had a significantly higher probability of psoriasis severity exacerbation (IPTW-adjusted OR = 1.46). Mild psoriasis patients who received high and low doses of BZRAs had 1.70- and 1.39-fold higher probabilities of psoriasis severity exacerbation, respectively, than the non-users. Furthermore, in the severe psoriasis population, more low-dose BZRA users improved psoriasis severity than non-users. In conclusion, this study provided clinical evidence of the effects of BZRA use on patients with psoriasis severity. Among patients with mild psoriasis, high-dose BZRA users may be associated with the changes in psoriasis severity. However, low-dose BZRA exposure only slightly exacerbated disease severity among patients with mild psoriasis. Accordingly, clinicians should evaluate the risks and benefits of the BZRA usage.