Selective 5-HT7 receptor agonists LP 44 and LP 211 elicit an analgesic effect on formalin-induced orofacial pain in mice

ABSTRACT The most recently identified serotonin (5-HT) receptor is the 5-HT7 receptor. The antinociceptive effects of a 5-HT7 receptor agonist have been shown in neuropathic and inflammatory animal models of pain. A recent study demonstrated the functional expression of 5-HT7 receptors in the substantia gelatinosa (SG) of the trigeminal subnucleus caudalis, which receives and processes orofacial nociceptive inputs. Objective To investigate the antinociceptive effects of pharmacological activation of 5-HT7 receptors on orofacial pain in mice. Material and Methods Nociception was evaluated by using an orofacial formalin test in male Balb-C mice. Selective 5-HT7 receptor agonists, LP 44 and LP 211 (1, 5, and 10 mg/kg), were given intraperitoneally 30 min prior to a formalin injection. A bolus of 10 µl of 4% subcutaneous formalin was injected into the upper lip of mice and facial grooming behaviors were monitored. The behavioral responses consisted of two distinct periods, the early phase corresponding to acute pain (Phase I: 0–12 min) and the late phase (Phase II: 12–30 min). Results LP 44 and LP 211 (1, 5, and 10 mg/kg) produced an analgesic effect with reductions in face rubbing time in both Phase I and Phase II of the formalin test. Conclusion Our results suggest that 5-HT7 receptor agonists may be promising analgesic drugs in the treatment of orofacial pain.

Current Issues in Functional Dyspepsia / 대한소화기학회지

Functional dyspepsia is one of the most common gastrointestinal disorders encountered in clinical practice. Functional dyspepsia is currently defined by Rome III criteria as the chronic dyspeptic symptoms (postprandial fullness, early satiety, epigastric pain or burning) in the absence of underling structural or metabolic disease that readily explain the symptoms. According to the Rome III consensus, functional dyspepsia can be subdivided into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Although the Rome III criteria have been published more than 8 years ago, not much effort has been put into validating these criteria and direct scientific evidence supporting the validity of the subdividing functional dyspepsia into PDS and EPS are lacking. This article is intended to review the validity of the Rome III criteria on the subdivisions of functional dyspepsia, i.e. PDS and EPS. The impact of sleep disorder, Helicobacter pylori-associated dyspepsia, and the emerging drug therapies in functional dyspepsia will also be discussed in this article.

Migraine in the triptan era: progresses achieved, lessons learned and future developments / Migrânea na era dos triptanos: progressos alcançados, lições aprendidas e desenvolvimentos futuros

Triptans, serotonin 5-HT1B/1D receptor agonists, more than revolutionizing the treatment of migraine, stimulated also ground breaking research that provided insights into the anatomy, physiology, and molecular pharmacology of migraine. This knowledge, in turn, is stimulating research on new mechanisms of action for the treatment of migraine. Accordingly, it is opportune to critically review the main advances in migraine science that happened in the triptan era. Herein we first review and conceptualize some of the progresses achieved in migraine science during the triptan era. We then review the class of the triptans - mechanism of action and clinical evidence. We close by briefly discussing the class of CGRP receptor antagonists, which is currently being developed for the acute treatment of migraine.

Os triptanos, agonistas serotoninérgicos 5-HT1B/1D, revolucionaram o tratamento da migrânea promovendo pesquisas que evidenciaram aspectos da anatomia, fisiologia e farmacologia molecular deste tipo prevalente de cefaléia primária. Esse conhecimento, por sua vez vem estimulando ainda mais a descoberta de novos mecanismos de ação para drogas anti-migranosas. Assim, é oportuno rever de forma crítica, os maiores avanços na ciência das cefaléias ocorridos durante a era dos triptanos. Inicialmente reveremos e conceituaremos alguns dos progressos obtidos nesta fase seguido de uma revisão profunda dos mecanismos de ação e evidências clínicas para o uso desta classe de fármacos. Finalmente, discutiremos a nova classe dos antagonistas dos receptores do peptideo geneticamente relacionado à calcitonina (CGRP) atualmente em desenvolvimento.

Differential response to gepirone but not to chlordiazepoxide in malnourished rats subjected to learned helplessness

The learned helplessness (LH) paradigm is characterized by learning deficits resulting from inescapable events. The aims of the present study were to determine if protein-calorie malnutrition (PCM) alters learning deficits induced by LH and if the neurochemical changes induced by malnutrition alter the reactivity to treatment with GABA-ergic and serotonergic drugs during LH. Well-nourished (W) and PCM Wistar rats (61 days old) were exposed or not to inescapable shocks (IS) and treated with gepirone (GEP, 0.0-7.5 mg/kg, intraperitoneally, N = 128) or chlordiazepoxide (0.0-7.5 mg/kg, intraperitoneally, N = 128) 72 h later, 30 min before the test session (30 trials of escape learning). The results showed that rats exposed to IS had higher escape latency than non-exposed rats (12.6 ± 2.2 vs 4.4 ± 0.8 s) and that malnutrition increased learning impairment produced by LH. GEP increased the escape latency of W animals exposed or non-exposed to IS, but did not affect the response of PCM animals, while chlordiazepoxide reduced the escape deficit of both W and PCM rats. The data suggest that PCM animals were more sensitive to the impairment produced by LH and that PCM led to neurochemical changes in the serotonergic system, resulting in hyporeactivity to the anxiogenic effects of GEP in the LH paradigm.

Náuseas e vômitos no pós-operatório: uma revisão do "pequeno-grande" problema / Postoperative nausea and vomiting: a review of the minor-major problem

JUSTIFICATIVA E OBJETIVOS: Apesar da investigação contínua e do desenvolvimento de novos fármacos e técnicas, as náuseas e vômitos no pós-operatório (NVPO) são freqüentes e podem contribuir para o desenvolvimento de complicações com conseqüente aumento dos custos hospitalares e dos recursos humanos. Os objetivos deste artigo são a revisão dos mecanismos fisiológicos, dos fatores de risco e das medidas terapêuticas disponíveis para o manuseio de NVPO. CONTEUDO: Várias são as estratégias de manuseio de NVPO sugeridas neste artigo, destacando-se, no entanto, as linhas de orientação emitidas por Gan em 2003. Estas constituem a contribuição mais recente para a estratificação de risco, prevenção e tratamento dos pacientes com NVPO. CONCLUSÕES: Embora o manuseio de NVPO tenha melhorado nos últimos anos, estes ainda ocorrem freqüentemente em grupos de risco elevado. A estratégia atual para a prevenção e manuseio de NVPO permanece por estabelecer e as linhas de orientação de Gan deverão ser adaptadas a cada população de pacientes e à instituição hospitalar.

Management of diabetic gastroparesis.

Diabetic gastroparesis is a long term complication of diabetes mellitus which could basically be defined as dysregulated gastric emptying leading to various pathological, biochemical and clinical changes in absence of any structural changes. Symptoms include nausea, vomiting, bloating, epigastric pain, anorexia, weight loss and so on. For symptomatic gastroparesis prokinetic drugs like metoclopramide, domperidone, cisapride, erythromycin and itcopride are used. Itopride is currently emerging as a prokinetic drug of choice. There is also scope of surgery.

Migraine: a common cause of headache.

Acute headaches in a child evoke anxiety in parents, of a possible catastrophic underlying intracranial pathology. Headaches constitute up to 2 to 6% of all emergency room visit. The prevalence of migraine is increasing. The majority of children have migraine without aura, and about one fifth have migraine with aura. Complicated migraine presents with dramatic neurologic signs and remains a diagnosis of exclusion. Children with migraine require reassurance, modification of life style and food habits, combined with judicious use of simple abortive medications and antiemetics. Prophylaxis in migraine is recommended for frequent or severe attacks and in complicated migraine.

Dexamethasone decreases migraine recurrence observed after treatment with a triptan combined with a nonsteroidal anti-inflammatory drug

BACKGROUND AND OBJECTIVES: Triptans are effective drugs for the acute treatment of migraine. However, 30-40 percent of the patients commonly present recurrence before 24 hours therefore requiring another dose. Nonsteroidal anti-inflammatory drugs (NSAID) such as tolfenamic acid and naproxen sodium combined with sumatriptan have demonstrated efficacy in reducing recurrence observed with the single use of this drug. Steroids also have been suggested to treat refractory migraine and status migranosus. The aim of this study was to evaluate whether patients presenting frequent recurrence with the combination triptan plus NSAID, would decrease it with the association of dexamethasone. METHOD: Twenty three patients, 17 women and 6 men with migraine according to IHS criteria were prospectively studied. All patients presented frequent recurrence ( > or = 60 percent, mean recurrence rate 74,8 percent) with the single use of sumatritpan 100mg or zolmitriptan 2,5mg or rizatriptan 10mg in at least 5 consecutive attacks, and didn't present a reduction of the recurrence rate superior than 20 percent with the combination of tolfenamic acid 200mg or rofecoxib 25mg in at least 5 other consecutive attacks (mean recurrence rate 60 percent). The patients had to treat 6 consecutive moderate or severe migraine attacks with their usual combination plus 4mg of dexamathasone with a maximum of twice a week, and fill out a diary reporting headache parameters. RESULTS: Twenty patients, 16 women and 4 men completed the study. Of those who completed the study, 11 took rizatriptan plus rofecoxib, 4 rizatriptan plus tolfenamic acid, 3 zolmitriptan plus rofecoxib, 1 zolmitriptan plus tolfenamic acid and 1 patient took sumatriptan plus tolfenamic acid, having the 20 patients taken as a third medication, a single tablet of 4mg of dexamethasone. All patients took oral formulations and none presented vomiting after that. Among all 20 patients, one female and one male patient presented recurrence in 3 out of the 6 attacks (50 percent) while the remaining 18 patients revealed recurrence in 1 or 2 treated attacks (mean 23,4 percent) (p<0,001). CONCLUSION: We concluded that the judicious use of oral dexamethasone might be useful for a limited population of migraine patients still presenting recurrence with the combination of a triptan and a NSAID. Case-control studies and studies with a randomized double-blind design are necessary to confirm these observations

Naproxen sodium decreases migraine recurrence when administered with sumatriptan

Forty to 78 per cent of the patients using sumatriptan for the acute treatment of migraine may present recurrence at least occasionally. The concomitant use of a NSAID (nonsteroidal anti-inflammatory drug) has been recommended to decrease the recurrence rate. Sixty seven patients that treated successfully 8 migraine attacks with 100 mg of sumatritpan PO and presented recurrence in at least 5 attacks were studied prospectively. The patients received 100 mg of sumatriptan and 550 mg of naproxen sodium PO to treat 4 consecutive moderate or severe migraine attacks. The recurrence rate, once at least 62.5 per cent (5 out of 8 attacks), decreased to 14.2 per cent (38 out of 268 attacks) with the combination of compounds (p<0.0001). We then studied two groups of 13 patients made randomicaly from the 67 initially evaluated, that were given sumatriptan 100 mg plus naproxen sodium 550 mg or placebo, in a double-blind design, to treat 3 other consecutive migraine attacks. Each group of patients treated 39 attacks. The recurrence among the patients taking sumatriptan plus placebo was 59 per cent (23 out of 39 attacks) and the recurrence presented by the group taking sumatriptan plus naproxen was 25.5 per cent (10 out of 39 attacks) (p<0.0003). We concluded that the combination of sumatriptan plus naproxen sodium decreases significantly migraine recurrence presented by patients taking sumatriptan alone.

Antinociceptive effect of sumatriptan in mice.

Antinociceptive effect of the antimigraine drug sumatriptan (5-HT1A agonist) was studied against acetic acid-induced writhing in mice. Sumatriptan produced the effect in a dose-dependent manner (1, 5, 10 and 20 mg/kg, s.c.). Naloxone (1 mg/kg i.p.) an opiate antagonist failed to reverse sumatriptan-induced antinociception. Cholinomimetic physostigmine (0.05 mg/kg, i.p.) potentiated and the muscarinic antagonist atropine (5 mg/kg, i.p.) blocked the antinociceptive effect of sumatriptan, respectively. The antinociceptive effect of sumatriptan was compared with an another 5-HT agonist (5-HT1A) buspirone which also produced antinociception. Like sumatriptan-analgesia, the buspirone response was also potentiated by physostigmine in atropine sensitive way. Further, buspirone potentiated the analgesic effect of sumatriptan. These observations suggest that 5-HT1A agonists produce antinociception possibly by modulating central cholinergic activity.

Utilidad de un procinético cisaprida en el tratamiento abortivo de la migraña / Utility of the prokinetic cisapride in the abortive treatment of migraine

Alrededor de 23 millones de americanos sufren de cefalea migrañosa y más de 11 millones experimentan incapacidad significativa. El tratamiento puede ser de dos tipos; abortivo y profiláctico. Se han utilizado agonistas de los receptores de la serotonina para la mejoría de los síntomas. Cisaprida un fármaco procinético tiene propiedades agonistas en los receptores 5HT2 y en los SHT4. Se estudiaron nueve pacientes 8 del sexo femenino y 1 del masculino con una media de 27 años. Se estableció diagnóstico de cefalea, se valoraron las características de la cefalea y la respuesta al tratamiento con cisaprida. Se valoró la respuesta a los 30, 30-60 y más de 60 min y mostraron que cisaprida disminuyo la cefalea a leve en 67 por ciento, moderada en 22 por ciento y severa 11 por ciento, disminuyo el dolor en el 56 por ciento en menos de 30 min entre 30-60 min el 33 por ciento y el 1 por ciento más de 60 min. El siguiente estudio mostró utilidad de la cisaprida en el tratamiento abortivo de la migraña

Nocturnal eating syndrome: a case report with therapeutic response to dexfenfluramine

Uma mulher com pulsäo alimentar noturna e com resposta à dexfenfluramina (DXF) é relatada. Episódios compulsivos automáticos todas as noites com ingestäo de glicídios, comidas semi-preparadas e presença de amnésia total dos episódios. Medicaçöes anorexígenas reduziam a pulsäo alimentar diurna sem modificar o padräo alimentar noturno. DXF 30mg/dia aboliu totalmente os episódios. A paciente preenche todos os critérios diagnósticos do DSM-III-R para distúrbio alimentar compulsivo. 5-HT participa dos processos neurais que regulam o sono sincronizado. O perfil agonista 5-HT da DXF pode determinar modificaçöes destes processos neurais gerando o efeito terapêutico documentado neste caso. Contudo, um efeito específico da DXF no controle comportamental de ingesta de glicídios näo pode ser descartados neste casos