Personalized Cardiology - Applications of Biotechnology in Cardiovascular Therapeutics - page 333

influence warfarin dosage requirements would be of great benefit in the manage-
ment of patients at risk for coagulation disorders. Polymorphisms in the vitamin K
epoxide reductase multiprotein complex (VKOR) also affect warfarin metabolism
in rats (Rost et al. 2004 ). Mutations in one of the complex's subunits, VKORC1,
confer warfarin resistance in some human disorders. Overexpression of the wild-
type protein made rats sensitive to the treatment. Future studies will genotype for
both CYP2C9 and VKORC1 when prescribing warfarin before surgery.
Heparin is used to prevent and treat thromboembolic diseases. One of the most
serious adverse reactions to heparin is an immune-related thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) can result in severe thromboembolic
complications and death. Heparin-induced antibodies recognize and bind to hepa-
rin-platelet factor 4 complexes and subsequently activate platelets via the platelet
Fc-receptor to mediate HIT. A single-nucleotide polymorphism commonly occurs
in the platelet Fc-receptor gene, resulting in an arginine or histidine at codon 131
(131Arg/His), and appears to affect platelet aggregation.
Antiplatelet Therapy
Prasugrel, an approved antiplatelet drug for cardiovascular thrombotic disease, is a
prodrug with rapid and almost complete absorption after oral ingestion of a loading
dose. It is metabolized into its active form, which binds irreversibly to the adenos-
ine diphosphate (ADP) P2Y12 receptor on platelets for their lifespan, thereby
inhibiting their activation and decreasing subsequent platelet aggregation. Hydrolysis
by intestinal carboxylesterases and oxidation by intestinal and hepatic cytochrome
P-450 enzymes convert prasugrel into its active metabolite. Prasugrel has a greater
antiplatelet effect than clopidogrel because it is metabolized more efficiently.
Genetic polymorphisms affecting the cytochrome P450 system may explain some
of the differences in metabolism between prasugrel and clopidogrel.
Nanotechnology-Based Personalized Therapy
of Cardiovascular Diseases
The future of cardiovascular diagnosis is already being impacted by nanosystems that
can both diagnose pathology and treat it with targeted delivery systems (Wickline
et al. 2006 ). The potential dual use of nanoparticles for both imaging and site-targeted
delivery of therapeutic agents to cardiovascular disease offers great promise for indi-
vidualizing therapeutics. Image-based therapeutics with site-selective agents should
enable verification that the drug is reaching the intended target and a molecular effect
is occurring. Experimental studies have shown that binding of paclitaxel to smooth
muscle cells in culture has no effect in altering the growth characteristics of the cells.
If paclitaxel-loaded nanoparticles are applied to the cells, however, specific binding
elicits a substantial reduction in smooth muscle cell proliferation, indicating that