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Antithrombotic agents: rationale and future directions
Volume 13 Number 5 May 1991
10. 11.
12.
13.
14.
smooth muscle proliferation in the vascular response to injury. Proc Natl Acad Sci USA 1988;85:2303-6. Ferns G, Reidy M, Ross R. Vascular effects of cyclosporine A in vivo and in vitro. Am J Path01 1990;137:403-13. Conte JV, Foegh ML, Calcagno D, Wallace RB, &unwell PW. Peptide inhibition of myointimal proliferation following angioplasty in rabbits. Transplantation Proceeedings 1989; 21:3686-g. Powell JS, Clozel J-P, Muller RKM, et al. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 1989;245:186-8. Bell L, Madri JA. Influence of the angiotensin system of endothelial and smooth muscle migration. Am J Path01 1990;137:7-12. Edelman ER, Adams DH, Karnovsky MJ. Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury. Proc Natl Acad Sci, USA, 1990;87:3773-7.
Dichek DA, Neville RF, Zwiebel JA, Freeman SM, Leon MB, Anderson WF. Seeding of intravascular stems with genetically engineered endothelial cells. Circulation 1989;80:1347-53. 16. Wilson JM, Birinyi LK, Salomon RN, Libby P, Callow AD, Mulligan RC. Implantation of vascular grafts lined with genetically modified endothelial cells. Science 1989;244: 15.
1344-6. 17.
Nabel EG, Plaua G, Nabel GJ. Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science 1990;249:1285-8.
ANTITHROMBOTIC AGENTS: RATIONALE AND PUTUREJ DIRECTIONS Despite advances in design and development of thromboresistant materials, including surfaces lined with endothelium, no artificial surface now available is free of the problem of thrombotic interactions between surface and blood, and no artificial surface is truly nonthrombogenic. In the foreseeable future, therefore, control of surfaceinduced thrombosis will require the supplementary effects of antithrombotic drugs. Improvements in antithrombotic agents are expected: greater efficacy, reduced toxicity, increased ease of administration, and economy will receive attention and, to varying degrees, will characterize new approaches to antithrombotic treatment. The following strategies and tactics for improving antithrombotic therapy can be anticipated. The use of anticoagulants will be rationalized and facilitated by better methods of administration of drugs now in use, including heparin and warfarin. In addition, low molecular weight heparin preparations made by enzymatic or chemical hydrolysis or fractionation of conventional heparin will be relatively free of platelet interactions and minimize hemorrhagic side effects. Heparin-like materials (heparinoids) and other glycosaminoglycans (e.g., dermatan sulfate) will also be exploited because of their favorite theraputic ratio. New antithrombins will include hirudin (prepared by recombinant DNA techniques), its derivatives and analogs, the irreversible serine protease inhibitor D-phenyl-alanylprolyl-arginine-chloromethyl ketone (PACK), and the
Special communication
76 1
highly selective thrombin inhibitors argidipine and argatroban. Inhibitors of activated factor X (ant&s) will include the leech derived antistasin and the tick anticoagulant peptide TAP. Activated protein C, a naturally occurring vitamin K-dependent anticoagulant that acts by inactivating factors Va and VIIIa, will also be available and will be subjected to large scale clinical trials. These products will be the result of recombinant DNA technology. Antiplatelet agents, in addition to the antithrombins, will include the current standbys aspirin, dipyridamole, ticlopidine, dextran, iloprost, and ibuprofen, as well as thromboxane synthase inhibitors and thromboxane receptor blockers. Competitors of fibrinogen and other adhesive proteins for binding sites on platelet surface glycoproteins GPIIb/IIIa and other integrins (receptors interacting with arg-gly-asp [RGD] peptides), therefore termed disintegrins, will include the snake venoms echistatin and applagin, as well as the synthetic peptides (RGDY) themselves, and also barbourin, which binds IIb/IIIa but lacks RGD. Monoclonal antibodies of great potential as inhibitors of platelet activity include those reacting with GPIIb/IIIa (the fibrinogen receptor), GPIb (the von Willebrand’s factor receptor), FcyRii (the Fc receptor), fibrinogen, and von Wiiebrand’s factor. Other approaches to control of platelet activity will include the use of drugs that increase cyclic AMP (e.g., phosphodiesterase inhibitors or stimulants of adenylate cyclase) or cyclic GMP (e.g., nitrates or stimulants of endothelium-derived relaxing factor). There will be dietary manipulation of levels of omega-3-fatty acids, which are incorporated into platelet lipids and eventually are converted into largely anti-aggregatory prostaglandins and thromboxane-analogs. Other potentially useful platelet inhibitors are Ca’ + channel blockers, serotonergic receptor blockers, and ethanol. Advances in thrombolytic therapy will be translated into clinical benefit in treating the consequences of blood-surface interaction. Current agents including SK, UK, TPA, Scupa, and Apsac will be joined by targeted agents with great specificity toward solid-phase fibrin or platelets, thereby minimizing the hemostatic defect that results from lysis in the fluid phase of the blood. Other strategies to reduce the hemorrhagic side effects of thrombolysis will be based on complexes of plasminogen activators such as TPA and Scupa or novel compounds such as UK-activated protein C. Edwin W. SaLmun, MD Beth Inael Hospital/Harvard Boston, Mass
Medical
School
CLINICAL TRIALS: CURRENT AND RECOMMENDATIONS
STATUS
Clinical trials in patients undergoing lower extremity bypass offer an excellent opportunity to evaluate antithrombotic therapy. In contrast to coronary artery bypass grafts (CAbGs), the primary end point of patency does not require arteriography. Noninvasive hemodynamic mea-
10. 11.
12.
13.
14.
smooth muscle proliferation in the vascular response to injury. Proc Natl Acad Sci USA 1988;85:2303-6. Ferns G, Reidy M, Ross R. Vascular effects of cyclosporine A in vivo and in vitro. Am J Path01 1990;137:403-13. Conte JV, Foegh ML, Calcagno D, Wallace RB, &unwell PW. Peptide inhibition of myointimal proliferation following angioplasty in rabbits. Transplantation Proceeedings 1989; 21:3686-g. Powell JS, Clozel J-P, Muller RKM, et al. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 1989;245:186-8. Bell L, Madri JA. Influence of the angiotensin system of endothelial and smooth muscle migration. Am J Path01 1990;137:7-12. Edelman ER, Adams DH, Karnovsky MJ. Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury. Proc Natl Acad Sci, USA, 1990;87:3773-7.
Dichek DA, Neville RF, Zwiebel JA, Freeman SM, Leon MB, Anderson WF. Seeding of intravascular stems with genetically engineered endothelial cells. Circulation 1989;80:1347-53. 16. Wilson JM, Birinyi LK, Salomon RN, Libby P, Callow AD, Mulligan RC. Implantation of vascular grafts lined with genetically modified endothelial cells. Science 1989;244: 15.
1344-6. 17.
Nabel EG, Plaua G, Nabel GJ. Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science 1990;249:1285-8.
ANTITHROMBOTIC AGENTS: RATIONALE AND PUTUREJ DIRECTIONS Despite advances in design and development of thromboresistant materials, including surfaces lined with endothelium, no artificial surface now available is free of the problem of thrombotic interactions between surface and blood, and no artificial surface is truly nonthrombogenic. In the foreseeable future, therefore, control of surfaceinduced thrombosis will require the supplementary effects of antithrombotic drugs. Improvements in antithrombotic agents are expected: greater efficacy, reduced toxicity, increased ease of administration, and economy will receive attention and, to varying degrees, will characterize new approaches to antithrombotic treatment. The following strategies and tactics for improving antithrombotic therapy can be anticipated. The use of anticoagulants will be rationalized and facilitated by better methods of administration of drugs now in use, including heparin and warfarin. In addition, low molecular weight heparin preparations made by enzymatic or chemical hydrolysis or fractionation of conventional heparin will be relatively free of platelet interactions and minimize hemorrhagic side effects. Heparin-like materials (heparinoids) and other glycosaminoglycans (e.g., dermatan sulfate) will also be exploited because of their favorite theraputic ratio. New antithrombins will include hirudin (prepared by recombinant DNA techniques), its derivatives and analogs, the irreversible serine protease inhibitor D-phenyl-alanylprolyl-arginine-chloromethyl ketone (PACK), and the
Special communication
76 1
highly selective thrombin inhibitors argidipine and argatroban. Inhibitors of activated factor X (ant&s) will include the leech derived antistasin and the tick anticoagulant peptide TAP. Activated protein C, a naturally occurring vitamin K-dependent anticoagulant that acts by inactivating factors Va and VIIIa, will also be available and will be subjected to large scale clinical trials. These products will be the result of recombinant DNA technology. Antiplatelet agents, in addition to the antithrombins, will include the current standbys aspirin, dipyridamole, ticlopidine, dextran, iloprost, and ibuprofen, as well as thromboxane synthase inhibitors and thromboxane receptor blockers. Competitors of fibrinogen and other adhesive proteins for binding sites on platelet surface glycoproteins GPIIb/IIIa and other integrins (receptors interacting with arg-gly-asp [RGD] peptides), therefore termed disintegrins, will include the snake venoms echistatin and applagin, as well as the synthetic peptides (RGDY) themselves, and also barbourin, which binds IIb/IIIa but lacks RGD. Monoclonal antibodies of great potential as inhibitors of platelet activity include those reacting with GPIIb/IIIa (the fibrinogen receptor), GPIb (the von Willebrand’s factor receptor), FcyRii (the Fc receptor), fibrinogen, and von Wiiebrand’s factor. Other approaches to control of platelet activity will include the use of drugs that increase cyclic AMP (e.g., phosphodiesterase inhibitors or stimulants of adenylate cyclase) or cyclic GMP (e.g., nitrates or stimulants of endothelium-derived relaxing factor). There will be dietary manipulation of levels of omega-3-fatty acids, which are incorporated into platelet lipids and eventually are converted into largely anti-aggregatory prostaglandins and thromboxane-analogs. Other potentially useful platelet inhibitors are Ca’ + channel blockers, serotonergic receptor blockers, and ethanol. Advances in thrombolytic therapy will be translated into clinical benefit in treating the consequences of blood-surface interaction. Current agents including SK, UK, TPA, Scupa, and Apsac will be joined by targeted agents with great specificity toward solid-phase fibrin or platelets, thereby minimizing the hemostatic defect that results from lysis in the fluid phase of the blood. Other strategies to reduce the hemorrhagic side effects of thrombolysis will be based on complexes of plasminogen activators such as TPA and Scupa or novel compounds such as UK-activated protein C. Edwin W. SaLmun, MD Beth Inael Hospital/Harvard Boston, Mass
Medical
School
CLINICAL TRIALS: CURRENT AND RECOMMENDATIONS
STATUS
Clinical trials in patients undergoing lower extremity bypass offer an excellent opportunity to evaluate antithrombotic therapy. In contrast to coronary artery bypass grafts (CAbGs), the primary end point of patency does not require arteriography. Noninvasive hemodynamic mea-