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BackgroundClinical trials for rare disorders have unique challenges due to low prevalence, patient phenotype variability and high expectations. These challenges are highlighted by our study on clonazepam in ARID1B patients, a common cause of intellectual disability. Previous studies on Arid1b-haploinsufficient mice showed positive effects of clonazepam on various cognitive aspects.MethodsThis study used a randomised, double-blinded, placebo-controlled, two-way crossover study (RCT), followed by an N-of-1 design. In the crossover study, ARID1B patients received clonazepam (max 0.5 mg, two times per day) or a placebo for 22 days with a 3-week washout period. Assessments included safety, tolerability, pharmacokinetics, pharmacodynamics on neurocognitive tasks, behaviour and cognitive function. During phase I of the N-of-1 trial the optimal dosage and individual treatment goals were determined. Phase II evaluated the treatment effect. This phase was composed of three periods: an open-label period with placebo (4 weeks), followed by a double-blinded period (6 weeks), followed by an open-label period in which the patient received clonazepam (4 weeks).ResultsIn the clonazepam group (n=16, 15 completing both periods), seven (44%) reported improvement on Clinician Global Impression of Improvement versus two (13%) on placebo. 13 (87%) showed ‘no change’ after placebo (two (13%) on clonazepam), while seven (44%) on clonazepam reported deterioration, often linked to side effects (n=6), suggesting potential benefit from lower dosing. Three N-of-1 trials with RCT responders saw two patients improve on clonazepam during double-blinding, but clinical evaluation deemed the improvements insufficient.ConclusionsOur approach shows the feasibility and strength of combining conventional RCT and N-of-1 studies for therapeutic studies in populations with intellectual disabilities, distinguishing real treatment effects from expectation bias. Our findings suggest that clonazepam has no additional therapeutic value in ARID1B patients.Trial registration numberEUCTR2019-003558-98, ISRCTN11225608.

The presence of pharmaceutical pollutants, such as clonazepam (CZP), in aquatic environments poses significant risks to ecosystems and human health. This study introduces a novel solid-phase extraction (SPE) method utilizing a urea-modified metal-organic framework (MIL-101(Fe)-Urea) for the selective preconcentration and quantification of CZP in environmental water samples, then analyzed by high performance liquid chromatography analysis. The MIL-101(Fe)-Urea adsorbent was synthesized through a post-synthetic modification approach and characterized using FTIR, PXRD, SEM, BET, and EDX techniques. Key extraction parameters, including pH, adsorbent dosage, extraction/desorption times, and sample volume, were optimized to achieve maximum adsorption efficiency. Under optimal conditions, the method demonstrated excellent linearity (R 2 = 0.997) within a concentration range of 20–1500 µg L −1 , with a low detection limit (LOD = 0.030 µg L −1 ), high recovery rates (94.9–99.0%), and a relative standard deviation of 1.4%. The developed method was successfully applied to real environmental water samples, confirming its practicality for environmental monitoring. This study highlights the potential of MIL-101(Fe)-Urea as an advanced adsorbent for the analysis of pharmaceutical contaminants, contributing to the development of efficient and environmentally friendly analytical techniques for water quality assessment.

Anything humans swallow is exposed to the foraging and transforming activities of the gut microbiota. This applies to therapeutic drugs as well as food components and can be a major source of interpersonal variation in drug efficacy and toxicity. Zimmermann et al. found that individual drug responses depend on the genetics of an individual's microbiota. They explored the metabolism of nucleoside drugs (which are used as antivirals and antidepressants) in mice inoculated with a variety of mutant microbiota. They then modeled the pharmacokinetics in different body compartments and identified the host and microbe contributions. In some individuals, up to 70% of drug transformation can be ascribed to microbial metabolism. Science , this issue p. eaat9931 Genetic manipulation of drug metabolism in human gut commensal bacteria resolves host and microbiome contributions. The gut microbiota is implicated in the metabolism of many medical drugs, with consequences for interpersonal variation in drug efficacy and toxicity. However, quantifying microbial contributions to drug metabolism is challenging, particularly in cases where host and microbiome perform the same metabolic transformation. We combined gut commensal genetics with gnotobiotics to measure brivudine drug metabolism across tissues in mice that vary in a single microbiome-encoded enzyme. Informed by these measurements, we built a pharmacokinetic model that quantitatively predicts microbiome contributions to systemic drug and metabolite exposure, as a function of bioavailability, host and microbial drug-metabolizing activity, drug and metabolite absorption, and intestinal transit kinetics. Clonazepam studies illustrate how this approach disentangles microbiome contributions to metabolism of drugs subject to multiple metabolic routes and transformations.

Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE. We did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2·5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35. Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference −10·3%, 95% CI −24·0 to 3·4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group. The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment. UCB Pharma.

Abstract BackgroundThe objectives of this review and meta-analysis of polysomnographic data are those to focus on the clinical use of clonazepam for the management of sleep disorders by re-analyzing clinical trials and randomized clinical trials which have been published in peer-reviewed journals.MethodsA review of the literature including clinical trials and randomized controlled trials was performed in PubMed®, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. A random effects model meta-analysis was then carried out for the four more frequently reported polysomnographic measures: total sleep time, sleep latency, sleep efficiency, and periodic leg movement during sleep (PLMS) index.ResultsA total of 33 articles were retrieved and screened in full text, of which 18 met the criteria for review; among the latter, nine met the criteria for meta-analysis. The studies included in the review involved patients with insomnia, REM sleep behavior disorder, sleep bruxism, and restless leg syndrome or PLMS which reported, most often, an increase in total sleep time with clonazepam. A clear sleep-promoting effect of clonazepam was found also by meta-analysis.Discussion and conclusionsOur results indicate that the pharmacological treatment of sleep disorders with clonazepam must always be personalized according to the type of patient, the risk of addiction and the concomitant presence of respiratory disorders are key factors to take into account. However, in light of the clinical evidence of the few studies in the literature on the different types of disorders, more studies on the use of clonazepam (also in association with first choice treatments) are definitely needed.

Background: BMS is a chronic pain syndrome affecting the oral mucosa. It consists of experiencing a burning or dysesthetic sensation. BMS prevalence varies, with up to 15% among women. An effective treatment is still unattainable. Material and Methods: A total of 60 patients with BMS qualified for a randomised trial, divided in two groups: the clonazepam-treated and tongue protector group. Treatment was provided for 4 weeks in both groups. In the former, the oral dosage of clonazepam 0.5 mg; in the latter, a tongue protector was used. Clinical oral examination was performed, and the presence of taste disorder and pain intensity, on the visual analogues scale, were recorded. Psychological domains were explored with the Beck depression inventory (depression), Athens insomnia scale (insomnia), Eyesenck personality questionnaire-revised (personality traits), and WHO quality of life questionnaire (quality of life). Results: Complete recovery was observed in three patients after clonazepam and one patient after tongue guard treatment. A greater improvement in the VAS scores, from baseline to the control values, was demonstrated in the clonazepam group, and it was statistically significant. In women, the level of depression significantly correlated with all domains of quality of life. Conclusions: BMS is an ongoing multi-specialist challenge. The development of new pathophysiological concepts of BMS offers hope for more effective treatment. Considering the influence of BMS on the quality of life and mental disorders in most patients, further research on the possibilities of therapy seems to be very important.

Benzodiazepines are frequently prescribed to treat anxiety and insomnia, but long-term use has been associated with the development of dependence, tolerance, and cognitive decline, especially among older adults. This study aimed to investigate the pattern of consumption and factors associated with inappropriate prescribing of benzodiazepines in primary health care. This is a cross-sectional analytical study, using dispensing records of diazepam, clonazepam, and nitrazepam from public pharmacies in a Brazilian municipality between 2018 and 2022. Metrics for benzodiazepine consumption were DDD (Defined Daily Dose) and DDD/1000PD (per 1000 population per day). Long-term/prolonged benzodiazepine use was defined as consuming at least 90 DDD and at least 2 dispensations per year. To ascertain associations between long-term use and predictor variables, a multivariate logistic regression model was utilized. A total of 40402 participants were included, with an average age of 55 years (SD = 0.30), 38.5% were older aged. Diazepam and nitrazepam exceeded the daily dose recommended. There was a reduction in diazepam consumption during the study period, as calculated by DDD/1.000PD, while the consumption of other benzodiazepines remained stable. However, a significant increase in diazepam consumption is noted when considering the last decade. Prolonged use was observed in 29.1% of participants, with a significant prevalence among the older people (34.8% of them were long-term users) and advancing age was identified as a risk factor for long-term use. Higher PDDs were also associated with long-term use and aging. Participants who used different benzodiazepines during the period had a higher risk of prolonged use. These results provide insights into the prevalence of problematic utilization of benzodiazepines in primary health care. Authorities and health care providers must take steps to encourage gradual cessation of prolonged benzodiazepine prescriptions and the embrace of suitable strategies for addressing anxiety and insomnia within primary health care settings.

Burning Mouth Syndrome (BMS) is a chronic neuropathic pain condition with limited treatment options. N-acetylcysteine (NAC), a thiol-based antioxidant with neuroprotective properties, has not been clinically evaluated as a topical agent for BMS. This study aimed to evaluate the efficacy of topically applied liquid NAC in reducing symptoms and improving quality of life of patients with BMS. In a multicenter, prospective, nonrandomized, open-label study, 114 patients with BMS were allocated to receive liquid NAC oral rinse, oral clonazepam, or combination therapy for eight weeks. Symptoms were assessed at baseline, week 4, and week 8 using the visual analog scale (VAS) and the Korean version of the Oral Health Impact Profile-14 (OHIP-14 K). Across all three groups, VAS scores declined significantly within groups from baseline to week 4 and to week 8; however, the magnitude of VAS change did not differ between groups at either time point. For OHIP‑14 K, significant within‑group decreases were observed in the liquid NAC and combination groups from baseline to weeks 4 and 8, whereas the clonazepam group showed a significant decrease only from week 4 to week 8 and not from baseline. At week 4, the combination group achieved a larger OHIP‑14 K reduction than either monotherapy; by week 8, between‑group differences were no longer significant. Topically applied liquid NAC, alone or in combination with clonazepam, effectively reduced pain and enhanced patient-reported outcomes. These findings support the potential of a localized and safe strategy targeting neuropathic mechanisms in BMS. Topically administered liquid NAC demonstrates potential as an effective and well-tolerated therapeutic strategy for managing BMS, offering symptom relief with minimal systemic burden. Although the combination with clonazepam did not demonstrate sustained superiority at 8 weeks, its principal advantage is a faster onset of improvement in OHIP‑14 K, evident by week 4.

Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and SE is a constant challenge for healthcare professionals, in both the pre-hospital and the in-hospital settings. Benzodiazepines (BZDs) are the first-line treatment for SE worldwide due to their efficacy, tolerability, and rapid onset of action. Although all BZDs act as allosteric modulators at the inhibitory gamma-aminobutyric acid (GABA) A receptor, the individual agents have different efficacy profiles and pharmacokinetic and pharmacodynamic properties, some of which differ significantly. The conventional BZDs clonazepam, diazepam, lorazepam and midazolam differ mainly in their durations of action and available routes of administration. In addition to the common intravenous, intramuscular and rectal administrations that have long been established in the acute treatment of SE, other administration routes for BZDs—such as intranasal administration—have been developed in recent years, with some preparations already commercially available. Most recently, the intrapulmonary administration of BZDs via an inhaler has been investigated. This narrative review provides an overview of the current knowledge on the efficacy and tolerability of different BZDs, with a focus on different routes of administration and therapeutic specificities for different patient groups, and offers an outlook on potential future drug developments for the treatment of prolonged seizures and SE. Graphical Abstract