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Enhancing the effectiveness of abortive therapy: a controlled evaluation of self-management training.

Research suggests that approximately one half of recurrent headache sufferers fail to adhere properly to drug treatment regimens with as many as two thirds of patients failing to make optimal use of abortive medications such as ergotamine. In spite of these findings there are no controlled studies that have attempted to evaluate methods for improving adherence to drug regimens for the treatment of chronic headache disorders. In an initial effort to address this adherence problem thirty-four recurrent migraine sufferers were randomized to abortive therapy with ergotamine tartrate plus caffeine (standard abortive therapy) or to standard abortive therapy accompanied by a brief educational intervention designed to facilitate the migraine sufferer's effective use of ergotamine. Patients who received the adjunctive educational intervention attempted to abort a greater percentage of their migraine attacks (70% vs 40%) and showed larger reduction in headache activity (e.g., 40% vs 26% reduction in month two of treatment). However, patients in both treatment groups used similar amounts of abortive medication when attempting to abort a migraine attack and showed similar reductions in analgesic medication use with abortive therapy. There results suggest that brief educational interventions designed to address the problem of patient adherence may yield significant improvements in standard therapies. We argue that such educational interventions deserve more attention in the headache treatment literature than they have received to date.

Adult↗

Migraine--treatment of acute attack.

The treatment of an acute attack of classical or common migraine is sleep, an antinauseant such as metoclopramide, an analgesic, either aspirin or paracetamol, and in some patients 1 or 2 mg of ergotamine tartrate. Treatment should be given as early in the attack as possible and all drugs should, if possible, be given in a soluble or effervescent form. When vomiting occurs early in the attack, treatment is best given by suppository, inhalation or intramuscular injection. Ergotamine tartrate is only necessary in about one third of attacks and when used is best given by suppository or inhalation. Doses of ergotamine tartrate higher than 2 mg per attack or 6 mgs per week may cause toxic symptoms as may the abuse of analgesics.

Acetaminophen↗

Alkaloid binding and activation of D2 dopamine receptors in cell culture.

Ergot and pyrrolizidine alkaloids, either extracted from endophyte-infected tall fescue, synthesized, or purchased commercially, were evaluated in cultured cells to estimate their binding to the D2 dopamine receptor and subsequent effects on cyclic AMP production in GH4ZR7 cells, transfected with a rat D2 dopamine receptor. Ergopeptide alkaloid (alpha-ergocryptine, bromocryptine, ergotamine tartrate, and ergovaline) inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited inhibition constants (K(I)) in the nanomolar range, whereas dopamine was less potent (micromolar). The lysergic acid amides (ergine and ergonovine) were 1/100th as potent as the ergopeptide alkaloids. Ergovaline and ergotamine tartrate were equally effective in inhibiting vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production, with consistent nanomolar effective concentration (EC50) values. The remaining ergopeptide alkaloids (alpha-ergocryptine and bromocryptine), lysergic acid amides (ergonovine and ergine), and dopamine were 1/100th as potent. Two representative pyrrolizidines, N-formylloline and N-acetylloline, exhibited no binding activity at the D2 dopamine receptor or effects on the cyclic AMP system within the concentration ranges of nanomolar to millimolar. Our results indicate that the commercially available ergot alkaloids ergotamine tartrate and ergonovine may be used interchangeably in the D2 dopamine receptor system to simulate the effects of extracted ergovaline and ergine and to examine responses in receptor binding and the inhibition of cyclic AMP.

Animals↗

Short treatments of normotensive and hypertensive rats by angiotensin II and nitric oxide inhibitor induce an increase of noradrenaline sensitivity in isolated vena portae preparations.

The aim of the study was to examine the influence of a short-term treatment of conscious Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) by angiotensin II (ANG II) and by ANG II in combination with either l -NAME, HOE 140 or minoxidil on the mean arterial blood pressure (MABP) and the noradrenaline sensitivity in isolated portal vein preparations. MABP was significantly increased by ANG II treatment and ANG II plus l -NAME. However, it was slightly affected by ANG II in association with HOE 140, and significantly lowered by ANG II plus minoxidil. In control animals noradrenaline increased the frequency and the tone of contractile force. While ANG II enhanced the contractile response to noradrenaline, neither in combination with l -NAME, HOE 140 nor minoxidil prevented such an increase in the response to noradrenaline. In the presence of ergotamine, the contractile response to noradrenaline was completely blocked not only in control animals, but also in animals treated with ANG II alone or in combination with minoxidil. However, ergotamine (3 microm) failed to block completely the contractile response to noradrenaline in vessels from animals treated by ANG II in combination with l -NAME or HOE 140. These data suggest that ANG II causes an increase of noradrenaline sensitivity in the isolated portal vein of rat. l -NAME and HOE 140 unmask a contractile response to noradrenaline in the presence of ergotamine which seems to be mediated not only by alpha-adrenoceptors, but may be compensated by an endothelial relaxation.

Angiotensin II↗

Nitroglycerin for ergotism. Experimental studies in vitro and in migraine patients and treatment of an overt case.

Ergotamine was used to induce arterial contraction in vitro (measurement of isometric tension in segments from 3 human temporal arteries) and in vivo (peripheral systolic blood pressure measured by strain gauge plethysmography in 5 migrainous patients). In both these models of ergotism, the directly acting vasodilator nitroglycerine (NTG) effectively relieved the ergotamine-induced arterial contractions. A case of ergotism treated successfully with NTG infusion is reported. The diagnosis was based on history and measurement of peripheral systolic blood pressure by strain gauge plethysmography. The latter technique was also used to monitor the response to treatment for 20 h. Blood levels of ergotamine during ergotism were in the therapeutic range. Possible explanations for this finding are discussed.

Adult↗

[Perianal ergotismus gangraenosus].

Ergotamine-containing drugs are widely used in the treatment of acute migraine attacks. Among others, spastic vasoconstrictions are one of the possible side effects usually affecting the lower extremities and sometimes leading to gangrene. The case of a 75 year old woman is presented who was suffering from migraine-attacks since adolescence. Due to longterm use of ergotamine containing suppositories she developed perianal ulcers. After withdrawal of the drug the ulcers healed up entirely. The spectrum of ergotamine-induced side-effects and possible intervention strategies are discussed.

Aged↗

Incidence and determinants of migraine prophylactic medication in the Netherlands.

OBJECTIVE: To estimate and examine the incidence and determinants of initiation of migraine-prophylactic therapy as well as the corresponding drug of choice over a period of 5 years following the use of specific abortive migraine drugs. METHODS: By accessing data from a large prescription database, an identification of patients treated with ergotamine or a triptan from 1 January 1994 to 31 December 1998 was made. The cumulative incidence of initiation of migraine-prophylactic drugs (beta-blockers, serotonin antagonists, specific calcium antagonists, amitriptyline, clonidine and valproic acid) was estimated in patients following the use of ergotamine or a triptan. An assessment of the migraine-prophylactic drug of first choice was also performed. A few baseline determinants were analysed to highlight a possible association with the initiation of prophylactic therapy: age, gender, type of abortive migraine drug use and year of prophylaxis. Additional determinants included the analysis of drug-utilisation patterns, such as the consumption and switch patterns of abortive migraine drug use as well as co-medication use prior to prophylaxis. For this particular analysis a reference group (patients not having commenced prophylaxis) was selected from the initial study population. RESULTS: After having satisfied eligibility criteria, a total of 3999 first-time users of ergotamine and triptans were included of whom 479 (12%) had initiated migraine-prophylactic therapy. This corresponded to an incidence density of 6.0 per 100 person-years and was highest for patients younger than 45 years and for multiple abortive migraine drug users. The incidence fell considerably from 12.0 person-years in 1994 to 5.1 person-years in 1998. More than half of the patients had been prescribed a beta-blocker as the migraine-prophylactic drug of first choice by both general practitioners and neurologists. The use of antidepressants and/or benzodiazepines and oral contraceptives was significantly higher in patients starting prophylaxis compared with those who did not. The consumption of abortive migraine drug use (4.0 defined daily doses per month vs 3.7 defined daily doses per month), and switch patterns (27.1% vs 30.9%) were similar for patients starting and not starting prophylaxis. CONCLUSION: The overall incidence of initiation of migraine-prophylactic therapy following the use of abortive migraine analgesics was 6.0% per year and fell considerably during 5 years of the study. Beta-blockers were the migraine-prophylactic drugs of first choice for general practitioners and neurologists. In our study we could not determine any factors clearly associated with the initiation of migraine prophylaxis besides prior use of antidepressants and benzodiazepines. A future assessment of the usage patterns of migraine-prophylactic drugs may provide detailed information concerning the effectiveness and tolerability.

Adrenergic beta-Antagonists↗

Effects of arsenate and ergot alkaloid compounds on prostacyclin synthesis in human umbilical endothelium.

Cultured human umbilical endothelium was incubated with various concentrations of o-arsenilic acid and ergotamine tartrate respectively for 72 hr at 37 degrees C, 5% CO2/95% air in 100% humidity. At the end of incubation, medium was removed for the determination of 6-keto-PGF1 alpha concentration by RIA method. Compared to the normal controls, arsenate (0.1 to 10.0uM) showed inhibition (17 to 24%) on the PGI2 production. Ergotamine tartrate gave an activatory effect (20 to 12%) in low concentration (0.1 to 1.0uM) incubation, but had inhibitory effect (25%) on the PGI2 production in higher concentration incubation (10.0uM). These results indicate arsenate in low and high concentrations does not play an important role on prostacyclin synthesis in human umbilical endothelium. However, ergotamine tartrate at higher concentration might be a main factor for the lower prostacyclin synthesis in Blackfoot disease, an endemic disease of the peripheral vascular system found in the southwest coast of Taiwan.

6-Ketoprostaglandin F1 alpha↗

Cellular adaptation in migraineurs with chronic daily headache.

Ergotamine and analgesic misuse are now recognized as causes of chronic daily headache and the condition responds well to drug withdrawal with reduced headache frequency. In this study, we have investigated whether medication misuse is associated with an alteration in membrane transduction which is sensitive to drug withdrawal. This was carried out by assay of the thrombin-stimulated generation of inositol phosphates in platelets from 12 migraine patients with chronic daily headache and analgesic misuse, 7 migraine patients with chronic daily headache and ergotamine misuse and 7 control subjects. After drug withdrawal, a significant decrease in headache frequency was seen at one month in both patient groups. Withdrawal of analgesics produced a significant decrease in thrombin-stimulated inositol phosphate production at one month; this was further decreased a month later with a reduction in Bmax of 60% and no significant change in KD. A similar pattern was obtained in ergot misuse patients, with the KD value decreasing by 56% one month after drug withdrawal. These results provide evidence of an adaptation in transduction with misuse of analgesics and ergotamine which correlates with headache frequency.

Adult↗

Ergot intoxication: historical review and description of unusual clinical manifestations.

Clinical ergotism as seen today results almost exclusively from the excessive intake of ergotamine tartrate in the treatment of migraine headache. Although both gangrenous and convulsive symptoms are seen in naturally occurring ergotism resulting from the ingestion of fungus infected rye, only gangrenous ergotism has been reported following the excessive ingestion of ergotamine tartrate. The symptoms of both iatrogenic and naturally occurring ergotism appear to result from regional ischemia caused by ergot induced vasospasm. This report discribes experiences in the diagnosis and management of two patients with unusual manifestations of iatrogenic ergotism. One patient presented with ischemia of all extremities and bilateral foot drop probably due to ischemic damage to the common peroneal nerves, a finding not previously described in ergot intoxication. The foot drop totally resolved in several months following the discontinuation of ergot. A second patient presented with unilateral leg ischemia and transient monocular blindness, both of which resolved after discontinuation of ergot. Both patients displayed typical angiographic findings of ergotism. There is no convincing evidence that any treatment other than discontinuation of ergotamine is of benefit in the treatment of iatrogenic ergotism.

Adult↗

GR43175 does not share the complex pharmacology of the ergots.

The aim of this study was to compare the effects of the selective 5-HT1-like receptor agonist, GR43175, with several ergot derivatives in several different pharmacological preparations. In the rat isolated uterus, ergotamine, dihydroergotamine, ergometrine and methylergometrine (all at concentrations of 1 microM) caused marked uterotonic activity whilst GR43175 (10 and 30 microM) was inactive. Similarly, in the pithed rat the ergot derivatives caused marked increases in diastolic blood pressure (in doses up to 1000 micrograms/kg intravenously), whilst GR43175 (in doses up to 1000 micrograms/kg intravenously) was inactive. In anaesthetized dogs, both ergotamine (0.3-1000 micrograms/kg intravenously) and GR43175 (1-1000 micrograms/kg intravenously) caused dose-dependent vasoconstriction in the carotid artery bed. However, the effects of ergotamine, unlike those of GR43175, were accompanied by increases in diastolic blood pressure and coronary vasoconstriction. These studies provide further evidence for the remarkably selective vasoconstrictor action of GR43175.

Animals↗

Chronic migraine and medication-overuse headache through the ages.

We set out to review early descriptions of chronic migraine and medication-overuse headache. The International Headache Society (IHS) recently gave criteria for chronic migraine and medication-overuse headache. Chronic migraine was absent from the 1988 IHS criteria. Peters and Horton described ergotamine-overuse headache in 1951. In the 1980s it was more fully appreciated that overuse of other acute headache medications could increase headache frequency. We reviewed published English-language papers and book chapters. Willis (1672), Oppenheim (1900), Collier (1922), Balyeat (1933), and von Storch (1937) all described chronic migraine. Lennox (1934), O'Sullivan (1936), Silfverskiold (1947), Graham (1955), Friedman (1955), and Lippman (1955) wrote about ergotamine-overuse headache. Graham (1955), Friedman (1955), Lippman (1955), and Horton and Peters (1963) outlined withdrawal protocols. Chronic migraine has been mentioned in the literature for centuries, while medication-overuse headache has been written about for decades. Graham, Friedman, and Lippman deserve credit for separately reporting the first ergotamine withdrawal programmes.

Ergotamines↗

5-Hydroxytryptamine levels and platelet aggregation responses in subjects with acute migraine headache.

Blood 5-hydroxytryptamine levels were reduced during migraine attacks in patients who had not taken any drugs but the aggregation responses to 5-hydroxytryptamine of the blood platelets from these patients were similar to responses of platelets from migrainous subjects between attacks. This confirms earlier findings that a permanent difference exists in the behaviour of platelets from migrainous subjects. Blood 5-hydroxytryptamine levels were reduced during migraine attacks in patients who had taken ergotamine. The aggregation responses of platelets taken from migrainous patients on ergotamine both during and between attacks were inhibited, which is in agreement with results previously found for aggregation responses following the in vitro pre-incubation of control platelets with ergotamine. Blood 5-hydroxytryptamine levels were maintained during migraine attacks in patients who had taken analgesics and there was no reduction in the aggregation responses of their platelets.

Analgesics↗

[Effect of ergot alkaloids on venous tonus determined in superficial hand veins in situ].

The venoconstrictor effect of dihydroergotamine in man was demonstrated by Rieckert and Pauschinger in 1967. In a study on the influence of local infusions of dihydroergotamine into superficial hand veins in man we found a direct venoconstrictor effect of the drug. In further studies the effects of dihydroergotamine were compared with those of other dihydrogenated and non-dihydrogenated ergot alkaloids and a dose-dependent venoconstrictor effect was observed after local infusion of dihydroergotamine, dihydroergostine, dihydroergovaline, ergotamine and methysergide into superficial hand veins in man. Dihydroergotamine was weight for weight somewhat less active than ergotamine. But as Mellander and Nordenfelt have shown that dihydroergotamine elicits only a weak effect on resistance vessels, this drug seems for the treatment of orthostatic hypotension to be preferable to ergotamine for which Owen and Stürmer have demonstrated a marked constriction of resistance vessels in the skin. Experiment with dihydroergotamine showed that the venoconstriction in these human veins is mainly due to alpha-adrenoceptor stimulation. As in the treatment of orthostatic hypotension drugs are usually given in oral form, the activity of dihydroergotamine was also investigated after oral administration and the venoconstrictor activity confirmed.

Blood Pressure↗

Complex interaction of ergovaline with 5-HT2A, 5-HT1B/1D, and alpha1 receptors in isolated arteries of rat and guinea pig.

Vascular effects of ergovaline mediated by 5-hydroxytryptamine(HT)2A, 5-HT1B/1D, and alpha1 receptors were studied in isolated arterial preparations of rat and guinea pig. In rat tail artery ergovaline behaved as a potent contractile partial agonist showing an agonist potency (pEC50) of 8.86 +/- 0.03, a maximum response (Emax) of 59 +/- 2% with respect to 5-HT, and a partial agonist affinity (pK(P)) of 8.51 +/- 0.06. Ergovaline was equipotent with ergotamine (pEC50, 8.69 +/- 0.07; Emax, 52 +/- 4%; pK(P), 8.36 +/- 0.11). Contractile responses to ergovaline and ergotamine were surmountably antagonized by the 5-HT2A receptor antagonist ketanserin (3 nM). Antagonist affinity (apparent pA2) for ketanserin against ergovaline and ergotamine was 9.19 +/- 0.08 and 9.36 +/- 0.17, respectively. Ergovaline showed extremely slow on-set and off-set kinetics in rat tail artery. The construction of cumulative concentration-response curves required about 4 h, and the contractile response to ergovaline (30 nM), which completely abolished the subsequent contractile response to 5-HT (10 nM to 1 mM), could not be reversed by wash-out. In guinea pig iliac artery moderately precontracted with prostaglandin F2alpha (0.05 to 0.5 microM) ergovaline behaved as an agonist (pEC50, 7.71 +/- 0.10) with a potency similar to that of 5-HT (pEC50, 7.60 +/- 0.05). The contractile response to ergovaline was inhibited by the 5-HT1B/1D receptor antagonist GR127935 (10 nM). The apparent pA2 value for GR127935 against ergovaline was 8.90 +/- 0.12. Ergovaline (10 nM) produced no contractile response in guinea pig iliac artery when added before the PGF2alpha-induced precontraction but caused insurmountable blockade of the contractile response to the 5-HT1B/1D receptor agonist 5-carboxamidotryptamine (5-CT). The apparent pA2 value for ergovaline against 5-CT was 8.56 +/- 0.18. In rat thoracic aorta ergovaline (2 microM) activated alpha1 adrenoceptors only with low efficacy (Emax, 12 +/- 3%) but surmountably antagonized norepinephrine-induced contractions with a pK(P) of 7.07 +/- 0.12. It is concluded that the powerful constrictor effect of ergovaline mediated by activation of vascular 5-HT2A and 5-HT1B/1D receptors may explain the vascular symptoms of fescue toxicosis observed in livestock grazing tall fescue pastures infected with the endophytic fungus Neotyphodium coenophialum.

Animals↗

[Ergotism caused by automedication].

The authors report 7 cases of gangrenous ergotism (six women and one man) secondary to an overdose of ergotamine ingested in order to relieve migraine crisis. In all cases, patients presented symptoms and signs of severe arterial constriction confirmed by echography and angiography. Hallucinations were absent. Ergotamine ingestion was discontinued and treatment was based on vasodilators and sympathectomy. After treatment, all seven patients showed clinical improvement with disappearance of the vasospastic symptoms and signs, and an increase in the plethysmographic index of blood perfusion, measured by Doppler echography. These changes were observed even in a patient who lost two toes of the right foot. Although, none of the patients presented hallucinations, the authors made reference to the historical first use of the ergot in magic and religious rites that took place in Eleusis, at the time of classic Greece, as well as the more recent mystic use of ergot in Salem, New England, in 1692. Migraine is indeed a serious disease, frequently causing despair to the patient, who attempts to alleviate the migraneous crisis with an overdose of ergotamine. Accordingly, physicians must be aware of prophylactic vasodilating drugs, reducing the risk of ergotism.

Adult↗

[Provocation tests for coronary spasm. Methods, value and indications].

Five methods are currently used to demonstrate coronary spasm: they use derivatives of ergotamine, alkalinisation, cold, adenosine triphosphate and exercise stress test. The criteria used to confirm spasm are either direct visualisation at coronary angiography or indirect electrocardiographic changes. The value of these test is beginning to be established: --their specificity is excellent with all methods (a positive test is diagnostic); --their sensitivity is mediocre (a negative test does not exclude the diagnosis). This depends on three factors: the choice of criteria of positivity: angiographic appearances is the most reliable; the timing of the test: it is more likely to be positive when the test is carried out close to episodes of chest pain; the method of provocation: the most sensitive tests use either the ergotamine derivatives or alkalinisation; --reproductibility is satisfactory at short and long term. These tests have diagnostic and therapeutic indications. It is preferable to perform diagnostic tests during coronary angiography in patients with normal coronary arteries and unexplained episodes of chest pain. However, in patients with fixed coronary lesions (except triple vessel and left main stem disease) when coronary bypass surgery is planned, the results of the test can help in the choice of associated therapy, such as plexectomy and calcium antagonist drugs. The repetition of the test is useful in the evaluation of antispastic therapy: when the test becomes negative the drug used is probably effective. In conclusion, with equal patient comfort and MSR, provocation tests using the ergotamine derivatives would seem to be the method of choice: alkalinisation is a good alternative.

Adenosine Triphosphate↗

Upregulated expression of peripheral serotonergic receptors in migraine and cluster headache by sumatriptan.

The double-label flow cytometric analysis of peripheral serotonergic pathways of migraine and cluster headache on a monocyte model has been used to evaluate the activity of drugs with a selective activity on central vascular 5-HT1D receptors, such as sumatriptan, ergotamine and ondansetron. The results indicated that sumatriptan and ergotamine progressively increase the peripheral expression of 5-HT (5-hydroxytryptamine, serotonin). The increase obtained in migraine after ergotamine is more evident than that obtained in cases of cluster headache. Ondansetron produced a moderate increase in serotonergic expression only in cluster headache. The events that occur at intracranic neural and vascular level may cause the described changes of 5-HT expression on the monocyte model as an indirect, reflective, peripheral registration of central serotonergic variations during headache attack as well as during the drug-sustained recovery phase.

Adult↗