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Carlos M. Villalón - One of the best experts on this subject based on the ideXlab platform.

  • the role of α1 and α2 adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin pretreated pithed rats
    Journal of Headache and Pain, 2017
    Co-Authors: Eduardo Riveramancilla, Victor H Avilesrosas, Guadalupe Manriquemaldonado, Alain H Altamiranoespinoza, Belinda Villanuevacastillo, Antoinette Maassenvandenbrink, Carlos M. Villalón
    Abstract:

    Dihydroergotamine (DHE) is an acute Antimigraine Agent that displays affinity for dopamine D2-like receptors, serotonin 5-HT1/2 receptors and α1/α2-adrenoceptors. Since activation of vascular α1/α2-adrenoceptors results in systemic vasopressor responses, the purpose of this study was to investigate the specific role of α1- and α2-adrenoceptors mediating DHE-induced vasopressor responses using several antagonists for these receptors. For this purpose, 135 male Wistar rats were pithed and divided into 35 control and 100 pretreated i.v. with ritanserin (100 μg/kg; to exclude the 5-HT2 receptor-mediated systemic vasoconstriction). Then, the vasopressor responses to i.v. DHE (1–3100 μg/kg, given cumulatively) were determined after i.v. administration of some α1/α2-adrenoceptor antagonists. In control animals (without ritanserin pretreatment), the vasopressor responses to DHE were: (i) unaffected after prazosin (α1; 30 μg/kg); (ii) slightly, but significantly, blocked after rauwolscine (α2; 300 μg/kg); and (iii) markedly blocked after prazosin (30 μg/kg) plus rauwolscine (300 μg/kg). In contrast, after pretreatment with ritanserin, the vasopressor responses to DHE were: (i) attenuated after prazosin (α1; 10 and 30 μg/kg) or rauwolscine (α2; 100 and 300 μg/kg); (ii) markedly blocked after prazosin (30 μg/kg) plus rauwolscine (300 μg/kg); (iii) attenuated after 5-methylurapidil (α1A; 30–100 μg/kg), L-765,314 (α1B; 100 μg/kg), BMY 7378 (α1D; 30–100 μg/kg), BRL44408 (α2A; 100–300 μg/kg), imiloxan (α2B; 1000–3000 μg/kg) or JP-1302 (α2C; 1000 μg/kg); and (iv) unaffected after the corresponding vehicles (1 ml/kg). These results suggest that the DHE-induced vasopressor responses in ritanserin-pretreated pithed rats are mediated by α1- (probably α1A, α1B and α1D) and α2- (probably α2A, α2B and α2C) adrenoceptors. These findings could shed light on the pharmacological profile of the vascular side effects (i.e. systemic vasoconstriction) produced by DHE and may lead to the development of more selective Antimigraine drugs devoid vascular side effects.

  • Pharmacological analysis of the mechanisms involved in the tachycardic and vasopressor responses to the Antimigraine Agent, isometheptene, in pithed rats
    Life sciences, 2004
    Co-Authors: Luis Felipe Valdivia, David Centurion, Pramod R. Saxena, Mercedes Perusquía, Udayasankar Arulmani, Carlos M. Villalón
    Abstract:

    Abstract The present study set out to investigate the pharmacological profile of the cardiovascular responses induced by the Antimigraine Agent, isometheptene, in pithed rats. For this purpose, intravenous (i.v.) administration of blocking doses of the antagonists prazosin (α 1 ; 100 μg/kg), rauwolscine (α 2 ; 300 μg/kg), the combination of prazosin (100 μg/kg) plus rauwolscine (300 μg/kg), propranolol (β; 1000 μg/kg), ritanserin (5-HT 2 ; 100 μg/kg) or equivalent volumes of saline (1 ml/kg) were used. Isometheptene (0.03, 0.1, 0.3, 1 and 3 mg/kg, i.v.) produced dose-dependent increases in heart rate and diastolic blood pressure which were highly reproducible as they remained unaltered after saline. These tachycardic responses to isometheptene remained unaffected after prazosin, rauwolscine, ritanserin or the combination prazosin plus rauwolscine, but were abolished after propranolol. In contrast, the isometheptene-induced vasopressor responses were not significantly modified after the above doses of rauwolscine, ritanserin or propranolol, but were markedly blocked after prazosin or the combination of prazosin plus rauwolscine; the latter blockade did not significantly differ from that produced by prazosin alone. Interestingly, in rats pretreated intraperitoneally (i.p.) with reserpine (5 mg/kg; −24 h), isometheptene-induced tachycardic responses were abolished whereas the corresponding vasopressor responses were markedly attenuated and subsequently blocked by prazosin. It is concluded that isometheptene-induced tachycardic responses seem to involve only an indirect (tyramine-like action) mechanism mediated by β-adrenoceptors, whilst the corresponding vasopressor responses are mediated by a predominantly indirect (tyramine-like action), as well as a minor direct (α 1 -adrenoceptors), sympathomimetic mechanism.

  • Pharmacological profile of the mechanisms involved in the external carotid vascular effects of the Antimigraine Agent isometheptene in anaesthetised dogs
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2001
    Co-Authors: Edwin W. Willems, Luis Valdivia, Pramod R. Saxena, Carlos M. Villalón
    Abstract:

    The present study set out to investigate the external carotid vascular effects of isometheptene in vagosympathectomised dogs, anaesthetised with pentobarbital. One-minute intracarotid (intra-arterial; i.a.) infusions of isometheptene (10, 30, 100 and 300 µg/min) produced dose-dependent decreases in external carotid blood flow, without affecting blood pressure or heart rate. The vasoconstrictor responses to 100 µg/min and 300 µg/min of isometheptene were clearly attenuated in animals pretreated with reserpine (5000 µg/kg). Moreover, after prazosin (an α_1-adrenoceptor antagonist; 100 µg/kg), the responses to isometheptene remained unaltered in untreated as well as reserpine-pretreated dogs. In contrast, the responses to isometheptene were attenuated by rauwolscine (an α_2-adrenoceptor antagonist; 300 µg/kg) in untreated animals, and were practically abolished in reserpine-pretreated dogs. Further investigation into the specific α_2-adrenoceptor subtypes, using selective antagonists, showed that BRL44408 (α_2A) and MK912 (α_2C) markedly attenuated this response, while imiloxan (α_2B) was ineffective. The involvement of 5-HT_1B and 5-HT_1D receptors seems highly unlikely since antagonists at 5-HT_1B (SB224289) and 5-HT_1D (BRL15572) receptors (both at 300 µg/kg) were ineffective. On this basis, it is concluded that isometheptene-induced canine external carotid vasoconstriction is mediated by both indirect (a tyramine-like action) and direct (acting at receptors) mechanisms, which mainly involve α_A- and α_2C-adrenoceptors, while the involvement of α_1-adrenoceptors seems rather limited.

  • The Antimigraine Agent alniditan selectively constricts porcine carotid arteriovenous anastomoses via 5-HT1B /1D receptors
    European Journal of Pharmacology, 1998
    Co-Authors: Peter De Vries, Carlos M. Villalón, Edwin W. Willems, Jan P.c. Heiligers, Pramod R. Saxena
    Abstract:

    Abstract In previous studies, we have shown that several 5-HT1B/1D receptor agonists, including sumatriptan, potently constrict porcine carotid arteriovenous anastomoses. This effect seems to be of high predictive value for Antimigraine activity. In the present experiments, we studied the effects of a new non-indole 5-HT1B/1D receptor agonist, alniditan, on systemic and carotid haemodynamics in anaesthetised pigs. In control animals, no significant changes in either systemic or carotid haemodynamics were observed after four consecutive i.v. injections of physiological saline (0.5 ml each, every 20 min; n=4). On the other hand, i.v. doses of alniditan (3, 10, 30 and 100 μg kg−1 in 0.5 ml saline, every 20 min; n=6) dose-dependently decreased total carotid conductance (maximum change: −31±6%) by a selective vasoconstrictor action on arteriovenous anastomoses (maximum change: −72±5%); the nutrient vascular bed dilated in response to alniditan (maximum change: +103±39%). The dose of alniditan that decreased arteriovenous anastomotic conductance by 50% was 24±8 μg kg−1 (64±20 nmol kg−1). Alniditan produced a slight bradycardia (maximum change: −4±1%) and a more pronounced hypotensive effect (maximum change: −23±5%). In six animals pre-treated with the potent and selective 5-HT1B/1D receptor antagonist, GR127935, the alniditan-induced changes in carotid haemodynamics were clearly antagonised, whereas the bradycardia and hypotension remained unaffected. These results suggest that alniditan selectively constricts porcine carotid arteriovenous anastomoses mainly via 5-HT1B/1D receptors and should be able to abort migraine headaches. The latter has indeed been confirmed in initial clinical studies in man.

Andrew A Parsons - One of the best experts on this subject based on the ideXlab platform.

  • sb 220453 a potential novel Antimigraine Agent inhibits nitric oxide release following induction of cortical spreading depression in the anaesthetized cat
    Cephalalgia, 2000
    Co-Authors: Simon J Read, Martin I Smith, A J Hunter, N Upton, Andrew A Parsons
    Abstract:

    Profound nitric oxide release associated with cortical spreading depression (SD), has been implicated in stroke, traumatic brain injury and migraine pathophysiology. SB-220453 represents a mechanistically novel, well-tolerated class of compounds which may have therapeutic potential in the treatment of conditions associated with neuronal hyperexcitability and inflammation. The aim of the present study was to investigate the effects of SB-220453 on the nitric oxide (NO) release associated with SD in the anaesthetized cat. In vehicle treated animals, KCl application for 6 min to the cortical suface produced repeated changes in extracellular direct current field potential with associated NO release. This activity was sustained for a median duration of 55 min (25–75% range, 32–59 min) and 59 min (25–75% range, 34–59 min), respectively. SB-220453 (1, 3 and 10 mg/kg i.p.) produced a dose-related inhibition of this activity and at the highest dose tested, the median duration of changes in extracellular field pote...

  • identification of cis 6 acetyl 4s 3 chloro 4 fluoro benzoylamino 3 4 dihydro 2 2 dimethyl 2h benzo b pyran 3s ol as a potential Antimigraine Agent
    Bioorganic & Medicinal Chemistry Letters, 1999
    Co-Authors: Wai N Chan, John Morris Evans, Michael S Hadley, Hugh J Herdon, Jeffrey C Jerman, Andrew A Parsons, Simon J Read, Tania O Stean, Mervyn Thompson, Neil Upton
    Abstract:

    Optimisation of novel cis- and trans-4-(substituted-amido)benzopyran-3-ol derivatives has led to the identification of SB-220453 20 with an in vivo pre-clinical CNS profile predictive of potential Antimigraine activity.

  • effects of the novel Antimigraine Agent frovatriptan on coronary and cardiac function in dogs
    Journal of Cardiovascular Pharmacology, 1998
    Co-Authors: Andrew A Parsons, Pravin Raval, Nick Tilford, Richard E Valocik, Paul F Koster, Robert Gagnon, Giora Z Feuerstein
    Abstract:

    : The effects of frovatriptan (VML 251/SB-209509) on coronary artery function were investigated in isolated coronary arteries from beagle dogs. Low concentrations of frovatriptan produced contraction with -logEC50 7.55 +/- 0.08 (n = 11). The maximal observed contraction attained was 56 +/- 7% of the control 5-hydroxytryptamine (5-HT; 10 microM) response. At high concentrations of frovatriptan (>6 microM), reversal of sumatriptan (10 microM)-induced contractions was noted. In arteries precontracted with the thromboxane mimetic, U46619, frovatriptan produced a bell-shaped concentration-response relation with a maximal response at 600 nM. Concentrations of frovatriptan >2 microM produced marked reversal of tone, with full relaxation of precontracted tissues at 200 microM. In anesthetized, open-chest mongrel dogs, intravenous (n = 5) or intracoronary (n = 5) artery administration of frovatriptan (0.0001-1 mg/kg) had no consistent effect on left ventricular end-diastolic pressure, left end-systolic pressure, cardiac contractility, aortic blood flow, systemic peripheral resistance, coronary blood flow, coronary vascular resistance, mean arterial blood pressure, or heart rate when compared with vehicle (n = 3). Intravenous sumatriptan produced minor effects on blood pressure and heart rate. Intracoronary artery administration of sumatriptan (0.0003 mg/kg) produced an increase in systemic peripheral resistance to 120.5 +/- 8.2% compared with vehicle (97.8 +/- 5.4%; p < 0.05). This dose of sumatriptan also produced a significant increase in coronary blood flow and decrease in coronary vascular resistance. Intravenous administration of sumatriptan produced a dose-related reduction in left ventricular diastolic pressure with a reduction to 58.3 +/- 8.3% and 41.7 +/- 25% of control values observed at 0.3 and 1 mg/kg, respectively; however, administration of sumatriptan by an intracoronary route had no effect. In a model of myocardial infarction, comparable doses of sumatriptan (1.0 mg/kg) or frovatriptan (0.1 mg/kg), in terms of their effect on carotid vascular resistance, had no significant effect on infarct size. Frovatriptan had no effect on coronary blood flow after reperfusion; however, sumatriptan produced a significant reduction in coronary blood flow for < or =3 h. These studies show that frovatriptan has the capability of relaxing coronary arteries in vitro, has no overall effect on cardiac function at rest with no effect on coronary hemodynamics after myocardial infarction, and has a profile superior to that of sumatriptan.

Josep M Jansat - One of the best experts on this subject based on the ideXlab platform.

  • identification of the human liver enzymes involved in the metabolism of the Antimigraine Agent almotriptan
    Drug Metabolism and Disposition, 2003
    Co-Authors: Miquel Salva, Josep M Jansat, Antonio Martineztobed, Jose M Palacios
    Abstract:

    Almotriptan is a novel highly selective 5-hydroxytryptamine 1B/1D agonist developed for the acute oral treatment of migraine. The in vitro metabolism of almotriptan has been investigated using human liver subcellular fractions and cDNA-expressed human enzymes, to study the metabolic pathways and identify the enzymes responsible for the formation of the major metabolites. Specific enzymes were identified by correlation analysis, chemical inhibition studies, and incubation with various cDNA expressed human enzymes. Human liver microsomes and S9 fraction metabolize almotriptan by 2-hydroxylation of the pyrrolidine group to form a carbinolamine metabolite intermediate, a reaction catalyzed by CYP3A4 and CYP2D6. This metabolite is further oxidized by aldehyde dehydrogenase to the open ring γ-aminobutyric acid metabolite. Almotriptan is also metabolized at the dimethylaminoethyl group by N -demethylation, a reaction that is carried out by five different cytochrome P450s, flavin monooxygenase-3 mediated N -oxidation, and MAO-A catalyzed oxidative deamination to form the indole acetic acid and the indole ethyl alcohol derivatives of almotriptan. The use of human liver mitochondria confirmed the contribution of MAO-A to the metabolism of almotriptan. Both, the γ-aminobutyric acid and the indole acetic acid metabolites have been found to be the major in vivo metabolites of almotriptan in humans. In addition, different clinical trials conducted to study the effects of CYP3A4, CYP2D6, and MAO-A on the pharmacokinetics of almotriptan confirmed the involvement of these enzymes in the metabolic clearance of this drug and that no dose changes are required in the presence of inhibitors of these enzymes.

  • absolute bioavailability pharmacokinetics and urinary excretion of the novel Antimigraine Agent almotriptan in healthy male volunteers
    The Journal of Clinical Pharmacology, 2002
    Co-Authors: Josep M Jansat, Joan Costa, Pau Salva, Francisco J Fernandez, Antonio Martineztobed
    Abstract:

    Absolute bioavailability, pharmacokinetics, and urinary excretion of almotriptan, a novel 5-HT 1B/1D receptor agonist, were studied in 18 healthy males following single intravenous (i.v.) (3 mg), subcutaneous (s.c.) (6 mg), and oral (25 mg) doses. Volunteers received each dose in a randomized sequence separated by a 7-day washout. Blood and urine samples for pharmacokinetic evaluations were taken for up to 24 hours after dosing. The disposition kinetics of almotriptan after i.v. and s.c. administration showed biphasic decline described by a two-compartment model. The fastest disposition phase was well observed, although estimates of the rate constant showed high variability. After s.c. administration of almotriptan, the bioavailability was 100% with a time to maximum plasma concentration (t max ) of 5 to 15 minutes, whereas after oral administration, the bioavailability was about 70% with a t max of 1.5 to 3.0 hours. No significant differences were observed between administration routes in the elimination half-life (t 1/2 ), obtaining mean values ranging from 3.4 to 3.6 hours. The volume of distribution, total clearance, and t 1/2 indicated that almotriptan was extensively distributed and rapidly cleared from the body irrespective of dose or route of administration. The primary route of elimination was renal clearance (approximately 50%-60% of total body clearance). About 65% of the i.v. and s.c. dose and 45% of the oral dose were excreted unchanged in urine in 24 hours, with nearly 90% of this in the first 12 hours. Renal clearance was approximately 2- to 3-fold that of the glomerular filtration rate in man, suggesting that almotriptan is eliminated in part by renal tubular secretion.

  • effect of mao a inhibition on the pharmacokinetics of almotriptan an Antimigraine Agent in humans
    British Journal of Clinical Pharmacology, 2002
    Co-Authors: Joseph C Fleishaker, Josep M Jansat, Kristi K Ryan, Barabara J Carel, David J A Bell, Moira T Burke, Nkechi E Azie
    Abstract:

    AIMS: To assess the effect of a reversible MAO-A inhibitor, moclobemide, on the single-dose pharmacokinetics of almotriptan and assess the clinical consequences of any interaction. METHODS: Twelve healthy volunteers received the following treatments in a randomized, open-label, two-way crossover design (with a 1 week washout between treatments): (A) one 150 mg moclobemide tablet every 12 h for 8 days and one 12.5 mg almotriptan tablet on the morning of day 8; and (B) one 12.5 mg almotriptan tablet on day 8. Plasma almotriptan was quantified by h.p.l.c.-MS-MS, while urinary concentrations were measured by h.p.l.c.-u.v. Vital signs, ECGs, and adverse events were evaluated after almotriptan administration. Treatment effects on pharmacokinetics and vital signs were assessed by analysis of variance. RESULTS: Mean almotriptan AUC was higher (483 +/- 99.9 vs 352 +/- 75.4 ng ml-1 h, P = 0.0001) and oral clearance was lower (26.6 +/- 4.00 vs 36.6 +/- 5.89 l h-1, P = 0.0001) when almotriptan was administered with moclobemide. Mean half-life was longer (4.22 +/- 0.78 vs 3.41 +/- 0.45 h, P = 0.0002) after coadministration with moclobemide. Renal clearance of almotriptan was unaffected by moclobemide. No serious adverse events occurred and no clinically significant vital sign changes were observed. CONCLUSIONS: Moclobemide increased plasma concentrations of almotriptan on average by 37%, but the combined administration of these two compounds was well tolerated. The degree of interaction was much less than that seen previously for sumatriptan or zolmitriptan given with moclobemide.

Christopher L.-h. Huang - One of the best experts on this subject based on the ideXlab platform.

  • physiological studies of cortical spreading depression
    Biological Reviews, 2007
    Co-Authors: Justin M. Smith, Michael F. James, Daniel P Bradley, Christopher L.-h. Huang
    Abstract:

    Cortical spreading depression (CSD) produces propagating waves of transient neuronal hyperexcitability followed by depression. CSD is initiated by K+ release following neuronal firing or electrical, mechanical or chemical stimuli. A triphasic (30-50 s) cortical potential transient accompanies localized transmembrane redistributions of K+, glutamate, Ca2+, Na+, Cl- and H+. Accumulated K+ in the restricted interstitial space can cause both further neuronal depolarisation and inward movement of K+ into astrocytes that buffers this increased extracellular K+ concentration ([K+])o. However, astrocyte interconnections may then propagate the CSD wave by K+ liberation through an opening of remote K+ channels by volume, Ca2+ or N-methyl-D-aspartate receptor activation. Changes in cerebral blood volume and in apparent water diffusion co-efficient (ADC) accompanying CSD were first studied using magnetic resonance imaging (MRI) in whole lissencephalic brains. Diffusion-weighted echoplanar imaging in gyrencephalic brains went on to demonstrate CSD features that paralleled classical migraine aura. The ADC activity persisted minutes/hours post KCl stimulus. Pixelwise analyses distinguished single primary events and multiple, spatially restricted, slower propagating, secondary events whose detailed features varied with the nature of the originating stimulus. These ADC changes varied reciprocally with T2*-weighted (i.e. referring to spin-spin relaxation times) waveforms reflecting local blood flow. There followed prolonged decreases in cerebral blood flow culminating in late cerebrovascular changes blocked by the Antimigraine Agent sumatriptan. CSD phenomena have possible translational significance for human migraine aura and other cerebral pathologies such as the peri-infarct depolarisation events that follow ischaemia and brain injury.

Simon J Read - One of the best experts on this subject based on the ideXlab platform.