Download PDF
Thromb Haemost 1991; 65(04): 344-350
DOI: 10.1055/s-0038-1648149
Original Article
Schattauer GmbH Stuttgart

Effect of TRK-100, a Stable Orally Active Prostacyclin Analogue, on Platelet Function and Plaque Size in Atherothrombotic Strokes

Yoshinari Isaka
1   The Department of Cardiovascular Medicine, Osaka National Hospital, Osaka, Japan
,
Nobuo Handa
2   The First Department of Internal Medicine, Osaka University Medical School, Osaka, Japan
,
Masatoshi Imaizumi
1   The Department of Cardiovascular Medicine, Osaka National Hospital, Osaka, Japan
,
Kazufumi Kimura
3   The Department of Nuclear Medicine, Biomedical Research Centen Osaka University Medical School, Osaka, Japan
,
Takenobu Kamada
2   The First Department of Internal Medicine, Osaka University Medical School, Osaka, Japan
› Author Affiliations
Further Information

Publication History

Received: 10 August 1990

Accepted after revision 13 December 1990

Publication Date:
02 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Patients with carotid atheromatous lesions were prospectively studied with indium-111 platelet imaging, platelet aggregability and B-mode real-time ultrasound tests to determine the shortterm effects of orally active prostacyclin analogue TRK-100 (40 μg, three times daily for 4 weeks). To establish baseline values, all patients underwent indium-111 platelet imaging, platelet aggregation study and B-mode ultrasound. The results were positive for carotid plaque and platelet accumulation. Visual analysis showed repeated platelet scintigrams to be unchanged in five patients without antithrombotic therapy; repeated ultrasound studies showed no change in eight of ten plaques, while one showed progression and one regression of the plaque. In five TRK-100 treated patients, five of seven lesions with platelet accumulation at the baseline became negative, and two remained unchanged during the treatment; repeated B-mode ultrasound tests indicated eight of nine plaques remained unchanged, while one showed plaque size reduction. Quantitative analysis demonstrated that, TRK-L00 significantly reduced the ADP aggregation (1 μM) from 55.2 ± 21.3"/" to 24.0 ± 14.7% (± Sp; p <0.05) and the platelet accumulation index (25.7 ± 17.2% vs L0.4 ± 10.4%; p <0.05). However, there was no significant reduction in plaque scores during TRK-100 therapy compared with the baseline (2.70 ± 2.75 mm vs 2.51 ± 2.58 mm). The data obtained suggested that short-tenn TRK-L00 therapy has an inhibitory effect on platelet accumulation in carotid atheroma but does not cause significant changes in plaque size.

 

  • References

  • 1 Moncada S, Gryglewski RJ, Blunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 1976; 263: 663-665
    CrossrefPubMedSearch in Google Scholar
  • 2 Utsunomiya I, Krausz M, Valeri R, Shepro D, Hechtman H. Tieatment of pulmonary embolism with prostacyclin. Surgery 1980; 88: 25-30
    PubMedSearch in Google Scholar
  • 3 Aiken J, Gornan R, Shebuski R. Prevention of blockade of partially obstructed coronary arteries with prostacyclin correlates with inhibition of platelet aggregation. Prostaglandins 1979; 17: 488-494
    PubMedSearch in Google Scholar
  • 4 Woods H, Ash G, Weston M, Bunting S, Moncada S, Vane J. Prostacyclin can replace heparin in hemodialysis in dogs. Lancet 1978; 2: 1075-1077
    PubMedSearch in Google Scholar
  • 5 Longmore D, Bennett G, Gueirrara D, Smith M. Prostacyclin - A solution to some problems of extracorporeal circulation. Lancet 1979; 2: 1002-1005
    PubMedSearch in Google Scholar
  • 6 Gryglewski RI, Nowak S, Kostha-Tiabka E, Bieron K, Dembbinska-Kiec A, Blaszczyk B, Kusmiderski J, Mrkowska E, Szmatola S. Clinical use of prostacyclin (PGI2) in ischemic stroke. Pharmacol Res Commun 1982; 14: 879-908
    CrossrefPubMedSearch in Google Scholar
  • 7 Whittle BJR, Moncada S, Whiting F, Vane JR. Carbacyclin - a potent stable prostacyclin analogue for the inhibition of platelet aggregation. Prostaglandins 1980; 19: 605-627
    CrossrefPubMedSearch in Google Scholar
  • 8 Adaikan PG, Kottegoda SR, Lau LC, Tai MY, Karim SNM. Inhibition of platelet aggregation and reversal of vasopressin-induced ECG-changes by a carboprostacyclin analogue. ONO 41,483 in primates. Prostaglandins Leukotriens Med 1982 9: 347-320
    PubMed
  • 9 Scolkens BA, Gehring D, Jang W. The orally active thiaminoprostacyclin HOE 892: Antiaggregatory and cardiovascular activities. Prostaglandins Leukotriens Med 1983; 10: 231-256
    PubMedSearch in Google Scholar
  • 10 Skuballa W, Vorbruggen H. Synthesis of clioprost (ZK 36374): a chemically stable and biologically potent prostacyclin analog. Adv Prostaglandin Thromboxane Leukotriens (US) 1983; 11: 299405
    PubMedSearch in Google Scholar
  • 11 Terawaki I, Thkakura T, Iguchi S, Wakitani K, Kira H, Okegawa T, Kawasaki A, Masuda Y. Effect of prostacyclin analog OP-2507 on acute ischemic cerebral edema in rats. Eur J Pharmacol 1983; 152: 63-70
    PubMedSearch in Google Scholar
  • 12 Sim AK, McGraw AR, Cleland ME, Nishio S, IJematsu T. Effect of stable prostacyclin analogue on platelet function and experimentallyinduced thrombosis in the microcirculation. Arzneim-Forsch 1985; 35: 1816-1818
    PubMedSearch in Google Scholar
  • 13 Umetsu T, Murata I, Thnaka I, Nishio S. Anti-thrombotic effect of TRK-100, a novel stable PGI2 analogue. Jpn J Pharmacol 1986; 43: 81-90
    PubMedSearch in Google Scholar
  • 14 Barnes RW, Bone GE, Reinertson J, Slaymaker EE, Hokanson DE, Strandness Jr DE. Noninvasive ultrasonic carotid angiography: prospective validation by contrast arteriography. Surgery 1976; 80: 328-335
    PubMedSearch in Google Scholar
  • 15 Fell G, Phillips DJ, Chikos PM, Harley JD, Thiele BL, Standness Jr DE. Ultrasonic Duplex scanning for disease of the carotid artery. Circulation 1981; 64: 1191-1195
    CrossrefPubMedSearch in Google Scholar
  • 16 Powers WJ, Siegel BA, Davis II HH, Mathias CJ, Clark HB, Welch MJ. Indium-111 platelet scintigraphy in cerebrovascular disease. Neurology 1982; 32: 938-943
    CrossrefPubMedSearch in Google Scholar
  • 17 Isaka Y, Kimura K, Etani H, Uehara A, Uyama O, Yoneda S, Kamada I, Kusunoki M. Effect of aspirin and ticlopidine on platelet deposition in carotid atherosclerosis. Assessment by indium-111 platelet scintigraphy. Stroke 1986; 17: 1215-1220
    PubMedSearch in Google Scholar
  • 18 Dewanjee MK, Rao SA, Didisheim P. Indium-111 tropolone, a new highly affinity platelet label. Preparation and evaluation of labeled parameters. J Nucl Med 1981 22. 981-987
    PubMedSearch in Google Scholar
  • 19 Isaka I, Kimura K, Yoneda S, Kusunoki M, Etani H, Uyama O, Tsuda X, Abe H. Platelet accumulation in carotid atherosclerosis: semiquantitative analysis with indium-111 platelets and technetium- 99 m human serum albumin. J Nucl Med 1984; 25: 556-563
    PubMedSearch in Google Scholar
  • 20 Born GVR. Aggregability of blood platelets by adenosine diphosphate and its reversal. Nature 1962; 194: 927-929
    PubMedSearch in Google Scholar
  • 21 Crouse JR, Harpold GH, Kahl FR, Toole JR, McKinney WM. Evaluation of a scoring system for extracranial carotid atherosclerosis extent with B-mode ultrasound. Stroke 1986; 17: 270-275
    CrossrefPubMedSearch in Google Scholar
  • 22 Nishio S, Matsuura H, Kanai N, Fukatsu Y, Hirano I, Nishikawa N, Kameoka K, Umetsu T. The in vitro and ex vivo antiplatelet effect of TRK-100, a stable prostacyclin analog, in several species. Jpn J Pharmacol 1988; 47: 1-10
    CrossrefPubMedSearch in Google Scholar
  • 23 Tanaka K, Gotoh I, Fukuuchi I, Amano I, Suzuki N, LJematsu D, Kawamura J, Yamawaki I, Itoh N, Obara K. Stable prostacyclin analogue preventing microcirculatory derangement in experimental cerebral ischemia in cats. Stroke 1988; 19: 1267-1274
    CrossrefPubMedSearch in Google Scholar
  • 24 Kato R, Uji Y, Ohno K. et al Phase I trial of new prostacyclin derivative of TRK-100. Jpn J Clin Pharmacol Ther 1986; 17: 267-268
    CrossrefPubMedSearch in Google Scholar
  • 25 Yuzawa M. The effect of prostaglandins on retinal vascular occlusion. Ophthalmology 1986; 28: 1381-1387
    PubMedSearch in Google Scholar
  • 26 Comerota AJ, Cranley JJ, Cook SE. Real-time B-mode carotid imaging in diagnosis of cerebrovascular disease. Surgery 1981; 89: 718-729
    PubMedSearch in Google Scholar
  • 27 Hennerici M, Rautenberg W, Tlockel U, Kladetzky RG. Spontaneous progression and regression of small carotid atheroma. Lancet 1985; 1: 1415-1419
    PubMedSearch in Google Scholar
  • 28 Bornstein NM, Norris JW. The unstable carotid plaque. Stroke 1989; 20: 1104-1106
    CrossrefPubMedSearch in Google Scholar
  • 29 Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease. Lancet 1985; l: 415-419
    PubMedSearch in Google Scholar
  • 30 Akers DL, Kerstein D, Rush DS, Bellan JA, Haynes DF, Kadowitz PJ, McNamara DB. Prostacyclin and Thomboxane, A2 formation by atherosclerotic carotid artery. Comparison with normal aorta, saphenous vein, and platelets. J Vasc Surg 1988 8. 520-526
    PubMedSearch in Google Scholar
  • 31 Moskowitz MA, Coughlin SR. Basic properties of the prostaglandins. Stroke 1981; 12: 696-701
    PubMedSearch in Google Scholar
  • 32 Moncada S, Vane JR. Unstable metabolites of arachidonic acid and their role in haemostasis and thrombosis. Br Med Bull 1978; 34: 129-135
    CrossrefPubMedSearch in Google Scholar
  • 33 Coughlin SR, Moskowitz MA, Zetter BR, Antoniades HN, Levine L. Platelet-dependent stimulation of prostacyclin sythesis by plateletderived growth factor. Nature 1980; 288: 600-602
    CrossrefPubMedSearch in Google Scholar
  • 34 Stratton JR, Ritchi JL. The effects of antithrombotic drugs in patients with left ventricular thrombi: assessment with indium-111 platelet imaging and two-dimensional echocardiology. Circulation 1984; 69: 561-568
    CrossrefPubMedSearch in Google Scholar
  • 35 Bornstein NM, Norris JW. The unstable carotid plaque. Stroke 1989; 20: 1104-1106
    CrossrefPubMedSearch in Google Scholar
  • 36 Harker LA, Ross R, Slichter SJ, Scott C. Homocysteine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis. J Clin Invest 1976; 58: 731-741
    CrossrefPubMedSearch in Google Scholar
  • 37 Friedman RI, Stemerman MB, Wenz B, Moore S, Gauldie J, Gent M, Tiell M, Spaet H. The effect of thrombocytopenia on experimental arteriosclerotic lesion formation in rabbits. Smooth muscle proliferation and re-endothelialisation. J Clin Invest 1977 60. 1191-1201
    PubMedSearch in Google Scholar
  • 38 Fuster v, Bowie JW, Lewis JC, Fass DN, Owen CA, Brown AL. Resistance to arteriosclerosis in pigs with von Willebrand’s disease. J Clin Invest 1981; 61: 722-730
    PubMedSearch in Google Scholar