Agentes dopaminérgicos centrales análogos N-aralquil metoxilados del 2-aminoindano / Central dopaminergic agents analogues of N-aralkyl methoxylated of 2-aminoindane

RESUMEN La neurotransmisión dopaminérgica interviene en los mecanismos que involucran los procesos motores, cognoscitivos, conductuales y neurocrinos y su mal funcionamiento la involucra en los trastornos neurodegenerativos que afectan al sistema nervioso central (SNC), tales como en la enfermedad de Parkinson y la enfermedad de Huntington, entre otras. Con el propósito de encontrar una solución terapéutica a estas patologías, en publicaciones anteriores hemos reportado la síntesis, la evaluación farmacológica y el estudio teórico computacional de los compuestos análogos mono y dihidroxilados (sobre el anillo indano) del N-aralquil-2-aminoindano 4-8, análogos 4,7-dimetoxi-2-aminoindano-N-aralquil, bajo sus formas metoxiladas sobre el anillo bencénico del fragmento aralquil 9 y el derivado fenólico 10, así como también los análogos diclorados del N-aralquil-2-aminoindano 11 con actividades dopaminérgicas centrales. En el presente trabajo se sintetizaron los clorhidratos del 2-aminoindano- N-[2-(mono o dimetoxi)-fenil)-1-metil-etil] 12-15 y su evaluación farmacológica mostraron respuestas agonísticas como potenciales agentes antihuntington y antipárkinson.

SUMMARY Dopaminergic neurotransmission is implicated in mechanisms that involve motor, cognoscitive, conductual and neurocrine process, and its malfunction involucrates it in neurodegenerative disorders affecting central nervous system (CNS), like Parkinson's disease and Huntington's disease, among others. On the purpose of finding some therapeutic for these pathologies, in previous researches we have reported synthesis, pharmacological evaluation and theoretical computational study of compounds analogues mono or di hydroxilated (on indane ring) of N-aralkyl-2-aminoindane 4-8, analogues 4,7-dimethoxy-2-aminoindane-N-aralkyl, under its methoxylated forms on benzene ring of aralkyl fragment 9 and phenolic derivate 10, also dichlorade analogs of N-aralkyl-2-aminoindane 11 with central dopaminergic activities. In this work were synthesized hydrochlorides of 2-aminoindane-N-[(mono or di methoxy)-phenyl-1-methyl-ethyl] (12-15) and its pharmacologic evaluation showed agonistic responses as potential agents anti Huntington and/or anti Parkinson.

La enfermedad de Parkinson: neurología para psiquiatras / Parkinson's disease: neurological bases for psychiatrists

Parkinson's disease is a progressive and degenerative disease due to the loss of the substantia nigra dopaminergic neurons in the mesencephalon. Its manifestations are: tremor at rest, rigidity and slowing of movements, and alterations in posture and gait. The early onset of dementia or the presence of hallucinations, not related to the dopaminergic treatment, are associated with the presence of dementia with Lewy bodies (DLB) or Alzheimer's disease. The scales used to assess the stage and severity of Parkinson's disease are: the scale of Stages of Hoehn and Yahr, and the Unified Parkinson's Disease Rating Scale. Although there is not a drug that stops the progression of Parkinson's disease, the current treatment for this illness consist in: a) dopamine replacement through the use of its precursor, levodopa, b) administering substances, like ropinirole, pramipexole, and bromocriptine, that increase dopamine activity to stimulate their receptors, and c) inhibiting the enzymes that destroy dopamine as the catechol- O-methyltrans-ferase with entacapone, and monoamine oxidase type B (MAO B) with selegiline and rasagiline. Surgical treatment of Parkinson's disease consists of ablative procedures and deep brain stimulation. This review describes their indications, administration and side effects.

La enfermedad de Parkinson es una enfermedad degenerativa y progresiva debida a la pérdida de las neuronas dopaminérgicas de la sustancia nigra del mesencéfalo. Sus manifestaciones son: temblor en reposo, rigidez y enlentecimiento de los movimientos, alteraciones en la postura y en la marcha. La aparición temprana de problemas en la memoria o alucinaciones, no debidas al tratamiento, indica la presencia de demencia con cuerpos de Lewy. Las escalas utilizadas para evaluar el estado y la gravedad de la enfermedad de Parkinson son: la Escala de los Estadios de Hoehn y Yahr y la Escala Unificada de Calificación de la Enfermedad de Parkinson (UPDRS). Aunque todavía no existe un medicamento que detenga la evolución de la enfermedad de Parkinson, el tratamiento actual consiste en mejorar los síntomas mediante: a) la reposición de la dopamina por medio del uso de su precursor (levodopa, L-Dopa), b) la administración de sustancias que aumentan la actividad dopaminérgica al estimular a sus receptores (ropinirol, pramipexol, bromocriptina) y c) la inhibición de las enzimas que destruyen la dopamina como la catecol- O- metiltransferasa (COMT) con la entacapona, y a la monoamino oxidasa tipo B (MAO B) con la selegilina y la rasagilina. Existe además el tratamiento quirúrgico de la enfermedad de Parkinson que consiste en procedimientos ablativos y la estimulación cerebral profunda. En esta revisión se describen los elementos básicos de la enfermedad, su cuadro clínico y sus complicaciones. En una segunda parte se aborda el tratamiento médico con sus indicaciones, administración y efectos secundarios, y para terminar se describirá el tratamiento quirúrgico.

Cabergoline Effect on Blood Sugar in Type 2 Diabetic Patients with Oral Agent Failure

Ergot-derived dopamine D2 receptor agonists are the usual treatment of hyperprolactinemia and Parkinson’s disease and recently bromocriptine has been approved for the treatment of type 2 diabetes. The aim of this study was the evaluation of short-term effect of cabergoline in poorly controlled diabetic patients with oral agent failure who refused insulin therapy. Methods: This study was performed in 17 overweight women and men with type 2 diabetes with persistent hyperglycemia in spite of treatment with maximum dose of sulfonylurea, metformin and pioglitazone. 10 patients (group I) randomized to be treated with cabergoline 0.5 mg weekly for 3 months and 7 patients (group II) with placebo. Fasting and postprandial plasma glucose concentration and HbA1c measured in beginning and end of the study. Results: FBS decreased from 210.70± 21.29 to 144.90± 26.56 mg/dl in cabergoline group whereas it decreased in placebo group insignificantly. Postprandial blood glucose decreased from 264.2±28 mg/dl to 203.6±34.34 mg/dl in cabergoline group whereas it increased in placebo group insignificantly.HbA1c decreased in cabergoline group from 8.48±0.44 to 7.7±0.11 whereas in control group it increased insignificantly from 8.7±0.33 to 8.8±0.16. Conclusion: Cabergoline improves glycemic control in type 2 diabetic patients with oral agent failure. It reduces both fasting and postprandial plasma glucose levels and causes 0.45–1.11 reduction in HbA1c.

Valvulopatía cardiaca asociada al uso de agonistas dopaminérgicos en pacientes con hiperprolactinemia / Valvular heart disease associated with use of dopaminergic agonists in patients with hyperprolactinemia

La cabergolina y la bromocriptina son fármacos agonistas dopaminérgicos utilizados para tratar la hiperprolactinemia, así como la enfermedad de Parkinson. Entre sus efectos adversos considerados como muy raros se ha descrito la capacidad de inducir cambios fibróticos en el aparato valvular cardiaco, inicialmente descritos en pacientes con enfermedad de Parkinson, en quienes se emplean dosis superiores a las que de manera habitual se emplean en el tratamiento de la hiperprolactinemia. Varios estudios han señalado la evidencia de estos hechos y de los posibles mecanismos por los cuales la afectación valvular ocurre. Existen hasta el momento pocas investigaciones sobre el asunto en pacientes con hiperprolactinemia, pero la mayoría de ellos indican que su empleo en este tipo de pacientes no produce afectación valvular clínicamente relevante, hecho que pudiera estar en relación con las dosis empleadas (como promedio 10 veces inferiores a las usadas en la enfermedad de Parkinson); sin embargo, se han detectado algunas anomalías subclínicas en el aparato valvular. Dado lo novedoso del tema y la poca evidencia de estos hechos en pacientes tratadas por hiperprolactinemia se ofreció una amplia revisión sobre el tema(AU)

Cabergoline and bromocriptine are dopaminergic agonists drugs used in hyperprolactinemia treatment, as well as in patients with Parkinson's disease. Among its adverse effects considered as very inusual is included the ability to induce fibrotic changes in cardiac valvular tract first described in patients with Parkinson disease using doses higher than those usually used in hyperprolactinemia treatment. Some studies have mentioned the evidence on these facts and of the possible mechanisms causing the valvular affection. Until now, there are not much researches on this subject in patients with hyperprolactinemia, but most indicated that its use in this kind of patient can not to produce a clinically relevant valvular afection, fact tha may to be related to the dose used (on average 10 times lower than those used in Parkinson's disease); however, some subclinical anomalies have been detected in valvular tract. Due to this novel subject and the scarce evident of these facts in patients treated by hyperprolactinemia, we offered an review of the subject(AU)

Abordagem prática da hiperprolactinemia no Distrito Federal / Practical approach to hyperprolactinemia at the Distrito Federal

A hiperprolactinemia é a afecção mais comumente relacionada ao eixo hipotálamo-hipofisário. Na abordagem diagnóstica da hiperprolactinemia, as causas medicamentosas devem ser descartadas. Adicionalmente, as doenças sistêmicas podem resultar em elevação da prolactina, como observado no hipotireoidismo, na insuficiência renal e na insuficiência hepática. Dentre os indivíduos assintomáticos, a macroprolactinemia deve ser investigada e descartada. Excluídas essas causas, deve ser realizada ressonância nuclear magnética, em busca de adenoma hipofisário secretor de prolactina. O "efeito gancho" também deve ser pesquisado em algumas circunstâncias. Os objetivos primários do tratamento em pacientes com prolactinomas são a normalização dos níveis de prolactina, com restauração das funções gonadal e sexual, e a redução do volume tumoral. Os agonistas dopaminérgicos são os tratamentos de escolha, considerando-se sua eficácia e segurança. A cirurgia transesfenoidal permanececomo opção nos raros casos em que a terapia medicamentosa não é efetiva. Novas drogas estão em investigação e, possivelmente, haverá outras opções para o tratamento da hiperprolactinemia no futuro.

Hyperprolactinemia is the commonest affection related to hypothalamus-pituitary axis. In the diagnostic approach of hyperprolactinemia, pharmacologic causes should be ruled out. Additionally, systemic diseases can result in prolactin elevation, as observed in hypothyroidism, renal and liver failure. Among asymptomatic individuals, macroprolactinemia should be investigated and ruled out. After excluding these causes, magnetic resonance image should be performed, looking for a prolactin-producing pituitary tumor. The "hook effect" should also be investigated in specific circumstances. The primary goals of therapy in patients who have prolactinomas are the normalization of prolactin levels, with restoration of gonadal and sexual function, and reduction of tumor size. Dopaminergic agonists are the treatment of choice, considering their efficacy and security. Transphenoidal surgery remains an option for the rare cases when medical therapy is ineffective. New drugs are under investigation, and possibly there will be other options for treatment of hyperprolactinemia in the future.

Síndrome das pernas inquietas: o que todo médico deve saber / Restless legs syndrome: what every physician should know

A síndrome das pernas inquietas é uma neuropatia causadora de relevante deterioração da qualidade devida nos pacientes acometidos. É conhecida desde a década de 40, mas somente nos últimos anos tem sidoamplamente investigada. Trabalhos recentes têm apontado a importância da história familiar na incidência eno prognóstico da doença, e alguns genes envolvidos já foram identificados. Embora a fisiopatogenia não estejatotalmente elucidada, sabe-se que deficiência de ferro e alterações das vias dopaminérgicas são a basepara o desenvolvimento do quadro. A síndrome das pernas inquietas é caracterizada por sintomas subjetivosde desconforto, principalmente em membros inferiores, acompanhada da urgência em movimentar as regiõesacometidas com relativa atenuação dos sintomas com a movimentação. Por se manifestar predominantementeao fim do dia, nos períodos de repouso e inatividade, o quadro resulta em má qualidade do sono e sonolênciaexcessiva diurna. A gravidade desse quadro é amplamente variável no tempo e no espaço. O diagnóstico éessencialmente clínico. As investigações laboratoriais geralmente são usadas para confirmação da causa. Asopções terapêuticas mostram os agentes dopaminérgicos como a classe mais eficiente de medicamentos, masse podem incluir opiáceos ou benzodiazepínicos em certos casos. Há muitas questões a respeito do mecanismoe do tratamento da síndrome das pernas inquietas, que demandam estudos mais consistentes

The restless legs syndrome is a neurological disorder responsible for reduced quality of life secondary to sleep deterioration. It has been described in the 40?s, but only recently more extensively investigated. The role playedby familiar history has only recently been identified with the determination of some possibly implicated genes.Although its physiopathology has not yet been completely elucidated, it seems possible that iron metabolism anddopaminergic mechanisms form the physiologic basis for understanding this disorder temporal development. Themain features of restless legs syndrome are urging to move the limbs often associated to subjective discomfortsensations, improved by moving or fidgeting. There is a circadian worsening with the symptoms increasing duringthe day and with inactivity, not uncommonly resulting in a bad sleep?s night and daytime sleepiness. The severityof restless legs syndrome symptoms varies in time and space. The diagnostic is essentially clinical. Laboratorywork up is mostly used for etiological confirmation. Therapeutic options show dopaminergic agents as the mostefficient drug class, but it can also include opiates or benzodiazepines in certain cases. There are many openquestions concerning restless legs syndrome mechanisms and treatment options that need to be addressed byconsistent research trials.