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Drugs

, Volume 27, Issue 1, pp 6–44 | Cite as

Flunarizine

A Review of Its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use
  • B. Holmes
  • R. N. Brogden
  • R. C. Heel
  • T. M. Speight
  • G. S. Avery
Drug Evaluation

Summary

Synopsis: Flunarizine1 is a ‘selective’ calcium entry blocker with a similar chemical structure and pharmacological profile to the related compound, cinnarizine. However, in contrast to cinnarizine it has a long plasma half-life and need only be given once a day.

The majority of therapeutic trials in the prophylaxis of migraine, occlusive peripheral vascular disease and vertigo of central or peripheral origin have been placebo-controlled, and have shown that the drug produces significantly greater beneficial effects than placebo as evaluated by subjective and objective criteria.

A small number of comparative studies have shown flunarizine to be at least as effective as pizotifen in migraine prophylaxis, and in a longer term study as effective as cinnarizine in vertigo of central origin. However, it has not been compared with other drugs which may be useful in these areas, such as methysergide in migraine prophylaxis, some antihistamines or phenothiazines in vertigo, or (understandably at this stage of its evolution) with surgical revascularisation in severe occlusive peripheral vascular disease. In preliminary placebo-controlled studies there was some evidence that flunarizine may improve impaired cognitive function in patients with cerebrovascular disorders, but such findings need further confirmation in additional carefully conducted studies. With a very long half-life, flunarizine may be given once daily; and drowsiness, the main side effect, can be minimised by taking the daily dose in the evening.

Thus, it appears that flunarizine will offer a useful alternative in some therapeutic areas that can be difficult to manage with previously available therapy. However, a definitive statement on its relative place in therapy of such conditions must await a few well-controlled comparative studies.

Pharmacodynamic Studies: Flunarizine reduces the transmembrane fluxes of calcium in situations where calcium is stimulated to enter the cell in excess, thus preventing the deleterious consequences of ‘calcium overload’ within the cell. It does not interfere with normal cellular calcium homeostasis, having little negative inotropic effect on heart muscle and has no action on the myogenic tone of blood vessels.

Potent and long lasting inhibition of calcium-related contraction of vascular smooth muscle induced by a variety of agents has been observed with flunarizine, the degree of inhibition varying with the origin of the blood vessel, the species and the nature of the stimulus. Electron microscopic studies strongly support the concept that the drug exerts its calcium-blocking effects at the level of the plasma membrane. In vitro and in vivo studies of flunarizine in animals demonstrate protection of endothelial cells against damage from calcium overload, whilst it has also been shown to inhibit in a dose-dependent way echinocyte formation and the concomitant membrane rigidity induced by calcium ion loading with a calcium ion ionophore in red blood cells. The effects of flunarizine on the tolerance of the brain to oxygen deprivation have been demonstrated in various animal models. Essentially, brain cell survival after hypoxia or anoxia is increased after acute as well as chronic treatment with flunarizine, the beneficial action of the drug again thought to be operating through prevention of cellular calcium overload.

Flunarizine has also demonstrated vestibular depressive effect in animals and humans. Studies in animals have revealed an antihistaminic action whilst promising anticonvulsant properties in animal studies led to preliminary trials of flunarizine in epileptic patients. An antiarrhythmic effect has been demonstrated in dogs, and an apparent antiserotonin effect is thought likely to be due to a direct action of the drug on the vascular smooth muscle cell.

Pharmacokinetic Studies: Peak plasma levels occur 2 to 4 hours after oral administration of flunarizine in healthy subjects. With repeated administration of 10mg daily, plasma concentrations increase very gradually, reaching a steady-state after about 5 to 6 weeks of drug administration. Steady-state plasma levels remain constant during prolonged treatment with 10 mg/day and range between 39 and 115 ng/ml. No correlation between plasma levels and therapeutic effect has been determined.

Flunarizine pharmacokinetics are characterised by a very large volume of distribution (apparent volume of distribution in healthy subjects 43.2 L/kg), and in animal studies drug concentrations in various tissues were several times higher than plasma levels, particularly in adipose tissue and skeletal muscle in which flunarizine accumulates. Flunarizine enters the central nervous system, but brain levels in animals are very low. Small amounts of radioactivity have been recovered from the placenta and fetuses of rats, and relatively large amounts from the breast milk of dogs, after maternal administration of radiolabeled drug.

0.8% of flunarizine was present as free drug in plasma, 90% being bound to plasma proteins and 9% in blood cells. Only a negligible amount of flunarizine is excreted unchanged in the urine. Metabolism in animals involves oxidative-N-dealkylation, aromatic hydroxylation and glucuronidation, but metabolic studies in man have yet to be reported. Biliary excretion in rats accounted for between 40 and 80% of a dose. In healthy subjects flunarizine was removed from the body with a long elimination half-life of around 18 days.

Therapeutic Trials: Flunarizine has undergone trials in several therapeutic areas, particularly migraine prophylaxis, peripheral vascular disease and vertigo, sometimes involving cerebral blood flow disturbances. In the areas studied to date, flunarizine shows a progressive onset of effect often over several months.

In open studies of both classical and common migraine, flunarizine 10mg demonstrated a reduction in attack frequency in patients with a previous attack rate of less than 8 per month. Frequency of attacks was significantly reduced by flunarizine 10mg compared with placebo, and patients evaluated flunarizine therapy as being significantly better than placebo, but no consistent suppression of severity nor duration of attacks was reported. Results of 3 comparative trials found flunarizine 10mg to be at least as effective as pizotifen (2 to 3mg daily), with flunarizine improving some evaluation criteria more than pizotifen.

The majority of trials of flunarizine 10mg in patients with peripheral venous insufficiency have been placebo-controlled and have resulted in significant improvements of subjective and objective symptoms, together with the patient’s or physician’s global evaluation. Flunarizine 10mg daily produced equivalent improvements in subjective symptoms to the venotropic drug troxerutin 900mg daily over a 2-month therapy period; whilst both drugs reduced leg diameter measurements in patients to a similar extent in the first month of treatment, but the effect of flunarizine improved in the second month whilst that of troxerutin remained stable. Doses of flunarizine 20mg daily for initial periods of 1 to 3 months, reducing to 15 or 10mg thereafter, have resulted in significant increases in walking distance in patients with intermittent claudication compared with placebo. Other symptoms of occlusive and obliterative arterial disease have not shown such consistent improvements on flunarizine therapy. Flunarizine 75mg as a single initial dose produced a significantly better effect than the related compound cinnarizine (150mg), but after 1 week’s therapy the improvements in symptoms were comparable. Similarly, in a longer term trial, flunarizine 10mg daily was reported to produce equivalent improvement of symptoms of peripheral arteriosclerosis to cinnarizine 150mg daily.

Trials in patients with vertigo of peripheral or central origin frequently included an initial open stage in which flunarizine 20 to 60mg daily was administered for periods ranging from 1 week to 2 months. This led into a double-blind phase, where the doses were gradually reduced to a maintenance level of 10mg daily. Significant improvements were seen in both classes of vertigo when flunarizine was compared with placebo. Flunarizine 60mg was reported to be as effective as cinnarizine 150mg in a short term study in patients with vertigo of peripheral origin. A longer term study (4 months) in vertigo of central origin, comparing flunarizine 10mg with cinnarizine 200mg, again demonstrated equivalent effects for both drugs on the subjective system scores, but flunarizine was rated as significantly better in the patients’ global evaluation of treatment.

Side Effects: Flunarizine has been well tolerated, and has seldom caused important side effects. The main adverse effect experienced by patients is that of drowsiness, which can often be avoided by taking the dose at night or reducing the dose. Weight gain, mainly in migraine patients, may also occur and is sometimes a reason for reducing the dose.

Dosage: A maintenance dose of flunarizine 10mg daily is recommended in adults. Due to the long half-life of flunarizine, this dose may be taken once daily in the evening in an attempt to minimise the side effect of drowsiness. Since the onset of maximum effect may be gradual, possibly related to the gradual onset of steady-state plasma concentrations with usual doses, in cases where full efficacy is required as quickly as possible the 10mg daily dose may be doubled during the first 2 weeks, but it should be reduced to 10mg thereafter. Doses of 5mg may be used in patients in whom side effects are a problem, and 5mg daily is recommended for children weighing less than 40kg.

Keywords

Migraine Intermittent Claudication Flunarizine Venous Insufficiency Cinnarizine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Amery, W.K..; Wauquier, A.; Van Nueten, J.M. and De Clerck, F.: The antimigrainous pharmacology of flunarizine (R14950), a calcium antagonist. Drugs under Experimental and Clinical Research. VII(I): 1–10 (1981).Google Scholar
  2. Amery, W.K.: Flunarizine a calcium channel blocker: A new prophylactic drug in migraine. Headache 23: 70–74 (1983).PubMedGoogle Scholar
  3. Ansink, B.J.J.; Danby, M.; Oosterveld, W.J. and Schimsheimer: The influence of the calcium entry blocker flunarizine on migraine and on the vestibular system in migraine patients. 12th Scandinavian Migraine Society Meeting, Hanasaari, Finland, 17–18 Jun (1983).Google Scholar
  4. Araki, G. et al.: Phase I study of KW-3149 (flunarizine hydrochloride). Kiso to Rinsho 16: 171–177 (1982).Google Scholar
  5. Awouters, F.; Niemegeers, J.E. and Janssen, P.A.J.: Cinnarizine and flunarizine potent inhibitors of anaphylactic shock in guinea pigs. Archives Internationales de Pharmacodynamie et de Therapie 217: 38–43 (1975).PubMedGoogle Scholar
  6. Baisch, E.M.; Ginsburg, R.; Bristow, M.R.; Guadiani, V.; Wallwork, J.; Stinson, E.B.; Schroeder, J.S. and Harrison, D.C.: Comparative effects of flunarizine and diltiazem on isolated human and rabbit hearts. Clinical Research 30: 82A (1982).Google Scholar
  7. Bctz, E.: Effect of a calcium entry blocker on the uptake of ruthenium red in reversibly injured endothelial cells, and on the development of subendothelial smooth muscle cell proliferates (atheroma). 13th World Congress of the International Union of Angiology, Symposium on Calcium Entry Blockers and Vascular Disease, Mayo Clinic, Rochester, USA, 12 Sept (1983).Google Scholar
  8. Boccalon: Comparison of flunarizine with naftidrofuryl in the treatment of arteriopathies of the legs. Analysis of the safety data. Unpublished report (Janssen, Nov 1981).Google Scholar
  9. Bolton, T.B.: Mechanisms of action of transmitters and other substances on smooth muscle. Physiological Reviews 59: 606–718 (1979).PubMedGoogle Scholar
  10. Boniver, R.: Vertigo, particularly of vascular origin, treated with flunarizine (R14950). Arzneimittel-Forschung 28: 1800–1804 (1978).PubMedGoogle Scholar
  11. Borgers, M.; Ghoos, E.; Thone, F. and Van Nueten, J.M.: Effects of flunarizine on the distribution of calcium in vascular smooth muscle. Blood Vessels 17: 123–130 (1980).PubMedGoogle Scholar
  12. Campaert, H.; Mertens, R.L.J.; Moncis, J. et al.: Flunarizine in the treatment of peripheral vascular symptoms in patients with varicose veins. A double-blind placebo controlled evaluation in 4 dermatological practices. Unpublished report (Janssen, Sept 1979).Google Scholar
  13. Chaikin, P.; Soledad, C.F.; Marriott, T.B. and Weintraub, H.S.: A clinical evaluation of the pharmacokinetics and pharmacologic effects of flunarizine on myocardial conduction: A single blind multiple dose study. Unpublished report (Janssen, 1982a).Google Scholar
  14. Chaikin, P.; Soledad, C.F.; Marriott, T.B. and Weintraub, H.S.: The pharmacokinetics of single doses of flunarizine in normal volunteers. Unpublished report (Janssen, April 1982b).Google Scholar
  15. Chaikin, P.; Abrams, L.S.; Flor, S.C. and Marriott, T.B.: The placental transfer of radioactivity following oral administration of l4C-flunarizine diHCL to pregnant wistar rats. Unpublished report (Janssen, 1982c).Google Scholar
  16. Clincke, G.H.C. and Wauquier, A.: Protective effects of flunarizine versus verapamil on water intake attenuated by normobaric hypoxia; in Wauquier et al. (Eds) Protection of Tissues against Hypoxia pp.287–290 (Elsevier Biomedical Press, Amsterdam, 1982).Google Scholar
  17. De Clerck, F. and David, J.L.: Pharmacological control of platelet and red blood cell function in the microcirculation. Journal of Cardiovascular Pharmacology 3: 1388 (1981).PubMedGoogle Scholar
  18. De Clerck, F.; De Brabander, M.; Neels, H. and Van de Velde, V.: Direct evidence for the contractile capacity of endothelial cells. Thrombosis Research 23: 505–520 (1981).PubMedGoogle Scholar
  19. De Clerck, F.; De Cree, J.; Brugmars, J. and Wellens, D.: Reduction by flunarizine of the increase of blood viscosity after ischemic forearm occlusion. Archives Internationales de Pharmacodynamie et de Therapie 230: 321–323 (1977).PubMedGoogle Scholar
  20. De Clerck, F. and Hladovec, J.: Impact of Ca2+ entry blockers on Ca2+ dependant mechanisms in red blood cells, platelets and endothelial cells. ‘International Workshop on Calcium Entry Blockers’. 24th Annual Meeting of the International College of Angiology, Antwerp-Brussels, 27–29 May (1982).Google Scholar
  21. De Clerck, F. and Van Nueten, J.M.: Platelet-mediated vascular contractions: Inhibition by flunarizine, a calcium-entry blocker. Biochemical Pharmacology 32: 765–777 (1983).PubMedGoogle Scholar
  22. De Clerck, A.C. and Wauquier, A.: Double blind study of the effectiveness of flunarizine in therapy resistant epilepsy in mentally retarded children. 10th Epilepsy International Symposium p. 169 (Vancouver, 1978).Google Scholar
  23. De Cree, J.; De Cock, W.; Geukers, H.; De Clerck, F.; Beerens, M. and Verhaegen, H.: The rheological effects of cinnarizine and flunarizine in normal and pathologic conditions. Angiology 30: 505–515 (1979).PubMedGoogle Scholar
  24. De Cree, J.; Geukers, H. and Verhaegen, H.: Effects of flunarizine (sibelium) on arterial blood flow. Munchener Medizinische Wochenschrift 120: 267–630 (1978).Google Scholar
  25. Desmedt, L.K.C; Niemegeers, G.J.E. and Janssen, P.A.J.: Anticonvulsive properties of cinnarizine and flunarizine in rats and mice. Arzneimittel-Forschung 25: 1408–1413 (1975).PubMedGoogle Scholar
  26. Diamond, S. and Schenbaum, H.: Flunarizine, a calcium channel blocker in the prophylactic treatment of migraine. Headache 23: 39 (1983).PubMedGoogle Scholar
  27. Dieu, D. and Godfraind, T.: A comparison of flunarizine and cinnarizine. British Journal of Pharmacology 72: 583P (1981).Google Scholar
  28. Di Pcrri, J.; Laghi Pasini, F.; Capelli, R. and Pecchi, S.: Comparison of the effects of flunarizine and nifedipine on peripheral blood flow in normal subjects and in peripheral obliterative arterial disease patients. 13th World Congress of the International Union of Angiology, Symposium on Calcium Entry Blockers and Vascular Disease, Mayo Clinic, Rochester. USA, 12 Sept, (1983).Google Scholar
  29. Domschky, K.; Nelson, M.; Damhayn, E. and Terjung, E.: Multicentre double-blind study concerning flunarizine versus placebo in patients with cerebral and peripheral circulatory disorders. Medizinische Welt 28: 1062–1064 (1977).PubMedGoogle Scholar
  30. Drillisch, C. and Girke, W.: Results of the treatment of migraine patients with cinnarizine and flunarizine. Medizinische Welt 31: 1870–1872 (1980).PubMedGoogle Scholar
  31. Eichstetter, F.: Double blind study of flunarizine versus placebo in patients with cerebral circulatory disturbance. Janssen Report (May 1976).Google Scholar
  32. Felix, R. and Rodermund, O.E.: The effects of a two month treatment period with flunarizine on crural ulcers in patients with chronic venous insufficiency. A placebo controlled double blind trial. Unpublished report (Janssen, Aug 1978).Google Scholar
  33. Flameng, W.; Verheyen, F.; Borgers, M.; De Clerck, F. and Brugmans, J.: The effect of flunarizine treatment on human red blood cells. Angiology 31: 516–525 (1979).Google Scholar
  34. Frenken, C.W.G.M.: Flunarizine, a new preventive approach to migraine. A double blind comparison with placebo. Preliminary report (Janssen, 1982).Google Scholar
  35. Gelmers, HJ.: Prophylaxis of Migraine: Comparison of the calcium-entry blocker flunarizine and pizotifen. Interim report (Janssen, 1982).Google Scholar
  36. Godfraind, T. and Dieu, D.: The inhibition by flunarizine of the norepinephrine evoked contraction and calcium influx in rat aorta and mesenteric arteries. Journal of Pharmacology and Experimental Therapeutics 217: 510–515 (1981).PubMedGoogle Scholar
  37. Godfraind, T.; Khowi, G. and Sturbois, X.: Action of flunarizine and lidoflazine on isoprenaline induced cardiac lesions. Archives Internationales de Pharmacodynamic et de Therapie 244: 330–332 (1980).Google Scholar
  38. Godfraind, T. and Miller, R.C.: Actions of prostaglandin F and noradrenaline on calcium exchange and contraction in rat mesenteric arteries and their sensitivity to calcium entry blockers. British Journal of Pharmacology 75: 229–236 (1982).PubMedGoogle Scholar
  39. Godfraind, T. and Miller, R.C.: Prostaglandin F mediated contraction and 4SCa-influx into rat mesenteric arteries: Inhibition by flunarizine, a calcium entry blocker. British Journal of Pharmacology 73: 252 (1981).Google Scholar
  40. Hcilmann, L.: Hämorheologische Veränderungen bei Risikoschwanger. Schaften unter der Therapie mit Flunarizin. Vasa 9: 338–344 (1980).Google Scholar
  41. Hernández, G.; Maldonado, S.; Molina, D.; Ruiz, J.L.; Troncoso, G. and Valle, D.: Flunarizina en al tratamiento de varices de miembros inferiores. Estudio comparativo centra tribenosido. Compendium de Investigaciones Clinicas Latinoamericanos 11: 7–11 (1982).Google Scholar
  42. Heykants, J.; Michielsen, L.; Lorreyne, W.; Woestenborghs, R.; Schcijgrond, H. and Reyntjens, A.: Bioequivalence study of two flunarizine formulations (a 5mg capsule and a 10mg tablet) in a group of 6 healthy subjects. Unpublished report (Janssen, Sept 1981).Google Scholar
  43. Heykants, J.; DeCree, J. and Hörig, Ch.: Steady-state plasma levels of flunarizine in chronically treated patients. Arzneimittel-Forschung 29: 1168 (1979).PubMedGoogle Scholar
  44. Hladovec, J. and De Clerck, F.: Protection by flunarizine against endothelial cell injury in vivo. Angiology 32: 448–462 (1981).PubMedGoogle Scholar
  45. Hofferberth, B.: Treatment of vertebrobasilar insufficiency with flunarizine/experience from a pilot study (preliminary communication). Arzneimittel-Forschung 30: 1817–1819 (1980).PubMedGoogle Scholar
  46. Iuscm, M. and Scharenberg, E.: Venous insufficiency treated with the Ca2+ entry blocker flunarizine. Unpublished report (Janssen. 1981).Google Scholar
  47. Janssen, D.: The calcium entry blocker flunarizine prevents adverse effects of maternal smoking on intrauterine growth. Second European Congress on Obstetric Anaesthesia and Analgesia, Rome, 6–9 April (1983).Google Scholar
  48. Jaspersen, J. and Waldmann, G.: The effects of sibelium (flunarizine) on the arterial and venous blood flow in the legs of patients with low endurance. Therapiewoche 27: 6331–6336 (1977).Google Scholar
  49. Kato, H.; Kurihara, J.; Ishii, K. and Kasuya, Y.: Vasodilating effect of flunarizine in anaesthetized dogs. Archives Internationales de Pharmacodynamie et de Therapie 249: 257–263 (1981).PubMedGoogle Scholar
  50. Krstic, N.; Radovic, A.; Savovski, K. and Dragonovic, D.: The influence of flunarizine upon the resistance of acute hypoxic hypoxia. Unpublished report (Janssen, 1979).Google Scholar
  51. Kubo, K.; Karasawa, A.; Yamada, K.; Nito, M.; Shuto, K. and Nakamizo, N.: Effects of (E)-l-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl) piperazine dihydrochloride (flunarizine) on cerebral circulation. Folia Pharmacologica Japonica 79: 383–400 (1982).PubMedGoogle Scholar
  52. Kubo, K. and Jageneau, T.: Effects of flunarizine on cerebral venous outflow and cerebral oxygen consumption in pancuronium immobilized dogs. Folia Pharmacologica Japonica 79: 529–541 (1982).PubMedGoogle Scholar
  53. Lapière, M.: Expérimentation clinique à double visu de la flunarizine dans 1-insuffisance veineuse. Ars Medici 36: 479 (1981).Google Scholar
  54. Lehrl, S.; Sollberg, G. and Schumacher, H.: Drug-related increase of intelligence level — considerations and a double-blind study with flunarizine (sibelium). Pharmacopsychiatrie Neuro Psychopharmakologie 11: 134 (1978).Google Scholar
  55. Loots, W.; Dom, J. and Hörig, Ch.: Intermittent claudication — attempts to make this disease objective on account of the results of treatment obtainable by means of sibelium. Medizinische Welt 31: 189–192 (1980).PubMedGoogle Scholar
  56. Louis, P.: A double blind placebo-controlled prophylactic study of flunarizine in migraine. Headache 21: 235–239 (1981).PubMedGoogle Scholar
  57. Louis, P. and Spierings, E.L.H.: Comparison of flunarizine (Sibelium) and pizotifen (Sandomican) in migraine treatment: A double blind study. Cephalgia 2: 197–203 (1982).Google Scholar
  58. Mangabcira-Albernaz, P.L.; Gananca, M.M.; Novo, N.F. and Rodrigues de Paiva, E.: Flunarizine and Cinnarzine as vestibular depressants. A statistical study. ORL Journal for Oto-Rhino-Laryngology and its Borderlands 40: 92–100 (1978).Google Scholar
  59. Meuldermans, W.; Hendriekx, J.; Hurkmans, R.; Swysen, E.; Woostenborghs, R.; Lauwers, W. and Heykants, J.: Excretion and metabolism of flunarizine in rats and dogs. Arzneimittel-Forschung 33: 1142–1151 (1983).PubMedGoogle Scholar
  60. Meuldcrmans, W.; Hurkmans, R. and Heykants, J.: A comparative study of the plasma protein binding and the distribution of flunarizine and cinnarizine in human blood. Unpublished report (Janssen, 1978).Google Scholar
  61. Meuldcrmans, W.; Swysen, E.; Hendrickx, J.; Hurkmans, R.; Lauwers, W. and Heykans, J.: The biliary and faecal excretion of flunarizine after oral administration in male and female Wistar rats. Janssen Report (March 1982).Google Scholar
  62. Michiels, M.; Hendriks, R.; Knaeps, F.; Woestenborghs, R. and Heykants, J.: Absorption and tissue distribution of flunarizine in rats, pigs and dogs. Arzneimittel-Forschung 33: 1135–1142 (1983).PubMedGoogle Scholar
  63. Middleton, R.S.W.: Flunarizine in cerebrovascular insufficiency. Safety evaluation. Unpublished report (Janssen, Dec 1980).Google Scholar
  64. Muler, A. and Blum, F.: Efficacite de la flunarizine dans le traitement des vertiges acoyphenes et hypoacousie de perception (Triade de Lucae). Unpublished report (Janssen, 1983).Google Scholar
  65. Nakayama, K. and Kasuya, Y.: Selective abolition of Ca dependent responses of smooth and cardiac muscles by flunarizine. Japanese Journal of Pharmacology 30: 731–742 (1980).PubMedGoogle Scholar
  66. Naylcr, W.G.: The protective effect of lidoflazine on ischemic and reperfused heart muscle. Royal Society of Medicine Congress and Symposium Series 29: 79–87 (1980).Google Scholar
  67. Nelson, M.; Dewitz, G.; Dom, J. and Hörig, Ch.: Trial of the activity of sibelium (flunarizine) in circulatory disorders — a multicentre double-blind study. Medizinische Welt 29: 1175–1181 (1978).PubMedGoogle Scholar
  68. Nihard, P.: Effect of calcium-entry blockers on arteries, capillaries and venules of the retina. Angiology 33: 37–45 (1982).PubMedGoogle Scholar
  69. Oosterveld, W.J.: Vestibular pharmacology of flunarizine compared to that of cinnarizine. Journal for Oto-Rhino-Laryngology and its Borderlands 36: 157 (1974a).PubMedGoogle Scholar
  70. Oosterveld, W.J.: Pilot evaluation of flunarizine (R14950) in vertigo — a double blind trial. Canadian Journal of Otolaryngology 3: 284 (1974b).Google Scholar
  71. Oostcrvcld, W.J.: Flunarizine in vertigo. A double-blind placebo controlled cross-over evaluation of a constant dose schedule. ORL Journal for Oto-Rhino-Laryngology and its related specialities 44: 72–80 (1982).Google Scholar
  72. Overweg, J.; Binnie, C.D.; Meyer, J.W.A.; Meinardi, H.; Nuijten, S.T.M; Schmaltz, S. and Wauquier, A.: Double-blind placebo-controlled trial of flunarizine as add-on therapy in epilepsy. Unpublished report (Janssen Pharmaceutica, 1983).Google Scholar
  73. Perhoniemi, V.; Salmenkivi, K.; Sundberg, S.; Johnsson, R. and Gordin, A.: Effects of flunarizine and pentoxifylline on walking distance and blood rheology in claudication. Unpublished Report (Janssen, 1983).Google Scholar
  74. Phillips, P.; Gascoigne, E.; Reuter, C. et al.: A multicentre evaluation of flunarizine in dizziness and balance disorders, a general practice study in the United Kingdom. Unpublished Report (Janssen, 1981).Google Scholar
  75. Pointel, J.P.: Double-blind comparison of flunarizine with naftidrofuryl in the treatment of patients with asteritis. A 3-month analysis of the safety data. Unpublished report (Janssen, Aug 1982).Google Scholar
  76. Roeckaerts, F.; Morias, J.; Platteau, K.; Mertens, R.L.J, and Peremans, W.: The efficacy of flunarizine in venous insufficiency. A double-blind placebo-controlled study. Current Therapeutic Research 26: 363–37 (1979).Google Scholar
  77. Roeckacrts, F. and Vanden Bussche, G.: Double-blind placebo-controlled studies with flunarizine in venous insufficiency. Angiology 31: 833–845 (1980).Google Scholar
  78. Rose, C.F.: Possible role for flunarizine in the prophylaxis of migraine: in Rose and Amery (Eds) Cerebral Hypoxia in the Pathogenesis of Migraine, pp.185–194 (Pitman, Bath 1982).Google Scholar
  79. Rudofsky, G.; Brock, F.E.; Ulrich, M. and Noble, F.: Clinical evaluation of flunarizine: Walking distance, ergometric performance and hemodynamic and biochemical effects. Angiology 30: 470–479 (1979).PubMedGoogle Scholar
  80. Scherer, H.; Schmidtmayer, E. and Hirche, H.: Die Wirkung von Bencyclan, Flunarizin und Naftidrofuryl auf den Nystagmus eines kalorischen Dauerreizes. Laryngologie, Rhinologie, Otologic 57: 773 (1978).Google Scholar
  81. Schetz, J.; Bostoen, H.; Clement, D.; Fornhoff, M.; Haerens, A.; Roekaerts, P. and Staessen, A.J.: Flunarizine in chronic obstructive peripheral arterial disease: A placebo-controlled, double-blind randomized multi centre trial. Current Therapeutic Research 23: 121–129 (1978).Google Scholar
  82. Schwerdtfeger, F.: Disturbed vestibular function: Results with flunarizine in a 2-phase trial against placebo. Arztliche Praxis 30: 515 (1978).Google Scholar
  83. Scott, C.K.; Persico, F.J.; Carpenter, K.S. and Chasin, M.: The effects of flunarizine, a new calcium antagonist on human red blood cells in vitro. Angiology 31: 320–330 (1980).Google Scholar
  84. Shiozaki, S.; Kubo, K.; Shuto, K.; and Nakamizo, N.: Effects of flunarizine on nystagmus and cochlear blood flow. Folia Pharmacologica Japonica 80: 429–439 (1982).PubMedGoogle Scholar
  85. Sicuteri, F.: Mast cells and their active substances: Their role in the pathogenesis of migraine. Headache 3: 86–92 (1963).PubMedGoogle Scholar
  86. Spedding, M.: Assessment of ‘Ca2+-antagonist’ effects of drugs in K+-depolarized smooth muscle. Naunyn-Schmeideberg’s Archives of Pharmacology 318: 234–240 (1982).Google Scholar
  87. Staessen, A.J.: Treatment of circulatory disturbances with flunarizine and cinnarizine. A multicentre double-blind and placebo-controlled evaluation. Vasa. Zeitschrift fuer Gefaesskrankheiten 6: 59–71 (1977).Google Scholar
  88. Strano, A.: Open clinical multicentre evaluation of flunarizine. Practitioner 54: 137–143 (1982).Google Scholar
  89. Taziaux, P.: Double-blind comparison of flunarizine with troxerutin in 5061 patients with venous insufficiency. 24th Annual Meeting International College of Angiology. Belgium, 27–29 May (1982).Google Scholar
  90. Van Alphen, M.W.S. et al.: The clinical safety of flunarizine in a standard dose of 10mg/day. Unpublished report (Janssen, Feb 1982).Google Scholar
  91. Van de Water, A.; Kubo, K.; Wouters, L.; Xhonneux, R. and Reneman, R.S.: The cardiac and haemodynamic effects of intravenous administrations of R14950 in closed-chest anaesthetized mongrel dogs. Unpublished report (Janssen, Sept 1981).Google Scholar
  92. Van Nueten, J.M.: Selectivity of Calcium Entry Blockers; in Godfraind, Albertini and Paoletti (Eds) Calcium Modulators pp. 199–208 (Elsevier Biomedical Press, 1982).Google Scholar
  93. Van Nueten, J.M. and Janssen, A.J.: Comparative study of the effect of flunarizine and cinnarizine on smooth muscles and cardiac tissues. Archives Internationales de Pharmacodynamic et de Therapie 204: 37–35 (1973).Google Scholar
  94. Van Nueten, J.M.; Van Beek, J. and Janssen, P.A.J.: Effect of flunarizine on calcium-induced responses of peripheral vascular smooth muscle. Archives Internationales de Pharmacodynamie et de Therapie 232: 42–52 (1978a).PubMedGoogle Scholar
  95. Van Nueten, J.M.; Van Beek, J. and Janssen, P.A.J.: The vascular effects of flunarizine as compared with those of other clinically used vasoactive substances. Arzneimittel-Forschung Drug Research 28: 2082–2087 (1978b).Google Scholar
  96. Van Nueten, J.M. and Vanhoutte, P.M.: Selectivity of calcium-antagonism and serotonin-antagonism with respect to venous and arterial tissues. Angiology 32: 476–484 (1981).PubMedGoogle Scholar
  97. Van Reempts, J.; Borgers, M. and Van Dael, L.: Protection with flunarizine against hypoxic-ischaemic damage of the rat cere bral cortex. A quantitative morphologic approach. Archives Internationales de Pharmacodynamic et de Therapie 262: 76–78 (1983).Google Scholar
  98. Vcrhaegen, H.; Roels, V.; Adriaensen, H.; Brugmans, J.; DeCock, W.; Dony, J.; Jageneau, A. and Schuermans, V.: The arteriolar effects of cinnarizine and flunarizine. Angiology 25: 261–277 (1974).Google Scholar
  99. Verstraete, M.: Current therapy for intermittent claudication. Drugs 24: 240–247 (1982).PubMedGoogle Scholar
  100. Wauquier, A.; Ashton, D. and Melis, W.: Behavioural analysis of Amygdaloid kindling in beagle dogs and the effect of clonazepam, diazepam, phenobarbitone, diphenylhydantoin, and flunarizine on seizure manifestation. Experimental Neurology 64: 579–586 (1979).PubMedGoogle Scholar
  101. Wauquier, A. and Melis, W.: Antagonism of KCI-induced spreading depression in rat cortex by flunarizine, a Ca2+ entry blocker. Unpublished report (Janssen, 1981).Google Scholar
  102. Wauquier, A.; Melis, W.; Van Loon, J. and Van Nueten, J.M.: Antagonism of diminished cerebral perfusion by the Ca2+-entry blocker flunarizine in a new dog model of global incomplete ischemia. Unpublished report (Janssen, Dec 1982).Google Scholar
  103. Wauquier, A.; Ashton, D.; Clincke, C. and Van Reempts, J.: Pharmacological protection against brain hypoxia: The efficacy of flunarizine, a calcium entry blocker; in Rose and Amery (Eds) Cerebral Hypoxia in the Pathogenesis of Migraine pp. 139–154 (Pitman, Bath 1982a).Google Scholar
  104. White, B.C.; Gadzinski, D.S.; Hoehner, P.J.; Krome, C; Hoehner, T.; White, J.D. and Trombley, J.H.: Effect of flunarizine on canine cerebral cortical blood flow and vascular resistance post cardiac arrest. Annals of Emergency Medicine 11: 119–126 (1982).PubMedGoogle Scholar
  105. Wörz, R. and Drillisch, C.: Migraine-Prophylaxe durcheinen Kalzuim-Eintrittsblocker. Münchener Medizinische Wochenschrift 125: 711–714 (1983).PubMedGoogle Scholar
  106. Zissis, N.P.; Alcvizos, V. and Dontras, A.S.: Flunarizine, an inhibitor of calcium-induced vascular constriction in geriatric patients. Current Therapeutic Research 29: 395–400 (1981).Google Scholar

Copyright information

© ADIS Press Limited 1984

Authors and Affiliations

  • B. Holmes
    • 1
  • R. N. Brogden
    • 1
  • R. C. Heel
    • 1
  • T. M. Speight
    • 1
  • G. S. Avery
    • 1
  1. 1.ADIS Drug Information ServicesBirkenhead, Auckland 10New Zealand

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