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Sumatriptan in drug combinations in the cerebral blood flow baboon model
SAFETY PHARMACOLOGICAL STUDIES OF DOTARIZINE IN THE RAT: INTERACTION WITH PROPANOLOL, DIGOXINE, DIPHENYLHYDANTOINE, DICLOPHENAC, NICARDIPINE AND METAMIZOL. Bras6 A., Brun R., Rulz T., Mart£nez L., ~ e r C., Sacristan A., Ortiz J.A. Centro de Investigaci6n Grupo Ferrer, c/Juan de Sada 32 Barcelona 08028, Spain.
Dotarizine (DOT), a benzhyldrylpiperazine, is a calcium channel blocker and 5-HT 2 receptor antagonist (ED 50= 34 mg/kg p.o). It is now in clinical trials in prophylaxis of migraine. We studied DOT interaction with drugs of different pharmacological fields commonly given in migraneous patients. Following pretreatment with DOT (100 mg/kg p.o, 1 h before) the drugs= pr0panolol (10 mg/kg), digoxine (250 ug/kg), diphenylhydantoine (3 mg/kg); diclofenac sodium (i,25 mg/kg), nicardipine (i mg/kg) and metamizol (200 mg/kg), were administered as 30 min. i.v. infusions in anaesthetised rats. Each interaction group was compared with control groups during 3 hours; 't' test and Anova were used for the statistical analysis. DOT did not affect courses of carotid blood pressure (systolic, diastolic, mean), heart rate, ~p/dt max and dp/dt min, of the drugs administered alone. We conclude that DOT will be an antimigraneous drug avoid of unexpected adverse effects in the tested combinations of drug treatments.
CALCIUM ANTAGONISTS AND CEREBROVASCULAR EFFECTS OF SEROTONIN R.S. Mirzoyan, D.D. Matsievsky and N.A: Romanytcheva Institute o f Pharmacology, Russian Academy o f Medical Sciences, Baltiyskaya str.8, 125315 Moscow, Russia Calcium channel blockers (nimodipine and nifedipine) were reported to prevent constrictions of isolated cerebral vessels induced by serotonin (Peroutka et al., 1984; Allen 1985; Takayasu et al., 1988). Considering the substantial role serotonin plays in migraine pathogenesis, the present study was designed to investigate the effects of nimodipine and nifedipine on serotonin-induced 'changes in cerebre,I haemodynamics. In the experiments in rats, usinq ultrasonic doppler techniques, serotonin at a dose of 20 IJg/kg decreased significantly 60 _+ 3.9%, n=26 the blood flow in the mii:ldle cerebral.artery, associated with the increased tone o f cerebral vessels. This percent is higher than that observed in carotid system circulation in cats treated with the same serotonin dosage (44 _+ 1.5%, n=ll0, P<0.O01). Nimodipine and nifedipine at a dose of 0.03 mg/kg i.v., found to induce a siqnificant increase in the middle cerebral artery blood Now in rats (Mirzoyan et al., 1994), failed to produce any action on cerebrovascular eff'ects of serotonin. While prior to nimodipine and nifedipine administration, serotonin decreased the cerebral blood flow by 41 _+ 4.8%, n=8 and 57 _+ 5.9%, n=7 respectively. Then under the action of these calcium channel blockers serotonin reduced the cerebral haemodynamics by 42 -+ 4.1%, n=8 and 46 + 4.9%, n=7. While tile results obtained are not consistent with that reported in the literature, this may be, however, attributed to different experimental conditions. Thus, in vivo experimefits nimodipine and nifedipine showed no protective effects on serotonergic constrictions of the cerebral vessels.
PANICOGENIC EFFECT OF SUMATRIPTAN: A PILOT STUDY. V. Loi, M. Lai, MR. Pisano*, M.Del Zompo Department of Neurosciences "B.B. Brodie", University of Cagliari, via Porcell 4, 09124 Cagliari, Italy. *Institute of Cardiology, University of Cagliari, via Ospedale 46, 09124 Cagliari, Italy.
Sumatriptan (SUM) is a 5HT1D agonist that is generally well tolerated and effective in the acute migraine attack treatment. Recent i n vitro experiments suggest that vasoconstriction activity caused by SUM is present both in cerebral and coronary vessels. Some patients affected by migraine without aura (IHS classification) attending the Headache Center of Department of Neurosciences of Cagliari. treated with a single dose of this drug during a migraine attack reported chest pain, palpitations, sweating, gasping or smothering sensation, fear of dying. paresthesias. The objective of this study was to determine whether in these subjects this symptomatology was caused by a coronary artery vasoconstriction or was centrally mediated• We asked our patients to take a dose of SUM under a careful cardiovascular control. Rating scales to evaluate anxiety were administered. There was no significant change in heart rate or ECG morphology. The results of our preliminary study suggest that in predisposed patients SUM can be anxiogenic. An explanation could be that during a migraine attack SUM can cross the blood brain barrier and interact with central 5HT receptors.
SUMATR1PTAN IN DRUG COMBINATIONS IN THE CEREBRAL BLOOD F L O W BABOON MODEL D.W. Oliver 1, I.C. Dormehl 2 and N. Hugo 2 t 2
Dept of Pharmacology, Potchefstroom Univ. for C.H.E., Potchefstroom, South Africa AEC Institute for Life Sciences, Univ. of Pretoria, Pretoria, South Africa
Sumatriptan, a 5-HTID receptor agonist, has established itself as an important therapeutic agent in the treatment of migraine. However, the mechanisms for the pharmacological effects of sumatriptan have not yet been fully illucidated. In the present study the effects of sumatriptan on cerebral blood flow (CBF) increases induced in the baboon model (by acetazolamide, nimodipine and ha]othane) (n=6), were investigated using 99mTc-HMPAO, and SPECT in a split-dose procedure. Two SPECT procedures followed each on the consecutive injections of 4 and 8 mCi of 99mTc-HMPAO. The tracer distributions from the two injections represented CBF-effects due to the preceding drug administrations. Sumatriptan selectively reduced drug-induced cerebral blood flow increases. The increases due to halothane anaesthesia and acetazolamide on CBF were not reversed by sumatriptan, while the increased CBF caused by the Ca2+-blocker nimodipine was attenuated by 47% to a level of CBF below tile normal flow baseline. These results support multiple mechanisms for sumatriptan, involving vascular neurotransmission and neurogenic inflammatory responses via serotonin receptor stimulation and Ca 2+ mobilization. Drug-drug interactions are further implicated through this study.
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Dotarizine (DOT), a benzhyldrylpiperazine, is a calcium channel blocker and 5-HT 2 receptor antagonist (ED 50= 34 mg/kg p.o). It is now in clinical trials in prophylaxis of migraine. We studied DOT interaction with drugs of different pharmacological fields commonly given in migraneous patients. Following pretreatment with DOT (100 mg/kg p.o, 1 h before) the drugs= pr0panolol (10 mg/kg), digoxine (250 ug/kg), diphenylhydantoine (3 mg/kg); diclofenac sodium (i,25 mg/kg), nicardipine (i mg/kg) and metamizol (200 mg/kg), were administered as 30 min. i.v. infusions in anaesthetised rats. Each interaction group was compared with control groups during 3 hours; 't' test and Anova were used for the statistical analysis. DOT did not affect courses of carotid blood pressure (systolic, diastolic, mean), heart rate, ~p/dt max and dp/dt min, of the drugs administered alone. We conclude that DOT will be an antimigraneous drug avoid of unexpected adverse effects in the tested combinations of drug treatments.
CALCIUM ANTAGONISTS AND CEREBROVASCULAR EFFECTS OF SEROTONIN R.S. Mirzoyan, D.D. Matsievsky and N.A: Romanytcheva Institute o f Pharmacology, Russian Academy o f Medical Sciences, Baltiyskaya str.8, 125315 Moscow, Russia Calcium channel blockers (nimodipine and nifedipine) were reported to prevent constrictions of isolated cerebral vessels induced by serotonin (Peroutka et al., 1984; Allen 1985; Takayasu et al., 1988). Considering the substantial role serotonin plays in migraine pathogenesis, the present study was designed to investigate the effects of nimodipine and nifedipine on serotonin-induced 'changes in cerebre,I haemodynamics. In the experiments in rats, usinq ultrasonic doppler techniques, serotonin at a dose of 20 IJg/kg decreased significantly 60 _+ 3.9%, n=26 the blood flow in the mii:ldle cerebral.artery, associated with the increased tone o f cerebral vessels. This percent is higher than that observed in carotid system circulation in cats treated with the same serotonin dosage (44 _+ 1.5%, n=ll0, P<0.O01). Nimodipine and nifedipine at a dose of 0.03 mg/kg i.v., found to induce a siqnificant increase in the middle cerebral artery blood Now in rats (Mirzoyan et al., 1994), failed to produce any action on cerebrovascular eff'ects of serotonin. While prior to nimodipine and nifedipine administration, serotonin decreased the cerebral blood flow by 41 _+ 4.8%, n=8 and 57 _+ 5.9%, n=7 respectively. Then under the action of these calcium channel blockers serotonin reduced the cerebral haemodynamics by 42 -+ 4.1%, n=8 and 46 + 4.9%, n=7. While tile results obtained are not consistent with that reported in the literature, this may be, however, attributed to different experimental conditions. Thus, in vivo experimefits nimodipine and nifedipine showed no protective effects on serotonergic constrictions of the cerebral vessels.
PANICOGENIC EFFECT OF SUMATRIPTAN: A PILOT STUDY. V. Loi, M. Lai, MR. Pisano*, M.Del Zompo Department of Neurosciences "B.B. Brodie", University of Cagliari, via Porcell 4, 09124 Cagliari, Italy. *Institute of Cardiology, University of Cagliari, via Ospedale 46, 09124 Cagliari, Italy.
Sumatriptan (SUM) is a 5HT1D agonist that is generally well tolerated and effective in the acute migraine attack treatment. Recent i n vitro experiments suggest that vasoconstriction activity caused by SUM is present both in cerebral and coronary vessels. Some patients affected by migraine without aura (IHS classification) attending the Headache Center of Department of Neurosciences of Cagliari. treated with a single dose of this drug during a migraine attack reported chest pain, palpitations, sweating, gasping or smothering sensation, fear of dying. paresthesias. The objective of this study was to determine whether in these subjects this symptomatology was caused by a coronary artery vasoconstriction or was centrally mediated• We asked our patients to take a dose of SUM under a careful cardiovascular control. Rating scales to evaluate anxiety were administered. There was no significant change in heart rate or ECG morphology. The results of our preliminary study suggest that in predisposed patients SUM can be anxiogenic. An explanation could be that during a migraine attack SUM can cross the blood brain barrier and interact with central 5HT receptors.
SUMATR1PTAN IN DRUG COMBINATIONS IN THE CEREBRAL BLOOD F L O W BABOON MODEL D.W. Oliver 1, I.C. Dormehl 2 and N. Hugo 2 t 2
Dept of Pharmacology, Potchefstroom Univ. for C.H.E., Potchefstroom, South Africa AEC Institute for Life Sciences, Univ. of Pretoria, Pretoria, South Africa
Sumatriptan, a 5-HTID receptor agonist, has established itself as an important therapeutic agent in the treatment of migraine. However, the mechanisms for the pharmacological effects of sumatriptan have not yet been fully illucidated. In the present study the effects of sumatriptan on cerebral blood flow (CBF) increases induced in the baboon model (by acetazolamide, nimodipine and ha]othane) (n=6), were investigated using 99mTc-HMPAO, and SPECT in a split-dose procedure. Two SPECT procedures followed each on the consecutive injections of 4 and 8 mCi of 99mTc-HMPAO. The tracer distributions from the two injections represented CBF-effects due to the preceding drug administrations. Sumatriptan selectively reduced drug-induced cerebral blood flow increases. The increases due to halothane anaesthesia and acetazolamide on CBF were not reversed by sumatriptan, while the increased CBF caused by the Ca2+-blocker nimodipine was attenuated by 47% to a level of CBF below tile normal flow baseline. These results support multiple mechanisms for sumatriptan, involving vascular neurotransmission and neurogenic inflammatory responses via serotonin receptor stimulation and Ca 2+ mobilization. Drug-drug interactions are further implicated through this study.
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