Current
Drug Targets – Cardiovascular & Haematological Disorders, Volume 2,
Number 1, 2002
Contents
Ca2+-Dependent Signaling
Pathways in the Heart:Potential Drug Targets for Cardiac Disease Pp.1-11
The Antithrombotic Efficacy
of Lotrafiban (SB 214857) in Canine Models of Acute Coronary Thrombosis Pp.13-25
Inhibition of PAI-1: A New
Anti-thrombotic Approach Pp.27-42
Trypanosoma cruzi
Trypanothione Reductase Inhibitors: Phenothiazines and Related Compounds Modify
Experimental Chagas´ Disease Evolution Pp.43-52
[Back to top] Ca2+-Dependent Signaling
Pathways in the Heart:Potential Drug Targets for Cardiac Disease
Ca 2+ is an important secondary messenger and any alteration to intracellular Ca 2+ signaling pathways or components of these pathways can have a profound physiological effect on any cell, particularly cardiomyocytes. Early approaches to investigate heart disease focused on many muscle proteins, however recent findings indicate that molecules considered as “non-muscle” proteins may be equally important players in etiology of many cardiac pathologies. Many of these "non-muscle" proteins play a role in Ca 2+ cycling or Ca 2+ -dependent signaling pathways in the heart. In this review we focus on Ca 2+ -dependent pathways in normal, growing, and diseased hearts. Understanding of these unique signaling pathways may hold answers tomany cardiac pathologies in children and adults.
[Back to top] The Antithrombotic Efficacy
of Lotrafiban (SB 214857) in Canine Models of Acute Coronary Thrombosis
In patients with acute coronary syndromes, inhibition of
platelet aggregation with parenteral aIIb
/bIII antagonists has proven effective
at preventing nonfatal myocardial infarction and repeat percutaneous coronary
interventions. Paradoxically, the efficacy observed for acute indications and
parenteral agents has not extended to oral agents and chronic prevention of
secondary thrombotic events, despite robust antithrombotic properties in
preclinical thrombosis models.
This report documents the preclinical data of Lotrafiban, an oral aIIb /bIII antagonist that recently failed in a phase III clinical trial (BRAVO) for the prevention of secondary thrombosis. Lotrafiban was characterized in a dog circumflex artery electrical injury model, and a cyclic flow reduction model ("Folts"). The data demonstrate that both oral (1.0-50.0 mg/kg) and intravenous (0.1-0.8ug/kg/min) administration of lotrafiban produced dose-related inhibition (45%-95%) of ex vivo platelet aggregation. In the electrical injury model, the dose-related inhibition correlated with a significant reduction in the frequency of coronary occlusion, size of the developing thrombus, and the extent of left ventricular ischemic damage. Effects on blood flow and bleeding time were also dose related. The combination of low dose lotrafiban (0.1ug/kg/min) and aspirin (5.0 mg/kg) generated additive antithrombotic effects, approximating the antithrombotic efficacy of a 2-4 fold higher dose of lotrafiban while only modestly prolonging the bleeding time. For purposes of comparison, the ADP receptor antagonist clopidogrel was also assessed in the electrical injury model. Clopidogrel (5.0-10.0 mg/kg, iv.) significantly reduced the resulting left ventricular infarct areas, but lacked the overall efficacy of lotrafiban. In the "Folts" model, lotrafiban inhibited cyclic blood flow reductions (CFR's) by 100% in animals insensitive to the antithrombotic effects of aspirin. Overall, the preclinical data demonstrated that aIIb /bIII antagonism with lotrafiban was a well tolerated and effective strategy for attenuating acute arterial thrombosis. The lack of a correlation between these preclinical data and the outcome of the clinical trial BRAVO are unexplained. However, the combined evidence suggests that these acute canine thrombosis studies may not completely capture the pathology reflected in chronic human atherothrombotic disease.
[Back to top] Inhibition of PAI-1: A New
Anti-thrombotic Approach
Proteolytic degradation of fibrin (fibrinolysis) is
mediated by plasminogen and its activators, tissue-type plasminogen activator
(tPA 1 ) and urokinase (uPA). Fibrinolysis is critical for preventing thrombus
growth and restoring blood flow following thrombotic vascular occlusion.
Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor
(serpin) superfamily, is the principal inhibitor of tPA and uPA in the
fibrinolytic system. High levels of circulating PAI-1 are associated with a
number of thrombotic diseases. In animal studies, transgenic mice
overexpressing human PAI-1 develop spontaneous thrombosis, whereas
PAI-1-deficient mice are more resistant to venous or arterial thrombosis.
Furthermore, inhibition of PAI-1 activity prevents thrombus formation in animal
models. The antithrombotic effects of PAI-1 inhibition are achieved by
enhancing endogenous fibrinolytic activity without directly affecting blood
coagulation and platelet function. Phenotypic analysis of PAI-1 deficiency in
both human and mouse suggests that inhibition of PAI-1 will not lead to severe
bleeding or other major adverse effects. Thus, PAI-1 inhibitors represent a new
class of antithrombotic drugs with a possible wider therapeutic index than
conventional antiplatelet and anticoagulant agents. This review summarizes the
role of PAI-1 in thrombotic diseases and recent progress in the development of
small molecule PAI-1 inhibitors.
[Back to top] Trypanosoma cruzi Trypanothione Reductase Inhibitors:
Phenothiazines and Related Compounds Modify Experimental Chagas´ Disease
Evolution
Chagas’ disease affects about 18 million people and 25% of the population of Latin America is at risk of acquiring Chagas’ disease. The chemotherapy of Chagas' disease is still an open field and remains as an unsolved problem. Nifurtimox and benznidazole are currently used to treat this disease, however, both drugs have high toxicity and are mutagenic with the result that the patients frequently fail to follow treatment.
T. cruzi enzimes such as trypanothione reductase, represent potential drug targets because they play an essential role in the life of this organism. This enzyme has been isolated, purified and studied by X ray crystallography. Phenothiazines and related compounds inhibit trypanothione reductase and a specially favoured fit is a phenothiazine with a 2- substitued with 2- chloro and 2- trifluoromethyl with a remote hydrophobic patch. The essential phenothiazine nucleus can adopt more than one inhibitory orientation in its binding site.
Phenothiazines and related compounds are drugs used in psychiatric treatments. These anti-depressants inhibit trypanothione reductase through the peroxidase/ H2O2/ system, and also exert other trypanocidal effects upon epimastigotes and tripomastigotes forms: clomipramine through an anticalmodulin action; trifluopherazine and thioridazine induced disruption of mitochondria and prometazine provoked serious cell membrane disorganization. Clomipramine and thioridazine were also effective in treatment of mice with experimental Chagas' disease, significantly modifying the natural evolution of the infection; cardiac function and survival of infected and treated animals were not different from non infected animals. Phenothiazines and related compounds are promising trypanocidal agents for treatment of Chagas´ disease.
Other trypanocidal agents as nifurtimox, benznidazol,Allopurinol, cystein protease inhibitors and others, are also discussed.