Cardiovascular disease inhibitors

As endothelins mediate potent vasoconstrictor effects, ECE inhibitors and endothelin receptor antagonists were developed for the treatment of cardiovascular diseases, such as acute and chronic heart failure, pulmonary hypertension and subarachnoid haemorrhage. As ETa recqrtors have potent mitogenic responses and may promote progression of ovarian and prostate cancer and bone metastases ETA receptors are also considered as a potential targets for anti-tumour activity. 

Recent data suggest that COX-2 inhibitors, including rofe-coxib, valdecoxib, and celecoxib, may increase the risk for MI and stroke.47 There is also some evidence that the non-selective NSAIDs may increase the risk for cardiovascular events.47,48 Rofecoxib was withdrawn from the market in late 2004 because of safety concerns. The FDA requested the withdrawal of valdecoxib from the market in 2005. The FDA also asked the manufacturers of celecoxib and non-selective NSAIDs (prescription and over-the-counter) to include information about the potential adverse cardiovascular effects of these drugs in their product labeling. The cardiovascular risk with COX-2 inhibitors and NSAIDs may be greatest in patients with a history of, or with risk factors for, cardiovascular disease. The American Heart Association recommends that the use of COX-2 inhibitors be limited to low-dose, short-term therapy in patients for whom there is no appropriate alternative.48 Patients with cardiovascular disease should consult a clinician before using over-the-counter NSAIDs. 

Low risk Has asymptomatic cardiovascular disease Has well-controlled hypertension Has mild, stable angina Has mild congestive heart failure (NYHA Class 1) Palient can be started on phosphodiesterase inhibitor... 

The calcineurin inhibitors cyclosporine and tacrolimus block T cell activation by inhibiting the production of IL-2. They are associated with significant adverse events, such as nephrotoxicity, cardiovascular disease, posttransplant diabetes, and neurotoxicity. 

ACE inhibitors and angiotensin-receptor blockers (ARB) have definite benefits in patients with nephropathy and are believed to have renoprotective effects in most patients. Due to their ability to cause an initial bump in serum creatinine, these agents should be used cautiously when employed in combination with the calcineurin inhibitors. The dihydropyridine calcium channel blockers have demonstrated an ability to reverse the nephrotoxicity associated with cyclosporine and tacrolimus (Table 52-8). In general, antihypertensive therapy should focus on agents with proven benefit in reducing the progression of cardiovascular disease and should be chosen on a patient-specific basis.55 See Chapter 2 for further recommendations for treating HTN. 

NSAIDs may accentuate the increased risk of cardiovascular events inherent in patients with RA. Increases in blood pressure and fluid retention may exacerbate existing cardiovascular disease. With the evidence associating COX-2 inhibitors with cardiovascular disease, clinicians must carefully evaluate the potential risks of NSAID therapy against the potential benefits.2 See Chap. 55 for additional discussion of NSAID therapy. 

APV, amprenavir ATV, atazanavir CNS, central nervous system CVD, cardiovascular disease D/C, discontinue ddC, zalcitabine ddl, didanosine DEXA, dual-energy x-ray absorptiometry d4T, stavudine EFV, efavirenz HDL, high-density lipoprotein HIV, human immunodeficiency virus HTN, hypertension IDV, indinavir LDL, low-density lipoprotein LPV/r, lopinavir+ ritonavir MRI, magnetic resonance imaging NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor RTV, ritonavir SQV, saquinavir TDF, tenofovir disoproxil fumarate TG, triglyceride TPV/r, tipranivir + ritonavir ZDV, zidovudine. 

The synthesis of benzo[Z>]furan derivatives has become a very active field because these molecules have been recently identified as having a variety of biological activities. For example, they can function as inhibitors of protein tyrosine phosphatase IB with antihyperglycemic properties <00JMC1293>, as well as potent and short-acting p-blockers in the treatment of various cardiovascular diseases . An inexpensive, reusable clay has been utilized to catalyze a facile cyclodehydration under microwave without solvent to form 3-substituted benzo[2>]furans from substituted a-phenoxy acetophenones 104. One of the important features of this procedure is that all the selected cyclodehydration reactions are complete in less than 10 minutes <00SL1273>. 

Calabro P, Yeh ET (2004) Multitasking of the 3-hydroxy-3methylglutaryl coenz-ime, a reductase inhibitor beyond cardiovascular diseases. Curr Atheroscleros Rep 6 36-41... 

In a study conducted by Szardenings et various combinatorial libraries of DPKs scaffolds were created to design and evaluate the activity of DPKs as inhibitors of the matrix metalloproteinases, namely, collegenase-1 and gelatinase B. This study created structure-activity relationships (SAR) for side chains attached to a DPK core structure. These enzymes are therapeutic targets with indications in the treatment of cancer, arthritis, autoimmunity, and cardiovascular disease. 

Formic acid is an inhibitor of cytochrome oxidase at the terminal end of the respiratory chain in mitochondria and causes histotoxic hypoxia at the cellular level. Therefore, persons with cardiovascular disease may be considered at special risk to the affects of formic acid. ... 

A series of bi- and tricyclic pyridoazepine-type lactams was studied as conformationally restrained peptide mimetics acting as ACE inhibitors or dual inhibitors, that is both ACE and neutral endopeptidase (NEP) inhibitors, especially by the groups of Flynn and Robl. ACE and NEP are zinc metalloproteases acting as vasopeptidases. The respective inhibitors are used in the treatment of hypertension, congestive heart failure, and other cardiovascular diseases. 

Advanced arteriosclerosis symptomatic cardiovascular disease moderate to severe hypertension hyperthyroidism hypersensitivity or idiosyncrasy to the sympathomimetic amines glaucoma agitated states history of drug abuse during or within 14 days following administration of monoamine oxidase (MAO) inhibitors (hypertensive crises may result). 

In order to ameliorate the atherosclerotic complications of cardiovascular diseases, various means of inhibiting platelet aggregation have been investigated. Several 1,2,3-thiadiazoles were synthesized by the Hurd and Mori s method as collagen-induced inhibitors of platelet aggregation <85JMC442), the most potent being compound (47). 

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