Terapia de insulina y glucosa para el tratamiento de intoxicación grave con bloqueantes de canales de calcio en pediatría. Reporte de un caso / Insulin/glucose therapy for the treatment of severe calcium channel blocker poisoning in pediatrics. Case report

La intoxicación por bloqueantes de los canales de calcio es un cuadro poco frecuente en la población pediátrica. Los signos y síntomas pueden progresar de forma rápida y llevar al colapso cardiovascular y muerte. El sostén hemodinámico con inotrópicos y vasopresores no suele ser efectivo. La terapia con insulina y glucosa es un complemento eficaz del tratamiento inicial, que está ampliamente estudiado, y se utiliza en diferentes patologías con compromiso hemodinámico. Se presenta el caso de una paciente pediátrica con antecedente de ingestión de dosis altas de amlodipina con fines suicidas, con descompensación hemodinámica refractaria al tratamiento de soporte inotrópico habitual. A partir del tratamiento con insulina y glucosa, se logró la estabilidad hemodinámica, con evolución favorable de la paciente.

Calcium channel blocker poisoning is a rare condition in the pediatric population. Signs and symptoms can be rapidly progressive and lead to cardiovascular collapse and death. Hemodynamic support with inotropics and vasopressors is usually not effective. The insulin/glucose therapy is an effective complement to the initial treatment, which is widely studied and used in different pathologies with hemodynamic compromise. The case of a pediatric patient with a history of high-dose ingestion of amlodipine for suicidal purposes, with hemodynamic decompensation refractory to usual inotropic support treatment, is presented. From the insulin/glucose treatment, hemodynamic stability was achieved with a favorable evolution

Canales de calcio como blanco de interés farmacológico / Calcium channels as a pharmacological target

Resumen Los canales de calcio son proteínas de membrana que constituyen la vía más importante para el ingreso del ion calcio (Ca2+) a la célula. Al abrirse, permiten el ingreso selectivo del ion, iniciando una variedad de procesos como contracción muscular, secreción endocrina y liberación de neurotransmisores, entre otros. Estas proteínas se agrupan en tres categorías de acuerdo con sus propiedades estructurales y funcionales: (i) Canales de Ca2+ operados por interacción receptor-ligando (ROCC), (ii) Canales activados por parámetros físicos (Transient Receptor Potencial, TRP) y (iii) Canales de Calcio dependientes de voltaje (VDCCs), siendo estos últimos los más estudiados debido a su presencia en células excitables. Dada la importancia de Ca2+ en la fisiología celular, los canales de Ca2+ constituyen un punto de acción farmacológica importante para múltiples tratamientos y, por tanto, son objeto de estudio para el desarrollo de nuevos fármacos. El objetivo de esta revisión es explicar la importancia de los canales de Ca2+ desde una proyección farmacológica, a partir de la exploración documental de artículos publicados hasta la fecha teniendo en cuenta temas relacionados con la estructura de los canales Ca2+, sus propiedades biofísicas, localización celular, funcionamiento y su interacción farmacológica.

Abstract Calcium channels are membrane proteins that constitute the most important route for the entry of the calcium ion (Ca2+) into the cell. When opened, they allow selective ion entrance, starting a variety of processes such as muscular contraction, endocrine secretion and neurotransmitters release, among others. These proteins are classified in three categories according to their structural and functional properties: (i) Receptor-operated calcium channels (ROCC), (ii) Channels activated by physical parameters (Transient Receptor Potential or TRP-channels) and (iii) Voltage-dependent calcium channels (VDCCs), the latter being the most studied due to its presence in excitable cells. Given the importance of Ca2+ in the cellular physiology, the calcium channels constitute targets for pharmacological action for multiple treatments, and therefore, they are object of study for the development of new medicaments. The objective of this review is to explain the importance of the channels of Ca2+ from a pharmacological projection, by exploring the articles published, bearing in mind topics related to the structure of the channels Ca2+, properties of their biophysics, cellular location, functioning and their pharmacological interaction.

Serie de Casos: Intoxicación por Amlodipino / Case Series: Amlodipine Intoxication

Resumen INTRODUCCIÓN: La intoxicación por distintas drogas es una importante causa de morbimortalidad en la edad pediátrica. No obstante, la intoxicación por amlodipino, que es un fármaco dihidropiridinico del grupo de calcioantagonistas ampliamente usado, no se encuentra bien documentada en Ecuador. El tratamiento se basa en implementar medidas para el shock clásico, en conjunto con medidas específicas para este tipo de intoxicación. CASOS CLÍNICOS: Presentamos dos reportes de casos clínicos de pacientes adolescentes ingresadas en unidad de cuidados intensivos pediátricos (UCIP), por intento autolítico mediante ingesta de amlodipino en conjunto con otros fármacos. EVOLUCIÓN: Durante su estancia hospitalaria presentaron cuadros evolutivos distintos. En ambos casos se necesitó manejo con drogas vasoactivas, modificando su dosis de acuerdo a respuesta clínica. En los dos casos se administró gluconato de calcio por horario y otras medidas de soporte descritas en el presente manuscrito. Finalmente, las dos pacientes presentaron buena evolución y fueron dadas de alta, con previa valoración y seguimiento de psicología y psiquiatría. CONCLUSIÓN: La intoxicación por amlodipino ha sido descrita escasamente debido a su baja frecuencia, a esto se añade el poco conocimiento basado en evidencia; motivos que la constituyen como un reto diagnóstico y terapéutico. Destacamos, en base a nuestra experiencia, la importancia de un alto índice de sospecha y de priorizar el inicio de vasopresores sobre la reanimación hídrica. Adicionalmente, recomendamos documentar la dosis exacta de ingesta e indagar sobre el consumo de otros fármacos para clasificar adecuadamente la gravedad de la intoxicación y establecer un plan de tratamiento. Finalmente, la monitorización y evaluación clínica constante y el apoyo de exámenes de laboratorio guiarán la conducta.(au)

BACKGROUND: Drug poisoning is an important cause of morbidity and mortality in pediatric patients. However, amlodipine poisoning, a widely used dihydropyridine calcium chanel blocker, is not fully documented in Ecuador. Treatment consists of classic measures for shock management and specific measures for this type of intoxication. CASE REPORTS: We present two case reports, both of teenage patients admitted into the pediatric intensive care unit for suicide attempt by taking amlodipine and some other drugs. EVOLUTION: During hospital stay, they presented a different evolutionary course. In both cases vasoactive drugs were needed, dosage was modified according to clinical course. Also in both patients, calcium gluconate was administered along with other support measures described in this paper. Finally, both patients presented a good outcome and were discharged after psychological and psychiatric assessment and follow up. CONCLUSION: The low frequency of amlodipine poisoning and the lack of evidence-based knowledge, constitute it as a diagnostic and therapeutic challenge. Based on our experience, we highlight the importance of early suspicion and prioritizing the use of vasopressors over fluid resuscitation. Additionally, we recommend documenting the exact dose of intake and inquiring about consumption of other drugs to properly classify the severity of the poisoning and stablish the treatment plan. Finally, constant clinical monitoring and support of laboratory tests will guide the conduct.(au)

Evaluation of smooth muscle relaxant potential of Bismarckia nobilis (Hildebr. & Wendl.) in diarrhea, hypertension and asthma by ex-vivo and in-vivo method / Evaluación del potencial relajante en músculo liso de Bismarckia nobilis (Hildebr. & Wendl.) en diarrea, hipertensión y asma por métodos ex vivo e in vivo

To explore the mechanistic basis behind smooth muscle relaxant prospective of Bismarckia nobilis in gastrointestinal, respiratory and cardiovascular ailments. The methanolic extract of B. nobilis and sub-fractions have been evaluated in vitro rabbit isolated tissues, in vivo castor oil-induced diarrhea in rats and charcoal meal activity in mice. The B. nobilis extract relaxed spontaneous and K+(80 mM)- induced contractions in rabbit isolated jejunum preparations, CCh (1 µM) and K+ (80 mM)-induced contractions in tracheal and bladder preparations, PE (1 µM) and K+ (80 mM)-induced concentrations in aorta preparations, likewise verapamil. Spasmolytic activity of dichloromethane fraction is stronger as compared to aqueous fraction. In vivo castor oil-induced diarrhea in rats and charcoal meal activity in mice further supported spasmolytic activity. B. nobilis extract possess anti-spasmodic, anti-diarrheal, airway relaxant and vasodilator activities possible mediated through calcium channel blocking mechanism, justifying therapeutic utility of B. nobilis in diarrhea, asthma and hypertension.

El objetivo de trabajo fue explorar el mecanismo de acción relacionado con el efecto relajante del músculo liso inducido por Bismarckia nobilis (B. nobilis) en enfermedades gastrointestinales, respiratorias y cardiovasculares. El extracto metanólico de B. nobilis y subfracciones fue evaluado in vitro en tejidos aislados de conejos. Además se evaluó diarrea in vivo inducida con aceite de ricino en ratas y la actividad de harina de carbón vegetal en ratones. El extracto de B. nobilis relajó tanto las contracciones espontáneas como las inducidas por K+(80 mM) en preparaciones de yeyuno aisladas de conejos, las contracciones inducidas por PE (1 µM) y K+(80 mM) inducidas en preparaciones de aorta; de manera similar a verapamilo. La actividad espasmolítica de la fracción de diclorometano es más potente en comparación con la fracción acuosa. La diarrea inducida in vivo por el aceite de ricino en ratas y la actividad de la harina de carbón vegetal en ratones apoyaron aún más la actividad espasmolítica. El extracto de B. nobilis posee actividades antiespasmódicas, antidiarreicas, relajantes de las vías respiratorias y vasodilatadoras, posibles a través del mecanismo de bloqueo de los canales de calcio, lo que justifica la utilidad terapéutica de B. nobilis en la diarrea, el asma y la hipertensión.

Amlodipino y choque vasodilatado en una unidad de cuidados intensivos de un hospital general: Reporte de caso / Amlodipine and vasodilated shock in an intensive care unit of a general hospital: Case report

Los calcio antagonistas son fármacos usados para diferentes patologías médicas; sin embargo la intoxicación puede ser grave. Presentamos el caso de una mujer joven intoxicada por amlodipino quien cursó con choque vasodilatado y disfunción multiorgánica, en quien se usó vasopresores múltiples a dosis por encima de las habituales para estabilizarla. (AU)

Calcium antagonists are used in a number of medical conditions, but intoxication with these drugs may be lethal.We present the case of a young women intoxicated with amlodipine who presented with vasodilated shock and multi organ disfunction in whom multiple vasopressors at maximum allowed doses were used to estabilize the patient. (AU)

DIGOXINA E VERAPAMIL INDUZEM HIPERTROFIA EM CARDIOMIÓCITOS DE RATOS SEDENTÁRIOS E/OU TREINADOS / DIGOXIN AND VERAPAMIL PROMOTE CARDIOMYOCYTE HYPERTROPHY IN SEDENTARY AND/OR TRAINED RATS / DIGOXINA Y VERAPAMILO INDUCEN HIPERTROFIA DE CARDIOMIOCITOS EN RATAS SEDENTARIAS Y/O ENTRENADAS

RESUMO Introdução: Cardiotônicos e bloqueadores de canais de cálcio são fármacos que alteram o Ca2+ intracelular e afetam o coração. Objetivo: Avaliar os efeitos da administração de verapamil e digoxina sobre a morfologia cardíaca de ratos submetidos ao treinamento intervalado (TAI). Métodos: Ratos Wistar machos divididos em seis grupos (N = 8): Controle, Digoxina (30,0 µg.kg-1/dia), Verapamil (5,0 mg.kg-1/dia), Treinado, Treinado+digoxina e Treinado+verapamil. O TAI foi realizado em esteira rolante (60 min/dia/60 dias) concomitantemente com a administração dos fármacos. Fragmentos do ventrículo esquerdo (VE) foram coletados para análise histológica. Resultados: A digoxina e o verapamil aumentaram a área total do VE (p < 0,002), capilares/área VE (p < 0,01) e área de cardiomiócitos (p < 2,8e-10), sendo que, nesta última variável, o verapamil promoveu efeito ainda maior que a digoxina. O TAI aumentou VE/PC (p < 4e-05), o diâmetro interno do VE (p < 2,7e-6), a área de cardiomiócitos (p < 1,8e-6) e reduziu o [Lac] (p < 2,6e-5). Houve interação entre TAI e fármacos na área total (p < 9,8e-5), capilares (p < 0,04), células/área (p < 0,004) e área de cardiomiócitos (p < 2e-16). Conclusão: A digoxina promoveu hipertrofia de cardiomiócitos e, quando associada ao TAI, potencializou a hipertrofia. O verapamil foi mais eficiente em aumentar a área de cardiomiócitos em comparação com a digoxina, porém somente de forma isolada.

ABSTRACT Introduction: Cardiotonics and calcium channel blockers are drugs that alter intracellular Ca2+ and can affect the heart. Objective: To evaluate the effects of administration of verapamil and digoxin on heart morphology of rats subjected to interval training (IT). Methods: Male Wistar rats were divided into groups (n = 8): Control, Digoxin (30.0µg.kg-1/day), Verapamil (5.0 mg.kg-1/day), Trained, Trained+digoxin and Trained+verapamil. The IT was performed on a treadmill (60 min/day/60 days) concurrently with the drugs administration. Fragments of the left ventricle (LV) were collected for histological analysis. Results: Digoxin and verapamil increased the total area of the LV (p<0.002), capillary/LV area (p<0.01) and cardiomyocytes area (p<2.8e-10), and in the latter variable, verapamil promoted even greater effect than digoxin. The IT increased LV/BW (p<4e-05), the inner diameter of the LV (p<2.7e-6), the area of cardiomyocytes (p<1.8e-6), and reduced the [Lac] (p<2.6e-5). There was interaction between IT and drugs in the total area (p<9.8e-5), capillaries (p<0.04), cell/area (p<0.004) and cardiomyocytes area (p <2.0e-16). Conclusions: Digoxin promoted cardiomyocyte hypertrophy and when associated with IT, potentiated the hypertrophy. Verapamil was more efficient in increasing the cardiomyocytes area compared with digoxin, but only when isolated.

RESUMEN Introducción: Cardiotónicos y bloqueadores de los canales de calcio son fármacos que alteran el Ca2+ intracelular y afectan al corazón. Objetivo: Evaluar los efectos de la administración de verapamilo y digoxina sobre la morfología del corazón de ratas sometidas a entrenamiento a intervalos (EI). Métodos: Ratas Wistar macho, divididas en seis grupos (N = 8): Control, Digoxina (30,0 µg.kg-1/día), Verapamilo (5,0 mg.kg-1/día), Entrenado, Entrenado+digoxina y Entrenado+verapamilo. El entrenamiento a intervalos se realizó en una cinta de correr (60 min/día/60 días), con la administración concomitante de fármacos. Se recogieron fragmentos del ventrículo izquierdo (VI) para el análisis histológico. Resultados: La digoxina y el verapamilo aumentaron el área total del VI (p < 0,002), capilares/área VI (p < 0,01) y el área de los cardiomiocitos (p < 2,8e-10) y, en esta última variable, el verapamilo promovió un efecto aún mayor que la digoxina. EI entrenamiento a intervalos aumentó VI/PC (p < 4e-05), el diámetro interior del VI (p < 2,7e-6), el área de los cardiomiocitos (p < 1,8e-6) y redujo el [Lac] (p < 2,6e-5). Hubo una interacción entre fármacos y el EI en el área total (p < 9,8e-5), capilares (p<0,04), células/área (p < 0,004) y el área de los cardiomiocitos (p < 2e-16). Conclusión: La digoxina promovió la hipertrofia de los cardiomiocitos y, cuando al asociarse con el EI, potenció la hipertrofia. El verapamilo fue más eficiente en el aumento de la zona de los cardiomiocitos en comparación con la digoxina, pero sólo de forma aislada.

Efecto vasodilatador e inhibidor de vasoconstricción del extracto hidroalcohólico de hojas de Olea europaea (olivo) sobre anillos aórticos de ratas / Vasodilator and vasoconstriction inhibitor effect of Olea europaea (olive) leaf hydroalcoholic extract on rat aortic rings

Objetivos: Evaluar el efecto vasodilatador, la inhibición de la vasoconstricción, así como el mecanismo responsable, del extracto hidroalcohólico de hojas de Olea europaea (olivo), sobre anillos aórticos en ratas. Diseño: Experimental. Lugar: Centro de Investigación y Desarrollo Científico, Facultad de Medicina, Universidad Nacional de San Agustín, Arequipa, Perú. Material biológico: Hojas de Olea europea y anillos aórticos de Rattus norvegicus, variedad albina swiss. Intervenciones: Se obtuvo un extracto hidroalcohólico de las hojas de Olea europaea. Se usó anillos aórticos de rata en cámara de órganos aislados y se registró la actividad vasomotora con un transductor de tensión isométrica. Se produjo contracción basal máxima con CaCl2 6 mM y se determinó el efecto vasodilatador con dosis de 25, 50 y 100 mg/mL de extracto hidroalcohólico de las hojas de Olea europaea. Se usó 1H-[1,2,4] oxadiazolo [4,3 alquinoxalin-1-one] (ODQ) y nifedipino para determinar el mecanismo de acción. Se comparó la inhibición de la vasoconstricción tras la incubación durante 30 minutos con extracto 100 mg/mL y con captopril 10 µM. Principales medidas de resultados: Porcentaje de vasodilatación y de vasoconstricción. Resultados: Se obtuvo una vasodilatación de 7,20 ± 1,49%, 9,84 ± 1,42% y 12,31 ± 1,16% para las dosis de 25, 50 y 100 mg/mL, respectivamente, siendo significativa con la dosis de 100 mg/mL. La vasodilatación se incrementó tras la administración de ODQ 100 mM. La vasodilatación se inhibió tras la incubación con ODQ 100 mM más nifedipino 5 µM. No se encontró diferencia significativa entre la inhibición de la vasoconstricción con captopril 10µM y extracto a 100 mg/mL. Conclusiones: El extracto hidroalcohólico de hojas de Olea europea, a una dosis de 100 mg/mL, tiene efecto vasodilatador sobre anillos aórticos de ratas, mediado por el bloqueo de canales de calcio; además, posee efecto inhibidor de la vasoconstricción.

Objectives: To determine the vasodilator and anti-vasoconstrictor effect of Olea europaea (olive) leaf hydroalcoholic extract on rat aortic rings and the mechanism involved. Design: Experimental. Location: Research and Scientific Development Center, Faculty of Medicine, Universidad Nacional de San Agustin, Arequipa, Peru. Biological material: Leaves of Olea europaea and aortic rings of Rattus norvegicus, swiss albina variety. Interventions: Hydroalcoholic extract was obtained from Olea europaea leaves. Rat aortic rings were placed in isolated organ chambers and the vasomotor activity was recorded with isometric tension transducer. Maximum basal contraction occurred at CaCl2, and 6 mM vasodilator effect was determined at 25, 50, and 100 mg/mL doses of the hydroalcoholic extract. 1H-[1,2,4] oxadiazole [4,3-alquinoxalin-1-one] (ODQ) and nifedipine were used to determine the mechanism of action. We compared the inhibition of vasoconstriction after incubation for 30 minutes with the extract 100 mg/mL and with captopril 10 µM. Main outcome measures: Percentage of vasodilation and vasoconstriction. Results: There was vasodilatation of 7.20 ± 1.49%, 9.84 ± 1.42%, and 12.31 ± 1.16% for respectively 25, 50, and 100 mg/mL doses of hydroalcoholic extract; it was significant at doses of 100 mg/ mL. Vasodilation increased after administration of ODQ 100 mM. Vasodilation was inhibited after incubation with ODQ 100 mM plus nifedipine 5 µM. No significant difference was found between vasoconstriction inhibition with captopril 10 µM or extract 100 mg/mL. Conclusions: Olea europaea leaves hydroalcoholic extract at 100 mg/mL dose had calcium channel blockade-vasodilator effect and vasoconstriction inhibitory effect on rat aortic rings.

Participación de los canales de calcio dependientes de voltaje en el desarrollo de la epilepsia / Participation of voltage-dependent calcium channels in the development of epilepsy

La epilepsia es una afección crónica producida por diferentes etiologías, caracterizada por la repetición de crisis debidas a una descarga excesiva de las neuronas cerebrales asociadas a síntomas clínicos o paraclínicos. Se debe a una despolarización rápida, en la membrana, de iones en una población de neuronas susceptibles, es decir, un cambio repentino en la carga intracelular negativa a positiva. Las causas más conocidas son: alteraciones genéticas, anoxia perinatal, traumatismos, tumores, malformaciones congénitas, alteraciones metabólicas, intoxicaciones farmacológicas, infecciones del sistema nervioso. Una crisis epiléptica es la aparición transitoria de signos y síntomas anormales causados por la actividad neuronal excesiva, mientras que la epilepsia se caracteriza por una permanente predisposición a generar crisis. En la despolarización de la membrana neuronal, los iones calcio desempeñan un papel importante debido a que son mensajeros intracelulares que regulan funciones como: liberación de neurotransmisores, neurosecreción, excitación neuronal, supervivencia de neuronas y regulación de expresión de genes. El ingreso de calcio a través de la membrana plasmática representa una forma para controlar el nivel intracelular de calcio. Se conoce poco sobre el mecanismo de entrada del calcio a la neurona pero un progreso notable representa la comprensión de la estructura, función y regulación de los canales de calcio dependientes de voltaje.

Epilepsy is defined as a chronic condition produced by different etiologies, characterized by the repetition of crises due to an excessive discharge of the cerebral neurons assoclated wlth cllnlcal symptoms. It responds to a fast ion depolarization in a population of abnormal neurons. Causes of epilepsy are: genetíc alteratíons, perínatal anoxía, traumatísms, tumors, congenital malformations, metabolic alterations, drug poisonings, and infections of the nervous system. Epileptic selzure Is the transitory occurrence of signs and abnormal symptoms caused by excessive or synchronous neurona! activity whereas, epilepsy Is characterized by a permaneni predisposition to genérate seizures. During depolarization of neurona! membrane, calcium ions play an important role because they are intracellular messengers that regúlate functions llke: neurotransmltter reléase, neurosecretlon, neuronal excltatlon, neuron survlval and gene expresslon regulatlon . The Influx of calcium through the plasmatlc membrane represents a way to control Intracellular calcium level. The mechanlsm of the entrance of calcium to the neuron Is llttle known, but understandlng the structure, functlon and regulatlon of voltage-gated calcium channels Is of remarkable progress.

Perfil vasodilatador del extracto y la fracción flavonoide acetilada obtenida de Calea prunifolia HBK / Vasorelaxant profile of the extract and an acetylated flavonoid fraction obtained from Calea prunifolia HBK

Introducción: Este estudio muestra el perfil vasodilatador en anillos aislados de aorta de ratas Wistar del extracto etanólico y de la fracción de flavonoides acetilada de Calea prunifolia HBK, especie utilizada popularmente en Colombia para el tratamiento de hipertensión arterial. Objetivos: Estudiar posibles mecanismos de acción inducidos por el extracto etanólico y la fracción flavonoide acetilada de C. prunifolia en anillos aislados de aorta de rata. Metodología: Luego de verificar el efecto hipotensor del extracto etanólico de C. prunifolia en ratas anestesiadas, se estudió la respuesta inducida por concentraciones crecientes (1 μg/mlû100 mg/ml) del extracto y la fracción flavonoide acetilada de C. prunifolia en anillos íntegros y en anillos sin endotelio expuestos a KCl (80 mM) o fenilefrina (1 μM). Adicionalmente, los anillos se preincubaron con una de las siguientes sustancias: L-NAME (0.1 mM, inhibidor de NO-sintetasa), azul de metileno (1 μM, inhibidor de guanilil-ciclasa), glibenclamida (1 μM, inhibidor de canales K+ATP), atropina (30 μM, antagonista muscarínico), propranolol (1 μM, bloqueador de receptor β), o indometacina (1 μM, inhibidor de ciclooxigenasa), así como la respuesta inducida por CaCl2 en solución de Krebs sin Ca2+ en presencia del extracto o de la fracción. Resultados: El extracto de C. prunifolia disminuyó en función de la dosis (5-75 mg/kg, iv.) la presión arterial sin afectar la frecuencia cardíaca en ratas Wistar anestesiadas. Tanto el extracto como la fracción flavonoide relajaron anillos de aorta precontraídos con KCl (80 mM) y fenilefrina (1 μM) con valores de CI50 de 35 y 67 μg/ml, y 34 y 66 μg/ml, respectivamente. Los mayores efectos, tanto del extracto como de la fracción, se observaron en anillos contraídos con CaCl2.

Introduction: This study shows the vasorelaxant profile in isolated aortic rings from Wistar rats of the ethanolic extract and the acetylated flavonoid fraction obtained from Calea prunifolia, specie used in Colombian folk medicine for the treatment of arterial hypertension. Objectives: To study possible action mechanisms implicated in the response induced by the ethanolic extract and the acetylated flavonoid fraction obtained from C. prunifolia in isolated aortic rings. Methodology: After verifying the hypotensive effect of the etanolic extract in anaesthetized rats, the response induced by the extract and the acetylated flavonoid fraction (1 μg/ml-100 mg/ml) in isolated aortic rings from Wistar rats contracted with KCl (80 mM) or phenylephrine (1 μM) was studied. Then, the effect of the extract and the fraction was assessed in deendothelized rings contracted with KCl or in intact rings contracted with KCl (80 mM) and preincubated with one of the following substances: L-NAME (0.1 mM, NO-sintasa inhibitor), methylene blue (1 μM, guanyl ciclasa inhibitor), glibenclamide (1 μM, K+ATP channel inhibitor), atropine (30 μM, muscarinic antagonist), propranolol (1 μM, b receptor blocker), or indomethacin (1 μM, COX inhibitor). The response induced in rings contracted with CaCl2 in Krebs solution without Ca2+ also was analised. Results: The ethanolic extract elicited a dose-response (5-75 mg/kg. iv.) decrease in the blood pressure levels without affecting heart rate in anaesthetized rats. Both, extract and fraction relaxed KCl (80 mM) and phenyle-phrine (1 μM) precontracted isolated aorta rings with IC50 of 35 and 67 mg/ml against KCl and 34 and 66 mg/ml against phenylephrine, respectively. Rings exposed to CaCl2 in KrebsÆ solution without Ca2+ showed the better response induced by both extract and fraction.

Intoxicación grave con verapamilo / Severe intoxication with verapamil

Los calcioantagonistas, cada vez más usados en cardiología, son causas infrecuentes de intoxicaciones secundarias a intentos de suicidio o por mal uso de los mismos. Informamos de un caso con las manifestaciones clínicas clásicas descritas en la literatura y realizamos una investigación del tratamiento actual de dicha intoxicación.

Calcium channel blockers are currently widely used to treat many cardiological alterations; however, overdose and poisoning have been associated with morbidity and mortality mainly in those patients with suicidal attempts. We report a case and review the pathophysiology of overdose, treatment, and prognosis.

Transmisión sináptica-canales de calcio y liberación de neurotransmisores / Synaptic Transmission-Calcium Channels and Neurotransmiters Releasing

La comunicación neuronal en el sistema nervioso está mediada, en la gran mayoría de animales, por la transmisión sináptica química. Generalmente esta comunicación ocurre mediante la liberación de una sustancia transmisora en el terminal presináptico. Este transmisor sináptico se une a receptores postsinápticos y da lugar a una respuesta postsináptica en la célula blanco. La liberación del transmisor en la región presináptica, al parecer, es desencadenada por un aumento transitorio del calcio intracelular en el sitio de liberación. Este aumento se logra, principalmente, por la activación de canales de calcio dependientes de voltaje (VGCC), lo que da lugar a un ingreso de iones de calcio en el citosol presináptico, que desencadena la fusión de las vesículas sinápticas y la liberación del neurotransmisor. En este artículo se revisan las características moleculares y funcionales de los VGCC necesarias para la comprensión de alteraciones patológicas como las canalopatías y la transmisión sináptica anormal. Metodología: se consultaron las bases de datos Medline, Pubmed y los e-journals de la Biblioteca de la Universidad de Columbia, correspondientes a los años 1990 a 2004. Resultados: durante la última década se han logrado avances significativos en los aspectos moleculares y en la genética de los canales dependientes de voltaje. La integración de este conocimiento con la neurofisiología funcional y la neurología clínica apenas se está iniciando.

Neuronal communication in the nervous system is mediated, in the vast majority of animals, by chemical synaptic transmission. In most cases this junctional communication occurs via the release of a transmitter substance, from a presynaptic nerve terminal. This synaptic transmitter binds post-synaptic receptors and results in a postsynaptic response on the target cell. Such release of transmitter from the presynaptic terminal appears to be universally triggered by a transient increase of intracellular calcium at the release site. This transient increase in calcium, is mostly brought about by the activation of voltage gated calcium channels (VGCC) which result in a Ca2+ influx into the presynaptic cytosol that triggers synaptic vesicle fusion and neurotransmitter release. Methodology: Databases such as Medline, Pubmed and Columbia University Library ejournals were consulted, in order to find articles published from January 1990 to November 2004. Conclusions: During the last decade significant advances have been achieved in the molecular and genetics of voltage gated channels. The integration of this knowledge with functional neurophysiology and clinical neurology is only starting.

Mecanismos celulares y moleculares de la neurotoxicidad por plomo

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Abstract: Lead, a heavy metal, has been used by humans for many technological aims, a fact that has determined its actual widespread distribution. Although various actions have been taken to diminish the use and distribution of lead in the environment, it remains a significant health problem. The evolution of technological processes applied in the industry has followed economic interest. Its only in recent times that criteria related to health and ecology have been considered while designing new industries. Particularly susceptible groups are children and workers involved in mining, metallurgy, paint manufacturing and battery recycling. The communities living in areas where those industries are settled have also a higher lead exposure risk. Its high biological toxicity has determined lead to become one of the most significant environmental contaminants with pathogenic potential for humans. The toxic mechanism of lead is essentially due to its capability to substitute other polyvalent cations (particularly divalent cations such as calcium and zinc) into the molecular machinery of living organisms. Thanks to its ionic structure, lead establishes very favorable interactions, usually with higher affinity, with chemical groups that normally coordinate divalent cations in proteins. The coordination of cations in proteins is usually achieved by negatively charged acidic residues. These residues establish ionic interactions with the positively charged ion, resulting in a change in the structure and electric charge of the protein. These interactions determine that lead may affect different biologically significant processes, including metal transporting proteins, ionic channels, cell adhesion molecules, diverse enzymes which have metallic cofactors, signaling molecules such as calmodulin and protein kinase C and DNA binding proteins, among other molecular targets. Lead interactions with the coordinating amino acid residues in proteins may induce an abnormal conformational configuration of proteins, as compared to the conformational structure acquired when interacting with commonly active cations, thus significantly altering its functional properties in the very complex molecular machinery. Among the biologically active sites usually occupied by lead, those related to calcium seem to have the most significant pathological importance for lead toxicity due to their widespread distribution and highly significant functional relevance for the normal cell function. Two of the principal calcium binding motifs in proteins, the EF-hand motif and the C2 motif, have an intrinsic high affinity for lead. In the case of EF-hand motifs, calmodulin is one of the most remarkable targets for lead due its importance in regulating cellular processes, being activated by lead at lower concentrations than required for calcium and displaying an abnormal activity. The C2 motif is expressed mainly in calcium dependent membrane associated proteins such as protein kinase C (PKC) or synaptotagmin. The principal characteristic in these motifs is an electrical change in the protein after the calcium binding, allowing its interaction with biological membranes. In synaptotagmin, according with the electrical characteristics of lead, the interaction of the complex lead-synaptotagmin with biological membranes is similar to the interaction calcium-synaptotagmin with membranes, which is eminently electrical. Hence, the conformation of this complex is probably different to the conformation with calcium, fact evidenced by the failure of lead-synaptotagmin to interact with other proteins of the exocitic machinery. In relation to lead neurotoxicity, membrane ionic channels seem to be among the most relevant molecular targets of lead. In particular, calcium and potassium channel function may be significantly impaired by lead, affecting the activation of calcium activated potassium channels, the inactivation process of calcium channels, and the ionic conductance of calcium channels. As occurs with other heavy metals, lead is capable of blocking the calcium channel, probably at the selectivity filter. The high affinity lead binding to the acidic residues of the filter provokes a slow flux of the metal trough the channel pore, blocking the calcium conductance. The regulation of ionic channels will be significantly altered also. Calmodulin is a common calcium sensing protein for many ionic channels and its alteration by lead could affect the channel operation. Abnormal functioning of regulatory and signaling proteins such as calmodulin, protein kinase C and synaptotagmins, which normally require calcium for its activity, may also display an abnormal functioning, thus determining a widespread metabolic influence of lead poisoning. Lead distributes evenly into the cell thus reaching intracellular organelles, including the endoplasmic reticulum, mitochondria and the cell nucleus. This results in significant alterations of intracellular calcium metabolism and regulation due in part to the malfunctioning of calcium channels and ionic pumps in plasma membrane, endoplasmic reticulum and mitochondria. Inadequate energy generation due to mitochondrial damage and malfunctioning in cation dependent enzymes, alterations in protein folding due to the direct binding of lead to calcium activated reticular chaperones, or indirectly, altering the intrareticular calcium levels, and the disruption of the structure of DNA binding motifs such as zinc fingers, among others, promotes alterations in gene expression and DNA reparation. Lead poisoning is one of the most important chronic environmental illnesses affecting children in modern life. Developing central nervous system is particularly susceptible to lead toxicity. At critical times in development, lead may have a disorganizing influence with long-lasting effects which may continue into teenage and beyond. Mechanisms originating this disorganizing influence in the central nervous system are a consequence of the interaction of lead with various targets as previously described; alterations of cell molecular machinery, at the systems level induce excitotoxic phenomena, interferes with neurotransmission at neurotransmitter synthesis, release and receptor activation levels, alters intracellular signaling and produce cell membrane peroxidative damage. Compared to adult lead poisoning, pediatric lead is most common and its effects may occur at reduced blood levels with subclinical symptoms; thus a high index of suspicion is necessary for physicians when dealing with pediatric patients. Long-term effects of lead may produce cognitive and motor impairment, with behavioral alterations. The particular vulnerability of the immature nervous system to the lead poisoning is probably due to the fact that in this stage of development the establishment of appropriate neural networks is highly dependent on the synaptic activity, which in turn could be altered by lead. Lead poisoning has been considered as a potential co-factor in complex neuropsychological alterations such as schizophrenia. In this sense it is worth to note the possibility that the physical and psychic symptoms of Vincent Van Gogh may have been due to chronic lead poisoning. The following are among the clinical symptoms described by Van Gogh in his autographed letters: initial debilitation, stomatitis with loss of teeth, recurring abdominal pains, anemia (with a "plumbic" skin tone), neuropathy of the radial and saturnine encephalopathy, including epileptic crises, progressive character changes and periods of delirium, all of which meet present criteria for diagnosis of Organic Mental Disorder due to cerebral lesion or somatic illness, and Organic Character Disorder (DSM-IV-R). Apha-thujone, found in absinthe and in many popular herbal medicines, may also have contributed to Van Gogh symptoms since he was a well-known absynthe drinker. Many countries, including Mexico, have implemented politics aimed to eliminate lead from the majority of their industrial processes. This has been carried out with considerable effort, and in some cases, with open confrontations between the scientific community and industrial sector. Although there have been actually significant advances to eliminate lead from many products (gasoline, painting manufacturing, etc.), lead is not degradable, thence once it is released in the environment it remains there for long periods of time. This implies that we should have to deal with lead poisoning in the years to come and to be aware of this diagnostic possibility in any suspicious case. This review is centered in the description of the molecular mechanisms of lead toxicity and its repercussion in the cellular excitability and central nervous system function.