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First report of field outbreaks of ergot-alkaloid toxicity in South Africa.

Outbreaks of clinical disease caused by the ingestion of ergotized Lolium rigidum (annual ryegrass), which resulted in a substantial loss in production, have been reported. A number of outbreaks of a hyperthermia syndrome in cattle, characterized by severe loss in milk production, loss of body mass and reduced fertility, are described. In one major outbreak in March to April 1994, a milling company reported that 2,646 dairy cows on 29 farms had developed clinical signs. In this outbreak, significant levels of ergotamine, ergosine, ergocornine and ergocryptine were found in the milled dairy rations fed to the affected cows. Barley screenings containing ergotized annual-ryegrass seed was identified as the toxic component and probable source of the ergot alkaloids in the ration. The clinical syndrome was reproduced experimentally by feeding suspected feed to a group of nine high-producing Ayrshire cows. An outbreak of gangrenous necrosis of the extremities in young cattle in the winter of 1987 was also suspected of having been caused by ergot alkaloids in grain screenings.

Animal Feed↗

Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists.

We report on 4 new cases of valvular heart disease in Parkinson's disease patients treated with the ergot derivative dopamine agonists pergolide and cabergoline. Noninflammatory fibrotic degeneration of cardiac valves has been reported to occur in patients with carcinoid syndrome and to occasionally complicate therapies with the anti-migraine ergot alkaloid ergotamine and methysergide and with the appetite suppressants fenfluramine and dexfenfluramine. In these cases, the pathogenesis is suspected to involve serotonin-mediated abnormal fibrogenesis by means of the 5-HT2B receptors, which are expressed in the fibroblasts of heart valves. Based on strikingly similar echocardiographic and histopathological features, we strongly suspect that ergot-derived dopamine agonists may cause a valvular heart disease nearly identical to that seen in those conditions. These cases add to a rapidly growing and worrying list of similar published reports, suggesting that we may well be facing a novel, yet unrecognized, complication of this class of agents, which are widely used not only in Parkinson's disease but also in restless legs syndrome and various common endocrine dysfunctions. Therefore, until more is known about the true prevalence of this side effect, we propose that an assessment of cardiac function be performed before and in the course of a long-term therapy with ergot derivative dopamine agonists.

Adult↗

Mass spectral characterization of ergot alkaloids by electrospray ionization, hydrogen/deuterium exchange, and multiple stage mass spectrometry: Usefulness of precursor ion scan experiments.

Six ergot alkaloids belonging to the lysergic acid derivatives (ergonovine (EGN) and methysergide hydrogen maleinate (MHM)) and peptide-type derivatives (ergocristine (EGR), ergotamine (EGT), ergocornine (EGC) and alpha-ergokryptine (EGK)) were studied by positive electrospray tandem mass spectrometry. The fragmentation mechanisms of these compounds were studied by collision-induced dissociation (CID) using triple quadrupole and ion trap mass spectrometers, and the nature of the major product ions further confirmed by hydrogen/deuterium (H/D) exchange experiments. A common abundant product ion at m/z 223 was characteristic of the two classes of ergot alkaloids. Therefore, a precursor ion scan of m/z 223 that triggers information data acquisition (IDA) in combination with CID experiments was used to identify other potential ergot alkaloids. Using this approach, it was possible to confirm the presence of ergosine, another peptide-type ergot alkaloid, in a rye flour extract at trace levels.

Deuterium↗

Gastric secretagogue action of ergot alkaloids in the perfused stomach of anesthetized rats.

The gastric secretagogue action of ergot alkaloids was studied in the perfused stomach of anesthetized rats. Ergometrine dose-dependently increased gastric acid secretion and other ergot alkaloids, methysergide, methylergometrine, ergotamine and dihydroergotamine were also found to stimulate gastric secretion. However, Hydergine and bromocriptine did not influence the basal secretion. The gastric secretagogue action of ergometrine was completely inhibited by atropine and was markedly reduced but not abolished by vagotomy. Intraventricular administration of ergometrine produced an increase of acid secretion. Ergometrine did not affect the blood glucose level while insulin decreased it. The effect of ergometrine was not inhibited by serotonin agonistic or dopamine antagonistic agents. These results suggest that some ergot alkaloids have a gastric secretagogue action mainly due to their central effect in anesthetized rats and these actions cannot be explained by serotonin antagonistic, dopamine agonistic and alpha-adrenergic blocking effects of ergot alkaloids. The mechanism of the secretagogue action of ergometrine was different from that of insulin.

Anesthesia↗

Interaction between some ergot alkaloids and the reactivity to dopamine of an identified neurone of Helix pomatia.

The effect of ergot alkaloids, some of them from the ergosine series, was tested on the response of an identified neurone of Helix pomatia to the application of dopamine (DA) which was membrane hyperpolarization (DA-I response). To evaluate the antagonistic potency of the ergot alkaloids, the dose-response relationship of the response to DA was established first in the absence and later in the presence of the tested compound. The sigmoidal dose-response curves obtained were used to determine the pA2 values of all the antagonists tested. Comparing them it was found that among the ergosines tested, the most potent was dihydroergosine, its pA2 value being (6.27) similar to the values obtained for dihydroergotoxine (6.66) and dihydroergotamine (6.36). The two other unhydrogenated compounds (ergosine and saccharinoergosine) had potencies of the same order as bromoergocryptine. The D-isomer (+) of the saccharino compound was the least potent, but it acted as a DA-receptor antagonists, as well as the dextroisomer of bromoergocryptine, bromoergocryptinine. By comparing the current-voltage relationship of the neurone in the presence and absence of the ergot alkaloids tested it was found that they had no non-specific effects on the membrane. The ergot alkaloids did not change the amplitude of depolarization of the neurone induced by gamma-aminobutyric acid (GABA) and acetylcholine (ACh).

Animals↗

Variability in the content and composition of alkaloid found in Canadian ergot. III. Triticale and barley.

The total alkaloid content and individual alkaloid composition were determined by colorimetry and high performance liquid chromatography, respectively, for Canadian triticale and barley ergot (Claviceps purpurea). The total alkaloid content was highly variable between individual sclerotia from the same or different sources and ranged from 0.042 to 0.752% for triticale and from 0.082 to 1.04% for barley; average values were 0.239% for Ottawa triticale, 0.289% for Prairie triticale, and 0.264% for barley. Ergocristine and its isomer ergocristinine were the major constituents in both grains. On average, Canadian ergot pooled from rye, wheat, triticale, and barley consists of ergocristine (31%), ergocristinine (13%), ergocristinine (13%), ergotamine (17%), ergotaminine (8%), ergocryptine (5%), ergocryptinine (3%), ergometrine (5%), ergometrinine (2%), ergosine (4%), ergostinine (2%), ergocornine (4%), ergocorninine (2%), and unidentified alkaloids (3%), and an average total alkaloid content of 0.236%. With the exception of rye and barley ergot from the maritime regions, Canadian rye, wheat, triticale, and barley ergot is fairly uniform in individual alkaloid composition.

Canada↗

Studies of the effect of natural and synthetic polypeptide type ergot compounds on a peripheral vascular bed.

1. Six ergot alkaloids were tested for their effect on vascular resistance and for alpha-adrenergic blocking activity on the innervated perfused hind limb of the dog. The results were compared with those obtained earlier for three compounds of the ergotamine group.2. Ergostine, dihydroergostine, 1-methylergostine and dihydroergocristine resembled ergotamine, dihydroergotamine and 1-methylergotamine in eliciting vasoconstriction at low vascular resistance and vasodilatation at high vascular resistance. The changeover occurred at the following "inversion points": ergostine and dihydroergostine as with ergotamine and dihydroergotamine at about 4 R.U.; 1-methylergostine as with 1-methylergotamine at about 2.3 R.U.; dihydroergocristine at about 1.9 R.U. [1 R.U. = 1 resistance unit = 1 mm Hg/ml. per min.]3. 1-methyldihydroergocristine consistently elicited vasodilatation (for initial vascular resistances down to 1.3 R.U.) and 5'-methylergoalanine always caused vasoconstriction (for initial values up to 5.8 R.U.).4. Ergostine and 5'-methylergoalanine had the most powerful vasoconstrictor effect, which was of the same order of magnitude as that of ergotamine. Dihydroergostine, like dihydroergotamine, was considerably less active. Both 1-methylergostine and 1-methylergotamine elicited only weak vasoconstriction. Moreover, when the initial vascular resistance exceeded the critical inversion value, they elicited only weak vasodilatation. Dihydroergocristine and 1-methyldihydroergocristine had the least effect on vascular resistance.5. The increase in vascular resistance by noradrenaline was inhibited in a dose-dependent manner by all the ergot alkaloids investigated. Ergostine, 5'-methylergoalanine and ergotamine had the greatest alpha-adrenergic blocking activity and 1-methylergostine, 1-methyldihydroergocristine and 1-methylergotamine the weakest. The activity of dihydroergostine, dihydroergocristine and dihydroergotamine fell between these two extremes.6. No correlation was found between the qualitative effect of these ergot alkaloids on vascular resistance (inversion point) and (a) their quantitative effect on this parameter or (b) their alpha-adrenergic blocking activity. Determination of the inversion point thus provides additional pharmacological information on the vasoactive properties of the ergot alkaloids.

Animals↗

Dopaminergic activity of some ergot alkaloid derivatives: relationship to their chemical structure.

Several ergot alkaloid derivatives have been tested for their ability to inhibit receptor binding of [3H]spiperone (D2 dopamine receptors) and [3H]dopamine (D3 dopamine receptors) in the bovine caudate nucleus. Dopaminergic activity was correlated to their chemical structure. The potencies of ergot alkaloids for displacing [3H]spiperone binding can be ranked in the following order: lisuride greater than ergosine greater than bromodihydroergosine greater than bromoergosine approximately dihydroergosine approximately ergosinine approximately dihydroergocryptine greater than bromoergocryptine greater than CH-29 717 greater than saccharinoergosinine = saccharinoergosine greater than dihydroergosinine. The potencies of these compounds for displacing [3H]dopamine binding can be ranked in the following order: lisuride greater than ergosinine approximately ergosine greater than dihydroergosine greater than bromodihydroergosine approximately CH-29 717 approximately bromoergocryptine approximately bromoergosine approximately dihydroergocryptine greater than saccharinoergosine, saccharinoergosinine, dihydroergosinine. Displacement of both radioligands was unaffected by GTP. Binding characteristics of ergot alkaloids examined revealed antagonist-like properties of binding to D2 and agonist-like properties of binding to D3 receptors. Introduction of bromine into position 2, selective hydrogenation of 9,10-dihydroderivatives, or isomerization in position 8 of the ergot alkaloid molecule did not drastically change binding parameters of these compounds. However, an alpha-configuration in position 8 combined with hydrogenation of the delta-9,10-double bond of dihydroergosinine, significantly decreased its affinity to both D2 and D3 receptors in comparison with dihydroergosine or ergosinine, suggesting stereoselectivity of dopamine receptors towards the pair dihydroergosine/dihydroergosinine.

Animals↗

Effects of some ergot alkaloids on dopamine receptors of molluscan smooth muscle.

Some ergot alkaloids relaxed catch contraction of an isolated molluscan smooth muscle (anterior byssus retractor muscle of Mytilus edulis). Haloperidol, a competitive dopamine antagonist, shifted the dose response curves of ergot alkaloids, but methysergide did not. Bromocriptine, a potent dopaminergic ergot alkaloid, did not relax catch contraction. These results suggest that relaxation of catch contraction by some ergot alkaloids is mediated through dopamine receptors of this muscle, but dopamine receptors of this muscle seem to be somewhat different from those of mammalian brain.

Animals↗

Ergot alkaloids. Current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology.

Ergot alkaloids are well known preparations. Ergot alkaloids used in obstetrics and gynaecology are ergometrine (ergonovine; EM), methylergometrine (methergine; ME) and bromocriptine. The pharmaceutical properties of ME EM) are critical. To guarantee stability, ME and EM ampoules should be stored in a cool, dark place. ME and EM tablets are unstable in all conditions and they show an unpredictable bioavailability, which prevents oral use of the drugs for any purpose. ME and EM are known for their strong uterotonic effect and, compared with other ergot alkaloids, for their relatively slight vasoconstrictive abilities. ME and EM do have a place in the management of the third stage of labour as they are strong uterotonics. They act differently from oxytocin and prostaglandins, and have different adverse effects. Oxytocin should be used as prophylaxis or a the drug of first choice; next, ME or EM should be used, and if none of these drugs produce the desired effects, prostaglandins should be used to control bleeding. Ergot alkaloid use in gynaecology has been limited and today is discouraged even in essential menorrhagia. It is suggested that EM and ME be used (parenterally) only in first trimester abortion curettage, to reduce blood loss. Bromocriptine has been used for lactation suppression. However, alternatives such as cabergoline, which possess fewer adverse effects, are now available and therefore preferred for this indication. In sum, there is no place for the prophylactic use of ME and EM in obstetrics or gynaecology. They can be used for therapeutic purposes in the third stage of labour. During use, the practitioner must be alert for adverse effects.

Ergonovine↗

Detection of ergot (Claviceps purpurea) in a dairy feed component by gas chromatography and mass spectrometry.

A dairy feed that contained barley malt screenings caused hyperthermia in dairy cattle. The feed was suspected of containing ergot and was subsequently analyzed to determine the ricinoleate component, a special and prominent feature of oil-rich ergot tissue. Triglyceride oil was extracted by organic solvents from the dairy feed, and the oil was saponified to release fatty acids. Ricinoleate, as a methyl ester, was selectively resolved from other fatty acids by silica gel chromatography and was analyzed by capillary gas chromatography coupled with chemical ionization mass spectrometry, which demonstrated the presence of the methyl ricinoleate molecule and proved that the feed contained ergot. The methodology may be refined to monitor for ergot in powdered dairy feed more routinely.

Animal Feed↗

Interactions in sheep between tall fescue ergot alkaloids and hepatotoxic carbon tetrachloride and Senecio pyrrolizidine alkaloids.

The interaction between ergot alkaloids in endophyte-infected (E+) tall fescue (Festuca arundinacea) seed and pyrrolizidine alkaloids (PA) in tansy ragwort (TR; Senecio jacobaea) when simultaneously fed to sheep was investigated. Because of the hepatogenic effects of prolactin (PRL), it was hypothesized that low serum PRL induced by ergot alkaloids would increase the susceptibility of sheep to hepatotoxicity induced by PA. Sheep are normally resistant to PA-induced hepatotoxicity. Twenty-four wether lambs weighing 34.1 +/- 2.3 kg were used after being randomly assigned to 1 of 6 treatments of 4 wethers each. The diets offered were a control basal diet containing endophyte-free (E-) tall fescue seed, control + carbon tetrachloride (CCL4), E+ tall fescue basal diet, E+2CCl4, E(-)+TR, or E+2TR. The diets were composed of 50% alfalfa meal, 34.5% rolled barley, 5% soybean meal, 4% cane molasses, 0.5% trace mineralized salt and 6% tall fescue (E- or E+) seed. In the 2 TR treatments 25% of the alfalfa was replaced by TR. Interaction between ergot alkaloids in E+ tall fescue and PA in TR was assessed by gamma glutamyl transferase (GGTP) activity and/or sulfobromophthalein (BSP) clearance rate, both of which measure liver function. Serum GGTP activity was measured on days 14 and 28; plasma BSP clearance was monitored on days 28 and 70 by collection of blood at 4, 8 and 16 min after i.v. BSP injection. Serum PRL assays were performed on days 14, 70 and 84. Serum GGTP activity was elevated by CCl4 drenching on days 14 and 28. On day 28 TR feeding reduced GGTP activity, but there was no difference between the 2 TR treatments. There was no difference in the mean BSP half-times (t1/2) and % BSP retentions on day 28 among any of the 6 treatments. On day 70, there was no difference in the t1/2 or % BSP retention 4 min after BSP injection among any of the treatments. At 8 min after BSP injection, however, % BSP retention was significantly higher for the control +CCl4 than for the E+2CCl4 treatment. At 16 min after BSP injection, the E+ treatment had a higher mean % BSP retention value than the E+2CCl4 treatment; there were no differences among the other treatments. Serum PRL levels were reduced by E+ or CCl4 on all 3 dates of PRL evaluation. The lack of interaction between ergot alkaloids in E+ tall fescue seed and PA in TR as assessed by GGTP activity and/or BSP clearance in sheep may imply that the target sites o the 2 alkaloids are metabolically different. The low serum PRL with E+ did not increase susceptibility of sheep to CCl4 or PA.

Alkaloids↗

[Ergotism caused by automedication].

The authors report 7 cases of gangrenous ergotism (six women and one man) secondary to an overdose of ergotamine ingested in order to relieve migraine crisis. In all cases, patients presented symptoms and signs of severe arterial constriction confirmed by echography and angiography. Hallucinations were absent. Ergotamine ingestion was discontinued and treatment was based on vasodilators and sympathectomy. After treatment, all seven patients showed clinical improvement with disappearance of the vasospastic symptoms and signs, and an increase in the plethysmographic index of blood perfusion, measured by Doppler echography. These changes were observed even in a patient who lost two toes of the right foot. Although, none of the patients presented hallucinations, the authors made reference to the historical first use of the ergot in magic and religious rites that took place in Eleusis, at the time of classic Greece, as well as the more recent mystic use of ergot in Salem, New England, in 1692. Migraine is indeed a serious disease, frequently causing despair to the patient, who attempts to alleviate the migraneous crisis with an overdose of ergotamine. Accordingly, physicians must be aware of prophylactic vasodilating drugs, reducing the risk of ergotism.

Adult↗

[Use of polymerase chain reaction for searching for producers of ergot alkaloids from among microscopic fungi].

The potential of the polymerase chain reaction for the detection of ergot alkaloid producers among microscopic fungi of the genera Penicillium and Claviceps was evaluated. Twenty-three strains of various species of fungi with a previously studied capacity for alkaloid production were used. The internal fragment of the gene encoding 4-dimethylallyltryptophan synthase, the enzyme catalyzing the first step in the biosynthesis of ergot alkaloids, was amplified using degenerated primers. This approach revealed an about 1.2-kb specific DNA fragment in micromycetes synthesizing ergot alkaloids with complete tetracyclic ergoline system. Microorganisms that produce alkaloids with modified C or D ergoline rings, as well as alpha-cyclopiazonic acid, did not yield the PCR fragment of the expected size. This fragment was also not found in fungi incapable of ergot alkaloid production.

Alkyl and Aryl Transferases↗

Effect of ergot alkaloids on 3H-flunitrazepam binding to mouse brain GABAA receptors.

In vitro effects of dihydroergotoxine, dihydroergosine, dihydroergotamine, alpha-dihydroergocriptine (ergot alkaloids), diazepam, methyl-beta-Carboline-3-carboxilate (beta-CCM), flumazenil (benzodiazepines), gamma-amino butyric acid (GABA) and thiopental (barbiturate) were studied on mouse brain (cerebrum minus cerebral cortex) benzodiazepine binding sites labeled with 3H-flunitrazepam. Specific, high affinity (affinity constant, Kd = 57.7 8.6 nM) binding sites for 3H-flunitrazepam on mouse brain membranes were identified. All benzodiazepine drugs inhibited 3H-flunitrazepam binding with nanomolar potencies. In contrast to benzodiazepines, all ergot drugs, GABA and thiopental produced an enhancement of 3H-flunitrazepam binding to its binding site at the GABAA receptor of the mouse brain. The rank order of potency was: neurotransmitter (GABA) > dihydroergotoxine > thiopental > alpha-dihydroergocriptine > dihydroergosine > dihydroergotamine. The results suggest that dihydrogenated ergot derivatives do not bind to the brain benzodiazepine binding sites labeled with 3H-flunitrazepam. However, an enhancement of 3H-flunitrazepam binding by all ergot drugs tested, clearly identifies an allosteric interaction with the benzodiazepine binding sites of GABAA receptors.

Animals↗

[The effect of some amino acids on the growth and biosynthesis of ergot alkaloids and quinocitrinins in the fungus Penicillium citrinum Thom 1910].

The effect of some amino acids, added to the medium either during inoculation or in the stationary growth phase, on the growth and biosynthesis of ergot alkaloids and quinocitrinins in the fungus Penicillium citrinum VKM FW-800 has been studied. Exogenously added amino acids were mostly utilized in primary metabolism. When added during inoculation, tryptophan and leucine virtually did not influence fungal growth and synthesis of the alkaloids, whereas the addition of isoleucine enhanced the biomass accumulation. When added in the stationary growth phase, tryptophan stimulated the synthesis of both ergot alkaloids and quinocitrinins. Leucine added in the stationary growth phase did not influence the synthesis of ergot alkaloids but inhibited the synthesis of quinocitrinins. Isoleucine inhibited the synthesis of both ergot alkaloids and quinocitrinins irrespective of the time of its addition to the medium.

Alkaloids↗

Bioconversions of ergot alkaloids.

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.

Animals↗

[Ergotism in migraine. Peripheral vascular complications in 14 patients with migraine].

The general occurrence of subclinical ergotism with reduced peripheral systolic blood pressures in patients taking ergotaminepreparations regularly for migraine and the frequent occurrence of milder symptoms indicates that severe ischaemia of the extremities is not as rare a complication as would appear from the few case reports published. The 14 cases reported here constitute the largest series published of migraine patients with acute ergotism. The patients, all women, were admitted to a vascular department over a period of 14 years. They suffered from severe ischaemia of one or more extremities after consumption of varying doses of ergotamine tartrate. Ten patients had previously exhibited symptoms of acute or chronic ergotism, but only eight were admitted with this diagnosis. Liver enzyme tests were abnormal in five out of six patients examined, while three patients had ECG signs of myocardial ischaemia, regressing during treatment. At the beginning of the period, hyperbaric oxygen at 3 ATAB was the standard treatment. Since 1980, the treatment of choice has been continous i.v. nitroglycerine infusion for 24 hours. Nine patients experienced prolonged postischaemic symptoms; one patient required a forefoot amputation and four patients had permanent ischaemic muscular damage. Increased bioavailability of ergotamine due to hepatic vasospasm is suggested as a cause of sudden reduced tolerance to ergotamine. Peripheral systolic pressures and liver function tests should be controlled in patients taking ergotamine regularly. Subclinical ergotism over a prolonged period may facilitate development of occlusive peripheral vascular disease.

Adult↗