The 5-HT1B and 5-HT1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans.

The advent of the triptans revolutionized acute migraine treatment. The older migraine-specific drugs, the ergot alkaloids (ergotamine and dihydroergotamine), also relieve migraine attacks through agonism at the 5-HT1B and 5-HT1D receptors, but the triptans have much greater specificity for these receptors. Unlike the ergot alkaloids, the triptans do not activate many other receptor types, and therefore are much better tolerated. This reduction in side effects greatly enhanced their clinical utility as it allowed a far greater proportion of patients to take a full therapeutic dose. As a result, the clinical use of ergotamine is minimal today, although dihydroergotamine still has a significant clinical role. There is extensive evidence that the seven triptans available today, sumatriptan, zolmitriptan, rizatriptan, eletriptan, naratriptan, almotriptan, and frovatriptan, are effective in the acute treatment of migraine. Available formulations include oral tablets, orally dissolving tablets, subcutaneous injections, nasal sprays, and in some countries, rectal suppositories. For optimal benefit, therapy needs to be individualized for a given patient both regarding the triptan chosen and the formulation. This chapter discusses the ergot alkaloids and the triptans, including mechanism of action, evidence for efficacy, clinical use, and adverse effects.

Information on migraine drugs in commonly available Indian drug information sources - Whether we satisfied the community needs?

Drug information can be obtained from various drug information sources that were available as government (National Formulary of India [NFI]; Central Drugs Standard Control Organization [CDSCO]), as well as commercial documents (Current Index of Medical Specialties [CIMS] and Monthly Index of Medical Specialties [MIMS]). Irrational drug usage may happen due to wide variation in the information available in these sources. In this study, we tried to assess these variations in a sample of drugs for the acute-specific management of migraine with ergot and Triptans antimigraine drugs in drug information sources such as NFI, CIMS, MIMS, and CDSCO. Scoring was done for various drug information based on the completeness of information about drugs used in acute-specific management of migraine. The scores for the completeness of drug information about the selected antimigraine drugs are 18.37% for CIMS (Ergotamine, Sumatriptan, Rizatriptan, and Zolmitriptan), 21.1% for NFI (Dihydroergotamine, Sumatriptan), 72.79% for MIMS (Ergotamine tartrate, Sumatriptan, Rizatriptan, Naratriptan, zolmitriptan, Almotriptan) and 21.77% for CDSCO (Ergotamine tartrate, Sumatriptan, Rizatriptan, Naratriptan, Zolmitriptan, eletriptan and almotriptan). The information for the antimigraine drugs available from various sources found to so much deficient. Necessary steps need to be taken in case of government public or hard documents to streamline drug information available with them as well the commercial documents as to provide reliable drug information uniformly for promoting rational use of the drug.

Coalescing beneficial host and deleterious antiparasitic actions as an antischistosomal strategy.

Conventional approaches for antiparasitic drug discovery center upon discovering selective agents that adversely impact parasites with minimal host side effects. Here, we show that agents with a broad polypharmacology, often considered 'dirtier' drugs, can have unique efficacy if they combine deleterious effects on the parasite with beneficial actions in the host. This principle is evidenced through a screen for drugs to treat schistosomiasis, a parasitic flatworm disease that impacts over 230 million people. A target-based screen of a Schistosoma serotoninergic G protein coupled receptor yielded the potent agonist, ergotamine, which disrupted worm movement. In vivo, ergotamine decreased mortality, parasite load and intestinal egg counts but also uniquely reduced organ pathology through engagement of host GPCRs that repressed hepatic stellate cell activation, inflammatory damage and fibrosis. The unique ability of ergotamine to engage both host and parasite GPCRs evidences a future strategy for anthelmintic drug design that coalesces deleterious antiparasitic activity with beneficial host effects.

Ergotamine Use and Overuse in Taiwan: A Retrospective Cohort Study.

OBJECTIVE: The aim of this study was to investigate the pattern of ergotamine prescription and overuse in Taiwan. BACKGROUND: Ergotamine is a frequently prescribed medication for the treatment of migraine, although excessive use may lead to medication-overuse headache. METHODS: We conducted a retrospective cohort study by using the Longitudinal Health Insurance Database 2005 in Taiwan. Patients enrolled in the study were between the ages of 18 and 80 years, received at least two prescriptions of ergotamine, and follow-up for more than 1 year at outpatient clinics during 1999 to 2013. Each ergotamine prescription was converted into a defined daily dose (DDD) and patients were sorted into two groups: occasional users, having fewer than 3 consecutive months of use, and regular users, with 3 consecutive months of use or more. Regular users were further divided into overusers (DDDs ≥ 10 per month) and non-overusers. RESULTS: A total of 41,023 migraine patients were enrolled in the study; 5803 patients were classified as regular users, with 859 of those being overusers. Of the ergotamine overusers, around 698/859 (82%) continued to use, and 443/859 (52%) remained overusers of ergotamine in the subsequent year after the index date. The most frequently prescribed prophylactic medications were propranolol and flunarizine, which were prescribed in 30.4% and 20.0% of overuse patients, respectively. CONCLUSIONS: Ergotamine overuse remains common in Taiwan, while prophylactic medicine is still underutilized. More education on ergotamine-overuse headache is needed to improve awareness.

Análisis de impacto presupuestal de medicamentos para el tratamiento del episodio agudo de migraña en Colombia / Analysis of the budget impact of medications for the treatment of acute migraine episodes in Colombia

INTRODUCCIÓN: El análisis de impacto presupuestal de los medicamentos para el tratamiento preventivo y del episodio agudo de pacientes con migraña en Colombia se desarrolla en el marco del mecanismo técnico-científico para la ampliación progresiva del plan de beneficios y la definición de la lista de exclusiones, establecido en el artículo 15 de la Ley 1751 de 2015. Estas tecnologías fueron seleccionadas por la Dirección de Beneficios, Costos y Tarifas del Aseguramiento en Salud del Ministerio de Salud y Protección Social (MinSalud), y remitidas al Instituto de Evaluación Tecnológica en Salud (IETS) para su evaluación. Este análisis de impacto presupuestal sigue las pautas del Manual Metodológico para la elaboración del análisis de impacto presupuestal y del Manual Metodológico de Participación y Deliberación publicados por el Instituto de Evaluación Tecnológica en Salud (IETS). Como etapa subsecuente al reporte de efectividad y seguridad, actualmente en elaboración, esta evaluación se ceñirá a los parámetros de la pregunta PICO que allí se especifiquen. La migraña es una condición neurológica altamente prevalente, que genera un impacto importante en la calidad de vida relacionada con la salud; se asocia con discapacidad funcional, que afecta, tanto aspectos de la vida social y familiar, como aspectos académicos y ocupacionales, generando pérdidas de productividad significativas y, por ende, una carga socioeconómica considerable. Ha sido reconocida por la Organización Mundial de la Salud (OMS) como una de las 20 primeras causas de discapacidad en el mundo y según el estudio de carga de enfermedad global del año 2010, la migraña representa la octava causa, en términos de años vividos con discapacidad (AVD). La migraña es un tipo de cefalea primaria que se manifiesta generalmente entre los 25 y 50 años de edad; afecta con mayor frecuencia a las mujeres, en una relación estimada de 3:1 comparado con hombres y presenta un componente hereditario importante, reportándose en familiares de primer grado, un riesgo de padecer migraña de 1.5 a 4 veces mayor que el de la población general. Aunque existe una importante variabilidad en la presentación clínica, la migraña generalmente se caracteriza por episodios de cefalea pulsátil unilateral, asociada a síntomas como náusea, vómito, fotofobia y fonofobia. Se estima una prevalencia entre 3% y 24% en la población mundial y de acuerdo con cifras reportadas para América Latina, en Colombia el 13.8% de las mujeres y el 4.8% de los hombres padecen de esta condición. De los 4.5 millones de personas que padecen de migraña en el país, aproximadamente 30% requieren tratamiento preventivo. La Clasificación Internacional de Cefaleas (ICHD, por su sigla en inglés), define la migraña crónica como la presencia de cefalea 15 o más días al mes, durante al menos tres meses, de los cuales, al menos ocho, deben cumplir criterios de migraña. Las formas crónicas de la migraña se asocian con mayor discapacidad y deterioro de la calidad de vida, en comparación con las formas episódicas, lo que genera la necesidad de instaurar terapias preventivas, cuyo objetivo es disminuir la frecuencia de los días de cefalea, la intensidad de los episodios, y la mejoría de la calidad de vida de estos pacientes. El tratamiento del episodio agudo de migraña, tiene como objetivo disminuir la duración y la intensidad del mismo, restaurar la funcionalidad del paciente y minimizar el uso de medicación de rescate. Dentro de las alternativas terapéuticas, se encuentran los agentes antimigrañosos específicos como los triptanes y los ergotamínicos y los agentes no específicos, como los analgésicos y los antiinflamatorios no esteroideos (AINES). Por otro lado, el tratamiento preventivo debe ser considerado en aquellos pacientes en quienes la frecuencia e intensidad de los episodios de cefalea generan un impacto significativo en la calidad de vida, a pesar del uso adecuado de medicamentos durante el episodio agudo y un adecuado control de factores desencadenantes, o cuando la frecuencia de los episodios es tan alta, que se genera un riesgo importante de sobreuso de medicamentos. Se recomienda que la duración del tratamiento preventivo sea de al menos un año, con el propósito de reducir la frecuencia de las crisis en al menos 50%, disminuir su intensidad, duración y limitar la dependencia a la medicación aguda. Este documento tiene como objetivo presentar el análisis de impacto presupuestal que tendría incorporar al Plan de Beneficios en Salud con cargo a la UPC (PBSUPC) los siguientes medicamentos: naratriptán, sumatriptán, sumatriptán/naproxeno, zolmitriptán, acetaminofén más ácido acetil salicílico más cafeína para el tratamiento del episodio agudo; flunarizina, y topiramato para el tratamiento preventivo de migraña en Colombia. El documento se encuentra organizado en cuatro secciones: la primera contiene una introducción que describe la indicación de interés y el objetivo del documento. La segunda parte describe todas las tecnologías evaluadas en el análisis de impacto presupuestal; la tercera el modelo y la cuarta la presentación de resultados. INSUMOS Y MÉTODOS: Esta sección presenta los supuestos, parámetros y métodos utilizados para el modelo de estimación del impacto presupuestal describiendo la siguiente información: Perspectiva: La perspectiva de este AIP corresponde al tercero pagador, que en este caso es el Sistema General de Seguridad Social en Salud. Horizonte temporal: El horizonte temporal de este AIP en el caso base corresponde a un año. Adicionalmente, se reportan las estimaciones del impacto presupuestal para los años 2 y 3, bajo el supuesto de la inclusión en el PBSUPC en el año 1. Población total: La población total en el análisis corresponde a hombres y mujeres mayores de 18 años en Colombia con diagnóstico de migraña e indicación para manejo farmacológico. RESULTADOS: Los resultados de este AIP, presentados en la tabla 10, indican que en el caso base y con los precios actuales, la inclusión de naratriptán, sumatriptán, sumatriptán/naproxeno, zolmitriptán, la combinación acetaminofén más ácido acetil salicílico y cafeína, como tratamiento para el episodio agudo de migraña implica un esfuerzo presupuestal en el escenario 1 de $1.420.755.082 en el año 1, de $6.952.980.454 en el año 2 y de $12.202.503.302 en el año 3. La segunda parte de los resultados, presentados en la tabla 11, indican que en el caso base y con los precios actuales, la inclusión de la flunarizina y el topiramato para el tratamiento preventivo de migraña, implica un esfuerzo presupuestal de $461.316.332 en el año 1, $5.893.128.981 en el año 2 y de $7.996.160.915 en el año 3. Finalmente, en las tablas 12 y 13 se presentan los análisis de sensibilidad para cada escenario.

Análisis de impacto presupuestal de medicamentos para el tratamiento preventivo de migraña en Colombia / Analysis of the budgetary impact of medications for the preventive treatment of migraine in Colombia

INTRODUCCIÓN: El análisis de impacto presupuestal de los medicamentos para el tratamiento preventivo y del episodio agudo de pacientes con migraña en Colombia se desarrolla en el marco del mecanismo técnico-científico para la ampliación progresiva del plan de beneficios y la definición de la lista de exclusiones, establecido en el artículo 15 de la Ley 1751 de 2015. Estas tecnologías fueron seleccionadas por la Dirección de Beneficios, Costos y Tarifas del Aseguramiento en Salud del Ministerio de Salud y Protección Social (MinSalud), y remitidas al Instituto de Evaluación Tecnológica en Salud (IETS) para su evaluación. Este análisis de impacto presupuestal sigue las pautas del Manual Metodológico para la elaboración del análisis de impacto presupuestal y del Manual Metodológico de Participación y Deliberación publicados por el Instituto de Evaluación Tecnológica en Salud (IETS). Como etapa subsecuente al reporte de efectividad y seguridad, actualmente en elaboración, esta evaluación se ceñirá a los parámetros de la pregunta PICO que allí se especifiquen. La migraña es una condic

Use of antimigraine medications and information needs during pregnancy and breastfeeding: a cross-sectional study among 401 Norwegian women.

PURPOSE: Migraine is highly prevalent among women of fertile age. The main objectives of this study were to describe the prevalence and patterns of use of antimigraine medications during pregnancy and breastfeeding and to identify maternal and migraine-related factors associated with medication use during pregnancy. METHODS: The study is a cross-sectional internet-based survey among pregnant women and new mothers with migraine conducted in Norway from October 1, 2013 to February 1, 2014. Descriptive statistics were used to explore patterns of medication use, and logistic regression analysis was performed to examine the association between maternal socio-demographic and migraine-related factors and use of antimigraine medications during pregnancy. RESULTS: Of the total 401 respondents, 34.9 % were pregnant and 65.1 % had delivered within the last 18 months. The majority reported use of antimigraine medications during pregnancy (73.3 %) and postpartum (64.8 %), yet less than a third considered their migraine to be optimally treated during pregnancy (31.7 %) and the breastfeeding period (27.2 %). The patterns of medication use markedly changed during pregnancy and postpartum. Women with moderate or severe migraine were more likely to use antimigraine medications during pregnancy compared to women with mild migraine. CONCLUSIONS: Despite the fact that antimigraine medications were commonly used, the majority of the women felt that their migraine was suboptimally treated during pregnancy and postpartum. There was a decline in the use of medicines in pregnancy and postpartum, and the patterns of use markedly changed. Efforts to improve treatment of women with migraine during pregnancy and breastfeeding should be undertaken.

Ergot Use and Overuse: A Pharmacoepidemiology Retrospective Cohort Study.

OBJECTIVE: The objective of this study was to estimate and to characterize the actual patterns of ergot use and overuse in France using a drug reimbursement database. METHODS: We included all people covered by the French General Health Insurance System (GHIS) from the Provence-Alpes-Côte-d'Azur (PACA) and Corsica administrative areas who had at least one prescription of ergot between May 2010 and December 2011. All prescriptions of ergots, migraine prophylactic treatment, and psychotropic medications were extracted from the GHIS database. We defined occasional ergot users (<3 months of prescription) and regular ergot users (>3 months of prescription). Among regular ergot users, we identified overusers and nonoverusers. RESULTS: We included 4358 patients who had at least one prescription of ergots (oral ergotamine tartrate, dihydroergotamine mesilate nasal spray, intravenous dihydroergotamine mesilate). Among ergot overusers, a large majority of patients had ergotamine tartrate overuse. The proportion of ergotamine tartrate overusers is maximum after 55 years. Compared with regular users, overusers use more frequently a prophylactic treatment (93/165 [56.4%] versus 398/1057, OR = 2.15, P < .001), antidepressants (72/165 [43.6%] versus 326/1057 [30.8%] OR = 1.79, P < .001), benzodiazepines (111/165 [67.3%] versus 613/1057 [58.0%], OR = 1.50, P < .001), weak opioids (95/165 [57.6%] versus 463/1057 [43.8], OR = 1.77, P < .001) and strong opioids (13/165 [7.9%] versus 24/1057 [2.3%], OR = 3.86, P < .001). The coexistence of ergot consumption and triptan overuse, and the possibility of both triptan and ergot overuse was described; triptan overusers were more described in ergotamine overusers than in nonoverusers. CONCLUSIONS: This work outlines a high prevalence of ergotamine tartrate overuse (11.1%). As ergotamine tartrate users are mostly aged more than 55 years, an evaluation of ergotamine cardiovascular risk profile is necessary in the elderly population.

Ergotamine and nicergoline - facts and myths.

Ergotamine, being a representative of naturally occurring ergoline alkaloids, derived from d-lysergic acid, and nicergoline, a d-lumilysergic acid derivative belonging to semi-synthetic ergot-derived alkaloids, display diversified affinity for adrenergic, serotoninergic, and dopamine receptors. Although introduction of triptans marginalized use of ergotamine, nicergoline is used in cerebral metabolic-vascular disorders, and dementia. Additionally, nicergoline exhibits a safety profile comparable to that of placebo, and none of the reviewed studies reported any incidence of fibrosis or ergotism with nicergoline treatment. In line with the recent data, activation of 5-HT2B receptor by ergot derivatives i.e. ergotamine, methysergide, pergolide, and carbegoline is involved in pathogenesis of drug-induced valvulopathy. In contrary structurally related drugs - lisuride and terguride do not increase the risk of valvular heart disease. It seems, that more detailed mechanistic studies on nicergoline and ergotamine might be beneficial for determining structural requirements related to activation of G-protein as well as alternative signal transduction pathways e.g. ß-arrestins or different kinases, and responsible for drug liabilities.

Structure and function of serotonin G protein-coupled receptors.

Serotonin receptors are prevalent throughout the nervous system and the periphery, and remain one of the most lucrative and promising drug discovery targets for disorders ranging from migraine headaches to neuropsychiatric disorders such as schizophrenia and depression. There are 14 distinct serotonin receptors, of which 13 are G protein-coupled receptors (GPCRs), which are targets for approximately 40% of the approved medicines. Recent crystallographic and biochemical evidence has provided a converging understanding of the basic structure and functional mechanics of GPCR activation. Currently, two GPCR crystal structures exist for the serotonin family, the 5-HT1B and 5-HT2B receptor, with the antimigraine and valvulopathic drug ergotamine bound. The first serotonin crystal structures not only provide the first evidence of serotonin receptor topography but also provide mechanistic explanations into functional selectivity or biased agonism. This review will detail the findings of these crystal structures from a molecular and mutagenesis perspective for driving rational drug design for novel therapeutics incorporating biased signaling.

Ergotamine-induced vasospastic ischemia mimicking arterial embolism: unusual case.

Ergotamine toxicity is an important and rare condition, including tachycardia, arterial spasm which occurring as a result of accidental overdosing or drug interactions. We assessed the consequences of delayed diagnosis of peripheral arterial vasoconstriction occurring after simultaneous macrolide use by a 35-year-old woman using an ergot-derived drug for migraine. Diagnosis of ergotamine intoxication begins with suspicion. Interventional radiologists and surgeons should be aware of this acute dangerous condition.

Utilización de ergotamina: ¿saben los médicos en Colombia cómo prescribirla? / Use of ergotamine: do physicians in Colombia know how to prescribe it?

Introducción: Los derivados ergotamínicos son medicamentos para abortar las crisis migrañosas, con un efecto vasoconstrictor, que poseen una forma específica de formulación. Se pretendió determinar la forma de prescripción de derivados ergotamínicos por médicos, las variables asociadas a inadecuadas prescripciones y las interacciones potenciales en pacientes de Colombia. Métodos: Se revisaron 86.411 fórmulas durante el mes de abril del 2012; se identificó la prescripción, con medicamento, dosis, intervalo, tiempo de uso e indicación. Se entrevistó a 288 pacientes seleccionados aleatoriamente, en los que además se buscó uso concomitante con: a) antihipertensivos; b) medicamentos para enfermedad cardíaca isquémica; c) antirretrovirales; d) otros antimigrañosos, y e) macrólidos a causa de sus interacciones. Resultados: Se obtuvieron 801 prescripciones a pacientes en 27 ciudades del país con edad promedio de 35,1 ± 14,1 años, el 82,5% en mujeres, el 96,5% de ellas realizadas por el médico de atención primaria, 524 (65,4%) de los casos para migraña; se hallaron 26 formas de prescripción distintas y 797 prescripciones incorrectas en cuanto a recomendaciones de uso (99,5%). La prescripción inadecuada se asoció significativamente a los centros de atención médica donde era atendido el paciente (p = 0,005). De los pacientes entrevistados, 266 (92,4%) lo tomaron según la errónea indicación. En total, 54 (6,7%) pacientes tomaban antihipertensivos, 24 (2,9%) macrólidos y 5 (0,6%) más otro antimigrañoso concomitantemente. Discusión: La mayoría de los pacientes están recibiendo ergotamina de manera inadecuada, sumado a las posibles interacciones que elevan el riesgo de problemas para la salud, como ergotismo y eventos coronarios. Deben implementarse medidas de evaluación, actualización yformación continua para médicos

Introduction: Ergot derivatives are drugs with vasoconstrictor effects that are used to abort migraine attacks. This study aims to determine how ergot derivatives are prescribed by physicians in Colombia, find variables associated with inappropriate prescribing, and review potential interactions in our patients. Methods: We reviewed 86 411 formulas during April 2012, identifying the prescription by drug, dose, interval, duration of use, and indication. We interviewed 288 randomly selected patients in whom we also investigated concomitant use of a) antihypertensive agents b) ischaemic heart disease treatments c) antiretrovirals d) other antimigraine drugs, and e) macrolides, because of their potential for interactions. Results: We identified 801 prescriptions from patients in 27 cities with a mean age of 35.1±14.1 years; 82.5% of the prescriptions were for women, 96.5% were written by primary care physicians, and 65.4% (n = 524) corresponded to migraine treatments. There were 26 different prescription types and 797 prescriptions were incorrect with regard to usage recommendations (99.5%). Inappropriate prescribing was significantly associated with the health centre providing patient care (P = .005). Of the patients who were interviewed by telephone, 266 (92.4%) took the drug according to the erroneous indication. A total of 54 patients (6.7%) were treated with antihypertensive drugs, 24 (2.9%) with macrolides, and 5 (0.6%) with another concomitant antimigraine drug. Discussion: Most patients take ergotamine improperly, apart from the fact that potential interactions may increase the risk of health problems such as ergotism and coronary events. Physicians will require assessment measures, updated information, and continuous training

Ergotism in Thailand caused by increased access to antiretroviral drugs: a global warning.

Ergotism is a toxic condition resulting from overexposure to the ergot compounds produced by various fungi of the genus Claviceps. Traditionally, such exposure was due to ingestion of infected grains, but long-term or excessive use of medications containing ergot derivatives or drug-drug interactions between these medications can result in ergotism. Ergotamine, typically used to treat migraine, has less than 5% bioavailability due to extensive first-pass metabolism by cytochrome P450 3A4 (CYP3A4). Concurrent intake of ergotamine and strong CYP3A4 inhibitors, such as the HIV protease inhibitors (PIs), can lead to clinical ergotism. A total of 13 cases of clinical ergotism in HIV-infected patients has been published since 1997 (most recently reviewed by Frohlich et al).

Use of ergotamine: do physicians in Colombia know how to prescribe it?

INTRODUCTION: Ergot derivatives are drugs with vasoconstrictor effects that are used to abort migraine attacks. This study aims to determine how ergot derivatives are prescribed by physicians in Colombia, find variables associated with inappropriate prescribing, and review potential interactions in our patients. METHODS: We reviewed 86 411 formulas during April 2012, identifying the prescription by drug, dose, interval, duration of use, and indication. We interviewed 288 randomly selected patients in whom we also investigated concomitant use of a) antihypertensive agents b) ischaemic heart disease treatments c) antiretrovirals d) other antimigraine drugs, and e) macrolides, because of their potential for interactions. RESULTS: We identified 801 prescriptions from patients in 27 cities with a mean age of 35.1±14.1 years; 82.5% of the prescriptions were for women, 96.5% were written by primary care physicians, and 65.4% (n=524) corresponded to migraine treatments. There were 26 different prescription types and 797 prescriptions were incorrect with regard to usage recommendations (99.5%). Inappropriate prescribing was significantly associated with the health centre providing patient care (P=.005). Of the patients who were interviewed by telephone, 266 (92.4%) took the drug according to the erroneous indication. A total of 54 patients (6.7%) were treated with antihypertensive drugs, 24 (2.9%) with macrolides, and 5 (0.6%) with another concomitant antimigraine drug. DISCUSSION: Most patients take ergotamine improperly, apart from the fact that potential interactions may increase the risk of health problems such as ergotism and coronary events. Physicians will require assessment measures, updated information, and continuous training.

Prophylactic interventions after delivery of placenta for reducing bleeding during the postnatal period.

BACKGROUND: There are several Cochrane systematic reviews looking at postpartum haemorrhage (PPH) prophylaxis in the third stage of labour and another Cochrane review investigating the timing of prophylactic uterotonics in the third stage of labour (i.e. before or after delivery of the placenta). There are, however, no Cochrane reviews looking at the use of interventions given purely after delivery of the placenta. Ergometrine or methylergometrine are used for the prevention of PPH in the postpartum period (the period after delivery of the infant) after delivery of the placenta in some countries. There are, furthermore, no Cochrane reviews that have so far considered herbal therapies or homeopathic remedies for the prevention of PPH after delivery of the placenta. OBJECTIVES: To assess the effectiveness of available prophylactic interventions for PPH including prophylactic use of ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies, administered after delivery of the placenta, compared with no uterotonic agents as well as with different routes of administration for prevention of PPH after delivery of the placenta. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2013), The Food and Drug Administration (FDA) (USA),  Medicines and Healthcare Products Regulatory Agency (MHRA) (UK), European Medicines Agency (EMA) (EU), Pharmaceuticals and Medical Devices Agency (PMDA) (Japan),  Therapeutic Goods Administration (TGA) (Australia), ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform (ICTRP), University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; Japan), Japan Pharmaceutical Information Center Clinical Trials Information (Japic-CTI; Japan), Japan Medical Association Clinical Trial Registration (JMACCT CTR; Japan) (all on 30 April 2013) and reference lists of retrieved studies SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing prophylactic ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies (using any route and timing of administration) during the postpartum period after delivery of the placenta with no uterotonic agents or trials comparing different routes or timing of administration of ergotamine, ergometrine, methylergometrine, herbal therapies, and homeopathic remedies, during the postpartum period after delivery of the placenta. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and the methodological quality of trials, extracted data using the agreed form. Data were checked for accuracy. MAIN RESULTS: Five randomised studies involving 1466 women met the inclusion criteria. All studies were classified as having an unclear risk of bias. Two studies (involving 1097 women) compared oral methylergometrine with a placebo, and one (involving 171 women) compared oral methylergometrine with Kyuki-chouketsu-in, a Japanese traditional herbal medicine. The remaining two studies (involving 198 women) did not report the outcomes of interest for this review. None of the included studies reported primary outcomes prespecified in the review protocol (blood loss of 1000 mL or more over the period of observation, maternal death or severe morbidity). Overall, there was no clear evidence of differences between groups in the following PPH outcomes: blood loss of 500 mL or more (risk ratio (RR) 1.45; 95% confidence interval (CI) 0.39 to 5.47, two studies), amount of lochia during the first 72 hours of the puerperium (mean difference (MD) -25.00 g; 95% CI -69.79 to 19.79, one study), or amount of lochia by four weeks postpartum (MD -7.00 g; 95% CI -23.99 to 9.99).The Japanese study with a relatively small sample size comparing oral methylergometrine with a Japanese traditional herbal medicine found that oral methylergometrine significantly increased the blood haemoglobin concentration at day one postpartum (MD 0.50 g/dL; 95% CI 0.11 to 0.89) compared to herbal medicine. Adverse events were not well-reported in the included studies. We did not find any studies comparing homeopathic remedies with either a placebo or no treatment. AUTHORS' CONCLUSIONS: There was insufficient evidence to support the use of prophylactic oral methylergometrine given after delivery of the placenta for the prevention of PPH. Additionally, the effectiveness of prophylactic use of herbal medicine or homeopathic remedies for PPH is still unclear as we could not find any clear evidence. Trials to assess the effectiveness of herbal medicines and homeopathic remedies in preventing PPH are warranted.

A case report of multiple fractures with arterial vasospasm associated with ergotamine use.

Vasospasm that develops in association with ergotamine use is a rarely seen but well-understood complication. A case is presented here of multiple fractures in which arteriospasm affecting all the arteries of the lower limb on the same side occurred 10 days post-trauma. In this case, the arteriospasm resulting from ergotamine addiction and high doses of ergotamine, which may be confused with post-traumatic angiospasm, was treated with a marcaine infusion by epidural catheter and heparin, iliomedin and nitronal infusion intravenously. This clinical condition should be borne in mind for all trauma cases determined to have arterial vasospasm, and the use of ergotamine must be queried when taking the anamnesis from the patient.

Distinctive anatomical and physiological features of migraine aura revealed by 18 years of recording.

The mechanisms underlying the initiation and propagation of the migraine aura, and the visual percept that is produces, remain uncertain. The objective of this study was to characterize and quantify a large number of visual auras recorded by a single individual over nearly two decades to gain insight into basic aura mechanisms. An individual made detailed drawings of his visual percept of migraine aura in real time during more than 1000 attacks of migraine aura without headache over 18 years. Drawings were made in a consistent fashion documenting the shape and location of the aura wavefront or scotoma in the visual field at one minute intervals. These drawings were digitized and the spatial and temporal features of auras were quantified and analysed. Consistent patterns of aura initiation, propagation and termination were observed in both right and left visual fields. Most aura attacks originated centrally (within 10° eccentricity), but there were also other distinct sites of initiation in the visual field. Auras beginning centrally preferentially propagated first through lower nasal field (69-77% of all auras) before travelling to upper and temporal fields, on both sides. Some auras propagated from peripheral to central regions of the visual field-these typically followed the reverse path of those travelling in the opposite direction. The mean velocity of the perceived visual phenomenon did not differ between attacks starting peripherally and centrally. The estimated speed of the underlying cortical event (2-3 mm/min) was in the same range as has been previously reported by others. Some auras had limited propagation and spontaneously 'aborted' after a few minutes, despite being initiated in similar locations to those that spread throughout the entire visual field. The visual percept of the aura changed corresponding with the presumed propagation from the V1 to the V2 region of the occipital cortex. In some cases the visual percept disappeared for several minutes before reappearing in a distant location, providing direct evidence that the aura can be clinically 'silent'. These results indicate that there can be multiple distinct sites of aura initiation in a given individual and suggest that the spatial pattern of propagation in the occipital cortex is non-concentric with a variable extent of propagation. The visual percept of migraine aura changes depending on the region of the occipital cortex that is involved.