El aminorex, la fenfluramina y la clorfentermina son sustratos transportadores de la serotonina. Implicaciones para la hipertensión pulmonar primaria
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R B Rothman1, M A Ayestas, C M Dersch
1Clinical Psychopharmacology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Md, USA. rrothman@intra.nida.nih.gov
Circulation
|August 24, 1999
Resumen
Ciertos medicamentos anorexicos aumentan el riesgo de hipertensión pulmonar primaria (HPP) al interactuar con los transportadores de serotonina (5-HT). El desarrollo de nuevos medicamentos que eviten estas interacciones de transportadores podría ofrecer tratamientos más seguros para la obesidad y otros trastornos.
Área de la Ciencia:
- Farmacología Farmacología.
- La neurociencia es la neurociencia.
- Investigación Cardiovascular Investigación Cardiovascular Investigación Cardiovascular Investigación Cardiovascular Investigación Cardiovascular
Sus antecedentes:
- La fentermina/fenfluramina (phen/fen) trata eficazmente la obesidad, pero conlleva riesgos como la valvulopatía cardíaca y la hipertensión pulmonar primaria (HPP).
- Los efectos secundarios graves de los agentes anorexicos existentes limitan su uso clínico, destacando la necesidad de alternativas más seguras.
- El desarrollo de medicamentos con efectos neuroquímicos similares al fen/fen pero sin resultados adversos es un objetivo terapéutico significativo.
Objetivo del estudio:
- Investigar la hipótesis de que la fenfluramina y otras drogas anorexicas aumentan el riesgo de PPH a través de las interacciones con los transportadores de serotonina (5-HT).
- Utilizar modelos de cerebro de rata para evaluar los efectos de los fármacos sobre el eflujo de 5-HT y la función del transportador de monoaminas como indicador del riesgo de PPH.
- Identificar las características específicas del fármaco asociadas con el desarrollo de PPH.
Principales métodos:
- Examinado in vivo el eflujo de 5-HT y in vitro la función del transportador de monoaminas en el cerebro de la rata.
- Se han probado medicamentos anorexicos seleccionados, incluidas la fenfluramina, el aminorex y la clorfentermina.
- Interacciones correlacionadas del transportador de fármacos con riesgo conocido o sospechado de hipertensión pulmonar primaria (HPP).
Principales resultados:
- Los fármacos asociados con un mayor riesgo de HPP (aminorex, fenfluramina, clorfentermina) fueron identificados como sustratos transportadores de 5-HT.
- Los fármacos no relacionados con el riesgo de PPH mostraron interacciones menos potentes con los transportadores de 5-HT.
- Se demostró una correlación entre la actividad del sustrato transportador de 5-HT y el riesgo de PPH.
Conclusiones:
- Se especula que los sustratos del transportador 5-HT pueden trasladarse a las células pulmonares, lo que podría causar PPH debido a la retención de fármacos, la toxicidad o la susceptibilidad individual.
- Propuso que los nuevos medicamentos puedan diseñarse como sustratos transportadores sin efectos secundarios adversos.
- Se sugieren posibles aplicaciones terapéuticas para estos medicamentos más seguros en el tratamiento de la obesidad, la drogodependencia y la depresión.
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