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PubMed1998

Urinary and biliary excretion of ergot alkaloids from steers that grazed endophyte-infected tall fescue.

Ergot alkaloids cause fescue toxicosis when livestock graze endophyte-infected (E+) tall fescue. Little is known about the bioavailability of the ergot alkaloid classes (lysergic acid, lysergic acid amides, or ergopeptine alkaloids) in livestock, and this hampers development of pharmacological strategies to ameliorate the toxicosis. One method used to determine bioavailability of ergot alkaloids is to examine urinary and biliary excretion patterns. Thus, our objectives were to compare ergot alkaloid excretion via urinary or biliary systems and to determine the rate of appearance or clearance of these alkaloids in cattle that were grazing E+ or endophyte-free (E-) tall fescue. In autumn 1996, bile and urine samples were collected from eight steers (203 kg), each grazing E+ and E- tall fescue, and total alkaloid excretion was quantified using competitive ELISA. Approximately 96% of the ergot alkaloids were excreted in urine. The same steers were used to examine the rate of appearance in, or clearance from, urine when switched from E+ to E-, or from E- to E+, pastures in comparison with steers that were continuously grazing E+ or E- tall fescue at 0, 2, 5, and 7 d. Steers were returned to their original pastures after 7 d, and urine was collected at 2, 5, and 7 d. Urinary alkaloid concentrations in steers switched from E- to E+ pastures were similar (P = .55) to those in steers that continuously grazed E+ tall fescue after 2 d. Steers switched from E+ to E- pastures had urinary alkaloid concentrations similar (P = .91) to those in steers that continuously grazed E- pastures after 2 d. In 1997, two trials were conducted in which steers (191 kg) were switched or remained on E+ or E- pastures, and urine was collected at 0, 12, 24, 48, and 96 h to estimate rate of alkaloid appearance or clearance. Steers switched from E- to E+ 1) had about 33% as much urinary alkaloids as steers grazing E+ pasture after 12 h, 2) were not different after 24 h (P = .76), 3) had twice those of the E+ steers at 48 h (P < .05), and 4) were not different after 96 h. Steers switched from E+ to E- tall fescue had approximately 33% less (P < .05) urinary alkaloids than those grazing E+ at 12 h, 67% less (P < .05) at 24 and 48 h, and were not different (P = .86) from steers continuously grazing E- pastures after 96 h. Urinary alkaloid excretion patterns were similar to ergot alkaloid solubility patterns from in vitro digestion of E+ tall fescue. We suggest that alkaloids, liberated from the forage by ruminal microorganisms, were rapidly absorbed as lysergic acid amides and biotransformed ergopeptine alkaloids.

Animal Feed↗
PubMed1991

Severe iatrogenic ergotism: incidence and clinical importance.

Ergot's derivatives are widely used to treat and prevent migraine and, associated with heparin, for the prevention of deep vein thrombosis. During a five-year period, 7 patients have been admitted in our hospital for severe vasospasm of one or several extremities due to ergot's derivatives. All patients presented with acute severe ischemia of the lower limb requiring iv infusion of vasodilator drugs. Ergotamine tartrate was the responsible drug in four patients and dihydroergotamine(DHE)-heparin in three patients. Intravenous administration of sodium nitroprusside (n = 6) relieved vasospasm in all but one of the patients within hours to days and no amputation was required. Ankle or great toe to arm systolic pressure index was normalized in the majority of the patients after treatment. A sympathectomy was performed in two patients which did not improve the clinical course. Distal necrosis developed in two patients (DHE-heparin). It is concluded that incidence of severe ergotism is less than 0.5/100,000/year in Geneva. This contrasts with the high prevalence (15%) of subclinical ergotism reported by others. No amputation was required in this series in spite of severe and prolonged vasospasms. Subclinical ergotism most probably precedes for weeks the onset of severe vasospasm, which calls for close monitoring of patients taking ergot's derivatives.

Adolescent↗
PubMed1970

Effect of rye ergot on growth and N-retention in growing pigs.

An experiment with five litter-mate barrows showed that severe reduction in feed intake and growth rate accompanied the inclusion of either 1.0 or 2.0% ergot in the ration. Levels of 0.10 and 0.05% ergot allowed moderate feed intake and weight gain but not equal to the pig fed the ergot-free ration. A subsequent experiment involving five lots of four litter-mate barrows each, indicated the possibility of reduced feed intake and growth performance by growing-finishing pigs fed rations containing 0.05 - 0.10% ergot. This was substantiated by a N-balance experiment in which control pigs retained 1.54 gm more N daily than pigs fed 0.10% ergot. The total alkaloid content of the ergot used in these experiments was 0.292%; the predominant alkaloid (71%) being ergocristine.

Alkaloids↗
PubMed1996

[Ambulatory care of chronic headache secondary to abuse of ergot preparations].

OBJECTIVE: To analyse the results of out-patient treatment with diminishing doses of oral dihydroergotamine for patients with chronic migraine resulting from ergotics abuse. DESIGN: A prospective and descriptive intervention study. SETTING: County hospital. Neurology out-patient clinic. PATIENTS: All the patients with chronic migraine as a side-effect of abuse of ergotic preparations who were referred to neurology out-patients over 18 months. INTERVENTIONS: 1) Patients were told verbally of the causes of their migraine; 2) suppression of the ergotics, using diminishing doses of dihydroergotamine (Dihydergot gotas); 3) Prophylactic treatment with flunarizine (Sibelium); 4) Symptomatic treatment with sodic naproxen (Antalgin 550); 5) monthly and three-monthly check-up. MEASUREMENTS AND MAIN RESULTS: Over 18 months 25 patients with migraines due to ergotic abuse (6.7% of total migraines) were included. 4 were men; 21 women. Their average age was 43 (SD: 13). At one month the response was excellent in 19 patients (76%), good in 3 (12%) and bad in 3 (12%). At three months, the response was excellent in 17 patients (68%), good in 4 (16%), bad in 2 (8%) and 2 did not attend for the check-up (8%). CONCLUSIONS: 1) Out-patient treatment with diminishing doses of oral dihydroergotamine is effective in treating chronic migraine due to ergotics abuse. 2) The general practitioner should intervene in the identification and prevention of ergotics abuse.

Administration, Oral↗
PubMedDate not supplied

Antagonistic effects of simultaneous exposure of ergot alkaloids on kidney adenosine triphosphatase system.

Much of the research on fescue toxicosis has concentrated on evaluating animal response to grazing endophyte-infected (E+) versus endophyte-free tall fescue or the effects of single toxins such as ergonovine (EN), ergovaline (EV), or ergotamine (ET) on animal performance. Such approaches have eliminated the opportunity to test the possible additive, synergistic, or antagonistic interactions of one or more ergot alkaloids with the other ergot alkaloids found in E+ tall fescue. This study was conducted to determine the effects of simultaneous exposure of pairs of EN, EV, and ET on the kidney adenosine triphosphatase (ATPase) system in vitro. Tests were performed using three separate rat kidney homogenates and were repeated four times at concentrations of 0, 75, and 200 microM. Individually, EN, EV, and ET induced dose-dependent inhibitions of kidney Na(+)/K(+) ATPase, with EN being most potent, followed by purified EV, and then by ET. The ergot alkaloids inhibited Mg(2+) ATPase to a lesser degree than Na(+)/K(+) ATPase, with EN again being the most potent toxin. Simultaneous exposure to any combination of the ergot alkaloid pairs tested (EV + ET, EV + EN, and ET + EN) resulted in significant interactions (P < 0.05), indicating antagonistic effects on the inhibition of Na(+)/K(+) ATPase and Mg(2+) ATPase for most concentration combinations. These interactions suggest that in studies of the effects of any ergot alkaloid on animal performance, effects of other ergot alkaloids may also be present. Effects may not be additive, as was the case in this study, and the presence of one toxin may enhance or hinder the effectiveness of others.

Animals↗
PubMed1986

Occurrence of peptide and clavine ergot alkaloids in tall fescue grass.

Evidence is presented that ergot alkaloids are ubiquitous in tall fescue pastures infected with the clavicipitaceous fungal endophyte Sphacelia typhina (or Acremonium coenophialum). Ergopeptide alkaloids, predominantly ergovaline, constituted 10 to 50 percent of the total ergot alkaloid concentration, which was as high as 14 milligrams per kilogram in sheaths and 1.5 milligrams per kilogram in blades. Ergot alkaloid concentrations were substantially increased by application of large amounts (10 millimoles per liter) of potassium nitrate or ammonium chloride to infected plants in the greenhouse. The results indicate that ergot alkaloids are probably responsible for the toxicity to cattle of this common pasture and lawn grass and that ergotism-like toxicoses may be caused by clavicipitaceous fungi other than Claviceps.

Ammonium Chloride↗
PubMed1983

Ergotism and the Salem witch panic: a critical analysis and an alternative conceptualization.

The controversial hypothesis that the Salem witchcraft panic of 1692 resulted from ergot poisoning was recently defended by Mary Matossian. She argued that (a) weather conditions in Salem were conducive to the growth of ergot, (b) new evidence concerning the age distribution of ergot sufferers is consistent with the ages of those who exhibited symptoms at Salem, and (c) the symptoms displayed and reported at Salem were those of convulsive ergotism. Each of these propositions is critically examined and rejected, and the events purportedly explained by the ergot hypothesis are accounted for within a social psychological framework. This perspective views the Salem crisis as a sociopolitical drama played out in terms of the worldview shared by seventeenth-century Puritans. The symptoms of demonic affliction are conceptualized as role enactments learned in and legitimated by the community, rather than as the results of disease.

Aged↗
PubMed2001

Biotechnology and genetics of ergot alkaloids.

Ergot alkaloids, i.e. ergoline-derived toxic metabolites, are produced by a wide range of fungi, predominantly by members of the grass-parasitizing family of the Clavicipitaceae. Naturally occurring alkaloids like the D-lysergic acid amides, produced by the "ergot fungus" Claviceps purpurea, have been used as medicinal agents for a long time. The pharmacological effects of the various ergot alkaloids and their derivatives are due to the structural similarity of the tetracyclic ring system to neurotransmitters such as noradrenaline, dopamine or serotonin. In addition to "classical" indications, e.g. migraine or blood pressure regulation, there is a wide spectrum of potential new applications of this interesting group of compounds. The biotechnology of ergot alkaloids has a long tradition, and efficient parasitic and submerse production processes have been developed; the biochemistry of the pathway and the physiology of production have been worked out in detail. The recent identification of a cluster of genes involved in ergot alkaloid biosynthesis in C. purpurea and the availability of molecular genetic techniques allow the development of strategies for rational drug design of ergoline-related drugs by enzyme engineering and by biocombinatorial approaches.

Biotechnology↗
PubMed1999

Evidence for an ergot alkaloid gene cluster in Claviceps purpurea.

A gene (cpd1) coding for the dimethylallyltryptophan synthase (DMATS) that catalyzes the first specific step in the biosynthesis of ergot alkaloids, was cloned from a strain of Claviceps purpurea that produces alkaloids in axenic culture. The derived gene product (CPD1) shows only 70% similarity to the corresponding gene previously isolated from Claviceps strain ATCC 26245, which is likely to be an isolate of C. fusiformis. Therefore, the related cpd1 most probably represents the first C. purpurea gene coding for an enzymatic step of the alkaloid biosynthetic pathway to be cloned. Analysis of the 3'-flanking region of cpd1 revealed a second, closely linked ergot alkaloid biosynthetic gene named cpps1, which codes for a 356-kDa polypeptide showing significant similarity to fungal modular peptide synthetases. The protein contains three amino acid-activating modules, and in the second module a sequence is found which matches that of an internal peptide (17 amino acids in length) obtained from a tryptic digest of lysergyl peptide synthetase 1 (LPS1) of C. purpurea, thus confirming that cpps1 encodes LPS1. LPS1 activates the three amino acids of the peptide portion of ergot peptide alkaloids during D-lysergyl peptide assembly. Chromosome walking revealed the presence of additional genes upstream of cpd1 which are probably also involved in ergot alkaloid biosynthesis: cpox1 probably codes for an FAD-dependent oxidoreductase (which could represent the chanoclavine cyclase), and a second putative oxidoreductase gene, cpox2, is closely linked to it in inverse orientation. RT-PCR experiments confirm that all four genes are expressed under conditions of peptide alkaloid biosynthesis. These results strongly suggest that at least some genes of ergot alkaloid biosynthesis in C. purpurea are clustered, opening the way for a detailed molecular genetic analysis of the pathway.

Alkyl and Aryl Transferases↗
PubMed1993

The study of the differential pulse voltammetric behaviour of ergot alkaloids and their determination by DC amperometric detection in a FIA system.

The ergot alkaloids possess strong pharmacological effects and are important drugs with widespread clinical uses. The ergot alkaloid preparations manufactured by Gedeon Richter Chemical Works Ltd have a very low active substance content (e.g. 1.0 mg in each Secadol (0.4 g) coated tablet); therefore a sensitive method of determination must be used. Because of this constraint the differential pulse voltammetric behaviour of ergot alkaloids was studied in respect of the effects of pH and composition of media and an automated FIA system with amperometric detection has been used to develop a selective and sensitive method for the routine quantitative assay of these alkaloids. A short summary is given of the experimental evidence to substantiate the stoichiometric equation proposed for the electrochemical oxidation of the lysergic acid type of ergot alkaloids, the mechanism may be generally applicable for compounds having the ergoloid skeleton. In the course of the work it was concluded that a simple DC amperometric method of detection in a FIA system could be applied to determine the content of ergot alkaloids of different pharmaceutical preparations. A suitable method designed to meet current analytical requirements has been developed and validated.

Autoanalysis↗
PubMed2005

Origins and significance of ergot alkaloid diversity in fungi.

Ergot alkaloids are a diverse family of indole-derived mycotoxins that collectively have activities against a variety of organisms including bacteria, nematodes, insects, and mammals. Different fungi accumulate different, often characteristic, profiles of ergot alkaloids rather than a single pathway end product. These ergot alkaloid profiles result from inefficiency in the pathway leading to accumulation of certain intermediates or diversion of intermediates into shunts along the pathway. The inefficiency generating these ergot alkaloid profiles may have been selected for as a means of accumulating a diversity of ergot alkaloids, potentially contributing in different ways to benefit the producing fungus.

Ergot Alkaloids↗
PubMed2002

Ergot and triptan overuse in Austria--an evaluation of clinical data and cost.

Austria is one of the countries, in which ergots are still the most commonly used acute anti-migraine drugs. Overuse and chronification is a clinical problem for ergots, but also for the recently developed triptans. In a retrospective study for the year 1999 we evaluated clinical data from all Austrian neurological hospitals including cost of withdrawal as well as the estimated cost for ergots and triptans on the pharmaceutical retail market. We identified a total of 96 patients that underwent withdrawal, all of whom because of ergot overuse, and some with considerable long-term side-effects. The cost of withdrawal (more than 1300 000) together with direct cost of medication amounted to more than 11 million. In contrast, cost of medication for triptans was 12.8 million for the same year, without any cost for withdrawal. If only cost aspects were to be considered in the prescription of acute anti-migraine drugs, our data would suggest to choose ergots rather than triptans. However, as scientific evidence is clearly in favour of triptans, decision making for the prescribing clinicians is more complex and will primarily focus on optimizing patient care, but also depend on the respective socio-economic situation.

Adult↗
PubMed2006

Post-genome research on the biosynthesis of ergot alkaloids.

Genome sequencing provides new opportunities and challenges for identifying genes for the biosynthesis of secondary metabolites. A putative biosynthetic gene cluster of fumigaclavine C, an ergot alkaloid of the clavine type, was identified in the genome sequence of ASPERGILLUS FUMIGATUS by a bioinformatic approach. This cluster spans 22 kb of genomic DNA and comprises at least 11 open reading frames (ORFs). Seven of them are orthologous to genes from the biosynthetic gene cluster of ergot alkaloids in CLAVICEPS PURPUREA. Experimental evidence of the identified cluster was provided by heterologous expression and biochemical characterization of two ORFs, FgaPT1 and FgaPT2, in the cluster of A. FUMIGATUS, which show remarkable similarities to dimethylallyltryptophan synthase from C. PURPUREA and function as prenyltransferases. FgaPT2 converts L-tryptophan to dimethylallyltryptophan and thereby catalyzes the first step of ergot alkaloid biosynthesis, whilst FgaPT1 catalyzes the last step of the fumigaclavine C biosynthesis, i. e., the prenylation of fumigaclavine A at C-2 position of the indole nucleus. In addition to information obtained from the gene cluster of ergot alkaloids from C. PURPUREA, the identification of the biosynthetic gene cluster of fumigaclavine C in A. FUMIGATUS opens an alternative way to study the biosynthesis of ergot alkaloids in fungi.

Aspergillus fumigatus↗
PubMed2005

An autopsy case of postpartum acute myocardial infarction associated with postpartum ergot alkaloids administration in old-aged pregnant women.

Cases of acute myocardial infarction (AMI) that occur during pregnancy or postpartum are rarely reported. Ergot derivatives are known to induce the spasmodic contraction of coronary arteries. Administration of ergot derivatives can cause AMI, even in normal healthy people. In several reported cases, ergot derivatives triggered severe AMI during the postpartum period. Here, we report the case of a forty-year-old woman who was successfully impregnated by artificial fertilization and died after treatment with ergot derivatives. The autopsy revealed AMI with severe coronary atherosclerosis. This is the first case that reports aggravation of pre-existent severe coronary atherosclerosis after postpartum infusion of ergot derivatives.

Adult↗
PubMed1980

Central monoamine synapses as sites of action for ergot drugs.

The acute and subacute effects of ergot drugs on central monoaminergic mechanisms were studied in the rat. The most significant findings are: 1. After acute treatment, lergotrile and bromocriptine were found to block apomorphine-induced locomotion and rearing, suggesting that these two ergot drugs can block postsynaptic DA receptors within the nucleus accumbens. 2. Several ergot drugs were shown to have high affinity for some 3H-ADTN binding sites. Earlier studies indicate that 3H-ADTN appears to label postsynaptic dopamine receptors located on nerve cells in the striatum. These ergot-sensitive 3H-ADTN binding sites appear not to be linked to the adenylate cyclase system. In addition, bromocriptine, unlike CM 29-712, was found to have a high affinity for 3H-spiperone binding sites in the striatum. 3. Bromocriptine and CM 29-712 increased norepinephrine turnover in periventricular and paraventricular hypothalamic areas, suggesting a blockade of norepinephrine receptors. CM 29-712 also increased DA turnover in the medial palisade zone of the median eminence. 4. Some ergot drugs also had affinity for 5-HT receptor binding sites, possibly reflecting a 5-HT agonistic action in some areas, as shown in behavioral studies. 5. Apomorphine and bromocriptine displaced in vivo 3H-spiperone binding in the hypothalamus, septal area, and substantia nigra, but not in the striatum. 6. Subacute treatment with bromocriptin and CM 29-712 were found to produce two types of changes in behavior: The apomorphine-induced locomotion was enhanced while the chewing and licking activity (stereotypies) was reduced. These behavioral changes may be associated with an increased affinity in the 3H-ADTN binding sites in the striatum. This treatment also produced persistent increases of DA turnover in the tuberculum olfactorium but not in striatum.

5-Hydroxytryptophan↗
PubMed1983

Interactions of ergot alkaloids with anterior pituitary D-2 dopamine receptors.

The interactions of ergot alkaloids with bovine anterior pituitary D-2 dopamine receptors have been investigated with radioligand binding techniques and computer modeling procedures. Ergot alkaloids of the ergoline class are found to interact with the receptor in an agonist-specific fashion, exhibiting heterogeneous competition curves which can be resolved into high- and low-affinity components. In the presence of guanine nucleotides, however, only the low-affinity binding component is observable. In contrast, ergot alkaloids possessing a cyclic peptide side chain (ergopeptines) interact with the receptor in a homogeneous fashion, exhibiting competition curves which are monophasic and unaffected by guanine nucleotides. Ergopeptines thus display the binding characteristics of antagonist ligands even though they possess pharmacologically demonstrated agonist properties. These ergot alkaloid receptor binding characteristics determined from indirect competition experiments are also directly demonstrable using radiolabeled ergoline and ergopeptine ligands. The radiolabeled ergopeptine [3H]dihydroergocryptine ([3H]DHE) is shown to label identical binding sites with the same pharmacological characteristics as the antagonist [3H]spiroperidol. However, the dissociation rate of [3H]DHE from these binding sites is much slower than [3H]spiroperidol and is inconsistent with its equilibrium-determined binding affinity. In addition, saturation experiments with radiolabeled antagonists and agonists and unlabeled ergopeptines indicate that ergopeptines interact with these receptor sites in a competitive fashion. A model is presented which may explain these unique binding properties of ergot alkaloid agonists to the pituitary D-2 dopamine receptor.

Animals↗
PubMed1977

Mesenteric and peripheral vascular ischemia secondary to ergotism.

At the present time ergotism is due primarily to excessive use or abuse of ergot preparations for migraine headaches. The diagnosis may be made with the evidence of vascular ischemia in the presence of a history of migraines and its treatment with this drug. The therapy for the vasospasm is directed chiefly at the discontinuation of the ergot preparation, with further treatment aimed at the relief of symptoms or prevention of complications. A case is presented of lower extremity ischemia with impending gangrene of both feet in a patient with a history of chronic schizophrenia. Arteriograms revealed symmetrical vasospasm in the lower extremities as well as spasm of the superior mesenteric artery and its intestinal branches. This is believed to be the first documented case of mesenteric vasospasm due to ergotism. Treatment was instituted with low molecular weight dextran, tolazoline, and reserpine with rapid and complete resolution. Caution is advised in the use of ergot preparations in neuropsychiatric disorders.

Adult↗
PubMed1998

Jewish mystical movements and the European ergot epidemics.

Chronic intake of ergot, a chemical present in bread blighted by ergot-producing fungi, results in a wide variety of neuropsychiatric and vascular symptoms. The symptomatology and epidemiology of outbreaks of ergot poisoning are traced, and are shown to coincide with the emergence of Jewish mystical movements, such as the early Pietist movement in Germany, Sabbateanism and Chasidism, thus suggesting that environmental ergotism contributed to these mystical movements. The interaction between ergotism and other nutritional, neuropsychiatric, social, psychological and historical influences is considered.

Disease Outbreaks↗