In this study the human glyceryltrinitrate (GTN) model of migraine was for the first time used to test the effect of a prophylactic drug. We chose to test val proate due to its well documented effect as a migraine pro...In this study the human glyceryltrinitrate (GTN) model of migraine was for the first time used to test the effect of a prophylactic drug. We chose to test val proate due to its well documented effect as a migraine prophylactic drug. Effica cy of this compound would support the usefulness of the model in prophylactic an timigraine drug development. Twelve patients with migraine without aura were inc luded in a randomized double blind crossover study. Valproate 1000 mg or placebo was given daily, each for a minimum of 13 days. On the last treatment day of ea ch arm a 20 min intravenous infusion of GTN (0.25 μg/kg/min) was given. Headach e was registered for 12 h after the infusion and headache intensity was scored o n a scale from 0 to 10. Fulfillment of IHS criteria was recorded for 24 h. The m iddle cerebral arteries were evaluated by transcranial Doppler and the diameter of the superficial temporal and radial arteries were measured with high frequenc y ultrasound. GTN evoked migraine fulfilling IHS criteria 1.1 in 6 patients afte r placebo and in 2 patients after valproate (P=0.125). Including additionally 3 patients on placebo and 1 patient on valproate who felt they had suffered a migr aine attack, but who had as associated symptoms only photophobia or phonophobia, a significant reduction in the number of patients with induced migraine after v alproate was seen (P=0.031). Median peak headache intensity was 1 (range 0-9) a fter valproate compared to 4.5 (range 0-8) after placebo (P= 0.120). Pretreatme nt with valproate as compared to placebo reduced the velocity in both middle cer ebral arteries after GTN (left P = 0.021, right P = 0.031). No effect of valproa te was seen in the diameter of the superficial temporal artery (P = 0.781) or th e radial artery (P = 0.367) before or after GTN. The study indicates that a prop hylactic effect of valproate may be demonstrated using the GTN human migraine mo del. Although, all headache parameters were reduced after valproate compared to placebo, only one parameter was statistically significantly reduced probably bec ause of the small number of patients. The sizeof the effect was similar to that of valproate in clinical trials. The GTN model may therefore be a valid tool for testing new prophylactic antimigraine drugs.展开更多
Prophylactic drug trials in migraine are long- lasting and expensive and require long- term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delaye...Prophylactic drug trials in migraine are long- lasting and expensive and require long- term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged- matched healthy subjects were included in a two- centre randomized double- blind cross- over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20- min intravenous infusion of GTN 0.25 μ g/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0- 7) compared with placebo (median 5, range 0- 10) (P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1- 5) compared with placebo (median 1, range 1- 7) (P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with (P = 0.003) and without pretreatment with propranolol (P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN- induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients (P = 0.003- 0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN- induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.展开更多
文摘In this study the human glyceryltrinitrate (GTN) model of migraine was for the first time used to test the effect of a prophylactic drug. We chose to test val proate due to its well documented effect as a migraine prophylactic drug. Effica cy of this compound would support the usefulness of the model in prophylactic an timigraine drug development. Twelve patients with migraine without aura were inc luded in a randomized double blind crossover study. Valproate 1000 mg or placebo was given daily, each for a minimum of 13 days. On the last treatment day of ea ch arm a 20 min intravenous infusion of GTN (0.25 μg/kg/min) was given. Headach e was registered for 12 h after the infusion and headache intensity was scored o n a scale from 0 to 10. Fulfillment of IHS criteria was recorded for 24 h. The m iddle cerebral arteries were evaluated by transcranial Doppler and the diameter of the superficial temporal and radial arteries were measured with high frequenc y ultrasound. GTN evoked migraine fulfilling IHS criteria 1.1 in 6 patients afte r placebo and in 2 patients after valproate (P=0.125). Including additionally 3 patients on placebo and 1 patient on valproate who felt they had suffered a migr aine attack, but who had as associated symptoms only photophobia or phonophobia, a significant reduction in the number of patients with induced migraine after v alproate was seen (P=0.031). Median peak headache intensity was 1 (range 0-9) a fter valproate compared to 4.5 (range 0-8) after placebo (P= 0.120). Pretreatme nt with valproate as compared to placebo reduced the velocity in both middle cer ebral arteries after GTN (left P = 0.021, right P = 0.031). No effect of valproa te was seen in the diameter of the superficial temporal artery (P = 0.781) or th e radial artery (P = 0.367) before or after GTN. The study indicates that a prop hylactic effect of valproate may be demonstrated using the GTN human migraine mo del. Although, all headache parameters were reduced after valproate compared to placebo, only one parameter was statistically significantly reduced probably bec ause of the small number of patients. The sizeof the effect was similar to that of valproate in clinical trials. The GTN model may therefore be a valid tool for testing new prophylactic antimigraine drugs.
文摘Prophylactic drug trials in migraine are long- lasting and expensive and require long- term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged- matched healthy subjects were included in a two- centre randomized double- blind cross- over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20- min intravenous infusion of GTN 0.25 μ g/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0- 7) compared with placebo (median 5, range 0- 10) (P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1- 5) compared with placebo (median 1, range 1- 7) (P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with (P = 0.003) and without pretreatment with propranolol (P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN- induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients (P = 0.003- 0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN- induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.
