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PubMed1993

Lack of effect of sumatriptan and UK-14,304 on capsaicin-induced relaxation of guinea-pig isolated basilar artery.

1. The objectives of this study were to assess the effects of sensory neuropeptide antagonists and presynaptically acting receptor agonists on capsaicin-induced relaxations of guinea-pig isolated basilar artery (GPBA). 2. Capsaicin, human alpha-calcitonin gene-related peptide (CGRP) and substance P (SP) caused concentration-related relaxations of GPBA which had been pre-contracted with prostaglandin F2 alpha (PGF2 alpha). Responses to capsaicin were not modified by the peptidase inhibitors, phosphoramidon (1 microM) and bestatin (100 microM). 3. The relaxant responses to capsaicin were blocked in a selective manner by ruthenium red (3 microM) and by the CGRP antagonist, CGRP8-37 (1 microM). CGRP8-37 also selectively inhibited the relaxant effects of CGRP. 4. The selective NK1 receptor antagonist, GR82334 (10 microM), inhibited SP-induced relaxations but had little effect on capsaicin-induced relaxations. 5. The 5-HT1 receptor agonist, sumatriptan, produced small contractions of GPBA under conditions of resting tone. In the presence of PGF2 alpha, sumatriptan had no further contractile effect. Sumatriptan (0.3 and 3 microM) did not modify capsaicin-induced relaxations of GPBA. 6. The alpha 2-adrenoceptor agonist, UK-14,304 (0.1 microM), had no effect on basal or PGF2 alpha-induced tone. UK-14,304 did not modify capsaicin-induced relaxations. 7. These results suggest that capsaicin causes relaxation of GPBA via a release of CGRP. This process is amenable to blockade by CGRP8-37 and ruthenium red, but not to modulation by either sumatriptan or UK-14,304.

Animals↗
PubMed1995

Canine renovascular responses to sumatriptan and 5-carboxamidotryptamine: modulation through endothelial 5-HT1-like receptors by endogenous nitric oxide.

1. In anaesthetized dogs, intra-left atrial (i.l.a.) administration of the 5-HT1-like receptor agonists, sumatriptan (1-10 micrograms kg-1) and 5-carboxamidotryptamine (0.03-0.3 micrograms kg-1) produced dose-related reductions in renal blood flow and vascular conductance, which were characterized by their rapid onset and recovery. 2. In these animals, i.v. administration of the inhibitor of nitric oxide (NO) synthase, NG-nitro-L-arginine methyl ester (L-NAME; 10 mg kg-1) significantly augmented the renal vasoconstrictor responses to i.l.a. sumatriptan and 5-carboxamidotryptamine. 3. The effects of L-NAME upon these responses to sumatriptan and 5-carboxamidotryptamine were significantly reversed by subsequent i.v. administration of L-arginine (1000 mg kg-1). 4. L-NAME significantly attenuated the systemic hypotensive responses to i.v. acetylcholine (0.3-3 micrograms kg-1) and this effect was also reversed by L-arginine. 5. L-NAME had no effect upon the renal vasoconstrictor response to i.l.a. administration of angiotensin II, nor did it affect the renal vascular conductance recovery response to brief mechanical occlusion of the renal artery. 6. These data suggest that sumatriptan and 5-carboxamidotryptamine stimulate the release of NO through the activation of a 5-HT1-like receptor located on the endothelial cells. 7. It is concluded that in canine renal vasculature, 5-HT1-like agonists (and presumably endogenous 5-hydroxytryptamine) can cause simultaneous activation of a 5-HT1-like receptor on both vascular smooth muscle and endothelial cells. The net renal vascular response to these agonists is therefore a function of both the vascular smooth muscle vasoconstriction and the concurrent vasodilator influence of NO released from the endothelium.

Acetylcholine↗
PubMed1995

Suppression by the sumatriptan analogue, CP-122,288 of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin.

1. The effects of an intravenously administered sumatriptan analogue were examined on c-fos-like immunoreactivity (c-fos-LI), a marker of neuronal activation, evoked within trigeminal nucleus caudalis (TNC) and other brain stem regions 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml, 0.1 mM), in pentobarbitone-anaesthetized Hartley guinea-pigs. 2. C-fos-LI was assessed in eighteen serial sections (50 microns) using a polyclonal antiserum. A weighted average, reflecting total expression within lamina I, IIo of TNC was obtained from three representative levels (i.e., at -0.225 mm, -2.475 mm and -6.975 mm.). 3. Capsaicin caused significant labelling within lamina I, IIo, a region containing axonal terminations of small unmyelinated C-fibres, as well as within the nucleus of the solitary tract, area postrema and medial reticular nucleus. A similar distribution of positive cells was reported previously after intracisternal injection of other chemical irritants such as autologous blood or carrageenin. 4. Pretreatment with a conformationally restricted sumatriptan analogue (with some selectivity for 5-HT1B and 5-HTID receptor subtypes) CP-122,288, reduced the weighted average by approximately 50-60% (P < 0.05) in lamina I, IIo at > or = 100 pmol kg-1, i.v., but did not decrease cell number within area postrema, nucleus of the solitary tract or medial reticular nucleus. A similar pattern was reported previously following sumatriptan, dihydroergotamine or CP-93,129 administration after noxious meningeal stimulation. 5. We conclude that modifications at the amino-ethyl side chain of sumatriptan dramatically enhance the suppression of c-fos expression within TNC, a finding consistent with its remarkable potency against neurogenic plasma protein extravasation within dura mater. CP-122,288 and related analogues may serve as an important prototype for drug development in migraine and related headaches.

Animals↗
PubMed1995

Sumatriptan-induced saphenous venoconstriction in the anaesthetized dog through 5-HT1-like receptor activation.

1. The role of vasoconstrictor 5-HT1-like receptors in the control of vascular reactivity in vivo has been relatively little studied, particularly with regards to venous function. Using an anaesthetized dog model, we have investigated the haemodynamic profile of the selective 5-HT1-like agonist, sumatriptan, focussing on the reactivity of the saphenous venous bed. The key feature of our experimental model was the implantation of ultrasonic crystals on the adventitial surface of the lateral saphenous vein to provide direct and continuous measurement of drug-induced changes in vein diameter. Saphenous vein pressure was measured simultaneously via a proximal branch. 2. Sumatriptan 1-30 micrograms kg-1, i.v., produced pronounced dose-related reductions in saphenous vein diameter which reached congruent to 40% at the highest dose tested. Sumatriptan also produced modest increases in mean blood pressure, total peripheral resistance and left ventricular end diastolic pressure but had little or no effect on cardiac output, heart rate, cardiac contractility or saphenous venous pressure. Sumatriptan-induced reductions in saphenous vein diameter were strongly antagonized by the 5-HT1-receptor antagonist, methiothepin (0.3 mg kg-1, i.v.) but were unaffected by the 5-HT2 antagonist, ketanserin (0.3 mg kg-1, i.v.). 3. Hence, 5-HT1-like receptor stimulation in vivo can result in a powerful local venoconstrictor effect.

Anesthesia↗
PubMed1990

Sumatriptan in acute migraine: pharmacology and review of world experience.

The introduction of sumatriptan, a novel abortive antimigraine agent, has generated a significant amount of preclinical and clinical interest during the past few years. At the scientific level, sumatriptan is unique in terms of its selective pharmacological properties. The effects of sumatriptan in various experimental paradigms have led to new insights into the pathophysiology of migraine. At the clinical level, sumatriptan appears to be an effective abortive anti-migraine agent with minimal side effects. Its ability to decrease, rather than exacerbate, the nausea and vomiting of migraine appears to be an important advance in the treatment of migraine.

Acute Disease↗
PubMed1995

Quality of life assessment among migraine patients treated with sumatriptan.

PURPOSE: Quality of life evaluations can enhance traditional measures of therapeutic efficacy. The purpose of our study was to evaluate the impact of sumatriptan on the quality of life of patients with migraine headaches. PATIENTS AND METHODS: Migraine patients who were given a prescription for sumatriptan completed an SF-36 questionnaire and a nine-item pain questionnaire. Six to 9 months later, patients were mailed another copy of the SF-36 and the nine-item pain questionnaire. We compared the pretreatment and posttreatment scores for the SF-36 and for each question of the nine-item pain questionnaire. RESULTS: The pretreatment SF-36 was completed by 255 patients. The pretreatment pain questionnaire was completed by 86 of these patients. Follow-up questionnaires were returned by 147 patients (58%). Three of the eight SF-36 scales: role functioning--physical, bodily pain, and social functioning showed significant (P < 0.05) improvement with treatment. On the nine-item pain-specific questionnaire, three items--pain interference with normal work, ability to walk or move about, and enjoyment of life showed statistically significant (P < 0.05) improvement after sumatriptan treatment. CONCLUSIONS: Sumatriptan caused a significant improvement in the quality of life of patients with very severe migraine. This improvement was measurable by both the general quality of life instrument and the pain-specific questionnaire.

Health Status↗
PubMedDate not supplied

Long-term efficacy of subcutaneous sumatriptan using a novel self-injector.

An open, multicenter study investigated the long-term efficacy, tolerability, and acceptability to patients of subcutaneous sumatriptan 6 mg, administered using a novel cartridge system self-injector, for the acute treatment of migraine. Eighty patients treated all migraine attacks for 6 months at home with a subcutaneous injection of sumatriptan 6 mg. A second injection could be taken after 1 to 24 hours if relief was inadequate, or if the headache recurred, and rescue medication could be taken 1 hour after the second injection. The primary end point was the percentage of attacks in which headache improved from severe or moderate before treatment to mild or absent at 1 hour after the first injection. A total of 1566 attacks were treated by the 80 patients and 69 patients completed 6 months of treatment. Headache relief was reported 1 hour after the first injection in a mean of 78% of attacks (83% in the first 3 months and 76% in the second 3 months). A second injection was required in a mean of 40% of attacks, and headache was mild or absent 1 hour after the second injection in a mean of 77% of attacks. Rescue medication was required after the second injection in a mean of 14% of attacks. At the end of the study, 87% of patients said that they would take the medication again, and at each clinic visit over 80% said that they found the injector easy to use. Adverse events were similar to those reported previously with sumatriptan and were mostly mild to moderate in intensity, short-lived, and resolved spontaneously. Subcutaneous sumatriptan 6 mg is an effective, well tolerated, and well accepted, long-term, acute treatment for migraine when self-injected by patients using the novel self-injector.

Acute Disease↗
PubMed2005

Resolution of concentration-response differences in onset of effect between subcutaneous and oral sumatriptan.

OBJECTIVE: To investigate whether the concentration-response relationships for onset of effect of oral and subcutaneous (s.c.) sumatriptan differ, and if so, then to explore whether a single model for the onset of effect can nonetheless be found for multiple dose sizes and both routes of administration. METHODS: Active and placebo response rates and mean plasma concentrations were collected from the literature for 0 < or =t < or = 2 hours. Plasma concentration-response relationships were plotted. Logarithmic models for the onset of effect (ie, active response rates), characterized by convexity factor A and location parameter B were constructed from the same data. RESULTS: The concentration-response relationships for s.c. and oral sumatriptan are qualitatively different. A single logarithmic model for the onset of effect provides good estimates of observed response rates during the first 2 hours post-dose for multiple dose sizes after both oral and s.c. routes of administration. The precision of this model resides in both its variables. Location parameters for this model differ for similar absolute doses by the two routes of administration. However, curve convexity (representing rate of onset of effect) is related to absolute dose (and hence plasma concentration) in the same way for sumatriptan tablets and injections. CONCLUSIONS: No simple plasma concentration-response relationship exists that is sufficiently robust to apply to both s.c. and oral sumatriptan. There are separate pharmacokinetic-pharmacodynamic relationships for rate of onset and extent of effect. The design of exploratory clinical trials for new acute therapies for migraine may be more efficient when these factors are considered, and these factors may help to describe the gap between experimental and ordinary clinical environments.

Administration, Oral↗
PubMed2003

Investigation of the effects of naratriptan, rizatriptan, and sumatriptan on jugular venous oxygen saturation in anesthetized pigs: implications for their mechanism of acute antimigraine action.

The effects of naratriptan, rizatriptan, and sumatriptan on arteriovenous oxygen saturation difference and carotid hemodynamics were compared in the anesthetized pig. Oxygen and carbon dioxide partial pressures in systemic arterial and jugular venous blood as well as hemoglobin oxygen saturation were determined by conventional blood gas analysis. Vehicle (n = 19) or naratriptan, rizatriptan, or sumatriptan (0.63, 2.5, 10, 40, 160, 630, and 2,500 microg/kg i.v.; n = 7/group) were infused cumulatively. In naratriptan-, rizatriptan-, and sumatriptan-treated animals, jugular venous oxygen saturation decreased dose dependently (geometric mean ED50 values of 3.1, 17.9, and 16.0 microg/kg, respectively) concomitantly with increases in carotid vascular resistance. Rizatriptan significantly and dose dependently, from 160 microg/kg, increased PvCO2 (P < 0.05 versus vehicle). Naratriptan and sumatriptan also tended to increase PvCO2 albeit nonstatistically significantly. All three triptans consistently evoked quantitatively similar carotid vasoconstriction, whereas decreases in jugular venous oxygen saturation (VOS) and increases in PvCO2 had different magnitudes and occurred only in around one-half of the animals studied. Maximal variations in PvCO2 were found to correlate highly with those in PvO2 (P = 0.002), but maximal variations in carotid resistance failed to correlate with those in PvCO2 (P = 0.76) or PvO2 (P = 0.28). The results demonstrate that the triptans investigated robustly produced carotid vasoconstriction, but elicited less consistent decreases in VOS and increases in jugular PvCO2, possibly suggestive of distinct mechanisms. Collectively, the data suggest that triptan-induced increases in arteriovenous oxygen saturation difference and carbon dioxide partial pressure in venous blood draining the head are class effects.

Anesthesia↗
PubMed2005

Open label study of intranasal sumatriptan (Imigran) for footballer's headache.

OBJECTIVE: To study the efficacy and practicality of treating headache in professional footballers with intranasal sumatriptan. METHODS: An open label drug trial was performed in elite Australian footballers using intranasal sumatriptan (20 mg) treatment for acute headache. The main outcome measures were treatment response at 30 minutes, two hours, and 24 hours using two criteria: (a) initial severity moderate or severe to nil or mild; (b) stricter criteria of initial severity moderate to severe to subsequent nil headache. RESULTS: Thirty eight attacks were analysed. The two hour response showed that 86% of attacks of migraine with aura and all of the attacks of migraine without aura responded to treatment with sumatriptan nasal spray. Complete relief of headache at two hours was reported by 71% of players with migraine with aura and 90% of those without aura. Recurrence rates were generally low, with 0% of migraine headaches and 25% non-migraine attacks recurring at 24 hours. Minor side effects were reported in 28 attacks. CONCLUSIONS: This pilot open label trial suggests that sumatriptan nasal spray may be a valuable, effective, and convenient treatment of headache in professional sport. There are potential risks of this drug that need to be considered.

Administration, Intranasal↗
PubMed1997

Intravenous chlorpromazine versus intramuscular sumatriptan for acute migraine.

OBJECTIVE: To establish whether there is any difference in the efficacy of a chlorpromazine regimen and a sumatriptan regimen for the management of the pain of acute severe migraine. SETTING: Two urban teaching hospital emergency departments. METHODS: Prospective, randomised, unblinded, crossover trial. All patients received intravenous metoclopramide 10 mg and 1000 ml of normal saline over 1 h; 20 were then randomised to receive intramuscular sumatriptan 6 mg and 23 to receive intravenous chlorpromazine, 12.5 mg increments to a maximum of 37.5 mg. Response to treatment was measured using visual analogue pain scales. RESULTS: No difference in efficacy between the sumatriptan regimen and the chlorpromazine regimen was found. Adverse effects were mild and equally distributed between the groups. CONCLUSIONS: The chlorpromazine and sumatriptan regimens studied are both very effective for the relief of the headache of severe migraine.

Adolescent↗
PubMed1993

SUMATRIPTAN: a receptor-targeted treatment for migraine.

Sumatriptan, recently introduced for the treatment of migraine, heralds the beginning of a molecular era in the pharmacological treatment of migraine headache. An indole (non-ergot alkaloid) derivative with agonist properties at a receptor resembling the 5-HT1D subtype (so-called 5-HT1-like receptor), sumatriptan is the first antimigraine medication to exhibit receptor-selective properties. Clinical data indicate that sumatriptan relieves headache, nausea, and photophobia in a majority of acute migraine patients, and it possesses favorable side effect and safety profiles. Of great importance, sumatriptan acts through a novel mechanism that we now know is shared by dihydroergotamine and other useful compounds for the treatment of acute migraine headaches. In this summary, we briefly review the drug's mechanism of action and the emerging clinical experience with its use.

Clinical Trials as Topic↗
PubMed2003

Role of 5-HT1B/D receptors in canine gastric accommodation: effect of sumatriptan and 5-HT1B/D receptor antagonists.

The 5-HT1B/D receptor agonist sumatriptan has been proposed to treat dyspeptic symptoms, because it facilitates gastric accommodation. It is unknown whether stimulation of 5-HT1B/D receptors is involved. Thus, in four conscious dogs, we compared the effects of sumatriptan alone or combined with N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1-biphenyl]-4-carboxamide hydrocloride (GR-127935), N-[3-[3 (dimethylamino)-ethoxy]-4-methoxyphenyl]-2'-[methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)]-[1,1-biphenyl]-4-carboxamide hydrocloride (SB-216641 hydrochloride), or 3-[4-(4-chloro-phenyl)piperazin-1-yl]-1,1-diphenyl-2-propanol hydrochloride (BRL-15572 hydrochloride) (respectively, nonselective 5-HT1B/D, selective 5-HT1B, and selective 5-HT1D receptor antagonists) on gastric accommodation to isobaric distensions performed with a barostat. An exponential and a linear model were used to fit the pressure-volume relationship. An exponential equation fitted the data better than a linear equation. Sumatriptan (800 nmol/kg iv) induced an immediate gastric relaxation (Deltavolume: 112 +/- 44 ml, P < 0.05). After sumatriptan, the pressure-volume curve was shifted toward significantly higher volumes. This effect was fully reversed by GR-127935 or SB-216641 but not by BRL-15572. In conclusion, 5-HT1B receptors seem to play an important role in modulating gastric accommodation to a distending stimulus. An exponential model for pressure-volume curves fits well with the concept of gastric adaptive relaxation.

Animals↗
PubMed1991

The safety and tolerability of sumatriptan: an overview.

Safety information was pooled from 4,859 patients, mainly treated in controlled clinical trials with a dispersible tablet of sumatriptan or by a subcutaneous injection, and from 1,164 patients who received placebo by these routes. Safety monitoring involved collection of all adverse events, regardless of their relationship to treatment, and included routine laboratory screening tests and some special investigations. Individuals experienced several groups of symptoms that might be considered to be features of migraine itself or of the post-migraine period or due to treatment. The commonest complaints were an unpleasant taste or pain on injection. After oral sumatriptan (100-300 mg), some events (nausea, malaise) were characteristic of migraine and others (fatigue, sedation, weakness) were characteristic of the recovery period. With subcutaneous sumatriptan (4-8 mg) similar events were observed, but certain distinctive symptoms variously described as heaviness, pressure sensation, tingling, feelings of heat or warmth, were more common and affected various parts of the body. Their early onset and transient nature suggests some pharmacological mechanism, as yet not identified. Despite the mixed picture of symptoms recorded after treatment, they were not serious, they were transient and they were accepted by patients. Close patient monitoring allowed detailed evaluation of any possible cardiovascular side-effects as seen with other anti-migraine agents, particularly ergotamine. The evidence is reassuring but, since experience in patients with symptomatic ischaemic heart disease is limited, it is recommended that they should initially be treated with sumatriptan under medical supervision for their first two or three attacks.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

The clinical profile of sumatriptan: cluster headache.

Cluster headache is a rare form of severe idiopathic headache characterized by unilateral short-lasting episodes of excruciating pain in association with autonomic disturbances. Subcutaneous sumatriptan has been investigated as an acute treatment for cluster headache in two randomized, double-blind, placebo-controlled, crossover trials. About 75% of patients given subcutaneous sumatriptan 6 mg reported headache relief within 15 min, in comparison with 26-35% given placebo (p < 0.001 in both studies). The need for rescue medication (100% oxygen by inhalation) at 15 min was significantly lower after sumatriptan treatment as were the severity of functional disability and incidence of non-headache symptoms. Results of a long-term study indicate that the tolerability and efficacy of sumatriptan 6 mg is maintained in long-term use, and that there is no evidence of tachyphylaxis.

Cluster Headache↗
PubMed2004

Pharmacokinetics of sumatriptan nasal spray in children.

The authors studied the pharmacokinetics of sumatriptan nasal spray after a single dose in children migraineurs outside of migraine attack. Seventeen subjects (9 females) ages 6 to 11 years were given one dose of sumatriptan nasal spray based on age and weight; children 6 to 8 years of age weighing </= 25 kg received 5 mg (n = 3), children ages 6 to 8 years weighing > 25 kg and children ages 9 to 11 years of age weighing </= 40 kg received 10 mg (n = 10), and children ages 9 to 11 years weighing > 40 kg received 20 mg (n = 4). Plasma sumatriptan concentrations were determined in serial blood samples obtained over 8 hours. Pharmacokinetic analysis included both noncompartmental and population modeling methods. The pharmacokinetic parameter estimates (geometric mean [95% confidence interval]) following 5, 10, and 20 mg sumatriptan were, respectively, as follows: maximum concentration = 8.1 ng/mL (3.6-18.4), 10.8 ng/mL (7.7-15.4), and 12.3 ng/mL (7.6-19.9); half-life = 1.4 hours (1.2-1.8), 1.7 hours (1.4-2.0), and 1.7 hours (1.3-2.3); and AUC = 27.8 ng*h/mL (9.7-79.8), 42.4 ng*h/mL (30.6-58.8), and 49.2 ng*h/mL (32.9-73.7). The median time to maximum concentration for all groups was 2 hours. Population pharmacokinetic modeling included pooled data from this study and from an adolescent study (n = 16). Clearance (CL/F) was 197 L/h for a 30-kg child with between-subject variability of 28%, and the volume of distribution was 751 L, normalized for an 11-year-old child with variability of 43%. The covariate analysis showed that volume increases with age and clearance increases with body size. The absorption was complex, often displaying double-peak plasma concentrations, with a rapid absorption phase and a delayed and rate-limited absorption phase. The dosing scheme based on age and weight resulted in maximal concentrations (C(max)) and systemic exposure (AUC) that were comparable to those observed in adolescents and adults treated with 20 mg. The age- and weight-adjusted dosing scheme appears to an appropriate initial dosing regimen for children with migraine headache. Appropriate safety and efficacy trials will need to be completed in children prior to recommending its use in children.

Administration, Intranasal↗
PubMed2005

In vivo disintegration profiles of encapsulated and nonencapsulated sumatriptan: gamma scintigraphy in healthy volunteers.

The goal of this exploratory pilot study was to use gamma scintigraphy to evaluate, under physiological conditions, disintegration profiles of encapsulated and nonencapsulated formulations of 100 mg sumatriptan. Using a crossover design, healthy volunteers (n = 10) ingested 100-mg doses of sumatriptan tablets radiolabeled with 111Indium, as well as encapsulated sumatriptan tablets that were prepared similarly, then placed within a gelatin capsule and backfilled with an excipient blend radiolabeled with 99mTechnetium. A gamma camera recorded scintigraphic images until 5 hours postdose. Initial disintegration of the gelatin capsule was observed at a mean (range) of 5 minutes (1-11 minutes); disintegration was complete within 14 minutes (5-24 minutes). For nonencapsulated versus encapsulated tablets, the mean (+/- standard deviation) time to initial disintegration (6 +/- 5 minutes vs 8 +/- 5 minutes) and time to complete disintegration (18 +/- 14 minutes vs 16 +/- 7 minutes) were comparable. Results of this study demonstrate that encapsulated and nonencapsulated sumatriptan have equivalent in vivo dissolution rates.

Adult↗
PubMed1999

The pharmacodynamics of sumatriptan in nitroglycerin-induced headache.

Migraine is a common disorder that causes significant morbidity in those afflicted. Many novel antimigraine compounds are in clinical development, yet full characterization of each one's pharmacodynamic behavior is a formidable task due to the difficulty in studying a migraineur during an attack. Nitroglycerin (NTG) administration commonly causes a headache with some features similar to those of a migraine. As such, NTG has been used as a model of vascular headaches, including migraine. The pharmacodynamic effects of nitroglycerin and sumatriptan on middle cerebral artery blood flow velocity (MCAv) and headache scores were studied in 10 healthy male volunteers. An intravenous infusion of NTG titrated to 0.5 mcg/kg/min over 30 minutes resulted in a median reduction from baseline in MCAv of 27% (range: 16.4%-37.3%). Nine of the subjects developed a headache with a median verbal score of 3.5 of 10 (range: 0-5). Subjects received sumatriptan either 2 mg intravenously or 6 mg subcutaneously, which abated clinical headache in 9 of the 10 subjects (p = 0.030). A median sumatriptan-induced increase in MCAv of 21% (p = 0.054) suggested a constricting effect on the NTG-induced dilated MCA. A two-compartment pharmacokinetic/indirect-effects pharmacodynamic model was fit to the sumatriptan concentration and MCAv data using iterative two-stage analysis. This model was unbiased and fit the concentration (r2 = 0.98) and the MCAv (r2 = 0.79) data well. These results suggest that NTG-induced headache and the development of pharmacokinetic/pharmacodynamic models could serve as a useful method for exploring the mechanisms of abortive migraine drugs.

Adult↗