The anthelmintic meclonazepam activates a schistosome transient receptor potential channel.

Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPMMCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPMMCLZ through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPMMCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPMMCLZ is distinct from the TRP channel targeted by PZQ (TRPMPZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPMMCLZ as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ.

Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation-induced autophagy through calcium signaling.

Mitochondria shape intracellular Ca2+ signaling through the concerted activity of Ca2+ uptake via mitochondrial calcium uniporters and efflux by Na+ /Ca2+ exchangers (NCLX). Here, we describe a novel relationship among NCLX, intracellular Ca2+ , and autophagic activity. Conditions that stimulate autophagy in vivo and in vitro, such as caloric restriction and nutrient deprivation, upregulate NCLX expression in hepatic tissue and cells. Conversely, knockdown of NCLX impairs basal and starvation-induced autophagy. Similarly, acute inhibition of NCLX activity by CGP 37157 affects bulk and endoplasmic reticulum autophagy (ER-phagy) without significant impacts on mitophagy. Mechanistically, CGP 37157 inhibited the formation of FIP200 puncta and downstream autophagosome biogenesis. Inhibition of NCLX caused decreased cytosolic Ca2+ levels, and intracellular Ca2+ chelation similarly suppressed autophagy. Furthermore, chelation did not exhibit an additive effect on NCLX inhibition of autophagy, demonstrating that mitochondrial Ca2+ efflux regulates autophagy through the modulation of Ca2+ signaling. Collectively, our results show that the mitochondrial Ca2+ extrusion pathway through NCLX is an important regulatory node linking nutrient restriction and autophagy regulation.

A versatile ratiometric fluorescence nanoprobe for the determination of clonazepam in patients' plasma samples.

Despite the necessity of the study of therapeutic drug monitoring of clonazepam (CLZ), there are only a few fast detection methods available for determining CLZ in biological media. This study aims to develop a cost-effective and ratiometric probe for the quantification of CLZ in plasma samples. Fluorescent polydopamine nanoparticles were produced through a self-polymerization process at a pH of 8.5. Rhodamine B molecules were employed as a fluorescent reference material, emitting stable fluorescence in the visible range. The fabricated probe exhibited a specific detection capability for CLZ. The fluorescence emission of the probe was enhanced in two concentration ranges: from 50 ng/mL to 1.0 µg/mL and from 1.0 to 15.0 µg/mL with a lower limit of quantification of 50 ng/mL, indicating the sensitivity of the probe for detecting CLZ plasma levels. The accuracy of the probe is favorable which could be recommended for CLZ monitoring in the biological media. Furthermore, this probe is highly specific towards CLZ in the presence of various interfering agents which is mainly caused by its ratiometric nature. The developed platform showed high reliability in quantifying CLZ concentrations in patients' plasma samples. Hence, the fabricated probe could be recommended as a reliable method for the routine detection of CLZ in clinical settings.

A Strategy for Rescuing a Child From Clonazepam Poisoning: A Case Study.

BACKGROUND: This report describes the successful rescue of a 12-year-old girl who ingested large quantities of clonazepam tablets. METHODS: The patient was promptly treated with flumazenil and hemoperfusion to alleviate the symptoms of central depression. Therapeutic drug monitoring was used to evaluate detoxification efficacy. The authors analyzed the rescue protocol for clonazepam poisoning based on the pathophysiology, clinical manifestations, and pharmacokinetics of clonazepam overdose. RESULTS: The patient responded well to the treatment and was discharged from the hospital without adverse events. CONCLUSIONS: This case study demonstrated the effectiveness and safety of combining flumazenil with hemoperfusion as a treatment for clonazepam poisoning. This study aimed to provide insights into more effective methods for treating clonazepam overdose and contribute to the ongoing issue of managing this condition.

Seizure control and complications in patients switching from clobazam to clonazepam due to drug shortage.

BACKGROUND: Antiseizure medication (ASM) shortages are a global problem that have a negative impact on outcomes such as seizure control in patients with epilepsy (PWE). In the case of clobazam (CLB) shortage, there is no study regarding the management strategy. This study aims to investigate the alteration in seizure frequency and the occurrence of side effects in PWE undergoing an abrupt switch from clobazam (CLB) to clonazepam (CLZ), during CLB shortage. MATERIAL AND METHODS: A retrospective study was conducted from electronic health records at our neurology outpatient clinic from January to July 2022. Change in seizure frequency and percentage of CLZ-associated side effects were determined as primary and secondary outcomes, respectively. Potential drug-drug interactions (Level C and above) were evaluated by using Lexicomp Drug Interaction Checker. RESULTS: The analysis included a total of 29 adult patients (15F, median age: 29). The switching ratio was 10 mg CLB for every 1 mg CLZ (10:1). Seizure frequency was higher during the CLZ period compared to the CLB period (p < 0.05), but no status epilepticus cases were observed. All patients exhibited potential drug-drug interactions, leading to reduced CLZ levels in 12 cases. A total of 36 CLZ-associated side effects were identified, with fatigue (19.4 %), drowsiness (16.6 %), and somnolence (13.8 %) being the most prevalent. A positive and strong correlation was found between CLZ dose and the number of side effects (r: 0.556; p: 0.002). CONCLUSION: The abrupt switch from CLB to CLZ was observed to increase seizure frequency without leading to status epilepticus in PWE. CLZ-associated side effects were found to be tolerable despite the abrupt switch. Future studies may explore the effect of alternative switching ratios.

Efficacy of intravenous clonazepam for paediatric convulsive status epilepticus.

AIM: To compare the efficacy of intravenous clonazepam (CLZ) for the initial management of convulsive status epilepticus (CSE) in children as a function of the first-line in-hospital dose used. METHOD: This monocentric retrospective study included children who received a first dose of CLZ for CSE at Montpellier University Hospital, France, between January 2016 and June 2019. Data from medical records (clinical, treatment, course) were collected and compared as a function of the first CLZ dose used. RESULTS: Among the 310 children treated for CSE, 105 received at least one CLZ dose (median age 3 years; quartile 1-quartile 3 [Q1-Q3] = 1 years 2 months-6 years 6 months). Among these 105 patients, 24 (22%) received a dose less than 0.03 mg/kg (low dose) and 69 (65%) received a dose of at least 0.03 mg/kg (high dose). Seizure cessation rate was not different between the low- and high-dose groups (62.5% vs 76%; odds ratio 0.53, 95% confidence interval [CI] 0.19-1.44, p = 0.29). The administration of a second dose of CLZ was more frequent in the low- than the high-dose group (37.5% vs 16%; odds ratio 3.2, 95% CI 1.1-9.1, p = 0.04). INTERPRETATION: Our study did not find any difference in seizure termination rate as a function of CLZ dose in children with CSE. However, a second CLZ dose was more frequently needed in the group receiving low (less than 0.03 mg/kg) CLZ.

Home nocturnal infrared video to record non-rapid eye movement sleep parasomnias.

To assess the feasibility, the acceptability and the usefulness of home nocturnal infrared video in recording the frequency and the complexity of non-rapid eye movement sleep parasomnias in adults, and in monitoring the treatment response. Twenty adult patients (10 males, median age 27.5 years) with a diagnosis of non-rapid eye movement parasomnia were consecutively enrolled. They had a face-to-face interview, completed self-reported questionnaires to assess clinical characteristics and performed a video-polysomnography in the Sleep Unit. Patients were then monitored at home during at least five consecutive nights using infrared-triggered cameras. They completed a sleep diary and questionnaires to evaluate the number of parasomniac episodes at home and the acceptability of the home nocturnal infrared video recording. Behavioural analyses were performed on home nocturnal infrared video and video-polysomnography recordings. Eight patients treated by clonazepam underwent a second home nocturnal infrared video recording during five consecutive days. All patients had at least one parasomniac episode during the home nocturnal infrared video monitoring, compared with 75% during the video-polysomnography. A minimum of three consecutive nights with home nocturnal infrared video was required to record at least one parasomniac episode. Most patients underestimated the frequency of episodes on the sleep diary compared with home nocturnal infrared video. Episodes recorded at home were often more complex than those recorded during the video-polysomnography. The user-perceived acceptability of the home nocturnal infrared video assessment was excellent. The frequency and the complexity of the parasomniac episodes decreased with clonazepam. Home nocturnal infrared video has good feasibility and acceptability, and may improve the evaluation of the phenotype and severity of the non-rapid eye movement parasomnias and of the treatment response in an ecological setting.

Systematic review of drug therapy for chorea in NXK2-1-related disorders: Efficacy and safety evidence from case studies and series.

BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

Clonazepam for the management of sleep disorders.

BACKGROUND: The 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. METHODS: A 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. RESULTS: A 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 CONCLUSIONS: Our 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.

Repositioning of Benzodiazepine Drugs and Synergistic Effect with Ciprofloxacin Against ESKAPE Pathogens.

Infectious diseases are among the leading causes of morbidity and mortality worldwide. Combating them becomes more complex when caused by the pathogens of the ESKAPE group, which are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. The purpose of this study was to investigate the repositioning potential of the benzodiazepines clonazepam and diazepam individually and in combination with the antibacterial ciprofloxacin against ESKAPE. The minimum inhibitory concentration and minimum bactericidal concentration against seven American Type Culture Collection (ATCC) reference standard strains and 64 ESKAPE clinical isolates were determined. In addition, the interaction with ciprofloxacin was determined by the checkerboard method and fractional inhibitory concentration index (FICI) of clonazepam against 11 ESKAPE and diazepam against five ESKAPE. We also list the results found and their clinical significance. Benzodiazepines showed similar antibacterial activity against Gram-positive and Gram-negative. The checkerboard and FICI results showed a synergistic effect of these drugs when associated with ciprofloxacin against almost all tested isolates. Viewing the clinical cases studied, benzodiazepines have potential as treatment alternatives. The results allow us to conclude that clonazepam and diazepam, when in combination with ciprofloxacin, have promising activity against ESKAPE, therefore, assuming the position of candidates for repositioning.

Comparative efficacy of prolonged-release melatonin versus clonazepam for isolated rapid eye movement sleep behavior disorder.

PURPOSE: Clonazepam and melatonin are recommended as first-line treatments for isolated rapid eye movement (REM) sleep behavior disorder (iRBD). This study aimed to compare their efficacy and safety in REM sleep without atonia (RWA) and RBD-related symptoms. METHODS: This prospective, open-label, randomized trial included patients with video-polysomnography-confirmed iRBD. The patients were randomly assigned to receive either clonazepam 0.5 mg or prolonged-release (PR) melatonin 2 mg 30 min before bedtime for 4 weeks. The primary outcome was changes in RWA on follow-up polysomnography (PSG). Secondary endpoints were changes in other PSG parameters, clinical global improvement-impression scale (CGI-I) scores, and sleep questionnaire scores. The safety endpoint was adverse events. RESULTS: Of 40 patients with probable RBD considered, 34 were enrolled in the study and randomized. Visual scoring parameters of RWA indices were reduced, and automatic scoring parameters tended to be improved after clonazepam treatment but not after PR melatonin treatment. The proportion of N2 sleep was increased, and N3 and REM sleep were decreased only in the clonazepam group. The clonazepam group tended to answer "much or very much improvement" on the CGI-I more frequently than the PR melatonin group (p = 0.068). Daytime sleepiness and insomnia symptoms were reduced after PR melatonin but not after clonazepam. Depressive symptoms increased after clonazepam. Four of the patients (13.3%) reported mild to moderate adverse events, which were similar between the two groups. CONCLUSION: Four weeks of clonazepam, but not PR melatonin, improved RWA. RBD symptom improvement tended to be better after clonazepam than PR melatonin in exchange for increased depressive symptoms and daytime sleepiness. CLINICALTRIALS: gov identifier: NCT03255642 (first submitted August 21, 2017).

REM behavior disorder: When Parkinson's disease meets Morpheus.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by the absence of normal muscle atonia during REM sleep, resulting in excessive motor activity while dreaming. RBD can be classified as isolated which is the strongest clinical marker of prodromal synucleinopathy, or secondary, associated with other neurological diseases, mainly Parkinson's disease (PD) and dementia with Lewy bodies. The diagnosis of RBD must be systematically documented by a video polysomnography in the case of isolated RBD. PD associated with RBD may represent a distinct phenotype compared to PD without RBD, indicating a more severe and widespread synucleinopathy. Clinically, it is associated with poorer motor and cognitive performance, more severe non-motor symptoms, and faster disease progression. Imaging studies have revealed broader brain damage and significant alterations in cerebral metabolism and neurotransmission in PD patients with RBD. The management of RBD involves safety precautions and pharmacotherapy. Safety measures aim to minimize the risk of injury during RBD episodes and include creating a safe sleeping environment and separating the patient from their bed partner if necessary. Pharmacotherapy options include clonazepam and melatonin. Clonazepam must be cautiously prescribed in older patients due to potential side effects.

A systematic review of treatment for patients with burning mouth syndrome.

BACKGROUND: Burning mouth syndrome is a chronic idiopathic intractable intraoral dysaesthesia that remains a challenge to clinicians due to its poorly understood pathogenesis and inconsistent response to various treatments. AIM: This review aimed to study the short- (≤3 months) and long-term (>3 months) effectiveness and sustainable benefit of different burning mouth syndrome treatment strategies and the associated side effects. MATERIALS AND METHODS: Randomised controlled trials of burning mouth syndrome treatment compared with placebo or other interventions with a minimum follow up of 2 months were searched from the PubMed, Embase and Cochrane database (published to July 2020). RESULTS: Twenty-two studies were selected based on the inclusion and exclusion criteria and analysed. Nine categories of burning mouth syndrome treatment were identified: Anticonvulsant and antidepressant agents, phytomedicine and alpha lipoic acid supplements, low-level laser therapy, saliva substitute, transcranial magnetic stimulation, and cognitive behaviour therapy. Cognitive behaviour therapy, topical capsaicin and clonazepam, and laser therapy demonstrated favourable outcome in both short- and long-term assessment. Phytomedicines reported a short-term benefit in pain score reduction. The pooled effect of alpha lipoic acid (ALA) pain score improvement was low, but its positive effects increased in long term assessment. CONCLUSION: A more significant volume in terms of sample size, multi-centres, and multi-arm comparison of therapeutic agents with placebo and longitudinal follow-up studies is recommended to establish a standardised burning mouth syndrome treatment protocol. Further studies are required to assess the analgesic benefits of topical clonazepam and capsaicin, alternative medicines with neurodegenerative prevention capability and psychology support in treating burning mouth syndrome and reducing systemic adverse drug reactions.Registration International Prospective Register of Systematic Reviews (PROSPERO):Protocol ID - CRD42020160892.

Population pharmacokinetics of clonazepam in saliva and plasma: Steps towards noninvasive pharmacokinetic studies in vulnerable populations.

AIM: Traditional studies focusing on the relationship between pharmacokinetics (PK) and pharmacodynamics necessitate blood draws, which are too invasive for children or other vulnerable populations. A potential solution is to use noninvasive sampling matrices, such as saliva. The aim of this study was to develop a population PK model describing the relationship between plasma and saliva clonazepam kinetics and assess whether the model can be used to determine trough plasma concentrations based on saliva samples. METHODS: Twenty healthy subjects, aged 18-30, were recruited and administered 0.5 or 1 mg of clonazepam solution. Paired plasma and saliva samples were obtained until 48 hours post-dose. A population pharmacokinetic model was developed describing the PK of clonazepam in plasma and the relationship between plasma and saliva concentrations. Bayesian maximum a posteriori optimization was applied to estimate the predictive accuracy of the model. RESULTS: A two-compartment distribution model best characterized clonazepam plasma kinetics with a mixture component on the absorption rate constants. Oral administration of the clonazepam solution caused contamination of the saliva compartment during the first 4 hours post-dose, after which the concentrations were driven by the plasma concentrations. Simulations demonstrated that the lower and upper limits of agreements between true and predicted plasma concentrations were -28% to 36% with one saliva sample. Increasing the number of saliva samples improved these limits to -18% to 17%. CONCLUSION: The developed model described the salivary and plasma kinetics of clonazepam, and could predict steady-state trough plasma concentrations based on saliva concentrations with acceptable accuracy.

Modulatory effect of long-term treatment with escitalopram and clonazepam on the expression of anxiety-related neuropeptides: neuromedin U, neuropeptide S and their receptors in the rat brain.

BACKGROUND: Newly identified multifunctional peptidergic modulators of stress responses: neuromedin U (NMU) and neuropeptide S (NPS) are involved in the wide spectrum of brain functions. However, there are no reports dealing with potential molecular relationships between the action of diverse anxiolytic or antidepressant drugs and NMU and NPS signaling in the brain. The present work was therefore focused on local expression of the aforementioned stress-related neuropeptides in the rat brain after long-term treatment with escitalopram and clonazepam. METHODS: Studies were carried out on adult, male Sprague-Dawley rats that were divided into 3 groups: animals injected with saline (control) and experimental individuals treated with escitalopram (at single dose 5 mg/kg daily), and clonazepam (at single dose 0.5 mg/kg). All individuals were sacrificed under anaesthesia and the whole brain excised. Total mRNA was isolated from homogenized samples of amygdala, hippocampus, hypothalamus, thalamus, cerebellum and brainstem. Real time-PCR method was used for estimation of related NPS, NPS receptor (NPSR), NMU, NMU and receptor 2 (NMUR2) mRNA expression. The whole brains were also sliced for general immunohistochemical assessment of the neuropeptides expression. RESULTS: Chronic administration of clonazepam resulted in an increase of NMU mRNA expression and formation of NMU-expressing fibers in the amygdala, while escitalopram produced a significant decrease in NPSR mRNA level in hypothalamus. Long-term escitalopram administration affects the local expression of examined neuropeptides mRNA in a varied manner depending on the brain structure. CONCLUSIONS: Pharmacological effects of escitalopram may be connected with local at least partially NPSR-related alterations in the NPS/NMU/NMUR2 gene expression at the level selected rat brain regions. A novel alternative mode of SSRI action can be therefore cautiously proposed.

Is quetiapine effective for obsessive and compulsive symptoms in patients with bipolar disorder? A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: The aim of this study is to examine the effects of quetiapine as an adjuvant treatment for obsessive-compulsive (OC) symptoms in patients with bipolar disorder (BD) type I. METHODS: In this 8-week double-blind placebo-controlled randomized clinical trial, 47 patients with BD in euthymic phase that had OC symptoms were randomly allocated to receive either quetiapine or placebo plus their routine medications (lithium + clonazepam). Yale-Brown Obsessive-Compulsive Scale (YBOCS) was used to assess the outcomes. Adverse effects were also recorded. RESULTS: Of 47 BD patients with OC symptoms that were randomly allocated in two groups of quetiapine (n = 24) and placebo group (n = 23), 40 patients (20 in quetiapine group and 20 in placebo group) completed the trial. Throughout the trial, the mean score of YBOCS in the quetiapine group dropped from 24.37 ± 1.51 to 15.26 ± 1.16 (P < .001) and in the placebo group decreased from 24.21 ± 1.33 to 23.94 ± 1.66 (P = 1.97). At the end of the study, 12 (60%) patients in the quetiapine group and 1 (5%) patient in the placebo group had more than 34% decline in YBOCS score (P < .001). No serious adverse effects were reported in two groups. CONCLUSIONS: Our double-blind placebo-controlled clinical trial showed that quetiapine may be an effective adjuvant agent for reducing OC symptoms in BD patients.

Clonazepam monotherapy for treating people with newly diagnosed epilepsy.

BACKGROUND: Epilepsy is one of the most common neurological disorders worldwide, with an age-adjusted prevalence of 4 to 8 per 1000 population and an age-adjusted incidence of 44 per 100,000 person-years in developed countries. Monotherapy represents the best therapeutic option in people with newly diagnosed epilepsy. This is an updated version of the original Cochrane Review published in 2019, Issue 11. OBJECTIVES: To assess the efficacy and tolerability of oral clonazepam used as monotherapy for newly diagnosed epilepsy, compared with placebo or a different anti-seizure medication. SEARCH METHODS: For the latest update of this review we searched the following databases on 14 September 2021: the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) (1946 to 13 September 2021). CRS Web includes randomized controlled trials (RCTs) or quasi-RCTs from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups, including Epilepsy. SELECTION CRITERIA: We included RCTs or quasi-RCTs comparing oral clonazepam used as monotherapy treatment versus placebo or a different anti-seizure medication (active comparator) in people of any age with newly diagnosed epilepsy, defined according to the clinical practical definition proposed by the International League Against Epilepsy (ILAE). DATA COLLECTION AND ANALYSIS: The following outcomes were considered: proportion of participants seizure-free at one, three, six, 12, and 24 months after randomization; proportion of responders (those with at least a 50% reduction in seizure frequency from baseline to end of treatment); proportion of participants with treatment-emergent adverse events (TEAEs) during the treatment period or leading to discontinuation during the treatment period; proportion of dropouts/withdrawals due to side effects, lack of efficacy or other reasons; and improvement in quality of life, as assessed by validated and reliable rating scales. Two review authors independently screened all titles and abstracts to assess the eligibility of publications identified by the searches. We independently extracted data from trial reports and cross-checked them for accuracy. Any disagreements between the two authors regarding data extraction were resolved by discussion and consensus. We scrutinized trials and evaluated the methodological quality of all included studies. We used GRADE assessment criteria to evaluate the certainty of the evidence. MAIN RESULTS: Two randomized controlled trials had already been included in the previous version of the review, with a total of 115 participants. One study compared clonazepam to carbamazepine as monotherapy for participants with newly diagnosed psychomotor epilepsy (a condition corresponding to what is now termed mesial temporal lobe epilepsy). One study (published as an abstract) compared clonazepam to ethosuximide as monotherapy for children with absence seizures. Based on the available data and the details on methodology provided, we judged both studies as being at unclear or high risk of bias for the domains assessed (apart from the selective reporting (reporting bias) domain - we judged one study as being at low risk of bias and the other study at high risk of bias). In the study comparing clonazepam to carbamazepine, no difference was found between the groups regarding the proportion of participants who were seizure-free at one month after randomization (risk ratio (RR) 1.97, 95% confidence interval (CI) 0.99 to 3.94; 30 participants; very low-certainty evidence), three months after randomization (RR 1.19, 95% CI 0.62 to 2.29; 26 participants; very low-certainty evidence), and six months after randomization (RR 0.50, 95% CI 0.09 to 2.73; 9 participants; very low-certainty evidence). No statistical difference was found between clonazepam and carbamazepine in terms of proportion of participants with TEAEs leading to discontinuation (RR 2.61, 95% CI 0.80 to 8.52; 36 participants; very low-certainty evidence) and in terms of dropouts/withdrawals due to side effects, lack of efficacy or other reasons (RR 1.56, 95% CI 0.61 to 4.02; 36 participants; very low-certainty evidence). The study did not provide any information on our other prespecified outcomes of interest. The study comparing clonazepam to ethosuximide did not provide any data on efficacy. The proportion of dropouts/withdrawal was higher in the group receiving clonazepam compared to the group receiving ethosuximide (RR 3.63, 95% CI 1.12 to 11.74; 79 participants; very low-certainty evidence). No information on other outcomes of interest was provided in this study. AUTHORS' CONCLUSIONS: We did not find any new studies since the last version of this review. There is only limited and very low-certainty evidence from randomized controlled trials on the efficacy and tolerability of clonazepam used in monotherapy for the treatment of epilepsy. No difference in efficacy and tolerability was found in a small trial comparing clonazepam to carbamazepine for the treatment of mesial temporal lobe epilepsy. Clonazepam was less well tolerated than ethosuximide in a trial of children with absence seizures, however no comparative data on efficacy were provided. There is currently insufficient evidence to support the use of clonazepam as monotherapy treatment for epilepsy.

Safety and efficacy of melatonin, clonazepam, and trazodone in patients with Parkinson's disease and sleep disorders: a randomized, double-blind trial.

BACKGROUND: Sleep disturbances are common non-motor symptoms of Parkinson's disease (PD). We aimed to compare the safety and efficacy of trazodone with melatonin and clonazepam in patients with PD and sleep complaints. METHODS: This single-center, double-blind, randomized clinical trial was conducted on PD patients with subjective sleep complaints. Eligible patients were randomized 1:1:1 to receive melatonin 3 mg/day, clonazepam 1 mg/day, or trazodone 50 mg/day for 4 weeks. The primary outcome measure was the changes in Pittsburgh Sleep Quality Index (PSQI) scores. The mean change in Epworth Sleepiness Scale (ESS) and RBD screening questionnaire (RBDSQ) was considered as the secondary outcome measures. RESULTS: A total of 112 eligible patients were randomized and 93 participants, melatonin (n = 31), trazodone (n = 31), and clonazepam (n = 31), completed the study. There was a significant decrease in PSQI scores after 4 weeks of treatment in all groups. The mean changes of PSQI from baseline were similar among the treatment arms (P = 0.325). Mean changes of RBDSQ and ESS from baseline were significantly different between study arms (P < 0.05). Melatonin intake was associated with a higher decrease in RBDSQ score compared to trazodone (P = 0.011) and clonazepam (P = 0.004). Trazodone intake was associated with a higher decrease in ESS score compared to clonazepam (P = 0.010). Mild adverse events were reported in three patients in the clonazepam, two patients in the trazodone group, and none in the melatonin group. CONCLUSIONS: Trazodone 50 mg/day, clonazepam 1 mg/day, and melatonin 3 mg/day were all tolerable and effective in improving sleep quality in patients with PD. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (registration number; IRCT20170821035819N2).

Postinfectious SARS-CoV-2 Opsoclonus-Myoclonus-Ataxia Syndrome.

BACKGROUND: The opsoclonus-myoclonus-ataxia syndrome (OMAS) represents a pathophysiology and diagnostic challenge. Although the diverse etiologies likely share a common mechanism to generate ocular, trunk, and limb movements, the underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication, and thus, the outcome depends on identifying the trigger mechanism. A recent hypothesis suggests increased GABAA receptor sensitivity in the olivary-oculomotor vermis-fastigial nucleus-premotor saccade burst neuron circuit in the brainstem. Therefore, OMAS management will focus on immunosuppression and modulation of GABAA hypersensitivity with benzodiazepines. METHODS: We serially video recorded the eye movements at the bedside of 1 patient with SARS-CoV-2-specific Immunoglobulin G (IgG) serum antibodies, but twice-negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR). We tested cerebrospinal fluid (CSF), serum, and nasopharyngeal samples. After brain MRI and chest, abdomen, and pelvis CT scans, we treated our patient with clonazepam and high-dose Solu-MEDROL, followed by a rituximab infusion after her formal eye movement analysis 10 days later. RESULTS: The recordings throughout her acute illness demonstrated different eye movement abnormalities. While on high-dose steroids and clonazepam, she initially had macrosaccadic oscillations, followed by brief ocular flutter during convergence the next day; after 10 days, she had bursts of opsoclonus during scotopic conditions with fixation block but otherwise normal eye movements. Concern for a suboptimal response to high-dose Solu-MEDROL motivated an infusion of rituximab, which induced remission. An investigation for a paraneoplastic etiology was negative. CSF testing showed elevated neuron-specific enolase. Serum IgG to Serum SARS-CoV2 IgG was elevated with negative RT-PCR nasopharyngeal testing. CONCLUSION: A recent simulation model of macrosaccadic oscillations and OMAS proposes a combined pathology of brainstem and cerebellar because of increased GABAA receptor sensitivity. In this case report, we report 1 patient with elevated CSF neuronal specific enolase, macrosaccadic oscillations, ocular flutter, and OMAS as a SARS-CoV-2 postinfectious complication. Opsoclonus emerged predominantly with fixation block and suppressed with fixation, providing support to modern theories on the mechanism responsible for these ocular oscillations involving cerebellar-brainstem pathogenesis.