Bioavailability and antimigraine efficacy of effervescent ergotamine

SYNOPSIS
In about 20% of migraine patients treatment with enterally administrated ergotamine tartrate proves unsuccessful. One of the causes for this might be a poor systemic availability of the drug from the ordinary solid tablets. The present study aimed to investigate the bioavailability and the therapeutic value of ergotamine tartrate in effervescent form.
In twenty volunteers the plasma ergotamine levels were measured by using a radioimmunoassay after oral administration of 2.0 mg ergotamine tartrate combined with 50.0 mg caffeine in effervescent form. Measurable plasma drug levels were found in 14 (70%) of the subjects and the mean maximum plasma ergotamine level of 0.45 ng/ml was achieved at 30 minutes.
In the clinical part of the study 25 migraine patients treated their migraine attacks with effervescent ergotamine. The therapeutic value of it was considered as good by 9, moderate by 11 and poor by 5 of the patients. Among 18 of them the therapeutic effect seemed to be equal to their earlier ergotamine medications. The results indicate that the plasma pharmacokinetics of ergotamine tartrate in effervescent form is similar to and possibly faster on the absorptive phase than that reported earlier after enteral administration. In patients who do not gain benefit from the usual ergotamine tablets or suppositories, effervescent ergotamine would appear to be an alternative worth consideration.     

Optimal routes of administration of ergotamine tartrate in cluster headache patients. A pharmacokinetic study

Bioavailability and rate of absorption of ergotamine were studied in eight cluster headache patients outside attacks. In a cross-over design, approximately 2 mg ergotamine tartrate was administered as effervescent tablets, suppositories, and from an inhalation device, with 0.25 mg intravenously as the reference. Ergotamine in plasma was measured by high performance liquid chromatography with fluorescence detection from 5 to 420 min. For all three routes of administration, a similar low (0.5-4.2%) bioavailability of ergotamine was estimated. Only inhalation of ergotamine resulted in early (at 5 min) peak concentrations of ergotamine in plasma and is therefore most likely to relieve the short-lived attacks of cluster headache. The inhalation route for ergotamine poses problems, however, and we suggest ways of improving the inhalation device.     

Acute migraine attack therapy: comparison of naproxen sodium and an ergotamine tartrate compound

The efficacy of safety of naproxen sodium and ergotamine tartrate were compared for the treatment of acute migraine attack in a randomized, parallel trial with 114 participating patients. At the start of symptoms, patients took either three tablets of naproxen sodium (275 mg each) or one of an ergotamine combination (containing 2 mg ergotamine tartrate, 91.5 mg caffeine, and 50 mg cyclizine chlorhydrate). Patients were followed for three months or until six attacks were monitored, whichever came first. Both medications substantially shortened the duration of migraine attacks and reduced the severity of symptoms. When the test medications were taken within 2 h of onset of attack, naproxen sodium was statistically significantly more effective than the ergotamine combination in reducing the severity of headache pain, nausea, and lightheadedness. The ergotamine combination was associated with significantly more vomiting, need for rescue medication, and side effects than was naproxen sodium. Four patients required discontinuation of the ergotamine combination and one of naproxen sodium. Both patients and investigators rated tolerance for naproxen sodium as superior to tolerance for the ergotamine combination. Naproxen sodium seems to be an effective and safe treatment for migraine attacks.     

Intramuscular ergotamine: plasma levels and dynamic activity

Ergotamine tartrate (0.5 mg) was injected intramuscularly into 10 subjects with migraine. The effect on peripheral arteries, measured as a decrease in toe-arm systolic gradients, developed slowly and was well sustained after 29 hr. In contrast, ergotamine was quickly absorbed (t1/2 = 3 min) and plasma levels (measured by HPLC) declined, with a biologic t1/2 of 2.5 hr. A hypothetic effect compartment model was adopted and kinetic and dynamic data were simultaneously fitted on a computer. Calculated from mean data, the rate constant for equilibration of the drug between plasma and effector site was 0.07 hr-1, with a t1/2 of 9.9 hr, and the steady-state plasma concentration resulting in 50% of maximal effect (Cpss50) was 0.24 ng/ml. The largest variability for the estimated kinetic and dynamic parameters among subjects was found for Cpss50 (coefficient of variation = 110%), indicating that, in addition to some kinetic variability, dynamic variability (difference in sensitivity) should be anticipated in the therapeutic use of ergotamine.     

Peripheral vascular effects and pharmacokinetics of the antimigraine compound, zolmitriptan, in combination with oral ergotamine in healthy volunteers

Members of the new class of antimigraine compounds, 5HT_1B/1D agonists, as well as ergotamine, may cause vasoconstriction through stimulation of 5HT receptors on peripheral vessels. The cardiovascular effects of 20 mg oral zolmitriptan (Zomig, formerly 311C90), 2 mg oral ergotamine and the combination were assessed in a randomized double-blind, placebo-corirolled crossover study in 12 healthy subjects. Pharmacodynamic measures included oscillometric blood pressure, systolic blood pressure at the toe and arm using a strain gauge technique, stroke volume and cardiac output using bioimpedance cardiography, high-resolution ultrasound to measure brachial arterial diameter and a novel Doppler method to measure blood flow velocity. Both drugs produced small degrees of peripheral vasoconstriction, including increases in diastolic blood pressure and blood flow velocity and decreases in arterial diameter and toe-arm systolic pressure gradient. These effects were generally additive with the combination but of no clinical importance. There were no significant changes in cardiac output, stroke volume heart rate or ECG. Zolmitriptan, at eight times the likely therapeutic dose, was generally well tolerated both alone and in combination with ergotamine. Ergotamine had no clinically important effects on zolmitriptan pharmacokinetics.     

Low biological availability of ergotamine tartrate after oral dosing in cluster headache

An attempt was made to determine the plasma ergotamine concentrations in nine male patients with cluster headache 15-600 min after oral therapeutic doses of ergotamine tartrate (Cafergot). Some of the patients were studied twice. Five patients received a constant dose of 2-4 mg daily for at least seven days. Four patients were given 1 mg five times on one day and three patients a single oral dose of 2 mg. Ergotamine was determined by means of high performance liquid chromatography with fluorescence detection--a new highly sensitive, specific method, the detection limit of which is less than 100 pg/ml for ergotamine. Ergotamine tartrate was not discovered in any of the plasma samples. In one patient ergotamine could not be detected in the cerebrospinal fluid one hour after a single oral dose of 2 mg. The oral biological availability is less than 1%, which is the maximal available fraction of unchanged ergotamine after oral administration. A clinical benefit was observed in several of our patients. These effects of the drug may be because of active metabolites being formed and/or to high affinity of ergotamine to cranial vessels.     

Treatment of the acute migraine attack current status

The main treatment of the acute migraine attack remains sleep, sedation, an anti-nauseant and analgesics, and in some patients 1 or 2 mg of ergotamine tartrate. Drugs containing large amounts of caffeine should not be used. Absorption of drugs may be impaired in a migraine attack. Metoclopramide is probably the anti-emetic of choice because it is an effective anti-nauseant and promotes normal gastrointestinal activity. Domperidone has a similar action but is said not to go through the blood-brain barrier, so is less likely to cause extrapyramidal reactions. All drugs, including analgesics such as aspirin and paracetamol, are best given in a soluble or effervescent form. Where vomiting occurs early in the attack, suppositories may be indicated. Ergotamine tartrate is necessary in about one third of attacks and is best given by suppository or by inhalation. Doses higher than 2 mg per attack or 6 mg in one week may cause toxic symptoms, the early signs of which are headache, nausea, vomiting and a feeling of not being very well. The non-drug treatments of an acute attack include pressing on the temporal artery, hot and cold compresses and relaxation.     

Ergotamine-induced anorectal strictures: report of five cases.

Dis Colon Rectum . 2002 Feb;45(2):271-2
Purpose: Ergotamine tartrate suppositories are used for treatment of migraine headache attacks. Chronic abuse may lead to severe anorectal complications such as ulceration, stricture, and rectovaginal fistula. These complications are rare, and only sporadic reports may be found. Nevertheless, awareness of this entity on the part of prescribing physicians and treating colorectal surgeons is essential for a successful outcome, because withdrawal of this medication is an inherent part of treatment.
Patients: Five female patients were referred for treatment of symptomatic strictures of the anal canal and lower rectum. All of these patients admitted prolonged, nearly daily use of three to seven ergotamine tartrate suppositories.
Results: Three patients with severe stenosis of the anal verge and anal canal were treated by Y-V anoplasty, and two patients with circular stricture of the lower third of the rectum had balloon dilatations. In all patients the use of ergotamine suppositories was stopped, and alternative medication was instituted. Long-term follow-up (3-12 years) showed complete resolution of symptoms.
Conclusion: In view of the availability of new effective drugs for treatment of migraine headache (serotonin agonists) and considering the potentially severe complications of chronic use of ergotamine, the use of this medication should be abandoned.
Comment: Ergotamine users beware of the sting in the tail! DSM.     

Ergotamine abuse: Results of ergotamine discontinuation, with special reference to the plasma concentrations

Twenty-three patients suffering from continuous headache linked with habitual daily use of ergotamine tartrate were studied. Their headaches were classified clinically, and possible side effects of ergotamine medication, plasma levels of ergotamine, and occurrence of withdrawal symptoms after discontinuation of drug abuse were recorded. Seventeen of the patients were clinically diagnosed as suffering from "ergotamine headache", and seven of them complained of coldness in the extremities. Plasma ergotamine levels were measured by using a radioimmunoassay. In almost half of the patients the 1 h plasma levels after the daily dose were below the detection limit of the procedure (0.12 ng/ml). The duration and severity of the withdrawal symptoms did not correlate with the doses and plasma levels of ergotamine. In only 4 of the 21 patients who were followed up for 3 to 6 months did headache symptoms not improve after ergotamine withdrawal. The results indicate that even small (0.5–1.0 mg/day) doses of ergotamine tartrate taken regularly may cause continuous headache symptoms and withdrawal symptoms after discontinuation.     

Aborting a Migraine Attack: Naproxen Sodium v Ergotamine plus Caffeine

SYNOPSIS
The tolerability and efficacy of naproxen sodium and of ergotamine tartrate plus caffeine (ergotamine) were compared in the treatment of acute migraine attacks and associated symptoms. In this multicenter, double-blind, parallel study of up to six headaches over a 3-month period, patients took naproxen sodium 825 mg, ergotamine 2 mg, or placebo at the time of the first symptom of an attack; 30 minutes later, if necessary, patients repeated naproxen sodium 275 mg, ergotamine 1 mg or placebo, as appropriate. Rescue medication was allowed 30 minutes following the second dose if needed. Active drugs provided notably better relief of head pain than did placebo; 1 hour following the first dose the difference between naproxen sodium and placebo was statistically significant. Naproxen sodium was as efficacious as ergotamine in the relief of migraine attacks and associated symptoms. Relief of vomiting, nausea, photophobia, and motor symptoms favored naproxen sodium over ergotamine; these differences were statistically significant for nausea and motor symptoms. Ergotamine-treated patients reported more complaints and had more severe and longer-lasting complaints than patients on the other two regimens. Overall tolerance ratings by both investigators and patients indicated that naproxen sodium and placebo were tolerated significantly better than ergotamine.     

Determination of the luminal diameter of the radial artery in man by high frequency ultrasound: a methodological study

The validity and reproducibility of measurements of the luminal diameter of the radial artery in man were investigated with Dermascan A, a 20 MHz ultrasound scanner. The luminal diameter of a reference object, a plastic tube, was measured with ultrasound to be 99.0% of stereomicroscopic measurements. By comparing the diameter of the reference object either filled with water or blood at 37 degrees C, the ultrasound velocity in human blood at 37 degrees C was calculated to be 1605 m/s. The intraobserver repeatability coefficients of in-vivo measurements of the radial artery in man were in the same range, whether measurements were repeated after 30 min (14%) or from day to day (12%). The interobserver repeatability coefficient was acceptable (15%) when the site of measurements was marked, whereas measurements without a mark resulted in a repeatability coefficient of 24%. The intravenous administration of 0.5 mg ergotamine tartrate to 5 subjects caused a decrease in the mean luminal diameter of the radial artery from 2.94 mm to 2.42 mm 1 h after ergotamine (p less than 0.05). This ultrasound method for measurements of the luminal diameter should thus be suitable for investigating the effects of physiological and pharmacological stimuli on the arteries per se.     

Impact of antimigraine compounds on cognitive processing: a placebo-controlled crossover study

OBJECTIVE: To evaluate potential cognitive impairment caused by acute antimigraine drugs. METHODS: We conducted a placebo-controlled, double-blind, crossover study to detect the short-term impact of sumatriptan, zolmitriptan, and ergotamine tartrate on cognitive processing as measured by event-related potentials and a d2 test. Sixteen healthy subjects were enrolled in the study and given placebo, sumatriptan 100 mg, zolmitriptan 2.5 mg, and ergotamine tartrate 2 mg on different days and in random order. Before and 2 hours after drug administration, visually evoked event-related potentials and a d2 test were measured. RESULTS: The N2 latency was significantly increased after ergotamine intake. No other significant differences could be observed in all other event-related potential parameters. In the d2 test, the GZ value was unchanged after ingestion of zolmitriptan and ergotamine, but improved significantly after taking placebo and sumatriptan. The number of relative errors and the concentration value did not change significantly. All results fell within the reference values for the d2 test in all examinations. CONCLUSION: Our data suggest that there may be a slight cognitive decline 2 hours after ingestion of ergotamine tartrate and, to an even lesser extent, zolmitriptan, but not after ingestion of sumatriptan or placebo. All changes recorded were very mild and unlikely to be clinically relevant.     

Medical therapy for menstrual migraine

A menstrual migraine occurs in approximately 7-10 % of women suffering from migraine. The migraine occurs from 2 days before until 3 days after the end of the menstrual period. The choice of treatment depends on the duration of the attack, which ranges from 3 to 7 days. An attack of up to 3 days duration should be treated with acetylsalicylic acid, ergotamine tartrate or naproxen, each in combination with an antiemetic (domperidone, metoclopramide). If there is no response, sumatriptan can be administered orally (25-100 mg) or subcutaneously (6 mg). In the attacks continue for more than 3 days, short-term prophylaxis with naproxen or the application of an estrogen-containing patch is indicated. Neither ovulation inhibitors nor traditional migraine prophylaxis has an influence on menstrual migraine. Patients should keep a headache diary. Short-term prophylaxis with ergotamine tartrate or tamoxifen is obsolete.     

Ergotamine vs. metoclopramide vs. their combination in acute migraine attacks

The effect of ergotamine tartrate was compared with that of the antiemetic agent metoclopramide and with those of two combinations in a double-blind trial of 24 adult female patients with migraine. The following combinations of the drugs were used in oral administration in a total of 176 acute migraine attacks: (a) Ergotamine 1 mg, (b) Metoclopramide 20 mg, (c) Ergotamine 1 mg + metoclopramide 20 mg, (d) Ergotamine 2 mg + metoclopramide 20 mg. The duration of attacks was significantly shorter on both of the combinations compared with the single drugs. The intensity of the pain was somewhat weaker and the appearance of nausea and vomiting somewhat but not significantly less during the combination treatments. In their overall opinion the patients favored the 2 mg + 20 mg combination significantly more than the others. Both ergotamine and metoclopramide are efficient in acute migraine attacks. Their combination seems to enhance the therapeutic response in some respects.     

Toxic Effects of Ergotamine Used for Migraine

SYNOPSIS
Forty-three patients (6 males and 37 females) who had used ergotamine tartrate 10 mg or more per week continuously over six months were studied. Twenty (47%) of the patients had symptoms and signs compatible with ergotism. This group had not used more ergotamine tartrate than the group, free of symptoms. Of the patients with symptoms, 13 had cardiovascular symptoms and 5 had clinical signs of peripheral neuropathy. Forty-three per cent of the patients examined had a normal electroencephalogram and the remainder relatively slight abnormalities. Eight patients had signs of peripheral neuropathy in their electroneuromyographic examination., The neurophthalmological examinations were all normal. Eighteen of 23 patients examined psychologically and psychiatrically were characterized as neurotic. Concomitant diseases were more often seen in the group with symptoms of ergotism; it is especially notable that all patients with collagen or diabetic disorders belonged to this group.     

Sublingual Flunarizine: a New Effective Management of the Migraine Attack. A Comparison versus Ergotamine

SYNOPSIS
Flunarizine was found to be effective in the acute treatment of isosorbide dinitrate induced migraine attacks, when given in a dosage of 10 mg sublingually.
The present study consists of two parts: in the first preliminary investigation, 7 out of 8 migraine patients who developed a typical migraine attack after isosorbide dinitrate were relieved of pain within about 10 minutes. On the basis of this result a second, randomized controlled open trial was performed, in which the acute efficacy of flunarizine was compared with ergotamine tartrate, 0.25 mg i.m., on 40 migraine patients. Flunarizine was found as effective as ergotamine (75% positive responses in the flunarizine group, 70% in the ergotamine group). The mean latency of the flunarizine effect was significantly lower than that of the ergotamine ( r < 0.001, Student's t test). Moreover sublingual flunarizine was found to be virtually devoid of side effects.     

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.     

Effect of a single test dose of lithium carbonate on sodium and potassium excretion in man.

1. The possible natriuretic and kaliuretic effects of a single dose of lithium, as used in lithium clearance studies, were investigated in 15 healthy subjects on fixed sodium (100 mmol/24 h) and potassium (70 mmol/24 h) intakes. Lithium carbonate (300 mg or 600 mg) or placebo tablets were administered, double-blind and in random order, midway through a 48 h urine collection (divided into six 8 h periods), at 23.00 hours. 2. During the three 24 h periods which preceded the administration of lithium or placebo (control days), rates of sodium and potassium excretion followed normal circadian patterns, but no differences in excretion rates between the 3 control days were observed. Placebo tablets did not affect excretion rates. 3. After the 300 mg dose of lithium carbonate, 24 h sodium excretion increased by approximately 17 mmol (P less than 0.05); almost all of the natriuretic effect occurred during the first two 8 h periods. No effect on potassium excretion was observed. 4. After the 600 mg dose of lithium carbonate, 24 h sodium excretion increased by approximately 48 mmol (P less than 0.001) and 24 h potassium excretion increased by approximately 19 mmol (P less than 0.01). These effects were confined to the first two 8 h periods and thus occurred before and during the usual lithium clearance period. 5. Plasma renin activity, measured in 10 subjects, increased after the 600 mg dose of lithium carbonate (P less than 0.005), but plasma concentrations of aldosterone and atrial natriuretic peptide were not significantly affected. Neither the 300 mg dose of lithium carbonate nor the placebo tablets affected hormone levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative effects of the antimigraine drugs sumatriptan and ergotamine on the distribution of cardiac output in anaesthetized pigs

The haemodynamic effects of sumatriptan, a 5-HT1-like receptor agonist, and ergotamine, an agonist at alpha-adrenergic, dopamine as well as 5-HT receptors, were compared using intracardiac injection of radioactive microspheres of different sizes in anaesthetized pigs. Ergotamine (0.02 mg.kg-1) and sumatriptan (0.3 mg.kg-1) decreased systemic vascular conductance and cardiac output. Only ergotamine raised arterial blood pressure. Both sumatriptan and ergotamine decreased arteriovenous anastomotic, but not capillary, blood flow in the head and body skin. Arteriovenous and capillary blood flow in the dura mater and nasal mucosa and capillary blood flow in the brain, kidneys, adrenals, intestine, heart, spleen and muscle remained unchanged. However, kidney conductance was decreased by both drugs, spleen conductance by sumatriptan and heart, liver and adrenal conductances were decreased by ergotamine. Thus, both sumatriptan and ergotamine constricted arteriovenous anastomoses in the skin, but not in the dura mater or nasal mucosa. Ergotamine constricted the vasculature more than sumatriptan, although both drugs may differentially decrease vascular conductances in some organs.