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
◉ Overview of Use During Lactation
Limited information suggests that low concentrations of Methylergonovine in breast milk are observed even when pregnant women take up to 0.75 mg daily. Current US product labels recommend avoiding breastfeeding for 12 hours after the last dose of Methylergonovine. This warning appears to be based on unpublished adverse events in breastfed infants after several days of Methylergonovine treatment. Short-term use of this drug during the colostrum period postpartum is not expected to result in significant drug transfer to the breastfed infant or increase the risk of adverse events in the infant. One case-control study documented no observed side effects in the infant.
For mothers who wish to breastfeed, it is best to avoid prolonged use of Methylergonovine, especially after milk production. If Methylergonovine is necessary, it is recommended to discontinue breastfeeding for 12 hours after the last dose. If the breastfed infant experiences adverse events such as tachycardia, vomiting, diarrhea, or restlessness, the medication should be discontinued immediately. Some sources recommend complete avoidance of Methylergonovine during breastfeeding. [1]
Although some studies have yielded mixed results, Methylergonovine appears to lower serum prolactin levels and may reduce milk production and shorten lactation, especially when used in the early postpartum period. This effect appears to be dose- and route of administration, with injectable doses having a greater effect than oral doses. Short-term use immediately postpartum does not appear to have an adverse effect on breastfeeding.
◉ Effects on breastfed infants
According to the manufacturer, there have been sporadic reports of adverse reactions in breastfed infants of mothers who had been taking Methylergonovine for several days. One or more of the following symptoms were observed during Methylergonovine treatment and disappeared upon discontinuation of the drug: elevated blood pressure, bradycardia, tachycardia, vomiting, diarrhea, restlessness, or clonic seizures. Another case reported to the manufacturer involved a breastfed infant who developed seizures approximately 4 to 6 days after the mother began taking Methylergonovine. The infant’s seizures began the day after the mother stopped taking the drug. The mother has since stopped taking the drug. The infant’s seizures disappeared after approximately six weeks. [6] Based on the available information, no causal relationship could be established for any adverse reactions. A working group of the French National Agency for Medicines and Health Products Safety (ANSM) reported 44 adverse reactions in 23 infants who were exposed to Methylergonovine through breast milk. (Some of these may be the same as those reported in the previous paragraph.) The working group considered that the records of adverse reactions such as tachycardia, vomiting, diarrhea and agitation were sufficient and should be added to the prescribing information. [7] A prospective case-control study compared the outcomes of infants born to mothers who received Methylergonovine (0.125 mg twice daily for 5 days or three times daily for 3 days) with those born to mothers who received amoxicillin (as a control group). Among the 29 mothers who received Methylergonovine, there was no difference in the health or development of the newborns in the treatment group and the control group at a 17-month follow-up. [8]
◉ Effects on lactation and breast milk
Ten postpartum women were given 0.2 mg of Methylergonovine orally for 7 consecutive days. The results showed no difference in serum prolactin concentration compared with 10 postpartum control women who received a placebo. There was also no significant difference in daily milk production between the two groups. [9]
Four women received a single intramuscular injection of 0.2 mg of Methylergonovine on the 3rd day postpartum. The results showed that serum prolactin levels began to decrease 45 to 60 minutes after administration. Serum prolactin levels remained about 50% lower than baseline levels for 2 to 3 hours after administration. [10]
Fourteen postpartum women received a single intramuscular injection of 0.2 mg of Methylergonovine within 1.5 hours postpartum. 80 to 90 minutes after injection, serum prolactin levels in women treated with Methylergonovine were 56% higher than normal postpartum levels, while serum prolactin levels in women who received a placebo were 285% higher than normal postpartum levels. Serum prolactin levels did not increase in 6 women in the treatment group, while they did not increase in 2 women in the control group. [11]
30 women who delivered at term received a single intramuscular injection of 0.2 mg Methylergonovine after delivery, followed by oral ergotamine 1 mg three times a day for 6 days. There was no difference in milk production (measured by the difference in milk weight before and after lactation) between the two groups in the first 6 days postpartum compared to 28 women who delivered at term and did not take Methylergonovine derivatives. [12]
30 postpartum women took 0.2 mg Methylergonovine orally three times a day for the first 7 days postpartum. Baseline (pre-lactation) serum prolactin levels were not different from those of the 30 postpartum women who did not take Methylergonovine on days 1 and 3 postpartum. However, on day 7 postpartum, serum prolactin levels were significantly lower in women who took Methylergonovine. Compared with the control group, women who took Methylergonovine also had reduced milk production on days 3 and 7 postpartum. [13] Ten women received a single intravenous injection of 0.4 mg Methylergonovine immediately postpartum and were compared with 10 control mothers who did not receive Methylergonovine; all mothers received continuous infusion of oxytocin postpartum. None of the mothers were allowed to breastfeed or express milk, nor were they allowed to take any hormones that inhibit lactation. Serum prolactin levels were measured during labor, immediately after administration, and at 9 a.m. every day for 5 days postpartum, and there was no statistically significant difference in prolactin levels between the two groups. [14] In a randomized study, 48 mothers took 0.125 mg Methylergonovine orally every 8 hours for the first 7 days postpartum. Another 44 mothers in the same hospital did not take Methylergonovine. There was no statistically significant difference in serum prolactin levels between the two groups on day 3 postpartum, but the prolactin levels of mothers who delivered vaginally were higher than those who delivered by cesarean section. At one month postpartum, no difference was found in exclusive breastfeeding rates or infant weight gain. [15] In a prospective randomized study, 444 postpartum mothers took 0.125 mg of Methylergonovine three times daily, while 436 postpartum mothers took a placebo. The average milk production in the untreated group was 880 g in the first 6 days postpartum, compared to only 563 g in the treated group. The difference in milk production remained between the two groups after 4 weeks. [16] A prospective case-control study compared postpartum lactation in mothers who took Methylergonovine (twice daily for 5 days or three times daily for 3 days) with those who took amoxicillin (as a control group). There were no significant differences in reported exclusive breastfeeding rates or decreased milk production between 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 ergosterol alkaloid with anti-aging properties. Methylergonovine maleate is the maleate salt of Methylergonovine, a semi-synthetic ergosterol alkaloid with vasoconstrictive and uterine-constrictive effects. Methylergonovine stimulates serotonergic and dopaminergic receptors and inhibits the release of endothelial relaxing factor, thereby leading to arterial vasoconstriction and enhanced uterine smooth muscle contraction. It is a homologue of Methylergonovine, but with an additional CH2 group. (Merck Index, 11th Edition) See also: Methylergonovine (containing the 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.)