La sobredosis aguda de quetiapina se asocia con riesgo de ritmo auricular ectópico / [Acute quetiapine overdose is associated with risk of ectopic atrial rhythm]

La sobredosis de quetiapina se asocia comúnmente con coma, depresión respiratoria, hipotensión, taquicardia y prolongación del intervalo QTc en el electrocardiograma. Aunque se ha establecido el efecto arritmogénico de los antipsicóticos sobre la arritmia ventricular, aún no se conoce bien su papel en las arritmias auriculares, específicamente las causadas por un ritmo auricular ectópico (RAE). Nuestro objetivo es presentar un caso y revisión sobre la asociación entre quetiapina y RAE. Los datos se obtuvieron de las historias clínicas y de la búsqueda bibliográfica en PubMed. Presentamos el caso de una mujer de 57 años que acudió a urgencias tras una sobredosis de quetiapina con una RAE de nuevo diagnóstico que revirtió horas después. Esta asociación puede deberse al mayor riesgo de quetiapina de bloqueo de los receptores muscarínicos cardíacos que puede provocar anomalías en la conducción. Debido a la posibilidad de degeneración a otras alteraciones del ritmo más graves, la implantación de marcapasos y el aumento de la mortalidad, existe la necesidad de una mayor conciencia de esta correlación. (AU)

Quetiapine overdose is commonly associated with coma, respiratory depression, hypotension, tachycardia, and QTc interval prolongation on the electrocardiogram. Although the arrhythmogenic effect of antipsychotics on ventricular arrhythmia has been established, their role in atrial arrhythmias is still not quite understood, specifically the ones caused by an ectopic atrial rhythm (EAR). We aim to present a case and review on the association between Quetiapine and EAR. Data were obtained from clinical records and bibliographic research on PubMed. We present the case of a 57-year-old woman brought to the emergency room after a Quetiapine overdose with a newly diagnosed EAR that reverted hours later. This association may be due to Quetiapine’s increased risk of cardiac muscarinic receptors blockade that can lead to conduction abnormalities. Because of the possibility of degeneration to other more serious rhythm alterations, pacemaker implementation and increased mortality, there is a need for greater awareness of this correlation. (AU)

Refractory hypotension secondary to chronic treatment with high doses of quetiapine.

Quetiapine is an atypical antipsychotic used in the treatment of depressive, schizophrenic, or bipolar disorders. It acts on dopamine D1 and D2, histamine, and 5HT1A and 5HT2 receptors. However, it also acts as an antagonist for α1 receptors causing cardiovascular side effects, including hypotension. We present the case of a patient chronically medicated with Quetiapine who developed hypotension refractory to vasoconstrictors and intraoperative fluid therapy. Noradrenalin has a strong α1 effect with lower affinity for ß2 receptors unlike adrenalin. This translates into peripheral vasoconstriction and an improved clinical picture. Therefore, it should be considered the vasoactive drug of choice in patients on high doses of Quetiapine.

Hipotensión refractaria secundaria a tratamiento crónico con altas dosis de quetiapina / Refractory hypotension secondary to chronic treatment with high doses of quetiapine

La quetiapina es un antipsicótico atípico que se usa en el tratamiento del trastorno depresivo, esquizofrénico o bipolar. Su acción reside en su acción sobre los receptores de la dopamina D1 y D2, histamina y serotonina 5HT1A y 5HT2. Sin embargo, también tiene antagonismo para los receptores α1, provocando efectos secundarios cardiovasculares, entre ellos la hipotensión. Presentamos el caso de un paciente medicado crónicamente con quetiapina que presentó hipotensión refractaria a vasoconstrictores y fluidoterapia intraoperatoria. La noradrenalina tiene un fuerte efecto α1 con una menor afinidad para los receptores β2 a diferencia de la adrenalina. Esto se traduce en una vasoconstricción periférica y la resultante mejoría del cuadro clínico. Por lo tanto, se debe considerar el fármaco vasoactivo de elección en la hipotensión refractaria en pacientes que tomen altas dosis de quetiapina.(AU)

Quetiapine is an atypical antipsychotic used in the treatment of depressive, schizophrenic, or bipolar disorders. It acts on dopamine D1 and D2, histamine, and 5HT1A and 5HT2 receptors. However, it also acts as an antagonist for α1 receptors causing cardiovascular side effects, including hypotension. We present the case of a patient chronically medicated with quetiapine who developed hypotension refractory to vasoconstrictors and intraoperative fluid therapy. Noradrenalin has a strong α1 effect with lower affinity for β2 receptors unlike adrenalin. This translates into peripheral vasoconstriction and an improved clinical picture. Therefore, it should be considered the vasoactive drug of choice in patients on high doses of quetiapine.(AU)

Síndrome de Wells secundario a dimetilfumarato. A propósito de un caso clínico / Dimethyl fumarate induced Wells syndrome. A case report

Introducción: El síndrome de Wells, también conocido como celulitis eosinofílica, es una rara dermatosis con aproximadamente 200 casos descritos en la bibliografía. Aquí presentamos un caso clínico de un paciente con esclerosis múltiple y síndrome de Wells secundario a dimetilfumarato (DMF). Caso clínico: Mujer de 41 años que en julio de 2021 inició el tratamiento con DMF. Una semana más tarde, comenzó con prurito en las extremidades derechas, seguido por la aparición de zonas eritematosas con vesículas. El hemograma mostró elevación del recuento de los eosinófilos hasta 2.000 µL. El estudio anatomopatológico evidenció un infiltrado eosinófilo a nivel de la dermis compatible con síndrome de Wells. La evolución clínica fue favorable, con resolución de las lesiones y normalización de la eosinofilia aproximadamente en cuatro semanas. No fue necesario administrar corticoesteroides. Conclusiones: La eosinofilia es rara en los pacientes con EM tratados con DMF y generalmente no precisa ajuste de dosis. A pesar de que las manifestaciones clínicas de la eosinofilia en estos pacientes sean raras, es importante que el médico reconozca los síntomas. Numerosos neurolépticos pueden causar eosinofilia y síntomas sistémicos; por lo tanto, los facultativos deben conocer los riesgos de la asociación entre DMF y neurolépticos, en particular por la quetiapina, que contiene fumarato.(AU)

Introduction: Wells syndrome, also known as eosinophilic cellulitis, is a rare dermatosis with approximately 200 cases previously described in the literature. Here, we present a case of a patient with multiple sclerosis with Wells syndrome induced by dimethyl fumarate (DMF). Case report: A 41-year-old Caucasian woman was treated with DMF in July 2021. One week later, she experienced itching on her upper and lower right arm, followed by the appearance of erythematous plaques covered with vesicles. The complete blood count showed an increased eosinophil count of up to 2,000 µL. The histological images demonstrated dermal eosinophil infiltration concordant with Wells syndrome. The clinical course was benign, with complete resolution of the lesions and normalization of the eosinophil count within four weeks. Administration of corticosteroids was not necessary. Conclusions: Eosinophilia is rare in patients with multiple sclerosis treated with DMF and usually does not require dosage adjustments. Although clinical manifestations of eosinophilia in these patients are very rare, it is important for practitioners to recognize the symptoms. Many neuroleptic drugs can induce eosinophilia and systemic symptoms; therefore, physicians must be aware of the risks associated with DMF and neuroleptic drugs, particularly for quetiapine, which contains fumarate.(AU)

Effect of the association of amantadine and quetiapine in the treatment of rem sleep behavior disorder: case report / Efeito da associação de amantadina e quetiapina no tratamento do distúrbio do comportamento do sono rem: relato de caso / Efecto de la asociación de amantadina y quetiapina en el tratamiento del trastorno del comportamiento del sueño rem: reporte de un caso

The aim was to report the case of a patient with REM sleep behavior disorder, unresponsive to standard treatment and with complete control of the condition after association of amantadine. Female patient, 45 years old, with systemic arterial hypertension and hypothyroidism, referred to neurological care, reporting frequent episodes of nocturnal agitation in the first hours of sleep, with walking and vocalization, waking up easily if called. She complains of drowsiness and anxiety, secondary to the impact of the RBD on her personal life. She mentions previous attempts at drug treatment with benzodiazepines (Bromazepam and Clonazepam), Zolpidem and Trazodone, all without clinical improvement, with Quetiapine being introduced at a low dose (not yet tried) 25mg, with a therapeutic target of 50mg with partial improvement only with 25mg. When trying 50mg, presenting a worsening of the picture. In a new follow-up, therapy with Amantadine 50 mg/day associated with Quetiapine 25 mg/day was started. The patient returned reporting a significant improvement in the condition, less frequent episodes associated with reduced nocturnal movement. After adaptation of the combined therapy, with adjustments in the dose of Amantadine, an increase of 50mg every 14 days up to 200 mg/day, with the possibility of using quetiapine 50mg (balance between the drugs), the patient evolved stable, with a great improvement in the quality of life and absence of new episodes of the sleep disorder.

O objetivo foi relatar o caso de uma paciente com transtorno comportamental do sono REM, sem resposta ao tratamento padrão e com completo controle do quadro após associação de amantadina. Paciente do sexo feminino, 45 anos, com hipertensão arterial sistêmica e hipotireoidismo, encaminhada a atendimento neurológico relatando episódios frequentes de agitação noturna nas primeiras horas de sono, com deambulo e vocalização, despertava facilmente se chamada. Queixa-se de sonolência e ansiedade, secundárias ao impacto do TCSREM em sua vida pessoal. Menciona tentativas prévias de tratamento medicamentoso com benzodiazepínicos (Bromazepam e Clonazepam), Zolpidem e Trazodona, todos sem melhora clínica, sendo introduzido Quetiapina em dose baixa (ainda não tentado) 25mg, com alvo terapêutico de 50mg com melhora parcial apenas com 25mg. Ao tentar 50mg, apresentando piora do quadro. Em novo retorno, iniciou-se terapia com Amantadina 50 mg/dia associada a Quetiapina 25 mg/dia. A paciente retornou referindo melhora significativa do quadro, episódios em menor frequência associados a redução na movimentação noturna. Após adaptação da terapia combinada, com ajustes da dose de Amantadina, aumento de 50mg a cada 14 dias até 200 mg/dia, sendo possível o uso da quetiapina 50mg (equilíbrio entre os fármacos) a paciente evoluiu estável, com grande melhora da qualidade de vida e ausência de novos episódios do distúrbio de sono.

El objetivo fue reportar el caso de un paciente con trastorno de conducta del sueño REM, que no responde al tratamiento estándar y con un control completo de la condición después de la asociación de amantadina. Paciente femenina, de 45 años de edad, con hipertensión arterial sistémica e hipotiroidismo, referida a atención neurológica, reportando episodios frecuentes de agitación nocturna en las primeras horas de sueño, con marcha y vocalización, despertándose fácilmente si se le llama. Se queja de somnolencia y ansiedad, secundarias al impacto de la RBD en su vida personal. Menciona intentos previos de tratamiento farmacológico con benzodiazepinas (Bromazepam y Clonazepam), Zolpidem y Trazodona, todos sin mejoría clínica, con la introducción de quetiapina a una dosis baja (aún no probada) de 25mg, con un objetivo terapéutico de 50mg con mejoría parcial solo con 25mg. Al intentar 50mg, presentando un empeoramiento de la imagen. En un nuevo seguimiento se inició tratamiento con 50 mg/día de amantadina asociado a 25 mg/día de quetiapina. El paciente retornó reportando una mejoría significativa en la condición, episodios menos frecuentes asociados a reducción del movimiento nocturno. Después de la adaptación de la terapia combinada, con ajustes en la dosis de Amantadina, un aumento de 50mg cada 14 días hasta 200 mg/día, con la posibilidad de utilizar quetiapina 50mg (equilibrio entre los fármacos), el paciente evolucionó estable, con una gran mejoría en la calidad de vida y ausencia de nuevos episodios del trastorno del sueño.

Severe irritability in a critically ill preterm infant: a case of delirium at the neonatal intensive care unit / Grave irritabilidade em prematuro criticamente doente: um caso de delirium na unidade de terapia intensiva neonatal

ABSTRACT Delirium is a common disorder in intensive care units, being associated with greater morbidity and mortality. However, in neonatal intensive care units, delirium is rarely diagnosed, due to the low familiarity of the neonatologist with the subject and the difficulties in the applicability of diagnostic questionnaires. This case report aimed to assess the presence of this disorder in this group of patients and identify the difficulties encountered in the diagnosis and treatment. We report the case of a premature newborn with necrotizing enterocolitis during hospitalization and underwent three surgical approaches. The newborn exhibited intense irritability, having received high doses of fentanyl, dexmedetomidine, clonidine, ketamine, phenytoin, and methadone, without the control of the symptoms. A diagnosis of delirium was then made and treatment with quetiapine was started, with a complete reversal of the symptoms. This is the first case reported in Brazil and the first describing the withdrawal of the quetiapine.

RESUMO Delirium é uma síndrome comum em unidades de terapia intensiva, associando-se a maiores morbidade e mortalidade. No entanto, nas unidades de terapia intensiva neonatal, ele raramente é diagnosticado em razão da baixa familiaridade do neonatologista com a suspeita diagnóstica e das dificuldades na aplicabilidade dos questionários diagnósticos. Este relato de caso tem como objetivos mostrar que delirium está presente nesse grupo de pacientes e apontar as dificuldades encontradas no seu diagnóstico e tratamento. Relatamos o caso de um recém-nascido prematuro com enterocolite necrosante, submetido a três abordagens cirúrgicas. O recém-nascido apresentou intensa irritabilidade, tendo recebido altas doses de fentanil, dexmedetomidina, clonidina, cetamina, fenitoína e metadona, sem controle dos sintomas. Em seguida, foi feita a hipótese diagnóstica de delirium e iniciado tratamento com quetiapina, com reversão completa dos sintomas. Este é o primeiro caso notificado no Brasil e o primeiro que descreve a suspensão da quetiapina.

Tromboembolismo pulmonar como posible reacción adversa a Quetiapina Reporte de caso / Pulmonary thromboembolism as a possible adverse reaction to Quetiapine Case report

Resumen Algunos estudios sugieren que existe una relación entre el uso de antipsicóticos y el riesgo de tromboembolismo venoso (TEV) y embolia pulmonar (EP). Sin embargo, los resultados siguen sin ser concluyentes. Se trata del caso de un Masculino de 23 años con antecedentes de Esquizofrenia y Depresión tratado quetiapina 800 mg, el cual es encontrado muerto en la cama de un hotel. En la necropsia sin lesiones traumáticas visibles, hallazgos histológicos de tromboembolismo pulmonar masivo con infartos pulmonares secundarios. Laboratorio de Toxicología detectó la presencia de quetiapina, no se detectó alcohol o drogas de abusos. Mediante el Algoritmo De Karch & Lasagna Modificado el tromboembolismo pulmonar fue una reacción adversa con una probabilidad de relación causal posible. Se han informado muchos casos de muerte súbita causada por EP con la exposición a antipsicóticos, pero la relación de su uso y el riesgo de TEV y EP sigue siendo controvertida.

Abstract Some studies suggest a relationship between antipsychotic use and the risk of venous thromboembolism (VTE) and pulmonary embolism (PE). However, the results remain inconclusive. This is the case of a 23-year-old male with a history of schizophrenia and depression treated with quetiapine 800 mg, who was found dead in a hotel bed. At necropsy with no visible traumatic lesions, histological findings of massive pulmonary thromboembolism with secondary pulmonary infarcts. Toxicology laboratory detected the presence of quetiapine, no alcohol or drugs of abuse were detected. Using the Modified Karch & Lasagna Algorithm, pulmonary thromboembolism was an adverse reaction with a probable causal relationship. Many cases of sudden death caused by PE have been reported with exposure to antipsychotics, but the relationship of their use and the risk of VTE and PE remains controversial.

Servicio de dispensación: interacción entre darunavir y quetiapina / Dispensing service: interaction between darunavir and quetiapine

Paciente varón de 52 años, con síndrome metabólico, virus de inmunodeficiencia humana (VIH), insomnio, trastorno de ansiedad generalizada, esquizofrenia y con medicación analgésica, que viene sufriendo numerosos episodios nocturnos de insomnio e intranquilidad. Tuvo que ser socorrido por el servicio de urgencias al presentar un estado de gran confusión, agitación y una profunda y marcada taquicardia. La revisión de la medicación nos permite asociar estos eventos adversos con un exceso de dosis de quetiapina producida por la interacción con darunavir. La intervención consiste en informar al médico de la sospecha de la influencia de la interacción de darunavir con quetiapina y en proponer la sustitución del antipsicótico por otro que utilice una vía metabólica diferente. Se espera que darunavir aumente las concentraciones plasmáticas de los antipsicóticos como quetiapina (inhibición de CYP3A). La administración concomitante de darunavir y quetiapina puede ser potencialmente grave dado que puede aumentar la toxicidad asociada a quetiapina. El psiquiatra sustituye quetiapina por clotiapina. A partir de este cambio en la medicación el paciente no vuelve a experimentar ninguno de los problemas que le aquejaban además de que ha recobrado el sueño. (AU)

Síndrome neuroléptico maligno secundario a quetiapina / Neuroleptic malignant syndrome secondary to quetiapine

Objetivo: Describir un caso clínico de una paciente tratada con quetiapina a alta dosis de larga duración en el que produjo una reacción adversa atípica.Descripción del caso clínico: Mujer de 82 años institucionalizada en una residencia para mayores de edad, acude a urgencias con síntomas de fiebre (39º), espasticidad y cambio de estado mental. Se excluyeron los diagnósticos diferenciales iniciales: accidente cerebrovascular e infección, por lo que con los síntomas presentados se diagnosticó de SNM. En el tratamiento farmacológico en el momento del ingreso destacó un dosis de quetiapina 400mg/24h; confirmado con su centro de residencia debido a las discrepancias con su prescripción electrónica. Según informes médicos, la paciente había recibido este tratamiento durante dos meses previo al ingreso, aunque el SNM es un efecto secundario poco común entre los antipsicóticos posee unas consecuencias fatales. El primer día de hospitalización se suspendió la quetiapina y recibió tratamiento específico contra el SNM, compuesto por dantroleno, fluidoterapia y cuidados de apoyo. El SNM se resolvió a los 3 días.Discusión: A pesar de que los antipsicóticos atípicos (AA) se consideren de mayor seguridad debido a su baja potencia para bloquear los receptores D2, pueden causar SNM incluso cuando se prescriben en monoterapia. Por ello, es fundamental un seguimiento de los tratamientos crónicos especialmente en personas mayores con un deterioro cognitivo de base.Esto enfatiza la importancia de la comunicación médico-farmacéutico para promover la seguridad de pacientes y la importancia de las notificaciones. (AU)

Aim: To describe a clinical case of a patient treated with quetiapine at high dose of long duration in which it produced an atypical adverse reaction.Description of the clinical case: An 82-year-old woman institutionalized in a nursing home for the elderly, went to the emergency room with the next symptoms; fever (39º), spasticity and change in mental state. After excluding other pathologies, she was diagnosed NMS. Pharmacological treatment at the time of admission a dose of quetiapine 400mg/24h attracted attention; which was confirmed with her center of residence due to discrepancies with her electronic prescription. According to medical reports, the patient had received this treatment for two months before admission, although NMS is an uncommon side effect among antipsychotics with fatal consequences. Hospitalization first´s day, quetiapine was discontinued and she received specific treatment for NMS, consisting of dantrolene, fluid therapy and supportive care. The NMS was resolved after 3 days.Discussion: Although atypical antipsychotics (AA) are considered safer because of their low potency in blocking D2 receptors, they can cause NMS even when prescribed in monotherapy. Therefore, a follow-up of chronic treatments is essential, especially in older people with a basic cognitive impairment.This case emphasizes the importance of medical-pharmaceutical communication´s to promote patient safety and the importance of reporting. (AU)

Hyponatraemia Associated with the Use of Quetiapine: Case Report. / Hiponatremia relacionada con el uso de quetiapina: reporte de caso clínico.

Hyponatraemia is the most common electrolyte disturbance in the elderly. It can be asymptomatic or produce a spectrum of symptoms, particularly in the central nervous system, such as altered state of consciousness, lethargy, headache, seizures and gait disturbances, all of which are a common reason for consultation in this population. This condition has a high impact on the functionality of the patient given the need for multiple hospital stays, as well as on mortality. Its aetiology is multifactorial and its most common causes include low salt intake, chronic diseases such as kidney disease and heart failure, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which is commonly caused by the chronic use of certain drugs, such as antidepressants, diuretics and antipsychotics, which are the most forgotten in clinical practice. The following clinical case presents the diagnostic approach of hyponatraemia and the importance of the medical history as a key tool to detect the aetiology of this clinical entity.

Hiponatremia relacionada con el uso de quetiapina: reporte de caso clínico

La hiponatremia es la alteración electrolítica más frecuente en el anciano y puede ser asintomática o producir un espectro de síntomas, especialmente del sistema nervioso central, tales como alteración del estado de conciencia, letargia, cefalea, convulsiones y alteraciones en la marcha, los cuales son un motivo frecuente de consulta de esta población. Esta entidad tiene un alto impacto en la funcionalidad del paciente, pues requiere múltiples hospitalizaciones, e incluso en mortalidad. Su etiología es multifactorial; entre sus causas más comunes están la baja ingesta de sal, las enfermedades crónicas como la nefropatía y la insuficiencia cardiaca y el síndrome de secreción inadecuada de hormona antidiurética (SIADH), que a su vez se produce comúnmente por el uso crónico de determinados fármacos, como los antidepresivos, los diuréticos y los antipsicóticos, que son los más olvidados en el abordaje clínico. Se presenta en este caso clínico el abordaje diagnóstico de la hiponatremia y la importancia de la anamnesis como instrumento clave para detectar la etiología de esta entidad clínica.

Hyponatraemia is the most common electrolyte disturbance in the elderly. It can be asymptomatic or produce a spectrum of symptoms, particularly in the central nervous system, such as altered state of consciousness, lethargy, headache, seizures and gait disturbances, all of which are a common reason for consultation in this population. This condition has a high impact on the functionality of the patient given the need formultiple hospital stays, as well as on mortality. Its aetiology ismultifactorial and its most common causes include low salt intake, chronic diseases such as kidney disease and heart failure, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which is commonly caused by the chronic use of certain drugs, such as antidepressants, diuretics and antipsychotics, which are the most forgotten in clinical practice. The following clinical case presents the diagnostic approach of hyponatraemia and the importance of the medical history as a key tool to detect the aetiology of this clinical entity.

High Doses of Drugs Extensively Metabolized by CYP3A4 Were Needed to Reach Therapeutic Concentrations in Two Patients Taking Inducers / Dos pacientes que tomaban inductores necesitaron dosis altas de medicamentos metabolizados en gran medida por el CYP3A4 para alcanzar concentraciones terapéuticas

ABSTRACT Introduction: In the last 20 years of clinical practice, the senior author has identified these 2 rare cases in which the patients needed extremely high doses of drugs metabolized by CYP3A4 to reach and maintain serum therapeutic concentrations. Methods: The high metabolic ability of these 2 patients was demonstrated by the low concentration-to-dose ratios (C/D ratios) of several drugs metabolized by CYP3A4. Results: Case 1 was characterized by a history of high carbamazepine doses (up to 2,000 mg/day) and needed 170 mg/day of diazepam in 2 days to cooperate with dental cleaning. The high activity of the CYP3A4 isoenzyme was manifested by fast metabolism for quetiapine and diazepam, which took more than 1 year to normalize after the inducer, phenytoin, was stopped. Case 2 was also very sensitive to CYP3A4 inducers as indicated by very low C/D ratios for carbamazepine, risperidone and paliperidone. The carbamazepine (2,800 mg/day) and risperidone (20 mg/day) dosages for this second patient are the highest doses ever seen for these drugs by the senior author. Risperidone induction appeared to last for many months and metabolism was definitively normal 3 years after stopping carbamazepine. On the other hand, olanzapine C/D ratios were normal for induction. Conclusions: The literature has never described similar cases of very high doses of drugs metabolized by CYP3A4. We speculate that these 2 patients may have unusual genetic profiles at the nuclear receptor levels; these receptors regulate induction of drugs.

RESUMEN Introducción: Durante sus últimos 20 años de práctica, el último autor ha identificado estos 2 infrecuentes casos que necesitaban dosis extremadamente altas de medicaciones metabolizadas por el CYP3A4 para alcanzar y mantener concentraciones séricas terapéuticas. Métodos: La gran capacidad metabólica de estos 2 pacientes se demostró por los bajos cocientes entre concentración y dosis (C/D) de varias medicaciones metabolizadas por el CYP3A4. Resultados: El caso 1 se caracterizaba por una historia de altas dosis de carbamazepina (1.500 mg/día) y la necesidad de tomar 170 mg de diazepam en 2 días para facilitar una limpieza dental. La gran actividad de la isoenzima CYP3A4 se manifestó por una gran capacidad metabólica de quetiapina y diazepam, cuya normalización tardó más de 1 año tras la toma de un inductor, fenitoína. El caso 2 tambien era muy sensible a la inducción, lo cual se demuestra por los bajos cocientes C/D de carbamazepina, risperidona y paliperidona. Las dosis de carbamazepina (2.800 mg/día) y risperidona (20 mg/día) de este segundo paciente son las más altas nunca vistas por el último autor. La inducción de risperidona duró muchos meses y su metabolismo era normal 3 años después de interrumpir la carbamazepina. El cociente C/D de olanzapina era normal para la inducción. Conclusiones: Nunca se habían descrito casos similares de dosis tan altas de medicaciones metabolizadas por el CYP3A4. Se especula con que estos pacientes podrían tener unos perfiles genéticos inusuales en los receptores nucleares que regulan la inducción de medicamentos.

High Doses of Drugs Extensively Metabolized by CYP3A4 Were Needed to Reach Therapeutic Concentrations in Two Patients Taking Inducers.

INTRODUCTION: In the last 20 years of clinical practice, the senior author has identified these 2 rare cases in which the patients needed extremely high doses of drugs metabolized by CYP3A4 to reach and maintain serum therapeutic concentrations. METHODS: The high metabolic ability of these 2 patients was demonstrated by the low concentration-to-dose ratios (C/D ratios) of several drugs metabolized by CYP3A4. RESULTS: Case 1 was characterized by a history of high carbamazepine doses (up to 2,000mg/day) and needed 170 mg/day of diazepam in 2 days to cooperate with dental cleaning. The high activity of the CYP3A4 isoenzyme was manifested by fast metabolism for quetiapine and diazepam, which took more than 1 year to normalize after the inducer, phenytoin, was stopped. Case 2 was also very sensitive to CYP3A4 inducers as indicated by very low C/D ratios for carbamazepine, risperidone and paliperidone. The carbamazepine (2,800 mg/day) and risperidone (20 mg/day) dosages for this second patient are the highest doses ever seen for these drugs by the senior author. Risperidone induction appeared to last for many months and metabolism was definitively normal 3 years after stopping carbamazepine. On the other hand, olanzapine C/D ratios were normal for induction. CONCLUSIONS: The literature has never described similar cases of very high doses of drugs metabolized by CYP3A4. We speculate that these 2 patients may have unusual genetic profiles at the nuclear receptor levels; these receptors regulate induction of drugs.

Un Espectro Bipolar Peculiar. A propósito de un caso / A Peculiar Bipolar Spectrum. Report of a case

Introducción: La depresión cada día cobra mayor importancia en la actualidad y cuando se trata del tipo bipolar representa el problema más acuciante en el contexto del espectro bipolar. Este impacto se basa principalmente en el curso crónico del padecimiento independientemente que existen varias alternativas farmacológicas en el mercado para su tratamiento aun las cifras de remisión son muy bajas. Objetivo: demostrar utilidad de la terapia electroconvulsiva en fase aguda de la depresión bipolar tipo II y eficacia de terapia trimodal en fase de mantenimiento. Métodos: se realizó examen físico y entrevista clínica a un paciente con diagnóstico de trastorno afectivo bipolar tipo II, además de exámenes de laboratorio para cuantificación de litio en sangre. Resultados: en la entrevista clínica se identifica la psicopatología relacionada con un episodio depresivo grave con síntomas psicóticos en un paciente bipolar tipo II tratado posteriormente con terapia electroconvulsiva y tratamiento farmacológico con litio, quetiapina y lamotrigina en fase de mantenimiento, evidenciando una evolución clínica satisfactoria restituyendo su integridad psicológica independientemente de un periodo de recaída durante el abordaje terapéutico. Conclusiones: Inadecuado uso en los episodios depresivos de bipolaridad II de antidepresivos tricíclicos y los de segunda generación en estrategias de monoterapia. Se recomienda el uso de terapia electroconvulsiva en depresiones psicóticas graves y combinación de quetiapina, carbonato de litio y lamotrigina en estrategia de mantenimiento(AU)

Introduction: The depression every day has bigger importance at the present time and when it is the bipolar type it represents the most pressing problem in the context of the bipolar spectrum. This impact is based mainly on the chronic course independently that several pharmacological alternatives exist in the market for the treatment the remission figures they are even very low. Objective: to demonstrate utility of the electroconvulsive therapy in acute phase of the bipolar depression type II and efficacy of trimodal therapy in maintenance phase. Methods: was carried out physical exam and clinic interview to a patient with diagnostic of bipolar disorders type II, also laboratory exams for lithium quantification in blood. Results: in the clinical interview it is identified the psychopathology related with a serious depressive episode with psychotics symptoms in a bipolar patient type II tried later with electroconvulsive therapy and pharmacological treatment with lithium, quetiapine and lamotrigine in maintenance phase, evidencing a satisfactory clinical evolution restoring his psychological integrity independently of a period of relapse during the therapeutic boarding. Conclusions: Inadequate use in the depressive episodes of bipolarity II of tricyclic antidepressants and those of second generation in monoterapia strategies. The use of electroconvulsive therapy is recommended in serious psychotic depressions and combination whit quetiapine, lithium carbonate and lamotrigine in maintenance strategy(AU)

Consentimientos informados y aprobación por parte de los comités de ética en los estudios de antipsicóticos atípicos para el manejo del delírium / Informed consent and the approval by ethics committees of studies involving the use of atypical antipsychotics in the management of delirium

Introducción: El delírium es una alteración aguda de la conciencia y la cognición que ha empezado a manejarse con antipsicóticos atípicos (AA). Debido a que las facultades mentales, por definición, se ven afectadas, los estudios en esta población generan dilemas éticos respecto a la participación voluntaria de los pacientes y su estado de vulnerabilidad. Objetivo: Valorar si los estudios realizados con AA para el tratamiento del delírium obtuvieron una aprobación por un comité de ética en investigación en seres humanos (CEISH), si hubo aplicación de un consentimiento informado (CI), si este era verbal o escrito y quién dio la aprobación para la participación en el protocolo. Diseño: Revisión sistemática en MedLine de los estudios de delírium que emplearon quetiapina y olanzapina y valoración de la existencia de aprobación por un CEISH y de la aplicación de un CI. Resultados: Se detectaron 11 estudios (6 de quetiapina y 5 de olanzapina), de los cuales 5 contaron con la aprobación del protocolo por un CEISH. Conclusiones: La mayoría de los estudios para el tratamiento del delírium no fueron sometidos a su aprobación por parte de un CEISH ni obtuvieron (de forma exclusiva) el CI de participación por parte del apoderado legal del paciente. Es fundamental que los futuros estudios de antipsicóticos y otros fármacos cuenten con la aprobación del protocolo por parte de un CEISH y de la firma del CI por parte del representante legal del paciente…

Introduction: Delirium is an acute alteration of consciousness and cognition. Atypical antipsychotics (AA) have recently become a main part of its treatment. Studies in this population generate a series of ethical dilemmas concerning the voluntary participation of patients and their state of vulnerability since their mental faculties are, by definition, compromised. Objective: To assess whether studies with AA for the treatment of delirium obtained an approval by an ethics committee on human research (ECHR), if an informed consent (IC) was obtained, whether the IC was verbal or written, and who gave the approval to participate. Method: Systematic review of Medline for studies of delirium where quetiapine and olanzapine were the main treatment, assessing the existence of an ECHR approval and implementation of an IC. Results: 11 studies were identified (6 of quetiapine and 5 of olanzapine). 5 had an ECHR approval. Conclusions: Most studies examining the treatment of delirium with quetiapine or olanzapine were not subject to approval by an ECHR and most of them did not obtain an IC from the patient’s legal guardian. It is essential that future studies of antipsychotics and other drugs for the treatment of delirium have the protocol approved by an ECHR and a written IC signed by the patient’s legal representative, since by definition delirium is a condition that compromises superior mental processes…

[Informed Consent and the Approval by Ethics Committees of Studies Involving the Use of Atypical Antipsychotics in the Management of Delirium]. / Consentimientos informados y aprobación por parte de los comités de ética en los estudios de antipsicóticos atípicos para el manejo del delírium.

INTRODUCTION: Delirium is an acute alteration of consciousness and cognition. Atypical antipsychotics (AA) have recently become a main part of its treatment. Studies in this population generate a series of ethical dilemmas concerning the voluntary participation of patients and their state of vulnerability since their mental faculties are, by definition, compromised. OBJECTIVE: To assess whether studies with AA for the treatment of delirium obtained an approval by an ethics committee on human research (ECHR), if an informed consent (IC) was obtained, whether the IC was verbal or written, and who gave the approval to participate. METHOD: Systematic review of Medline for studies of delirium where quetiapine and olanzapine were the main treatment, assessing the existence of an ECHR approval and implementation of an IC. RESULTS: 11 studies were identified (6 of quetiapine and 5 of olanzapine). 5 had an ECHR approval. CONCLUSIONS: Most studies examining the treatment of delirium with quetiapine or olanzapine were not subject to approval by an ECHR and most of them did not obtain an IC from the patient's legal guardian. It is essential that future studies of antipsychotics and other drugs for the treatment of delirium have the protocol approved by an ECHR and a written IC signed by the patient's legal representative, since by definition delirium is a condition that compromises superior mental processes.

Formulation and evaluation of buccoadhesive quetiapine fumarate tablets

The aim of present study was to develop and evaluate buccoadhesive Quetiapine Fumarate (QF) tablets, which is extensively metabolised by liver. Buccoadhesive tablets of QF were prepared using HPMC K4M, HPMC K15M and combination of carbopol and HPC as mucoadhesive polymers by direct compression method. Sodium deoxycholate was added to formulation to improve the permeation of drug. The formulations were tested for bioadhesion strength, ex vivo residence time, swelling time and in vitro dissolution studies and ex vivo permeation studies. Optimized formulation (F3) showed 92% in vitro release in 8 h and 67% permeation of drug through porcine buccal mucosa and followed fickian release mechanism with zero order kinetics. FTIR studies of optimized formulation showed no evidence of interaction between the drug and polymers. In vivo mucoadhesive behaviour of optimized formulation was performed and subjective parameters were evaluated.

O objetivo do presente estudo foi desenvolver e avaliar os comprimidos bucoadesivos de fumarato de quetiapina (FQ), que é extensivamente metabolizada no fígado. Os comprimidos bucoadesivos de FQ foram preparados utilizando-se HPMC K4M, HPMC K15M e a combinação de carbopol e HPC como polímeros mucoadesivos pelo método de compressão direta. O desoxicolato de sódio foi adicionado à formulação para melhorar a permeação do fármaco. As formulações foram testadas quanto à força de bioadesão, tempo de residência ex vivo, tempo de inchamento, dissolução in vitro e permeação ex vivo. A formulação otimizada (F3) mostrou 92% de liberação in vivo em 8 h e 67% de permeação do fármaco através da mucosa bucal de porco e seguiu o mecanismo fickiano de liberação com cinética de ordem zero. Os estudos de FTIR da formulação otimizada não mostraram evidência da interação entre o fármaco e os polímeros. O comportamento mucoadesivo in vivo da formulação otimizada foi efetuado e avaliaram-se os parâmetros subjetivos.

Estudo de bioequivalência e avaliação farmacocinética de duas formulações de quetiapina em voluntários sadios após administração de dose única / Bioequivalence study and pharmacokinetic evaluation of two quetiapine formulations in healthy volunteers after a single dose administration

O estudo foi realizado para comparar a biodisponibilidade/bioequivalência de duas formulações de quetiapina 25 mg comprimidos (quetiapina do Aché Laboratórios Farmacêuticos S/A formulação teste e Seroquelâ da Astrazeneca Ltda. formulação referência, Brasil) em 48 voluntários de ambos os sexos. O estudo foi realizado através de um desenho aberto, randomizado, cruzado em dois períodos com tempo de washout de uma semana. As amostras de plasma foram obtidas ao longo de um intervalo de 36 horas. As concentrações de quetiapina foram determinadas através de um equipamento LC-MS-MS, utilizando clozapina como padrão interno. A partir dos dados obtidos, calcularam-se os seguintes parâmetros farmacocinéticos: ASC0-t, ASC0-¥ e Cmax. A média geométrica de Quetiapina/Seroquel® 25 mg foi de 99,96 % para ASC0-t, 100,12% para ASC0-¥ e 92,59 % para Cmax; os intervalos de confiança de 90% foram de 93,58 – 106,77%, 93,88 – 106,78% e 83,22 – 103,01%, respectivamente. Uma vez que os intervalos de confiança de 90% para Cmax, ASC0-t e ASC0-¥ estiveram dentro da faixa de 80 – 125% proposta pelo FDA e pela ANVISA (Agência Nacional de Vigilância Sanitária do Brasil), conclui-se que o comprimido de quetiapina de 25 mg foi bioequivalente ao comprimido de Seroquelâ de 25 mg e, dessa forma, o produto teste pode ser considerado intercambiável na prática médica.

Quetiapina en bajas dosis, una alternativa para tratar el insomnio relacionado a la depresión en el trastorno afectivo bipolar II / Low doses of quetiapine: one option for bipolar II affective disorder depression insomnia related treatment

Introduction: there in convenient have no addictive, well tolerated and efficient options for the symptomatic treatment of insomnia, at the onset of a stabilizer like lamotrigine treatment of mild major depressive episodes in the bipolar II affective disorder. Method: thirty (30<9 bipolar II patients whit insomnia related to mild mjor depressive episode (DSM-IV) were treated whit quetiapine under 100 mg/day at the first month of lamotrigine treatment. They were evaluated at the onset and at he thirty days whit the Montgomery-Asberg Depression Rating Scale (MADRS) and the Oviedo Sleep Quality Questionnaire (COS). Results: twenty (20) patients finished the studio, eighteen (18) each insomnia relief whit 57.7 mg/day mean doses of quetiapine. Conclusions: low doses quetiapine seems a good option for insomnia treatment of mild major depressive episodes in the bipolar II affective disorder. Although controlled trials are necessary.

Introducción: es conveniente contra con alternativas no adictivas, eficaces y bien toleradas para tratar sintomáticamente el insomnio en el inicio del tratamiento con estabilizadores como lamotrigina, en episodios depresivos moderados del trastorno afectivo bipolar II. Método: 30 pacientes bipolares II con insomnio relacionado a un episodio depresivo mayor moderado según el DSM-IV, fueron tratados con dosis inferiores a los 100 mg/día de quetiapina, durante su primer mes de tratamiento con lamotrigina, fueron evaluados a inicio y a los 30 días de tratamiento con la Escala de Depresión de montgomery-Asberg (Montgomery-Asberg Depression Rating Scale), y el Cuestionario de Oviedo de Calidad del Sueño COS. Resultados: los pacientes que completaron el protocolo fueron veinte (20), de ellos 18 consiguieron mejoría del insomnio con dosis promedio de 57,7 mg/día de quetiapina. Conclusiones: quetiapina en bajas dosis parece ser una buena alternativa para el tratamiento del insomnio en episodios depresivos moderados de trastorno afectivo bipolar II. Sin embargo, se requieren estudios con grupo de control.

Neutropenia aguda en un paciente con delírium tratado con quetiapina / Acute neutropenia in a patient with delirium treated with quetiapine

Introducción: La neutropenia es reconocida como un efecto adverso observado con los medicamentos antipsicóticos, principalmente la clozapina. Aunque rara, la administración de quetiapina puede llevar a la aparición de este efecto adverso con altas tasas de morbimortalidad. Objetivo: Describir un caso de neutropenia asociada con el uso de quetiapina en un paciente con delírium, quien posteriormente con la suspensión del medicamento presenta la resolución del cuadro. Método: Reporte de caso de un hombre de 38 años de edad. Resultado y conclusiones: Aun cuando el riesgo de neutropenia asociado con quetiapina es relativamente bajo, es importante la implementación rutinaria de un cuadro hemático tanto al inicio de la administración de quetiapina como de manera periódica. Siempre que sea posible se debe evitar combinar quetiapina con medicamentos con reconocida asociación con neutropenia...

Introduction: Neutropenia is a side effect of the use of antipsychotic drugs, mainly clozapine. Although rare, the administration of quetiapine may lead to the development of this adverse effect with high rates of morbidity and mortality. Objective: To describe a case of neutropenia associated with the use of quetiapine in a patient with delirium and its subsequent resolution when the medication was withdrawn. Method: Case report. Results and conclusions: Although the risk of neutropenia associated with the use of quetiapine is relatively low, it is important to implement routine hemograms at the beginning of the treatment with quetiapine, and on a regular basis. Whenever possible, combinations of quetiapine and other drugs with netropenia as a recognized side effect must be avoided...