メチセルジド

Crystals

Solid

MP IS UNCHARACTERISTIC SHOWING DECOMP ABOVE APPROX 165 °C; ODORLESS OR HAS NOT MORE THAN SLIGHT ODOR; WHITE TO YELLOWISH WHITE OR REDDISH WHITE CRYSTALLINE POWDER; 1 G SOL IN 200 ML WATER, 165 ML ALCOHOL, 3400 ML CHLOROFORM; PRACTICALLY INSOL IN ETHER /MALEATE/

Decomposes above 165 °C; sol in methanol, less soluble in water (1:250); practically insoluble in absolute ethanol; practically insoluble in absolute ethanol /Methysergide dimaleate/

Water spray, dry chemical, carbon dioxide, or foam as appropriate for surrounding fire and materials.

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Below 86 °F (30 °C); tight container.

Store in tight, light-resistant container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.

Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labeled container for disposal. Wash spill site.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

This material is assumed to be combustible. As with all dry powders, it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.

/Wear/ chemically compatible /gloves/ and safety goggles and glasses /for eye protection/. Protect exposed skin.

Engineering controls such as exhaust ventilation are recommended.

Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used.

Treatment for overdose consists of removal of the offending drug by induction of emesis, or gastric lavage in the case of very recent intake, repeat dose administration of activated charcoal and catharsis. I.V. fluids may be given as a general supportive measure. Treatment of peripheral vasospasm should consist of warmth, but not heat, and protection of the ischemic limbs. (L1712)

Methysergide may reverse the analgesic activity of narcotic analgesics. Concurrent use with vasoconstrictor agents including ergot alkaloids, sumatriptan, and nicotine (eg smoking) may result in enhanced vasoconstriction.

/The authors/ report a 31-year-old man with cluster headaches who developed severe, prolonged myocardial ischemia following combination therapy with ergotamine tartrate and methysergide. /Investigators/ reviewed the cardiovascular complications of each agent alone and in combination. Given the pharmacologic similarity of these agents, /investigators/ propose that they may have additive or synergistic cardiac toxicity, at least in vulnerable individuals.

A 28 year old housewife was admitted complaining of excrutiating pain in her feet. On examination her feet were pale and cold. Her hands were also cold but of normal colour. Her carotid, axillary, and femoral pulses were the only palpable peripheral pulses. She had suffered from migraine and duodenal ulceration for some years and had taken numerous drugs including propoxyphene, benzodiazepine derivatives, diclofenac, cimetidine, chlordiazepoxide, raubasine, sucralfate, ergotamine tartrate, and oxprenolol. The precise dosages and duration of these treatments could not be established, but we ascertained that she had been taking oxprenolol and ergotamine tartrate tablets for a considerable time before admission. Arteriography showed severe spasm of most parts of the femoral arteries, the distal parts of the brachial arteries, and the radial arteries. Intravenous infusion of heparin (500 units/hour) and dopamine (150-300 4g/min) resulted in moderate improvement in the circulation except in the left foot, which remained painful and developed a mottled appearance. A cannula was placed in the left femoral artery, and nitroglycerin (1 mg/hour) and heparin (500 units/hour) were infused. This caused a dramatic improvement. After 24 hours the peripheral pulses were palpable and the cannula was removed. Intravenous treatment was reduced over the next two days, and she made a satisfactory recovery.

A 21 year old policeman was admitted to hospital with progressive severe pain in his legs and feet of one week's duration. He had suffered from migraine for 10 years and had been taking methysergide (3 mg) and propranolol (120 mg) daily for two weeks. On examination his feet were pale, cold, and poorly perfused and only the femoral pulses were palpable in his legs. Aortography disclosed extreme bilateral narrowing of the superficial femoral arteries consistent with severe spasm. Intravenous infusions of 10% dextran 40 in saline (Rheomacrodex) and heparin (500 units/hour) and a lumbar epidural block with 1 % lignocaine failed to afford any improvement. Infusion of isoprenaline (1-2 ug/min) the next day resulted in mild improvement. Nevertheless, both feet gradually became gangrenous, and bilateral below knee amputations were performed six days after admission.

For more Interactions (Complete) data for METHYSERGIDE (7 total), please visit the HSDB record page.

There are no specific studies on the use of Methysergide in nursing mothers. Ergot alkaloids, in general, appear in mothers' milk. Methysergide is a semi-synthetic compound structurally related to ergotamine, and thus it may appear in breast milk. Ergot alkaloids have been reported to cause nausea, vomiting, diarrhea and weakness in the nursing infant and suppression of prolactin secretion and lactation in the mother. Because of the potential for serious adverse reactions in nursing infants from Methysergide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Ergoline alkaloids have been shown to have the significant affinity towards the 5-HT1 and 5-HT2 serotonin receptors, D1 and D2 dopamine receptors, and alpha-adrenergic receptors. This can result in a number of different effects, including vasoconstriction, convulsions, and hallucinations. Methysergide as a serotonin antagonists acts on central nervous system, which directly stimulates the smooth muscle leading to vasoconstriction. Some alpha-adrenergic blocking activity has also been reported. Suggestions have been made by investigators as to the mechanism whereby Methysergide produces its clinical effects, but this has not been finally established, although it may be related to the antiserotonin effect. (A308, A2914, A2915, A2916)

Few cases of acute methysergide intoxication have been reported. The possible symptom complex is therefore not fully known. The following symptoms are based on these few case reports. Euphoria, hyperactivity, tachycardia, dilated pupils, and dizziness have been reported in a child with a dose of 20-24 mg of methysergide. In adults, peripheral vasospasm, with diminished or absent pulses, coldness, mottling and cyanosis, has been observed at a dose of 200 mg. Ischemic tissue damage has not been reported in acute overdosage with methysergide.

/HUMAN EXPOSURE STUDIES/ The effects of acute oral administration of the antiserotoninergic drugs methysergide (3 mg) and metergoline (4 mg) on basal, submaximal (0.6 ug/kg i. m.) and maximal (6 ug/kg) pentagastrin-stimulated gastric acid secretion, as well as on basal and food-induced gastrin release, have been evaluated in healthy volunteers. Methysergide significantly increased basal and submaximal pentagastrin-stimulated gastric acid secretion, and metergoline significantly inhibited gastric acidity in all experiments. Basal and stimulated serum gastrin concentrations were not modified by either drug. The effect of methysergide on gastric acid secretion was opposed to that of serotonin and was probably dependent on its antiserotoninergic action...

/SIGNS AND SYMPTOMS/ Few cases of acute Methysergide intoxication have been reported. The possible symptom complex is therefore not fully known. The following symptoms are based on these few case reports. Euphoria, hyperactivity, tachycardia, dilated pupils, and dizziness have been reported in a child with a dose of 20-24 mg of methysergide. In adults, peripheral vasospasm, with diminished or absent pulses, coldness, mottling and cyanosis, has been observed at a dose of 200 mg. Ischemic tissue damage has not been reported in acute overdosage with methysergide.

/CASE REPORTS/ Neuropathologic manifestations due to chronic ergotism are rare. /Investigators/ report the case of a 40-year-old patient who presented clinical signs and symptoms of a spinal lesion and also the symptoms of neuropathy involving the right sciatic nerve, more precisely the internal and external popliteal nerves, following ingestion of methysergide. Complete recovery was achieved with calcium blocker treatment. Ergotism should be considered in patients treated by ergot alkaloids presenting an atypical clinical manifestations.

/CASE REPORTS/ A 25-year-old woman sought medical attention because of iliocaval manifestations of retroperitoneal fibrosis while she was taking methysergide. Laboratory studies yielded substantially increased serum procollagen III levels and anticardiolipin antibodies accompanied with anti-beta(2) glycoprotein I, findings not previously described with this disorder. Clinical and laboratory manifestations resolved after cessation of methysergide therapy.

For more Human Toxicity Excerpts (Complete) data for METHYSERGIDE (18 total), please visit the HSDB record page.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

methysergide

Sansert®

Ergot alkaloids

Not Applicable

no-DILI-concern

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Oral administration of 1, 2, and 5 mg/kg/day of methysergide to dogs failed to produce any major signs of toxicity over a period of 6 months.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Daily doses as high as 5 mg/kg failed to elicit major toxic signs in dogs. Significantly increased mortality of rats was not achieved until dietary levels of 150 mg/kg per day were administered for 17 weeks. /Methysergide maleate/

FDA Pregnancy Risk Category: X /CONTRAINDICATED IN PREGNANCY. Studies in animals and or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk which clearly outweighs any possible benefit to the patient./

N - Nervous system

QN - Nervous system

Methysergide has been shown, <i>in vitro</i> and <i>in vivo</i>, to inhibit or block the effects of serotonin, a substance which may be involved in the mechanism of vascular headaches. Serotonin has been variously described as a central neurohumoral agent or chemical mediator, as a "headache substance" acting directly or indirectly to lower pain threshold, as an intrinsic "motor hormone" of the gastrointestinal tract, and as a "hormone" involved in connective tissue reparative processes.

Methysergide is serotonin antagonists acts on central nervous system (CNS), which directly stimulates the smooth muscle leading to vasoconstriction. Some alpha-adrenergic blocking activity has been reported. Suggestions have been made by investigators as to the mechanism whereby Methysergide produces its clinical effects, but this has not been finally established, although it may be related to the antiserotonin effect.

Methysergide has been shown, in vitro and in vivo, to inhibit or block the effects of serotonin, a substance which may be involved in the mechanism of vascular headaches. Serotonin has been variously described as a central neurohumoral agent or chemical mediator, as a "headache substance" acting directly or indirectly to lower pain threshold (others in this category include tyramine; polypeptides, such as bradykinin; histamine; and acetylcholine), as an intrinsic "motor hormone" of the gastrointestinal tract, and as a "hormone" involved in connective tissue reparative processes. Suggestions have been made by investigators as to the mechanism whereby methysergide produces its clinical effects, but this has not been finally established.

Considering structure/effect relationships, it has been demonstrated that methylation of the indole nitrogen in the lysergic acid ring of the alkanolamides fundamentally alters their pharmacologic behavior and is associated with inhibition or blockade of a great variety of serotonin-induced effects...

... Here /investigators/ asked whether systemic (i.p.) and intrathecal (i.t.) administrations of a nonselective serotonergic antagonist, methysergide, might produce paradoxical antinociception similar to naloxone in the mouse formalin test. A diluted formalin solution was injected into the mouse plantar region of the hind paw and the duration of licking responses was measured at periods of 0-5 min (1st phase) and 20-40 min (2nd phase) after formalin injection. Methysergide administered i.p. and i.t. showed an attenuated licking duration only in the 2nd phase. The effect observed in the 2nd phase was reversed in the 5,7-dihydroxytriptamine, but not N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated group of mice, suggesting that descending serotonergic, but not noradrenergic, systems are involved in the methysergide antinociception. To further investigate the mechanism by which methysergide inhibited the nociceptive behaviors induced by formalin, the antinociceptive effect of methysergide was also tested in substance P (i.t.) and excitatory amino acids (i.t.), such as glutamate, N-methyl-D-aspartic acid, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and kainic acid, which are major components in the formalin-induced nociceptive transmission in the spinal cord pain models. The duration of nociceptive behaviors shown in these models was significantly shortened by i.p. and i.t. administration of methysergide. These results suggest that methysergide also produces a paradoxical antinociception in various pain models including the formalin test, similar to the results of naloxone.

Calcitonin gene-related peptide (CGRP) is involved in ocular neurogenic inflammation in the rabbit, causing vasodilatation in the anterior uvea, breakdown of the blood-aqueous barrier, increase in the intraocular pressure (IOP) and rise in the adenosine 3':5'-cyclic monophosphate (cyclic AMP) content in the aqueous humour. So far there is no means of preventing these CGRP-induced ocular effects. In the present study, the effect of intravenous methysergide (1-10 mg kg-1, b.w.) on CGRP-induced changes in the IOP, blood-aqueous barrier and cyclic AMP content in the aqueous humour was studied in vivo. The effect of methysergide on CGRP-induced vasodilatation both in vivo and in vitro was also investigated. Methysergide decreased intraocular pressure but had only a transient effect on blood pressure. Methysergide decreased the regional blood flow in ocular tissues by 53-65%, but did not have such a vasoconstrictor effect in most extra-ocular tissues studied. Methysergide inhibited CGRP-induced vasodilatation, increase in the IOP, breakdown of the blood-aqueous barrier and increase in the cyclic AMP content in the aqueous humour in vivo. In vitro, methysergide alone did not have effects on the vascular tone in isolated ophthalmic artery of rabbit. However, it potentiated noradrenaline (NA)-induced contraction. There were no differences in the IC50 values for CGRP on the NA-induced contraction in the presence and absence of methysergide, indicating that methysergide has no direct effect on the vasorelaxant effect of CGRP in vitro. The present study demonstrates that in the rabbit eye methysergide inhibits CGRP-induced changes. One inhibitory mechanism of methysergide may be to enhance the effect of a vasoconstrictor (NA) to antagonize the vasodilator effect of CGRP. The present findings suggest that a methysergide-sensitive mechanism may be used to limit some pathophysiological conditions in the eye that involve neurogenic inflammation and the release of CGRP.

The intravenous administration of L-5-hydroxytryptophan (5-HTP), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), p-chloroamphetamine (PCA), LSD and methysergide to acute spinal rats, transected at C1, stimulated the flexor reflexes induced by electrical stimulation applied to the skin of the toe. The enhancement produced by 5-HTP, 5-MeODMT and PCA, was not antagonized by the prior administration of a dose of LSD or methysergide, although the enhancement produced by 5-MeODMT, LSD and methysergide, but not that produced by 5-HTP and PCA, was antagonized by cyproheptadine. In rats treated with 5,6-dihydroxytryptamine (intracisternal administration, 2 weeks previously) supersensitivity was observed to the effects of 5-HTP, a precursor of 5-HT, while subsensitivity was observed for the effects of PCA, a releaser of 5-HT. However, no supersensitivity was observed for the effects of 5-MeODMT, LSD and methysergide. These results suggest that methysergide may have an agonistic action on the 5-HT receptors in spinal cord and that supersensitivity to 5-HTP in rats treated with 5,6-dihydroxytryptamine was due to the lack of uptake of 5-HT into terminals of descending 5-HT fibres or to the change in 5-HT receptors which were not sensitive to 5-MeODMT, LSD, methysergide or cyproheptadine.

Five healthy men were given 1.0 mg methysergide maleate intravenously and 2.7 mg methysergide maleate orally in a cross-over study. ... Methylergometrine had a significantly longer elimination half-life than methysergide (223 +/- 43 min vs 62.0 +/- 8.3 min and 174 +/- 35 min vs 44.8 +/- 8.1 min in the oral and intravenous studies respectively).

Hepatic

Methysergide is metabolized in the liver. (A308)

Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS.

Drugs used to cause constriction of the blood vessels.

Rapid

Five healthy men were given 1.0 mg methysergide maleate intravenously and 2.7 mg methysergide maleate orally in a cross-over study. The systemic availability of methysergide was only 13%, most probably due to a high degree of first-pass metabolism to methylergometrine. We also found evidence of extrahepatic clearance of methysergide. After oral administration the plasma concentrations of the metabolite were considerably higher than those of the parent drug and the area under the plasma concentration curve (AUC) for methylergometrine was more than ten times greater than for methysergide. /These/ findings may be relevant to the treatment of migraine if methylergometrine contributes to the effect of methysergide. Methylergometrine had a significantly longer elimination half-life than methysergide (223 +/- 43 min vs 62.0 +/- 8.3 min and 174 +/- 35 min vs 44.8 +/- 8.1 min in the oral and intravenous studies respectively).

The pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) was studied in male Sprague-Dawley rats. MS was administered iv in doses of 0.71 (0.25 mg/kg) or 2.8 mumol/kg (1.0 mg/kg). The metabolite MEM was administered as iv doses of 0.74 (0.25 mg/kg) or 2.9 mumol/kg (1.0 mg/kg). The steady state characteristics of these compounds were also studied after constant rate iv infusion of MS at two different rates, 0.70 and 14.0 nmol/min per kg. Plasma protein binding and blood/plasma partitioning for MS were determined over a range of concentrations. Plasma and blood concentrations of MS and MEM were measured by HPLC with fluorescence detection. The plasma clearance of MS was high and ranged from 74.2-102 mL/min per kg. The two iv doses of MS were not equivalent after dose correction; clearance, volume of distribution at steady-state and terminal half-life were significantly greater for the higher dose. Plasma clearance from the two iv infusions of MS were in accordance with that from the lower iv dose. Protein binding as well as the plasma/blood partitioning, of MS was constant over the range of concentrations observed in the disposition studies, averaging 84.2% and 1.67%, respectively. The metabolite MEM had a plasma clearance five to six times lower than that of the parent drug but a similar volume of distribution at steady state. The formation of MEM after MS administration was relatively low and appeared to be saturable since the formation clearance of MEM decreased significantly from 3.5 to 1.9 mL/min per kg for the low and the high rate of iv infusion of MS, respectively.

About 30% of oral dose of (N-methyl-(14)C)-methysergide was excreted in 48-hr urine and about 50% in expired air of human subjects. Excretion of (14)C was maximal 2 hr after dosing, and excretion of (14)C in expired air (as (14)CO2) was almost complete in 8 hr.

MEDICATION

Methysergide is a synthetic derivative of the ergoline family, which occur naturally in various species of vines of the Convolvulaceae (morning glory) family and in some species of lower fungi like other ergoline alkaloids. Methysergide antagonizes the effects of serotonin in blood vessels and gastrointestinal smooth muscle, but has few of the properties of other ergot alkaloids. It is used prophylactically in migraine and other vascular headaches and to antagonize serotonin in the carcinoid syndrome and is sold under the brand names Sansert and Deseril in 2mg dosages. (L1918, L1924)

British patent 854,569 (1960); Hoffman, Troxler, US patent 3,218,324 (1965 to Sandoz).

... Lysergic acid hydroxybutylamide (methylergonovine)... methylation of indole N of latter compound yields 1-methyl-methylergonovine (methysergide).

Methysergide maleate, USP (Sansert), is avail in 2-mg tablets. /Maleate/

Deseril, Desernil, Desernyl, Deseryl

Methylation in the number 1 position of the ring structure enormously enhances the antagonism to serotonin which is present to a much lesser degree in the partially methylated compound (methylergonovine maleate) as well as profoundly altering other pharmacologic properties.

/Methysergide/ ... is a congener of sysergic acid diethylamide (LSD).