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.

Vasorelaxant activity of Euphorbia furcillata Kunth mainly by activation of NO/cGMP pathway and calcium channel blockade / Actividad vasorrelajante de Euphorbia furcillata Kunth principalmente por activación de la vía NO/GMPc y bloqueo de canales de calcio]

The aim of current study was to determinate ex vivo and chromatographic fingerprint by HPLC of four extracts of Euphorbia furcillata K. Ethyl acetate extract of Euphorbia furcillata (EaEEf) was the most effective and potent extract (Emax=98.69±1.24%) and its effect was partially endothelium-dependent. Functional vasorelaxant mechanism of action of EaEEf was determinate, EaEEf showed efficient relaxation of KCl [80 mM]-induced contraction and norepinephrine and CaCl2 contraction curves showed diminution of maximal contraction in the presence of EAEEf and EaEEf-relaxation curve was shifted to the right in the presence of L-NAME (nitric oxide synthase inhibitor) and ODQ (guanylate cyclase inhibitor). Chromatographic fingerprints analysis suggests presence of diterpenoid such as abietane, tigliane, and ingenane skeletons. Our experiments suggest the EaEEf vasorelaxant activity could be attributed to diterpenoid molecules whose mechanism involves nitric oxide production and calcium channel blockade.

Se determinó el efecto vasorrelajante ex vivo y los perfiles cromatográficos mediante HPLC de cuatro extractos de Euphorbia furcillata K.. El extracto de acetato de etilo de E. furcillata (EaEEf) fue el más eficaz y potente en la contracción inducida por norepinefrina (Emax=98.69±1.24%) y el efecto fue parcialmente dependiente del endotelio vascular. Se determinó el mecanismo de acción vasorrelajante para EaEEf, este mostró ser eficaz sobre la contracción inducida por KCl [80 mM] y la curva de contracción en respuesta a norepinefrina y CaCl2 en presencia de EaEEf mostró disminución en la contracción máxima, mientras que la curva de relajación de EaEEf en presencia de L-NAME (inhibidor de óxido nítrico sintasa) y ODQ (inhibidor de guanilato ciclasa) se desplazó hacia la derecha. El análisis cromatográfico de EaEEf sugiere la presencia de moléculas diterpenoides como abietano, tigliano y esqueletos de ingenano. Nuestros resultados sugieren que el efecto vasorrelajante de EaEEf podría atribuirse a moléculas diterpenoides, cuyo mecanismo de acción involucra la producción de óxido nítrico y bloqueo de canales de calcio.

Hipertrofia gengival induzida por anlodipina: [revisão] / Amlodipine induced gingival overgrowth: [review]

JUSTIFICATIVA E OBJETIVOS: A hipertrofia gengival (HG) é reconhecidamente um grave efeito adverso a medicamentos, frequentemente encontrado em pacientes em uso de imunossupressores, anticonvulsivantes ou anti-hipertensivos. Nesta última classe, se destaca a nifedipina, porém tem sido crescente o númerode casos secundários ao uso da anlodipina. O objetivo deste estudo foi observar na literatura os dados existentes sobre a epidemiologia, características clínicas e histopatológicas, a prevenção e o tratamento da HG associada a este fármaco. CONTEÚDO: A coleta de dados foi realizada através dos Bancos de Dados BIREME, Pubmed e Medline. As palavras pesquisadas foram: aumento gengival, hipertrofia gengival, hiperplasia gengival, amlodipine induced gingival overgrowth, gingival overgrowth induced by calcium channel blockers, drug induced gingival overgrowth. No bando de dados BIREME foram encontrados 24 artigos referentes ao assunto pesquisado, na Pubmed e Medline foram encontrados 47 artigos pertinentes ao contexto enfocado. Do total, foram utilizados 34 artigos na revisão de literatura. CONCLUSÃO: A anlodipina é um fármaco que comprovadamente atua no tecido gengival causando o seu aumento. Sendo assim, a HG induzida por este fármaco tem aspectos clínicos característicos e é uma reação adversa individualizada devido à influência multifatorial. Em razão do atual aumento do uso deste bloqueador de canal de cálcio, a incidência da HG torna-se cada vez mais crescente. Desta forma, por gerar comprometimento funcional e estético ao indivíduo acometido, é de suma importância o conhecimento desta condição pelos profissionais de saúde para que ocorra a correta identificação do quadro e o estabelecimento precoce de uma conduta terapêutica adequada.

BACKGROUND AND OBJECTIVES: Gingival hyperplasia(GH) is admittedly a severe adverse effect of medications, frequently found in the immunosupressors, anticonvulsivants or antihypertensives users. Among this last class of medications, nifedipine is featured, but adverse effects due amlodipine using have been increasing. The aim of this study was to examine the existing data on the literature about epidemiology, clinical and histopathological features, prevention and treatment of GH due this medication. CONTENTS: The data collection was performed through BIREME, Pubmed and Medline databases. The words searched were: gingival enlargement, gingival hypertrophy, gingival hyperplasia, amlodipine induced gingival overgrowth, gingival overgrowth induced by calcium channel blockers, drug induced gingival overgrowth. In the BIREME databases were found 24 articles concerningon the topic searched, in Pubmed and Medline were found 47 relevant articles focused on the context. Totally, 34 articles ofthe literature review were used. CONCLUSION: Amlodipine is a drug that acts in the gingival tissue inducing its enlargement. Therefore, GH induced by thisdrug has typical clinical features and is an individualized adverse effect by the multifactorial influence. Due to the current increasein the use of calcium channel blocker, the incidence of GH becomes increasingly common. However, by the functional and esthetic commitment of the affected individual, is of high importance the knowledge about this condition by health professionals aiming the correct identification of this case and the early establishment of an appropriate treatment.

Non-paraneoplastic Lambert-Eaton myasthenic syndrome: a brief review of 10 cases / Síndrome miastênica de Lambert-Eaton não paraneoplásica: uma breve revisão de dez casos

Lambert-Eaton myasthenic syndrome (LEMS) is an immune-mediated disorder of the presynaptic neuromuscular transmission, which more frequently occurs as the remote effect of a neoplasm, in the paraneoplastic form (P-LEMS), or in a non-paraneoplastic form (NP-LEMS); but few studies describe the clinical features of NP-LEMS. We analyzed the clinical manifestations, laboratory findings, electrophysiological studies, and treatment responses in ten Brazilian patients suffering from NP-LEMS. The mean age was 41.5 years. More often neurological findings were hyporeflexia or areflexia with a post-exercise improvement. Treatment response occurred with pyridostigmine, guanidine, prednisone, azathioprine, and cyclosporine; but not response was observed after intravenous immunoglobulin and plasma exchange. Age at onset, clinical manifestations, and electrophysiological abnormalities can help more in the diagnosis than serum antibodies; the symptomatic treatment with pyridostigmine was effective; and the immunosuppressive treatment with prednisone, azathioprine, or cyclosporine was more beneficial than plasma exchange or intravenous immunoglobulin treatment.

A síndrome miastênica de Lambert-Eaton (LEMS) é uma desordem imunomediada da transmissão neuromuscular pré-sinaptica, que mais frequentemente ocorre como efeito à distância de uma neoplasia, na forma paraneoplásica (P-LEMS), ou na forma não paraneoplásica (NP-LEMS); porém poucos estudos têm descrito as características da NP-LEMS. Nós analisamos as manifestações clínicas, laboratoriais, eletrofisiológicas, e resposta ao tratamento em dez pacientes brasileiros com NP-LEMS. A idade média foi de 41,5 anos. A manifestação neurológica mais freqüente foi hiporeflexia ou arreflexia com melhora após o exercício. A resposta ao tratamento ocorreu com piridostigmina, guanidina, prednisona, azatioprina, e ciclosporina; mas não com imunoglobulina intravenosa e plasmaférese. A idade de início, manifestações clínicas e eletrofisiológicas ajudaram mais no diagnóstico do que os anticorpos séricos; o tratamento sintomático com piridostigmina foi efetivo; e o tratamento imunossupressor com prednisona, azatioprina, ou ciclosporina beneficiou mais do que a plasmaférese ou a imunoglobulina intravenosa.