Aerosol delivery of ergotamine tartrate via a breath-synchronized plume-control inhaler in humans.

OBJECTIVE: To compare systemic delivery of ergotamine tartrate (ET) via a breath-synchronized, plume-control inhaler (BSPCI) (Tempo ET) with a sublingual ergot preparation and a commercial inhaler. METHODS: Study 1 determined plasma ET concentrations in seven healthy subjects after administration of ET by a 2 mg tablet (Lingraine) and a BSPCI delivering 258 microg of ET. Study 2 determined plasma ET concentrations in 16 healthy subjects after administration via an ET metered dose inhaler (ME) (Medihaler) delivering 2052 microg of ET and a BSPCI delivering 129 microg of ET. Gamma scintigraphy with (99m)Tc validation was used to quantify lung deposition. RESULTS: For both studies, ET C(max) was higher with the BSPCI (study 1: sublingual ET 134 pg/mL at 37 min; BSPCI 3743 pg/mL at 3 min; study 2: metered-dose inhaler 1109 pg/mL at 4 min; BSPCI 1210 pg/mL at 2.5 min). Mean dose normalized AUC was several-fold higher with the BSPCI compared with sublingual ET and ME dosing. Lung deposition of ET with the BSPCI was 33.5, 8.9, 11.4, and 13.2% for whole, central, intermediate, and peripheral lung, respectively, with a 1.5 peripheral : central ratio. CONCLUSION: Based on these open-label studies, the BSPCI allows rapid delivery of potentially therapeutic plasma concentrations of ET at approximately 1/15th the dose of comparators.

Highly specific quantification of ergotamine in urine, blood, and hair samples by liquid chromatography-tandem mass spectrometry.

Ergotamine has been used for therapeutic purposes since the 1950s, usually to treat vascular headache. It is highly toxic and in large, repeated doses can produce all the symptoms of ergot poisoning. A selective and sensitive method, based on liquid chromatography-tandem mass spectrometry (LC-MS2), has been developed for quantifying ergotamine in biological fluids with use of a quick and easy sample preparation. Ergotamine and the internal standard, trideuterated lysergic acid diethylamide, were extracted from human urine, blood, and hair by means of liquid-liquid extraction at alkaline pH. Gradient elution on a cyanopropyl column was used for chromatographic separation. Positive ion electrospray ionization and tandem mass spectrometry determination by collision-induced dissociation were performed in an ion trap mass spectrometer. The method was validated and successfully applied to a case of iatrogenic ergotism resulting from the intake of ergotamine tartrate for treating headache. For the first time, ergotamine was identified and quantified in hair. The ergotamine concentrations measured were 320 pg/mL in blood, 100 pg/mL in urine, 24 pg/mg in proximal hair, and 15 pg/mg in distal hair.

Effect of ergotamine on plasma metabolite and insulin-like growth factor-1 concentrations in cows.

Bovine plasma was assayed to determine if ergotamine affected plasma metabolite and insulin-like growth factor-1 (IGF-1) concentrations. In Experiment 1, four cows received a single bolus intravenous injection of ergotamine tartrate (19 microg/kg body wt.) or saline vehicle in a crossover design 2 days after prostaglandin-induced luteolysis. Treatmentxtime affected plasma glucose, triglyceride, total cholesterol and IGF-1 concentrations. Glucose and cholesterol were increased after ergotamine. Triglycerides were elevated within 1 h after ergotamine, but were decreased 3 h after ergotamine treatment. Plasma IGF-1 decreased in response to ergotamine. Blood constituents were unchanged after treatment with saline. In Experiment 2, six cows received a single bolus intravenous injection of ergotamine (20 microg/kg body wt.) or saline vehicle in a crossover design 10 days after receiving norgestomet (6 mg) via subcutaneous ear implant. Treatmentxtime affected glucose, triglycerides, total cholesterol and IGF-1 concentrations. Glucose and cholesterol were increased after ergotamine. Triglycerides were elevated 1 h after ergotamine and decreased 3-7 h after ergotamine. Plasma IGF-1 decreased after ergotamine treatment. Blood constituents were unresponsive to the saline vehicle. Results indicated ergotamine altered plasma metabolite and IGF-1 concentrations in cows.

Physiological responses of Brahman and Hereford steers to an acute ergotamine challenge.

Research was conducted to evaluate the sensitivity of Bos indicus and Bos taurus cattle to a tall fescue ergopeptine alkaloid by assessing vital sign responses. Eight Polled Hereford and seven Red Brahman steers received bolus i.v. injections of ergotamine tartrate and saline vehicle in a simple cross-over design. Physiological traits measured 30 min and immediately before and 30, 60, and 90 min after treatment were respiration rate, rectal temperature, skin temperature at the tailhead and tail tip, systolic and diastolic blood pressure, and heart rate. Blood samples were collected immediately before and 105 min after treatments to determine plasma prolactin and cortisol concentrations. Steers were fed a fescue-free diet in drylot. Ambient temperature and relative humidity averaged 31 degrees C and 55%, respectively, during data collection. No breed x treatment x time interactions were apparent for vital signs. The treatment x time interaction was significant (P < .05) for blood pressure and skin temperature. Ergotamine increased (P < .01) blood pressure and decreased (P < .01) skin temperature. The breed x treatment x time interactions were significant for prolactin (P < .1) and cortisol (P < .01). Ergotamine decreased plasma (P < .01) prolactin and increased (P < .01) cortisol concentrations in both breeds, despite some breed variation. Across all traits, Brahman and Hereford steers responded similarly to acute ergotamine exposure, indicating that the breeds are alike in acute sensitivity to a systemically administered ergopeptine alkaloid associated with fescue toxicosis.

[Vascular ergotism through inhalation of grain dust]. / Vaskulärer Ergotismus durch Getreidestaubinhalation.

HISTORY AND CLINICAL FINDINGS: For 6 months a 42-year-old farmer without cardiovascular risk factors had been suffering from increasing pain in both feet and calves. Angiography two months apart had demonstrated progressive narrowing of all lower-leg arteries. Pain-free walking had become restricted to 50 m, there were no palpable pulses in the right foot and those in the left foot were markedly reduced. INVESTIGATIONS: Occlusion pressure of the right foot was 55 mm Hg. Repeat angiography showed proximal occlusion of all three lower-leg arteries. Biopsy and biochemical tests excluded degenerative and inflammatory causes of the vascular disease. DIAGNOSIS, TREATMENT AND COURSE: Enquiry of the patient discovered that he had been exposed to ergotamine-containing milling dust in the preparation of rye flour. Inhalational intake of ergotamine was proven by a high plasma ergotamine level. Attempted treatment with prostaglandin E1 (intraarterially for 16 days), doxazosin (2 mg/d) and acetylsalicylic acid 300 mg/d) had only little effect on symptoms. But complete avoidance of exposure to flour dust slowly decreased the plasma level of ergotamine within 4 months, after which all lower-leg arteries had almost completely re-opened. CONCLUSIONS: This is the first reported case proving that chronic ergotamine inhalation can cause ergotism affecting peripheral arteries. As the plasma ergotamine level fell only slowly it must be assumed that ergotamine had accumulated in a, so far unknown, body depot with slow release into the blood.

Quantitative determination of the dopamine agonist lisuride in plasma using high-performance liquid chromatography with fluorescence detection.

An HPLC method for the determination of lisuride hydrogen maleate in plasma is described. After addition of ergotamine tartrate as internal standard, plasma is extracted with diethyl ether. Following evaporation of the solvent and redissolving in methanol the extract is injected on a silica HPLC column and lisuride is monitored by fluorescence detection using an excitation wavelength of 322 nm and an emission wavelength of 405 nm. The method is sufficiently accurate and precise with a detection limit of 20 pg/ml lisuride in plasma. The usefulness of the method is demonstrated by measurements of lisuride levels after oral intake of a 0.6 mg dose of the drug by a healthy male volunteer, showing a peak level of 1266 pg/ml, 45 min after intake.

Identification and quantification of ergotamine in human plasma by gas chromatography-mass spectrometry.

A highly sensitive and simple gas chromatographic-mass spectrometric method is described for the identification and quantification of ergotamine in plasma or serum. Ergotamine is extracted with chloroform from the alkalinized sample and detected by electron ionization mass spectrometry. This analytical method was selected for an intense high-mass ion ideal for the specific quantification. It shows good linearity in the range from 50 pg/ml to 50 ng/ml for ergotamine in plasma. The practicability of this method is demonstrated by determining the plasma concentration of ergotamine in a sample from a patient.

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

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

Measurement of ergotamine in human plasma by triple sector quadrupole mass spectrometry with negative ion chemical ionization.

By use of negative ion chemical ionization and collision-activated decomposition in a triple quadrupole mass spectrometer a method has been developed for the quantification of ergotamine in human plasma at levels down to 2 pg ml-1.

Ergotamine toxicity and serum concentrations of ergotamine in migraine patients.

Twenty-five migraine patients (9 males and 16 females) aged 22-71 who had used between 7 and 60 mg ergotamine tartrate per week for 1.5-30 y volunteered to participate in the study. Side-effects attributable to ergotamine were wide ranging and included daily headache and pain in the limbs. Wide variation in sensitivity to the drug was observed and side-effects were not always proportional to the dose of ergotamine. Random serum ergotamine concentrations were estimated in all patients and 10 of them volunteered to take a 2 mg oral challenge of ergotamine tartrate. Ergotamine was not detected in 44% of the random estimations even though all patients exhibited clinical signs of ergotamine tartrate overdose. The remaining 56% estimations all showed low drug concentrations. After the 2 mg oral challenge of ergotamine in the 10 patients, significantly higher concentrations, but still within therapeutic range, were detected in the sera when compared with mean concentrations achieved after the same oral dose of the drug in healthy, non-migrainous subjects.

Immunoassay of ergotamine and dihydroergotamine using a common 3H-labelled ligand as tracer for specific antibody and means to overcome experienced pitfalls.

A highly sensitive radioimmunoassay for the determination of ergotamine and dihydroergotamine is described. The limit of detection is about 9 pg/mL blood plasma for both compounds. The specificity of the gamma-globulin, which was prepared from rabbit antiserum, was investigated in the presence of compounds synthesized as possible metabolites. It was found that the tricyclic peptide moiety common to both molecules is an essential structural feature for binding to the gamma-globulin. From dilution experiments with the radioactively labelled compound it followed that ergotamine and to a lesser extent also its dihydro derivative are adsorbed on various tube wall materials using known buffer solutions. A practically insuperable obstacle is rearrangement of ergotamine under the experimental conditions, forming a stereoisomer by inversion at the C-8 position. The equilibrium of ergotamine in equilibrium ergotaminine found in human plasma remains stable under the incubation conditions of the radioimmunoassay.

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.

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).

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

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

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%).

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.

Determination of ergot alkaloids in plasma by high-performance liquid chromatography and fluorescence detection.

Liquid chromatographic methods for the determination of ergotamine and methylergometrine in plasma have been developed. The samples are extracted with an organic solvent at pH 9.0 cleaned by extractions and finally injected on an ODS-Hypersil reversed-phase column with acetonitrile-ammonium carbonate buffer as the mobile phase. THe polarity of solvents used for extraction and the mobile phase are varied with the compounds of interest. Ergocristine is used as internal standard for ergotamine, and methysergide for the determination of methylergometrine. The stability of samples and standard solutions for calibration are discussed. Conditions for high selectivity and sensitivity of detection are given. Concentrations down to 100 pg/ml of plasma can be detected with a 3-ml sample.

Systemic availability of ergotamine tartrate in healthy subjects after single and repeated oral doses.

The studies presented indicate that ergotamine tartrate taken orally in single or repeated 2 mg doses is biologically available in most of the subjects examined. The peak plasma concentration of the drug in the ng/ml range is attained at 1-2 hours. It seems probable that there is a second rise in the plasma concentrations of the drug, possibly indicating an accumulation of ergotamine or some of its immunoreactive metabolites, and this needs further evaluation.