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Ergot alkaloids and their dihydrogenated methanesulphonate (ms) salts were determined and measured in human plasma. High-performance liquid chromatography (HPLC) with fluorometric detection was used for separation of ergot alkaloids in plasma. Several ergot alkaloids and their derivatives, including lysergide (LSD), can be identified in cases of poisoning.
The effect of various ergot alkaloids on prolactin (Pr) secretion in adult female rats was determined by radioimmunoassay. Ergocorine (ECO) and ergocristine (ECR) in doses of 0.25 to 1.0 mg lowered serum Pr markedly by 1 h with the effect persisting for 24 h at the larger doses. Several other ergots had similar effects while the dihydro derivatives had diverse responses. The pro-oestrous surge of Pr could be blocked by ECR or ECO without interfering with the oestrous cycle. ECO or ECR could suppress the rise in serum Pr induced by oestradiol benzoate (OeB) (5-50 mug) in oophorectomized rats. Perphenazine (PE) stimulation of Pr could be partially antagonized by ECO depending on dose and timing of injections. ECO 2 mg produced an abrupt cessation of lactation with concomitant fall in serum Pr, and ovine prolactin restored this function. Evaluation of pituitary Pr concentration in lactating and intact rats receiving ECO leads to the conclusion that release of Pr from the pituitary is affected. ECO 1 or 2 mg produced a regression of dimethyl-benz(a)anthracene (DMBA) induced rat mammary tumours which could not be reversed by OeB 5 mug, with persisting low serum Pr. PE 1 mg was able to raise serum Pr and stimulated tumour growth. Several of the ergot alkaloids have a profound inhibiting effect on Pr secretion and may be used for studies on Pr action, as well as in medical therapeutics.
The inhibitory effects of dopamine and various ergot alkaloids on prolactin secretion were studied using continuously perfused columns of dispersed rat anterior pituitary cells. Bromocriptine (5 nmol/l) and lisuride hydrogen maleate (5 nmol/l) both inhibited prolactin secretion, the effects persisting for more than 3 h after the end of the administration of the drugs. A similar although less long-lasting effect was observed with lergotrile (50 nmol/l) and the new ergoline derivative, pergolide (5 nmol/l). These effects contrasted with the rapid disappearance of the action of dopamine. The potency estimates of the ergots relative to that of dopamine were: lergotrile, 2.3; bromocriptine, 13; lisuride, 15; pergolide, 23. Ther dopamine-receptor blocking drugs, metoclopramide and haloperidol, antagonized the prolactin release-inhibiting activity of the compounds; bromocriptine and lisuride showed the highest resistance to this dopaminergic blockade. The results suggested that the direct effect of the ergot derivatives on dispersed pituitary cells was mediated through dopamine receptors and emphasized the long-lasting action of bromocriptine and lisuride in vitro.
Ergot alkaloids cause fescue toxicosis when livestock graze endophyte-infected tall fescue. It is generally accepted that ergovaline is the toxic component of endophyte-infected tall fescue, but there is no direct evidence to support this hypothesis. The objective of this study was to examine relative and potential transport of ergoline and ergopeptine alkaloids across isolated gastric tissues in vitro. Sheep ruminal and omasal tissues were surgically removed and placed in parabiotic chambers. Equimolar concentrations of lysergic acid, lysergol, ergonovine, ergotamine, and ergocryptine were added to a Kreb's Ringer phosphate (KRP) solution on the mucosal side of the tissue. Tissue was incubated in near-physiological conditions for 240 min. Samples were taken from KRP on the serosal side of the chambers at times 0, 30, 60, 120, 180, and 240 min and analyzed for ergot alkaloids by competitive ELISA. The serosal KRP remaining after incubation was freeze-dried and the alkaloid species quantified by HPLC. The area of ruminal and omasal tissues was measured and the potential transportable alkaloids calculated by multiplying the moles of transported alkaloids per square centimeter of each tissue type by the surface area of the tissue. Studies were conducted to compare alkaloid transport in reticular, ruminal, and omasal tissues and to determine whether transport was active or passive. Ruminal tissue had greater ergot alkaloid transport potential than omasal tissue (85 vs 60 mmol) because of a larger surface area. The ruminal posterior dorsal sac had the greatest potential for alkaloid transport, but the other ruminal tissues were not different from one another. Alkaloid transport was less among reticular tissues than among ruminal tissues. Transport of alkaloids seemed to be an active process. The alkaloids with greatest transport potential were lysergic acid and lysergol. Ergopeptine alkaloids tended to pass across omasal tissues in greater quantities than across ruminal tissues, but their transport was minimal compared to lysergic acid and lysergol.
Vasospasm related to ergot intoxication has been recognised since the Middle Ages when it occurred due to ingestion of rye contaminated with Claviceps purpurea. Today ergotism is a rare cause of peripheral ischaemia, most often associated with ergotamine tartrate therapy for migraine headaches. Recognition of the typical angiographic pattern is important, as the classic drug history may not be obtained, and the cause of the ischaemia can be overlooked. Early diagnosis is important as the outcome may be serious if left untreated. Arterial vasospasm, collateralisation, and secondary thrombus formation are the major angiographic findings. Ergotism responds to conservative therapy which includes drug withdrawal, intravenous nitroprusside, fluid therapy and heparinisation. We describe the angiographic findings of four cases and report on the results of therapy.
Monoaminergic neuronal systems have been implicated in the mechanisms of action of most ergot derivatives (including those that are clinically useful and those that are "hallucinogenic"). Among the various assays that have been useful in determining the extent of such involvement is drug discrimination. In this procedure, animals are trained to respond in one way (e.g., press the right lever) following saline and to respond differently (e.g., press the left lever) after either a particular ergot or a neurotransmitter agonist, and are subsequently tested with other ergots, transmitter agonists or antagonists (alone or in combination with the training drug). The results to date indicate that: 1) There are similarities in the discriminable effects of lergotrile, lisuride and bromocriptine, which probably involve catecholaminergic neuronal systems (DA or NE). 2) These effects are clearly separable from those of ergonovine and LSD, which may be relatively more serotonergic. More precise delineation of the mechanisms underlying these cues (e.g., D1, D2-selective agonism, antagonism, etc.) awaits further testing with highly specific pharmacological interventions.
The effects of ergot drugs on central monoaminergic mechanisms, particularly dopaminergic mechanisms, have been investigated in histochemical, biochemical and behavioral studies. It is concluded that the behavioral effects and the antiparkinsonian properties of ergot drugs can to a large extent be explained by the hypothesis that ergot drugs act at various dopamine receptor sites in the brain as partial agonists, the ratio of agonist-antagonist activity varying from one dopamine receptor population to another.
A patient was seen with absent pulses and vague symptoms. History and clinical findings supported a diagnosis of ergotism due to heavy use of ergotamine suppositories. The patient continued to use ergotamine despite warnings and was seen on two additional occasions with ergotism. Previously a heavy user of ergotamine, she became sensitive to small doses, demonstrating marked vasospasm after only one suppository. This phenomenon, not previously reported, is postulated secondarily to drug interaction. The patient is presented with a review of the pharmacology, toxicity, and treatment of ergotamine-induced ergotism. Alerted to the possibility of drug interactions, physicians may safely use ergotamine in the treatment of migraine headache with careful monitoring for signs and symptoms of early toxicity.
Ergot's derivatives are widely used in the treatment of migraine and in the prophylaxy of deep venous thrombosis in association with heparin. Clinical ergotism is rarely observed and can affect all the arteries, especially of the inferior limbs. Vasospasm of the peripheral arteries and collateral formation are specific findings on angiography. We report the illustrative case of a 38 years old woman hospitalized for a small bowel occlusion. She suffers from chronic migraine treated by ergotamine tartrate. During her hospitalization, she develops an acute ischemia of the lower limbs. An ergotism was clinically suspected and confirmed by Duplex sonography which demonstrate multiple vasospasm. Under iv sodium nitroprusside and peridural analgesia the spasm resolved in 24 hours. The control Duplex sonography confirm the normality of the lower limb arteries. This examination modality allow a non-invasive diagnosis and evolution control of arteriospasm.
In three experiments pigs were offered diets contaminated with milled ergot sclerotia. In a metabolism study 0-5 per cent (w/w) of American wheat ergot decreased urinary nitrogen losses and improved the efficiency of nitrogen retention. When early weaned piglets ingested a diet contaminated with 2-5 per cent of the ergot, feed intake was reduced and growth rate decreased. Reduction in growth rate was also evident in growing pigs given a diet containing ergotised English wheat. These latter pigs had lesions in stomach, intestine and liver, consistent with a toxic insult. With respect to feed intake and growth these results agreed with those of an earlier study, although a toxic response was produced by a lower dosage rate and there was additional internal evidence of toxicity. Improved nitrogen retention was contrary to earlier evidence at higher dose rates but may merely reflect a tonic action which, at higher doses, becomes toxic.
The macrolide class of antibiotics, including erythromycin and troleandomycin, is associated with clinically significant adverse drug interactions. This results from macrolide inhibition of cytochrome P-450 metabolism of numerous xenobiotics, resulting in elevated serum drug levels and clinical intoxication. Animal studies, however, suggest that clarithromycin, the newest approved macrolide antibiotic, has has less potential for adverse drug reactions. We describe a patient who, on her fifth day of clarithromycin therapy, developed clinical ergotism (i.e., hypertension, lingual ischemia, and peripheral cyanosis) several hours after administration of her usual 2-mg dose of ergotamine tartrate. To our knowledge, this is the first report of clinical ergotism precipitated by clarithromycin-ergotamine interaction and suggests that, like other macrolide antibiotics, ergot preparations should be avoided in patients who are taking clarithromycin.
We report a case of ergotamine tartrate induced severe vasospasm in the renal arteries and the arteries of the lower extremities. Classic features seen on peripheral angiography make the diagnosis. Anticoagulation, thrombolysis, vasodilation, steroids, and prostaglandin inhibitors all have been successfully used to treat symptomatic ergot induced arterial vasospasm. Although balloon angioplasty of ergot induced vasospasm has been described in case reports, ergot vasospasm is a self limited and medically treatable condition that does not require peripheral mechanical intervention, unless the immediate threat of necrosis and gangrene exists.
The number of reserpine-induced PGO waves in the cat is decreased by administration of ergot derivatives. The inhibition is dose-dependent and the various ergot derivatives show differing potencies. The action of the ergot derivatives may result from stimulation of central serotonin receptors. In addition, possible involvement of dopaminergic systems is discussed.
A woman was admitted after ergotamine tartrate overuse for migraine headaches and her symptoms of arterial vasospasm were treated with PGE1, the first reported use of the vasodilator for ergot intoxication. The advantages of producing local vasodilatation without systemic effect, as well as inhibiting the formation of arterial microthrombi, suggest PGE1 as the agent of choice for relief of symptoms due to peripheral vasoconstriction caused by ergot. Treatment with PGE1 may allow sufficient collateral to preserve limb function and integrity, while awaiting remission of anatomic changes after withdrawal of ergot.
The specific binding of [3H]spiperone (35 pM), as defined by the D-2 antagonist sulpiride, was potently displaced by ergot derivatives of both the ergoline and ergopeptine type, and by dopamine agonists and antagonists. The potency of the ergot derivatives ranged widely from an IC50 value of 3 nM for bromocriptine to a value of 1000 nM for the partial ergoline, LY-141865. GTP and its stable analogue, guanyl-5'-yl-imidodiphosphate (Gpp(NH)p), did not affect the affinity (100 pM) or density (30 pmol/g wet wt) of [3H]spiperone binding sites, but did decrease the potency of a number of ergoline compounds including pergolide, lergotrile and LY-141865, as well as dopamine agonists to displace [3H]spiperone binding. The affinities of the ergopeptines, bromocriptine and dihydroergocryptine, and of the isolysergic acid ergoline, lisuride, and dopamine antagonists were unaltered by the presence of guanine nucleotides. The effect was specific for guanine nucleotides, with near maximal effects on agonist affinity observed in the presence of a 100 microM concentration of nucleotide. The relative decrease in affinity found in the presence of GTP or Gpp(NH)p varied widely for individual ergot derivatives and dopamine agonists. The largest decrease was seen with dopamine itself, and agonists such as the tetralins and with LY-141865. Many ergolines had shifts in potency between those seen for agonists and antagonists, suggesting a partial agonist action at D-2 receptors. Guanine nucleotide sensitivity may represent a valuable in vitro method for studying the agonist/antagonist properties of dopaminergic drugs, such as the semi-synthetic ergoline compounds.
Plasma levels of prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and corticosterone (CORT) were measured in parturient Rockland-Swiss (R-S) albino mice following the daily administration for 10 days of 0.5 mg ergocornine (ERGO), 0.5 mg bromocriptine (BROMO), or sesame oil (OIL). The dams were provided with replete foster young on a daily basis so as to prevent the decline in suckling activity that normally occurs in undernourished pups of ergot-treated dams. Circulating PRL levels were significantly reduced by both ergot drugs but plasma levels of the other hormones measured were not altered. Thus, ergot drugs have relatively specific effects on PRL even in parturient animals receiving sustained high levels of suckling stimulation.
Over the past decade the various triptan derivatives have been accepted as the most effective available agents for relieving migraine attacks. Prior to that, for a period of half a century, ergotamine was the only 'specific' available for this purpose. In 1918, Stoll had isolated it from the various alkaloids present in extracts of the sclerotia of the fungus Claviceps purpurea (ergot), which grow on rye and, to a lesser extent, on other grasses. By 1925 ergotamine was beginning to be used to treat migraine attacks. However, as ergotamine was present in extracts of ergot, which had been used to treat migraine first in Italy in 1862, and then by Edward Woakes (1868) in England, and after him by Albert Eulenburg in Germany (1883), the drug had actually come into unrecognised use for the disorder more than half a century before ergotamine itself was known to exist. Unfortunately, because of ergotamine's chemical and pharmacokinetic properties, extracts of ergot of rye were incapable of producing consistent therapeutic results, so that general acceptance that the first specific substance for migraine treatment existed had to wait until pure ergotamine was available for administration.
A patient with diffuse and focal cerebral dysfunction was found to have absent peripheral pulses. Cerbral angiography revealed evidence of an arteritis with bilateral high grade carotid stenosis. When there was no laboratory confirmation of the arteritis, an iatrogenic etiology (ergotism) was suspected. This was later confirmed by the patient. The pertinent literature on ergotism is reviewed, and it is emphasized that ergotism may develop in patients on therapeutic doses of the drug.