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Biomedical subjects

H K Iversen

Publications and source records attributed to H K Iversen.

At least 19 recordsLinked to original sources
PubMed2006

Dipyridamole may induce migraine in patients with migraine without aura.

Dipyridamole inhibits phosphodiesterase 5 (PDE5) and adenosine re-uptake. The most prominent side-effect is headache. We examined the migraine-generating effects of dipyridamole as well as the cerebral blood velocity response in a single-blind study, including 10 patients with migraine without aura and 10 healthy subjects. Dipyridamole 0.142 mg/kg per min was administered intravenously. Headache intensity was scored on a verbal rating scale along with pain characteristics and accompanying symptoms. Blood velocity in the middle cerebral artery (V(mca)), blood pressure and heart rate were recorded repeatedly. Headache was induced in all migraine patients and in eight of 10 healthy subjects (P = 0.47) with no significant difference in headache intensity (P = 0.53). However, five patients but only one healthy subject experienced the symptoms of migraine without aura, according to ICHD-2 criteria, within 12 h (P = 0.14). Four patients reported photophobia after dipyridamole compared with no healthy subjects (P = 0.087). V(mca) decreased (P < 0.001) during and after dipyridamole infusion with no difference between groups (P = 0.15) coinciding with initiation, but not cessation of immediate headache. Thus, dipyridamole induces symptoms of migraine and an initial decrease in V(mca) in migraine patients, but not significantly more than in healthy subjects. This relatively low frequency of migraine induction, compared with nitric oxide donors and sildenafil, is probably due to the less specific action of dipyridamole on the cGMP signalling pathway as well as a possible bidirectional effect of adenosine on migraine induction.

Administration, Oral↗
PubMed2004

The prophylactic effect of valproate on glyceryltrinitrate induced migraine.

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 valproate due to its well documented effect as a migraine prophylactic drug. Efficacy of this compound would support the usefulness of the model in prophylactic antimigraine drug development. Twelve patients with migraine without aura were included 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 each arm a 20 min intravenous infusion of GTN (0.25 microg/kg/min) was given. Headache was registered for 12 h after the infusion and headache intensity was scored on a scale from 0 to 10. Fulfillment of IHS criteria was recorded for 24 h. The middle cerebral arteries were evaluated by transcranial Doppler and the diameter of the superficial temporal and radial arteries were measured with high frequency ultrasound. GTN evoked migraine fulfilling IHS criteria 1.1 in 6 patients after 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 migraine attack, but who had as associated symptoms only photophobia or phonophobia, a significant reduction in the number of patients with induced migraine after valproate was seen (P = 0.031). Median peak headache intensity was 1 (range 0-9) after valproate compared to 4.5 (range 0-8) after placebo (P = 0.120). Pretreatment with valproate as compared to placebo reduced the velocity in both middle cerebral arteries after GTN (left P = 0.021, right P = 0.031). No effect of valproate was seen in the diameter of the superficial temporal artery (P = 0.781) or the radial artery (P = 0.367) before or after GTN. The study indicates that a prophylactic effect of valproate may be demonstrated using the GTN human migraine model. Although, all headache parameters were reduced after valproate compared to placebo, only one parameter was statistically significantly reduced probably because of the small number of patients. The size of 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.

Adult↗
PubMed2004

A double-blind study of SB-220453 (Tonerbasat) in the glyceryltrinitrate (GTN) model of migraine.

The need for experimental migraine models increases as therapeutic options widen. In the present study, we investigated SB-220453 for efficacy in the glyceryltrinitrate (GTN) human experimental migraine model. SB-220453 is a novel benzopyran compound, which in animal models inhibits neurogenic inflammation, blocks propagation of spreading depression and inhibits trigeminal nerve ganglion stimulation-induced carotid vasodilatation. We included 15 patients with migraine without aura in a randomized double-blind crossover study. SB-220453 40 mg or placebo was followed by a 20-min GTN infusion. Headache, scored 0-10, was registered for 12 h, and fulfillment of International Headache Society (IHS) criteria was recorded until 24 h. Four subjects had a hypotensive episode after SB-220453 plus GTN but none after GTN alone. The reaction was unexpected, since animal models and previous human studies had shown no vascular or sympaticolytic activity with SB-220453. The study was terminated prematurely due to this interaction. GTN was consistent in producing headache and migraine that resembled the patients' usual spontaneous migraine. Nine patients had GTN on both study days. Peak headache score showed a trend towards reduction after SB-220453 compared with placebo (median 4 vs. 7, P = 0.15). However, no reduction was seen in the number of subjects experiencing delayed headache (8 vs. 8), number of subjects reporting migraine (6 vs. 8), migraine attacks fulfilling IHS criteria 1.1 or 1.7 (6 vs. 7) or IHS 1.1 alone (4 vs. 5). SB-220453 had no significant pre-emptive anti-migraine activity compared with placebo in this human model of migraine. Interaction between SB-220453 and GTN was discovered. This is important for the future development of the compound and underlines the usefulness of experimental migraine models.

Adult↗
PubMed2004

The effect of propranolol on glyceryltrinitrate-induced headache and arterial response.

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 microg/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.

Adult↗
PubMed2003

The effect of nitric oxide synthase inhibition on histamine induced headache and arterial dilatation in migraineurs.

We have previously proposed that histamine causes migraine via increased NO production. To test this hypothesis, we here examined if the NOS inhibitor, L-NG methylarginine hydrochloride (L-NMMA:546C88), could block or attenuate histamine induced migraine attacks and responses of the middle cerebral, temporal and radial arteries. In a double blind crossover design 12 patients were randomized to receive pretreatment with L-NMMA (6 mg/kg) or placebo i.v. over 15 min followed on both study days by histamine (0.5 microg/kg/min) i.v. for 20 min. Headache scores, mean maximal blood velocity (Vmean) in the middle cerebral artery (MCA) (transcranial doppler) and diameters of temporal and radial arteries (high resolution ultrasound) were repeatedly measured. Pre-treatment with L-NMMA, had no effect on histamine induced headache or migraine, but also had no effect on the magnitude of histamine induced-decrease in MCA blood velocity, or dilatation of neither the temporal nor the radial artery. L-NMMA constricted the temporal artery by 8% before histamine infusion, whereas the radial artery was unaffected. The temporal artery dilated 4-5 times more than the radial artery during histamine infusion. In conclusion the use of a NOS inhibitor in the highest possible dose did not block the histamine-induced headache response or arterial dilatation. Either the concentration of L-NMMA reaching the smooth muscle cell was insufficient or, histamine dilates arteries and causes headache via NO independent mechanisms. Our results showed for the first time a craniospecificity for the vasodilating effect of histamine and for the arterial effects of NOS inhibition.

Adult↗
PubMed2002

CGRP may play a causative role in migraine.

Calcitonin gene-related peptide (CGRP) has been detected in increased amounts in external jugular venous blood during migraine attacks. However, it is unknown whether this is secondary to migraine or whether CGRP may cause headache. In a double-blind crossover study, the effect of human alphaCGRP (2 microg/min) or placebo infused intravenously for 20 min was studied in 12 patients suffering from migraine without aura. Headache intensity was scored on a scale from 0 to 10. Two patients were excluded due to severe hypotension and one because she had an infection. In the first hour median peak headache score was 1.0 in the halphaCGRP group vs. 0 in the placebo group (P < 0.01). During the following 11 h all patients experienced headaches after halphaCGRP vs. one patient after placebo (P = 0.0004). The median maximal headache score was 4 after CGRP and 0 after placebo (P = 0.006). In three patients after halphaCGRP, but in no patients after placebo, the delayed headache fulfilled the IHS criteria for migraine without aura. As intravenous administration of halphaCGRP causes headache and migraine in migraineurs, our study suggests that the increase in CGRP observed during spontaneous migraine attacks may play a causative role.

Adult↗
PubMed2001

Human migraine models.

The need for experimental models is obvious. In animal models it is possible to study vascular responses, neurogenic inflammation, c-fos expression etc. However, the pathophysiology of migraine remains unsolved, why results from animal studies not directly can be related to the migraine attack, which is a human experience. A set-up for investigations of experimental headache and migraine in humans, has been evaluated and headache mechanisms explored by using nitroglycerin and other headache-inducing agents. Nitric oxide (NO) or other parts of the NO activated cascade seems to be responsible for the induced headache and migraine. Perspectives are discussed.

Animals↗
PubMed2000

Headache characteristics during the development of tolerance to nitrates: pathophysiological implications.

Recent studies suggest that nitric oxide (NO) plays an important role in nitrate-induced headache and in spontaneous migraine attacks. Organic nitrates act as prodrugs for NO and headache is a predominant adverse effect of nitrates but often disappears during continuous treatment. Insight into tolerance to headache could lead to insight into vascular headache mechanisms in general. The specific aim of the present study was therefore to characterize the headache and accompanying symptoms during continuous nitrate administration until a state of tolerance to headache had developed. 5-isosorbide-mononitrate (5-ISMN) 30 mg three times daily was administered orally for 7 days in 11 healthy subjects in a double-blind, randomized placebo controlled cross-over design. Wash-out between periods was 14 days or more. Haemodynamic data from the present study were compared to the observed changes of headache over time. Headache during 5-ISMN was longer lasting and more severe compared to placebo (P<0.004). In 10 subjects the headache fulfilled the pain sub-criteria for migraine and in five subjects all diagnostic criteria for migraine without aura were fulfilled. Conversely, 20 min of intravenous infusion of glyceryl trinitrate caused a milder headache and no migraine. The present results therefore suggest that NO may elicit a migraine attack in many healthy subjects if a high enough dose is given for several hours. A close temporal association between the disappearance of headache and the attenuation of the 5-ISMN induced dilatation of the superficial temporal artery was observed. In contrast, tolerance in the middle cerebral artery already appeared after 24 h, which was earlier than the development of tolerance to headache. If vasodilatation is the cause of headache the results point to extracerebral arteries. However, cytotoxic and pain modulating central nervous system effects of NO, the time courses of which are unknown, may also play a role, involving both intra- and extracranial arteries.

Administration, Oral↗
PubMed2000

Induction of nitrate tolerance is not a useful treatment in cluster headache.

UNLABELLED: The aims of the present study were to investigate whether induction of nitrate tolerance is a useful treatment in cluster headache and to correlate any changes in attack frequency of cluster headache and nitrate-induced headache to the vascular adaptation during continuous nitrate administration. The results were compared to results obtained from studies of nitrate tolerance in healthy subjects. MATERIALS AND METHODS: 5-isosorbide-mononitrate (5-ISMN) 30 mg was administered orally three times daily for 4 weeks in nine sufferers of chronic cluster headache in a double-blind, randomized placebo-controlled cross-over design. Blood velocity in the middle cerebral artery was measured with transcranial Doppler and the diameters of the temporal and radial arteries were measured with high frequency ultrasound. The haemodynamic data were compared to changes in the frequency of cluster headache attacks and interval headaches over time. RESULTS: Tolerance was complete within 24 h in the middle cerebral arteries and after 7 days in the symptomatic temporal artery, while tolerance of the radial artery was not observed within this period. The time profiles of tolerance were almost identical to the time profiles observed in healthy subjects. A close temporal association between the disappearance of nitrate-induced headache and tolerance of the temporal artery was observed but tolerance had no effect on cluster headache attack frequency. CONCLUSIONS: Induction of tolerance to nitrates cannot be used to treat cluster headache. If pain is related to arterial dilatation the results point to extracerebral rather than cerebral arteries as the site of nociception. However, other peripheral and central pain-modulating effects of nitric oxide, the time courses of which are unknown, should also be taken into consideration.

Adult↗
PubMed1997

[Effects of nitrogen oxide donor glyceryl trinitrate on pressure pain threshold in humans].

The purpose of the present study was to examine the effect of the nitric oxide (NO) donor glyceryl trinitrate (GTN) on nociceptive thresholds in man. On two different study days twelve healthy subjects received a stair case infusion of GTN (0.015, 0.25, 1.0, 2.0 micrograms/kg/min 20 min each dose) or placebo in a randomized double-blind cross-over design. Before the infusion and after 15 min of infusion on each dose, pressure pain detection- and tolerance thresholds were determined by pressure algometry in three different anatomic regions (finger, a temporal region with interposed myofascial tissue and a temporal region without interposed myofascial tissue). Relative to placebo the three higher GTN doses induced a decrease in both detection- and tolerance-thresholds in the temporal region with interposed myofascial tissue. No such changes were observed in the two other stimulated regions. These results could reflect central facilitation of nociception by NO. However, convergence of nociceptive input from pericranial myofascial tissue and from cephalic blood vessels dilated by NO may provide a more likely explanation.

Adult↗
PubMed1996

Histamine-1 receptor blockade does not prevent nitroglycerin induced migraine. Support for the NO-hypothesis of migraine.

It has previously been shown that in migraine sufferers infusion of glyceryl trinitrate (GTN) and histamine causes an immediate headache during the infusion and a genuine migraine attack one to several hours after the infusion. This identical time profile indicates a common mechanism of action. To evaluate whether GTN causes headache via liberation of histamine, we studied the effect of GTN 0.5 micrograms.kg-1.min-1 for 20 min in seven migraine sufferers, once after pretreatment with the histamine-1 (H1)-receptor blocker mepyramine (0.5 mg.kg-1) and once without pretreatment. This mepyramine dose is known to completely abolish histamine-induced headache. After pretreatment with mepyramine five patients experienced migraine, and without pretreatment six patients did so. The median peak headache score was 7 on a 0-10 scale with and without mepyramine pretreatment. The arterial responses, evaluated with transcranial Doppler, were also unaffected by the mepyramine pretreatment. Our results demonstrate that neither headache nor arterial dilatation due to GTN infusion is caused by histamine release. In all likelihood the common mediator of migraine induction by GTN and histamine is nitric oxide.

Adult↗
PubMed1996

Effect of a nitric oxide donor (glyceryl trinitrate) on nociceptive thresholds in man.

Several animal studies suggest that nitric oxide (NO) plays a role in central and peripheral modulation of nociception. Glyceryl trinitrate (GTN) exerts its physiological actions via donation of NO. The purpose of the present study was to examine the effect of this NO donor on nociceptive thresholds in man. On two different study days separated by at least a week 12 healthy subjects received a staircase infusion of GTN (0.015, 0.25, 1.0, 2.0 micrograms/kg/min, 20 min each dose) or placebo in a randomized double-blind crossover design. Before the infusion and after 15 min of infusion on each dose, pressure pain detection and tolerance thresholds were determined by pressure algometry (Somomedic AB, Sweden) in three different anatomic regions (finger, a temporal region with interposed myofascial tissue and a temporal region without interposed myofascial tissue). Relative to placebo, the three higher GTN doses induced a decrease in both detection and tolerance thresholds in the temporal region with interposed myofascial tissue (p = 0.003 detection and p = 0.002 tolerance thresholds, Friedman). No such changes were observed in the other two stimulated regions. These results could reflect central facilitation of nociception by NO. However, we regard convergence of nociceptive input from pericranial myofascial tissue and from cephalic blood vessels dilated by NO as a more likely explanation of our findings.

Adult↗
PubMed1996

Headache induced by a nitric oxide donor (nitroglycerin) responds to sumatriptan. A human model for development of migraine drugs.

Experimental "vascular" headache in humans may be used in characterizing new migraine drugs. The effects of sumatriptan on nitroglycerin-(NTG)-induced headache and arterial responses were therefore studied. Following a double-blind randomized crossover design, 10 healthy volunteers received sumatriptan 6 mg s.c. or placebo succeeded by 20 min NTG (0.12 microgram/kg/min) infusion. Headache was rated on a 10 points scale. Temporal and radial artery diameters and velocity in the middle cerebral artery (MCA) were measured with ultrasound. Sumatriptan reduced the NTG-induced headache, median score 1.5 versus 4 after placebo (p < 0.01) and decreased temporal and radial artery diameters 75 +/- 3 and 86 +/- 3% of baseline respectively (p < 0.05). Blood velocity in the MCA was unaffected. The NTG model may prove to be a valuable tool in the development of future migraine drugs. The results suggest that NTG headache in non-migraineurs may share mechanisms with migraine headache.

Adult↗
PubMed1995

Venous plasma levels of endothelin-1 are not altered immediately after nitroglycerin infusion in healthy subjects.

Endothelin-1 and nitric oxide play an important regulatory role in the control of vascular smooth muscle tone. Nitroglycerin (NTG), a nitric oxide donating drug, may inhibit endothelin production. In this double-blind placebo-controlled crossover study, plasma levels of endothelin-1 were measured before and immediately (5-30 s) after 80 min infusion of NTG (glyceryl trinitrate) or saline in 12 healthy subjects. On two different days separated by at least 1 week, NTG in four different doses, 0.015, 0.25, 1.0, and 2.0 micrograms. kg-1. min-1, or placebo (isotonic saline) was infused successively for 20 min each dose. During the infusion blood pressure and heart rate were measured. NTG infusion significantly decreased systolic blood pressure from 112.4 to 103.4 mmHg and pulse pressure from 39.3 to 29.5 mmHg. Heart rate increased from 62.7 to 73.1 beats. min-1. No changes in endothelin-1 plasma levels were induced by NTG infusion (2.4 pg.ml-1 before NTG vs. 2.7 pg.ml-1 after NTG) and placebo infusion also did not affect plasma endothelin-1. It is concluded that venous plasma levels of endothelin-1 are not altered immediately after NTG infusion.

Adult↗
PubMed1995

Arterial diameter during central volume depletion in humans.

The luminal diameter of the radial artery was followed by high frequency ultrasound during 50 degrees head-up tilt-induced central volume depletion in ten healthy subjects of whom six were tilted twice and pretreated with the serotonin receptor antagonist methysergide or placebo following a double-blind randomized design. Eight subjects without active treatment experienced presyncopal symptoms after 16-45 (mean 32 min). Central volume depletion was indicated by an increase in mean thoracic electrical impedance [from 31.5 (SEM 1.6) to 33.4 (SEM 1.7) omega; P < 0.05]. Cardiac output decreased [from 4.1 (SEM 0.3) to 2.2 (SEM 0.3) 1.min-1] and heart rate [HR, from 64 (SEM 3) to 100 (SEM 7) beats.min-1], mean arterial pressure (MAP, from 77 (SEM 4) to 89 (SEM 2) mmHg [10.3 (SEM 0.53 to 11.9 (SEM 0.27) kPa]) and total peripheral resistance (TPR, from 19 (SEM 2) to 34 (SEM 4) mmHg.min.1-1 [2.5 (SEM 0.27) to 4.5 (SEM 0.53) kPa.min.1-1]) increased; but with the appearance of presyncopal symptoms, HR, MAP and TPR were reduced to 65 (SEM 8) beats.min-1, 46 (SEM 4) mmHg [6.1 (SEM 0.53) kPa] and 18 (SEM 3) mmHg.min.1-1 [2.4 (SEM 0.4) kPa.min-1.1-1], respectively (P < 0.05). Vascular resistance was reflected in the arterial diameter which decreased from 2.42 (SEM 0.17) to 2.27 (SEM 0.14) mm during head-up tilt and increased to 2.71 (SEM 0.14) mm with the appearance of presyncopal symptoms (P < 0.05). Methysergide reduced the resting radial (15 +/- 2%) and temporal artery diameters (10 +/- 3%) (P < 0.05); however, it affected neither tilt-tolerance nor the central cardiovascular response to tilt. The results suggested a serotonergic influence on arterial tone at rest, and demonstrated that vessels as large as the radial artery participated in vascular control during central volume depletion independent of such a serotonergic influence.

Adult↗
PubMed1995

Cerebral blood flow velocities are reduced during attacks of unilateral migraine without aura.

It has been disputed whether or not large intracranial arteries are dilated during migraine attacks. In order to answer this question the present transcranial Doppler study focused on side-to-side differences of middle cerebral artery blood velocity during unilateral attacks of migraine without aura in 25 patients. Blood velocity in the middle cerebral artery was lower on the headache side (59 cm/s) than on the non-headache side (65 cm/s) during the migraine attack. No such difference was found outside of attack (65 cm/s both sides). The difference (headache side minus non-headache side) was on average -6.1 cm/s during attack compared to -0.4 cm/s outside of attack (p = 0.01). Assuming that rCBF is unchanged during attacks of migraine without aura, our results suggest a 9% increase in middle cerebral artery lumen (cross-sectional area) on the affected side during unilateral attacks of migraine without aura. The findings, however, do not necessarily mean that arterial dilatation is the only or even the most significant cause of pain.

Adult↗
PubMed1995

Increased cerebrovascular pCO2 reactivity in migraine with aura--a transcranial Doppler study during hyperventilation.

Cerebrovascular reactivity during hypocapnia was tested in 20 migraineurs (8 with aura, 12 without aura) and 30 sex- and age-matched healthy subjects, and during nitroglycerin-induced headache in 12 healthy subjects. Before and during hyperventilation, mean blood-flow velocity (Vmean) in the middle cerebral artery was measured with transcranial Doppler. In each subject a pCO2 reactivity index (RI) was calculated as (delta Vmean/baseline Vmean)/delta pCO2. Interictally, patients with migraine with aura showed higher RI (p < 0.05 ANOVA and multiple range test) than controls, whereas migraineurs without aura did not differ from healthy subjects. Ictal and interictal RIs were similar in 9 patients suffering from migraine without aura. No side-to-side differences were detected in RI. During nitroglycerin-induced headache, the RIs were no different from those recorded during migraine attacks and in non-nitroglycerin-provoked healthy controls (p > 0.05, ANOVA and multiple range test). The exaggerated response in migraine with aura might predispose for the characteristic changes in rCBF seen during attacks.

Adult↗