USF researchers get grants to develop new drugs against flu bug TAMPA, Fla. (Oct. 25, 2006) – Members of the University of South Florida’s drug discoverygroup, the Center for Molecular Diversity in Drug Design, Discovery, and Delivery, or CMD5,and collaborators, have received two USF, peer-reviewed grants to develop anti-viral drugs tofight influenza, a world-wide killer. The team will empl
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Xray.orgPharmacologic Agents in Stroke Prevention,
Acute Stroke Therapy, and Interventional
J.J. Connors, III, MD
Pharmaceutical agents have moved far beyond just the aspirin and heparin that were the mainstays of stroke and
interventional therapy as recently as 10 to 15 years ago. Our understanding of the mechanisms of thrombus formation
and vascular response to damage as well as our armamentarium has tremendously improved in the past decade. Direct
thrombin inhibitors, powerful antiplatelet agents, new fibrinolytic agents, and statins now allow far greater manip-
ulation of the intraprocedural and postprocedural clot cascade and atherogenesis. It is mandatory that current-day
interventionists understand the correct and appropriate use of these agents to achieve the desired outcomes of therapy.
J Vasc Interv Radiol 2004; 15:S87–S101
AbESTT ϭ Abciximab in Emergent Stroke Treatment Trial, FDA ϭ Food and Drug Administration, HERO ϭ Hirulog and Early Reperfusion or Occlusion, INR ϭ International Normalized Ratio, MI ϭ myocardial infarction, NINDS ϭ National Institute of Neurological Disorders and Stroke, PROACT ϭProlyse in Acute Cerebral Thromboembolism, TIA ϭ transient ischemic attack, tPA ϭ tissue-type plasminogen activator, WARRS ϭ Warfarin versus Aspirin inRecurrent Stroke Study, WASID ϭ Warfarin versus Aspirin for Symptomatic Intracranial Disease.
THE CONCEPT OF
and can be thought of as blood sludge.
posed of platelets. Injury to the endothe- Platelets adhere to these matrix proteins, factor initiates coagulation and leads to mechanical damage secondary to in-dwelling central venous catheters and tent platelet stimulant, stimulates plate- lets to adhere to the site of vascular in- to fibrin, which stabilizes these platelet From the Department of Interventional Neuroradi- thrombotic events that can be fatal.
ology, Miami Cardiovascular Institute, Baptist Hos-pital, 8900 North Kendall Drive, Miami, Florida activated by adhesion factors (eg, colla- 33176. Received March 11, 2003; revision requested April 23; final revision received October 9; accepted October 10. Address correspondence to the author;
The author has not identified a potential conflict of DOI: 10.1097/01.RVI.0000112975.88422.5D
S88 • Pharmacologic Agents in Stroke Management
thrombin that is already in the clot.
compared with unfractionated heparin.
Unfractionated Heparin and Low-
Unfractionated Heparin.—Heparin is been shown to be of clinical benefit.
Connors • S89
nists (27,28). Hirudin also is better than Bivalirudin.—Bivalirudin is a 20- vantageous in lower-risk individuals.
Heparin and Low-molecular-weight Hep- arin.—Heparin has adverse effects.
utes, it is prolonged in patients withhepatic dysfunction (25).
Direct Thrombin Inhibitors
Thrombin Inhibitors over Heparin.—Di-rect thrombin inhibitors have poten- not cleared by the plasma proteins).
be effective in clinical trials of patients agents is approved by the FDA as yet.
Future Directions Concerning Throm- bin Inhibitors.—On the basis of ran- going coronary angioplasty (23,27,28).
S90 • Pharmacologic Agents in Stroke Management
ered to have failed aspirin therapy.
Clopidogrel.—Clopidogrel is in the event. For patients with atrial fibrilla- effect is irreversible for the life of the Aspirin.—The inhibition of the en- regimen should be in this situation.
other pathways of platelet activation.
might be statistically insignificant.
unclear. Results of earlier trials led to Extended-release Dipyridamole Plus gelheim Pharmaceuticals).—The results ied within 3 months of stroke or TIA.
Connors • S91
one crucial exception: atrial fibrillation (46,47). Atrial fibrillation results in a with an average annual risk of 5% (48).
malized Ratio [INR], 2.0 –3.0) (48). For Warfarin
nosis) or for arterial dissection, nor, to vention in an elderly population (51).
stroke (ie, the cervical carotid artery is (INR, 1.4 –2.8) have equivalent effects warfarin. Initial effects of warfarin ad- but peak effects may take 3 to 5 days.
A single dose lasts for 2 to 5 days.
efit from warfarin than from aspirin.
200 to 500 mL of fresh frozen plasma.
that the design of the trial did not test Comparative Efficacy.—There is lit- temporary practice (INR, 2.0 –3.0).
the antiplatelet agents listed earlier.
S92 • Pharmacologic Agents in Stroke Management
acute stroke therapy, no study has es- removes all indications for warfarin tion of stroke in all patients with isch- been “presumed” to be “best medical therapy” for years. In a trial of warfa- rin versus aspirin specifically for intra- particularly in the “large vessel” cate- Angiotensin-Converting Enzyme
tures essentially all serum cholesterol.
the difference was not statistically sig- effect is about 10%). Thus, statins are a stantial reduction in stroke risk. In the agent as described earlier in relation to tion trial (58), investigators studied the (“dual”) antiplatelet medication is bet- tirely separate from their effects on se- lesterol levels—is still present (56). For Volume 15
Connors • S93
tial financial gain from production.
are other vascular risk factors present.
ACUTE STROKE THERAPY
Alteplase.—Alteplase (Activase; Ge- tered and then traveling to the clot like Background
efficacy for this clinical situation.
Streptokinase.—Streptokinase (Strep- performed, all with uniform failure.
influence the “systemic lytic state.” well as its antigenicity. Its serum half- Alfimeplase.—This agent is not ap- large-vessel occlusion (61). Direct local intraarterial infusion of the fibrinolytic S94 • Pharmacologic Agents in Stroke Management
alteplase is the most difficult to use of Tenecteplase.—Tenecteplase (TNKase; trials as well as acute stroke trials, the in the presence of N-methyl-d-aspar- (69). Also, an early trial of vampire bat alteplase for intraarterial therapy is its Considerations Regarding Stroke
Intraarterial Lytic Infusion for
Emergency Stroke Therapy
FDA with that one trial, the trial itself had positive results (P ϭ .04), with a Volume 15
Connors • S95
concentrations do indeed slow lysis.
mate of the lysing ability of alteplase is is capable of dissolving 4 g of clot (not Complications Associated with Lytic
tially fill the entire femoral artery (20 this setting would be about 1.6 U (80).
(79,80,81) have indicated that there is a tually slow down lysis considerably.
The hypothesis of “plasminogen steal” uated in detail in the field of oncology, als range from 0.7% to 2.0% (85,86).
ies that this is the case. Both higher and bolus regimen, and total infusion time.
with reteplase (88), but at least some of this difficulty in the interventional ra- Heparin and Bleeding.—Heparin may of any lytic agent is still an issue. Only action of certain lytic agents if used in to be effective in the range of 0.01 to 20 g/mL (77). MI trials (83,84) have useful anywhere from 0.1–10 U/h; bleeding episodes than in those whodemonstrated the bell-shaped curve of activity for certain fibrin-specific lytic S96 • Pharmacologic Agents in Stroke Management
tors, are capable of “disaggregation” direct clinical indicator of this fact.
anticoagulation during therapy (78).
pletely by these agents than by lytics.
Glycoprotein IIb/IIIa Inhibitors
interest in the role of glycoprotein IIb/ and thrombolysis in general (90 –92).
Glycoprotein IIb/IIIa Receptor Inhibi- tors in Interventional Cases.—For use be of value, reversibility is also an is- its effects can be reversed with platelet transfusion (98). The reversal of eptifi- later time to treatment (average, 5 h).
increased risk of intracranial bleeds (or layer forms at the injury site; this is the rapid binding to platelets (Ͻ1 min).
is not fully elucidated. There is a small Volume 15
Connors • S97
platelet and lytic agent use specifically for stroke therapy is in its infancy. Pre- Combination Therapy for Acute
result in increased fibrinolytic activity Combination Therapy for
is the case, the initial target of therapy lytic agents, including urokinase (100).
early results, no substantial benefit has with intraarterial lytic infusion. A pos- with glycoprotein IIb/IIIa inhibitors.
form at sites of vessel injury. “White” S98 • Pharmacologic Agents in Stroke Management
INSTOR (www.strokeregistry.org) is sis. Following statistical analysis of the improve patient outcomes by (a) as- References
on patient outcomes; (b) evaluating the cellular biology of blood coagulation.
ally and collectively; and (c) providing 2. Antiplatelet Trialists’ Collaboration.
ised trials of antiplatelet therapy. I.
farction, and stroke by prolonged an-tiplatelet therapy in various catego- ries of patients. BMJ 1994; 308:81–106.
Verapamil.—Verapamil is a blocker muscle and, thereby, vasodilatation.
nary embolism: a controlled clinicaltrial. Lancet 1960; 1:1309 –1312.
7. Weitz JI, Hudoba M, Massel D, et al.
Nicardipine.—Nicardipine is also a products where it is protected from in-hibition by heparin-antithrombin but 9. Bar-Shavit R, Eldor A, Vlodavsky I.
Connors • S99
ties. J Clin Invest 1989; 84:1096 –1104.
24. Hursting MJ, Alford KL, Becker JC, et Pharmacotherapy 2000; 20:318 –329.
26. Organisation to Assess Strategies for 15. International Stroke Trial Collabora- 16. Publication Committee for the Trial of 28. Bittl JA, Strony J, Brinker JA, et al.
17. Kay R, Sing Wong K, Yu YL, et al.
40. Diener HC, Cunha L, Forbes C, et al.
European Stroke Prevention Study. II.
29. Eriksson BI, Ekman S, Lindbratt SS, et N Engl J Med 1995; 333:1588 –1593.
stroke. Stroke 2002; 33:1934 –1942.
19. Lefevre G, Duval M, Gauron S, et al.
31. Kong DF, Topol EJ, Bittl JA, et al.
trial. Circulation 1998; 98:678 – 686.
44. Gotoh F, Tohgi H, Hirai S, et al.
21. Fox I, Dawson A, Loynds P, et al.
direct thrombin inhibitor, in humans.
45. Oishi M, Mochizuki Y, Shikata E, et al.
23. Bittl JA, Chaitman BR, Feit F, et al.
ised trial. Lancet 2001; 358:1855–1863.
33. Secondary prevention of vascular dis- S100 • Pharmacologic Agents in Stroke Management
vascular events in high-risk patients.
Curr Atheroscler Rep 2002; 4:319 –325.
73. Zaidat OO, Suarez JI, Santillan C, et emic stroke? Stroke 2002; 33:1723–1726.
attack. Lancet 2001; 358:1033–1041.
60. The National Institute of Neurological brillation. Drugs 1999; 58:997–1009.
clusion. Stroke 2002; 33:1821–1826.
activator for acute ischemic stroke.
74. Lisboa RC, Jovanovic BD, Alberts MJ.
61. Tomsick T, Brott T, Barsan W, et al.
ischemic stroke. Stroke 2002; 33:2866 – 50. van Es RF, Jonker JJ, Verheugt FW, et 75. Qureshi AI, Ali Z, Suri MF, et al. In- lytic therapy. AJNR 1996; 17:79 – 85.
study): a randomised controlled trial.
76. Semba CP, Bakal CW, Calis KA, et al.
in acute middle cerebral artery stroke.
52. Furlan A, Higashida R, Weschler L, et phia, Pa: Lippincott, 1995; 99 –101.
66. Liberatore GT, Samson A, Bladin C, et 54. Bucher HC, Griffith LE, Guyatt GH.
Vasc Interv Radiol 2000; 11:299 –303.
activator. Nature 1995; 377:340 –344.
69. Qureshi AI, Pande RU, Kim SH, et al.
82. Torr SR, Nachowiak DA, Fujii S, Sobel limits fibrinolytic potential. J Lab Clin 58. Yusuf S, Sleight P, Pogue J, et al. Ef- 72. Suarez JI, Zaidat OO, Sunshine JL, et Volume 15
Connors • S101
sis Proteolysis 1997; 11:129 –135.
107. Chanda J, Brichkov I, Canver CC.
course and relation to vascular injury.
86. Califf RM, Topol EJ, George BS, et al.
perience. AJNR 2002; 23:1284 –1290.
ment of acute myocardial infarction.
109. Haley EC Jr., Kassell NF, Torner JC.
Study. J Neurosurg 1993; 78:537–547.
tropaste). AJNR 2003; 24:1234 –1236.
100. Collet JP, Montalescot G, Lesty C, et 89. Decrinis M, Pilger E, Stark G, et al.
Thromb Vasc Biol 2001; 21:142–148.
101. Ferguson JJ, Taqi K. IIb-IIIa receptor tion. Am Heart J 1999; 138:S164 –170.
102. Eisenberg PR, Sobel BE, Jaffe AS.
J Am Coll Cardiol 1992; 19:1065–1069.
infusion for treatment of vasospasm.
dose reteplase: results from TIMI 14.
AQT90 FLEX analyzerClinical sheet D-dimerIntended use The D-dimer test is intended as an aid in the diagnosis of venous thromboembolism (deep vein thrombosis and pulmonary embolism). SummaryUnder normal physiological conditions, the hemostatic system maintains the balance between two opposing processes: • The coagulation process leads to the formation of thrombin, which converts fibrinogen to