2-[[5-Methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine | 61718-81-8

• 物质功能分类: 原料药 - 神经系统用药 - 抗抑郁、躁狂药
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-[[5-Methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine
• CAS: 61718-81-8
• 化学式: C₁₅H₂₁F₃N₂O₂
• 分子量: 318.33
• InChiKey: CJOFXWAVKWHTFT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  56.8
• 氢给体数：
  1
• 氢受体数：
  7

ADMET

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用概述：有限的信息表明，母亲每日服用最高300毫克的氟伏沙明会在母乳中产生低水平，预计不会对哺乳婴儿造成任何不良影响，特别是如果婴儿年龄超过2个月。如果母亲需要氟伏沙明，这不是停止母乳喂养的理由。一个安全评分系统发现母乳喂养期间使用氟伏沙明是可能的。有一名婴儿血清中氟伏沙明水平升高，但大多数接受检测的婴儿血清中检测不到。另一名婴儿在母亲开始服用氟伏沙明后出现腹泻、呕吐和兴奋。对生长和发育的长期随访有限，发现母乳喂养的婴儿没有不良影响。监测通过母乳接触氟伏沙明的婴儿是否有腹泻、呕吐、睡眠减少和激动。 ◉ 对哺乳婴儿的影响：一名母亲在分娩后17周开始每天服用100毫克氟伏沙明，她的婴儿从出生到5个月大一直接受母乳喂养。在母亲住院期间进行的10周观察中，医疗和护理工作人员没有注意到婴儿有任何不良影响。婴儿在4个月和21个月大时正常的Bayley发育评分。 在两名婴儿中没有发现不良影响，一名部分母乳喂养的26个月大婴儿在母亲每天服用150毫克时，其丹佛发育评分正常，另一名完全母乳喂养的3周大婴儿在母亲每天服用50毫克时。 三名母亲平均每天服用117毫克氟伏沙明，她们的婴儿在头4个月完全母乳喂养，在第5和第6个月至少50%。她们的婴儿根据国家生长标准，6个月体重增长正常，母亲报告她们的婴儿没有异常影响。 一项研究调查了母乳喂养母亲服用SSRI抗抑郁药的副作用，发现一名母亲服用氟伏沙明的婴儿没有需要医疗注意的不良反应。没有关于母亲氟伏沙明剂量、母乳喂养程度或婴儿年龄的具体信息报告。 一名长期接受喹硫平400毫克和氟伏沙明200毫克治疗的女性，在孕期和产后期间持续用药。她部分母乳喂养她的婴儿（程度未说明）3个月。在婴儿正常发育的情况下没有发现不良事件。 对247名在妊娠晚期暴露于抗抑郁药的婴儿进行评估，以了解新生儿适应不良（PNA）的情况。在247名婴儿中，有154名发展为PNA。与那些完全或部分母乳喂养的婴儿相比，完全用配方奶粉喂养的婴儿患PNA的风险大约高出3倍。其中4名婴儿在子宫内接触低剂量的氟伏沙明，没有一个患有PNA。 一名5个月大的婴儿在母亲开始每天服用50毫克氟伏沙明后2天内出现了严重腹泻（每天15次）、轻度呕吐（每天2到3次）、激动和睡眠减少。母亲停药后24小时内症状缓解，一周后母亲重新开始服用氟伏沙明后症状再次出现。找不到胃肠道症状的其他原因。氟伏沙明很可能是反应的原因。作者推测婴儿可能对药物的代谢异常，导致高血清浓度。 ◉ 对泌乳和母乳的影响：氟伏沙明已在非孕期、非哺乳患者中引起催乳素水平升高和乳汁分泌过多。在一例中，一名19岁的男性在服用利培酮后出现了催乳素过多性男性乳房发育和乳汁分泌过多。在一项研究中，法国药物警戒中心报告的催乳素血症及其症状（例如，男性乳房发育）病例中，发现氟伏沙明引起催乳素血症的风险比其他药物高4.5倍。对已建立泌乳的母亲而言，催乳素水平可能不会影响她的哺乳能力。 在一项小型的前瞻性研究中，8名初产妇服用5-羟色胺再摄取抑制剂（SRI；3人服用氟西汀，各有1人服用西酞普兰、度洛西汀、艾司西酞普兰、帕罗西汀或舍曲林）与423名未服用SRI的母亲进行了比较。服用SRI的母亲乳汁分泌激活（哺乳II期）的起始时间平均延迟了16.7小时，与对照组相比（服用SRI的母亲在产后85.8小时，未服用的母亲在69.1小时），这使得未治疗组延迟喂养行为的风险加倍。然而，哺乳II期的延迟可能在临床上并不重要，因为两组在产后4天以上经历喂养困难的比例没有统计学上的显著差异。 一项病例对照研究比较了在分娩时和分娩期间全程服用SSRI抗抑郁药的母亲（n = 167）和在孕期仅服用SSRI的母亲（n = 117）与未服用抗抑郁药的母亲对照组（n = 182）在产后2周的主要母乳喂养率。在服用SSRI的两个组中，33人服用西酞普兰，18人服用艾司西酞普兰，63人服用氟西汀，2人服用氟伏沙明，78人服用帕罗西汀，87人服用舍曲林

◉ Summary of Use during Lactation:Limited information indicates that maternal fluvoxamine doses of up to 300 mg daily produce low levels in breastmilk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. If fluvoxamine is required by the mother, it is not a reason to discontinue breastfeeding. A safety scoring system finds fluvoxamine use to be possible during breastfeeding. One infant was reported to have an elevated serum level of fluvoxamine, but most who have been tested have undetectable serum levels. Another infant developed diarrhea, vomiting and stimulation after maternal initiation of fluvoxamine. A limited amount of long-term follow-up on growth and development has found no adverse effects in breastfed infants. Monitor infants exposed to fluvoxamine through breast milk for diarrhea, vomiting, decreased sleep, and agitation. Mothers taking an SSRI during pregnancy and postpartum may have more difficulty breastfeeding, although this might be a reflection of their disease state. These mothers may need additional breastfeeding support. Breastfed infants exposed to an SSRI during the third trimester of pregnancy have a lower risk of poor neonatal adaptation than formula-fed infants. ◉ Effects in Breastfed Infants:One infant whose mother began taking fluvoxamine 100 mg daily 17 weeks postpartum was breastfed from birth to 5 months of age. The medical and nursing staff did not note any adverse effect in the infant during the 10 weeks of observation during maternal hospitalization. The infant had normal Bayley developmental scores at age 4 months and 21 months. No adverse effects were found in 2 infants, a partially breastfed 26-month-old during maternal intake of 150 mg daily, who also had a normal Denver Developmental Score, and an exclusively breastfed 3-week-old during maternal intake of 50 mg daily. Three mothers who took an average fluvoxamine dose of 117 mg once daily breastfed their infants exclusively for 4 months and at least 50% during months 5 and 6. Their infants had 6-month weight gains that were normal according to national growth standards and the mothers reported no abnormal effects in their infants. One study of the side effects of SSRI antidepressants in nursing mothers found no adverse reactions that required medical attention in one infant whose mother was taking fluvoxamine. No specific information on maternal fluvoxamine dosage, extent of breastfeeding or infant age was reported. A woman who was treated chronically with quetiapine 400 mg and fluvoxamine 200 mg daily took the drugs throughout pregnancy and postpartum. She partially breastfed her infant (extent not stated) for 3 months from birth. No adverse events were seen in the infant who developed normally. A cohort of 247 infants exposed to an antidepressant in utero during the third trimester of pregnancy were assessed for poor neonatal adaptation (PNA). Of the 247 infants, 154 developed PNA. Infants who were exclusively given formula had about 3 times the risk of developing PNA as those who were exclusively or partially breastfed. Four of the infants were exposed to low doses of fluvoxamine in utero and none had PNA. A 5-month-old infant developed severe diarrhea (15 times daily), mild vomiting (2 to 3 times daily), agitation and decreased sleep within 2 days after maternal initiation of fluvoxamine 50 mg daily. Symptoms resolved within 24 hours after the mother discontinued the drug and recurred a week later after fluvoxamine was restarted in the mother. Other causes of the gastrointestinal symptoms could not be found. Fluvoxamine was probably the cause of the reaction. The authors speculate that the infant might have abnormal metabolism of the drug that resulted in high serum concentrations. ◉ Effects on Lactation and Breastmilk:Fluvoxamine has caused increased prolactin levels and galactorrhea in nonpregnant, nonnursing patients. In one case, euprolactinemic gynecomastia and galactorrhea occurred in a 19-year-old man who was also taking risperidone. In a study of cases of hyperprolactinemia and its symptoms (e.g., gynecomastia) reported to a French pharmacovigilance center, fluvoxamine was found to have a 4.5-fold increased risk of causing hyperprolactinemia compared to other drugs. The prolactin level in a mother with established lactation may not affect her ability to breastfeed. In a small prospective study, 8 primiparous women who were taking a serotonin reuptake inhibitor (SRI; 3 taking fluoxetine and 1 each taking citalopram, duloxetine, escitalopram, paroxetine or sertraline) were compared to 423 mothers who were not taking an SRI. Mothers taking an SRI had an onset of milk secretory activation (lactogenesis II) that was delayed by an average of 16.7 hours compared to controls (85.8 hours postpartum in the SRI-treated mothers and 69.1 h in the untreated mothers), which doubled the risk of delayed feeding behavior in the untreated group. However, the delay in lactogenesis II may not be clinically important, since there was no statistically significant difference between the groups in the percentage of mothers experiencing feeding difficulties after day 4 postpartum. A case control study compared the rate of predominant breastfeeding at 2 weeks postpartum in mothers who took an SSRI antidepressant throughout pregnancy and at delivery (n = 167) or an SSRI during pregnancy only (n = 117) to a control group of mothers who took no antidepressants (n = 182). Among the two groups who had taken an SSRI, 33 took citalopram, 18 took escitalopram, 63 took fluoxetine, 2 took fluvoxamine, 78 took paroxetine, and 87 took sertraline. Among the women who took an SSRI, the breastfeeding rate at 2 weeks postpartum was 27% to 33% lower than mother who did not take antidepressants, with no statistical difference in breastfeeding rates between the SSRI-exposed groups. An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified. A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575; fluvoxamine n = 18) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.

来源:Drugs and Lactation Database (LactMed)