Consumo do benzodiazepínico clonazepam (Rivotril®) no estado do Rio de Janeiro, Brasil, 2009-2013: estudo ecológico / Consumption of the benzodiazepine clonazepam (Rivotril®) in Rio de Janeiro State, Brazil, 2009-2013: an ecological study

Resumo O objetivo do estudo é estimar a prevalência do uso de clonazepam no Estado do Rio de Janeiro (RJ). Estudo ecológico e descritivo do consumo de clonazepam (2009-2013), com dados do Sistema Nacional de Gerenciamento de Produtos Controlados da Anvisa. O consumo foi medido pela Dose Diária Definida, com indicadores por população total e com 18 anos e mais utilizando a DDD padronizada de 8mg (anticonvulsivante) e a de 1mg (hipnosedativo). Os Municípios da Região Metropolitana foram agrupados segundo os Índices de Desenvolvimento Humano (IDH) e de GINI, submetidos à análise de conglomerados e apresentados segundo o consumo de clonazepam. No Estado do RJ, o consumo entre 2009 e 2013 aumentou de 0,35 para 1,97 DDD/1000 habitantes. Os valores são maiores para os indivíduos acima de 18 anos. Empregando-se 1mg ao invés de 8mg, chega-se a 21 DDD/1000 habitantes acima de 18 anos, em 2013. Rio de Janeiro e Niterói, com os maiores IDH, apresentaram em 2013 os maiores consumos, 3,38 e 4,52 DDD, respectivamente. Os dados sugerem que até 2% da população adulta é usuária de clonazepam, possivelmente como hipnosedativo. Deve-se atentar para o uso ampliado e fora de indicações terapêuticas, dados o potencial de abuso e as reações adversas ao clonazepam.

Abstract This descriptive, ecological study of clonazepam consumption in Rio de Janeiro State (RJ) estimated use prevalence from 2009 to 2013 using data from the National Controlled Product Management System operated by Brazil's health surveillance agency, Anvisa. Consumption was measured by total population and by population over 18 years old, using the standardised Daily Defined Doses of 8 mg (anticonvulsant) and 1 mg (sedative-hypnotic). The municipalities of the Rio de Janeiro Metropolitan Region were grouped by Human Development Index (HDI) and GINI index, subjected to cluster analysis and ranked by clonazepam consumption. From 2009 to 2013, consumption in the state rose from 0.35 to 1.97 DDD/1000 population, but the figures are higher for individuals over 18 years of age. A DDD of 1 mg instead of 8mg returns consumption in 2013 of 21 DDD/1000 population over 18 years of age. Consumption in 2013 was highest - 3.38 and 4.52 DDD, respectively - in Rio de Janeiro and Niterói, which have the highest HDIs. This suggests that up to 2% of the adult population uses clonazepam, possibly as a sedative-hypnotic. This broad use and use outside therapeutic indications deserves attention, given clonazepam's potential for abuse and adverse reactions.

Tratamientos farmacológicos en pacientes con síndrome de boca urente: revisión sistemática / Pharmacologic treatment of burning mouth syndrome: a systematic review

El objetivo fue determinar mediante una revisión sistemática, cuáles tratamientos farmacológicos para el Síndrome de Boca Urente (SBU) logran una reducción de síntomas, según Escala Visual Análoga (EVA). Se realizó una búsqueda bibliográfica en la bases de datos PubMed y SciELO, Trip Database, Scopus Database, EBSCO host y LILACS entre el 2005 y 2015. De 72 artículos, se seleccionaron un total de 11. Los tratamientos sistémicos usados fueron, Hipericum perforatum, Catuama, Clonazepam, Ácido alfa lipoico y Lafutidina. Entre los tratamientos tópicos, Aceite de oliva virgen enriquecido con licopeno, Lisozima lactoperoxidasa, Clonazepam y Capsaicina. Los fármacos que obtuvieron mejores resultados para el tratamiento del SBU fueron Lafutidina, Catuama, Clonazepam tópico y sistémico, y en menor grado Capsaicina.

The aim of this study was to determine through a systematic review, which is the best drug treatment for burning mouth syndrome (SBU), measured on a Visual Analogue Scale. A scientific literature search was conducted in PubMed and SciELO, Trip Database, Database Scopus, EBSCO host and LILACS data between 2005 and 2015. Of a total of 72 articles, 11 were included for analysis. Systemic treatments were Lycopene-enriched virgin olive oil, Hypericum perforatum, Catuama, Clonazepam, Alpha lipoic acid; topical treatments were Lysozyme lactoperoxidase, Clonazepam, Capsaicin and Lafutidine. The best results obtained were with Lafutidine, Catuama, topical and systemic Clonazepam, and to a lesser degree Capsaicin.

A Comparative Study to Assess the Efficacy and Safety of Combination Capsules of Paroxetine and Clonazepam in comparison to Paroxetine in patients suffering from Co-morbid Depression and Anxiety.

Depression and anxiety disorders are distinct illnesses that often coexist. Patients suffering from both disorders have more psychological, physical, and social impairment than do patients suffering from either illness alone. An open label comparative multicentric study was conducted to assess the efficacy and safety of therapy with fixed dose combination capsules of Paroxetine (25 mg) controlled release (CR) and Clonazepam (0.5 mg) in comparison to Paroxetine (25 mg) controlled release (CR) tablets in Indian patients suffering from co-morbid depression and anxiety. Patients between 18-65 years of age and established diagnosis of co-morbid depression and anxiety (as per Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) with a total Hamilton Rating Scale for Depression (HAM-D) score 14 and total Hamilton Rating Scale for Anxiety (HAM-A) score 12 were screened for enrolment in the study after taking their informed consent. The primary efficacy variables were the change in the score on the Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) at the end of treatment as compared to baseline. There was a significant decline in the mean HAM-D score from 21.4 ± 2.5 (range: 17-27) at baseline to 11.7 ± 1.8 (range: 8-15) at the end of the treatment in Group A and from 20.4 ± 2.1 (range: 16-23) at baseline to 12.0 ± 1.1 (range: 10-14) at the end of the treatment in Group B. In conclusion, we found that the fixed dose combination capsules of Paroxetine (25 mg) controlled release (CR) and Clonazepam (0.5 mg) are more effective and equally well tolerated as Paroxetine (25 mg) controlled release (CR) tablets in the management of patients with co-morbid depression and anxiety at our centre.

Association of oxamniquine praziquantel and clonazepam in experimental Schistosomiasis mansoni

The antischistosomal activity of clonazepam, when administered alone or in association with oxamniquine and praziquantel, was experimentally evaluated in mice infected with Schistosoma mansoni. The animals were treated 45 days post-infection with a single dose, by oral route, according to three treatment schedules: clonazepam 25 mg/kg and sacrificed 15 min, 1h or 4 h after treatment; clonazepam 1.0, 2.5 or 10.0 mg/kg and sacrificed 15 days post-treatment or with the dose of 10 mg/kg in association with oxamniquine 50 mg/kg or praziquantel 200 mg/kg, single dose, orally, every schedule with a control group. The efficacy of the drugs in vivo was assessed by means of worm counts and their distribution in mesentery and liver, mortality and oogram changes. In the chemotherapeutic schedules used, clonazepam did not present antischistosomal activity and the result of the association of this drug with oxamniquine or praziquantel was not significantly different from the one obtained when these two last drugs were administered alone. In the in vitro experiments, the worms exposed to 0.6 mg/mL clonazepam remained motionless throughout the 8-day-period of observation, without egg-laying, whereas the worms of the control group showed normal movements, egg-laying and hatching of miracidia on the last day of observation. The results obtained in the present study confirm the action of clonazepam on S. mansoni adult worm, in vitro, causing total paralysis of males and females. However, no additive or synergistic effects were observed when clonazepam were used in association with oxamniquine or praziquantel.

Clonazepam Treatment of Pathologic Childhood Aerophagia with Psychological Stresses

The treatment of pathologic aerophagia has rarely been discussed in the literature. In this retrospective study, the authors investigated the effects of clonazepam on the management of pathologic childhood aerophagia (PCA) with psychological stresses (PS), but not with mental retardation. Data from 22 consecutive PCA patients with PS (aged 2 to 10 yr), who had been followed up for over 1 yr, were reviewed. On the basis of videolaryngoscopic views, the authors observed that the pathology of aerophagia was the result of reflex-induced swallowing with paroxysmal openings of the upper esophageal sphincter due to unknown factors and also observed that these reflex-induced openings were subsided after intravenous low dose benzodiazepine administration. Hence, clonazepam was administered to treat paroxysmal openings in these PCA patients with PS. Remission positivity was defined as symptom-free for a consecutive 1 month within 6 months of treatment. The results of treatment in 22 PCA patients with PS were analyzed. A remission positive state was documented in 14.3% of PCA patients managed by reassurance, and in 66.7% of PCA patients treated with clonazepam (p=0.032). Thus, clonazepam may produce positive results in PCA with PS. Future studies by randomized and placebo-controlled trials are needed to confirm the favorable effect of clonazepam in PCA.

Comparative bioavailability study of clonazepam after oral administration of two tablet formulations.

OBJECTIVE: To assess the bioavailability of clonazepam from two brands of 2 mg tablet formulations--Epitril and reference brand. METHODS: A two-way randomised cross-over bioavailability study was carried out in 12 healthy male volunteers. Coded plasma samples were analysed for levels of clonazepam by high performance liquid chromatography (HPLC) method. RESULTS: The mean Cmax, Tmax t1/2 beta and AUC (0-48) for Epitril were: 16.31 +/- 3.07 ng/mL, 1.63 +/- 0.48 h, 46.97 +/- 12.26 h and 207.70 +/- 57.07 ng/ml.h; for reference brand were 19.75 +/- 5.95 ng/mL, 1.42 +/- 0.29 h, 46.88 +/- 11.29 h and 215.70 +/- 50.89 ng/ml.h respectively. These were comparable and the differences were not statistically significant. CONCLUSION: Based on above pharmacokinetic parameters, Epitril was bioequivalent to reference brand.

Tremor ortostático primário: relato de quatro casos / Primary orthostatic tremor: report of 4 cases

Relatamos quatro casos de tremor ortostático primário. O motivo do relato está na raridade da doença e no seu diagnóstico diferencial com outros tremores, muitas vezes confuso. Nossos casos foram estudados eletrofisiologicamente e a frequência dos tremores variou entre 15 e 20 Hz. Existem diferenças clínicas, eletrofisiológicas e terapêuticas entre o tremor ortostático primário e outros tremores de membros inferiores, de acordo com a literatura e com as características de nossos quatro casos.

Oral clonazepam sensitive focal status epilepticus (FSE).

Focal status epilepticus (FSE) and Epilepsia partialis continua (EPC) are relatively uncommon disorders. Antiepileptic drugs do not usually alter the FSE-EPC. An 11 year old female patient with progressive neurologic deficits and FSE showed a remarkable response to clonazepam, both clinically and electrophysiologically.

Temblor ortostático: una causa de dificultad en permanecer quieto de pie / Orthostatic tremor: a cause of difficulty in standing up

Orthostatic tremor is characterized by a fine tremor of lower limb muscles that produces instability while standing still and alleviates on walking or sitting. We report 2 patients, aged 54 and 72 years old, in whom the tremor caused falls. The clinical features, a negative neurological examination, the alleviation on walking or sitting and the good response to clonazepam allowed the diagnosis. This disease should be considered in the differential diagnosis of standing still instability

Programa de ansiedade e Depressäo - UFRJ. Série Psicofarmacologia - 20: Segurança e tolerância aos efeitos dos benzodiazepínicos: parte 3 / Safety and tolerability to the effects of benzodiazepines

Neste artigo, o terceiro e último de uma série, nós descrevemos três síndromes dismnésticas associadas ao uso de benzodiazepínicos: esquecimento benigno, confabulaçöes e amnésia transitória global. Em seguida, apresentamos um levantamento de algumas modalidades de efeitos adversos encontradas em uma amostra de 70 pacientes com fobia social submetidos a tratamento prolongado com clonazepam

Programa de Ansiedade e Depressäo - UFRJ. Série Psicofarmacologia - 15: Clonazepam na fobia social - 49 pacientes tratados em aberto durante um ano / Clonazepam in social phobia: 49 patients treated in an open trial during one year

A Fobia Social é um transtorno comum, podendo acarretar depressäo, suicídio, abuso de álcool e sedativos bem como grande incapacitaçäo social e profissional. Vários estudos atestam a eficácia do clonazepam na Fobia Social; contudo, todos säo de curta duraçäo. Realizamos um ensaio aberto, prospectivo, com um ano de duraçäo, utilizando o clanazepam em 49 pacientes com Fobia Social (DSM-III-R). Procuramos avaliar: 1- a eficácia clínica a longo prazo (um ano) do clonazepam na Fobia Social; 2- se há desenvolvimento de tolerância aos efeitos terapêuticos do clonazepam durante um ano de tratamento. Os pacientes foram diagnósticados através de uma entrevista semi-estruturada (SCID-I) e aferidos em seguimento de um ano, através dos seguintes instrumentos: CGI, escala de Liebowitz para Fobia Social, escala de Sheehan para incapacitaçäo. Observamso que 39 dos 49 (79,6 por cento) pacientes apresentaram melhora significativa (acentuada + moderada) da Fobia Social. Näo houve o desenvolvimento de tolerância aos efeitos terapêuticos do clonazepam durante o período de um ano de tratamento, mas sim à maioria dos efeitos adversos, mostrando-se um fármaco seguro e bem tolerado. O clonazepam parece ser uma alternativa promissora de tratamento para a Fobia Social. Entretanto, a ocorrência de síndromes de abstinência e risco de dependência física aos benzodiapínicos deve pesar na relaçäo risco/benefício ao optarmos pelo clonazepam

Modificación de la densidad de los movimientos oculares rápidos bajo la administración de los agonistas y los antagonistas de los receptores a las benzodiazepinas / Modification of rapid eye movement density under administration of agonists and antagonists of benezodiazepine receptors

Las benzodiazepinas (BZ) tienen efectos sobre algunas de las variables del sueño en el hombre, pero el mecanismo por el cual modifican los movimeintos oculares rápidos (MOR), que ocurren durante el sueño paradójico (SP), no está suficientemente descrito. El mecanismo de acción de las BZ puede explicarse por su interacción con sitios de unión selectivos localizados en el sistema nervioso central (SNC) y en la periferia, o por su interacción con los receptores descritos para neuromoduladores como la adenosina (AD). El presente estudio se realizó para tratar de distinguir farmacológicamente cuál de los posibles sitios de unión descritos para las BZ participan en las modificaciones observadas con las BZ en el SP y en los MOR. Treinta y dos sujetos voluntarios sanos, de uno y otro sexo, fueron estudiados bajo tres diferentes condiciones experimentales, para determinar la participación del flumazenil (FLU), un antagonista de los receptores centrales a las BZ, el PK 11195 (PK), un antagonista de los receptores post sinápticos a la AD, en las modificaciones del SP que generalmente inducen las BZ. Los resultados que las BZ estudiadas, flunitrazepan y clonazepam, disminuyen el número y la desnidad de MOR (DMOR) y que el FLU, el PK y la CAF no revierten este efecto. Más aún, el FLU tiende a disminuir la DMOR como un efecto intrínseco. Los datos obtenidos muestran que los receptores a la AD probablemente no participan en la regulación de los MOR e indirectamente sugieren que el complejo supramolecular (receptor, a BZ, receptor a GABA y canal de cloro) puede participar en la modulación de los MOR, aunque es necesario realizar otros estudios con ligandos más específicos, para poder confirmar esta interpretación