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PubMed1991

The antimigraine drugs ergotamine and dihydroergotamine are potent 5-HT1C receptor agonists in piglet choroid plexus.

1. Fozard & Gray (1989) proposed that migraine is mediated by stimulation of 5-HT1C receptors. We have examined the interaction of two effective anti-migraine agents, ergotamine and dihydroergotamine (DHE), with these receptors. Binding (inhibition of labelling by [3H]-mesulergine) and agonist activity (phosphoinositide hydrolysis) were measured in piglet choroid plexus, a tissue rich in 5-HT1C receptors. 2. The pKD for [3H]-mesulergine binding was 8.4. Ergotamine and DHE both inhibited [3H]-mesulergine binding with a pKD of 7.1. This was similar to the potency of m-chlorophenylpiperazine (m-CPP) (pKD 7.4) and rather less than that of 5-hydroxytryptamine (5-HT) (pKD 8.1). 3. Both ergotamine and DHE were full agonists (pEC50S 7.5 and 7.6 respectively) with potencies similar to that of 5-HT (pEC50 7.7) and greater than that of m-CPP (pEC50 7.1). Mesulergine 10(-7) M produced near-parallel rightward shifts of the concentration-response curves for all these agents of 1.8-2.2 log units, consistent with an action of the agonists at the same receptor. 4. There was no effect of prazosin, spiperone, mepyramine or atropine on the phosphoinositide hydrolysis induced by ergotamine, ruling out an action via alpha 1-adrenoceptors, 5-HT2, histamine H1, or muscarinic receptors. 5. It is concluded that, together with 5-HT, ergotamine and DHE are the most potent 5-HT1C agonists reported so far. These findings do not support the theory that 5-HT1C receptor activation causes migraine.

Animals↗
PubMed1982

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.

Acute Disease↗
PubMed1994

Comparison between venoconstrictor effects of sumatriptan and ergotamine in migraine patients.

The vasoconstrictor activity of sumatriptan and ergotamine were compared by injecting these drugs in the hand vein of migraine subjects. We used the "venotest method", which permits the evaluation of the venoconstrictor effect of small doses of drugs, acting locally in the hand vein. Sumatriptan injected at increasing doses in the hand vein provoked contraction only at high doses (500 micrograms): venoconstriction lasted 5-15 minutes and was similar in intensity and duration to that induced by 0.5-1 micrograms of 5-hydroxytryptamine (5-HT). Likewise, ergotamine induced contraction only at a dose of 50 micrograms: this venoconstrictor effect was long lasting (at least 1 hour). Ergotamine-induced hand vein contraction, almost completely inhibited by ketanserin, seems mediated at least in part by 5-HT2 receptors, like the one induced by 5-HT and sumatriptan, already observed in a previous study. Clinical doses of ergotamine (0.25 mg intramuscular) and of sumatriptan (6 mg subcutaneous) do not provoke hand vein contraction for at least 1 hour: this could be due to a low activity of these drugs on the 5-HT2 vein receptors or a technique that is unsuitable to detect the vasoconstrictor effect of drugs given by the systemic route. The long lasting venoconstrictor effect of ergotamine may be due to a slow dissociation from receptor sites. The short vasoconstriction induced by sumatriptan could account for the recurrence of headache in many sumatriptan-treated migraine subjects.

Adult↗
PubMed1982

Mechanism of ergotamine-induced decrease of peripheral systolic blood pressure in man.

We have previously reported a consistent decrease of peripheral-central systolic blood pressure (SBP) gradients after ergotamine. SBP was measured with cuffs and it is unknown whether measured values reflect changes of intra-arterial SBP or increase of vessel wall tone beneath the cuffs. We hence studied the effect of ergotamine tartrate 0.5 mg intravenously on finger-arm systolic gradients after the following procedures: Infiltration around finger arteries with papaverine (n = 2) and dihydralazine (n = 3), occlusion of blood supply to a finger by an inflated cuff before and 2 hours after ergotamine (n = 6). A normal reduction in finger-arm systolic gradients was seen. The ergotamine-induced decrease of peripheral SBP must therefore be due to a fall in peripheral intra-arterial SBP i.e. to contraction of arteries proximal to the digital arteries. Intra-arterial injection of 10 micrograms ergotamine tartrate caused similar decrease in finger-arm systolic gradients as intravenous administration of 0.5 mg (n = 1) indicating a peripheral site of action.

Adult↗
PubMed1996

Effects of ergotamine and dihydroergotamine on 5-hydroxytryptamine-2A receptors in the isolated rat aorta.

Ergotamine contracted isolated rat aorta rings with an intrinsic activity of 50% of that of 5-hydroxytryptamine. (5-HT, 0.1 mmol/l). Dihydroergotamine did not contract the tissue, but insurmountably blocked contraction in response to ergotamine and 5-HT. The 5-HT2A receptor antagonist, ketanserin (0.1 mumol/l), inhibited ergotamine (pKB 8.0) and 5-HT (pKB 8.1) induced contractions. These results indicate that in the rat aorta ergotamine is a partial 5-HT2A receptor agonist, whilst dihydroergotamine is an insurmountable 5-HT2A receptor antagonist. The present data could explain why ergotamine displays more cardiovascular and uterotonic side effects than dihydroergotamine.

Animals↗
PubMed1998

Reproductive hormonal responses to ergotamine and ergonovine in cows during the luteal phase of the estrous cycle.

We conducted research to evaluate whether ergot alkaloids associated with endophyte-infected tall fescue could alter plasma concentrations of hormones important to reproductive function in cows. Six primiparous, estrous-cycling Holstein cows nursing calves received single i.v. injections of ergotamine tartrate, ergonovine maleate, or saline vehicle in a simple cross-over design. Each cow received one compound per estrous cycle, d 15 or 16 after estrus, and all compounds over three estrous cycles. Blood samples were collected at 20-min intervals for 40 min before and 240 min after treatments to assess plasma concentrations of prolactin, LH, FSH, and the response by PGF2alpha metabolite 13,14-dihydro-15-keto-prostaglandin F2alpha (PGFM). Ambient temperature and respiratory rates were measured hourly. Ambient temperature averaged 26 degrees C during data collection. Treatment x time was a significant source of variation for respiration rate and plasma concentrations of every hormone evaluated except FSH. Ergotamine elevated (P < .01) respiration rates 2 to 4 h after treatment. Ergotamine and ergonovine reduced (P < .001) plasma concentrations of prolactin for 2 to 4 h after treatment compared to concentrations before treatment. Plasma concentrations of LH were lowered (P < .01) by ergonovine during the 3rd h after treatment and by ergotamine during the 4th h after treatment. Most cows exhibited secretory PGFM responses after ergotamine and ergonovine treatments compared with an absence of a PGFM response in all cows after saline (P < or = .01). Results indicated that ergot alkaloids implicated as causative agents for fescue toxicosis can alter plasma concentrations of reproductive hormones during the late luteal phase of the estrous cycle in cows.

Animals↗
PubMed1991

[Headache caused by analgesic and/or ergotamine abuse].

Headache induced by ergotamine-abuse was described 40 years ago. More recently there is ample evidence suggesting that chronic headache may also be provoked by analgesic abuse. A recent Classification of the International Headache Society has defined this kind of headache as an autonomous disease. It consists in a daily chronic headache with paroxysmal attacks associated with daily or almost daily assumption of analgesics and/or ergotamine. It is debated whether the term "abuse" or "dependence" is correct. Almost 5% of patients of the Headache Centres in Italy were found to be drug abusers. Most of these patients originally suffered from migraine. The therapeutic approach consists in hospitalization, withdrawal of analgesics and/or ergotamine, treatment of the withdrawal headache (which appears within 48 hours and lasts even 1-2 weeks) and finally in a prophylactic therapy. Although several treatments have been suggested for the abstinence syndrome, only fluid replacement, antiemetics, hypnotic-sedative drugs and rarely mild analgesics are necessary. A review of the literature shows the following success rates in the relief of the headache: above 50% relief in more than 60% of patients within a follow up period of 1 to 3.5 years as mean. Even if caffeine and barbiturates, which are often contained in the analgesic and ergotamine preparations, might be considered the cause of the abuse and withdrawal syndrome, they don't seem to play a fundamental role in this syndrome. An impairment of the central antinociceptive system was hypothesized to be involved in the pathogenesis of the headache associated with analgesic and/or ergotamine abuse. Recently there has been evidence of a possible hyposensitivity of the adrenergic and serotoninergic receptors of the central nervous system. It is still to be proved whether drug abuse is the cause or the consequence of the headache chronicization. The remarkable improvement of headache after analgesic withdrawal suggests a causal factor.

Analgesics↗
PubMed1983

Ergotamine and dihydroergotamine enhance guanylate cyclase activity.

Both ergotamine and dihydroergotamine enhanced guanylate cyclase (E.C.4.6.1.2) activity two- to threefold in rat aorta, heart, liver and kidney. Dose-response relationships revealed that ergotamine and dihydroergotamine caused a maximal stimulation of hepatic guanylate cyclase activity at the 0.1 microM concentration. There was no further augmentation with increasing the concentration of either ergot alkaloid to the millimolar range. No enhancement of guanylate cyclase activity was noted with decreasing the concentration of ergotamine and dihydroergotamine to 0.001 microM. At all concentrations, ergotamine was a more potent stimulator of guanylate cyclase activity than was dihydroergotamine. Both ergotamine and dihydroergotamine also increased tissue cyclic GMP levels at the same concentrations as above. Varying the concentration of the guanylate cyclase co-factor manganese had no effect on these ergot alkaloids' augmentation of guanylate cyclase activity except that with no manganese present the same amount of maximal activation could not be achieved. Since bromocriptine, another ergot alkaloid, also enhances guanylate cyclase activity, it appears that ergot alkaloids have a common mechanism of action which involves the guanylate cyclase-cyclic GMP system at the cellular level.

Animals↗
PubMed1985

Linear pharmacokinetics of intravenous ergotamine tartrate.

Ergotamine tartrate 0.5, 0.25 and 0.125 mg was administered i.v. to 6 volunteers in a cross-over study. Its pharmacokinetic characteristics were evaluated from plasma concentration-time data determined by HPLC. The clearance and volume of distribution were independent of the dose. The ratio between blood and plasma ergotamine concentrations in 4 subjects ranged from 0.41-0.67, indicating the lack of binding to blood cells. Ergotamine was found to be a high clearance drug, average 2.21/min/70 kg body wt. suggesting extrahepatic clearance. A possible transient decrease in liver blood flow caused by ergotamine did not seem to affect the linearity of its kinetics.

Adult↗
PubMed1983

Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers.

Fifteen migraine patients were administered 2 mg ergotamine tartrate in a partial cross-over design as a single, oral tablet, rectal suppository and rectal solution. Eight of these patients were in a previous investigation given 0.5 mg ergotamine tartrate intravenously. The blood samples were taken up to 54 h after oral and suppository while it was followed for only 3 h after rectal solution. The chemical analysis was performed by applying h.p.l.c. method with a limit of sensitivity of 0.1 ng/ml ergotamine base in plasma. No ergotamine was detected in the blood samples after the oral route, whereas small and very variable quantities was found in blood after the rectal route. Regular calculation of bioavailability could therefore not be performed. An estimate of the maximal possible bioavailability was found to yield a mean value of 2% (tablets); 5% (suppositories) and 6% (rectal solution). Rectal solution elicited faster absorption and the extent of absorption was significantly higher (P less than 0.05) than for the suppository.

Absorption↗
PubMedDate not supplied

Determination of ergotamine tartrate in tablets by liquid chromatography with fluorescence detection.

A method is presented for the liquid chromatographic (LC) determination of ergotamine tartrate in tablets that is applicable even in the presence of other ingredients such as phenobarbital, belladonna alkaloids, and caffeine. The sample is transferred to a volumetric flask, a small volume of formic acid is added to dissolve and stabilize the ergotamine, and the solution is diluted to volume with methanol. The solution is mixed and filtered through paper. The LC system consists of a Rheodyne injector fitted with a 20 microL loop and a C18 reverse phase column; the mobile phase is acetonitrile-water-triethylamine (700 + 300 + 0.5). Ergotamine tartrate is determined fluorometrically at an excitation wavelength of 250 nm and an emission wavelength of 430 nm. Recovery studies were conducted at the 0.3 and 1.0 mg levels. Average recoveries were 99.6 and 100.8%, respectively; relative standard deviations (RSDs) were 1.08 and 2.21%, respectively. Some commercial preparations containing ergotamine tartrate in combination with other ingredients were also analyzed. The RSDs for 5 determinations of each of 2 ground composites were 0.09 and 0.34%.

Chromatography, Liquid↗
PubMed1976

Evidence for stimulation of 5-HT receptors in canine saphenous arteries by ergotamine.

Changes in tension of spiral strips from dog saphenous arteries were monitored isometrically. Dose-response curves for noradrenaline, 5-HT and ergotamine were established without and after a 30 min incubation with phentolamine or pizotifen. Phentolamine was about 15 times more potent in antagonizing responses to noradrenaline (pA2 value=7.4) than those to 5-HT (pA2 value=6.2) but it was nearly equipotent in antagonizing responses to ergotamine (pA2 value=6.5) and those to 5-HT. Pizotifen was about 500 times less potent in antagonizing noradrenaline effects than 5-HT but again nearly equipotent when tested against ergotamine and 5-HT. It is suggested that in canine saphenous arteries the stimulant activity of ergotamine is mediated mainly through 5-HT receptors.

Animals↗
PubMed1982

Kinetics of ergotamine after intravenous and intramuscular administration to migraine sufferers.

The kinetics of ergotamine has been investigated in migrainous patients using a new, specific, sensitive HPLC assay (detection limit 100 pg/ml plasma). 10 patients were given ergotamine tartrate 0.5 mg i.v. and 5 of them received the same dose i.m. 2-3 weeks later. Blood samples were collected for up to 54 h following administration and the plasma concentration were analysed. After intravenous administration the plasma ergotamine declined rapidly, with and initial distribution half-life of 3 min followed by a mean terminal half-life of 1.86 h (range 90-155 min). The mean total plasma clearance was 11.0 ml kg-1 min-1, and the volume of distribution (Vd beta) was 1847.6 ml kg-1. Individual t1/2 beta showed a positive linear correlation with the individual Vd beta. The intramuscular absorption of ergotamine was rapid and maximum plasma levels were usually obtained 10 min following administration. The biological availability was incomplete and variable at 46.6% (range 28.3-60.8%).

Absorption↗
PubMed1993

Erythromycin-associated ergotamine intoxication: arteriographic and electrophysiologic analysis of a rare cause of severe ischemia of the lower extremities and associated ischemic neuropathy.

Vasospasm associated with ergotamine is a well-known phenomenon. In this case report we present a rare drug interaction between erythromycin and ergotamine at normal doses causing lower extremity ischemia in a 36-year-old woman. Nitroprusside proved to be the treatment of choice. The response was dramatic and took place in a matter of hours in this patient. Ischemic monomelic neuropathy is a recently described entity in which axonal necrosis is caused by a loss of distal extremity blood flow. The association between erythromycin and ergotamine may be a dangerous pharmacologic combination; drugs that have a hepatic cycle with ergotamine derivatives must be used with caution.

Adult↗
PubMed1995

Ergotamine-induced complex rectovaginal fistula. Report of a case.

PURPOSE: This report stresses the importance of local complications caused by ergotamine abuse for the treatment of migraine headaches. METHODS: We present an unusual case of a complex rectovaginal fistula (RVF) caused by long-term ergotamine suppository abuse. RESULTS: A 39-year-old female was referred after she had undergone a transverse colostomy for temporary fecal diversion. Evaluation, including proctoscopy, gastrograffin enema, vaginogram, and pelvic computerized tomography revealed a RVF 6 cm proximal to the dentate line with distal rectal stricture. Surgical intervention included take down of the transverse colostomy with reanastomosis, proctectomy with excision of the fistula, creation of a colonic "J-pouch" with a coloanal anastomosis, and construction of a temporary loop ileostomy. The patient had an uneventful recovery, and her ileostomy was closed three months later. Pathologic examination of the surgical specimen failed to reveal any specific etiology of the RVF. However, her ten-year use of up to five ergotamine suppositories per day for migraine treatment is associated with a local ischemic effect. Pathophysiology of this rare cause of RVF and the surgical procedure are discussed. CONCLUSION: If evidence of any side effects of ergotamine suppositories is seen, early discontinuation of the drug should be considered to avoid complications such as RVF and/or strictures.

Administration, Rectal↗
PubMed2004

5-HT1B receptors, alpha2A/2C- and, to a lesser extent, alpha1-adrenoceptors mediate the external carotid vasoconstriction to ergotamine in vagosympathectomised dogs.

It has previously been suggested that ergotamine produces external carotid vasoconstriction in vagosympathectomised dogs via 5-HT1B/1D receptors and alpha2-adrenoceptors. The present study has reanalysed this suggestion by using more selective antagonists alone and in combination. Fifty-two anaesthetised dogs were prepared for ultrasonic measurements of external carotid blood flow. The animals were divided into thirteen groups (n=4 each) receiving an i.v. bolus injection of, either physiological saline (0.3 ml/kg; control), or the antagonists SB224289 (300 microg/kg; 5-HT1B), BRL15572 (300 microg/kg; 5-HT1D), rauwolscine (300 microg/kg; alpha2), SB224289 + BRL15572 (300 microg/kg each), SB224289 + rauwolscine (300 microg/kg each), BRL15572 + rauwolscine (300 microg/kg each), rauwolscine (300 microg/kg) + prazosin (100 microg/kg; alpha1), SB224289 (300 microg/kg) + prazosin (100 microg/kg), SB224289 (300 microg/kg) + rauwolscine (300 microg/kg) + prazosin (100 microg/kg), SB224289 (300 microg/kg) + prazosin (100 microg/kg) + BRL44408 (1,000 microg/kg; alpha2A), SB224289 (300 microg/kg) + prazosin (100 microg/kg)+ imiloxan (1,000 microg/kg; alpha2B), or SB224289 (300 microg/kg) + prazosin (100 microg/kg) + MK912 (300 microg/kg; alpha2C). Each group received consecutive 1-min intracarotid infusions of ergotamine (0.56, 1, 1.8, 3.1, 5.6, 10 and 18 microg/min), following a cumulative schedule. In saline-pretreated animals, ergotamine induced dose-dependent decreases in external carotid blood flow without affecting arterial blood pressure or heart rate. These control responses were: unaffected by SB224289, BRL15572, rauwolscine or the combinations of SB224289 + BRL15572, BRL15572 + rauwolscine, rauwolscine + prazosin, SB224289 + prazosin, or SB224289 + prazosin + imiloxan; slightly blocked by SB224289 + rauwolscine; and markedly blocked by SB224289 + rauwolscine + prazosin, SB224289 + prazosin + BRL44408 or SB224289 + prazosin + MK912. Thus, the cranio-selective vasoconstriction elicited by ergotamine in dogs is predominantly mediated by 5-HT1B receptors as well as alpha2A/2C-adrenoceptor subtypes and, to a lesser extent, by alpha1-adrenoceptors.

Animals↗
PubMed2002

Ergotamine-induced anorectal strictures: report of five cases.

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.

Adrenergic alpha-Agonists↗
PubMed2003

Ergotamine and dihydroergotamine: a review.

The ergot alkaloids were the first specific antimigraine therapy available. However, with the advent of the triptans, their use in the treatment of migraine has declined and their role has become less clear. This review discusses the pharmacology, efficacy, and safety of the ergots. In randomized clinical trials, oral ergotamine was found to be superior to placebo, but inferior to 100 mg of oral sumatriptan. In contrast, rectal ergotamine was found to have higher efficacy (73% headache relief) than rectal sumatriptan (63% headache relief). Intranasal dihydroergotamine was found to be superior to placebo, but less effective than subcutaneous and intranasal sumatriptan. Ergotamine is still widely used in some countries for the treatment of severe migraine attacks. It is generally regarded as a safe and useful drug if prescribed for infrequent use, in the correct dose, and in the absence of contraindications; however, safer and more effective options do exist in the triptans. In patients with status migrainous and patients with frequent headache recurrence, ergotamine is still probably useful.

Dihydroergotamine↗