RESUMEN
Clopidogrel is a widely used anti-platelet agent for the prevention of arterial thrombosis. Clopidogrel is administered as a pro-drug and metabolised to its active metabolite by the hepatic cytochrome P450 2C19 (CYP2C19) enzyme. The active metabolite is responsible for the anti-platelet activity of clopidogrel. Recent studies demonstrate that single nucleotide polymorphisms, (SNP's), in the gene for CYP2C19 result in significantly reduced production of the active metabolite of clopidogrel. Additional studies demonstrate that patients with SNP's in the CYP2C19 gene, including CYP2C19*2,*3,*4, and *5, have reduced production of the active metabolite of clopidogrel, reduced inhibition of platelet aggregation and increased incidence of coronary, cerebrovascular, and coronary stent thrombosis. We have been interested in determining the CYP2C19 genotype in cases of coronary stent thrombosis whilst on clopidogrel treatment and provide two case reports of coronary stent thrombosis whilst taking clopidogrel with subsequent CYP2C19 genotyping. As patients at risk of atherothrombosis in general, and stent thrombosis in particular, may be receiving or considered for anti-platelet therapy including clopidogrel, genotyping for CYP2C19 SNP's may be of benefit in the selection of appropriate anti-platelet therapy.
Asunto(s)
Resistencia a Medicamentos/genética , Inhibidores de Agregación Plaquetaria/administración & dosificación , Polimorfismo de Nucleótido Simple , Stents , Trombosis/genética , Trombosis/terapia , Ticlopidina/análogos & derivados , Hidrocarburo de Aril Hidroxilasas , Clopidogrel , Estenosis Coronaria/genética , Estenosis Coronaria/terapia , Citocromo P-450 CYP2C19 , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Infarto del Miocardio/genética , Infarto del Miocardio/terapia , Agregación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/genética , Inhibidores de Agregación Plaquetaria/farmacocinética , Trombosis/etiología , Ticlopidina/administración & dosificación , Ticlopidina/farmacocinéticaRESUMEN
Earlier we generated novel derivatives of the hydroxamate-based histone deacetylase inhibitor (HDACi), Oxamflatin (Ox), which demonstrate considerable HDACi activity. Here the effects of one such derivative, Metacept-1 (MCT-1), alone or in combination with tamoxifen on mammary tumour growth have been assessed in a syngeneic orthotopic model. MCT-1 alone resulted in a trend towards inhibition of growth of 4T1.2 mammary tumours. Since the combination of MCT-1 and tamoxifen up-regulates estrogen receptor expression in 4T1.2 cells in vitro, we tested this combination and found a significant reduction in primary tumour growth over tamoxifen treatment alone. Taken together, these observations suggest that the novel HDACi MCT-1 may warrant further exploration in the treatment of estrogen receptor positive breast carcinoma, particularly when used in combination with conventional agents such as tamoxifen.