Vasoactive Effects of Acute Ergot Exposure in Sheep.

Ergotism is a common and increasing problem in Saskatchewan's livestock. Chronic exposure to low concentrations of ergot alkaloids is known to cause severe arterial vasoconstriction and gangrene through the activation of adrenergic and serotonergic receptors on vascular smooth muscles. The acute vascular effects of a single oral dose with high-level exposure to ergot alkaloids remain unknown and are examined in this study. This study had two main objectives; the first was to evaluate the role of α1-adrenergic receptors in mediating the acute vasocontractile response after single-dose exposure in sheep. The second was to examine whether terazosin (TE) could abolish the vascular contractile effects of ergot alkaloids. Twelve adult female sheep were randomly placed into control and exposure groups (n = 6/group). Ergot sclerotia were collected and finely ground. The concentrations of six ergot alkaloids (ergocornine, ergocristine, ergocryptine, ergometrine, ergosine, and ergotamine) were determined using HPLC/MS at Prairie Diagnostic Services Inc., (Saskatoon, SK, Canada). Each ewe within the treatment group received a single oral treatment of ground ergot sclerotia at a dose of 600 µg/kg BW (total ergot) while each ewe in the control group received water. Animals were euthanized 12 h after the treatment, and the pedal artery (dorsal metatarsal III artery) from the left hind limb from each animal was carefully dissected and mounted in an isolated tissue bath. The vascular contractile response to phenylephrine (PE) (α1-adrenergic agonist) was compared between the two groups before and after TE (α1-adrenergic antagonist) treatment. Acute exposure to ergot alkaloids resulted in a 38% increase in vascular sensitivity to PE compared to control (Ctl EC50 = 1.74 × 10-6 M; Exp EC50 = 1.079 × 10-6 M, p = 0.046). TE treatment resulted in a significant dose-dependent increase in EC50 in both exposure and control groups (p < 0.05 for all treatments). Surprisingly, TE effect was significantly more pronounced in the ergot exposed group compared to the control group at two of the three concentrations of TE (TE 30 nM, p = 0.36; TE 100 nM, p < 0.001; TE 300 nM, p < 0.001). Similar to chronic exposure, acute exposure to ergot alkaloids results in increased vascular sensitivity to PE. TE is a more potent dose-dependent antagonist for the PE contractile response in sheep exposed to ergot compared to the control group. This study may indicate that the dry gangrene seen in sheep, and likely other species, might be related to the activation of α1-adrenergic receptor. This effect may be reversed using TE, especially at early stages of the disease before cell death occurs. This study may also indicate that acute-single dose exposure scenario may be useful in the study of vascular effects of ergot alkaloids.

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 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.

Ergotism: a change of persepective.

Clinical ergotism is a rare disorder, and clinical and therapeutic implications have continued to attract attention. The Holy Fire or St. Anthony's Fire was the primary vascular manifestation, causing burning pain and gangrene in the feet and hands related to the arterial spasm properties of ergot. The chronic use of ergotamine and migraine has also been associated with ergotism. Severe vasospasm and acute peripheral ischemia of the extremities can develop. However, in modern times, the spectrum of poisoning by alkaloids has broadened to include antiviral therapies in patients with HIV and abuse of stimulants. These changes have made taking an accurate medical history and conducting an accurate detailed differential diagnosis more essential. The purpose of this review is to highlight the importance of ergotism as a cause of peripheral vascular ischemia and analyze changes associated with this poisoning.

Growing steers grazing high versus low endophyte (Neotyphodium coenophialum)-infected tall fescue have reduced serum enzymes, increased hepatic glucogenic enzymes, and reduced liver and carcass mass.

It is well established that grazing Neotyphodium coenophialum-infected forages results in reduced BW gain and serum prolactin concentrations of cattle. The objective of this study was to determine the potential effects of toxic endophyte-infected tall fescue consumption on blood metabolites, carcass characteristics, and content of proteins critical for AA metabolism in the liver, kidney, and LM tissue of growing steers. Steers grazed a low toxic endophyte (LE; 0.023 microg/g ergot alkaloids) tall fescue-mixed grass pasture (n = 9; BW = 266 +/- 10.9 kg; 5.7 ha) or a high toxic endophyte (HE; 0.746 microg/g of ergot alkaloids) tall fescue pasture (n = 10; BW = 267 +/- 14.5 kg; 5.7 ha) from June 14 through at least September 11 (> or =89 d). No difference was observed for BW (P < 0.10) for the overall 85-d growth period. Also, no differences were observed for ribeye area/100 kg of HCW (P > 0.91), backfat (P > 0.95), or backfat/100 kg of HCW (P > 0.67). However, ADG (P < 0.01), final BW (P < 0.05), HCW (P < 0.01), dressing percentage (P < 0.01), ribeye area (P < 0.01), whole liver wet weight (P < 0.01), and whole liver wet weight/100 kg of end BW (P < 0.01) were greater for LE steers than HE steers. After 85 d of grazing, serum concentrations of alkaline phosphatase (P < 0.05), alanine aminotransferase (P < 0.01), aspartate aminotransferase (P < 0.03), cholesterol (P < 0.01), lactate dehydrogenase (P < 0.01), and prolactin (P < 0.01) were less for HE than LE steers. At slaughter, hepatic content of cytosolic phosphoenolpyruvate carboxykinase (P < 0.01) was greater in HE steers than LE steers. Hepatic content of aspartate aminotransferase (P < 0.01) also was greater, whereas renal and LM content were not (P > or = 0.42). No differences (P > or = 0.15) were observed for hepatic, renal, and LM content of alanine aminotransferase, glutamate dehydrogenase, glutamine synthetase, and 3 glutamate transport proteins. These data indicate that the HE steers displayed classic endophyte toxicity symptoms for growth and blood variables, classic symptoms that were concomitant with novelly identified altered glucogenic capacity of the liver and decreases in carcass characteristics.

Highly specific quantification of ergotamine in urine, blood, and hair samples by liquid chromatography-tandem mass spectrometry.

Ergotamine has been used for therapeutic purposes since the 1950s, usually to treat vascular headache. It is highly toxic and in large, repeated doses can produce all the symptoms of ergot poisoning. A selective and sensitive method, based on liquid chromatography-tandem mass spectrometry (LC-MS2), has been developed for quantifying ergotamine in biological fluids with use of a quick and easy sample preparation. Ergotamine and the internal standard, trideuterated lysergic acid diethylamide, were extracted from human urine, blood, and hair by means of liquid-liquid extraction at alkaline pH. Gradient elution on a cyanopropyl column was used for chromatographic separation. Positive ion electrospray ionization and tandem mass spectrometry determination by collision-induced dissociation were performed in an ion trap mass spectrometer. The method was validated and successfully applied to a case of iatrogenic ergotism resulting from the intake of ergotamine tartrate for treating headache. For the first time, ergotamine was identified and quantified in hair. The ergotamine concentrations measured were 320 pg/mL in blood, 100 pg/mL in urine, 24 pg/mg in proximal hair, and 15 pg/mg in distal hair.

[Ergotism. A case report and review of the literature]. / Ergotismo. Presentación de un caso y revisión de la bibliografía.

INTRODUCTION: Ergotism is characterised by an intensive generalised vasoconstriction of small and large blood vessels. The symptoms derive from the regional ischemia caused by the vasospasm produced by ergotamine. Nowadays, ergotism is almost exclusively due to the excessive ingestion of ergotamine tartrate used in the treatment of migraine. The main treatment consists in withdrawing the medication. CASE REPORT: Our study involves a 53-year-old male with a history of migraine since his youth, who was treated with ergotaminic preparations up until the day before admission to hospital. He was admitted because of a 7-day history of symptoms including bilateral and symmetrical anaesthesia of the fingers and a general feeling of weakness, associated with intense pain and cyanosis of the right thenar eminence. On admission, it was not possible to measure his AT in the upper limbs and his peripheral pulses dropped in a generalised manner. Aetiologies involving vasculitis were ruled out. An angiography study showed segmented stenosis of arteries in the upper and lower limbs. Ergotaminic agents were withdrawn and nifedipine was indicated. The symptoms disappeared, the physical examination was normal and results of a control angiography study were also normal. CONCLUSIONS: Ergotamine intoxication can be detected by a thorough interview and physical examination; it should be suspected when faced with symptoms that are compatible with vasospasms and a history of ingestion of the drug, in the absence of any prothrombotic, liver, kidney or vasculitic pathology. This condition is treated by withdrawing the drug and administration of vasodilators if the symptoms are intense. In this paper, we review the history, pathophysiology, initial symptoms and signs, diagnosis and treatment of ergotamine poisoning.

Ergotismo. Presentación de un caso y revisión de la bibliografía / Ergotism. A case report and review of the literature

Introducción. El ergotismo se caracteriza por una intensa y generalizada vasoconstricción de los vasos sanguíneos pequeños y grandes. Los síntomas resultan de la isquemia regional causada por el vasoespasmo que produce la ergotamina. En la actualidad, el ergotismo resulta casi exclusivamente de la ingesta excesiva de tartrato de ergotamina para el tratamiento de la migraña. El principal tratamiento es la suspensión del fármaco. Caso clínico. Se trata de un hombre de 53 años con historia de migraña desde su juventud, tratada con ergotamínicos hasta un día antes de su ingreso. Ingresó por manifestaciones de siete días de evolución, con anestesia bilateral y simétrica de los dedos de las manos y sensación de debilidad generalizada, asociados a dolor intenso y cianosis de la eminencia tenar derecha. Cuando ingresó no fue posible medir la tensión arterial en las extremidades superiores, y sus pulsos periféricos estaban disminuidos de manera generalizada. Se descartaron etiologías de vasculitis. Una angiografía mostró estenosis segmentaria de las arterias en las extremidades superiores e inferiores. Se suspendieron los ergotamínicos y se indicó nifedipina. La sintomatología desapareció, la exploración física fue normal y una angiografía de control fue normal. Conclusiones. La intoxicación por ergotamina puede detectarse mediante un interrogatorio y exploración física completos; se debe sospechar ante manifestaciones compatibles con vasoespasmo y el antecedente de ingesta del fármaco, en ausencia de patología protrombótica o vasculítica, hepatopatía o nefropatía. El tratamiento del cuadro es con suspensión del fármaco, y vasodilatadores si las manifestaciones son intensas. En este artículo se revisa la historia, fisiopatología, síntomas y signos de presentación, diagnóstico y tratamiento de la intoxicación por ergotamina

Introduction. Ergotism is characterised by an intensive generalised vasoconstriction of small and large blood vessels. The symptoms derive from the regional ischemia caused by the vasospasm produced by ergotamine. Nowadays, ergotism is almost exclusively due to the excessive ingestion of ergotamine tartrate used in the treatment of migraine. The main treatment consists in withdrawing the medication. Case report. Our study involves a 53-year-old male with a history of migraine since his youth, who was treated with ergotaminic preparations up until the day before admission to hospital. He was admitted because of a 7-day history of symptoms including bilateral and symmetrical anaesthesia of the fingers and a general feeling of weakness, associated with intense pain and cyanosis of the right thenar eminence. On admission, it was not possible to measure his AT in the upper limbs and his peripheral pulses dropped in a generalised manner. Aetiologies involving vasculitis were ruled out. An angiography study showed segmented stenosis of arteries in the upper and lower limbs. Ergotaminic agents were withdrawn and nifedipine was indicated. The symptoms disappeared, the physical examination was normal and results of a control angiography study were also normal. Conclusions. Ergotamine intoxication can be detected by a thorough interview and physical examination; it should be suspected when faced with symptoms that are compatible with vasospasms and a history of ingestion of the drug, in the absence of any prothrombotic, liver, kidney or vasculitic pathology. This condition is treated by withdrawing the drug and administration of vasodilators if the symptoms are intense. In this paper, we review the history, pathophysiology, initial symptoms and signs, diagnosis and treatment of ergotamine poisoning

Convulsive ergotism: epidemics of the serotonin syndrome?

Between 1085 and 1927, epidemics of "convulsive ergotism" were widespread east of the Rhine in Europe due to consumption of grain contaminated with ergot, which is produced by the fungus Claviceps purpurea. West of the Rhine, consumption of ergot-contaminated food caused epidemics of gangrenous ergotism. The clinical features of convulsive ergotism--muscle twitching and spasms, changes in mental state, hallucinations, sweating, and fever lasting for several weeks--suggest serotonergic overstimulation of the CNS (ie, the serotonin syndrome). The ergot alkaloids are serotonin agonists. Dihydroergotamine binds to serotonin receptors in the dorsal horn of the spinal cord, which is the site of neuropathological changes in convulsive ergotism. Dihydroergotamine given to human beings can cause the serotonin syndrome. Ergots produced by different strains of Claviceps purpurea, and those growing in different soils, may have different ergot alkaloid compositions. An alkaloid, present in high concentrations in ergots from east of the Rhine, may have caused convulsive ergotism at a circulating concentration insufficient to produce peripheral ischaemia. The serotonin syndrome may, therefore, have been a public-health problem long before it was recognised as a complication of modern psychopharmacology.

Evidence that enforced sunlight exposure can cause hyperthermia in cattle ingesting low levels of ergot of rye (Claviceps purpurea), when air temperature and humidity conditions are only moderate.

OBJECTIVE: To determine the rectal temperature response of cattle, following the oral administration of ergot of rye (Claviceps purpurea), under pen conditions of enforced sunlight compared with those of enforced shade. DESIGN AND PROCEDURE: Hereford cross steers were divided into two groups of 18. One group was dosed once, on a Monday morning, with finely ground rye grass ergots at a rate of 180 mg/kg body weight and held in the sun for 7 h each day until Friday afternoon. The other group was not dosed but was similarly held in the sun during the same period. Their rectal temperatures were measured early morning and mid afternoon, from Monday to Friday inclusive. The process was repeated for each group, but this time they were held in the shade. The four treatment options were run concurrently by conducting the experiments over 6 weeks and using 3 animals in each treatment group, each week. RESULTS: The thermic response over all weeks, of the ergot treated, sunlight exposed cattle, was deemed greater than for the other groups, based on the following four parameters. The increase in rectal temperature between early morning and mid afternoon, the size of the mid afternoon rectal temperature rise, the difference between the maximum mid afternoon rectal temperature recorded by an animal in the sun compared with that recorded by the same animal in the shade, and finally the number of animals in a treatment group that recorded rectal temperatures > 40.00 degrees C. The difference in the daily increase in body temperature between the ergot treated, sun exposed cattle and the ergot treated, shaded cattle, was greater than that observed between the sun exposed and shade restricted control cattle. Nine of 18 ergot treated and sun exposed cattle developed hyperthermia; no cattle in the other three groups did. CONCLUSIONS: Some sunlight exposed cattle, dosed with a low amount of ergot of rye, can experience a body temperature elevation above the normal range, even under mild ambient temperature and humidity conditions. Sunlight exposure causes an increase in body temperature in normal cattle that is probably attributable to solar radiant heat. Ergot ingestion causes an increase in body temperature in shaded cattle that is probably attributable to ambient temperature and humidity effects. This response can be increased by sun exposure and this increase is attributable to solar radiant heat effects and possibly also solar radiation. A response to radiant heat is consistent with the known physiological effects of ingested ergot alkaloids, but a response to solar radiation is not.

Fescue toxicosis.

Most of the tall fescue pastures in the United States are infected by an endophyte, N. coenophialum. The fungus derives nutrients from the plant while supplying the plant with toxins for defense. The most detrimental toxins for animals in tall fescue are ergopeptine alkaloids, especially ergovaline. Ergovaline functions as a dopamine D2 agonist and alters prolactin and several other hormones in the body. Pregnant mares are most susceptible during their last month of gestation. Clinical signs include prolonged gestation, dystocia, retained placentas, agalactia, and dysmature foals that are either stillborn or weak.

[Roles of arterial dysplasia, chronic ergotism and other factors in a case multiple spontaneous arterial dissections]. / Rôles d'une dysplasie artérielle, d'un ergotisme chronique et d'autres facteurs dans un cas de dissections artérielles multiples spontanées.

INTRODUCTION: Spontaneous dissection of cervical and visceral arteries are rare and usually associated with an underlying arterial disease. EXEGESIS: The authors report the unusual case of a 50-year-old woman with high blood pressure who presented spontaneous dissection of cervico-cephalic, renal and hepatic arteries and of the descending aorta. She had been taking ergotamine tartrate for ten years for migraine. She also suffered from Raynaud's syndrome worsened by treatment. CONCLUSION: The respective roles of arterial dysplasia, chronic ergotism, renovascular hypertension and migraine are discussed.

Ergotismo: ¿iatrogenia o idiosincrasia? / Ergotism: Iatrogenic or idiosyncrasy?

El ergotismo continúa siendo una causa rara de insuficiencia arterial crónica y aguda en pacientes en edad productiva, que si no es detectada y tratada a tiempo puede causar daño neurológico permanente o pérdida de la extremidad y como consecuencia invalidez del paciente. En un lapso de dos años se recibieron en el servicio cuatro pacientes con diagnóstico de ergotismo, tres mujeres y un hombre, se manejaron con interrupción de la ergotamina, vasodilatadores y dos de ellos con simpatectomía lumbar; dos de los pacientes presentaron secuelas y determinar si el ergotismo es una iatrogenia causada por el uso prolongado de este medicamento

Injection of a dopamine antagonist into Holstein steers to relieve symptoms of fescue toxicosis.

Two experiments were conducted to determine whether administering a dopamine antagonist to steers fed endophyte-infected (E+) tall fescue would increase serum prolactin (PRL) and reduce rectal temperature. Steers in both experiments were housed in environmentally controlled chambers (32 degrees C; 50% relative humidity). In Exp. 1, 10 steers were allotted randomly to receive s.c. injections of either 0, .006, .03, or .06 mg of Ro 24-0409 (dopamine antagonist)/kg BW. The experiment was designed in four phases: endophyte-free seed (E-) without antagonist (d -11 to 0); E- with antagonist (d 0 to 7); E+ with antagonist (d 7 to 28); E+ without antagonist (d 28 to 38). In Exp. 2, 22 Holstein steers were allotted randomly to the same treatments and design, except three steers were maintained on E- without antagonist. Steers were fed individually with intakes measured daily. In Exp. 1, feed intake and rectal temperature were not improved (P > .05) by antagonist injection. In Exp. 2, antagonist injections increased (P < .05) PRL. Ingestion of E+ decreased (P < .05) feed intake and serum PRL. Antagonist injection decreased (P < .05) rectal temperature and increased (P < .05) serum PRL.

Effect of ergotamine and ergonovine on thermal regulation and cardiovascular function in cattle.

Research was conducted to determine whether individual ergot alkaloids could induce signs of fescue toxicosis. Nine Angus heifers received single i.v. injections of ergotamine tartrate, ergonovine maleate, and saline vehicle in a simple cross-over design. Each heifer received a different compound each week and all treatments during the study. Physiological traits measured 15 min before and 30, 60, and 90 min after treatment were respiration rate, rectal and skin temperatures, systolic and diastolic pressures, and heart rate. Blood samples were collected 5 min before and 105 min after treatments to assess plasma prolactin concentrations. Heifers were on a fescue-free diet in drylot. Ambient temperature averaged 35 degrees C during data collection. A treatment x time interaction existed (P < .05) for respiration rate and prolactin concentrations. Ergot alkaloids altered (P < .05) all traits across time, except rectal temperature. Heifers under the influence of ergot alkaloids exhibited significantly lower skin temperature, heart rate, and prolactin and had higher respiration rate and blood pressure. Results indicated that individual ergot alkaloids administered i.v. induced signs of fescue toxicosis in cattle.

Ergotismo: diagnóstico y tratamiento. Revisión de la literatura e informe de un caso clínico / Diagnosis and treatment of ergotism in a patient. Review of the literature and a clinical case report

Presentamos la historia clínica de un paciente del sexo masculino de 53 años con datos francos de isquemia en extremidades asociado con el consumo de antimigrañosos. Con el tratamiento médico desaparecen los sintomas y signos de isquemia. Demostramos como método diagnóstico la arteriografía previa y de control, los hallazgos característicos descritos en la literatura, así como el uso de ultrasonido Doppler color, no descrito con anterioridad

Milk production in Angus, Brahman, and reciprocal-cross cows grazing common bermuda grass or endophyte-infected tall fescue.

Milk yield and quality were measured on 139 Angus, Brahman, and reciprocal-cross cows grazing common bermuda grass or endophyte-infected tall fescue for 4 yr to evaluate interactions of direct and maternal breed effects and heterosis for these traits with forage environment. Milk yield was estimated by method of milking machine, and milk fat, protein, and somatic cell counts were evaluated in a commercial dairy laboratory. Monthly estimates were made beginning on an average d 61 of lactation and continued monthly for six estimates in 3 yr and five estimates in 1 yr. Data were averaged over month within year, and the model included sire breed, sire in sire breed, dam breed, forage, and age averages. Somatic cell counts were transformed using natural logarithms prior to analyses. Forage effects for milk yield were dissimilar among sire breed x dam breed subclasses (P < .10), resulting in higher levels of heterosis on common bermuda grass than on tall fescue. Maternal breed effects for milk yield favored Angus on bermuda grass (P < .05) but not on tall fescue, whereas direct breed effects were similar on both forages and favored Brahman. Milk fat was reduced on tall fescue compared to bermuda grass by an average of .6% (P < .01), and direct breed effects were similar across forages and averaged 1.04% (P < .01) in favor of Brahman. Heterosis and maternal breed effects for milk fat were not important. There was little evidence of direct and maternal breed effects or heterosis for milk protein or somatic cell counts. These data suggest that heterosis for milk yield is larger on common bermuda grass than on tall fescue and that grazing endophyte-infected tall fescue is detrimental to milk fat.