Author: Bridson, John D ; Groves, David G ; Wong, Helen ; Leach, Austin ; Grayson, Antony D ; Lewin, Robert J P ; Moore, Roger K G ; Chester, Michael R

Chronic refractory angina is an increasingly prevalent, complex chronic pain condition, which results in frequent hospitalization for chest pain. We have previously shown that a novel outpatient cognitive-behavioral chronic disease management program (CB-CDMP) improves angina status and quality of life in such patients. In the present study of 271 chronic refractory angina patients enrolled in our CB-CDMP, total hospital admissions were reduced from 2.40 admissions per patient per year to 1.78 admissions per patient per year (P<0.001). The rising trend of total hospital bed day occupancy prior to enrollment fell from 15.48 days per patient per year to a stable 10.34 days per patient per year (P<0.001). There were 32 recorded myocardial infarctions prior to enrollment compared to eight in the year following enrollment (14% vs. 2.3%, P<0.001) and overall mortality was lower that comparable groups treated with surgery. This study shows that educating patients and demystifying angina using a brief outpatient CB-CDMP produces an immediate and sustained reduction in hospital admission costs that represents a major potential health care saving. This benefit accrues in addition to the known effects of CB-CDMP on symptoms and quality of life. These data suggest that a CB-CDMP approach to symptom palliation represents a low cost alternative to palliative revascularization.

01 Jun 2003·Current Medicinal Chemistry-Cardiovascular & Hematological Agents

Structure-activity Relationships of Snake Toxins Targeting Platelet Receptors, Glycoprotein Ib-IX-V and Glycoprotein VI

Review

Author: Yang Shen ; Elizabeth E. Gardiner ; Robert K. Andrews ; Michael C. Berndt

Initiation of thrombus formation involves the platelet adhesion receptors, glycoprotein (GP)Ib-IX-V and GPVI, that bind von Willebrand factor (vWF) and collagen, respectively. These interactions trigger intracellular signals leading to degranulation, elevation of cytosolic Ca2+, cytoskeletal rearrangements, and "inside-out" activation of the integrin, GPIIb-IIIa (alphaIIbbeta3) that binds von Willebrand Factor (vWF) or fibrinogen and mediates platelet aggregation. GPIbalpha (the vWF-binding subunit of GPIb-IX-V) of the leucine-rich repeat protein family and GPVI of the immunoglobulin superfamily not only have a parallel physiological function, but recent studies of these receptors have revealed structure-activity relationships amongst snake venom toxins which target them. Two families of venom proteins, the C-type lectin-like proteins and metalloproteinase-disintegrins, target GPIbalpha, GPVI and/or the collagen-binding integrin, GPIa-IIa (alpha2beta1). Members of the C-type lectin family interact specifically with GPIbalpha (echicetin, alboaggregin-B, agglucetin), GPVI (convulxin, ophioluxin) or GPIa-IIa (rhodocetin), whereas related proteins accomplish dual receptor occupancy and bind GPVI and GPIbalpha (alboaggregin-A, alboluxin), or GPIbalpha and GPIa-IIa (aggretin). These latter venom proteins mimic physiological ligands, vWF or collagen, which also recognize more than one receptor. Similarly, metalloproteinase-disintegrin family proteins target GPlbalpha (mocarhagin, crotalin), GPVI (alborhagin) or GPIa-IIa (jararhagin), resulting in inhibition or induction of platelet aggregation by proteolytically dependent or independent mechanisms. Anti-thrombotics based on snake venom GPIIb-IIIa inhibitors have been investigated clinically, however analogous proteins recognizing GPIb-IX-V or GPVI are yet to be therapeutically exploited.

01 Jan 2001·Thrombosis and HaemostasisQ2 · MEDICINE

Crotalin, a vWF and GP Ib Cleaving Metalloproteinase from Venom of Crotalus atrox

Q2 · MEDICINE

Article

Author: Wu, Wen-Bin ; Huang, Tur-Fu ; Peng, Hui-Chin

SummaryBinding of von Willebrand factor (vWF) to a variety of extracellular matrix (ECM) components and to platelet glycoprotein (GP) Ib-IX-V complex is important in mediating platelet adhesion and aggregation in the early stage of hemostasis. We previously purified a potent antithrombotic protein, named crotalin, functionally acting as a GP Ib antagonist (1). In this study, we further characterized crotalin as a P-I metalloproteinase with a molecular mass of 25 kDa as determined by gel filtration and two-dimensional SDS-PAGE. Crotalin is a vWF binding and cleaving metalloproteinase. In addition, crotalin cleaved platelet GP Ib as judged by flow cytometry and Western blotting. The multiple effects of crotalin on vWF and platelet GP Ib antagonized ristocetin-, but not collagen and thrombin-induced platelet aggregation, suggesting that its effect is specific. We also found that crotalin auto-proteolytically degraded to ~14 and ~10 kDa fragments in the presence of SDS. Interestingly, both degradation fragments, intact and reduced crotalin were able to bind vWF, suggesting the binding of crotalin to vWF is conformation-independent. In conclusion, the results presented further explain the potent antithrombotic effect of crotalin in vivo. In addition, the multiple effects of crotalin may be used as a tool to determine the binding motifs that are responsible for the vWF-ECMs or vWF-GP Ib interaction.

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Brain Cancer	Preclinical	IE	Celtic Biotech Ltd.	-

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