sumatriptan, Imitrex
Distribution and excretion of sumatriptan in human milk.

Wojnar-Horton RE, Hackett LP, Yapp P, Dusci LJ, Paech M, Ilett KF.

Department of Pharmacy, King Edward Memorial Hospital for Women, Subiaco, Western Australia.

1. The excretion of a 6 mg subcutaneous dose of sumatriptan in breast milk was studied in five lactating volunteer subjects with a mean age of 27.6 years and a mean body weight of 75 kg. Drug concentrations in milk and plasma over the ensuing 8 h were measured by high-performance liquid chromatography. 2. The mean milk:plasma ratio estimated from the areas under the milk and plasma concentration-time curves (AUC) was 4.9 (95% CI 4.1-5.7), indicating a significant transfer of sumatriptan into the milk compartment. 3. The mean total recovery of drug in milk was estimated to be only 14.4 micrograms (95% CI 6.1-22.7 micrograms), or 0.24% of the 6 mg administered dose. On a weight-adjusted basis this corresponded to a mean infant exposure of 3.5% of the maternal dose (95% CI 0.3-6.7%). 4. If oral bioavailability in the infant is similar to that in adults (14%), the weight-adjusted infant dose is reduced to 0.49%. Furthermore, allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in a very premature neonate to 0.7% in a 30 week old infant. 5. Since sumatriptan is usually administered as a single dose at infrequent intervals, the low level of excretion in breast milk suggests that continued breast feeding following its use will not pose a significant risk to the suckling infant. Even this minor exposure could be largely avoided by expressing and discarding all milk for 8 h after the dose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8866921&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Autoradiographic distribution of [3H]sumatriptan-binding sites in post-mortem human brain.

Pascual J, del Arco C, Romon T, del Olmo E, Castro E, Pazos A.

Department of Physiology and Pharmacology, University Hospital Marques de Valdecilla, University of Cantabria, Spain.

The anatomical distribution of [3H]sumatriptan-binding sites was analysed in brain tissue sections from 11 subjects. Relevant concentrations of [3H]sumatriptan-binding sites were seen in areas such as visual cortex > locus niger > globus pallidus > layers IV-V of the frontal cortex > subiculum > entorhinal cortex > nucleus tractus solitarius > nucleus trigeminalis caudalis. This distribution of [3H]sumatriptan-binding sites in the human brain shows some differences when compared with that of 5HT1D receptors, confirming that, besides 5HT1D, sumatriptan also binds to 5HT1F receptor subtype. Some species differences are evident between the distribution of [3H]sumatriptan-binding sites in the human brain and that reported for guinea-pig and rat brains, emphasizing that caution is needed in extrapolating experimental data from animals to humans. Furthermore, these data help to explain some of the therapeutic actions of sumatriptan. The remarkable levels of binding found in areas as nucleus tractus solitarius and nucleus trigeminalis caudalis suggest that in migraine attacks sumatriptan could exert its specific anti-emetic effects and, partly at least, induce analgesia by directly acting over these brain nuclei.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8869766&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Evidence for 5-HT1-like receptor-mediated vasoconstriction in human pulmonary artery.

MacLean MR, Clayton RA, Templeton AG, Morecroft I.

Division of Neuroscience and Biomedical Systems, University of Glasgow.

1. The 5-hydroxytryptamine (5-HT) receptors mediating contraction of human isolated pulmonary artery rings were investigated. Responses to the agonists 5-carboximidotryptamine (5-CT, non-selective 5-HT1 agonist), sumatriptan (5-HT1D-like receptor agonist), 5-HT and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 5-HT1A receptor agonist) were studied. Responses to 5-HT and sumatriptan in the presence of the antagonists, methiothepin (non-selective 5-HT1+2-receptor antagonist), ketanserin (5-HT2A receptor antagonist) and the novel antagonist, GR55562 (5-HT1D receptor antagonist) were also studied. 2. All agonists contracted human pulmonary artery ring preparations in the following order of potency 5-CT > 5-HT = sumatriptan > 8-OH-DPAT. Maximum responses to 5-HT, 5-CT and sumatriptan were not significantly different. 3. Methiothepin 1 nM and 10 nM, but not 0.1 nM reduced the maximum contractile responses to 5-HT but did not alter tissue sensitivity to 5-HT. Methiothepin 0.1 nM, 1 nM and 10 nM had a similar effect on responses to sumatriptan. 4. The 5-HT2A receptor antagonist ketanserin (10 nM, 100 nM and 1 microM) also reduced the maximum contractile response to both 5-HT and sumatriptan without affecting tissue sensitivity to these agonists. 5. The novel 5-HT1D receptor antagonist, GR55562, inhibited responses to 5-HT and sumatriptan in a true competitive fashion. 6. The results suggest that the human pulmonary artery has a functional population of 5-HT1D-like receptors which are involved in the contractile response to 5-HT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8886409&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Investigations with GMC2021 in experimental models predictive of antimigraine activity and coronary side-effect potential.

Saxena PR, De Vries P, Heiligers JP, Maassen VanDenBrink A, Bax WA, Barf T, Wikstrom H.

Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, Netherlands. Saxena Farma.Fgg.Eur.NL

Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine carotid arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of GMC2021 (3-[2-(dimethylanimo)ethyl]-5-[(trifluoromethyl)sulfonyl]oxy][1 H]indole oxalate, a close analogue of sumatriptan. GMC2021 (30, 100, 300 and 1000 micrograms.kg-1, i.v.) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow to the skin and ears was moderately increased. The mean +/- S.E.M. dose of GMC2021 eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was found to be 1.1 +/- 0.3 mumol.kg-1 and the highest dose (1000 micrograms.kg-1) produced a 67 +/- 4% reduction. The carotid haemodynamic effects of GMC2021 were reduced by the selective 5-HT1D receptor antagonist, GR127935 (N-[methoxy-3-(4-methyl-1- piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1 , 1-biphenyl]-4-carboxamide hydrochloride), which completely antagonizes porcine carotid haemodynamic responses to sumatriptan (ED50: 0.16 mumol.kg-1, i.v.). Compared to sumatriptan (pD2: 6.12 +/- 0.15; Emax: 31.3 +/- 12.3% of contractions to 100 mM K+), GMC2021 was less potent in constricting the human isolated coronary artery (pD2: 5.45 +/- 0.2; Emax: 21.0 +/- 4.8% of contractions to 100 mM K+). The above results suggest that GMC2021 constricts carotid arteriovenous anastomoses partly by a 5-HT1D receptor and partly by another, probably novel, receptor and that GMC2021 should be able to abort migraine headaches in patients, with perhaps a less propensity for coronary side effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8891578&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Effect of antimigraine drugs on dural blood flows and resistances and the responses to trigeminal stimulation.

Lambert G, Michalicek J.

Institute of Neurological Sciences, Prince Henry of Wales Hospital, Little Bay, NSW, Australia.

The effects of 2 antimigraine drugs sumatriptan and dihydroergotamine on dilatation of the middle meningeal artery elicited by stimulation of the trigeminal ganglion at the entry point of the first and second divisions was investigated in cats. Carotid and middle meningeal arterial blood flows and resistances were measured in 9 cats anesthetised with chloralose. Electrical stimulation of either trigeminal ganglion produced a frequency-dependent decrease in resistance of the carotid artery ipsilaterally and the middle meningeal artery bilaterally. The intravenous injection of sumatriptan increased carotid and meningeal vascular resistance, but this response was not prolonged. The intravenous injection of dihydroergotamine produced a larger and more prolonged vasoconstriction in these 2 beds than did sumatriptan. Dihydroergotamine, but not sumatriptan, blocked some components of the vascular response induced by stimulation of the trigeminal ganglion. Dihydroergotamine and sumatriptan have a different spectrum of activity on cranial circulatory beds and neither of them is able to reduce trigeminal-induced vasodilatation by blocking antidromic activation of trigeminal nerve fibres in cats at the doses used in these experiments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8891594&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Hypertension increases the contractions to sumatriptan in the human internal mammary artery.

Yildiz O, Cicek S, Ay I, Demirkilic U, Tuncer M.

Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

BACKGROUND: The internal mammary artery is the graft of choice for myocardial revascularization. The tendency to spasm increases toward the distal end of the internal mammary artery, which is the portion generally used for anastomosis. The distal internal mammary artery is more pharmacologically responsive to 5-hydroxytryptamine and several other vasoconstrictor agents than its midsection. METHODS: We examined the effects of 5-hydroxytryptamine and a 5-hydroxytryptamine1-like receptor agonist sumatriptan on internal mammary artery segments (length, 3-4 mm) obtained from patients undergoing coronary artery bypass grafting. To unmask a 5-hydroxytryptamine1-like receptor-mediated contractile response, threshold concentrations of potassium chloride were used. RESULTS: 5-Hydroxytryptamine induced concentration-dependent contractions in all, quiescent and potassium chloride precontracted, preparations. Sumatriptan induced marked contraction in some of the quiescent internal mammary artery rings, whereas it elicited marked and concentration-dependent contractions in all of the preparations given a moderate tone by a threshold concentration of potassium chloride. The sensitivity to sumatriptan was higher in potassium chloride-precontracted distal arteries than it was for the quiescent distal segments. Additionally, the sensitivity to and the efficacy of sumatriptan were much more markedly potentiated by precontraction in the preparations taken from hypertensive patients. CONCLUSIONS: The more marked potentiation of the responses in arteries from hypertensive patients may be one of the factors influencing the patency rates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8893574&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Effects of S20749, a close analogue of sumatriptan, on porcine carotid haemodynamics and human isolated coronary artery.

Saxena PR, Maassen vandenBrink A, Heiligers JP, Scalbert E, Lemaitre BG.

Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, Dutch Migraine Research Group, The Netherlands.

Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine arteriovenous anastomoses. Sumatriptan also constricts the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of S20749 (1-[2-(dimethylamino)ethyl]-naphthalene-7-methylsulfonamide), a close analogue of sumatriptan. S20749 (30, 100, 300 and 1000 micrograms.kg-1) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow was moderately increased. These changes were statistically significant with the highest two doses. S20749 moderately constricted the human isolated coronary artery (pD2: < or = 4.5: Fmax: > 11% of the contraction to 100 mM K+). The above results suggest that S20749 should be able to abort migraine headaches in patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8899861&dopt=Abstract sumatriptan Imitrex