(6Ar,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide;but-2-enedioic acid | 57432-61-8

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 垂体激素类药
• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 麦角林及其衍生物
• 英文名称: (6Ar,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide;but-2-enedioic acid
• CAS: 57432-61-8
• 化学式: C24H29N3O6
• 分子量: 455.5
• InChiKey: NOFOWWRHEPHDCY-BZEWFBLPSA-N

物化性质

• 熔点：
  1720C (dec)
• 沸点：
  561.98°C (rough estimate)
• 密度：
  1.2744 (rough estimate)
• 溶解度：
  在水中的溶解度25 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  1.64
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  143
• 氢给体数：
  5
• 氢受体数：
  7

ADMET

毒理性

• 在妊娠和哺乳期间的影响

哺乳期使用总结：有限的信息表明，母亲每日服用甲麦角新碱（methylergonovine）剂量高达0.75毫克时，乳汁中含量较低。美国目前的产品标签建议在最后一次服用甲麦角新碱后避免哺乳12小时。这个警告似乎是基于未发表的报告中，哺乳期婴儿在母亲接受几天甲麦角新碱治疗后出现的不良反应。在乳糜期的哺乳初期使用较短疗程的药物，预计不会将显著量的药物转移给哺乳婴儿，也不会对婴儿造成不良反应。在一项病例对照研究中记录了婴儿没有副作用。 对于希望哺乳的母亲来说，最好避免在乳糜期后长时间使用甲麦角新碱。当需要使用时，在最后一次服用甲麦角新碱后停止哺乳12小时是谨慎的。如果在哺乳婴儿中看到不良反应，如心动过速、呕吐、腹泻或烦躁不安，应停止使用该药物。一些来源建议在哺乳期间完全避免使用甲麦角新碱。 尽管几个不完善的研究结果有些混乱，但似乎甲麦角新碱可能会降低血清催乳素，可能会减少乳汁产量和哺乳持续时间，尤其是在产后立即使用时。这种效果似乎与剂量和给药途径有关，注射剂量比口服有更大的影响。产后立即短期使用似乎对哺乳没有不利影响。 对哺乳婴儿的影响：根据制造商的报告，有孤立的案例显示，接受几天甲麦角新碱治疗的哺乳母亲所生的婴儿出现了不良反应。在甲麦角新碱治疗期间观察到以下一种或多种症状，并在停药后消失：血压升高、心动过缓、心动过速、呕吐、腹泻、不安或阵挛性抽搐。另一例报告给制造商的病例是一名在母亲接受大约4到6天的甲麦角新碱治疗后的哺乳婴儿出现了癫痫发作。婴儿的癫痫发作是在母亲哺乳后治疗的第二天开始的。根据母亲的要求停用了药物。婴儿的癫痫在大约六周后解决。根据现有的信息，无法确定任何不良反应的因果关系。 法国国家药物安全机构（ANSM）的一个工作组报告了23例通过母乳暴露于甲麦角新碱的婴儿，共有44次不良反应。（其中一些可能与上一段报告的案例相同。）工作组认为心动过速、呕吐、腹泻和烦躁不安的案例足够充分，可以添加到处方信息中。 一项前瞻性病例对照研究比较了母亲产后服用甲麦角新碱0.125毫克，每天两次，连续5天或每天三次，连续3天与服用阿莫西林的母亲（作为对照组）的婴儿结果。在29位服用甲麦角新碱的母亲中，治疗组和对照组在产后17个月的随访中，新生儿的健康或发育没有差异。 对哺乳和母乳的影响：10名产后受试者口服甲麦角新碱0.2毫克，每天三次，连续7天，与10名产后对照组女性服用安慰剂相比，血清催乳素浓度没有差异。两组之间的每日乳汁量也没有显著差异。 4名女性在产后第3天肌肉注射甲麦角新碱0.2毫克，导致血清催乳素在注射后45到60分钟开始下降。在注射后2到3小时内，血清催乳素水平保持在基线水平的大约50%以下。 14名女性在产后前1.5小时内肌肉注射甲麦角新碱0.2毫克。注射后80到90分钟，接受甲麦角新碱的妇女的血清催乳素正常产后升高了56%，而接受安慰剂注射的妇女的血清催乳素升高了285%。6名治疗妇女的血清催乳素没有增加，而对照组有2名妇女。 30名分娩足月婴儿的女性在分娩后接受了一次肌肉注射甲麦角新碱0.2毫克，随后口服麦角胺1毫克，每天三次，连续6天。与28名分娩足月婴儿且未接受任何麦角衍生物的女性相比，两组在产后前6天的乳汁产量（通过哺乳前后体重的差异来衡量）没有差异。 30名产后女性在产后前7天每天三次口服甲麦角新碱0.2毫克。与对照组相比，治疗组的基线（哺乳前）血清催乳素在第1天和第3天没有差异。然而，在产后第7天，治疗组的血清催乳素水平显著低于对照组。在产后第3天和第7天，治疗组的乳汁产量也低于对照组。 10名女性在产后立即接受了一次静脉注射0.4毫克甲麦角新碱，与10名未接受甲麦角新碱的对照组母亲进行比较；所有女性在产后接受了连续的催产素输注。这些女性不允许哺乳或从乳房抽取乳汁，也不接受抑制泌乳的激素。在分娩时、给药后立即以及产后每天上午9点测量5天的血清催乳素水平，发现两组之间催乳素水平没有统计学差异。 在一项

◉ 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]

来源:Drugs and Lactation Database (LactMed)

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  T
• 安全说明：
  S36/37/39,S45
• 危险类别码：
  R23/24/25,R62
• WGK Germany：
  3
• 海关编码：
  2939690000
• 包装等级：
  III
• 危险类别：
  6.1(b)
• 危险品运输编号：
  UN 1544

制备方法与用途

生物活性

Methylergometrine maleate（甲基麦角新碱）是一种具有血管收缩和子宫收缩作用的麦角生物碱，是Methysergide的有效代谢产物。它是一种选择性的、口服有效的5-HT受体拮抗剂，其pA2值为9.6。该化合物还具备抗偏头痛及多巴胺能活性，并可用于预防和控制产后出血。

靶点

• 5-HT (pA2 = 9.6 nM)

体外研究

甲基麦角新碱和Methysergide均能够向右移动5-HT浓度反应曲线并降低最大效应，表明它们是非竞争性5-HT拮抗剂。与Methysergide相比，Methylergometrine作为5-HT诱导响应的拮抗剂约强40倍，其计算得到的表观pA2值分别为9.6和8.0。

体内研究

甲基麦角新碱在牛脑中动脉及人类冠状动脉中的血管收缩作用比Methysergide更强，这与5-HT1B受体相关。长期口服给药会导致Methysergide代谢为Methylergometrine。