Natural product; serotonin (pA2 = 9.6 nM)

Methysergide and methylergonovine both extract noncompetitive antagonists of 5-HT by shifting the concentration response curve of 5-HT to the right and inhibiting its maximal impact. Methysergide and methylergonovine have antagonistic effects on 5-HT-induced responses that are about 40 times more potent than each other, with computed apparent pA2 values of 9.6 and 8.0, respectively [3].

Methylergonovine is more effective than ergonovine as a vasoconstrictor of the bovine coronary and middle cerebral arteries, and it affects the absorption of 5-HT1B in humans. Methysergonovine can turn into methysergonovine as a result of subacute coronary artery disease [2].

Methylergometrine, the main metabolite of methysergide, has 40-times greater 5 HT antagonistic potency than methysergide in isolated segments of human temporal artery. It is suggested that methylergometrine is the "active" drug when methysergide is used in migraine prophylaxis, and that the two compounds should be compared in prophylactic trials in migraine[3].

This report describes the actions of the non-peptide ergot alkaloids methysergide, methylergometrine and ergometrine at two types of 5-HT receptor mediating vascular contraction; the well established 5-HT2 receptor in rabbit aorta and a non-5-HT2 receptor in rabbit saphenous vein which resembles the 5-HT1-like receptor in dog saphenous vein. In the rabbit aorta ergometrine (1 mumol/l) and methylergometrine (0.3 mumol/l), but not methysergide, produced small contractions (14% and 7% respectively of the maximal response to 5-HT). This contraction was not related to activation of 5-HT2 receptors since it was resistant to blockade by ketanserin (0.3 mumol/l). When examined as antagonists of 5-HT-induced contractions of rabbit aorta, each ergot displayed nanomolar affinity at the 5-HT2 receptor but only methysergide behaved as a simple competitive antagonist (pKB = 8.25). Methylergometrine and ergometrine produced surmountable blockade which was accompanied by a non-parallel displacement of the 5-HT concentration-effect curves. The selective 5-HT1-like receptor agonist GR43175 (less than or equal to 30 mumol/l) was devoid of affinity at the 5-HT2 receptor in rabbit aorta. In the rabbit saphenous vein each of the ergots produced concentration-dependent contractions which resulted in overtly biphasic concentration-effect curves. Only the first phase of contraction mimicked the effects of 5-HT and GR43175 since contractions were not blocked by MDL 72222 (1 mumol/l), but were surmountably antagonised by methiothepin (10 nmol/l), ketanserin (0.3 mumol/l) and spiperone (0.3 mumol/l).Naunyn Schmiedebergs Arch Pharmacol . 1990 Aug;342(2):120-9.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal doses of methylergonovine up to 0.75 mg daily produce low levels in milk. Product labeling in the U.S. currently recommends avoiding breastfeeding for 12 hours following the last dose of methylergonovine. This warning appears to be based on unpublished adverse reactions in breastfed infants after several days of maternal methylergonovine therapy. The use of shorter courses of the drug after delivery during the colostral phase of lactation are not expected to transfer appreciable amounts of drug to the breastfed infant or risk adverse effects in the infant. The lack of infant side effects was documented in one case-control study.
Long courses of methylergonovine, especially after the milk comes in, are best avoided in mothers who wish to nurse. When they are required, withholding breast feeding for 12 hours following the last dose of methylergonovine is prudent. If adverse reactions in the breastfed infant are seen, such as tachycardia, vomiting, diarrhea or agitation, the drug should be discontinued. Some sources recommend avoiding methylergonovine altogether during breastfeeding.[1]
Although results of several imperfect studies are somewhat mixed, it appears that methylergonovine can decrease serum prolactin and possibly the amount of milk production and duration of lactation, especially when used in the immediate postpartum period. The effect seems to be related to the dosage and route of administration, with injected doses having a greater impact than oral. A short course immediately postpartum does not appear to have a detrimental effect on lactation.
◉ Effects in Breastfed Infants
According to the manufacturer, there are isolated reports of adverse effects in breast-fed infants whose mothers were receiving methylergonovine for several days. One or more of the following symptoms were observed during methylergonovine therapy and disappeared upon withdrawal of the medication: elevated blood pressure, bradycardia, tachycardia, vomiting, diarrhea, restlessness, or clonic cramps. Another case reported to the manufacturer was a breast-fed infant who presented with seizures after about 4 to 6 days of maternal methylergonovine therapy. The infant's seizures began on the second day of treatment of the mother after breastfeeding. Medications were discontinued per the mother. The infantile seizures resolved about six weeks later.[6] It is not possible to determine the causality of any of the adverse effects with the information available.
A working group of the French national medication safety agency (ANSM) reported 23 cases of infants exposed to methylergonovine via breastmilk who had a total of 44 adverse reactions. (Some of these might be the same as those reported in the previous paragraph.) The working group considered tachycardia, vomiting, diarrhea and agitation to be sufficiently well documented to add to the prescribing information.[7]
A prospective case-control study compared the outcome of infants whose mothers had taken methylergonovine postpartum 0.125 mg 2 times daily for 5 days or 3 times daily for 3 days to mothers who had taken amoxicillin which served as a control group. Of 29 mothers who had taken methylergonovine, there were no differences in neonatal health or development at follow-up at 17 months postpartum between the treatment and control groups.[8]
◉ Effects on Lactation and Breastmilk
Oral methylergonovine in a dose of 0.2 mg 3 times daily for 7 days in 10 postpartum subjects caused no difference in serum prolactin concentrations from placebo administered to 10 postpartum control women. No significant difference found in the daily milk volumes between the groups.[9]
A single intramuscular injection of methylergonovine 0.2 mg given to 4 women on day 3 postpartum caused a decrease in serum prolactin beginning 45 to 60 minutes after the dose. For 2 to 3 hours after the dose, serum prolactin levels remained about 50% lower than baseline levels.[10]
A single intramuscular injection of methylergonovine 0.2 mg was given to 14 women during the first 1.5 hours postpartum. At 80 to 90 minutes after the injection, the normal postpartum rise in serum prolactin was 56% in the women who received methylergonovine compared to a 285% in serum prolactin in women who received a placebo injection. Six treated women had no increase in serum prolactin compared to 2 of the control women.[11]
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.[12]
Thirty postpartum women were given methylergonovine 0.2 mg orally 3 times daily for the first 7 days postpartum. Baseline (prior to nursing) serum prolactin was no different from those of 30 postpartum women who received no methylergonovine on days 1 and 3 postpartum. However, on day 7 postpartum, serum prolactin levels were significantly less in the treated women. Milk production was also reduced in the treated women on days 3 and 7 postpartum compared to controls.[13]
Ten women received a single intravenous dose of 0.4 mg of methylergonovine immediately postpartum were compared to 10 control mothers who received no methylergonovine; all women received a continuous infusion of oxytocin postpartum. None of the women were allowed to nurse or extract milk from their breasts or to receive hormones to suppress lactation. Serum prolactin measured during labor, immediately after administration of the drug and daily at 9 am for 5 days postpartum found no statistical differences in prolactin levels between the 2 groups.[14]
In a randomized study, 48 patients were given methylergonovine 0.125 mg orally every 8 hours for the first 7 days postpartum. Another 44 in the same hospital were not given methylergonovine. No statistical differences were found in the serum levels of prolactin at 3 days postpartum between the groups, although women with normal deliveries had higher prolactin levels than those delivered by cesarean section. At 1 month postpartum, no differences were found in the percentage of exclusive breastfeeding or in the weight gain of infants.[15]
In a prospective, randomized study, 444 postpartum mothers were given 0.125 mg of methylergonovine 3 times a day, while 436 were given placebo. Milk production among untreated women averaged 880 grams during the first 6 days, while among treated patients it was only 563 grams. After 4 weeks there were still differences in the quantity of milk produced.[16]
A prospective case-control study compared lactation in mothers had taken methylergonovine postpartum 0.125 mg 2 times daily for 5 days or 3 times daily for 3 days to mothers who had taken amoxicillin which served as a control group. The rates of exclusive breastfeeding and reports of decreased lactation were not significantly different in the two groups.[8]

[1]. Crystallographic and NMR Investigation of Ergometrine and Methylergometrine, Two Alkaloids from Claviceps purpurea. Molecules. 2020 Jan 14;25(2). pii: E331.

[2]. History of methysergide in migraine. Cephalalgia. 2008 Nov;28(11):1126-35.

[3]. Methylergometrine antagonizes 5 HT in the temporal artery. Eur J Clin Pharmacol. 1987;33(1):77-9.

Methylergonovine Maleate is an ergoline alkaloid. It has a role as a geroprotector.
Methylergonovine Maleate is the maleate salt of methylergonovine, a semi-synthetic ergot alkaloid with vasoconstrictive and uterotonic effects. Methylergonovine stimulates serotoninergic and dopaminergic receptors as well as inhibits the release of endothelial-derived relaxation factor. This results in arterial vasoconstriction and increased uterine smooth muscle contractions.
A homolog of ERGONOVINE containing one more CH2 group. (Merck Index, 11th ed)
See also: Methylergonovine (has active moiety).

C24H29N3O6

455.5

455.206

C, 63.28; H, 6.42; N, 9.22; O, 21.07

57432-61-8

5281072

Off-white to gray solid powder

1.2744 (rough estimate)

638.4ºC at 760mmHg

172ºC (dec)

1.6500 (estimate)

1.965

5

7

6

33

668

3

CC[C@@H](CO)NC(=O)[C@H]1CN([C@@H]2CC3=CNC4=CC=CC(=C34)C2=C1)C.C(=C\C(=O)O)\C(=O)O

NOFOWWRHEPHDCY-DAUURJMHSA-N

InChI=1S/C20H25N3O2.C4H4O4/c1-3-14(11-24)22-20(25)13-7-16-15-5-4-6-17-19(15)12(9-21-17)8-18(16)23(2)10-13;5-3(6)1-2-4(7)8/h4-7,9,13-14,18,21,24H,3,8,10-11H2,1-2H3,(H,22,25);1-2H,(H,5,6)(H,7,8)/b;2-1-/t13-,14+,18-;/m1./s1

(6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide;(Z)-but-2-enedioic acid

Methergine; 57432-61-8; Erezingen; Methergine; Methylergobasine maleate; Methylergonovine maleate salt; USAF uctl-8; Methylergonovine Maleate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~219.54 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.57 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)