clonazepam

Recently, sexual assaults have included the use of benzodiazepines to impair the victim. Our aim was to examine the physiological, cognitive, and behavioral effects of flunitrazepam (FN) and clonazepam (CLO). In the first study, ten healthy volunteers received a single oral dose of 2 mg of FN. Mini Mental State Examination (MMSE), behavioral reports and staff observations were then collected. In the second study, ten healthy volunteers received a single oral dose of 3 mg of CLO. Vital signs, performance on the MMSE and Digit Symbol Substitution Test, and behavioral changes were examined. FN significantly decreased systolic and diastolic blood pressure 4 h post drug ingestion with diastolic remaining low at 6 h. CLO was associated with changes in temperature and decreased systolic pressure. FN affected memory and attention 4 h following ingestion. CLO affected memory and attention throughout the study (6 h), and psychomotor performance was decreased 2 h post ingestion. In both studie...

To describe a distinct parasomnia involving sexual behaviour, which we have named sexsomnia. We have used a case series as a basis for the description of sexsomina. Eleven patients with distinct behaviours of the sexual nature during sleep are described. The features in common with other nonrapid eye movement arousal parasomnias, such as sleepwalking are documented. Some patients had simply been referred to a tertiary sleep clinic for investigation of unrelated sleep problems. A small number had been involved in medicolegal issues. Sexsomnia has some distinct features that separate it from sleepwalking. The automatic arousal is more prominent, motor activities are relatively restricted and specific, and some form of dream mentation is often present. A significant number of patients with this unusual parasomnia behaviour were identified only after specific questions were asked, suggesting that the behaviour is more common than previously thought.

Objectives: An accurate and precise spectrofluorimetric method was developed and validated for the determination of non-selective adrenergic drug named; oxymetazoline hydrochloride (OMZ) in its pure form and nasal drops. Method: Based on nucleophilic substitution reaction of target drug with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) to form a highly fluorescent fluorophore with emission measured at 543 nm after excitation at 400 nm. Results: Under optimum conditions, the proposed method obeys Beer's law in the range of (1-12 µg mL-1) and the reaction mechanism was presented. Conclusion: The method was validated according to ICH guidelines for accuracy, precision and was successfully applied for the determination of the drug in its pure form and nasal drops. The obtained results were statistically compared with those of the reported method and found to be in good agreement.

A rapid, sensitive and specific method for quantifying clonazepam in human plasma using diazepam as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by liquid-liquid extraction using a hexane/diethylether (20 : 80, v/v) solution. The extracts were analysed by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS-MS). Chromatography was performed on a Jones Genesis C8 4 µm analytical column (100 × 2.1 mm i.d.). The method had a chromatographic run time of 3.0 min and a linear calibration curve over the range 0.5-50 ng/ml (r2 >0.9965). The limit of quantification was 0.5 ng/ml. This HPLC/MS/MS procedure was used to assess the bioequivalence of two clonazepam 2 mg tablet formulations (clonazepam test formulation from Ranbaxy Laboratories Ltd and Rivotril from Roche Laboratórios Ltda as standard reference formulation).

Introduction Atrial fibrillation (AF) is a common cardiac arrhythmia that predicts stroke and death. Current treatments have risk, and insufficient benefits for rhythm control, stroke and mortality. Panic Disorder (PD) epidemiologically predicts AF and stroke. Methods On incidental observation, one clonazepam treated PD patient also had cessation of paroxysmal AF. Consequent review of other patients with DSM5 PD, fixed-dose clonazepam PD treatment, and cardiologist confirmed AF thus allowed examination of AF response, and of nonresponder characteristics. Results Seven of the eleven patients were clonazepam responders, with apparent major or full reduction of both PD and AF. All had paroxysmal lone (idiopathic) AF without antiarrhythmic medication. Of four AF nonresponders, three had only modest PD control, two had structural heart disease, and three were on procainamide. None of the seven responders had any of these characteristics. AF onset age never preceded PD onset age. Clonazepam doses were 1-5 mg daily (divided doses q8h or q12h). Conclusion This case series suggests the novel and potentially significant observation that clonazepam might produce AF improvement in some patients with PD and lone AF.

This study was performed to evaluate the optimal doses and clinical efficacy of clonazepam as a first-line drug in acute mania, as well as to determine its effective plasma concentrations. Clonazepam was administered orally to 11 newly admitted inpatients. On day 0, the loading dose was ...

To describe a distinct parasomnia involving sexual behaviour, which we have named sexsomnia. We have used a case series as a basis for the description of sexsomina. Eleven patients with distinct behaviours of the sexual nature during sleep are described. The features in common with other nonrapid eye movement arousal parasomnias, such as sleepwalking are documented. Some patients had simply been referred to a tertiary sleep clinic for investigation of unrelated sleep problems. A small number had been involved in medicolegal issues. Sexsomnia has some distinct features that separate it from sleepwalking. The automatic arousal is more prominent, motor activities are relatively restricted and specific, and some form of dream mentation is often present. A significant number of patients with this unusual parasomnia behaviour were identified only after specific questions were asked, suggesting that the behaviour is more common than previously thought.

ABSTRACTBackground: The use of benzodiazepines is associated with increased risk of fall-related injuries in the elderly. However, it is unclear if the risks vary across the products and how they depend on the pattern of use and dosage. Specifically, the possibility of cumulative effects of past benzodiazepine use has not been thoroughly investigated.Methods: We used the administrative database for a cohort of 23,765 new users of benzodiazepines, aged 65 years and older, in Quebec, Canada, between 1990 and 1994. The associations between the use of seven benzodiazepines and the risk of fall-related injuries were assessed using several statistical models, including a novel weighted cumulative exposure model. That model assigns to each dose taken in the past a weight that represents the importance of that dose in explaining the current risk of fall.Results: For flurazepam, the best-fitting model indicated a cumulative effect of doses taken in the last two weeks. Uninterrupted use of fl...

Recent reports have supported the innovative use of clonazepam in the treatment of various psychiatric conditions. This report alerts clinicians that, although helpful in some patients, clonazepam can cause behavioral disinhibition and worsening of symptoms in other patients. Recent reports in the literature have supported the innovative use of clonazepam, a high-potency benzodiazepine, in the treatment of various psychiatric conditions, including mania [1,2], schizoaffective disorder [2,3], and panic disorder [4]. There have been reports [5-81 of behavioral disinhibition with other benzodiazepines, so it could be expected that the same effect might be seen with clonazepam [lo]

Solubility of drugs in binary and ternary solvent mixtures composed of water and pharmaceutical cosolvents at different temperatures were predicted using the Jouyban-Acree model and a combination of partial solubility parameters as interaction descriptors in the solution. The generally trained version of the model produced the overall mean percentage deviation values for the back-calculated solubility of drugs in binary solvents of 34.3% and the predicted solubilities in ternary solvent mixtures of 38.0%. In addition, the applicability of the trained model for predicting the solvent composition providing the maximum solubility of a drug was investigated. The results of collected solubility data of drugs in various mixed solvents and the newly measured solubility data of five drugs in ethanol + propylene glycol + water mixtures at 25 • C showed that the model provided acceptable predictions and could be used in the pharmaceutical industry.

Aim of this work is to prepare poly(DL-lactide-co-glycolide) (PLGA) nanoparticles by dialysis method without surfactant and to investigate drug loading capacity and drug release. The size of PLGA nanoparticles was 269.9+118.7 nm in intensity average and the morphology of PLGA nanoparticles was spherical shape from the observation of SEM and TEM. In the effect of drug loading contents on the particle size distribution, PLGA nanoparticles were monomodal pattern with narrow size distribution in the empty and lower drug loading nanoparticles whereas bi-or trimodal pattern was showed in the higher drug loading ones. Release of clonazepam from PLGA nanoparticles with higher drug loading contents was slower than that with lower loading contents.

The purpose of this study was to characterize the nature of the relation between periodic leg movements during sleep (PLMS) and cortical arousals to contribute to the debate on the clinical significance and treatment of PLMS. Methods: A prospective, placebo-controlled, single-blind, parallel group study was carried out including 46 drugnaive patients with idiopathic restless legs syndrome (RLS). Each patient underwent 2 consecutive full-night polysomnographic studies. The first night was the baseline night. Prior to the second night, 1 group received a single oral dose of 0.25mg pramipexole, whereas a second group received a single oral dose of 0.5mg clonazepam, and the remaining patients received placebo. Sleep stages, cyclic alternating pattern (CAP), and leg movement activity were scored following standard criteria; symptoms of RLS were also assessed. Results: Pramipexole suppressed PLMS without affecting electroencephalographic (EEG) instability (CAP) and arousals (corresponding to CAP A3 and, partially, A2 subtypes), whereas clonazepam did the opposite, reducing non-rapid eye movement sleep EEG instability without effects on PLMS. Both drugs were effective on sensory RLS symptoms. Interpretation: This study demonstrates that a selective pharmacological approach can disconnect PLMS from arousal events, suggesting an indirect relation between each other. These results might weaken the hypothesis of a direct pathological role of PLMS in sleep disruption and can be important for the discussion on the existence of a distinct entity called periodic limb movements disorder. Moreover, the study opens the doors to the possibility of a joint treatment for RLS targeting sensory and motor symptoms, as well as sleep instability.

This long-term extension of an 8-week randomized, naturalistic study in patients with panic disorder with or without agoraphobia compared the efficacy and safety of clonazepam (n = 47) and paroxetine (n = 37) over a 3-year total treatment duration. Target doses for all patients were 2 mg/d clonazepam and 40 mg/d paroxetine (both taken at bedtime). This study reports data from the long-term period (34 months), following the initial 8-week treatment phase. Thus, total treatment duration was 36 months. Patients with a good primary outcome during acute treatment continued monotherapy with clonazepam or paroxetine, but patients with partial primary treatment success were switched to the combination therapy. At initiation of the long-term study, the mean doses of clonazepam and paroxetine were 1.9 (SD, 0.30) and 38.4 (SD, 3.74) mg/d, respectively. These doses were maintained until month 36 (clonazepam 1.9 [SD, 0.29] mg/d and paroxetine 38.2 [SD, 3.87] mg/d). Long-term treatment with clonazepam led to a small but significantly better Clinical Global Impression (CGI)YImprovement rating than treatment with paroxetine (mean difference: CGI-Severity scale j3.48 vs j3.24, respectively, P = 0.02; CGI-Improvement scale 1.06 vs 1.11, respectively, P = 0.04). Both treatments similarly reduced the number of panic attacks and severity of anxiety. Patients treated with clonazepam had significantly fewer adverse events than those treated with paroxetine (28.9% vs 70.6%, P G 0.001). The efficacy of clonazepam and paroxetine for the treatment of panic disorder was maintained over the long-term course. There was a significant advantage with clo-nazepam over paroxetine with respect to the frequency and nature of adverse events.

Mitochondrial calcium (Ca(2+)) dyshomeostasis constitutes a critical step in the metabolic crossroads leading to cell death. Therefore, we have studied here whether 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP37157; CGP), a blocker of the mitochondrial Na(+)/Ca(2+)-exchanger (mNCX), protects against veratridine-elicited chromaffin cell death, a model suitable to study cell death associated with Ca(2+) overload. Veratridine produced a concentration-dependent cell death, measured as lactate dehydrogenase released into the medium after a 24-h incubation period. CGP rescued cells from veratridine-elicited death in a concentration-dependent manner; its EC(50) was approximately 10 microM, and 20 to 30 microM caused near 100% cytoprotection. If preincubated for 30 min and washed out for 3 min before adding veratridine, CGP still afforded significant cytoprotection. At 30 microM, CGP blocked the veratridine-elicited free radical production, mitochondrial depolar...

Summary of Recommendations:Modifying the sleep environment is recommended for the treatment of patients with RBD who have sleep-related injury. Level AClonazepam is suggested for the treatment of RBD but should be used with caution in patients with dementia, gait disorders, or concomitant OSA. Its use should be monitored carefully over time as RBD appears to be a precursor to neurodegenerative disorders with dementia in some patients. Level BClonazepam is suggested to decrease the occurrence of sleep-related injury caused by RBD in patients for whom pharmacologic therapy is deemed necessary. It should be used in caution in patients with dementia, gait disorders, or concomitant OSA, and its use should be monitored carefully over time. Level BMelatonin is suggested for the treatment of RBD with the advantage that there are few side effects. Level BPramipexole may be considered to treat RBD, but efficacy studies have shown contradictory results. There is little evidence to support the use of paroxetine or L-DOPA to treat RBD, and some studies have suggested that these drugs may actually induce or exacerbate RBD. There are limited data regarding the efficacy of acetylcholinesterase inhibitors, but they may be considered to treat RBD in patients with a concomitant synucleinopathy. Level CThe following medications may be considered for treatment of RBD, but evidence is very limited with only a few subjects having been studied for each medication: zopiclone, benzodiazepines other than clonazepam, Yi-Gan San, desipramine, clozapine, carbamazepine, and sodium oxybate. Level CCitation:Aurora RN; Zak RS; Maganti RK; Auerbach SH; Casey KR; Chowdhuri S; Karippot A; Ramar K; Kristo DA; Morgenthaler TI. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med 2010;6(1):85-95.

The present study is an unsubstantiated qualitative assessment of the abused drugs-tramadol and clonazepam. The aim of this study is to evaluate whether the effects of tramadol, clonazepam, and their combination on mitochondrial electron transport chain (ETC) complexes were influential at therapeutic or at progressively increasing doses. The study comprised of a total of 70 healthy male rats, aged 3 months. According to the drug intake regimen, animals were divided into seven groups: control, tramadol therapeutic, clonazepam therapeutic, combination therapeutic, tramadol abuse, clonazepam abuse, and combination abuse group. At the end of the experiment, brain mitochondrial ETC complexes (I, II, III, and IV) were evaluated. Histopathological examinations were also performed on brain tissues. The results showed that groups that received tramadol (therapeutic and abuse) suffered from weight loss. Tramadol abuse group and combination abuse group showed significant decrease in the activi...

Background: Whether mitochondrial Ca 2ϩ extrusion is mediated by NCLX (mitochondrial sodium/calcium exchanger) or LETM1 (leucine zipper-EF-hand-containing transmembrane protein 1) and controls matrix redox state is unknown. Results: NCLX, but not LETM1, increases Ca 2ϩ extrusion, limits NAD(P)H production, and promotes matrix oxidation. Conclusion: NCLX controls the duration of matrix Ca 2ϩ elevations and their impact on redox signaling. Significance: NCLX is a potential target for the treatment of redox-dependent diseases. Mitochondria capture and subsequently release Ca 2؉ ions, thereby sensing and shaping cellular Ca 2؉ signals. The Ca 2؉ uniporter MCU mediates Ca 2؉ uptake, whereas NCLX (mitochondrial Na/Ca exchanger) and LETM1 (leucine zipper-EFhand-containing transmembrane protein 1) were proposed to exchange Ca 2؉ against Na ؉ or H ؉ , respectively. Here we study the role of these ion exchangers in mitochondrial Ca 2؉ extrusion and in Ca 2؉-metabolic coupling. Both NCLX and LETM1 proteins were expressed in HeLa cells mitochondria. The rate of mitochondrial Ca 2؉ efflux, measured with a genetically encoded indicator during agonist stimulations, increased with the amplitude of mitochondrial Ca 2؉ ([Ca 2؉ ] mt) elevations. NCLX overexpression enhanced the rates of Ca 2؉ efflux, whereas increasing LETM1 levels had no impact on Ca 2؉ extrusion. The fluorescence of the redox-sensitive probe roGFP increased during [Ca 2؉ ] mt elevations, indicating a net reduction of the matrix. This redox response was abolished by NCLX overexpression and restored by the Na ؉ /Ca 2؉ exchanger inhibitor CGP37157. The [Ca 2؉ ] mt elevations were associated with increases in the autofluorescence of NAD(P)H, whose amplitude was strongly reduced by NCLX overexpression, an effect reverted by Na ؉ / Ca 2؉ exchange inhibition. We conclude that NCLX, but not LETM1, mediates Ca 2؉ extrusion from mitochondria. By controlling the duration of matrix Ca 2؉ elevations, NCLX contributes to the regulation of NAD(P)H production and to the conversion of Ca 2؉ signals into redox changes. Ca 2ϩ is a versatile intracellular messenger controlling most cellular processes. In order to maintain normal signaling function, tight spatial/temporal control of Ca 2ϩ is essential. To achieve such tight regulation, cells are equipped with a number of proteins mediating the transport of Ca 2ϩ across the plasma membrane, the endoplasmic reticulum, and the inner mitochondrial membrane (1). Mitochondria contribute to the shaping of Ca 2ϩ signals through Ca 2ϩ uptake and release (2-9). At the same time, the associated [Ca 2ϩ ] mt 3 transients act as signals to stimulate energy metabolism. The amplitude and duration of [Ca 2ϩ ] mt elevations reflect the balance between uptake and release mechanisms (10-13). Uptake is performed by the recently identified mitochondrial Ca 2ϩ uniporter (MCU) (14, 15), whose activity is tightly controlled by the regulatory molecules MICU1, MICU2, MCUR1, and EMRE (16-19). The MCU forms a channel with high selectivity but low affinity for Ca 2ϩ (10, 20). Despite this low affinity, mitochondria can accumulate large amounts of Ca 2ϩ during cell stimulation when exposed to microdomains of high Ca 2ϩ concentration (21), forming in the vicinity of intracellular Ca 2ϩ release or plasma membrane Ca 2ϩ entry channels (22, 23). Mitochondrial Ca 2ϩ uptake activates several Ca 2ϩ-dependent matrix enzymes that stimulate energy metabolism (24, 25) and ATP synthase-dependent respiration (26). Prolonged (pathological) accumulation of Ca 2ϩ in the matrix space can lead to mitochondrial Ca 2ϩ overload, followed by mitochondrial permeability transition pore opening (27-29), resulting in the activation of cell death signals (30, 31). To avoid this transition from stimulatory to detrimental effects of Ca 2ϩ , mitochondria possess two membrane systems to extrude Ca 2ϩ : the Na ϩ /Ca 2ϩ exchanger and the H ϩ /Ca 2ϩ exchanger (5, 6). Two mitochondrial inner membrane proteins, namely NCLX (32) (sodium/calcium exchanger protein, mitochondrial; or sodium/ potassium/calcium exchanger 6, mitochondrial; or solute carrier family 24 member 6) and LETM1 (33) (LETM1 and EF

Mitochondria play a major role in cellular calcium homeostasis. Despite decades of studies, the molecules that mediate and regulate the transport of calcium ions in and out of the mitochondrial matrix remain unknown. Here, we investigate whether SLP-2, an inner membrane mitochondrial protein of unknown function, modulates the activity of mitochondrial Ca 2+ transporters. In HeLa cells depleted of SLP-2, the amplitude and duration of mitochondrial Ca 2+ elevations evoked by agonists were decreased compared to control cells. SLP-2 depletion increased the rates of calcium extrusion from mitochondria. This effect disappeared upon Na + removal or addition of CGP-37157, an inhibitor of the mitochondrial Na + /Ca 2+ exchanger, and persisted in permeabilized cells exposed to a fixed cytosolic Na + and Ca 2+ concentration. The rates of mitochondrial Ca 2+ extrusion were prolonged in SLP-2 over-expressing cells, independently of the amplitude of mitochondrial Ca 2+ elevations. The amplitude of cytosolic Ca 2+ elevations was increased by SLP-2 depletion and decreased by SLP-2 over-expression. These data show that SLP-2 modulates mitochondrial calcium extrusion, thereby altering the ability of mitochondria to buffer Ca 2+ and to shape cytosolic Ca 2+ signals.

Mitochondria dynamically buffer cytosolic Ca(2+) in cardiac ventricular cells and this affects the Ca(2+) load of the sarcoplasmic reticulum (SR). In sinoatrial-node cells (SANC) the SR generates periodic local, subsarcolemmal Ca(2+) releases (LCRs) that depend upon the SR load and are involved in SANC automaticity: LCRs activate an inward Na(+)-Ca(2+) exchange current to accelerate the diastolic depolarization, prompting the ensemble of surface membrane ion channels to generate the next action potential (AP). To determine if mitochondrial Ca(2+) (Ca(2+) (m)), cytosolic Ca(2+) (Ca(2+) (c))-SR-Ca(2+) crosstalk occurs in single rabbit SANC, and how this may relate to SANC normal automaticity. Inhibition of mitochondrial Ca(2+) influx into (Ru360) or Ca(2+) efflux from (CGP-37157) decreased [Ca(2+)](m) to 80 ± 8% control or increased [Ca(2+)](m) to 119 ± 7% control, respectively. Concurrent with inhibition of mitochondrial Ca(2+) influx or efflux, the SR Ca(2+) load, and LCR size, dura...

Dystonia of the limbs may be due to a wide range of aetiologies and may cause major functional limitation. We investigated whether the previously described pathological 4 to 7 Hz drive to muscles in cervical dystonia is present in patients with aetiologically different types of dystonia of the upper and lower limbs. To this end, we studied 12 symptomatic and 4 asymptomatic carriers of the DYT1 gene, 6 patients with symptomatic dystonia due to focal basal ganglia lesions, and 11 patients with fixed dystonia, a condition assumed to be mostly psychogenic in aetiology. We evaluated EMG-EMG coherence in the tibialis anterior (TA) of these and 15 healthy control subjects. Ten of 12 (83%) of symptomatic DYT1 patients had an excessive 4 to 7 Hz common drive to TA, evident as an inflated coherence in this band. This drive also involved the gastrocnemius, leading to co-contracting electromyographic bursts. In contrast, asymptomatic DYT1 carriers, patients with symptomatic dystonia, patients with fixed dystonia, and healthy subjects showed no evidence of such a drive or any other distinguishing electrophysiological feature. Moreover, the pathological 4 to 7 Hz drive in symptomatic DYT1 patients was much less common in the upper limb, where it was only present in 2 of 6 (33%) patients with clinical involvement of the arms. We conclude that the nature of the abnormal drive to dystonic muscles may vary according to the muscles under consideration and, particularly, with aetiology.

We report a case of non-familial hyperekplexia which characteristically developed apnea and feeding difficulties in the neonatal period. The abnormal startle response was evident from the second week of life onwards. The infant showed a marked improvement of the startle response and muscle hypertonia with clonazepam. Clobazam was also tried with no apparent response. A prominent long latency C response was observed on EMG examination, suggesting a possible cortical neuronal hyperexcitability origin for the abnormal startle response observed in hyperekplexia.

Background. Burning mouth syndrome (BMS) is a common disorder frequently affecting women past the 5th decade of age. It is characterized by oral burning, mainly involving the tongue, lip, and anterior palate, but without oral lesions or alteration showing in blood tests and/or instrumental findings. Objective. We proposed to exclude alterations due to thyroid function and echographic abnormality in formulating BMS diagnosis. The aim of this study was to propose a blood and instrumental protocol including thyroid function and echography to obtain a correct BMS diagnosis. In the absence of such an assessment, a number of patients with oral burning and hypothyroidism may erroneously be considered BMS patients. Study design. For this study, a group of 123 patients initially diagnosed with BMS was selected, following use of the current preliminary diagnostic protocol for BMS (study group). A further 123 patients with dental problems and without oral burning were selected as a control group. All patients were submitted to further protocol based on a study of their thyroid function and echography. Results. Thirteen control patients showed some thyroid alteration compared with 85 patients of the study group. In relation to these further examinations, a therapeutic protocol based on use of thyroxine, lipoic acid, or clonazepam was applied for patients belonging to the study group. Fifty-eight patients (47%) showed hypothyroidism and were treated with thyroxine, and 37 (64%) of these showed a positive response (VAS 1 and 0). Twenty-seven patients (22%) evinced euthyroidism with an inhomogeneous parenchyma thyroid echographic pattern. These were treated with lipoic acid, and 23 (85%) of them responded positively (VAS 1 and 0). Thirty-eight patients (31%) showed euthyroidism and no echographic alteration. Only these were considered to be true BMS patients and were treated with lipoic acid. Only 10 (26%) of these patients responded positively (VAS 1 and 0). Conclusions. This study reveals that subjects with thyroid alterations are often considered to be BMS patients and that hypothyroidism could be responsible for oral burning and/or dysgeusia in some supertaster subjects. For these reasons, we propose that the study of thyroid function be inserted in the diagnostic process for BMS patients. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:e22-e27)

We describe cervical dystonia occurring in a 31-year-old, previously well, primigravid, primiparous Chinese woman at 4 weeks' amenorrhea, which was ameliorated with low-dose clonazepam and disappeared completely by the end of the second trimester without recurring despite her being tapered off benzodiazepine therapy. Investigations were unremarkable for structural and biochemical causes of dystonia. Chorea, paraballismus, and restless legs syndrome are known to occur during pregnancy, attributable to high estrogen levels. Dystonia, on the other hand, has not been described to occur de novo in pregnancy. This association should be considered in women of reproductive age who present with cervical dystonia.

The withdrawal syndrome from benzodiazepine (BZD) can be severe and in some cases may impede cessation of the use of the drug. We present here a case series of benzodiazepine detoxification by flumazenil infusion, stabilised with clonazepam. Patients were treated with flumazenil 1.35 mg/day for a median of 7 days. Self-reported physical withdrawal symptoms were recorded daily. In addition to flumazenil, antidepressants were given before treatment commenced and clonazepam was administered nightly with both being continued after discharge. Twenty-nine patients were treated. No patients dropped out from the treatment programme. Nine patients (31%) required a temporary reduction/cessation of the infusion. The linear trend in the reduction of the daily withdrawal scores in the overall study population was significant. The linear trends were also significant in the group of patients for whom a temporary reduction/suspension of the flumazenil was required. Six months after treatment, 15 patients (53%) were abstinent from clonazepam and other BZDs. For five (21%) the BZD dependence were reinstated. More than two-thirds of the subjects tolerated the procedure well and about half had a good long term response. Slow flumazenil infusion appears to merit consideration as a possible future treatment. Suggestions for future research are examined.

Contents: Bipolar disorder following a left basal —¿ ganglia stroke/Recruitment for post-natal de pression studies/Tricyclic —¿induced seizures and absent ECT response/Alzheimer's diseaseand Lewy body dementia/Psychiatric morbidity in the relatives ofschizophrenic ...

Data from 12 patients (in two control study groups) provide preliminary results of an ongoing double-blind comparison of clonazepam and imipramine in the treatment of panic disorder. In both treatment groups, the patients' global improvement was substantial over the first few weeks and persisted over the 6-month treatment period based on assessments by the therapist and the patient; side effects were mild. Faintness was slightly more prevalent among patients on clonazepam treatment but disappeared after the first few weeks. Mild, persistent tachycardia was reported among patients receiving imipramine. No tolerance emerged, and discontinuation was successful in 2 patients from each group after 6 months of treatment. Eight patients needed continued medication (25-50 mg/day of imipramine, 0.5-2.0 mg/day of clonazepam) to maintain substantial improvement. Findings confirm earlier reports from open studies that low doses of both drugs eliminate panic attacks (about 50 mg/day for imip...

The authors present four patients displaying panic disorder and a history of epileptic seizures to illustrate difficulties regarding differential diagnosis between epileptic seizures and panic attacks. The cases describe the aversive properties of epileptic seizures, the role of visual seizure-triggering stimuli as phobic cues, and the effectiveness and safety of clomipramine treatment of panic attacks as an adjunct to concurrent antiepileptic medication. Depression and Anxiety 15:190-192, 2002.

Endoplasmic reticulum (ER) Ca 2؉ refilling is an active process to ensure an appropriate ER Ca 2؉ content under basal conditions and to maintain or restore ER Ca 2؉ concentration during/after cell stimulation. The mechanisms to achieve successful ER Ca 2؉ refilling are multiple and built on a concerted action of processes that provide a suitable reservoir for Ca 2؉ sequestration into the ER. Despite mitochondria having been found to play an essential role in the maintenance of capacitative Ca 2؉ entry by buffering subplasmalemmal Ca 2؉ , their contribution to ER Ca 2؉ refilling was not subjected to detailed analysis so far. Thus, this study was designed to elucidate the involvement of mitochondria in Ca 2؉ store refilling during and after cell stimulation. ER Ca 2؉ refilling was found to be accomplished even during continuous inositol 1,4,5-trisphosphate (IP 3)-triggered ER Ca 2؉ release by an agonist. Basically, ER Ca 2؉ refilling depended on the presence of extracellular Ca 2؉ as the source and sarcoplasmic/endoplasmic reticulum Ca 2؉ ATPase (SERCA) activity. Interestingly, in the presence of an IP 3-generating agonist, ER Ca 2؉ refilling was prevented by the inhibition of trans-mitochondrial Ca 2؉ flux by CGP 37157 (7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one) that precludes the mitochondrial Na ؉ /Ca 2؉ exchanger as well as by mitochondrial depolarization using a mixture of oligomycin and antimycin A. In contrast, after the removal of the agonist, ER refilling was found to be largely independent of trans-mitochondrial Ca 2؉ flux. Under these conditions, ER Ca 2؉ refilling took place even without an associated Ca 2؉ elevation in the deeper cytosol, thus, indicating that superficial ER domains mimic mitochondrial Ca 2؉ buffering and efficiently sequester subplasmalemmal Ca 2؉ and consequently facilitate capacitative Ca 2؉ entry. Hence, these data point to different contribution of mitochondria in the process of ER Ca 2؉ refilling based on the presence or absence of IP 3 , which represents the turning point for the dependence or autonomy of ER Ca 2؉ refilling from trans-mitochondrial Ca 2؉ flux.

Considering the physiological Ca2+ dynamics within the ER (endoplasmic reticulum), it remains unclear how efficient protein folding is maintained in living cells. Thus, utilizing the strictly folding-dependent activity and secretion of LPL (lipoprotein lipase), we evaluated the impact of ER Ca2+ content and mitochondrial contribution to Ca2+-dependent protein folding. Exhaustive ER Ca2+ depletion by inhibition of sarcoplasmic/endoplasmic reticulum Ca2+-ATPases caused strong, but reversible, reduction of cell-associated and released activity of constitutive and adenovirus-encoded human LPL in CHO-K1 (Chinese-hamster ovary K1) and endothelial cells respectively, which was not due to decline of mRNA or intracellular protein levels. In contrast, stimulation with the IP3 (inositol 1,4,5-trisphosphate)-generating agonist histamine only moderately and transiently affected LPL maturation in endothelial cells that paralleled a basically preserved ER Ca2+ content. However, in the absence of e...

The central and peripheral effects of clonazepam (central benzodiazepine receptor agonist) on intestinal myoelectricai activity and the origin of the effects were evaluated in conscious rats, chronically fitted with Nichrome electrodes implanted on the jejunum and with an intracerebroventricular (i.c.v.) cannula. Administered intraperitoneally (i.p.) in 12-h fasted rats, clonazepam (0.05 to 0.5 mg/kg) dose dependently disrupted jejunal cyclic migrating myoelectric complexes, characterizing the fasted state, which were replaced by a permanent irregular spiking activity, lasting 259 _+ 37 min for clonazepam at the dose of 0.5 mg/kg. This disruption of migrating myoelectric complexes occurred after a delay which increased with increasing clonazepam doses. In contrast, injected i.c.v, at doses from 1/zg/kg to 1 mg/kg, clonazepam did not alter the migrating myoelectric complexes pattern of the small intestine. Injected i.p., flumazenil (central benzodiazepine receptor antagonist) (1 mg/kg) but not PK 11-195 (peripheral benzodiazepine receptor antagonist) (5 mg/kg) suppressed the effects of i.p. clonazepam (0.1 mg/kg). Administered i.c.v., 10 min prior to clonazepam (0.1 mg/kg i.p.), devazepide (CCK g receptor antagonist) at a dose as low as 10 ng/kg reduced the migrating myoelectric complex disruption induced by clonazepam. L365-260 (CCK B receptor antagonist) administered i.c.v reduced the migrating myoelectric complex disruption at 10-fold higher doses and loxiglumide (CCK A receptor antagonist) injected i.c.v, at 100-fold higher doses. When administered i.p. neither devazepide nor L365-260 affected the duration of migrating myoelectric complex disruption induced by clonazepam (0.1 mg/kg i.p.) or its delay of occurrence at doses lower than 0.1 mg/kg. It is concluded that (i) in a range of therapeutic doses, clonazepam alters the motility of the proximal small intestine in fasted rats and (ii) these effects could result from activation of central type receptors located peripherally and could be mediated through the central release of cholecystokinin (CCK) and/or activation of the central CCK neurons involving CCK A and CCKa receptors.

Most patients remain symptomatic after an initial intervention with approved treatments for generalized social anxiety disorder. This randomized controlled trial provides systematic, prospectively derived data on the relative benefits of "next-step" pharmacotherapies to improve outcomes for individuals with generalized social anxiety disorder who remain symptomatic after initial treatment. This three site, 12-week, double-blind randomized controlled trial compared the relative benefits of three strategies for patients remaining symptomatic (Liebowitz Social Anxiety Scale [LSAS] score >50) after a 10-week trial of sertraline alone: the addition of up to 3.0 mg/day of clonazepam (sertraline plus clonazepam), a switch to up to 225 mg/day of venlafaxine, or prolonged sertraline treatment with placebo (sertraline plus placebo). A total of 397 participants received at least one dose of sertraline; 181 nonresponders (LSAS score >50) at week 10 were randomly assigned to sertraline plus clonazepam, switch to venlafaxine, or sertraline plus placebo. Overall, 21% of patients achieved remission (LSAS score ≤30) at the endpoint, and 27% of patients assigned to sertraline plus clonazepam achieved remission compared with patients assigned to sertraline plus placebo (17%) or venlafaxine (19%), but the differences did not reach significance. Sertraline plus clonazepam was associated with a significantly greater drop in LSAS severity (p=0.020) and disability (p=0.0028) compared with sertraline plus placebo; no significant differences were observed on these parameters between venlafaxine and either sertraline plus placebo or sertraline plus clonazepam. In supplemental analysis, the overall response rate (LSAS score ≤50) was 46%, including a significantly greater proportion of patients in the sertraline plus clonazepam group (56%) compared with the sertraline plus placebo group responding (36%; p=0.027); differences did not reach significance between venlafaxine and sertraline plus placebo or sertraline plus clonazepam. The findings suggest that the clonazepam augmentation strategy provides relative benefits for sertraline nonresponders in social anxiety disorder.

Spontaneous thalamc~:ortical epileptiform activity was elicited in rodent thalamocortical slices by a medium containing no added Mg 2÷. Multiple varieties of activity were generated in these slices, including simple thalamocortical burst complex (sTBC) activity that resembled the spike-wave discharges of generalized absence epilepsy, and complex thalamocortical burst complex (cTBC) activity that resembled generalized tonic-clonic seizure discharges. In a further pharmacological characterization of this activity, the effects of the broad-spectrum anticonvulsants valproic acid, a-methyl-ot-phenylsuccinimide (the active metabolite of methsuximide) and clonazepam were studied. All three drugs were found to be effective in controlling both sTBC and cTBC activity when applied in clinically relevant concentration ranges. The effectiveness of valproic acid against spontaneous rhythms in vitro was not due to augmentation of GABAergic inhibition. No effect of valproic acid on GABA-activated chloride currents was evident in patch-clamp recordings of acutely isolated thalamic or cortical neurons. The equivalent general clinical and experimental spectrum of action of broadly effective anticonvulsants provided an additional correlation between the clinical efficacy of anticonvulsant drugs and their effects against epileptiform discharges in rodent thalamocortical slices. This further validates spontaneous generalized low-Mg 2+ thalamocortical activity as a potentially valuable in vitro model of the primary generalized epilepsies, in which the cellular mechanisms underlying generation and control of these seizure discharges can be studied.

Three patients, aged 71, 50, and 41 years, presented with myoclonic activity arising in the relaxation period preceding sleep onset and causing severe insomnia. Polygraphic studies showed that the myoclonic activity began in spinally innervated muscles, propagating at low speed to rostra1 and caudal muscular segments. Myoclonus arose whenever patients relaxed mentally and showed diffuse electroencephalographic alpha activity and was independent of posture. The jerks disappeared during sleep. Clonazepam afforded symptomatic improvement. Propriospinal myoclonus arising from a spinal generator may be facilitated by changes in supraspinal control related to vigilance levels. When arising during relaxation and drowsiness, it may cause severe insomnia.

Hyperekplexia is an autosomal dominant disorder caused by a point mutation in the a1 subunit of the glycine receptor, characterized by excessive startle responses followed by temporary generalized stiffness. Clonazepam, effective in open case studies, potentiates, through unknown mechanisms, the neurotransmitter g-aminobutyric acid (GABA). Vigabatrin increases GABA by inhibition of the GABA catabolic enzyme GABA-transaminase. Effects of clonazepam (1 mg for 1 day) and vigabatrin (1000 mg per day for 5 days) were investigated in a double-blind placebo-controlled cross-over study in 4 patients with hyperekplexia. The pharmacodynamic parameters were startle reflexes, studied 3 times during the day. At each time, 2 trains of 10 auditive stimuli (113 dB) were given at intervals of 10 and 60 s. Startle movements were quantified with summed areas of EMG-bursts of the orbicularis oculi, sternocleidomastoid, biceps and thenar muscles. The degrees of stiffness and drowsiness were quantified with visual analogue scores (VAS) 10 times during the day, by both the patient and the observer. Clonazepam, but not vigabatrin, reduced startle activity significantly in both paradigms. The degree of stiffness and drowsiness was not significantly influenced by either drug.

Rapid eye movement sleep behaviour disorder is characterized by dream-enacting behaviour and impaired motor inhibition during rapid eye movement sleep. Rapid eye movement sleep behaviour disorder is commonly associated with neurodegenerative disorders, but also reported in narcolepsy with cataplexy. Most narcolepsy with cataplexy patients lack the sleep-wake, and rapid eye movement sleep, motor-regulating hypocretin neurons in the lateral hypothalamus. In contrast, rapid eye movement sleep behaviour disorder and hypocretin deficiency are rare in narcolepsy without cataplexy. We hypothesized that rapid eye movement sleep behaviour disorder coexists with cataplexy in narcolepsy due to hypocretin deficiency. In our study, rapid eye movement sleep behaviour disorder was diagnosed by the International Classification of Sleep Disorders (2nd edition) criteria in 63 narcolepsy patients with or without cataplexy. Main outcome measures were: rapid eye movement sleep behaviour disorder symptoms; short and long muscle activations per hour rapid eye movement and non-rapid eye movement sleep; and periodic and non-periodic limb movements per hour rapid eye movement and non-rapid eye movement sleep. Outcome variables were analysed in relation to cataplexy and hypocretin deficiency with uni-and multivariate logistic/linear regression models, controlling for possible rapid eye movement sleep behaviour disorder biasing factors (age, gender, disease duration, previous anti-cataplexy medication). Only hypocretin deficiency independently predicted rapid eye movement sleep behaviour disorder symptoms (relative risk = 3.69, P = 0.03), long muscle activations per hour rapid eye movement sleep (ln-coefficient = 0.81, P50.01), and short muscle activations per hour rapid eye movement sleep (ln-coefficient = 1.01, P50.01). Likewise, periodic limb movements per hour rapid eye movement and non-rapid eye movement sleep were only associated with hypocretin deficiency (P50.01). A significant association between hypocretin deficiency and cataplexy was confirmed (P50.01). In a sub-analysis, hypocretin deficiency suggested the association of periodic limb movements and rapid eye movement sleep behaviour disorder outcomes (symptoms, non-periodic short and long muscle activity) in rapid eye movement sleep. Our results support the hypothesis that hypocretin deficiency is independently associated with rapid eye movement sleep behaviour disorder in narcolepsy. Thus, hypocretin deficiency is linked to the two major disturbances of rapid eye movement sleep motor regulation in narcolepsy: rapid eye movement sleep behaviour disorder and cataplexy. Hypocretin deficiency is also significantly associated with periodic limb movements in rapid eye movement and non-rapid eye movement sleep, and provides a possible pathophysiological link between rapid eye movement sleep behaviour disorder and periodic limb movements in narcolepsy. The study supports the hypothesis that an impaired hypocretin system causes a general instability of motor regulation during wakefulness, rapid eye movement and non-rapid eye movement sleep in human narcolepsy.

We describe a recent case of presumed redback spider (Latrodectus hasselti) envenomation observed near Noumea in New Caledonia. This is the first local reported case in this archipelago, where L. hasselti is currently considered a native species. We highlight the challenge of providing appropriate analgesia in this situation and believe that the use of specific redback spider antivenom should be considered in New Caledonia.

In this study, we examined the effect of the central-type benzodiazepine agonist, clonazepam, and the indoleamine hormone, melatonin, on central dopaminergic function using the 6-hydroxydopamine model of dopamine receptor supersensitivity. Unilateral lesioning of the nigrostriatal pathway with 6-hydroxydopamine was carried out in Sprague-Dawley rats. Two weeks after surgery, the animals were examined for the presence of dopaminergic supersensitivity by their response to the dopamine receptor agonist, apomorphine. Clonazepam, melatonin and its analogs, 6-chloromelatonin and 2-iodomelatonin, significantly inhibited apomorphine-induced turning behavior (P < .01). Pretreatment with a central-type benzodiazepine antagonist, flumazenil, significantly reduced the effect of melatonin and clonazepam (P < .01). The peripheral-type benzodiazepine antagonist, PK 11195, caused some attenuation of melatonin's effect (P < .05), but it was significantly less potent than flumazenil. Bic...

Intrastriatal injection of the GABAA antagonist, bicuculline, caused about a 75% decrease in the inhibitory effect of the central-type benzodiazepine (BZ) agonist, clonazepam or the indoleamine hormone, melatonin, on apomorphine-induced rotation in a 6-hydroxydopamine model of dopaminergic supersensitivity. Pretreatment witlh the peripheral-type BZ antagonist, PK 11195 (intrastriatally or intraperitoneally), also attenuated the antidopaminergic effect of these drugs but with much less potency than bicuculline. However, the combination of both bicuculline and PK 11195, injected directly into the striatum, completely blocked the antidopaminergic action of clonazepam or melatonin. These results indicate that the antidoparninergic action of clonazepam and melatonin in the striatum involves two distinct mechanisms: (1) a predominant GABAergic activation via the BZ/GABA* receptor complex, and (2) a secondary mechanism linked to a PK 11195 sensitive BZ receptor pathway. Recent studies indicate that PK 11195 blocks BZ-induced inhibition of the adenylyl cyclase-cyclic AMP pathway in the striatum. Since cyclic AMP has been implicated in the rotational behaviour of 6-nydroxydopamine-lesioned animals, it is possible that the antidopaminergic action of clonazepam and melatonin also involves suppression of this second messenger.

... 3. Walker RG, Bennett WM, Davies BM, Kincaid-Smith P. Structural and functional effects of long-term lithium therapy . Kidney Int 1982; 21:Suppl 11:S13–S19. 4. ... 2. Mahdi S. Abdullah, Noori S. Al-Waili, Nawras K. Baban, Glenn J. Butler, Laith Sultan. ...

epilepsy and porphyria cutanea tarda. Valproic acid and phenobarbital monotherapy controlled seizures but exacerbated porphyric symptomatology, while clobazam, clonazepam and lamotrigine monotherapy were well tolerated as regards porphyric disturbances but did not completely control seizures. Tonicclonic seizures were eventually controlled by a combination of clonazepam (9 mg/ day) and lamotrigine (150 mg/day), but absences persisted and this treatment caused significant adverse effects consisting of sedation and memory disturbances. Levetiracetam monotherapy (3 g/day) was accompanied by complete control of seizures; memory disturbances and sedation also resolved, and no porphyrinogenetic activity of levetiracetam was observed. This is the first report of the safe use of levetiracetam in porphyria cutanea tarda.