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PubMed1975

Analysis of ergotamine - 5-HT interaction on the isolated rat stomach preparation.

The effect of ergotamine on the isolated rat stomach and its influence on the response to ACh and 5-HT were investigated. The log dose-response curve of ergotamine was bell-shaped. Extension of the incubation time of ergotamine resulted in a parallel shift to the left of the curve. The response to ergotamine was inhibited by methyserigide and piperoxan. Incubation with ergotamine resulted in a decrease of the pD2-value of 5-HT together with a marked suppression of the maximum of the 5-HT curve. The response to ACh was affected in accordance with the prediction of an action of ACh and ergotamine on different receptors. The prolonged receptor stimulation by 5-HT or ACh resulted in a decrease of the apparent affinity towards their receptors. Incubation with ACh resulted in a parallel shift to the right of the 5-HT curve. However no inconsistency with the theoretical prediction of an action on separate receptors was observed with the ACh curve in the presence of 5-HT. It is concluded that ergotamine is a partial agonist on the D-tryptamine receptors of tbe isolated rat stomach. The marked decrease of the maximum of the 5-HT curve by ergotamine is probably caused by the slowly reversible character of its antagonism. The parallel shift to the left of the ergotamine curve with the extension of the incubation time and the persistence of its antagonism both are probably caused by a slow diffusion into and from the biophase.

Acetylcholine↗
PubMed1989

Reduced serotonin vascular sensitivity in ergotamine abusers.

The action of ergotamine on the 5-hydroxytryptamine (5-HT) venous sensitivity was studied in ergotamine abuser and non-abuser migraine patients. Ergotamine abusers showed reduced 5-HT hand vein contraction during abuse, compared to seven days after ergotamine withdrawal. In non-ergotamine users, the 5-HT venoconstriction was not significantly modified 12 h after a single intramuscular ergotamine (0.25 mg) administration. Even the administration of ergotamine locally into the vein did not change the venospasm of 5-HT given acutely in the same vein. Therefore, it seems that the 5-HT antagonism does not contribute to the therapeutic effect of ergotamine during the migraine attack. Moreover, the reduced 5-HT responsiveness during ergotamine abuse may possibly be compatible with the chronic headache present in some abusers, the withdrawal headache attacks and the abuse itself.

Adult↗
PubMed1996

Reduced distensibility of the common carotid artery in patients treated with ergotamine.

To investigate the effect of vascular smooth muscle contraction on mechanical vessel wall properties of proximal "elastic" arteries, we investigated the effect of the vasoconstrictor ergotamine on the distensibility of the common carotid artery in 10 migraine patients with ergotamine intake, in 10 control patients with migraine headache but no prior ergotamine intake, and in 10 healthy control subjects. The patients and control subjects were matched for age, blood pressure, and sex. In the ergotamine group, 2.2 +/- 1.4 mg ergotamine tartrate (0.25 to 6 mg) was taken within 12 hours before investigation. Differences in mean 24-hour blood pressure between the study groups were excluded by 24-hour blood pressure recording and differences in arterial wall thickness by high-resolution and differences in arterial wall thickness by high-resolution B-mode ultrasound. A multigate Doppler system was used for measurement of vessel wall movements by M-mode Doppler analysis. Blood pressure was determined by sphygmomanometry. The end-diastolic diameter of the common carotid artery was insignificantly reduced in the ergotamine group compared with the healthy control subjects and control patients (healthy control subjects, 6.6 +/- 0.4 mm; control patients, 6.7 +/- 0.5 mm; patients with ergotamine intake, 6.3 +/- 0.4 mm; P = NS). Arterial distensibility was significantly lower in the patients with ergotamine intake (17.4 +/- 4.0 10(-3)/kPa) than in the healthy control subjects (22.3 +/- 5.1 10(-3)/kPa) and control patients (22.8 +/- 3.6 10(-3)/kPa) (one-way ANOVA, P = .014). The results show that ergotamine reduces the distensibility of the common carotid artery. The data suggest that vascular smooth muscle contraction can modulate the buffering function of the arterial system independently of blood pressure changes.

Adult↗
PubMed1981

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.

Administration, Oral↗
PubMed1983

Treatment of chronic orthostatic hypotension with ergotamine.

The acute and chronic effects of ergotamine were examined in four patients with chronic orthostatic hypotension. Chronic oral administration of ergotamine tartrate produced significant increases in standing blood pressure and marked clinical improvement, without appreciable recumbent hypertension. The blood pressure increases were not associated with significant changes in plasma norepinephrine or plasma renin activity. No major toxicity was observed at doses of 2-6 mg/day over treatment periods of 3-18 months. Hemodynamic studies on the effects of i.v. ergotamine tartrate (0.25-0.50 mg) revealed that the ergotamine-induced increase in blood pressure in the supine position was associated with an increase in total peripheral resistance (from 1616 +/- 165 to 2574 +/- 583 U) without a change in cardiac output. During 45-60 degrees upright tilt, ergotamine increased both total peripheral resistance (1801 +/- 296 to 3262 +/- 1107 U) and cardiac output (2.42 +/- 0.46 to 3.34 +/- 0.54 l/min). Forearm plethysmographic studies revealed decreased forearm blood flow and venous volume and increased vascular resistance with ergotamine. The orthostatic hypotensives had more platelet alpha-receptors (390 +/- 31 receptors/cell) than the control subjects (234 +/- 17 receptors/cell). The increased receptor level was associated with abnormally low circulating levels of norepinephrine and increased pressor responsiveness to infused norepinephrine in three of the four patients. Chronic ergotamine therapy appeared to reduce platelet alpha-receptor number to normal. The results indicate that ergotamine is of value in certain patients with chronic orthostatic hypotension and that the blood pressure effects are related to vasoconstriction in both arterial and venous beds.

Adult↗
PubMed1982

Ergotamine in plasma and CSF after i.m. and rectal administration to humans.

An attempt was made to study the kinetics of penetration of ergotamine across the blood-brain barrier. A single therapeutic dose of ergotamine was given to 18 hospitalized patients; eight patients received 0.5 mg i.m., three patients 4 mg rectally, and seven patients 2 mg rectally. Plasma samples were drawn between 0.25 and 72 h and one CSF sample was taken from each patient between 0.5 and 6.5 h after administration. The ergotamine concentrations were measured using a RIA method. The 0.5 mg intramuscular injection showed the highest plasma levels of ergotamine, with a mean peak concentration of 1.27 ng/ml reached at 0.5 h. The 4 mg rectal administration resulted in mean plasma ergotamine levels of 0.44 ng/ml in the time interval of 0.75-2 h. The 2 mg ergotamine rectally resulted in mean plasma levels of 0.15-0.17 ng/ml 1-8 h after administration of ergotamine. Neither the plasma samples taken after 10 h nor the CSF samples had ergotamine concentrations above the detection limit of the RIA method (0.1 ng ergotamine/ml).

Blood-Brain Barrier↗
PubMedDate not supplied

Clinical pharmacokinetics of ergotamine in migraine and cluster headache.

Ergotamine has been in use for the treatment of migraine for a century and is still considered to be the most effective therapeutic agent for acute attacks. Only during the last few years have assays been developed, enabling its pharmacokinetics to be studied. Appropriate assays for determining ergotamine concentrations in plasma are radioimmunoassay and high-performance liquid chromatography. There is great interindividual variation in absorption of ergotamine in both patients and normal volunteers. Bioavailability is of the order of 5% or less by oral or rectal administration. After intramuscular or intravenous administration, plasma concentrations decay in a biexponential fashion. The elimination of half-life is 2 to 2.5 hours and clearance is about 0.68 L/h/kg. As yet, formal pharmacokinetics following oral dosing have not been determined. There is some evidence that ergotamine enters the cerebrospinal fluid. Metabolism occurs in the liver, and the primary route of excretion is biliary. Up to 90% of migraine patients experience complete or partial symptom relief after ergotamine, providing the drug is given as early in their attack as possible. Efficacy is greatest after parenteral administration, although adverse effects may make the rectal or inhaled routes preferable. There is some evidence to suggest that good responses are associated with plasma concentrations of 0.2 ng/ml or above within one hour of administration. The mode of action of ergotamine in migraine may be by means of selective arterial vasoconstriction on certain cranial vessel beds or, alternatively, by depression of central serotonergic neurons mediating pain transmission or circulatory regulation. Principal adverse effects of ergotamine include nausea, vomiting, weakness, muscle pains, paraesthesiae and coldness of the extremities. Ergotamine dependence is not uncommon, resulting in an exacerbation of the above symptoms. Dosage must therefore be limited to no more than 10mg per week to minimise toxicity.

Administration, Oral↗
PubMed1990

Pressor effect of inhaled ergotamine in orthostatic hypotension.

Treatment of orthostatic hypotension due to autonomic failure frequently necessitates use of pressor agents. Because venous pooling contributes significantly to this disorder, the venoconstrictive properties of ergotamine offer theoretical advantages over pure arteriolar pressor agents. However, the low and erratic bioavailability of oral preparations has hindered the use of ergotamine. Accordingly, the efficacy of inhaled ergotamine tartrate (1 puff, 0.36 mg) was compared to placebo in 8 patients with severe autonomic failure. Blood pressure was monitored in the seated position with an automated device. Ergotamine produced significant increases in systolic (29 +/- 5 mm Hg, p less than 0.01 by analysis of variance) and diastolic (13 +/- 1 mm Hg, p less than 0.001) blood pressures compared to placebo (-9 +/- 5 and -2 +/- 3, respectively). Upright blood pressure 2 hours after administration was significantly greater with ergotamine (119 +/- 8/69 +/- 6 mm Hg) vs placebo (82 +/- 7/59 +/- 5 mm Hg, p less than 0.05). Motionless standing time, a measurement of functional capacity, also improved with ergotamine (200 +/- 58 vs 85 +/- 22 seconds). No side effects were noted, but patients with coronary or peripheral artery disease were excluded. Inhaled ergotamine may provide an effective and practical therapy for disabling orthostatic hypotension due to autonomic failure.

Administration, Inhalation↗
PubMed1983

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.

Administration, Oral↗
PubMed1985

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.

Acute Disease↗
PubMed1992

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.

Anesthesia↗
PubMed1957

The action of ergotamine on the intracranial venous pressure and on the cerebral venous outflow of the dog.

The effect of ergotamine and dihydroergotamine on the cerebral circulation was studied in the dog, anaesthetized with chloralose, by recording the intracranial venous pressure and the venous outflow from the superior cerebral vein. Under optimal experimental conditions, ergotamine (5 to 10 mug./kg.) and dihydroergotamine (100 mug./kg.) gave a marked and long-lasting cerebral vasoconstriction accompanied by a slight hypertension. The cerebral vasoconstriction provoked by ergotamine may be very small and was sometimes absent when the cerebral blood-flow was low. This vasoconstrictor effect is more pronounced the higher the initial intracranial venous pressure and hence the cerebral blood-flow. After the induction of a cerebral vasodilatation by 48/80 or strychnine, the vasoconstrictor action of ergotamine was more pronounced. The effect was not observed when CO(2) was employed to modify the intracranial venous pressure. Simultaneous registration of the cerebral, nasal cavity, and kidney vascular responses demonstrated the relative specificity of the action of ergotamine on the cerebral vessels. The small doses of ergotamine used may weaken or abolish the vasoconstrictor action of adrenaline on cerebral vessels. The modification of the responses of the cerebral circulation which such factors as anaesthesia, respiratory acidosis, and operative trauma can produce have been confirmed and emphasized. The results support the view that the vasoconstrictor action of ergotamine on the cerebral vessels might account for the therapeutic value of this drug in migraine.

Animals↗
PubMed1974

Investigations on the mode of action of ergotamine in the isolated femoral vein of the dog.

1 Experiments on spiral strips cut from the femoral vein of dogs suspended in Krebs-Henseleit solution were carried out.2 Ergotamine caused stimulation in concentrations about 350 times lower than noradrenaline (ED(50) of ergotamine = 2.2 x 10(-9) M; ED(50) of noradrenaline = 7.6 x 10(-7) M), but the maximal responses to ergotamine were only about one third those to noradrenaline.3 The pA(2) value of ergotamine against noradrenaline was 8.8.4 The effects of ergotamine can be blocked by prior administration of phentolamine. The pA(2) value for phentolamine against ergotamine was 6.8 and the pA(2) value for phentolamine against noradrenaline was 7.5.5 It is concluded that the stimulant action of ergotamine on smooth vascular muscle probably is mediated mainly via alpha-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1978

The effect of ergotamine on tissue blood flow and the arteriovenous shunting of radioactive microspheres in the head.

1 The radioactive microsphere method was used to study the effects of ergotamine (5, 10 and 20 mug/kg, i.v.) on systemic and regional haemodynamic variables in chloralose-urethane anaesthetized cats. The influence of the drug was also studied on the number of 15 mum microspheres escaping entrapment in the head to emerge in the left external jugular vein.2 Ergotamine decreased the heart rate and cardiac output. Since arterial blood pressure remained unchanged, calculated total peripheral resistance increased.3 The regional distribution of cardiac output obtained with 15 mum microspheres agreed well with previous studies in cats where 25 mum spheres were used. The most pronounced difference was that in the present investigation more microspheres, apparently escaping through arteriovenous anastomoses (AVAs), were detected in the lungs than when larger spheres had been used.4 Coronary blood flow decreased, while uterine blood flow was increased by the drug. The microsphere content of the lungs, which receive the spheres not only via bronchial arteries but also via AVAs, was greatly reduced by all doses of ergotamine. Ergotamine did not influence tissue blood flow to other major organs such as the brain, kidneys, skin, liver, skeletal muscle or the gastrointestinal tract.5 In the 16 experiments, 0.46 +/- 0.05 (s.e. mean)% of the total microspheres injected (equivalent to 11.7 +/- 1.4% of microspheres detected in the left-side of the head) appeared within 2 min of microsphere injection into the left external jugular vein. The highest dose of ergotamine significantly reduced the shunting of the microspheres in the head.6 Since 15 mum microspheres are only likely to reach the lungs by passing into the venous circulation through large glomus-type AVAs, we conclude that ergotamine reduces the fraction of microspheres appearing in the lungs by causing strong vasoconstriction in the AVAs in the head.7 In conformity with the closure of head AVAs is the finding that ergotamine reduced the jugular venous Po(2) and O(2) saturation thereby increasing the A-V O(2) saturation difference.8 It is quite possible that decreased A-V shunting may be the prominent mechanism of the antimigraine action of the drug, since sudden opening of AVA's has been implicated in the pathophysiology of migraine-syndrome.

Animals↗
PubMed1982

Ergotamine absorption and toxicity.

Adverse reactions to ergotamine were noted in 16 out of 41 studies in which therapeutic doses of the drug were given to normal, healthy volunteers. In 17 of the studies 0.25 mg ergotamine was given by injection, 6 i.v. and 11 i.m., in 20 studies 2 mg ergotamine was given by mouth, and 4 subjects received 2 mg ergotamine by suppository. Plasma and urinary ergotamine was measured by radio-immunoassay. Adverse reactions were significantly more frequent in subjects in whom plasma ergotamine exceeded 1.8 ng/ml. Pharmacokinetic data derived from the study are presented and their relevance to the therapeutic use of ergotamine are discussed.

Administration, Oral↗
PubMedDate not supplied

Sumatriptan and ergotamine overuse and drug-induced headache: a clinicoepidemiologic study.

Drug-induced headache, particularly ergotamine-induced headache, is a common problem in migraine treatment. Some case reports suggest that even the new serotonergic antimigraine drugs such as sumatriptan can lead to overuse and subsequent drug-induced headache. We performed a controlled study to identify the rate of sumatriptan overuse and sumatriptan-induced headache and compared it to the rate of ergotamine overuse and ergotamine-induced headache. Two thousand sixty-five consecutive heachache patients, all experienced in intake of sumatriptan (n = 631) or ergotamine (n = 620), were enrolled over a three-year study period. The rates of overuse and drug-induced headache and the clinical features of the subgroups were compared. Risk factors for sumatriptan overuse were identified. The rates of ergotamine and sumatriptan overuse were 14.2% and 3.5%, respectively (p < 0.001). Drug-induced headache could be found more frequently in cases of ergotamine overuse than in cases of sumatriptan overuse (68% versus 32%; p < 0.01). Development of sumatriptan overuse was most common in patients with previous drug-induced headache (68%), combined headache as the primary headache type (45%), and subcutaneous application of sumatriptan (45%). We conclude that sumatriptan intake can lead to overuse and subsequent drug-induced headache. The risk for overuse and drug-induced headache is significantly lower than in patients with ergotamine intake. This might be caused in part by the relatively short period of sumatriptan availability on the market. The new generation of serotonin-1B/D-receptor agonists in the treatment of headache should have a potential for overuse similar to that of traditional headache drugs.

Adult↗
PubMed1981

Arterial response to ergotamine tartrate in abusing and non-abusing migraine patients.

Ten former ergotamine abusers were given ergotamine tartrate 0.5 mg/70 kg intravenously. The arterial response was followed by measuring systolic blood pressures with strain gauge on arm, fingers, ankles and toes. Distal systolic blood pressures were significantly reduced relative to the arm level for 22 hours. The arterial response in these 10 patients was compared to the response in 17 migraine patients tested with the same technique. No differences were found. We conclude that hypersensitivity or tolerance to ergotamine tartrate is not observed in previous ergotamine abusers. Previous abuse is a relative contraindication to the use of ergotamine. But if ergotamine is the only effective drug, normal dosage can be used according to the present results.

Adult↗
PubMed2006

Effects of ergotamine and ergovaline on the electromyographic activity of smooth muscle of the reticulum and rumen of sheep.

OBJECTIVE: To investigate the effects of IV administration of ergotamine and ergovaline and intraruminal administration of ergotamine on electromyographic (EMG) activity of reticuloruminal smooth muscle in conscious sheep. ANIMALS: 3 sheep with indwelling electrodes in the musculature of the reticulum and rumen. PROCEDURE: In a crossover design study, reticuloruminal motility before and after IV administration of ergotamine (5, 10, 20, and 40 nmol/kg) or ergovaline (2.5, 5, and 10 nmol/kg) was evaluated; EMG effects were compared with those of corresponding control treatments (IV administration of saline [0.9% NaCl] solution or acetone, respectively) in sheep. Ergotamine (800 nmol/kg) or water was also administered intraruminally and their effects compared. RESULTS: After IV administration of ergopeptides, vagally dependent cyclical A and B sequences of contraction of the reticulorumen were immediately inhibited, preceding increases in baseline EMG activity (tonus). The return of cyclical contractions was associated with an increase in contraction amplitude. The effects were dose dependent; administration of 40 nmol of ergotamine/kg resulted in responses that continued for 3 to 4 hours. The effects of intraruminal administration of ergotamine were variable; after 8 hours, EMG activity was increased from baseline for < 2 hours in 1 sheep, 10 hours in another, and > 15 hours in the third. CONCLUSIONS AND CLINICAL RELEVANCE: In sheep, the effects of ergotamine and ergovaline on reticuloruminal motility after IV administration and the duration of responses following intraruminal administration suggest that disruption of digestion may occur in animals grazing endophyte-infected pasture that has a high ergopeptide content.

Animals↗