Association Between Migraine and Ischemic Cardio-Cerebrovascular Disease (CCVD) and Effects of Triptans and Ergotamine on the Risk of Ischemic CCVD in Patients with Migraine in the Korean NHIS-HEALS Cohort.

BACKGROUND AND OBJECTIVES: Triptans and ergotamine are commonly used to treat migraine, a risk factor for ischemic stroke. This study aimed to investigate the association between migraine and ischemic cardio-cerebrovascular disease (CCVD). Further analyses were performed to examine whether symptom-relieving treatment of migraine with triptans and ergotamine reduces ischemic CCVD in migraineurs. METHODS: Participants from the Korean NHIS-HEALS cohort database were divided into patients reporting headache without migraine (HA), migraineurs who received at least one prescription for triptans or ergotamine (TE), and migraineurs who were prescribed neither triptans nor ergotamine (NTNE). Ischemic CCVDs comprised ischemic cerebrovascular diseases and cardiovascular diseases. Using cox proportional hazards regression models, primary and secondary analysis for risk of ischemic CCVDs was compared. RESULTS: Among 62,272 patients diagnosed with migraine or HA, men with migraine or HA numbered 14,747 and 8935, respectively, while the numbers of women were 27,836 and 10,754, respectively. The median follow-up was 6.65 years. The overall incidence rate of CCVDs was 4728/38,590 (12.25%) in females and 3158/23,682 (13.33%) in males. Compared with the HA group, the hazard ratios (HRs) (95% CIs) of the TE and NTNE groups for ischemic CCVDs were 1.18 (1.01-1.39) and 1.39 (1.28-1.50), respectively, in males, and 1.22 (1.09-1.37) and 1.53 (1.42-1.65), respectively, in females, after full adjustment for confounding variables. Compared with the NTNE group, the HRs (95% CIs) of the TE group for ischemic CCVDs were 0.86 (0.73-0.999) in males and 0.80 (0.72-0.88) in females. CONCLUSIONS: Migraine increased the risk of ischemic CCVDs in both sexes, and migraineurs treated with triptans and ergotamine were at lower risk of ischemic CCVDs than migraineurs who did not take those medications, especially in women.

Acute Ischemia of Lower Extremities Caused by Ergotamine Toxicity due to Pharmacologic Interaction With Cobicistat in an HIV-Positive Patient.

Ergotism is an uncommon condition that affects patients with exposure to ergot alkaloids causing ischemia of extremities. We report the case of lower extremities ischemia caused by ergot toxicity in a human immunodeficiency virus (HIV) positive individual due to the interaction between ergot alkaloid and Cobicistat. In addition, we present a brief review of medical, and pharmacological aspects of this condition. To our knowledge, this is the second reported case describing this interaction.

Treatment with potassium bromide mitigates ataxia and reduces tremor in lambs with perennial ryegrass toxicosis.

Aims: To assess the use of potassium bromide (KBr) as a therapeutic intervention for perennial ryegrass toxicosis (PRGT) in lambs fed ryegrass seed containing lolitrem B. Methods: Male lambs aged 10-12 months (n = 43) were assigned to receive ryegrass seed containing lolitrem B, at a dose of 0.16 mg/kg/day (Groups 2, 3 and 4), or lucerne chaff and molasses (Groups 1 and 5). Lambs in Groups 2 and 3 were observed for clinical signs and gait changes until defined signs of PGRT were observed, when they were transferred, with lambs in Group 1, to the Testing phase of the trial. Lambs in Group 3 were then treated with a single oral dose of 300 mg/kg bromide. Lambs in Groups 4 and 5 received KBr daily from the start of the trial (540 mg/kg bromide over 3 days then 20 mg/kg daily) and were transferred to the Testing phase after 18 days. Clinical examination and gait assessment, and surface electromyography of the triceps muscle, measuring root-mean-square (RMS) voltages, were carried out on Days 0, 1 and 2 of the Testing phase followed by necropsy, histopathology, measurement of concentrations of bromide in serum and CSF and faecal cortisol metabolites (FCM). Results: In Group 3 lambs, mean composite gait scores decreased between Testing phase Day 0 and Days 1 and 2 (p < 0.001), but increased in lambs in Group 2 between Day 0 and Day 2 (p = 0.015). Scores for lambs in Group 3 on Day 2 were lower than for lambs in Group 2 (p < 0.001). Mean RMS voltages on Day 2 were higher in lambs in Group 2 than Group 3 (p = 0.045). Mean concentrations of bromide in serum were >800 µg/mL in lambs in Groups 3 and 4 on Day 2. Concentrations of FCM were higher in lambs from Group 2 than in Groups 1 or 5, but were similar in Groups 2, 3 and 4. Histopathological findings in the cerebellum of lambs from Groups 2, 3 and 4 were similar, showing pyknosis of neurons within the granular layer of the cerebellum and Purkinje neuron proximal axonal spheroid formation. Conclusions and clinical relevance: A single oral dose of 300 mg/kg bromide in lambs with neurological signs of PRGT resulted in reduced composite gait scores and reduced RMS voltages, indicating a significant improvement in clinical signs of ataxia, movement disorder and muscle tremor associated with the neurotoxic effects of lolitrem B.

Acute coronary syndrome with elevation of ST associated with ergotamine abuse.

There are few case reports of cases of carotid and aortic dissection related to the ergotamine abuse, but the cases that affect the coronary arteries is a very rare coronary. We present a patient of a 48-year-old female with an ST-segment elevation myocardial infarction attributable to chronic ergotamine use. The coronary angiography showed dissection of right coronary artery proximal.

Headache in an HIV-Positive Patient: Dangerous Interaction.

Ergotism is an ischaemic complication due to vasoconstriction throughout the body due to ingestion of ergotamine. A 34-year-old Hispanic man with HIV infection treated with saquinavir, ritonavir and abacavir/lamivudine presented to the emergency department complaining of left foot pain 1 week prior to admission. The affected extremity was cold with absence of pedal and tibial pulses. Arterial Doppler revealed absent arterial flow from the popliteal artery later confirmed by arteriography. Medication reconciliation revealed a recent prescription for migraine headache containing ergotamine. Drug was discontinued and the patient was started on cilostazol, enoxaparin and nitroglycerin patches on the affected limb. Complete resolution of symptoms and arteriography findings occurred 2 days after therapy began.

Development of a model for investigation of perennial ryegrass toxicosis in sheep.

AIMS To develop a clinical model of perennial ryegrass toxicosis (PRGT) based on feeding a known dose of lolitrem B and ergotamine, and to produce a consistent clinical presentation for assessment of disease pathophysiology, neurological changes and neurohistopathology. METHODS Male lambs, aged between 10-12 months, were randomly assigned to either Treatment (n=9) or Control (n=9) groups. Lambs in the Treatment group received feed containing a novel endophyte-infested perennial ryegrass seed, commencing on Day 0 of the Feeding phase with a low induction dose, then increasing after 3 days to provide 0.16 mg/kg live bodywight (LBW)/day of lolitrem B and 0.054 mg/kg LBW/day ergotamine. Lambs were examined daily and when defined signs of PRGT were observed they were transferred to the Testing phase. Neurological examinations, assessment of gait, surface electromyography (EMG) and mechanosensory nociceptive threshold testing were carried out and blood samples collected during both phases of the trial, with a full necropsy, histopathological examination and measurement of faecal cortisol metabolites (FCM) performed on Day 2 of the Testing phase. RESULTS Typical clinical signs of PRGT, including ataxia of vestibulocerebellar origin leading to stumbling, were observed in all Treatment lambs. The median interval from the start of the Feeding phase to entry into the Testing phase was 21 (min 18, max 34) days. Histopathological characterisation of neurological lesions included the presence of Purkinje cell vacuolation, pyknotic granular layer neurons and proximal axonal Purkinje cell spheroids. Lesions were most apparent within the vestibulocerebellum. Mean root-mean-square voltages from triceps EMG increased in Treatment lambs between Feeding phase Day 0 and Testing phase Day 2 (p<0.001). Daily water intake during the Testing phase for the Treatment group was less than in Control group lambs (p=0.002), and concentrations of FCM at necropsy were higher in Treatment compared to Control lambs (p=0.02). CONCLUSIONS AND CLINICAL RELEVANCE Lolitrem B and ergotamine dosing in feed on a live weight basis combined with neurological/gait assessment provides an effective model for investigation of PRGT and potential therapeutics. Assessment of gait changes using defined criteria and RMS voltages from EMG appear to be useful tools for the assessment of the severity of neurological changes.

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)

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.

Isquemia de miembros inferiores secundaria a ergotamina. Reporte de casos y revisión de literatura / Lower limb ischaemia secondary to ergotamine. Case reports and a review of the literature

El ergotismo es en la actualidad un trastorno raro, asociado a la administración iatrogénica de ergotamina en pacientes que padecen de cefaleas migrañosas. La intensidad del vasoespasmo que presenta esta entidad clínica en la mayoría de los casos resulta en isquemia aguda de las extremidades. Presentamos 2 casos de isquemia aguda de las extremidades, en pacientes de sexo femenino, de mediana edad, con signos y síntomas que amenazaban la viabilidad de los miembros inferiores. El estudio por ultrasonido y la arteriografía (en el caso 1) confirmaron la presencia de espasmo arterial bilateral difuso. Inmediatamente se procedió a interrumpir la administración de ergotamina y se instauró terapia vasodilatadora. Los síntomas de las pacientes empezaron a mejorar a las 48-72 h de iniciado el tratamiento (AU)

Ergotism is a rare disorder associated with the iatrogenic administration of ergotamine in patients with migraine headaches. The intense vasospasm that occurs in this clinical condition results in acute limb ischaemia in the majority of cases. Two cases are presented of acute limb ischaemia in middle age female patients with signs and symptoms that threatened the viability of lower limbs. Duplex ultrasound and arteriography (in the first case) confirmed the presence of a bilateral diffuse arterial spasm. Ergotamine treatment was discontinued immediately and vasodilator therapy was administered. The patient's symptoms began to improve 48-72 h after starting therapy (AU)

Acute leg ischaemia in an HIV-infected patient receiving antiretroviral treatment.

An HIV-infected patient treated with tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat developed severe acute ischaemia of both legs during a migraine episode. After being interrogated he admitted taking an ergotamine-containing preparation. Ergotism due to interaction between ergotics and cobicistat was diagnosed. We describe the first reported case of this interaction.

Ergotamine-Induced Takotsubo Cardiomyopathy.

Takotsubo cardiomyopathy (TC) is a recently increasing diagnosed disease showed by transient apical or mid-apical left ventricular dysfunction. It is known as a disease of postmenopausal women, which is usually triggered by emotional or physical stress. Although the trigger is mostly endogenous, some drugs have also been reported as the cause. Published case reports of TC associated with drug usage consist of sympathomimetic drugs, inotropic agents, thyroid hormone, cocaine, and 5-fluorouracil. We present an unusual case of TC in which the possible trigger is ergotamine toxicity.

Proctitis química por ergotamina: «no siempre es una colitis ulcerosa» / Chemical proctitis due to ergotamine: «not always an ulcerative colitis»

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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.