Ergotamine, particularly the peptide portion of the molecule, is extensively metabolized in the liver by the cytochrome P-450 (CYP) enzyme system, mainly by the 3A4 isoenzyme; 90% of the metabolites are excreted in bile.
This study investigated if genetic differences exhibited in endophyte-resistant and -susceptible mouse lines had persisted after 13 generations in which the integrity of lines was maintained yet selection ceased. Experimental groups were mouse lines fed an endophyte-free (E-) or -infected (E+) diet. The in vitro metabolism of the ergot alkaloid ergotamine in mouse liver microsomes was characterized by LC-MS/MS and compared between both lines before and after exposure to E+ feed. ... Microsomal incubations produced nine predominate peaks in the HPLC assay. The peaks were confirmed by LC-MS/MS to be ergotamine, ergotamine epimer, monohydroxylated metabolites (M1, M2, M1e, M2e) and dihydroxylated metabolites (M3--5). A gender difference for metabolite formation was observed on the E- diet, in that females produced a greater amount of M1, M1e and M3--5 than males. When challenged with the E+ diet, mice showed differences in concentration of M3 for line (resistant > susceptible) and gender (female > male) and of M4 and M5 for gender (female > male). Gender differences in the metabolism of ergotamine have not been shown before in these lines of mice or other species used to study ergot alkaloid metabolism. ...
IDENTIFICATION AND USE: Ergotamine tartrate is used to prevent or abort vascular headaches, including migraine and cluster headaches. It is also used in veterinary medicine. HUMAN STUDIES: There have been reports of drug abuse and psychological dependence in patients on ergotamine tartrate therapy. In addition to the adverse effects which may occur with usual doses or prolonged administration of high doses (especially adverse vasospastic effects, nausea, and vomiting), acute overdosage of ergotamine may cause lassitude, impaired mental function, confusion, depression, drowsiness, delirium, severe dyspnea, hypotension, hypertension, rapid and weak pulse, unconsciousness, spasms of the limbs, seizures (rarely), shock, and death. Ergotism is manifested by intense arterial vasoconstriction, producing signs and symptoms of peripheral vascular ischemia. Ergotamine induces vasoconstriction by a direct action on vascular smooth muscle. In chronic intoxication with ergot derivatives, headache, intermittent claudication, muscle pains, numbness, coldness, and pallor of the digits may occur. If the condition is allowed to progress untreated, gangrene can result. Nausea and vomiting, due to a direct effect on CNS emetic centers, occur in approximately 10% of patients after oral administration of ergotamine, and in about twice that number after parenteral administration. Leg weakness is common, and muscle pains that occasionally are severe may occur in the extremities. Numbness and tingling of the fingers and toes are other reminders of the ergotism that this alkaloid may cause. Precordial distress and pain suggestive of angina pectoris, as well as transient tachycardia or bradycardia, also have been noted, presumably as a result of coronary vasospasm induced by ergotamine. Ergotamine has been tested for its ability to induce chromosomal damage in human lymphocyte cells. Treatment with 0.1, 0.25 and 0.5 ug/mL significantly increased frequency of aberrations. Ergotamine is contraindicated in pregnant women. ANIMAL STUDIES: It is suggested that dietary ergotamine is atherogenic in the rabbit. Daily oral doses of 1.0 mg/kg of ergotamine tartrate resulted in death of 4 of 6 sheep in 10 days. Postmortem exam revealed intestinal inflammation. 0.5 mg/day over a period of 10 days was not fatal. Extended exposure of bulls to ergotamine appeared to reduce fertilization potential of sperm. Single-day oral treatment of rats with ergotamine (10 mg/kg) causes fetal deaths. In early pregnancy, from days 4-10, mortality was only 0-11%, and on days 14 and 15, 62% and 59% respectively. Typical anomalies resulting from "edema syndrome" were seen only on days 13-16. Male mice were injected with 25, 50 and 100 mg/kg ergotamine, and significant number of chromosome aberrations were observed with higher doses. Almost all damage was in form of chromatid aberrations. Dominant lethal test with mice using ergotamine was negative in doses up to 100 mg/kg. Several accidental poisonings in cows were described in the literature.
Ergoline alkaloids tend to act as a group, producing complex and variable effects of partial agonism or antagonism at adrenergic, dopaminergic, and serotonergic receptors. Variables relating to these effects are influenced by the agent, dosage, species, tissue, physiological, and endocrinological state, and experimental conditions. In particular, 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. Ergometrine is also known to have a non-receptor specific oxytocic activity. Ergotamine acts on migraine by one of two proposed mechanisms: 1) activation of 5-HT1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leading to vasoconstriction, which correlates with the relief of migraine headache, and 2) activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system, resulting in the inhibition of pro-inflammatory neuropeptide release. (A2914, A2915, A2916)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
Vasoconstrictive complications of a serious nature may occur at times. These include ischemia, cyanosis, absence of pulse, cold extremities, gangrene, precordial distress and pain, EKG changes and muscle pains. Although these effects occur most commonly with long-term therapy at relatively high doses, they have also been reported with short-term or normal doses. Other cardiovascular adverse effects include transient tachycardia or bradycardia and hypertension. Ingestion of ergoline alkaloids is also known to cause the disease ergotism. Ergotism occurs in two forms, gangrenous and convulsive, likely depending on the different kinds and amounts of ergoline alkaloids present. (A1497, L1452, A2913)
◉ Summary of Use during Lactation:There is limited published experience with ergotamine during breastfeeding and it might cause adverse effects in the infant and decrease milk supply. Most authorities consider ergotamine to be contraindicated during nursing.
◉ Effects in Breastfed Infants:A study in which ergotamine was administered to mothers of newborns immediately postpartum in a dose of 1 mg 3 times daily for 6 days found no effect on weight gain in the breastfed infants. Milk intake, and therefore infant dosage, might have been minimal during the first few days before the mothers' milk came in fully.
◉ Effects on Lactation and Breastmilk:Thirty women who delivered fullterm infants received a single intramuscular dose of methylergonovine 0.2 mg after delivery, followed by oral ergotamine 1 mg 3 times daily for 6 days. Compared to 28 women who delivered fullterm infants and received no ergot derivatives, there was no difference in the milk production, as measured by weight differences before and after nursing, between the 2 groups during the first 6 days postpartum.
来源:Drugs and Lactation Database (LactMed)
吸收、分配和排泄
吸收
舌下给药麦角胺的生物利用度尚未确定。
The bioavailability of sublingually administered ergotamine has not been determined.
Following oral administration, absorption of ergotamine tartrate is quite variable; peak plasma concentrations are attained within 0.5-3 hours. Orally administered ergotamine tartrate undergoes first-pass metabolism.
The unchanged drug is erratically secreted in the saliva and only traces of unchanged drug are excreted in urine and feces. Following a single oral dose of ergotamine in individuals with normal renal and hepatic function in one study, only about 4% of the dose was excreted in urine within 96 hours; the remainder of the dose was presumably excreted in feces. Ergotamine is eliminated by dialysis.
[EN] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
申请人：UNIV EMORY
公开号：WO2013181135A1
公开（公告）日：2013-12-05
The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.
[EN] SPIROLACTAM CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP À BASE DE SPIROLACTAME
申请人：MERCK SHARP & DOHME
公开号：WO2013169567A1
公开（公告）日：2013-11-14
The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
[EN] AZOLE COMPOUNDS AS PIM INHIBITORS<br/>[FR] COMPOSÉS D'AZOLE UTILISÉS EN TANT QU'INHIBITEURS DES PIM
申请人：AMGEN INC
公开号：WO2012129338A1
公开（公告）日：2012-09-27
The invention relates to bicyclic compounds of formulas I and Ia, and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.
[EN] ASH1L INHIBITORS AND METHODS OF TREATMENT THEREWITH<br/>[FR] INHIBITEURS DE ASH1L ET MÉTHODES DE TRAITEMENT AU MOYEN DE CEUX-CI
申请人：UNIV MICHIGAN REGENTS
公开号：WO2017197240A1
公开（公告）日：2017-11-16
Provided herein are small molecule inhibitors of ASH1L activity and small molecules that facilitate ASH1L degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L.
CONJUGATES OF CEREBLON BINDING COMPOUNDS AND G12C MUTANT KRAS, HRAS OR NRAS PROTEIN MODULATING COMPOUNDS AND METHODS OF USE THEREOF
申请人：Araxes Pharma LLC
公开号：US20180015087A1
公开（公告）日：2018-01-18
Conjugates of a cereblon-binding compound and compounds having modulatory activity against G12C mutant KRAS, HRAS or NRAS G12C proteins are provided. Methods associated with preparation and use of such conjugates, pharmaceutical compositions comprising such conjugates and methods to modulate the activity of G12C mutant KRAS, HRAS or NRAS G12C proteins for treatment of disorders, such as cancer, are also provided.
