Toxigenic Endophyte-Infected Tall Fescue and Ergot Alkaloids.

"Fescue toxicosis" and reproductive ergotism present identical toxidromes in late-gestational mares and, likely, other equids. Both toxic syndromes are caused by ergopeptine alkaloids (EPAs) of fungal origin, and they are collectively referred to as equine ergopeptine alkaloid toxicosis (EEPAT). EPAs are produced by either a toxigenic endophyte (Epichloë coenophiala) in tall fescue and/or a nonendophytic fungus (Claviceps purpurea), infecting small grains and grasses. EEPAT can cause hypoprolactinemia-induced agalactia/dysgalactia, prolonged gestation, dystocia, and other reproductive abnormalities in mares, as well as failure of passive transfer in their frequently dysmature/overmature/postmature foals. Prevention relies on eliminating exposures and/or reversing hypoprolactinemia.

[Ergotism-a weed from Mesopotamia became an epidemic pathogen in Europe]. / Der Ergotismus ­ ein Ackerunkraut aus Mesopotamien wurde in Europa zum noch immer aktuellen Epidemie-Erreger.

In Mesopotamian wheat fields rye grew as weed and after certain developments rye reached Europe and there became a cultivable plant and the dominant grain in certain regions. With the rye also its parasite, the Claviceps purpurea, reached Europe. This ascomycete infects particular rye grains and in its developmental cycle grows to sclerotia bigger than each grain. These forms, the so-called ergots, contain the poisonous ergotalcaloids. After their intake they produce two characteristic forms of ergotism.The clinical picture of the Ergotismus gangraenosus already before the knowledge of its origin, was known as "Ignis sacer", "Anthony's Fire" and "Cold Gangrene". In this non-febrile affection mostly of the limbs, the muscles were decomposed without bleeding and without pain and thereafter the bones detached. Sooner or later the patients died.The other form, Ergotismus convulsivus, mostly described in the German literature as "Kriebelkrankheit" (Crawly disease), begins with the sensation of running ants upon the limbs and continues with painful contractions of hands and feet. In many cases there is a loss of mind and language. Finally, death occurs.The intake of ergotalcaloids predominantly with products of rye flour and meal but also during processing the harvested rye are discussed as well as the "Carry-over" by meat and milk. It is stressed that the compliance with the legal Austrian and EU regulations for the maximum contents of sclerotia and ergotalcaloids resp. in products for human and animal nourishments only can be guaranteed by continuing the technics of separating the sclerotia and their parts.

Medieval surgery (eleventh-thirteenth century): barber surgeons and warfare surgeons in France.

PURPOSE: From the eleventh to the thirteenth century, three major events marked surgery in France: the appearance of an epidemic linked to ergotism which led to numerous amputations, the emergence of barber surgeons for civilian practice, and the organization of war surgery for the First Crusade. MATERIAL AND METHODS: If a certain separation between medicine and surgery had appeared at the beginning of the Middle Ages, it would have been from 1215 (at the time of the Lateran Council) that the real separation between medicine and surgery was made. Before this date, the surgery was done by the clergy (monks) who had some experience of surgical practice. After the Council de Lateran, the barbers will take charge of the surgery. RESULTS: In the Middle Ages, the first cause of amputation was linked to poisoning by ergot of rye, intoxication due to the ingestion of contaminated bread. Due to ergotamine-related vasoconstriction, many patients will die with a frequency ranging from 10 to 20% in times of starvation. For survivors, gangrenes will lead to amputations made at the beginning by monks, then by the barber surgeons after 1215. With the name of barber surgeon, barbers are initially responsible for small surgical procedures, then for amputations given the epidemics linked to ergotism which led to numerous amputations. By this practice, they will acquire the knowledge of anatomy and the knowledge of the surgery. Apart from this civilian practice of surgery carried out by barber surgeons, the military practice of surgery will appear with the conquests of England and the start of the crusades which will require a more professional organization of surgery. CONCLUSION: After 1371, as only barbers surgeons had some surgical practice, their knowledge surpassed knowledge of the university. This supremacy of the barber surgeon over the surgeons of the university will be demonstrated by Ambroise Paré.

Ergotism with acute limb ischemia, provoked by HIV protease inhibitors interaction with ergotamine, rescued by multisite transluminal balloon angioplasty.

Acute limb ischemia induced by arterial vasospasm remains an exceptional situation, favoured by the use of arterial vasoconstrictors. The risk of these substances is largely underestimated in the general population, especially with the co-administration of strong cytochrome inhibitors like human immunodeficiency virus (HIV) protease inhibitors. A 33-year-old woman, who used to take dihydroergotamine for orthostatic hypotension, was prescribed a post-exposure HIV prophylaxis including lopinavir and ritonavir. One day later, she presented an acute bilateral limb ischemia with a sudden pain in both calves, initially while walking and then at rest with bilateral ischemic toes. Angiography confirmed diffuse arterial vasospasm of the lower limb arteries. A first-line therapy with isosorbide dinitrate and amlodipine was ineffective, with rapid clinical worsening. A combination of intra-arterial injections and intra-venous infusions of vasodilators, transluminal balloon angioplasty and bilateral 4-Compartment fasciotomies permitted rapid improvement and finally resulted in both lower limbs rescue. This case and literature review illustrate ergotism due to ergotamine overdose after taking HIV protease inhibitors. It also demonstrates the benefit of an interventional procedure besides medical therapy with vasodilators in severe arterial vasospasm. All along the lower limb arterial tree, transluminal balloon angioplasty restored the blood flow, without vasospasm recurrence. CONCLUSION: In case of ergotism with acute lower limbs ischemia, combining medical vasodilator therapy with interventional procedure can restore the arterial blood flow, thus allowing to save lower limbs.

Ergotism, a relatively unknown mimic of vasculitis: A case report and review of literature / Ergotismo: un imitador poco conocido de vasculitis. Reporte de caso y revisión de la literatura

ABSTRACT Introduction: Ergotism is a vasospasm that affects visceral and peripheral muscle arteries. Classically, symmetrical involvement of lower limb arteries is described, and is often associated with a history of chronic consumption of ergotamine derived medications (Cafergot). Case report: A 22 year-old healthy man with infectious mononucleosis syndrome, who presented with a sudden onset of paraesthesias in the lower limbs, as well as livedo reticularis. The initial diagnosis was a medium-sized vessel vasculitis (polyarteritis nodosa). The symptoms were preceded by the administration of Cafergot for headache treatment, and resolved spontaneously. The magnetic resonance angiography (MRA) of the lower limbs showed occlusion of peroneal arteries, with filiform distal flow. Other infectious, autoimmune and cardiovascular origins were ruled out. Discussion: Ergotism is an important differential diagnosis in the study of the patient with vasculitis, especially in acute onset presentations. Its treatment is the suspension of the causal drug, with vasodilator and surgical vascular procedures, if necessary. Conclusions: Ergotism is an imitator of vasculitis, especially in young patients with a history of difficult to control migraine. The concomitant administration of CYP3A4 inhibitors (mainly, protease inhibitors and macrolides) enhances the toxic effects of ergot.

RESUMEN Introducción: El ergotismo es un vasoespasmo que afecta las arterias musculares periféricas y viscerales. Clásicamente se describe la afectación simétrica de las arterias de las extremidades inferiores, a menudo asociada con el consumo crónico de medicamentos derivados de ergotamina (Cafergot®). Caso clínico: Varón sano de 22 anos con síndrome de mononucleosis, presentó parestesias en las extremidades inferiores y livedo reticularis de forma súbita, el diagnóstico inicial fue una vasculitis de mediano vaso (poliarteritis nodosa). Los síntomas fueron precedidos por la administración de Cafergot® para el tratamiento de cefalea, y se resolvieron espontáneamente. La angiografía por resonancia magnética (ARM) de las extremidades inferiores mostró oclusión de las arterias peroneas, con flujo distal filiforme. Se descartaron otras etiologías infecciosas, autoinmunes y cardiovasculares. Discusión: Los ergotismos son un diagnóstico diferencial importante en el estudio del paciente con vasculitis, especialmente en presentaciones de inicio agudo. Su tratamiento es la suspensión del fármaco causal, vasodilatadores y procedimientos vasculares quirúrgicos, si es necesario. Conclusiones: El ergotismo es un imitador de vasculitis, especialmente en pacientes jóvenes con antecedentes de migrana de difícil control. La administración concomitante de inhibidores del CYP3A4 (principalmente, inhibidores de proteasa y macrólidos) potencia los efectos tóxicos del ergot.

Targeting the 5-HT system: Potential side effects.

Targeting the serotonin (5-HT) system is no simple task: there are at least 15 5-HT receptors, in addition to a number of transporters and metabolizing enzymes. Multiple 5-HT receptor variants exist due to genetic variations and/or post translational modifications, splice variants or editing variants. Some receptors may form homo and heteromers. The 5-HT system is targeted by multiple drugs to treat a variety of diseases. Given the homology amongst the 5-HT and neighbouring receptor classes, only few drugs are actually selective for a single target. In fact, many 5-HT drugs act on a combination of targets, i.e. several receptors and/or transporters or enzymes. For instance, a number of antidepressants or antipsychotics act on 5-HT and other transmitter systems. Recently developed drugs may show target selectivity by design, based on the current state of knowledge, whereas many older compounds hit multiple targets since they were developed using phenotypic screens, as was done well into the 1980's. Ergot analogues, antipsychotics or antidepressants, fall into this category. As our knowledge developed over the last 25-30 years, some targets have very well-defined liabilities: for instance, 5HT2B or 5-HT2A receptor agonists, will produce valvulopathies or hallucinations, respectively, whereas 5-HT3 receptor antagonists, may lead to constipation. This short review will be limited in scope as there are multiple targets and even more compounds to discuss. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Sobre el mal de los ardientes o del fuego de San Antonio / Saint Anthony's fire illness

Resumen El ergotismo es el resultado de la intoxicación con alcaloides derivados del ergot. Durante la edad media y hasta el siglo XIX fue el responsable de grandes epidemias en Europa por el consumo de granos contaminados con el cornezuelo del centeno provocando manifestaciones isquémicas características y afección del sistema nervioso. El ergotismo como se conoció en el Medioevo ha desaparecido, pero aún hoy en día se reportan casos en el marco de uso terapéutico de ergotamínicos. Se pretenden describir algunos de sus aspectos históricos y clínicos distintivos.

Abstract Ergotism is the result of intoxication with alkaloids derived from ergot. During the middle ages and until the nineteenth century it was responsible for major epidemics in Europe for the consumption of grains contaminated with ergot, causing characteristic ischemic manifestations and nervous system involvement. Ergotism as it was known in the Middle Ages has disappeared, but even today cases are reported in the therapeutic use of ergotamine. Some of its distinctive historical and clinical aspects are intended to be described.

Insuficiencia arterial aguda severa vinculada a ergotismo / Severe acute arterial insufficiency linked to ergotism / Insuficiência arterial aguda severa vinculada a ergotismo

El ergotismo es un síndrome clínico poco frecuente pero potencialmente letal vinculado a la intoxicación aguda o crónica con el uso de alcaloides del ergot en el tratamiento de la migraña. Se caracteriza por un vasoespasmo severo generalizado que puede generar isquemia periférica o visceral y conducir a disfunción orgánica múltiple y muerte. Existen numerosos fármacos de metabolismo hepático que pueden alterar la metabolización de la ergotamina pudiendo alcanzar concentraciones tóxicas incluso a bajas dosis. Presentamos el caso de un paciente infectado con virus de la inmunodeficiencia humana bajo tratamiento antirretroviral que incluía inhibidores de la proteasa y que se había automedicado con ergotamina. El paciente presentó posteriormente sintomatología sensitivo motora deficitaria de miembros superiores e inferiores, acompañada de elementos de hipoperfusión distal severa. Se solicitó Doppler arterial que evidenció vasoespasmo de ejes arteriales de miembros. Se realizó diagnóstico de ergotismo secundario a la asociación de ergotamina - ritonavir, ingresando a cuidados intensivos. Se inició tratamiento en base a suspensión de ambos fármacos, vasodilatación arterial con nitroprusiato y antiagregación con ácido acetilsalicílico. En relación con este caso se presenta una revisión del mecanismo de toxicidad de la ergotamina, sus interacciones farmacológicas, así como diagnóstico y tratamiento disponibles para esta patología. (AU)

Ergotism is a rare but potentially lethal clinical syndrome linked to acute or chronic poisoning with the use of ergot alkaloids in the treatment of migraine. It is characterized by a severe generalized vasospasm that can generate peripheral or visceral ischemia and lead to multiple organ dysfunction and death. There are numerous drugs of hepatic metabolism that can alter the metabolism of ergotamine and can reach toxic concentrations even at low doses. We present the case of a patient infected with human immunodeficiency virus under antiretroviral treatment that included protease inhibitors and who had self-administered with ergotamine. The patient subsequently presented motor sensory deficit symptoms of upper and lower limbs, accompanied by elements of severe distal hypoperfusion. Arterial Doppler was requested, which showed vasospasm of the arterial axis of the limbs. A diagnosis of ergotism secondary to the ergotamine-ritonavir association was made, entering intensive care. Treatment was started based on suspension of both drugs, arterial vasodilatation with nitroprusside and antiaggregation with acetylsalicylic acid. In relation to this case, we present a review of the ergotamine toxicity mechanism, its pharmacological interactions, as well as the diagnosis and treatment available for this pathology. (AU)

O ergotismo é uma síndrome clínica pouco frequente, porém potencialmente letal vinculado à intoxicação aguda ou crônica pelo uso de alcalóides do Ergot no tratamento da enxaqueca. Caracteriza-se por um vaso espasmo severo generalizado que pode gerar isquemia periférica ou visceral e levar a disfunção orgânica múltipla e morte. Existem múltiplos fármacos de metabolismo hepático que podem alterar a metabolização da ergotamina podendo alcançar concentrações tóxicas inclusive em doses baixas. Apresentamos o caso de um paciente infectado com vírus da imunodeficiência humana recebendo tratamento antirretroviral que incluía inibidores da protease e que se automedicou com ergotamina. O paciente apresentou posteriormente sintomatologia sensitiva motora deficitária de membros superiores e inferiores, acompanhada de elementos de hipoperfusao distal severa. Solicitou-se Doppler arterial que mostrou vaso espasmo dos eixos arteriais de membros. Realizou-se diagnóstico de ergotismo secundário à associação ergotamina - ritonavir, e transferiu-se o paciente a cuidados intensivos. Iniciou-se tratamento com a suspensão de ambos os fármacos, vasodilatação arterial com nitroprussiato e antiagregaçao com ácido acetilsalicílico. Apresenta-se uma revisão do mecanismo de toxicidade da ergotamina, suas interações farmacológicas, seu diagnóstico e os tratamentos disponíveis para esta patologia. (AU)

Claviceps purpurea e Bipolaris sp. como causa de ergotismo em bovinos no estado de Santa Catarina / Claviceps purpurea e Bipolaris sp. as a cause of ergotism in cattle in Santa Catarina State

Claviceps purpurea é o fungo associado ao ergotismo. Esta é uma enfermidade causada pela ingestão de escleródios chamados de ergot, que contém alcalóides que atuam em receptores adrenérgicos, dopaminérgicos e seratoninérgicos causando efeito direto em vasos sanguíneos, musculatura lisa e sistema nervoso central e autônomo. Descrevem-se dados epidemiológicos, sinais clínicos e lesões de uma enfermidade de bovinos caracterizada por hipertermia, taquicardia, taquipneia e ulcerações na coroa do casco de bovinos. Entre 2000 e 2014 foram diagnosticados 13 surtos, três da forma distérmica, sete da forma gangrenosa e três da forma convulsiva. Porém, em cinco destes sete surtos, nos locais onde esses animais pastoreavam havia alta incidência de inflorescências de Sporobolus indicus conhecido como "capim-mourão", infectadas por um fungo com coloração enegrecida, identificado como Bipolaris sp. A enfermidade foi reproduzida experimentalmente em cinco bovinos com a administração destas inflorescências. Os bovinos em experimentação receberam inflorescências de S. indicus respectivamente nas doses diárias de 0,1g/kg, 0,2g/kg, 0,2g/kg, 0,26g/kg e 0,34g/kg por um período de 4, 7, 9 e 30 dias. Após três a sete dias de ingestão das inflorescências infectadas, quatro dos cinco bovinos apresentaram diarreia e manifestaram taquicardia, taquipneia e hipertermia em algum período durante a ingestão. Estes sinais coincidiram com os dias mais quentes deste período. Um bovino manifestou hiperemia na coroa do casco e perda de pêlos da extremidade da cauda. Baseado na reprodução experimental é possível afirmar que o capim Sporobolus indicus infectado pelo fungo Bipolaris sp é capaz de causar diarreia, hipertermia, taquicardia, taquipneia, hiperemia na coroa do casco e perda de pêlos da extremidade da cauda.(AU)

Claviceps purpurea is the fungus associated with ergotism. Ergotism is a disease caused by the ingestion of esclerodios called ergot, which contains alkaloids that act on dopaminergic and adrenergic receptors, causing seratoninergic effect on blood vessels, smooth muscles and central nervous and autonomic system. The present study describes epidemiological data, clinical signs and lesions of a bovine cattle disease characterized by hyperthermia, tachycardia, tachypnea and injuries in the coronary band of the hooves. Initially the cause was attributed to the fungus Claviceps purpurea. Between 2000 and 2014, 13 outbreaks were described, being three of distermic form, seven of gangrenous and three of the convulsive form. However, in five out of the seven of the gangrenous form outbreaks, it has been observed a high incidence of smut grass (Sporobolus indicus) inflorescences infected by a blackened fungus, classified as Bipolaris sp., in the places where the bovine grazed. The disease was reproduced experimentally by administration of inflorescences of smut grass contaminated by Bipolaris sp. Five bovine received daily doses of 0.1g/kg, 0.2g/kg, 0.2g/kg, 0.26g/kg and 0.34g/kg during 4, 7, 9, 30 and 30 days respectively. After three to seven days of eating contaminated inflorescences four cattle had diarrhea, tachycardia, tachypnea and intermittent hyperthermia. These clinical signs happened on the warmest days and during the warmest temperatures of the day. A bovine showed hyperemia in the coronary band of the hoof and loss of tail tip hair. According to data obtained during the experimental reproduction, smut grass contaminated by Bipolaris sp. can cause hyperthermia, tachycardia, tachypnea, injuries in the coronary band of the hoof and loss of the tail tip hair in bovine cattle.(AU)

Nine draft genome sequences of Claviceps purpurea s.lat., including C. arundinis, C. humidiphila, and C. cf. spartinae, pseudomolecules for the pitch canker pathogen Fusarium circinatum, draft genome of Davidsoniella eucalypti, Grosmannia galeiformis, Quambalaria eucalypti, and Teratosphaeria destructans.

This genome announcement includes draft genomes from Claviceps purpurea s.lat., including C. arundinis, C. humidiphila and C. cf. spartinae. The draft genomes of Davidsoniella eucalypti, Quambalaria eucalypti and Teratosphaeria destructans, all three important eucalyptus pathogens, are presented. The insect associate Grosmannia galeiformis is also described. The pine pathogen genome of Fusarium circinatum has been assembled into pseudomolecules, based on additional sequence data and by harnessing the known synteny within the Fusarium fujikuroi species complex. This new assembly of the F. circinatum genome provides 12 pseudomolecules that correspond to the haploid chromosome number of F. circinatum. These are comparable to other chromosomal assemblies within the FFSC and will enable more robust genomic comparisons within this species complex.

A Concise History of Mycotoxin Research.

Toxigenic fungi and mycotoxins entered human food supplies about the time when mankind first began to cultivate crops and to store them from one season to the next, perhaps 10,000 years ago. The storage of cereals probably initiated the transition by mankind from hunter-gatherer to cultivator, at the same time providing a vast new ecological niche for fungi pathogenic on grain crops or saprophytic on harvested grain, many of which produced mycotoxins. Grains have always been the major source of mycotoxins in the diet of man and his domestic animals. In the historical context, ergotism from Claviceps purpurea in rye has been known probably for more than 2000 years and caused the deaths of many thousands of people in Europe in the last millennium. Known in Japan since the 17th century, acute cardiac beriberi associated with the consumption of moldy rice was found to be due to citreoviridin produced by Penicillium citreonigrum. This toxin was believed to be only of historic importance until its reemergence in Brazil a few years ago. Other Penicillium toxins, including ochratoxin A, once considered to be a possible cause of Balkan endemic nephropathy, are treated in a historical context. The role of Fusarium toxins in human and animal health, especially T-2 toxin in alimentary toxic aleukia in Russia in the 1940s and fumonisins in equine leucoencephalomalasia, is set out in some detail. Finally, this paper documents the story of the research that led to our current understanding of the formation of aflatoxins in grains and nuts, due to the growth of Aspergillus flavus and its role, in synergy with the hepatitis B virus, in human liver cancer. During a period of climate change and greatly reduced crop diversity on a global basis, researchers tasked with monitoring the food system need to be aware of fungal toxins that might have been rare in their working careers that can reappear.

Ergotism: Case Report and Review of the Literature.

A case of ergotism is presented to illustrate the role of duplex ultrasonography in the diagnosis and management of this nonatherosclerotic cause of peripheral arterial disease. Historical aspects of ergotism are discussed together with reference to the relative vulnerability of different segments of the arterial circulation. Our case emphasizes the potential for complete reversibility of the vascular changes if recognized early.

Ergotismo del sistema nervioso central: Reporte de dos muertes maternas asociadas a vasoespasmo cerebral por medicamentos derivados del ergot en Antioquia, Colombia, y revisión de la literatura / Ergotism of the central nervous system: Report of two maternal deaths associated with cerebral vasospasm due to ergot-derived drugs in Antioquia, Colombia, and review of the literature

Objetivo: presentar dos casos de muerte materna asociados al uso de medicamentos derivados del ergot (ergotismo agudo severo), y realizar una revisión de la literatura de la presentación de eventos adversos en el sistema nervioso central en puérperas expuestas a estos medicamentos. Materiales y métodos: se presentan dos casos de muerte materna posparto, el primero se asoció al uso de bromocriptina para supresión de lactancia y el segundo al uso metilergometrina para controlar hemorragia poscesárea. Las pacientes fueron atendidas en instituciones de tercer nivel de complejidad en la ciudad de Medellín, Colombia. Se realizó revisión de la literatura, registrada en la base de datos Medline vía PubMed. Los términos empleados para la búsqueda fueron: derivados del ergot, bromocriptina, angeítis cerebral posparto, ergotismo, enfermedad vascular cerebral posparto. Se buscaron, sin límite de tiempo, reportes de caso, reportes de series de caso y revisiones de tema. Se buscaron informes o alertas de seguridad de agencias reguladoras tales como: la Federal Drugs Administration (FDA), la European Medicines Agency (EMA) y del Instituto Nacional de Vigilancia de Medicamentos y Alimentos (Invima). Se consultaron artículos en inglés, francés y español. Resultados: se incluyeron 16 publicaciones que cumplieron con los criterios de búsqueda. Se lograron identificar 33 casos. Dos fueron fatales, uno asociado al uso de metilergonovina venosa para el alumbramiento y el otro a ergometrina oral usado como abortivo en la semana 20 de gestación. En las neuroimágenes predominan los hallazgos isquémicos (sugestivos de vasoespasmo cerebral). En tres casos se reportó hemorragia intracerebral, uno de estos fue un caso fatal. Los síntomas más frecuentes de presentación fueron la cefalea intensa, seguida de la convulsión. Solo en nueve casos se logró identificar el antecedente de hipertensión o preeclampsia, y en cuatro migraña. La indicación para el uso de bromocriptina en todos los casos fue suprimir la lactancia. En los tres casos reportados en que se usó metilergonovina fue para realizar alumbramiento. En el sistema de farmacovigilancia colombiano no se encontraron reportes de eventos adversos serios asociados a estos medicamentos. Conclusión: se debe reconocer el ergotismo del sistema nervioso central en el puerperio por el uso de medicamentos tales como la bromocriptina y la metilergonovina, como una entidad potencialmente fatal. Es importante crear una cultura de reporte de eventos adversos serios de estos medicamentos en nuestro país.

Objective: To report two cases of maternal death associated with ergot-derived drugs (acute sever ergotism), and to conduct and review of the literature on central nervous system adverse events during the postpartum period in women exposed to these medications. Materials and methods: Two cases of maternal death during the postpartum period. The first was associated with the use of bromocriptine for breast milk suppression, and the second was associated with the use of methylergometrine for the control of bleeding after Cesarean section. The patients received care at Level III institutions in the city of Medellín, Colombia. A review of the literature was conducted in the Medline database through Pubmed. The terms used for the search were: ergot derivatives, bromocriptine, postpartum cerebralangiitis, ergotism, postpartum cerebral vascular disease. The search was conducted without a time limitation and included, case reports, case series reports, and reviews. The search also included safety reports or alerts from regulatory agencies such as the FDA, the European Medicines Agency (EMA), and Invima. Articles in English, French and Spanish were reviewed. Results: Overall, 16 publications that met the search criteria were included, and 33 cases were identified. Two of the cases were fatal, one associated with the use of intravenous methylergonovine for delivery and the second one was associated with the use of oral ergometrine to induce abortion at 20 weeks of gestation. Neuroimaging studies show, predominantly, ischemic findings (suggestive of cerebral vasospasm). In three cases, intracranial haemorrhage was reported, and one of the three cases was fatal. The most frequent presenting symptoms were intense headache, followed by seizures. It was possible to identify a history of hypertension and/or preeclampsia only in nine cases, and a history of migraine in four. The vast majority of patients were otherwise healthy. In all the cases, the indication for using bromocriptine was breast milk suppression. In the three reported cases in which methylergonovine was used, the indication was to assist delivery. No reports of serious adverse events associated with these drugs were found in the Colombian pharmacovigilance system. Conclusion: Ergotism of the central nervous system due to the use of drugs such as bromocriptine and methylergonovine must be recognised during the postpartum period because it is life-threatening. It is important to create a culture of reporting of serious adverse events associated with these medications in our country.

Ergotismo por uso simultáneo de ergotamínico y terapia antirretroviral: Report of one case / Ergotism due to simultaneous use of ergot alkaloids and high activity antiretroviral therapy

High activity antiretroviral therapy may exacerbate the activity of ergot alkaloids due to an inhibition of cytochrome P450. We report a 57 years old female with AIDS treated with lamivudine, zidovudine, atazanavir, ritonavir and cotrimoxazole presenting with ischemic signs in the four limbs. There was acrocyanosis and weak radial and ulnar pulses. A family member referred that the patient used ergot alkaloids for headaches. An ergotism due to the simultaneous use of ergot alkaloids and antiretroviral therapy was suspected. The latter was discontinued and intravenous nitroglycerin, nifedipine and pentoxifyline were started with good results.

Case Series of HIV Infection-Associated Arteriopathy: Diagnosis, Management, and Outcome Over a 5-Year period at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University.

Patients infected with human immunodeficiency virus (HIV) can present with 4 pathology types: drug-induced vasospasm (ergotism), arterial limb ischemia, critical limb ischemia, and aneurysm. Although these problems are common vascular problems, they result in increased morbidity and mortality in HIV-infected patients, especially aneurysm. Patients with these problems tend to be diagnosed with difficulty because of atypical symptoms and signs. Because of lack of data in treatment outcome literature, our report explores and provides information on HIV infection-related arteriopathy. There were 17 patients in our 5-year review. There was no death in patients except the aneurysm type. The survival of aneurysm patients was significantly lower than from other pathologies (P = .003). Our case series showed good short-term outcome, and patients were not at risk for less beneficial surgical procedures.

Cases of ergotism in livestock and associated ergot alkaloid concentrations in feed.

Ergot-induced disease in humans was known long before Biblical times and has been the root cause for countless human epidemics spanning from the early fourteenth century to the late sixteenth century. In contrast, many of these same ergot alkaloids have been utilized for their medicinal properties to mitigate migraine headaches and have had indications as anti-carcinogens. Although ergot alkaloids have been used for centuries by humans, basic pharmacokinetic data has not been documented for clinical disease in livestock. Consequently, a threshold dose and accurate dose-response data have yet to be established. Throughout the past several years, new detection techniques have emerged to detect these alkaloids at the parts per billion (ppb) level which has allowed for new efforts to be made with respect to determining threshold levels and making accurate clinical diagnoses in affected animals. This perspectives article provides a critical initial step for establishing a uniform interpretation of ergot toxicosis from limited existing data.

A systematic review and meta-analysis assessing adverse event profile and tolerability of nicergoline.

OBJECTIVE: To evaluate the safety profile of nicergoline compared with placebo and other active agents from published randomised controlled trials. DESIGN: Systematic review and meta-analysis of nicergoline compared with placebo and other active agents across various indications. DATA SOURCES: MEDLINE, Medline-in-process, Cochrane, EMBASE, EMBASE alerts, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR) and Cochrane Methodology Register (CMR) for all the randomised controlled trials, open-label or blinded, in adults treated with nicergoline. Studies published until August 2013 were included. REVIEW METHOD: 29 studies were included for data extraction. The studies included in this review were majorly from European countries and mostly in cerebrovascular disease (n=15) and dementia (n=8). RESULTS: The treatment withdrawals were comparatively lower in the nicergoline group as compared with the placebo group (RR=0.92; 95% CI 0.7 to 1.21) and other active comparators (RR=0.45; 95% CI 0.10 to 1.95), but the difference was non-significant. Incidence of any adverse events (AEs) was slightly higher (RR=1.05; 95% CI 0.93 to 1.2) while incidence of serious AEs was lower (RR=0.85; 95% CI 0.50 to 1.45) in the nicergoline compared with placebo group. Frequency of anxiety was significantly lower in nicergoline as compared with placebo (p=0.01). Other AEs including diarrhoea, gastric upset, dizziness and drowsiness were less frequent in the nicergoline group when compared with placebo/active drugs, but the difference was non-significant. Frequency of hypotension and hot flushes was slightly higher in the nicergoline group but the difference was non-significant. None of the studies reported any incidence of fibrosis or ergotism with nicergoline treatment. CONCLUSIONS: Nicergoline is an ergot derivative, but its safety profile is better than other ergot derivatives like ergotamine and ergotoxine. This systematic review and meta-analysis suggests that nicergoline has a good safety profile. None of the studies included in this systematic review reported any incidence of fibrosis or ergotism with nicergoline.

Ergotism and factitious hypotension associated with interaction of ergotamine with CYP3A4 inhibitors.

BACKGROUND: Although uncommon, severe ergotism continues to occur. The purpose of this study is to describe causes and clinical effects of ergotism in recent years. METHODS: This is an observational case series with data obtained retrospectively from all patients with ergotism referred to Ramathibodi Poison Center in Bangkok, Thailand from January 2006 to August 2013. RESULT: Twelve cases of ergotism were identified. All cases involved ergotamine 1 mg/caffeine 100 mg combination tablets. Nine cases (75%) were precipitated by drug-drug interactions with CYP3A4 inhibitors. The other cases involved suicidal attempt (2 cases) and pediatric unsupervised ingestion (1 case). Ten patients (83%) had signs of peripheral vascular insufficiency. Five of these patients initially had factitiously low or unmeasurable blood pressure using non-invasive technique and had paradoxical increase following intravenous vasodilator administration. Two patients required partial foot amputations due to gangrene. Two patients, including a 15-month-old boy with an unsupervised ingestion, died. DISCUSSION: In this series, most cases of severe ergotism were associated with interaction with CYP3A4 inhibitors, which increase ergotamine bioavailability. Factitious low blood pressure in these cases was likely caused by severe vasospasm. CONCLUSION: Critical ergotism continues to occur in Thailand, most commonly associated with the drug-drug interactions.

Mycotoxicoses of ruminants and horses.

In the current study, mycotoxicoses of ruminants and horses are reviewed, with an emphasis on the occurrence of these diseases in South America. The main mycotoxicoses observed in grazing cattle include intoxications by indole-diterpenoid mycotoxins (Paspalum spp. contaminated by Claviceps paspali, Lolium perenne infected by Neotyphodium lolii, Cynodon dactylon infected by Claviceps cynodontis, and Poa huecu), gangrenous ergotism and dysthermic syndrome (hyperthermia) caused by Festuca arundinacea (syn. Festuca elatior) infected by Neotyphodium coenophialum (syn. Acremonium coenophialum), and photosensitization in pastures contaminated by toxigenic Pithomyces chartarum. Other mycotoxicoses in grazing cattle include slaframine toxicity in clover pastures infected by Rhizoctonia leguminicola and diplodiosis in cattle grazing in corn stubbles. The mycotoxicoses caused by contaminated concentrated food or byproducts in cattle include poisoning by toxins of Aspergillus clavatus, which contaminate barley or sugar beetroot by-products, gangrenous ergotism or dysthermic syndrome caused by wheat bran or wheat screenings contaminated with Claviceps purpurea, and acute respiratory distress caused by damaged sweet potatoes (Ipomoea batatas). The main mycotoxicosis of horses is leukoencephalomalacia caused by the fumonisins B1 and B2 produced by Fusarium spp. Poisoning by C. purpurea and F. elatior infected by N. coenophialum has also been reported as a cause of agalactia and neonatal mortality in mares. Slaframine toxicosis caused by the ingestion of alfalfa hay contaminated by R. leguminicola has also been reported in horses.