SRP om thalidomid i Biologi A og Kemi A

Abstract

Thalidomide, a drug used as a non-CNS-depressant sedative during 1957-62, proved to be teratogenic, as estimated 10,0000 babies deformed due to this drug were born during this period. The abnormalities included limb truncations, ear abnormalities, visceral organ defects and urogenital defects. Since then, a number of theories trying to explain the teratogenic mechanism have evolved. The most convincing of these involves free radicals produced by thalidomide that in turn target growth factors in the developing limbs. Thus, thalidomide was the first drug to highlight the importance of chirality in pharmacologically active substances, as the drug was sold as a racemic mixture containing enantiomers with indeed very different therapeutic effects. This discovery revealed that the enantiomers of a drug can host different therapeutic effects or potencies of a given effect. Asymmetric synthesis of single enantiomers has solved some problems in relation to stereoselective drug action, but racemisation of the single enantiomers of thalidomide and its chemical analogs has rendered such an effort useless in the case of thalidomide. Structureactivity relationship studies of the single enantiomers are also made clinically irrelevant by this fact. Studies of the structure of thalidomide has led to the suggestion that, due to its similarity to barbituric acid, the sedative effects are due to the presence of the glutarimide ring. Other studies have revealed that metabolic activation may be necessary for some of the therapeutic effects of thalidomide, and that fluorination of the benzene ring in the molecule can potentiate its antiangiogenic effects. The therapeutic potential of thalidomide, which has now been approved in a number of countries for the treatment of ENL and multiple myeloma, is severely hindered by its teratogenic action, but as far as this effect is strictly prevented, thalidomide and its analogs seem to present a new, promising future for these patients.

Indledning: Thalidomid – hvad er det?

Thalidomid er et lægemiddelstof, som oprindeligt blev udnyttet for dets sedative og antiemetiske virkning, som bl.a. skulle hjælpe kvinder, som led af kvalme under graviditeten. Snart efter stoffets indførelse på markedet i 1950’erne i flere europæiske lande blev det klart, at mange af de mødre, som indtog stoffet, senere hen fik børn med alvorlige misdannelser, især på ekstremiteterne, hvorfor stoffet hurtigt blev taget af markedet. Allerede efter et par år blev stoffets gavnlige effekt på den alvorlige hudlidelse leprareaktionen, som sker hos patienter med spedalskhed, opdaget.