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PubMed1997

Mixed effect modeling of sumatriptan pharmacokinetics during drug development. I: Interspecies allometric scaling.

Allometric scaling is an empirical examination of the relationships between the pharmacokinetic parameters and size (usually body weight), but it can also involve brain weight for metabolized drug. Through all species, the protein binding of sumatriptan is similar (14-16%), and its metabolic pathway undergoes extensive oxidative deamination involving the monoamine oxidase A isoenzyme. These similarities across species suggested the possible relevance of an allometric analysis. Toxicokinetic data were collected from rats, pregnant rabbits, and dogs in animal pharmacokinetic studies where sumatriptan was administered intravenously to the animals at doses of 5 mg/kg. 0.25 mg/kg, and 1 mg/kg, respectively. Animal data were pooled and analyzed in one step using a mixed effect modeling (population) approach. The kinetic parameters predicted in any species were close to the observed values by species: 77 L/hr vs. 80 L/hr in man for total clearance, 137 L vs. 119 L for distribution volume at steady state. The value of the mixed effect modeling approach compared to the two-step method was demonstrated especially with the possibility of including covariates to describe the status of animal (e.g., pregnancy) in the model. Knowledge of the animal kinetics, dynamics, and metabolism of a drug contributes to optimal and expeditious development. Valuable information for the design of the first-dose-in-man study may emerge from more creative data analysis based on all the information collected during the preclinical and ongoing nonclinical evaluation of a new drug.

Animals↗
PubMed2000

Sumatriptan increases the proliferation of peripheral blood mononuclear cells from HIV-infected individuals and healthy blood donors in vitro.

HIV infection is characterized by the loss of CD4+ T cells as well as the loss of T-cell function, leading to severe immunodeficiency. The proliferative capacity of T cells measured in vitro as responses to antigens and mitogens is severely reduced during HIV infection. An increased level of the intracellular second messenger adenosine 3',5'-cyclic monophosphate (cAMP) has been shown to cause impaired proliferative capacity of peripheral blood mononuclear cells (PBMC) from HIV-infected individuals in vitro. Sumatriptan, a 5HT1d receptor agonist, inhibits the activity of adenylyl cyclases, the enzymes responsible for regulation of the intracellular levels of cAMP. In a preliminary study sumatriptan increased the proliferative responses of PBMC to a polyclonal activator in vitro in 9 of 10 HIV-seropositive individuals (p=0.007), and in 7 of 9 healthy blood donors (p=0.05). This was probably due to a decrease in the intracellular level of cyclic AMP.

Adult↗
PubMed1990

Lack of antinociceptive activity of sumatriptan in rodents.

The present study attempts to determine whether the novel anti-migraine drug sumatriptan has antinociceptive activity in rodents. Sumatriptan had little or no antinociceptive activity against a range of noxious stimuli and we therefore conclude that it is unlikely that the beneficial effects of the drug in treating migraine are due to a non-specific analgesic action.

Animals↗
PubMed1997

Sumatriptan blocks spreading depression in isolated chick retina.

Spreading depression is a neurohumoral phenomenon that has been related to the pathophysiology of migraine. The recently introduced 5HT1D agonist anti-migraine compound sumatriptan blocks neurogenic extravasation and induces cerebral vasoconstriction, but the actual mechanism of action against migraine remains obscure. Retinal spreading depression (RSD) velocity has been measured in isolated chick retinas in the presence of 0.05-2.00 mM sumatriptan. This drug reversibly blocks RSD in a concentration-dependent manner. Since the preparation is blood-vessel free, this effect must be related to the nervous tissue.

Animals↗
PubMed2000

The potential anti-migraine compound SB-220453 does not contract human isolated blood vessels or myocardium; a comparison with sumatriptan.

The mechanistically novel benzopyran derivative SB-220453, which is undergoing clinical evaluation in migraine, exhibits a high affinity for a selective, but not yet characterized, binding site in the human brain. It inhibits nitric oxide release and cerebral vasodilatation following cortical spreading depression as well as carotid vasodilatation induced by trigeminal nerve stimulation in the cat. The aim of our study was to investigate the contractile properties of SB-220453 on a number of human isolated blood vessels (coronary artery, saphenous vein and middle meningeal artery) as well as atrial and ventricular cardiac trabeculae. While sumatriptan induced marked contractions in three blood vessels investigated, SB-220453 was devoid of any effect. In atrial and ventricular cardiac trabeculae, neither SB-220453 nor sumatriptan displayed a positive or negative inotropic effect. Since SB-220453 did not contract the middle meningeal artery, we conclude that potential anti-migraine effects are not mediated via a direct cerebral vasoconstriction. The lack of activity of SB-220453 in coronary artery, saphenous vein and cardiac trabeculae demonstrates that the compound is unlikely to cause adverse cardiac side-effects.

Adult↗
PubMed2000

Release of calcitonin gene-related peptide (CGRP) from guinea pig dura mater in vitro is inhibited by sumatriptan but unaffected by nitric oxide.

Migraine attacks can be provoked by administration of nitroglycerin, suggesting a role for nitric oxide (NO). The fact that release of the neuropeptide CGRP from trigeminal sensory nerves occurs during the pain phase of migraine and that NO can augment transmitter release prompted us to study CGRP release from the in situ dura mater in guinea pig skulls. Release of CGRP by capsaicin or by high potassium concentration was concentration-dependent and counteracted in calcium-free medium. The anti-migraine compound, sumatriptan, inhibited CGRP release via the 5-HT1-receptor. The NO donors, nitroglycerin, sodium nitroprusside and S-nitroso-N-acetylpenicillamine did not influence CGRP release, alone or together with the stimulants. We concluded that the skull preparation is well suited for scrutinizing CGRP release from dura mater. The fact that sumatriptan inhibits CGRP release as in migraine patients suggests a use for the present preparation in headache research.

Animals↗
PubMed1996

Use of high sumatriptan dosages during episodic cluster headache: three clinical cases.

The authors describe three patients with episodic cluster headache whose attacks were all treated with subcutaneous sumatriptan. The patients described had a high frequency of attacks (more than two per day); therefore, far higher dosage of the drug was taken than commonly used in cluster headache. The patients did not experience any particular side effects, neither during the treatment period nor on abrupt withdrawal of the drug. Moreover, neither tachyphylaxis nor addiction were observed. The authors point out both the efficacy of sumatriptan, confirmed in all the treated attacks, and its safety even at higher dosages than recommended.

Adult↗
PubMed1996

Impact of sumatriptan on clinic utilization and costs of care in migraineurs.

BACKGROUND: Although migraine headaches affect a large segment of the population, no objective measure of therapeutic success is currently available. Comparing visit frequency and associated costs of care before and after introduction of a new therapy represents an important surrogate measure of success. METHODS: One hundred four patients regularly attending a headache clinic for migraines at a tertiary care hospital were instructed in the use of a new abortive migraine therapy. Medical appointment and financial systems were searched retrospectively for visit frequency and associated patient care and institutional costs. The number of visits and mean costs 18 months before and after initiation of therapy were compared using the signed rank test and paired t-test, respectively. RESULTS: The median number of visits made by study subjects to the headache clinic fell significantly following sumatriptan test dosing (P < 0.001). Prior to the new treatment, mean total patient care and institutional costs were $228.59 and $112.81 per person, respectively, and fell to $135.93 and $78.16 (P < 0.001) after therapy began. CONCLUSIONS: These data suggest that many patients with migraine benefit from sumatriptan, seek medical attention in a headache clinic less often, and incur fewer costs following initiation of treatment with this drug.

Adult↗
PubMed1997

Sumatriptan relieves migrainelike headaches associated with carbon monoxide exposure.

We report a 58-year-old woman with long-standing migraine who developed a pattern of weekend headaches which occurred only while staying at her Connecticut vacation home. The headaches promptly responded to sumatriptan. Investigation revealed a high carbon monoxide level in her home due to a defective furnace. Replacing the furnace eliminated the headaches. This case highlights the importance of searching for secondary causes of headache even in patients responsive to sumatriptan. It also suggests that carbon monoxide may trigger headaches mediated by trigeminovascular inflammation.

Carbon Monoxide Poisoning↗
PubMed2001

Sumatriptan can alleviate headaches due to carotid artery dissection.

Cluster headaches can be mimicked by a spontaneous carotid artery dissection. We report a 45-year-old man with a spontaneous carotid artery dissection whose unilateral headache responded to sumatriptan. An oral dose of 50 mg of sumatriptan relieved 90% of the pain after 2 hours. A second dose the next day achieved similar results within 4 hours. The diagnosis of dissection was made later by magnetic resonance angiogram and conventional angiography. This case illustrates that a positive response to a triptan can not be used to distinguish the first attack of cluster headache from a carotid artery dissection.

Carotid Artery Diseases↗
PubMed2000

Serotonergic targets in the treatment of antidepressant induced sexual dysfunction: a pilot study of granisetron and sumatriptan.

Antidepressant induced sexual dysfunction is a common adverse event that is particularly evident with serotonergic antidepressants. There is a paucity of clinical trial evidence on the treatment of this problem. While there is some evidence of involvement of the serotonin (5-HT2) receptor subtype in this phenomenon, other serotonergic receptor systems are not well studied. In this trial, 35 patients on maintenance therapy with a variety of serotonergic antidepressants, who reported antidepressant induced sexual dysfunction, were enrolled. Patients were given both granisetron 1 mg, and sumatriptan 100 mg, in a crossover design, to be used 1 h before intercourse. Sexual dysfunction was measured using the Feiger scale. There was a high dropout rate in the trial, reflecting both embarrassment with the pharmacological treatment of sexual dysfunction and difficulties with planning and timing the medication. Nevertheless, there was a significant effect of granisetron in this study, with scores decreasing from 23.7 (SD 2.52) to 16.0 (SD 6.42) on the Feiger scale (n = 14, P = 0.001, Wilcoxon sign rank test). Sumatriptan failed to show a significant change from baseline at the 0.01 level of significance. While the small sample size, high dropout rates and open label design are limitations to this study, it suggests efficacy of the granisetron in antidepressant induced sexual dysfunction and the role of the 5-HT3 receptor in this phenomenon.

Adult↗
PubMed2002

Sumatriptan challenge in bipolar patients with and without migraine: a neuroendocrine study of 5-HT1D receptor function.

An association between bipolar disorder and migraine has been lately recognized and an abnormality of central serotonergic function is suggested as the underlying neurophysiological disturbance. To examine the role of serotonin in bipolar disorder and migraine, we used the neuroendocrine challenge paradigm, and we chose sumatriptan, a 5HT1D agonist, as the pharmacological probe. We studied nine bipolar patients with migraine, nine bipolar patients without it, seven migraine patients, and nine matched normal controls. A post-hoc analysis showed subsensitivity of serotonergic function, reflected in a blunted growth hormone response to sumatriptan challenge in bipolar patients who also suffered from migraine.

Adult↗
PubMed2006

Subcutaneous sumatriptan provides symptomatic relief at any pain intensity or time during the migraine attack.

Over the years the paradigm of treating early during the migraine attack has become well established in clinical practice. It is also recommended that the 5-HT(1B/1D) agonists be administered early during the migraine attack for efficacy. This is because it has been proposed that most migraineurs are less responsive to delayed treatment, owing to the development of central sensitization of the pain transmission. The main objective of this prospective, cross-over study at a specialist clinic was to evaluate if these recommendations should also apply to the subcutaneous formulation of sumatriptan. Results are based on 20 adult International Headache Society migraineurs. Two attacks (n=40) were treated with 6 mg subcutaneous sumatriptan as early as possible after the onset of migraine headache and two attacks (n=40) as late as the patients could bear. The median intra-individual difference between the two strategies in time from first occurrence of pain to injection was 5.7 h and the median intra-individual difference in pain intensity at the time of injection was 29 visual analogue units. No significant differences were found in time to freedom from pain, pain severity at 1 and 2 h, area under the curves from injection to pain free or in headache recurrence after injection. At the end of the study, most of the patients claimed that their medication was as effective when given early as when given late in the course of the attack. The discrepancy between our present findings and retrospective analyses of trials on oral triptans probably has more to do with the less disturbed pharmacokinetics early during the migraine attack than with central sensitization. Consequently, we recommend nonoral formulations of triptans, which do not necessarily have to be administered early during the migraine attack to provide efficacy. In conclusion, it is reassuring for migraineurs that it is worthwhile taking their medication in an appropriate formulation even if they have not been able to do so early in the course of the attack.

Adult↗
PubMed1992

CP-93,129, sumatriptan, dihydroergotamine block c-fos expression within rat trigeminal nucleus caudalis caused by chemical stimulation of the meninges.

1. The effects of intravenously administered 5-HT1B receptor agonists were examined on c-fos like immunoreactivity, an indicator of neuronal activation, within the brain stem. C-fos was induced by injecting an algesic, vasoconstrictor substance (0.3 ml of autologous blood) or a pro-inflammatory molecule, carrageenin (1 mg in 0.1 ml saline) into the cisterna magna of pentobarbitone-anaesthetized Sprague-Dawley rats and was visualized in serial sections (50 micrometers) by use of a polyclonal antiserum. 2. As previously reported, the injection of blood caused significant labelling within laminae I, IIo of the trigeminal nucleus caudalis, a major nociceptive brain stem nucleus, as well as within nucleus of the solitary tract and area postrema. A similar pattern of expression with fewer cells per section was detected after carrageenin instillation. The number of expressing cells was reduced by 54% in trigeminal nucleus caudalis but not within the nucleus of the solitary tract or area postrema when blood was injected in adult rats neonatal capsaicin treatment. 3. Pretreatment with 5-HT1 agonists with some selectivity for the 5-HT1B receptor, CP-93,129 (460 nmol kg-1 x 2, i.v.), sumatriptan (720 nmol kg-1 x 2, i.v.) or dihydroergotamine (86 nmol kg-1 x 2, i.v.) reduced positive cells by 39%, 31%, and 33% respectively in trigeminal nucleus caudalis but not in nucleus of the solitary tract or area postrema after blood instillation. Pretreatment with the analgesic morphine (15 mumol kg-1, s.c.) also decreased the number of positive cells by 63% in trigeminal nucleus caudalis. 4. CP-93,129 (460 nmol kg-1 x 2, i.v.) reduced the number of c-fos labelled cells by 47% within lamina I, IIo after carrageenin instillation. 5. Drug-induced blockade appeared to be tissue-dependent. Pretreatment with sumatriptan (720 nmol kg-1 x 2, i.v.) did not block c-fos expression in trigeminal nucleus caudalis following formalin application to the nasal mucosa.6. Drug-induced blockade may be mediated by an action on primary afferent (trigeminovascular) fibres in as much as CP-93,129 (460 nmol kg-' x 2, i.v.) did not reduce the number of expressing cells within the trigeminal nucleus caudalis following blood instillation in rats treated as neonates with capsaicin.7. We infer from these results that the analgesic actions of agonists at 5-HTB receptors (the receptor subtype analogous to 5-HTID in man) need not depend upon the presence of vasodilatation and, that 5-HTID receptor-mediated blockade of neurotransmission contributes significantly to the analgesic effects of these drugs in headache.8. Based on the demonstrated effects of 5-HTB/D agonists against the actions of two chemicallyunrelated meningeal stimulants, we suggest that treatment with 5-HTID agonists may be useful for the alleviation of pain in other headache conditions associated with meningeal irritation. Bacterial, viral(including AIDS meningovascular inflammation) and other forms of chemical meningitis merit further investigation.

Animals↗
PubMed1993

Subcutaneous sumatriptan in the treatment of acute episodes of posttraumatic headache.

Seven patients with posttraumatic headaches refractory to other medical treatment were treated with sumatriptan, 6 mg subcutaneously, at the peak of a headache. In all, the throbbing temporal part of the headache disappeared leaving a persistent occipital pain. It is postulated that involvement of the trigeminovascular system is involved in part of the pain of posttraumatic headache, making it amenable to treatment with sumatriptan.

Adult↗
PubMed1993

Abnormal photoreactivity in ictal migraine: reversal by sumatriptan.

The reactivity of posterior cerebral artery (PCA) to light stimulation was studied with transcranial Doppler in 9 migraine patients (5 with aura, 4 without aura) within six hours of the onset of headache (mean 115 +/- 78 minutes). The PCA mean flow velocity was recorded while the patient was in the dark and with the eyes closed and, subsequently, while the light was on and with the eyes open. Both symptomatic and asymptomatic sides were recorded. The same test was repeated thirty minutes after injection of sumatriptan 6 mg subcutaneously and again on the third day after cessation of the attack. Photoreactivity was calculated, for each side and for each situation, as percent relative increase of the corresponding averaged mean flow velocity recorded in darkness. The results showed that, although absolute flow velocities were not statistically different between sides and situations, photoreactivity was significantly increased on the symptomatic side during attacks (+28% vs 15% respectively). After sumatriptan, photoreactivity became symmetrical and (nonsignificantly) inferior to the values recorded in the interictal period. These findings suggest that, during headache, peripheral resistance branches of PCA on the symptomatic side are hypersensitive to vasodilatory stimuli. This could represent the counterpart of the clinical scotomata and photophobia commonly experienced by migraine patients during attacks.

Adolescent↗
PubMedDate not supplied

Comparison of contingent negative variation between migraine interval and migraine attack before and after treatment with sumatriptan.

We compared in a placebo controlled, double blind, crossover within-subject design, the amplitude and area integral of contingent negative variation (CNV) using a 2 second interstimulus interval in migraine patients between attack and interval before and after treatment. The study was conducted on 14 female subjects suffering from migraine without aura. The measurements were performed in a balanced sequence at four different times on each patient, twice during the migraine interval and once in each of two migraine attacks. The CNV in the patients was measured first (baseline), then medication was administered on a double-blind basis with an autoinjector, using either 6 mg sumatriptan or a placebo solution. Thirty minutes after administration the CNV parameters were measured again and the changes between pre- and post-treatment were taken as dependent variables. CNV amplitude baseline readings did not differ significantly between the four conditions. Neither administration of placebo nor sumatriptan led to a significant change in CNV parameters independent of whether significant clinical improvement of migraine headache occurred or not. According to our findings CNV-mechanisms between attack and interval are not subject to short-term changes, even though a small, not significant tendency towards a decrease in CNV amplitude during migraine attacks appears to exist. Therefore, it can be assumed that changes in the systems which are depicted by CNV readings are not involved in initiating and terminating acute migraine attacks.

Adult↗
PubMed1994

Subcutaneous sumatriptan in a clinical setting: the first 100 consecutive patients with acute migraine in a tertiary care center.

The first 100 consecutive patients at our center receiving subcutaneous sumatriptan (6 mg) were evaluated over a total of 455 migraine attacks. Parameters included overall efficacy, average time to relief, recurrence rate, average time to recurrence, adverse events, comparison to previous abortive agents, and subjective global ratings. Overall efficacy (defined as headache severity reduction from severe or moderate to mild or none) was 84%. Average time to relief was 40 minutes. Nine percent failed to respond at all. Recurrence rate was 46.5% with 36% of patients having no recurrence. Fourteen percent of patients reported 100% recurrence (minimum 3 attacks; average 5.4 attacks). Time to recurrence varied widely, but averaged 9.1 hours. Eighty-one percent rated the drug better or much better than previous abortive medications in terms of sumatriptan's ability to abort the attack. Seventy-seven percent reported some adverse event (generally mild and transient) with 23% reporting no adverse events. Sixty-nine percent reported a global rating of Good to Excellent and 31% rated Poor or Fair. The rate of recurrence and average time to recurrence were the most significant factors affecting the global ratings. These parameters were further evaluated with respect to a variety of subgroups: 1) migraine alone 2) migraine with co-existent tension-type headache 3) drug-induced headache (analgesic rebound headache) 4) posttraumatic headache 5) preventive versus no preventive medication 6) presence or absence of adverse events 7) presence or absence of recurrence and 8) average duration of migraine with no medication.

Acute Disease↗