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Ergot is caused by a fungus (Claviceps species) which has been found on hundreds of plants in almost every country of the world. The fungus can adapt itself to form many different varieties. New species of the fungus and new hosts are still discovered today. The alkaloids in ergot have caused hundreds of thousands of deaths in the Middle Ages after consumption of contaminated cereal grains, but during the last two decades there has not been a recorded outbreak of ergotism. Grain standards in most countries are very strict and do not permit grain which contains ergot to reach commercial food channels. All involved in cereal grain production and ulilization should be cognizant of the potential danger, however, since ergot contamination at levels above those permitted by grain standards cannot necessarily be detected by the normal evaluation of a flour sample in the cereal chemistry laboratory. There always have been and always will be ergot infections and a possible danger to human health, but man has learned to minimize the potential problem by using proper agricultural practices. Futhermore, techniques for the removal of ergot from contaminated grains have been developed. While human ergotism is a disease of the past, ergotism in animals still occurs frequently. The problem is not a simple one because of many unanswered questions. What is the tolerance of different breeds or species of livestock to ergot? What are the effects of low-level long-term ingestion of ergot on livestock? What is the difference in toxicity to animals of ergot from different cereal ingestion of ergot on livestock? What is the difference in toxicity to animals of ergot from different cereal grain varieties? What is the effect of storage and processing of cereal grain products on the potential ergot toxicity? The last and most important chapter in the history of ergot concerns ergot as a source of pharmacologically useful alkaloids which have found applications in internal medicine and obstetrics. The future promises to bring some new ergot alkaloids and some new uses. Recent research data indicate the possibility of using ergot alkaloids in contraceptives, which would be truly remarkable.
A short survey of the history of ergot, of the original and, for a long time, only source of ergot alkaloids, is given. Once a dreaded poison, ergot has changed its role over the centuries to become a rich treasure house of valuable pharmaceuticals. In the Middle Ages it was the cause of epidemics of ergotism, which cost tens of thousands of people their lives. Ergot was first mentioned by the German physician Lonitzer in 1582 as a remedy used by midwives for quickening childbirth. The isolation of pharmacologically useful alkaloids started in 1906 with the discovery of ergotoxine and its adrenolytic activity by Barger, Carr and Dale. In 1918, Stoll isolated ergotamine, the first chemically pure ergot alkaloid, which found widespread therapeutic use in obstetrics and internal medicine. In 1935 the specific oxytocic principle of ergot, ergonovine, was discovered simultaneously in four separate laboratories. Since then, worldwide investigations on ergot alkaloids resulted in the elucidation of their structures and total syntheses and preparation of valuable therapeutics such as Methergine, Hydergine, Dihydergot, and others.
Growing pigs were fed freshly milled ergot sclerotia (Claviceps purpurea Fr (Tul)) from North American wheat containing 0-31 per cent of total alkaloids of which 30 per cent was ergotoxine, 30 per cent ergosine, 20 per cent ergotamine and 20 per cent other ergot alkaloids. Pigs were induced to ingest a diet heavily contaminated with ergot (10 per cent w/w). The presence of ergot reduced feed intake and growth of the pigs, but there was no evidence of peripheral necrosis, of internal or external haemorrhage, or of changes in haemotological characteristics. Balance experiments in which the diet was contaminated with 4 per cent (w/w) of ergot showed that 90 per cent of the alkaloids were absorbed by the pigs, but none could be detected in tissues or urine. The ingestion of ergot did not affect the digestibility of the diet, but the urinary excretion of nitrogen was increased and the retention of nitrogen reduced. The presence of ricinoleic acid was shown to be a useful diagnostic feature of ergot contamination of diets, digesta and faeces; it was not found in body tissues.
The interactions of ergot alkaloids and of other drugs with dopamine (DA) and alpha-adrenergic receptors were investigated. The tested ergot alkaloids inhibit synaptosomal tyrosine hydroxylase activity and reverse the apomorphine-elicited inhibition of synaptosomal tyrosine hydroxylase activity. Thus, ergot alkaloids interact as both agonists and antagonists with the presynaptic DA receptors. Ergot alkaloids also compete effectively for the binding of 3H-DA and 3H-haloperidol to bovine striatal membranes. These results show that these drugs are mixed agonist-antagonists with respect to the postsynaptic DA receptors. To determine the effects of ergot alkaloids and of neuroleptics on the alpha-adrenergic receptors in the CNS, we have measured their effects on the binding of 3H-dihydroergocryptine and 3H-WB-4101 to cerebral cortical membranes. The displacing potencies of the tested ergot alkaloids and of the neuroleptics indicated that they have a high affinity for the alpha-adrenoreceptors in the CNS. The mechanisms underlying the therapeutic efficacy of mixed agonist-antigonists of DA and alpha-adrenergic receptors in Parkinson's disease and in geriatric disorders were considered.
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.
Ergot alkaloids are very important pharmaceutical substances with wide medical use. Their bioproduction is usually followed by chemical modification. Bioconversions of ergot alkaloids on an industrial scale have become more important in recent years. The aim of this study is to collect the available data on ergot alkaloid bioconversions and to show their potential applications. The paper deals with conversions of clavines, e.g. biooxidations, glycosylations of the alkaloids, and bioconversions of lysergic acid derivatives. A part of it is aimed at bioconversions of ergot alkaloids in mammalian organisms and obtaining their metabolites by biotransformation. The use of immobilized systems and cofermentation is also discussed.
This study reports a case of allergy to ergot-derived drugs in a patient with a prolactin (PRL)-secreting microadenoma. The anamnesis revealed allergic reactions to the administration of analgesics and antibiotics. The administration of dopamine agonist drugs, such as bromocriptine (BRC; 2.5 mg) or lisuride (0.2 mg), induced after a few minutes the appearance of nausea, vomiting, postural hypotension, headache, edema of the glottis with dispnea and acroedema. The edemas disappeared a few hours after the administration of antihistaminic drugs while nausea, vomiting, postural hypotension and headache persisted for a few days. Therefore, the patient was tested with another dopamine agonist non-ergot-derived drug, quinagolide (CV 205-502), which did not cause side effects or allergic reactions. Furthermore, not only was the responsiveness to the drug optimal but it also normalized the PRL levels, and menses reappeared after more than a 5-year amenorrhea. This report suggests that ergot-derived drugs, such as lisuride and BRC, seldom induce allergic reactions apart from common side effects. Consequently, the feasibility of using a new drug with a different molecular structure (non-ergot derived) effective in the therapy of hyperprolactinemic syndromes represents a good alternative to conventional therapy.
The alcaloids from rye-ergot are known and used for their vasoconstrictive properties, which can induce secondary ergotism. The extremities will be particularly involved. Vasoconstriction will also concern the gastrointestinal tract as well as the peripheric and the central nervous system, possibly with neuro-psychiatry symptoms. Cardiac and renal involvement has been described. Migraine, thrombosis prophylaxis and obstetrical situations are the most frequent therapeutic indications. Precise patient history, clinical and the typical angiological findings are necessary for diagnosis. The importance of an early diagnosis is emphasized. The responsible agent can then be stopped with thorough in-time vasodilatating treatment, and restitution will occur. Three cases are reported. The patients were referred to the rheumato-orthopedic clinic because of limbs claims. They suffered from different grades of ergotism, and one had to be amputated at the right hand. The following discussion is based on a review of the literature.
Severe extremity ischemia developed in four patients who had ingested methysergide maleate or ergot for the relief of headache. Symptoms involved the upper extremity in two patients and the lower extremity in two. Spontaneous reversal of the ischemic picture was obtained by simple discontinuation of ergot in most instances, although intra-arterial vasodilators were used in one case. Angliography disclosed arterial spasm and was a useful adjunct in confirming the cause of ischemia in each of the patients. It was especially useful when a history or ergot ingestion was not immediately available.
Ergot alkaloid enantiomer derivatives were resolved using capillary zone electrophoresis. The effect of cyclodextrins, added to the background electrolyte, on the migration time and the resolution was studied. Good separation for epimeric ergot alkaloid derivatives was also obtained using phosphate buffer at pH 2.5. Separation was improved by supplementing the background electrolyte with 30 mM of gamma-cyclodextrin. Good resolution of racemic ergot alkaloid derivatives in their enantiomers was achieved in a background electrolyte containing either beta-cyclodextrin or its derivative, or gamma-cyclodextrin.
A series of ergot alkaloids, together with the DA agonists apomorphine and piribedil, were tested for protective effects against audiogenic seizures in an inbred strain of mice (DBA/2) and for induction of circling behaviour in mice with unilateral destruction of one nigrostriatal DA pathway. The order of potency against audiogenic seizures was apomorphine greater than ergocornine greater than bromocryptine greater than ergometrine greater than LSD greater than methysergide greater than piribedil while that observed in the rotating mouse model was apomorphine greater than ergometrine greater than ergocornine greater than bromocryptine greater than piribedil. LSD caused only weak circling behaviour even when administered in high doses (greater than 1 mg/kg). Methysergide was ineffective. Prior administration of the neuroleptic agent haloperidol blocked the effect of DA agonists and of ergot alkaloids in both animal models. The possible action of ergot alkaloids as DA agonists is discussed.
Several new ergot drugs were tested for behavioral and neurochemical effects related to serotonergic function. Lergotrile and bromocriptine potentiated the so-called "5-HT syndrome", a set of behaviours associated with increased serotonergic neurotransmission consequent to monoamine oxidase inhibition and tryptophan loading. Metergoline antagonized this behavior. In studies of receptor binding using 3H-5-HT or 3H-LSD, metergoline was the most potent at displacing specific ligand binding. Since the ergots also affect dopaminergic function, these results are discussed for their information on both dopaminergic and serotonergic actions of these drugs and their implications for clinical use of ergots.
Sumatriptan and the ergot alkaloids are useful tools for deciphering drug mechanisms in migraine and related headaches. Both neuronal and vascular mechanisms have been proposed on the basis of actions of 5-HT at receptors resembling the 5-HT1D subtype. In this Viewpoint article, Michael A. Moskowitz argues that blockade of neural transmission and the neurogenic inflammatory response provides a mechanism by which sumatriptan and ergot alkaloids alleviate vascular headaches. He postulates, with similar arguments, that sumatriptan and ergot alkaloids may block headaches that develop from meningovascular inflammatory disorders such as from viral and bacterial meningitis and from the sequelae of head injury.
1 Cross-reactivity of ergot alkaloids with an antiserum produced against lysergic acid conjugated with human serum, albumin was utilized to develop a radioimmunoassay for ergotamine, dihydroergotamine, dihydroergotoxine, ergometrine and methylergometrine in biological fluids. The antisera showed no cross-reactivity with simpler indole structures. 2 A procedure for extraction and concentration of alkaloids in biological fluids was developed. 3 The assay is sensitive for 1.8 ng/ml ergotamine, 1.5 ng/ml dihydroergotamine, 2.2 ng/ml dihydroergotoxine, 0.7 ng/ml ergotmetrine and 0.5 ng/ml methylergometrine. 4 The assay is sufficiently sensitive to permit the measurement of urine and plasma ergot alkaloid levels and it is suitable for determination in cases where a known ergot alkaloid is used.
The effects of several ergot alkaloid derivatives on the concentration of cyclic AMP in intact rabbit retinae were investigated in vitro. All compounds were found to be potent inducers of cyclic AMP production, half-maximal stimulation being obtained at 10(-6)M, and maximal stimulation at 10(-4)M concentrations. The range of effective concentrations was very well comparable with that of dopamine (or apomorphine) in the same experimental conditions. Furthermore, the accumulation of cyclic AMP induced by the ergot derivatives was blocked by fluphenazine, at 10(-4)-5 X 10(-4)M, or lithium, at 5 X 10(-2)M concentrations. Both antipsychotic drugs were found to be very potent inhibitors of dopamine-(or apomorphine-) induced production of cyclic AMP in the same preparation. A potential dopamine-mimetic activity of ergot derivatives (or of other dopamine-like drugs) can be specifically tested on isolated rabbit retinae in vitro, either before undertaking experiments in vivo or in correlation with behavioural studies.