sumatriptan, Imitrex
Sumatriptan absorption from different regions of the human gastrointestinal tract.

Warner PE, Brouwer KL, Hussey EK, Dukes GE, Heizer WD, Donn KH, Davis IM, Powell JR.

School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA.

Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7724476&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Role of the serotonin receptor subtype 5-HT1D on basal and stimulated growth hormone secretion.

Mota A, Bento A, Penalva A, Pombo M, Dieguez C.

Department of Pediatric, Hospital de D. Estefania, Lisbon, Portugal.

At present, four main types of serotonin (5-HT) receptors have been identified in the brain (5-HT1, 5-HT2, 5-HT3, and 5-HT4). In addition, the 5-HT1 have been further subclassified. We have taken advantage of a new selective 5-HT1D receptor agonist 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide succinate, Sumatriptan, to evaluate the role of 5-HT1D receptors on GH secretion. To this end, several tests with or without sumatriptan were undertaken in normal prepubertal children. Furthermore, we assessed the effect of Sumatriptan on basal GH secretion and the GH response to GHRH in obese children. In normal children, Sumatriptan administration (3 mg, sc) resulted in an increase in basal GH levels at 30 min (7.7 +/- 1.5 micrograms/L; P < 0.05) and increased GH responses to GHRH (47.3 +/- 6.4 vs. 29.6 +/- 9.7 micrograms/L; P < 0.05). The Sumatriptan-induced increase in GH responses to GHRH was dependent on the stimulus tested. Pretreatment with Sumatriptan did not modify the GH response to clonidine or pyridostigmine, as assessed by the peak GH response and the area under the curve. In contrast, it increased the GH response to arginine. In the obese subjects, the GH response to GHRH was reduced (7.3 +/- 1.0 vs. 29.6 +/- 9.7 micrograms/L at 30 min) compared to that in control children (P < 0.05). Sumatriptan administration did not alter the basal GH value (peak GH, 1.7 +/- 0.3 micrograms/L at 30 min). However, Sumatriptan administration clearly increased the effect of GHRH, resulting in a GH peak of 14.6 +/- 3.1 micrograms/L at 30 min (P < 0.01). To assess the specificity of Sumatriptan on anterior pituitary hormone secretion, we studied its effect on TSH and PRL responses to TRH as well as LH-releasing hormone-induced LH and FSH secretion. Administration of Sumatriptan did not alter the response of any of these hormones. Our results indicate that 5-HT1D receptors have a stimulatory effect on GH secretion, possibly by inhibiting hypothalamic somatostatin release.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7775648&dopt=Abstract sumatriptan Imitrex



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

Whiting MV, Cambridge D.

Biology Division, Wellcome Research Laboratories, Beckenham, Kent.

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7780652&dopt=Abstract sumatriptan Imitrex



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

Cutrer FM, Schoenfeld D, Limmroth V, Panahian N, Moskowitz MA.

Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7780655&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
The safety of concomitant use of sumatriptan and antidepressant treatments.

Blier P, Bergeron R.

Department of Psychiatry, McGill University, Montreal, Quebec, Canada.

It is presently contraindicated to use the antimigraine drug sumatriptan with selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, or lithium. Consequently, many patients undergoing these pharmacotherapies for psychiatric disorders may not benefit from the therapeutic effect of sumatriptan in acute migraine attacks. Because sumatriptan does not appear to cross the blood-brain barrier and has a short half-life, it was deemed relatively safe to prescribe sumatriptan with antidepressant treatments. Fourteen patients receiving fluoxetine, fluvoxamine, sertraline, moclobemide, lithium, or buspirone did not experience significant side effects when they took oral sumatriptan for the relief of migraine on a total of 103 episodes. It is concluded that the combined use of sumatriptan with the above-mentioned antidepressant treatments may be safe.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7782482&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
Effects of sumatriptan on isolated rabbit heart.

Paterna S, Di Pasquale P, Antona A, D'Amico C, Bucca V, Arrostuto A, Palazzoadriano M, Licata G.

Department of Internal Medicine, University of Palermo, Italy.

Sumatriptan provokes, in healthy subjects as well as in those who suffer from hemicrania, a slight increase in both systolic and diastolic arterial pressure. It has also been shown to increase the pressure of pulmonary circulation and to reduce the calibre of coronary arteries. The present investigation was undertaken to study the effects of sumatriptan (75 ng/l) on isolated rabbit hearts. Fifteen isolated rabbit hearts, perfused according to Langerdoff's procedure, were divided into two groups: Group I (5 hearts), perfused with Krebs-Henseleit solution, as a control, and Group II (10 hearts), perfused with Krebs-Henseleit mixed with sumatriptan succinate (75 ng/l). After 30 min of perfusion, the basal values of heart rate (HR) dp/dt, systolic ventricular pressure (SVP), diastolic ventricular pressure (DVP) and coronary flow (CF) were measured. The above values in either control or treated hearts were measured 5, 15, 30, 45, 60 min after recording the baseline values. HR, SVP, DVP, dp/dt and CF did not show significant differences in the two groups. The present data suggest that sumatriptan does not exert any action on isolated rabbit hearts.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7796711&dopt=Abstract sumatriptan Imitrex



sumatriptan, Imitrex
A comparison of the contractile effects of 5-hydroxytryptamine, sumatriptan and MK-462 on human coronary artery in vitro.

Ferro A, Longmore J, Hill RG, Brown MJ.

Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital.

1. MK-462 (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H- indol-3-yl]ethylamine) is a novel selective 5-HT1D-receptor agonist which in clinical trials has been shown to be an effective antimigraine agent. As angiographic studies have shown that sumatriptan (an established 5-HT1D-receptor agonist) can cause coronary artery vasoconstriction in patients, we compared the effects of MK-462 with those of 5-HT and those of sumatriptan, on isolated segments of human coronary artery in vitro. 2. Coronary arteries were obtained from explanted hearts from patients (n = 22, 2 females, 20 males, aged 21-60 years) undergoing cardiac transplantation. Endothelium-denuded ring segments of coronary artery, 2mm long were mounted in organbaths for isometric tension recording. For each arterial ring segment, a cumulative concentration-effect curve to either 5-HT, sumatriptan or MK-462 was determined. After maximal response to each agonist had been obtained, ketanserin (a 5-HT2 receptor antagonist) 0.6 microM was added to the tissue bath, followed by methiotepin (0.6 microM) and the reduction in tension produced by the addition of each antagonist was determined. 3. Out of 22 coronary arteries studied, only 10 showed any response (contraction) to 5-HT. Not all arteries which responded to 5-HT contracted in response to both sumatriptan and MK-462 (one ring from each artery being exposed to a single agonist in each case).(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8527286&dopt=Abstract sumatriptan Imitrex