Acta Neurochirurgica

, Volume 107, Issue 1–2, pp 11–15 | Cite as

Dose escalation trial of a novel calcium antagonist, AT877, in patients with aneurysmal subarachnoid haemorrhage

  • M. Shibuya
  • Y. Suzuki
  • K. Sugita
  • I. Saito
  • T. Sasaki
  • K. Takakura
  • S. Okamoto
  • H. Kikuchi
  • T. Takemae
  • H. Hidaka
Clinical Research

Summary

The initial dose-escalating clinical trial of a novel calcium antagonist, AT877, in patients with aneurysmal subarachnoid haemorrhage is reported. AT877 is characterized by its strong spasmolytic activity, its inhibition of intracellular calcium ion activity, and the inhibiton of several protein kinases.

A total of 113 patients (Hunt and Hess grades I to IV) who had undergone surgery within 3 days of aneurysmal rupture entered the study. Patients were divided into 5 groups according to the total daily dose of AT877: I: 20 mg; II: 40 mg; III: 60 mg; IV: 90 mg; and V: 120–180 mg. AT877 was given by intravenous infusion over 30 min two or three times a day for 14 days after surgery.

Although AT877 did not completely abolish angiographic vasospasm, severe vasospasm was seen less frequently in patients given higher doses. Vasospasm was the cause of a poor clinical outcome (Glasgow outcome scale rating 3 or greater) in 19%, 7%, 9%, 8%, and 6% of the patients in groups I to V, respectively. The results indicated a favourable clinical effect of AT877 at doses above 40 mg per day. Only mild hypotension was seen, even when 60 mg of AT877 was infused over 30 min.

AT877 appears to be effective in patients with subarachnoid haemorrhage. Part of its effect may be attributable to protection of the brain from ischaemic insults due to chronic cerebral vasospasm. However, the drug still needs to be evaluated in a placebo-controlled double-blind trial (which is currently being carried out).

Keywords

Subarachnoid haemorrhage chronic cerebral vasospasm calcium antagonist AT877 HA 1077 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SG, Chou SN, Kelly DL, Weir BK, Crabbe RA, Lavik PJ, Rosenbloom SB, Dorsey FC, Ingram CR, Mellits De, Bertsch LA, Boisvert DP, Hundley MB, Johnson RK, Strom JA, Transou CR (1983) Cerebral arterial spasm —A controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 308: 619–624PubMedGoogle Scholar
  2. 2.
    Asano T, Ikegaki I, Satoh S, Suzuki Y, Shibuya M, Takayasu M, Hidaka H (1987) Mechanism of action of a novel antivasospastic drug, HA 1077. J Pharmacol Exp Ther 241: 1033–1040PubMedGoogle Scholar
  3. 3.
    Auer LM, Scneider GH, Auer T (1986) Computerized tomography and prognosis in early aneurysm surgery. J Neurosurg 65: 217–221PubMedGoogle Scholar
  4. 4.
    Findlay JM, Weir BKA, Steinke D, Tanabe T, Gordon P, Grace M (1988) Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of subarachnoid hemorrhage. J Neurosurg 69: 723–735PubMedGoogle Scholar
  5. 5.
    Fisher CM, Kistler JP, Davis JM (1980) Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6: 1–9PubMedGoogle Scholar
  6. 6.
    Flamm ES, Adams ES Jr, Beck DW, Pinto RS, Marler JR, Walker MD, Godersky JC, Loftus CM, Biller J, Boarine DJ, O'Dell C, Banwart K, Kongable G (1988) Dose-escalation study of intravenous nicardipine in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 68: 393–400PubMedGoogle Scholar
  7. 7.
    Hidaka H, Inagaki M, Kawamoto S, Sasaki Y (1984) Isoquinoline sulfonamides, novel and potent inhibitors of cyclic nucelotide dependent protein kinase and protein kinase C. Biochemistry 23: 5036–5041PubMedGoogle Scholar
  8. 8.
    Hunt WE, Hess R (1968) Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 28: 14–20PubMedGoogle Scholar
  9. 9.
    Jan M, Buchheit F, Tremoulet M (1988) Therapeutic trial of intravenous nimodipine in patients with established cerebral vasospasm after rupture of intracranial aneurysms. Neurosurgery 23: 154–157PubMedGoogle Scholar
  10. 10.
    Jennett B, Bond M (1975) Assessment of outcome after severe brain damage. A practical scale. Lancet 1: 480–484PubMedGoogle Scholar
  11. 11.
    Kassell NF, Sassaki T, Colohan ART, Nazar G (1985) Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 16: 562–572PubMedGoogle Scholar
  12. 12.
    Ljunggren B, Brandt L, Saveland H, Nilsson PE, Cronqvist S, Andersson KE, Vinge E (1984) Outcome in 60 patients treated with early aneurysm operation and intravenous nimodipine. J Neurosurg 61: 864–873PubMedGoogle Scholar
  13. 13.
    Petruk KC, West M, Mohr G, Weir BKA, Benoit BG, Gentili F, Disney LB, Khan MI, Grace M, Holness RO, Karwon MS, Ford RM, Cameron GS, Tucker WS, Purves GV, Miller JDR, Hunter KM, Richard MT, Durity FA, Chan R, Clein LJ, Maroun FB, Godon A (1988) Nimodipine treatment in poor-grade aneurysm patients. J Neurosurg 68: 505–517PubMedGoogle Scholar
  14. 14.
    Philippon J, Grob R, Dagreou F, Guggiari M, Rivierez M, Viars P (1986) Prevention of vasospasm in subarachnoid haemorrhage: A controlled study with nimodipine. Acta Neurochir (Wien) 82: 110–114, 1986Google Scholar
  15. 15.
    Pickard JD, Murray GD, Illingworth R, Shaw MDM, Teasdale GM, Foy PM, Humphrey PRD, Lang DA, Nelson R, Richards P, Sinar J, Bailey S, Skene A (1989) Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. Br Med J 298: 636–642Google Scholar
  16. 16.
    Seifert V, Eisert WG, Stolke D, Goetz C (1989) Efficacy of single intracisternal bolus injection of recombinant tissue plasminogen activator to prevent delayed cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 25: 590–598PubMedGoogle Scholar
  17. 17.
    Shibuya M, Suzuki Y, Takayasu M, Asano T, Harada T, Ikegaki I, Satoh S, Hidaka H (1988) The effects of an intracellular calcium antagonist, HA1077, on delayed cerebral vasospasm in dogs. Acta Neurochir (Wien) 90: 53–59Google Scholar
  18. 18.
    Takayasu M, Suzuki Y, Shibuya M, Asano T, Kanamori M, Okada T, Kageyama N, Hidaka H (1986) The effects of HA compound calcium antagonists on delayed cerebral vasospasm in dogs. J Neurosurg 65: 80–85PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • M. Shibuya
    • 5
  • Y. Suzuki
    • 5
  • K. Sugita
    • 5
  • I. Saito
    • 1
    • 5
  • T. Sasaki
    • 1
    • 5
  • K. Takakura
    • 1
    • 5
  • S. Okamoto
    • 2
    • 5
  • H. Kikuchi
    • 2
    • 5
  • T. Takemae
    • 3
    • 5
  • H. Hidaka
    • 4
    • 5
  1. 1.Department of NeurosurgeryTokyo UniversityJapan
  2. 2.Department of NeurosurgeryKyoto UniversityJapan
  3. 3.Department of NeurosurgeryShinshu UniversityJapan
  4. 4.Department of PharmacologyNagoya UniversityJapan
  5. 5.Department of NeurosurgeryNagoya UniversityJapan

Personalised recommendations