sumatriptan, Imitrex
Subcutaneous sumatriptan in cluster headache: a time study of the effect on pain and autonomic symptoms.

Hardebo JE.

Department of Medical Cell Research, University of Lund, Sweden.

A subcutaneous injection of 6 mg sumatriptan rapidly and effectively stopped attacks of cluster headache. After a time lag of 4-14 minutes (mean 7 minutes) pain dramatically dropped to zero within seconds to single minutes (mean 56 seconds). This rapid effect may indicate that mere vasoconstriction is the mechanism behind the beneficial effect of sumatriptan in cluster pain. The findings support a scenario in cluster headache where an inflammation in the cavernous sinus affects the sympathetic fibers traversing the cavernous region. This leads to the miosis, ptosis and forehead anhidrosis but also to a dilated internal carotid arterial tree distal to the lesion. The dilatation, in combination with an obliterated drainage of the cavernous sinus by the inflammatory process, leads to progressive stasis in the sinus, to cause the painful attack. The attack terminates when the enhanced load on the sinus is reduced by constriction of vessels supplying the sinus, as is achieved by administration of sumatriptan. The present observation that other accompanying symptoms during attacks (nasal congestion, rhinorrhea, lacrimation and swelling of eyelids) disappeared in parallel with the pain points to the possibility that these symptoms may be directly related to venous stasis or activation of pain fibers, rather than resulting from a primary parasympathetic activation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8382200&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats.

Goadsby PJ, Edvinsson L.

Department of Neurology, Prince Henry Hospital, Little Bay Sydney, Australia.

Both clinical and physiological consideration of migraine suggests that the pathophysiology of the syndrome is intimately linked to the trigeminal innervation of the cranial vessels, the trigeminovascular system. Studies were conducted in cats and humans to examine the interaction of these systems with the effective acute antimigraine drugs dihydroergotamine and sumatriptan. In the animal studies cats were anesthetized and prepared for routine physiological monitoring as well as for blood sampling from the external jugular veins. Cerebral blood flow was monitored continuously using laser Doppler flowmetry and the effect of trigeminal ganglion stimulation on both cerebral blood flow and jugular vein peptide levels determined prior to and after administration of either sumatriptan or dihydroergotamine. Stimulation of the trigeminal ganglion led to a frequency-dependent increase in cerebral blood flow, with a mean maximum of 43 +/- 9% at a stimulus frequency of 20 per second. There was a marked reduction in these responses by some 50% after administration of either sumatriptan or dihydroergotamine. Trigeminal ganglion stimulation at a frequency of 5 per second also led to a release into the cranial circulation of calcitonin gene-related peptide (CGRP), with the level rising from 67 +/- 3 to 82 +/- 5 pmol/liter on the side of stimulation. These increases were also markedly antagonized by both sumatriptan and dihydroergotamine. Human studies were conducted as part of the overall evaluation of sumatriptan for the treatment of acute migraine. In 7 of 8 patients responding to subcutaneous sumatriptan administration, elevated CGRP levels (60 +/- 8 pmol/liter) were normalized, with the headache being relieved (40 +/- 8 pmol/liter).(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8388188&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Inhibition by sumatriptan of central trigeminal neurones only after blood-brain barrier disruption.

Kaube H, Hoskin KL, Goadsby PJ.

Department of Neurology, Prince Henry Hospital, Little Bay Sydney, N.S.W., Australia.

1. The 5-hydroxytryptamine (5-HT1)-like agonist, sumatriptan, is highly efficient in the relief of migraine headache and its accompanying symptoms. 2. Experimental evidence has indicated that its site of action may be on the cranial vessels or on the trigeminal innervation of the cranium, or both, since sumatriptan does not pass the blood-brain barrier easily under normal circumstances. It is, however, not clear whether the blood-brain barrier is normal or abnormal during a migraine attack. 3. In this study, single unit activity and trigeminal somatosensory evoked potentials in central trigeminal neurones were monitored during electrical stimulation of the superior sagittal sinus. 4. Intravenous administration of sumatriptan (100 micrograms kg-1) did not alter trigeminal evoked activity unless the permeability of the blood-brain barrier had been increased by infusion of an hyperosmolar mannitol solution. After blood-brain barrier disruption, sumatriptan decreased the peak-to-peak amplitude of evoked potentials by 40 +/- 6% and the probability of firing of single units by 30 +/- 9%. Mannitol infusions alone in control animals caused no changes in evoked potentials or single unit activity. 5. The data suggest that in normal circumstances sumatriptan does not have sufficient access to trigeminal neurons to alter their function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8395298&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Evidence against strong correlation between chest symptoms and ischemic coronary changes after subcutaneous sumatriptan injection.

Tomita M, Suzuki N, Igarashi H, Endo M, Sakai F.

OBJECTIVE: To evaluate the adverse events possibly caused by sumatriptan injection and explore the relationship between chest symptoms along with sumatriptan injection and coronary ischemia among Japanese patients with migraine. METHODS: A cumulative total of 112 subcutaneous injections in 62 patients were evaluated. ECG was continuously monitored before and until 5 minutes after injection on 92 occasions. PATIENTS: Sixteen men and 46 women aged from 16 to 60 (mean 39+/-12) years. Their clinical diagnoses were migraine with aura, migraine without aura, cluster headache, and others. RESULTS: Chest symptoms occurred following 17% of all injections and in 15% of all patients. None of these chest symptoms was accompanied by ECG changes. CONCLUSIONS: Although the risk of coronary ischemia with sumatriptan treatment is commonly stated, our data suggest that chest symptoms following sumatriptan injection are not strongly associated with coronary ischemia in the Japanese population. The mechanism of chest symptoms following sumatriptan administration should be further elucidated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12211529&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Extracellular recordings of membrane potential from guinea-pig isolated trigeminal ganglion: lack of effect of sumatriptan.

O'Shaughnessy CT, Connor HE, Feniuk W.

Department of Neuropharmacology, Glaxo Group Research Ltd, Ware, UK.

The aim of this study was to investigate the effect of the anti-migraine drug and selective 5-HT1 receptor agonist, sumatriptan, on membrane potential of guinea-pig isolated trigeminal ganglion. Ganglia were divided into three longitudinally, placed in two-compartment baths and the d.c. potential between compartments was recorded extracellularly. Drugs were applied to the Krebs superfusion fluid of one compartment. KCl (3 mmol/l) and GABA (0.1 mmol/l) caused depolarization (0.30 +/- 0.05 and 0.55 +/- 0.08 mV respectively, n = 11-19). 5-HT (1-10 mumol/l) caused small depolarizations (0.06 +/- 0.02 mV, n = 8) but sumatriptan (0.1-10 mumol/l) had no effect on trigeminal ganglion membrane potential. Collagenase pretreatment, to enhance desheathing, or modification of the composition of the Krebs solution failed to reveal any effect of sumatriptan. These data provide no evidence to suggest that sumatriptan inhibits neurotransmission in trigeminal ganglion. However, 5-HT1 receptors may be present in insufficient numbers in the trigeminal ganglion to elicit a change in membrane potential. Further studies are required to investigate the effect of sumatriptan at the level of the sensory nerve terminals within the intracranial vasculature, where 5-HT1 receptors may be concentrated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8395343&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
The safety of sumatriptan in asthmatic migraineurs.

Lloyd DK, Pilgrim AJ.

Glaxo Group Research Ltd, Uxbridge, Middlesex, UK.

A recent report has questioned the safety of sumatriptan in asthmatic migraineurs. To investigate this, we have reviewed the sumatriptan clinical trial safety database of over 75 completed trials. Within the clinical trial database, 375 asthmatic patients were identified who treated 1214 migraine attacks with sumatriptan. The incidence and nature of adverse events in the asthmatic patient subgroup who received sumatriptan was similar to that in the complete clinical trial population. Six reports of asthma were recorded as adverse events, but only one case was classified by the investigator as related to treatment. There is no clinical or pharmacological evidence to suggest that the safety profile of sumatriptan is altered in asthmatic patients compared to other migraine sufferers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8395345&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Dual coupling of cloned human 5-hydroxytryptamine1D alpha and 5-hydroxytryptamine1D beta receptors stably expressed in murine fibroblasts: inhibition of adenylate cyclase and elevation of intracellular calcium concentrations via pertussis toxin-sensitive G protein(s).

Zgombick JM, Borden LA, Cochran TL, Kucharewicz SA, Weinshank RL, Branchek TA.

Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652.

The second messenger coupling of cloned human 5-hydroxytryptamine (5-HT)1D alpha and 5-HT1D beta receptors stably expressed in murine fibroblasts (LM (tk-)) was investigated. Clonal cell lines expressing similar receptor densities (Bmax = 750-950 fmol/mg) were used in this study. 5-HT (EC50 = 1.5-2.0 nM) and sumatriptan (EC50 = 6-14 nM), a selective 5-HT1D agonist, produced dose-dependent inhibition of forskolin-stimulated cAMP accumulation in intact cells transfected with the 5-HT1D alpha or 5-HT1D beta receptor gene. The maximal inhibitory responses elicited by these agonists were slightly greater with the 5-HT1D alpha receptor (approximately 90%) than the 5-HT1D beta receptor (approximately 80%). 5-HT (EC50 = 1.7-2.4 nM) and sumatriptan (EC50 = 8-18 nM) also evoked dose-dependent elevations in intracellular calcium concentrations ([Ca2+]i), with EC50 values that were indistinguishable from those for inhibition of forskolin-stimulated cAMP accumulation. Cells expressing 5-HT1D beta receptors displayed significantly larger 5-HT-induced increases in [Ca2+]i than did cells expressing 5-HT1D alpha receptors (206 nM versus 114 nm increase; p < 0.01). Dose-dependent elevations in inositol phosphates (IP) were also observed after application of 5-HT (EC50 = 29-54 nM) or sumatriptan (EC50 = 73-481 nM); the maximal increases in IP accumulation were modest (51-69%) for both 5-HT1D subtypes. In contrast to the cAMP and calcium responses, the concentration-response curves for IP accumulation were shifted to the right at least 10-fold. Methiothepin, a nonselective 5-HT1 antagonist, competitively antagonized the cAMP response, yielding an apparent dissociation constant (Kb) of 3-4 nM for the 5-HT1D receptors. Methiothepin (10 microM) significantly reduced the elevations in [Ca2+]i (> 90%) and IP (> 75%) evoked by saturating concentrations (1 microM) of agonists. All three functional responses were significantly attenuated (> 90%) by pretreatment with 100 ng/ml pertussis toxin. The sumatriptan-induced elevation of [Ca2+]i via activation of the 5-HT1D subtypes may provide a molecular mechanism of action by which sumatriptan could directly constrict cerebral blood vessels and alleviate migraine symptoms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8396718&dopt=Abstract sumatriptan Imitrex