Thèse (M.A.)--Université Laval, 2003. / Bibliogr.: f. 59-62. Publié aussi en version électronique.

Syftet med denna studie var att undersöka hur stor effekt kombinationsbehandling med naproxen och sumatriptan har vid migrän hos vuxna människor jämfört med monoterapi med naproxen eller sumatriptan samt placebo. Studien utformades som en litteraturstudie och sökningar skedde i PubMed via Linnéuniversitetets bibliotek med sökorden ”migraine AND triptan* AND NSAID AND efficacy”, ”migraine AND sumatriptan AND naproxen AND combination AND efficacy” samt ”naproxen AND sumatriptan”. Sökningarna ledde till granskning av 6 studier.     Sammanfattningsvis hade kombinationsbehandlingen statistiskt signifikanta fördelar gällande flera effektmått vid behandling av migrän, bland annat smärtfrihet 2 timmar efter behandling och ihållande smärtfrihet upp till 24 timmar efter behandling, jämfört med såväl monoterapierna som placebo, medan biverkningsrisken inte ökade statistiskt signifikant med kombinationsterapin. Tidigt insättande av behandling, när migränen fortfarande är mild, gav bäst resultat, och effekten kvarstod under flera behandlingstillfällen. Patienter, som behandlades med kombinationsterapin, kunde statistiskt signifikant snabbare återgå till normal funktion i vardagsliv och på arbete, med minskat produktionsbortfall som följd, och de var också nöjdare med kombinationsbehandlingen än med monoterapierna och placebo. Trots dessa resultat blir långt ifrån alla bra. Knappt varannan patient, som behandlas med sumatriptan och naproxen vid mild migrän, är smärtfria efter 2 timmar. Vid måttlig till svår migrän är det ungefär 1 av 3 som är smärtfria 2 timmar efter kombinationsbehandling. Effektivare läkemedel mot migrän är önskvärt. / The purpose of this study was to analyse the efficacy of the combination of naproxen and sumatriptan when used for migraine in adults, and compare with monotherapy with naproxen or sumatriptan and placebo. The study was a literature study and searches were carried out in PubMed via the Linnaeus University library with the keywords ”migraine AND triptan* AND NSAID AND efficacy”, ”migraine AND sumatriptan AND naproxen AND combination AND efficacy” and also ”naproxen AND sumatriptan”. The searches resulted in 6 studies that were reviewed.     In summary, the combination therapy resulted in statistically significant improvements for multiple endpoints in the treatment of migraine, including patients being free of pain 2 hours after treatment and sustained pain-free response up to 24 hours after treatment, compared with both monotherapies and placebo, while the potential for adverse events did not increase statistically significantly with the combination therapy. Early intervention, when migraine was still mild, gave best results, and the effect persisted for several treatment sessions. Patients treated with combination therapy returned statistically significantly faster to normal function in everyday life and at work, with reduced downtime, and they were also more satisfied with the combination therapy than with mono therapy or placebo. Despite this, far from everybody gets well with treatment. Hardly every second patient treated for mild migraine with sumatriptan and naproxen is free from pain after 2 hours and when treating more severe forms of migraine only about 1 in 3 is free from pain after 2 hours. More effective treatments of migraine are needed.

The studies in this thesis research were conducted to investigate if sensitivity to induced cortical spread depression (CSD) or the consequence of a CSD event is affected by sumatriptan induced latent sensitization. Previous studies in our lab showed persistent exposure of sumatripan to rats produced a latent state of sensitization. Using persistent sumatripan exposed rats as a model for medication overuse headache, behavior, electrical stimulation threshold to provoke a CSD event and the immunoreactivity of c-Fos in the trigeminal nucleus caudalis (TNC) were characterized. Current results showed no statistical difference of electrically induced CSD thresholds in anesthetized rats measured at day 20 in sumatripan exposed rats compared with saline treated rats. Topiramate (80 mg/kg, i.p.) used clinically for prophylaxis of migraine headache significantly increased CSD threshold in both saline and sumatriptan infused rats. CSD events appear to be associated with trigeminal vascular system activation in TNC because c-Fos expression significantly enhanced in rats with electrically stimulated CSD events. As compared to saline treated rats, sumatriptan-exposed rats demonstrated a significantly higher number of c-Fos positive cells following the electrically stimulated CSD event. Under environmental stress (bright light), sumatripan exposed rats demonstrated decreased response thresholds to periorbital and hindpaw tactile stimuli (i.e., allodynia) and enhanced c-Fos expression in TNC. A single dose of topiramate (80 mg/kg, i.p.) reversed environmental stress induced allodynia and c-Fos over-activity. Taken together, these results suggest that latent sensitization induced by persistent sumatripan exposure seems not correlated to the threshold of electrically stimulated CSD in current model. However, CSD enhanced the responses of trigeminal system in rats with sumatriptan-induced latent sensitization. The protective effects of topiramate shown in this model may be related to blocking the initiation of CSD events resulting from environmental stimulation as well as inhibiting the consequences of CSD events in primary afferents. These findings correlate with clinical observations of protective effects of topiramate for migraine prophylaxis.

No description available.

Migraines are recurrent debilitating headaches that predominately afflict young women. The pathophysiology of migraines is still not well understood but is related to neurovascular dysfunction. Meningeal blood vessel dilation, extravasation of pro-inflammatory cytokines and activation of trigeminal afferent neurons promote migraine generation. Serotonin (5-HT) is an endogenous vasoactive peptide with diverse physiology. In meningeal blood vessels, serotonin causes vasoconstriction, however in coronary arteries, serotonin causes both vasodilation and vasoconstriction. In diseased coronary arteries, with impaired endothelial function, vasoconstriction predominates. Selective meningeal blood vessel serotonin agonists, termed ‘triptans’, have become the therapy of choice for migraine headaches. However, due to their constrictive effects on the coronary vasculature, triptans are not recommend in patients with known coronary artery disease, patients with greater than one coronary artery risk factor or patients with atherosclerotic cardiovascular disease risk (ASCVD) greater than ten percent. Triptan associated chest pain is a well-known phenomenon. Age, hypertension, dyspepsia, and Raynauds phenomenon are associated with triptan associated chest pain. Hypertension is the strongest risk factor for triptan associated chest pain in males. Although triptan associated chest pain is assumed to be cardiovascular due to its constrictive effect on the coronary vasculature, only a few cases of myocardial infarction, with documented ST elevation and/or troponin elevation, have been reported. Herein we report the case of a male patient with inferolateral ST elevation myocardial infarction, within minutes of receiving subcutaneous sumatriptan for migraine headache. The patient had a normal echocardiogram and electrocardiogram prior to sumatriptan use, and a normal cardiac catheterization afterwards.

In this dissertation I introduce a simple experimental approach for studying afferent pain fibre physiology. I developed an en bloc dural-skull preparation that pairs electrophysiological stimulations, pharmacological manipulations, and the UV photolysis of caged compounds in and around selectively identified individual C-fibre nociceptors with microfluorometric imaging of Ca2+ responses. This allows the observation of physiological functioning in individual nociceptive fibre free nerve endings. I show high-resolution functional imaging of single action potential-evoked fluorescent transients, as well as sub- and supra-threshold calcium signaling events within individual nociceptive fibre terminations. Utilizing the dural-skull preparation I was able to identify a peripheral mechanism of action in the terminals of CGRP nociceptive fibres for an effective migraine therapeutic, the selective 5-HT1 receptor agonist, sumatriptan. I found sumatriptan to cause an approximately 40% reduction in the amplitude of action potential-evoked Ca2+ transients in the peripheral terminals of CGRP nociceptive fibres that was mediated selectively through the inhibition of N-type Ca2+ channels. Observations from this study support a peripheral site of action for sumatriptan in inhibiting the activity of dural pain fibres and adds to our understanding of the mechanisms that underlie the clinical effectiveness of 5-HT1 receptor agonists such as sumatriptan. While μ-opioid receptor agonists remain the most powerful analgesics for the treatment of severe pain, their mechanism of action in peripheral primary afferent pain fibres remain to be established. Further exploiting the dural-skull preparation I found activation of μ-opioid receptors in individual CGRP terminals had a dual modulatory effect; inhibition of N-type Ca2+ channel signaling and a frequency dependent, BKCa channel-mediated, suppression of action potential firing. These results establish possible anti-nociceptive mechanisms of μ-opioid receptor activation in the peripheral terminals of CGRP nociceptive fibres and identify new pathways to target for peripherally mediated analgesia. The development and subsequent testing of the dural-skull preparation in this dissertation displays its utility and opens up a new window for studying nociceptive fibre physiology and pathophysiology.

No description available.

O Teste da Simulação de Falar em Público (SFP) é um teste sensível a drogas que interferem com a neurotransmissão mediada por serotonina (5-HT), e algumas evidências sugerem que ele possa recrutar os mesmos sistemas neuronais envolvidos na fisiopatogenia do Transtorno do Pânico (TP). Diferentes fármacos que, direta ou indiretamente, modulam receptores serotoninérgicos, já foram testados em voluntários saudáveis submetidos ao SFP, mas nenhum estudo, até o momento, utilizou drogas que permitissem avaliar o papel de receptores do tipo 5-HT1D na ansiedade. O sumatriptano, um agonista específico de receptores 5-HT1D, parece ser um bom candidato como sonda farmacológica, tendo em vista sua ampla utilização na prática clínica para o tratamento de enxaqueca, com segurança e boa tolerabilidade. A hipótese testada neste estudo foi a de que, devido à ativação de receptores pré-sinápticos 5-HT1D e conseqüente redução na liberação de 5-HT, o sumatriptano aumentaria o medo provocado pelo SFP. Para tanto, foi conduzido um estudo duplo cego, randomizado, utilizando 36 voluntários saudáveis do sexo masculino, distribuídos em três grupos de tratamento: placebo (n = 12), 50mg (n = 12) ou 100mg (n = 12) de sumatriptano, administrado duas horas antes do SFP. Antes, durante, e após o SFP, medidas subjetivas de ansiedade foram registradas através da Escala Analógica Visual do Humor (VAMS) e da Escala dos Sintomas Somáticos (ESS). Também foram tomadas medidas fisiológicas de ansiedade (pressão arterial, freqüência cardíaca, dosagem hormonal e eletrocondutância da pele). Os resultados foram submetidos à análise multivariada de variância, sendo a medida basal utilizada como covariada (MANCOVA). O grupo tratado com 100mg de sumatriptano apresentou aumento mais pronunciado da ansiedade subjetiva do que os grupos tratados com 50mg de sumatriptano e com placebo durante as fases de preparação e de desempenho. O grupo tratado com 100 mg de sumatriptano também mostrou-se mais alerta na fase de preparação e desempenho do que o grupo placebo. Não foram observados efeitos significativos do tratamento sobre as medidas de pressão arterial, freqüência cardíaca e eletrocondutância da pele. O sumatriptano provocou redução dos níveis de prolactina, independentemente da fase da sessão experimental, mas não interferiu nos níveis de cortisol plasmático. Por outro lado, observou-se um amento dos níveis de cortisol plasmático imediatamente após o SPF, em comparação com os níveis pré-teste, independente do grupo de tratamento. A redução da disponibilidade de 5-HT levou a um aumento do medo provocado pelo SFP, o que está de acordo com a proposição de que a diminuição de 5-HT na matéria cinzenta periaquedutal dorsal (MCPD) aumenta o medo incondicionado. Devido a esse efeito ansiogênico do uso agudo do sumatriptano também poder ocorrer na prática clínica, em pacientes com migrânea, deve-se atentar para a possibilidade da manifestação de sintomas semelhantes aos de ataque de pânico em pacientes ansiosos. A diminuição da função 5-HT também provocou redução dos níveis plasmáticos de prolactina, provavelmente pela facilitação da transmissão dopaminérgica. Por sua vez, embora discreto, o aumento dos níveis plasmáticos do cortisol sugerem uma atuação do eixo hipotálamo-hipófise-adrenal (HHA) pelo SFP. A interpretação da resposta do cortisol ao estresse psicológico é complexa e depende de vários fatores, como tema do discurso, tipo de avaliação social, falta de controle da situação, tamanho amostral e estratégias de regulação emocional do voluntário. Mais estudos são necessários para elucidar o papel dos receptores 5-HT1D na ansiedade e para compreender a resposta do cortisol ao estresse psicológico. / The Simulated Public Speaking Test (SPS) is an experimental model sensitive to drugs that interfere with the neurotransmission mediated by serotonin (5-HT). It has been proposed that the SPS recruits the same neural systems involved in the pathophysiology of panic disorder (PD). Different drugs that directly or indirectly modulate serotonin receptors, have been tested in healthy volunteers submitted to the SFP, but no study have been carried out so far for assessing the role of 5-HT1D receptors in anxiety. Sumatriptan, a specific agonist of 5-HT1D receptors, seems to be a good candidate as a probe drug, given its wide use in clinical practice for the treatment of migraine, with good safety and tolerability. The hypothesis tested in this study was that, due to the activation of presynaptic 5-HT1D receptors and consequent reduction in the release of 5-HT, sumatriptan would increase the fear caused by the SPS. To that end, we conducted a double-blind, randomized study using 36 healthy male volunteers who were divided into three treatment groups: placebo (n = 12), 50mg (n = 12) or 100mg (n = 12) of sumatriptan, administered two hours before the SFP. Before, during, and after the SPS, subjective measures of anxiety were recorded by Visual Analogue Mood Scale (VAMS) and the Bodily Symptom Scale (BSS). Physiological measures were also taken for anxiety (blood pressure, heart rate, hormone dosage and skin conductance). The results were submitted to multivariate analysis of variance (MANCOVA) with the baseline measures as covariate. The group treated with 100 mg of sumatriptan was more anxious than, respectively, 50mg and placebo groups during the test, and also proved to be more alert in preparation and performance than the placebo group. There were no significant effects of treatment on measures of blood pressure, heart rate and skin eletrocondutance. Sumatriptan caused a reduction of prolactin levels, independently of the experimental phase of the session, but did not interfere with plasma cortisol levels. On the other hand, there was an increased of plasma cortisol levels immediately after the SPF, compared with the pre-test, independently of treatment group. The reduced availability of 5-HT led to an increase of fear caused by the SFP, which is consistent with the proposition that a reduction of 5-HT in the dorsal periaqueductal gray (MCPD) increases unconditioned fear. Because of this anxiogenic effect of acute use of sumatriptan also can occur in clinical practice in patients with migraine should be alert to the possibility of manifestation of symptoms similar to panic attacks in patients anxious. The decreased function of 5-HT also caused a reduction in plasma levels of prolactin, probably by facilitating dopamine transmission. In turn, although slight, the increase in plasma cortisol levels suggest a role of the hypothalamic-pituitary-adrenal (HPA) for the SFP.The interpretation of the cortisol response to psychological stress is complex and depends on several factors, such as theme of the discourse, type of social assessment, lack of control of the situation, sample size, emotional regulation strategies of the volunteer. Further studies are needed to elucidate the role of 5-HT1D receptors in anxiety and to understand the cortisol response to psychological stress.

O Teste da Simulação de Falar em Público (SFP) é um teste sensível a drogas que interferem com a neurotransmissão mediada por serotonina (5-HT), e algumas evidências sugerem que ele possa recrutar os mesmos sistemas neuronais envolvidos na fisiopatogenia do Transtorno do Pânico (TP). Diferentes fármacos que, direta ou indiretamente, modulam receptores serotoninérgicos, já foram testados em voluntários saudáveis submetidos ao SFP, mas nenhum estudo, até o momento, utilizou drogas que permitissem avaliar o papel de receptores do tipo 5-HT1D na ansiedade. O sumatriptano, um agonista específico de receptores 5-HT1D, parece ser um bom candidato como sonda farmacológica, tendo em vista sua ampla utilização na prática clínica para o tratamento de enxaqueca, com segurança e boa tolerabilidade. A hipótese testada neste estudo foi a de que, devido à ativação de receptores pré-sinápticos 5-HT1D e conseqüente redução na liberação de 5-HT, o sumatriptano aumentaria o medo provocado pelo SFP. Para tanto, foi conduzido um estudo duplo cego, randomizado, utilizando 36 voluntários saudáveis do sexo masculino, distribuídos em três grupos de tratamento: placebo (n = 12), 50mg (n = 12) ou 100mg (n = 12) de sumatriptano, administrado duas horas antes do SFP. Antes, durante, e após o SFP, medidas subjetivas de ansiedade foram registradas através da Escala Analógica Visual do Humor (VAMS) e da Escala dos Sintomas Somáticos (ESS). Também foram tomadas medidas fisiológicas de ansiedade (pressão arterial, freqüência cardíaca, dosagem hormonal e eletrocondutância da pele). Os resultados foram submetidos à análise multivariada de variância, sendo a medida basal utilizada como covariada (MANCOVA). O grupo tratado com 100mg de sumatriptano apresentou aumento mais pronunciado da ansiedade subjetiva do que os grupos tratados com 50mg de sumatriptano e com placebo durante as fases de preparação e de desempenho. O grupo tratado com 100 mg de sumatriptano também mostrou-se mais alerta na fase de preparação e desempenho do que o grupo placebo. Não foram observados efeitos significativos do tratamento sobre as medidas de pressão arterial, freqüência cardíaca e eletrocondutância da pele. O sumatriptano provocou redução dos níveis de prolactina, independentemente da fase da sessão experimental, mas não interferiu nos níveis de cortisol plasmático. Por outro lado, observou-se um amento dos níveis de cortisol plasmático imediatamente após o SPF, em comparação com os níveis pré-teste, independente do grupo de tratamento. A redução da disponibilidade de 5-HT levou a um aumento do medo provocado pelo SFP, o que está de acordo com a proposição de que a diminuição de 5-HT na matéria cinzenta periaquedutal dorsal (MCPD) aumenta o medo incondicionado. Devido a esse efeito ansiogênico do uso agudo do sumatriptano também poder ocorrer na prática clínica, em pacientes com migrânea, deve-se atentar para a possibilidade da manifestação de sintomas semelhantes aos de ataque de pânico em pacientes ansiosos. A diminuição da função 5-HT também provocou redução dos níveis plasmáticos de prolactina, provavelmente pela facilitação da transmissão dopaminérgica. Por sua vez, embora discreto, o aumento dos níveis plasmáticos do cortisol sugerem uma atuação do eixo hipotálamo-hipófise-adrenal (HHA) pelo SFP. A interpretação da resposta do cortisol ao estresse psicológico é complexa e depende de vários fatores, como tema do discurso, tipo de avaliação social, falta de controle da situação, tamanho amostral e estratégias de regulação emocional do voluntário. Mais estudos são necessários para elucidar o papel dos receptores 5-HT1D na ansiedade e para compreender a resposta do cortisol ao estresse psicológico. / The Simulated Public Speaking Test (SPS) is an experimental model sensitive to drugs that interfere with the neurotransmission mediated by serotonin (5-HT). It has been proposed that the SPS recruits the same neural systems involved in the pathophysiology of panic disorder (PD). Different drugs that directly or indirectly modulate serotonin receptors, have been tested in healthy volunteers submitted to the SFP, but no study have been carried out so far for assessing the role of 5-HT1D receptors in anxiety. Sumatriptan, a specific agonist of 5-HT1D receptors, seems to be a good candidate as a probe drug, given its wide use in clinical practice for the treatment of migraine, with good safety and tolerability. The hypothesis tested in this study was that, due to the activation of presynaptic 5-HT1D receptors and consequent reduction in the release of 5-HT, sumatriptan would increase the fear caused by the SPS. To that end, we conducted a double-blind, randomized study using 36 healthy male volunteers who were divided into three treatment groups: placebo (n = 12), 50mg (n = 12) or 100mg (n = 12) of sumatriptan, administered two hours before the SFP. Before, during, and after the SPS, subjective measures of anxiety were recorded by Visual Analogue Mood Scale (VAMS) and the Bodily Symptom Scale (BSS). Physiological measures were also taken for anxiety (blood pressure, heart rate, hormone dosage and skin conductance). The results were submitted to multivariate analysis of variance (MANCOVA) with the baseline measures as covariate. The group treated with 100 mg of sumatriptan was more anxious than, respectively, 50mg and placebo groups during the test, and also proved to be more alert in preparation and performance than the placebo group. There were no significant effects of treatment on measures of blood pressure, heart rate and skin eletrocondutance. Sumatriptan caused a reduction of prolactin levels, independently of the experimental phase of the session, but did not interfere with plasma cortisol levels. On the other hand, there was an increased of plasma cortisol levels immediately after the SPF, compared with the pre-test, independently of treatment group. The reduced availability of 5-HT led to an increase of fear caused by the SFP, which is consistent with the proposition that a reduction of 5-HT in the dorsal periaqueductal gray (MCPD) increases unconditioned fear. Because of this anxiogenic effect of acute use of sumatriptan also can occur in clinical practice in patients with migraine should be alert to the possibility of manifestation of symptoms similar to panic attacks in patients anxious. The decreased function of 5-HT also caused a reduction in plasma levels of prolactin, probably by facilitating dopamine transmission. In turn, although slight, the increase in plasma cortisol levels suggest a role of the hypothalamic-pituitary-adrenal (HPA) for the SFP.The interpretation of the cortisol response to psychological stress is complex and depends on several factors, such as theme of the discourse, type of social assessment, lack of control of the situation, sample size, emotional regulation strategies of the volunteer. Further studies are needed to elucidate the role of 5-HT1D receptors in anxiety and to understand the cortisol response to psychological stress.