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PubMedDate not supplied

[Daily chronic headache in patients with migraine induced by abuse of ergotamine-analgesics: response due to a protocol of outpatient treatment].

Chronic daily headache appears in migraine patients due to chronic consumption of analgesics-ergotamine. This entity was considered intractable without hospital admission. Our aim was to study the response of this headache to an outpatient treatment protocol. The therapeutic protocol included: 1. Oral information to the patient about the role of analgesics in the chronification of the headache; 2. Abrupt withdrawal of analgesics-ergotamine; 3. Administration of naproxen as symptomatic medication, and 4. Prophylactic treatment. After 2.5 months of treatment we evaluated both the frequency and the intensity of pain episodes as well as analgesic consumption. Thirty patients (8.6% of the outpatient consultations) suffered from chronic daily headache secondary to chronic analgesic abuse. Twenty five were females and 5 were males, their mean age +/- SD being 43 +/- 11 years. The mean +/- SD number of units of analgesics-ergotamine taken per week was 28 +/- 12. Three patients exclusively abused analgesics, the remainder either ergotamine, caffeine and various analgesics (18) or caffeine or several analgesics not containing ergotamine (9). In 29 patients the response was positive. Twenty (67%) showed an excellent improvement (> 75%) in frequency and intensity and completely gave up analgesics. The remaining nine (30%) improved moderately (50-75%). Only 3 patients in this group carried on taking analgesics. One patient showed no improvement. Our work confirms the epidemiological magnitude of chronic daily headache and shows that this is a treatable entity on an outpatient basis combining the abrupt withdrawal of analgesics-ergotamine, and their replacement by naproxen, with prophylactic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Ergotamine tartrate dependency: features and possible mechanisms.

Based on our clinical experience and the data reviewed and presented in this report, we propose that a state of physical dependency to ergotamine tartrate exists. This dependency state is characterized by the irresistible and dependable use of ergotamine tartrate and is contingent upon a self-sustaining, rhythmic headache/medication cycle that reflects the dependency. The headache and accompaniments (withdrawal headache?) represent the primary withdrawal symptoms. The presence of this state appears to render patients refractory to other forms of preventative therapy, which can be effective only when ergotamine is discontinued and the cycle broken. If the condition is left untreated, it is likely though by no means certain that the more traditional aspects of ergotism will evolve, although variable susceptibility and tolerance to ergotamine tartrate have been demonstrated. The mechanism of this disorder remains uncertain but might be related to the influence of ergotamine tartrate on the limbic-hypothalamic-pituitary-adrenal axis and other aminergic centers (locus ceruleus), areas considered by some as the central loci for the pathogenesis and associated symptoms of migraine.

Adult↗
PubMed2002

Cardiovascular, respiratory, and body temperature responses of sheep to the ergopeptides ergotamine and ergovaline.

OBJECTIVE: To compare the effects of the ergot alkaloid ergovaline with effects of ergotamine on blood pressure, heart rate, respiratory rate, and body temperature in conscious sheep. ANIMALS: 3 sheep with indwelling arterial catheters. PROCEDURE: Ergotamine and ergovaline were injected IV (20 nmol/kg), and their effects on arterial blood pressure, heart rate, respiratory rate and pattern, body temperature, and skeletal muscle electromyographic activity were compared with control values obtained following injections of saline (0.9% NaCI) solution or acetone. RESULTS: Both ergopeptides caused immediate and significant increases in blood pressure (50 to 75 mm Hg) without concomitant increases in heart rate. Ergovaline but not ergotamine significantly increased pulse pressure (35 mm Hg). Both ergopeptides resulted in decreased respiratory rate and increased respiratory depth within the first hour of administration. Body temperature was decreased slightly upon ergopeptide administration but continued to increase thereafter, with greater increases developing with ergovaline than with ergotamine. Increased body temperatures of 3.0 to 3.5 C were maintained for at least 10 hours. Respiratory rate was increased to rates as high as 210 to 220 breaths/min in association with hyperthermia. Ergopeptides had no effect on skeletal muscle electromyographic activity. CONCLUSIONS AND CLINICAL RELEVANCE: In sheep, ergovaline has similar effects to ergotamine on cardiovascular and pulmonary function and body temperature but is more potent. These effects are consistent with clinical signs observed in the toxicoses developed when ruminants ingest grass with high concentrations of ergopeptides.

Animals↗
PubMed1980

Solubility and dissolution rate studies of ergotamine tartrate.

The solubility of ergotamine tartrate in aqueous solutions of tartaric acid, citric acid, hydrochloric acid, and caffeine and the dissolution rate of ergotamine tartrate in aqueous mixtures containing hydrochloric acid, caffeine, citric acid, or sodium acetate were studied. The Noyes-Whitney model of dissolution is useful for predicting the dissolution rate of ergotamine tartrate in most of the dissolution media. The relative slowness with which ergotamine chloride (a substance with low water solubility) precipitated when ergotamine tartrate was dissolved in 0.1 M HCl resulted in the solid dissolving faster in this medium than was predicted using the Noyes-Whitney equation.

Caffeine↗
PubMed1991

Ergotamine, flunarizine and sumatriptan do not change cerebral blood flow velocity in normal subjects and migraneurs.

Changes in the diameter of extracranial and intracranial arteries resulting in changes in cerebral blood flow have previously been assumed to be the most important pathophysiological factor in migraine. To test this hypothesis 20 normal subjects, and three groups of patients (n = 29) with migraine were investigated by means of transcranial Doppler sonography. Blood flow velocities in the middle cerebral (MCA) and in basilar (BA) arteries were measured. Data from patients were obtained in the interval between migraine attacks, during migraine attacks and following treatment with either ergotamine (0.5 mg i.m.; n = 10); flunarizine, a calcium overload blocker (20 mg i.v.; n = 13); or a 5-HT1-like agonist (sumatriptan, 4 mg s.c.; n = 6). Ergotamine and sumatriptan are constrictors of cerebral arteries in animal experiments. The arithmetic mean of flow velocity in the BA was reduced in normal subjects (45 cm/s) as compared with patients with migraine measured in between attacks (53 cm/s). Mean flow velocity in MCA was not different in normals (72.5 cm/s) as compared with migraineurs (75 cm/s). Neither ergotamine nor the 5-HT1 agonist and flunarizine resulted in a significant change in blood flow velocity in MCA and BA. This was true irrespective of whether the drugs were given in the headache-free period, during a migraine attack or during the withdrawal phase of drug-induced headache. Ergotamine was effective in improving headache during migraine attacks and sumatriptan attenuated headache during drug withdrawal from chronic analgesic intake. These results indicate that the action of ergotamine and the 5-HT1-receptor agonist is probably not mediated by their vasoconstrictor action on cerebral arteries.

Adult↗
PubMed1982

Correlation between pharmacokinetics and clinical effects of ergotamine in patients suffering from migraine.

The systemic availability of ergotamine after a single therapeutic oral or rectal dose was studied using a radioimmunoassay during the headache free state in 24 patients suffering from migraine. Plasma concentrations of the drug were compared with anamnestic data about its clinical effects in the same patients. Among 12 patients with a good therapeutic response to medication, the mean plasma ergotamine levels stayed in the range 0.20 to 0.50 ng/ml for 6 h. Their mean plasma levels at 30 min (0.33 ng/ml) and 1 h (0.40 ng/ml) were significantly higher than those (0.06 and 0.08 ng/ml, respectively) in 9 patients with only a moderate therapeutic response. In 9 patients with a moderate and 3 with a poor therapeutic response, the mean plasma level generally stayed below 0.10 ng/ml. The mean peak concentrations in moderate (0.13 ng/ml) and poor (0.11 ng/ml) responders appeared later (at 3 h) than in good responders (at 1 h). Side effects of the medication appeared to be associated with relatively low plasma levels of ergotamine and also with delayed maximum plasma concentrations of the drug. The present results suggest that the time of the maximum plasma drug level is an important determinant of the clinical effects of ergotamine, and that a good therapeutic response may be expected if a plasma ergotamine level of 0.20 ng/ml or more is achieved within 1 hour after oral or rectal administration.

Adult↗
PubMed1979

Systemic availability of ergotamine tartrate after oral, rectal and intramuscular administration.

Plasma ergotamine levels were measured in 33 volunteers (subgroups 11, 12 and 10) after a single dose of ergotamine administered by various routes. Ergotamine tartrate was given in doses normally used in the treatment of acute migraine--2.0 mg orally, 2.0 mg combined with 100 mg caffeine rectally and 0.5 mg i.m. Plasma ergotamine concentrations were determined by radioimmunoassay. The highest and longest lasting levels were found after i.m. administration, the peak concentration being 1.94 +/- 0.34 (SEM) ng/ml at 1/2 h. The corresponding maximum concentrations after oral and rectal administration were 0.36 +/- 0.08 ng/ml at 2 h and 0.42 +/- 0.09 ng/ml at 1 h. In most of the subjects the plasma ergotamine level began to rise again at 24 to 48 h. The cause of the elevation is not known but it might favour possible accumulation of the drug. Absorption from suppositories was at least as good as after oral administration and the former route may therefore be advantageous for migraine patients in whom nausea and vomiting during an attack may prevent efficient oral medication.

Administration, Oral↗
PubMed1979

Presynaptic inhibition by ergotamine of the responses to cardioaccelerator nerve stimulations in the cat.

The effects of ergotamine on the tachycardia elicited by postganglionic stimulation of the cardioaccelerator nerve have been investigated in both intact and spinal (desmethylimipramine-pretreated) cats. Ergotamine (2.5--20 microgram kg-1) selectively antagonized the response to low-frequency (0.3--3 Hz) stimulation. The responses elicited by stimulation of the nerve with higher frequencies (greater than 10 Hz) either remained unaltered or were facilitatated by the drug. Pretreatment of the cats with pimozide (0.2 mg kg-1) completely antagonized the inhibitory effects of ergotamine on the sympathetic neuron. Although phentolamine (0.5 mg kg-1) did appear to attenuate the effects of ergotamine, the changes were, however, not statistically significant. Since the drug did not reduce the cardiac effects of isoprenaline or tyramine, it is concluded that ergotamine interferes with the release of noradrenaline from the cardioaccelerator nerve, mainly by stimulating the presynaptic dopaminergic receptors. This effect may be an important mechanism by which the drug causes bradycardia in almost all species regardless of the blood pressure response.

Animals↗
PubMed1992

Is dietary ergotamine atherogenic in the rabbit?

The effect of dietary ergotamine on pre-lesional indicators of atherosclerosis was studied in rabbits. The experimental purified diets contained 0.08% (w/w) cholesterol and either 0, 40 or 200 mg ergotamine-tartrate/kg. After 6 wk, serum total cholesterol concentration and the ratio of serum total cholesterol: high-density lipoprotein-cholesterol were significantly increased by ergotamine in a dose-dependent manner. Dietary ergotamine raised the total level of glycosaminoglycans and the relative proportion of chondroitin sulphate in the abdominal aorta. It is suggested that dietary ergotamine is atherogenic in the rabbit.

Animals↗
PubMed1986

Mutual inhibition and synergistic effects of ergotamine and the calcium antagonist darodipine.

The interaction between ergotamine 3 and 30 micrograms/kg i.v. and darodipine (PY108-068) 30 micrograms/kg i.v. was studied in anaesthetized cats. Ergotamine decreased heart rate, cardiac output and total peripheral conductance dose-dependently. Ergotamine caused regional vasoconstriction (measured with tracer microspheres) in the heart, kidneys, adrenals, liver, spleen, skin and arterio-venous shunts but dilatation in the pancreas and skeletal muscle, possibly attributable to serotoninergic stimulation. Darodipine reversed most ergotamine effects except those on the spleen, skin and arterio-venous shunts. Since constriction of arterio-venous shunts was not inhibited, ergotamine is unlikely to lose its effectiveness in migraine patients under concomitant dihydropyridine treatment, while unwanted vasoconstrictor effects are likely to be diminished.

Animals↗
PubMed1976

Quantitative thin-layer chromatographic analysis of ergotamine tartrate and caffeine in the nanogram range.

Direct, quantitative, thin-layer chromatographic methods for the determination of ergotamine tartrate and caffeine in the presence of each other in blood and in pharmaceutical preparations are described. The blood is centrifuged, the plasma decanted from the coagulum and deproteinized with acetone-methanol. After removal of the solvent mixture, the active ingredients are extracted from the remaining aqueous solution with chloroform. In the case of the pharmaceutical preparations, the active ingredients are also extracted with chloroform or methanol. Ergotamine tartrate and caffeine are separated on pre-coated silica gel 60 F254 plates and measured directly on the thin-layer plate, ergotamine tartrate being determined by the fluorescence method, excitation wavelength 365 nm, at lambdamax.=450 nm and caffeine by the reflactance method at lambdamax.=274 nm. The analytical methods are suitable for the bioavailability studies of these drugs in blood as they enable the determination of 20 ng ergotamine tartrate with a coefficient of variation of 6.7% and the determination of 200 ng caffeine with a coefficient of variation of 6.1%. The methods have also proved useful in the determination of the active ingredients of drug forms such as tablets and suppositories and can be well reproduced with a maximum coefficient of variation of 4.9% for ergotamine tartrate and 3.5% for caffeine.

Biological Availability↗
PubMed1999

Canine external carotid vasoconstriction to methysergide, ergotamine and dihydroergotamine: role of 5-HT1B/1D receptors and alpha2-adrenoceptors.

The antimigraine drugs methysergide, ergotamine and dihydroergotamine (DHE) produce selective vasoconstriction in the external carotid bed of vagosympathectomized dogs anaesthetized with pentobarbital and artificially respired, but the receptors involved have not yet been completely characterized. Since the above drugs display affinity for several binding sites, including alpha-adrenoceptors and several 5-HT1 and 5-HT2 receptor subtypes, this study has analysed the mechanisms involved in the above responses. Intracarotid (i.c.) infusions during 1 min of methysergide (31-310 microg min(-1)), ergotamine (0.56-5.6 microg min(-1)) or DHE (5.6-31 microg min(-1)) dose-dependently reduced external carotid blood flow (ECBF) by up to 46+/-4, 37+/-4 and 49+/-5%, respectively. Blood pressure and heart rate remained unchanged. The reductions in ECBF by methysergide were abolished and even reversed to increases in animals pre-treated with GR127935 (10 microg kg(-1), i.v.). The reductions in ECBF by ergotamine and DHE remained unchanged in animals pre-treated (i.v.) with prazosin (300 microg kg(-1)), but were partly antagonized in animals pre-treated with either GR127935 (10 or 30 microg kg(-1)) or yohimbine (1000 microg kg(-1)). Pre-treatment with a combination of GR127935 (30 microg kg(-1)) and yohimbine (1000 microg kg(-1)) abolished the responses to both ergotamine and DHE. The above doses of antagonists were shown to produce selective antagonism at their respective receptors. These results suggest that the external carotid vasoconstrictor responses to methysergide primarily involve 5-HT1B/1D receptors, whereas those to ergotamine and DHE are mediated by 5-HT1B/1D receptors as well as alpha2-adrenoceptors.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2005

Interactions of metoclopramide and ergotamine with human 5-HT(3A) receptors and human 5-HT reuptake carriers.

The actions of metoclopramide and ergotamine, drugs which are used as a combined migraine medication, on human (h)5-HT3A receptors and 5-HT reuptake carriers, stably expressed in HEK-293 cells, were studied with patch-clamp- and ([3H]5-HT)-uptake techniques. At clinical concentrations, metoclopramide inhibited peak and integrated currents through h5-HT3A receptors concentration-dependently (IC50 = 0.064 and 0.076 microM, respectively) when it was applied in equilibrium (60 s before and during 5-HT (30 microM) exposure). The onset and offset time constants of metoclopramide action were 1.3 and 2.1 s, respectively. The potency of metoclopramide when exclusively applied during the agonist pulse decreased more than 200-fold (IC50 = 19.0 microM, peak current suppression). Metoclopramide (0.10 microM) did not alter the EC50 of 5-HT-induced peak currents. In contrast to the lack of competitive interaction between metoclopramide and 5-HT in this functional assay, metoclopramide inhibited specific [3H]GR65630 binding to human h5-HT3A receptors in a surmountable manner. This seeming discrepancy between functional studies and radioligand binding experiments may be accounted for by (1) the slow kinetics of inhibition of peak currents by metoclopramide compared with the fast onset and offset kinetics of 5-HT-induced currents and (2) the low efficacy of metoclopramide in inhibiting radioligand binding (e.g. only 20% binding inhibition compared to 79% peak current suppression by 200 nM metoclopramide). At low concentrations (1-10 nM), ergotamine had no effect on 5-HT (30 microM)-induced peak currents. Above clinical concentrations, ergotamine (>3 microM) inhibited them. When both drugs were applied together (0.10 microM metoclopramide +0.001 to 0.01 microM ergotamine), an inhibition of both, peak and integrated current responses was observed. Neither metoclopramide (< or =30 microM) nor ergotamine (< or =30 microM) had an effect on the 5-HT reuptake carrier as they did not alter the citalopram-sensitive [3H]5-HT uptake.

Adrenergic alpha-Agonists↗
PubMed2000

The influence of ergotamine abuse on psychological and cognitive functioning.

Migraine patients abusing ergotamine often have chronic daily headaches associated with tiredness, sleep and memory disturbances, and reduced general well-being. We quantified psychological and cognitive functioning in 12 migraine patients with and 12 without ergotamine abuse (> or = 5 days/week for > or = 6 months) and 12 healthy controls. Psychological functioning assessed by Symptom Checklist-90 (SCL-90) and Profile Of Mood State (POMS), was impaired in ergotamine abusers compared to healthy controls. Cognitive functioning divided into four domains: attention (critical flicker frequency analysis and mental control subscale of the Wechsler Memory Scale (WMS), speed of information processing (reaction time tasks and lexical decision tasks), memory (four subscales of the WMS) and cognitive flexibility (trailmaking test and WMS digits backwards), was impaired in ergotamine abusers in speed of information processing and cognitive flexibility. These differences disappeared after correction for total SCL-90 scores. In conclusion, ergotamine abuse is associated with high psychological distress but not with structural impaired cognitive functioning.

Cognition↗
PubMed1999

Increased proinflammatory cytokines production by ergotamine in male BALB/c mice.

The ergopeptine alkaloid ergotamine (ET) mimics the effects of ergopeptine alkaloids found in endophyte-infected (E+) fescue forage considered causative for fescue toxicosis. Altered immune capacity, compromised intake and thermoregulation, and inflammatory changes are observed in fescue toxicosis. Taken together, these suggest the cytokine pattern may be altered by ergot alkaloids. Thus, the objective of this study was to determine whether major splenocyte-derived cytokines--interleukin 2 (IL-2), interleukin 4 (IL-4), interferon gamma (IFN-gamma)--and macrophage-derived cytokines--interleukin 1beta, (IL-1beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha)--were affected by ergotamine. Two sets of male BALB/c mice (n = 5/treatment) were treated with ergotamine tartrate (s.c.) for 10 d at doses of 0 (control), 0.4, 2, 10, or 50 mg/kg body weight. Twenty-four hours after the last treatment, splenocytes (S) were isolated from one set of animals and macrophages (Mphi) from the other set for determination of IL-2, IL-4, INF-gamma, and IL-1beta, IL-6, TNF-alpha, respectively. Following activation with 5 microg/ml concanavalin A (Con A) (S) and 10 microg/ml lipopolysaccharide (LPS) (Mphi), cells were incubated for 48 and 24 h, respectively, and supernatants were collected and assayed for respective cytokines by enzyme-linked immunosorbent assay (ELISA). Additionally, differential white blood cell (WBC) counts were performed and the neutrophil (N):lymphocyte (L) ratio calculated. Ergotamine treatment significantly increased IL-6 levels at the 2.0 mg/kg dose and greater and TNF-alpha at the highest dose. There was no treatment effect on IL-1beta, IL-2, IL-4, and IFN-gamma. Also, no effect was observed upon total and differential WBC counts as well as N:L ratio. Ergotamine affected the proinflammatory cytokine IL-6, and this increase may contribute to fescue tosicosis.

Animals↗
PubMedDate not supplied

Regional myocardial perfusion and wall thickness and arteriovenous shunting after ergotamine administration to pigs with a fixed coronary stenosis.

The hemodynamic effects of antimigraine drug ergotamine, which is considered contraindicated in patients with coronary artery disease, were studied in pigs with a normal myocardial circulation (doses of 8, 16, and 32 micrograms/kg, i.v.) or with acute coronary stenosis (8 micrograms/kg). In both groups of animals, ergotamine decreased heart rate, cardiac output, and arteriovenous anastomotic blood flow while increasing aortic blood pressure and systemic vascular resistance. No effects on total ventricular blood flow and its distribution within the myocardium were found in normal animals. In animals with a clamp on the left anterior descending coronary artery (LAD), the blood flow to the LAD-perfused area was reduced from 1.10 +/- 0.16 to 0.67 +/- 0.05 cm3/min/g. The endocardium was affected more than the epicardium and the endo/epi flow ratio decreased from 1.18 +/- 0.05 to 0.74 +/- 0.07. Ergotamine increased the blood flow to the ischemic zone towards normal values, and the endo/epi flow ratio to 1.05 +/- 0.21. However, myocardial wall thickness parameters, which showed functional deterioration during ischemia, did not change after ergotamine. The present study provides no clear support for cardiovascular contraindications to ergotamine administration.

Animals↗
PubMed1992

Ketoprofen and ergotamine in acute migraine.

The objectives of this study were to evaluate and compare the efficacy and tolerability of ketoprofen and ergotamine in the treatment of acute migraine attacks without aura. The study design was a single-centre, double-blind, placebo-controlled, cross-over comparison of a single dose of ketoprofen (100 mg) and ergotamine (2 mg) suppositories in the treatment of acute migraine attacks. Fifty patients were included in the statistical evaluation. Ketoprofen was found to be more efficient than ergotamine and placebo in reducing the severity of pain. Ketoprofen was found to be more satisfactory than ergotamine and placebo with regard to influence on working ability, and better than placebo in global assessment. We conclude that ketoprofen (100 mg suppository) is superior to ergotamine (2 mg suppository) and placebo in the symptomatic treatment of acute migraine attacks, and has better tolerability.

Acute Disease↗
PubMed1981

Ergotamine abuse. Do patients benefit from withdrawal?

A follow-up study of 40 patients (migraine 39, cluster headache 1) previously treated for ergotamine abuse was conducted. Their statements regarding ergotamine intake were checked using butalbital (contained in the suppositories abused by 90% of the patients) as a tracer, and later by contact with the family doctor. Eleven patients abused ergotamine again during a median observation time of 21 months. Nineteen patients had more than a 50% reduction in headache days after withdrawal and half of the patients were relieved of other symptoms of ergotamine toxicity. Even with a failure rate of approximately 25% it is concluded that efforts to withdraw after abuse of ergotamine are worthwhile.

Adult↗