Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants and aspirin. Despite progress in the sciences, these drugs still remain a challenge and mystery. The development of low molecular weight heparins (LMWHS) and the synthesis of heparinomimetics represent a refined use of heparin. Additional drugs will continue to develop. However, none of these drugs will ever match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as adenosine diphosphate receptor inhibitors, GPIIb/IIIa inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains the approach of choice to manage thrombotic disorders. The new anticoagulant targets, such as tissue factor, individual clotting factors, recombinant forms of serpins (antithrombin, heparin co-factor II and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin and site specific serine proteases inhibitors complexes have also been developed. There is a major thrust on the development of orally bioavailable anti-Xa and IIa agents, which are slated to replace oral anticoagulants. Both the anti-factor Xa and anti-IIa agents have been developed for oral use and have provided impressive clinical results. However, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons, the US Food and Drug Administration did not approve the orally active antithrombin agent Ximelagatran for several indications. The synthetic pentasaccharide (Fondaparinux) has undergone clinical development. Unexpectedly, Fondaparinux also produced major bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and clopidogrel have validated COX-1 and P2Y12 receptors as targets for new drug development. Prasugrel, a novel thienopyridine, Cangrelor and AZD 6140 represent newer P2Y12 antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas Prasugrel requires metabolic activation. While clinically effective, recent results have prompted a closure of a clinical trial with Prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive, however, none of these are expected to replace the conventional drugs in polytherapeutic approaches. Heparins, warfarin and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders for years to come.
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PMID:Changing trends in anti-coagulant therapies. Are heparins and oral anti-coagulants challenged? 1850 23

Chemoprevention of colorectal cancer is a promising science that has particular importance due to the limited success of current treatments for most advanced common malignancies. Many chemopreventive agents have been studied including cyclooxygenase (COX) inhibitors. Two isoforms of the COX enzymes are COX-1 and COX-2. COX-1 is constitutively expressed in normal tissue, serving an important role in tissue homeostasis, whereas COX-2 is an inducible enzyme, which is markedly overexpressed at sites of inflammation and colorectal neoplasms. The preventive efficacy of traditional nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and/or COX-2, has considerable support from animal and epidemiological studies; however, there are well-documented toxicities associated with NSAID use. These adverse effects are attributed to NSAIDs' inhibition of COX-1. The development of COX-2 specific inhibitors gave hopes of bypassing the associated traditional NSAID toxicities while better targeting tissues sustaining inflammation and neoplasia. The PrsSAP, APC and APPROVe trials demonstrated the efficacy of COX-2 specific inhibitors in preventing the recurrence of sporadic colorectal polyps. However, the trials were terminated early due to discovery of significant cardiovascular toxicity, although the exact extent of this toxicity remains unclear. The exact mechanisms through which NSAIDs exert their cancer preventing effects are currently unknown; inhibition of COX-2 is of great importance, but COX-2 independent pathways exist as well. In addition, the efficacy of NSAID use for cancer prevention can differ significantly between individuals. Personalized medicine in this field is also greatly anticipated. Combination therapy is under extensive research in order to improve efficacy while reducing toxicity profiles. Chemoprevention of colorectal cancer is largely possible, but the ultimate drug and proper patient selection, among other elements of the cancer prevention equation, are still needed.
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PMID:Role of cyclooxygenase-2 in pathogenesis and prevention of colorectal cancer. 2108 6


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