Recent Patents on Cardiovascular Drug Discovery (Discontinued) - Volume 3, Issue 2, 2008

Brain natriuretic peptide (BNP) plays an important role in cardiovascular homeostasis. Plasma BNP increases markedly in left ventricular dysfunction from several causes, and its levels in heart failure (HF) correlate with symptoms severity. BNP has recently emerged as a potentially important clinical marker for the diagnosis of HF in patients with unexplained dyspnea. Other clinical applications of BNP, such as screening for asymptomatic ventricular dysfunction, establishing the prognosis or guiding the titration of drug therapy, are under investigation and have not yet been sufficiently validated for widespread clinical use. Laboratory-based and point-of-care analyses are available for BNP and N-terminal proBNP as fully-automated immunoassays. Several patented inventions and reagents for the diagnosis of various heart pathologies provide helpful information, particularly in conjunction with other clinical tests. They also have prognostic value for future cardiovascular events. Patents owned by Scios Inc. recommended recombinant BNP for managing acute decompensated HF. However, this treatment apparently has safety problems and no proven clinical advantage over existing treatments in terms of improved survival and prevention of subsequent hospitalizations.

Atherosclerosis is the one of the commonest causes of morbidity and mortality in the world. This review examines some of the recent patents taken out on biomarkers of cardiovascular risk, novel dietary supplements and new methods to treat cardiovascular disease. Though current approaches based on risk stratification into primary and secondary prevention and calculation of risk using simple risk factors are well established, there remains a need to develop more specific biomarkers of risk integrating many of the aspects of the atherosclerotic process including oxidized lipoproteins or inflammation-modified proteins. Diet is established as the mainstay of long-term cardiovascular management with great potential benefits but in the modern environment compliance tend to be low. Many approaches investigate the role of dietary supplementation with omega-3 fatty acids and other agents or the use of nutriceutical compounds capable of competing with cholesterol for absorption. A statin-based strategy is the mainstay of cardiovascular lipid -related risk management. However statins are not universally tolerable and are limited in the effects they have on some fractions of the risk profile especially low high density lipoprotein (HDL)-cholesterol. Many new drugs are in development to raise HDL or mimic its effects. These include novel agents to target nuclear factor receptors already familiar from previous successful drugs such as bile acid sequestrants, fibrates and thiazolidinediones as well as novel approaches investigating key regulatory enzymes such as stearoyl-CoA desaturase. Similarly as inflammation is a central part of atherosclerosis other novel approaches are targeting the multiplicity of inflammation-associated pathways including 5-lipoxygenase and purinergic receptors.

The beneficial effects of statins in hypertension stem from their effects on endothelial function, their interactions with the renin-angiotensin system, and their influence on large artery compliance. Substantial evidence has recently accumulated showing that statins exert pleiotropic effects in vascular function. These include an increase in the synthesis of NO, inhibition of vascular smooth muscle cell proliferation and migration, anti-inflammatory actions, downregulation of angiotensin II type 1 receptor expression, and anti-oxidative effects. These effects occur before reduction of cholesterolemia. Available data support only a modest BP-lowering effect of statins which is most prominent in those patients with poorly controlled hypertension. Even though they only cause a minor reduction in BP, they may play a role in the prevention of cardiovascular disease. Statins may be useful therapeutic agents in hypertensives with high serum total cholesterol, in patients with poorly controlled hypertension even without hypercholesterolemia, in normocholesterolemic well-controlled hypertensive subjects with high C reactive protein levels, and in those subjects who need secondary prevention. Future research is needed to further characterize the impact of statins alone or in combination with antihypertensive agents to prevent or delay the development of stage 1 hypertension. This review article also includes relevant patents.

Despite enormous therapeutic advances, coronary artery disease (CAD) remains a global public health problem. Effective prevention of cardiovascular morbidity and mortality will require the development of new diagnostic and therapeutic strategies aimed at treating early, subclinical disease stages. These novel approaches are increasingly based on the molecular understanding of disease development. Molecular imaging, as it applies to CAD, describes diagnostic strategies targeting biomarkers associated with the development of atherosclerotic lesions. In analogy to applications in oncology, identification of subclinical disease and disease activity appear feasible. Novel therapeutic strategies include the development of targeted transport vehicles allowing drug delivery to specific cells or cell structures. Nanotechnology is expected to contribute to molecular strategies in the diagnosis and treatment of CAD. Of particular interest are bioengineered nanoparticles, which can be utilized as transport vehicles of diagnostic or therapeutic agents. However, further development is required before nanotechnology can be applied clinically. This manuscript also includes some recent patents on this topic.

Potassium channels, which are essential to a wide range of physiological processes, are involved in many diseases. Thus, alterations in such important proteins due to congenital deficiencies or to undesirable side-effects of common medications might lead to dysfunctions. Heart is one of those tissues where potassium channels play a crucial role. The maintenance of cardiac action potential appears to be the consequence of the varied activity of several types of potassium channels. Recently, compounds that modify cardiac potassium channel activity and so alter action potential duration have been developed as new anti-arrhythmic agents. However, several cardiomyopathies appear as undesirable side-effects of the use of drugs that directly or indirectly act on the same potassium channels. Thus, new patents have been created allowing the prediction of the inherited predisposition to any known potassium-linked cardiac channelopathy.

The results obtained in the CAPRIE study in 1996 led to the introduction of the clopidogrel as a new antiplatelet drug in the secondary prevention of acute myocardial infarct (AMI), ischemic stroke (IS) and symptomatic peripheral artery disease (PAD). Clopidogrel showed a similar efficacy and safety than acetylsalicylic acid (ASA). More recently, the combined use of clopidogrel with ASA has evidenced a better protection than ASA alone in some patients: patients with past history of AMI, angina pectoris, intermittent claudication or PAD, IS or TIA, coronary bypass, and diabetes mellitus, patients on treatment with statins, and patients with symptomatic carotid stenosis ≥50%. We review the reported evidence on the efficacy of clopidogrel in the secondary prevention of ischemic stroke.

Objectives: To systematically review data to determine if Endovenous Laser Ablation (EVLA), Radio Frequency Ablation (RFA), and Foam Sclerotherapy (FS) have any advantages or disadvantages in comparison with conventional surgical ligation and stripping of great saphenous vein (GSV) varices. EVLA versus Surgery: The failure rate of GSV closure after EVLA was between 0% to 34%. In comparison the recurrence rate after high ligation and stripping was up to 28% in a meta analysis of 7 studies. The overall complication rate after EVLA is about 20%. This showed no difference from that after primary LSV surgery which is between 17% and 20%. RFA versus Surgery: There was no significant difference between RFA and surgery in terms of symptoms improvement. However, the pain score was better in the RFA groups. Moreover, there was significant difference in the sick leave taken after each treatment with the mean of 6.5 days and 4.7 days for RFA, and 15.6 days and 12.4 days for surgery. RFA versus EVLT: Immediate technical success was obtained in all (100%) of EVLA procedures and in (96%) of RFA cases. The overall complication rate was (20.8%) after EVLA and 7.6% after RFA. Foam Sclerotherapy: The recurrence rate after Sclerotherapy reached 30.5 % after one year, and 51% after 10 years. However, the rates were better for Foam than the liquid sclerosants. When compared to surgery, sclerotherapy had higher recurrence rate than that after surgery. The median time to return to normal activities was significantly reduced in the foam sclerotherapy group (2 days) compared to the surgical group (8 days). Current & Future Development: When comparing the recurrence rate and overall complication rate and symptoms relief, surgery was not inferior to endovenous procedures. Reported follow up periods for the endovenous procedures were relatively short.

Conivaptan, a dual vasopressin receptor antagonist, is a member of an emerging class of medications for the treatment of euvolemic hyponatremia. These agents induce a free-water diuresis as compared to the natriuretic effect of loop diuretics and make them an intriguing prospect for the treatment of congestive heart failure. Article also includes recent patents on this topic.

Kawasaki Disease (KD) is an acute febrile systemic vasculitis of unknown etiology that primarily affects children younger than five years of age. The most reliable treatment for acute-phase KD is the combination of aspirin and high dose (2g/kg) intravenous immunoglobulin (IVIG) therapy. However, IVIG therapy is occasionally associated with serious thromboembolism, probably because of a rapid increase in plasma IgG concentration. Therefore, patients with KD, who are associated with endothelial impairment, are not free from the risk of thromboembolism associated with IVIG therapy. High levels of IgG, immune complex formation, and increased platelet aggregation could increase blood viscosity after IVIG infusion. Increased serum viscosity reduces arterial and capillary blood flow, leading to thrombosis. We have previously reported that single high-dose IVIG therapy for acute KD raises plasma viscosity. Although there is scarce epidemiological information as to the prevalence of thromboembolism associated with IVIG therapy, the occurrence of these complications must be taken into consideration. This article also includes relevant patents on this topic.

Monoclonal antibodies are antibodies that are identical because they were produced by one type of immune cell, all clones of a single parent cell. This has become an important tool in biochemistry, molecular biology and medicine. The role of Complement system in inflammation has been well established. Inflammation is a cornerstone of the post-myocardial infarction. Also, during a heart bypass procedure, the “Complement activation” causes an inflammatory response that can lead to side effects such as chest pain, heart attack, stroke, heart failure, or death. One such agent which causes Complement inhibition is Pexelizumab. Pexelizumab (Alexion Pharmaceuticals), a recombinant humanized single chain monoclonal antibody to C5, blocks the conversion of C5 to C5a and C5b-9. Pexelizumab is an Alexion-engineered monoclonal antibody fragment designed to inhibit complement-mediated tissue damage associated with reperfusion injury and inflammation that occurs during open heart surgery. Recent Phase III trials have evaluated the role of Pexelizumab in patients undergoing Coronary Artery Bypass Graft surgery and also in the treatment of acute myocardial infarction. In the ischemia/reperfusion setting of cardiopulmonary bypass surgery, Pexelizumab appears to reduce cardiac enzyme release and possibly mortality. Pexelizumab can also be used as adjunctive therapy to fibrinolysis and primary Percutaneous Coronary Intervention. If approved, pexelizumab would represent not only the first of a new class of therapeutics called terminal complement inhibitors for the reduction of death and peri-operative myocardial infarction in patients undergoing CABG-CPB surgery but also a new approach to improving outcomes for patients undergoing CABG surgery. Present article also includes relevant patents on the topic.

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