哺乳期抗菌药物的应用

母乳喂养对婴儿的成长有利，值得提倡。但乳母在哺乳期需进行药物治疗时．对哺乳产生一定的影响。本文就哺乳期乳母进行抗菌药物治疗时药物向乳汁转运的方式、乳母用药对婴儿安全性的影响及影响因素等相关问题进行了综述。     

哺乳期妇女用药注意事项

母乳含有丰富的营养物质和免疫物质,因此应大力提倡喂养,但许多药物可经乳汁排出,虽然排出量极少,多数无害,但必须认识到由于婴儿每日吸乳量大,乳汁中药物浓度较高,哺乳期母体使的某些药物有可能使吸乳婴儿产生治疗效应或毒性效应。从乳汁排泄多寡可将影响吸乳儿的药物分为哺乳期禁用和慎用两类。     

哺乳期的用药及哺乳母亲的护理体会

由于婴幼儿处于生长发育过程,如果用药不当,可造成不良后果,严重可危及生命,所以,提倡哺乳合理用药。1 母亲患疾病时的药物治疗与哺乳由于目前大量的新药进入临床,有些药物在母亲血浆和乳汁中的浓度尚不清楚的情况下,母亲一般禁止使用,某些疾病在药物治疗时要慎重。1.1 患高血压时应用肼苯达嗪对婴儿无害,可应用;β受体阻滞剂—心得安等在乳汁中的浓度尚不清楚的情况下,母亲一般禁止使用,某些疾病必须药物治疗时要慎重。1.2 患心脏病时洋地黄制剂如地高辛能分泌至乳汁,但婴儿吸收仅为1%,对婴儿无害,可持续应用。抗心律失常类     

哺乳期生理药代动力学模型的研究及应用现状

母乳喂养是婴儿出生后喂养的最佳形式,对婴儿的健康发育十分重要。目前临床上存在母亲用药导致婴儿出现毒性反应的病例,且大多数药物缺乏关于母乳喂养期间用药安全性的信息,这导致尽管很多药物可能是安全的,哺乳期女性仍然选择终止治疗或停止喂养。为了鼓励母乳喂养,需要在母亲开始母乳喂养或药物治疗之前进行药物治疗风险评估。不幸的是,由于人类哺乳期研究受限较大,目前的临床数据匮乏,而以体外和动物模型为主的实验数据也并不能完全拟合人体生理。因此,经过验证的非临床方法——基于生理学的药代动力学(PBPK)模型可能是一种有效的方法,预测药物转移到母乳中的程度,填补这一领域的信息空白。本文概述了哺乳期的用药现状、体内外研究现状和方法,以及哺乳期PBPK模型的研究实例。PBPK模型在哺乳期药物研究中意义重大,今后的发展应整合现有模型及相关数据,结合实际情况选择合适的模型,不断提高哺乳期PBPK模型对临床常用药物预测的准确性。     

乳母用药对乳儿的影响

乳母用药时,不仅要考虑到药物对母体的作用,还应注意到药物对乳婴的影响,影响的大小取决于药物本身的毒性、药物在乳汁中的浓度、婴儿吸入乳汁的量和药物被吸收而到达血中的浓度。药物通过乳汁排泄可能是被动转运过程,因此受药物的脂溶性、酸碱度<由于乳汁呈酸性,碱性药物易进入乳     

母乳中的帕罗西汀对婴儿的影响

哺乳期妇女使用ＳＳＲＩ类药物对婴儿的安全性引起人们的关注。 16例哺乳期妇女依病情口服帕罗西汀一日10～ 5 0ｍｇ ,10天后采用高效液相色谱仪检测母乳及母亲、婴儿血清中帕罗西汀的浓度。结果 10 8个母乳样品中本品的浓度在 2～ 10 1ｎｇ/ｍｌ之间 ,且后乳的药物浓度高于前乳 ,可以看到显著的梯度效果。尽管 2 4小时母乳有谷 峰浓度 ,但本品分泌进入母乳的过程尚不清楚。而在 16例母婴血样中 ,婴儿的血样中未检测到本品。此研究证实本品应用于哺乳期妇女 ,其婴儿血液中本品的浓度很低 ,尚未观察到婴儿有何不良反应。与其它ＳＳＲＩ类药…     

哺乳期用药咨询策略与实践案例分析

摘 要 目的：总结对哺乳期母亲开展用药咨询的工作经验,为促进哺乳期合理用药提供参考。 方法：对临床药师参与哺乳期乳腺炎、避免葡萄糖 6 磷酸脱氢酶（G6PD）缺乏乳儿用药风险、产后抑郁用药选择、哺乳期抗幽门螺杆菌三联方案替换治疗等典型案例进行分析,探讨临床对哺乳期用药咨询的需求方向、临床药师应关注的切入点、临床药师提供哺乳期用药咨询的策略与技巧。 结果：临床在哺乳期常见疾病的用药选择、特殊乳儿的用药风险评估、哺乳期可替代药物治疗方案的选择等方面对药学服务存在迫切需求。临床药师应兼顾临床、药动学知识,基于循证证据、注重与患者沟通技巧、尊重患者价值观,可以对哺乳期药物治疗效果和用药安全起到很好的促进和保障作用。 结论：特殊人群用药是临床药师服务临床的切入点之一,哺乳期用药咨询可以使哺乳期母亲得到有效治疗的同时,保障乳儿的安全性,加强医患沟通,值得推广。     

浅谈哺乳期妇女的用药

哺乳期母体用药机会很多,药物进入乳汁必然对婴儿产生一定的影响,对于这方面的问题应引起大家的足够重视。 1 通过乳汁可能对婴儿产生影响的药物 1.1 必须禁止哺乳的药物:产妇患有必须长期用药的疾病,如恶性肿瘤、甲状腺机能亢进等,用抗肿瘤药物和硫脲嘧啶、放射性碘时,药物进入母乳可能对婴儿产     

口服拉贝洛尔母乳药动学的风险评估与哺乳期合理用药

目的：基于口服拉贝洛尔在妊娠期高血压产妇的乳汁药动学,评估哺乳期用药风险和干预哺乳时间,促进哺乳期合理用药。方法：选取2016年10月-2017年7月住院分娩的60例妊娠期高血压产妇泌乳后口服拉贝洛尔片的乳汁,采用超高效液相色谱串联质谱法（UPLC-MS/MS）测定乳汁药物浓度,并计算药动学相关参数和用药风险评估指标。结果：妊娠高血压产妇产后继续服用拉贝洛尔（100 mg,q8h,n=60）,乳汁中药动学参数：达峰时间（t_max）为（2.7±0.9）h、达峰浓度（C_max）为（268.0±71.9）ng·mL^-1、半衰期（t_1/2）为（4.1±1.7）h。母乳用药风险评估指标,TID （theoretical infant dose,理论婴儿剂量）为（0.026±0.012）（95% CI：0.025~0.027）mg·kg^-1·d^-1,RID （relative infant dose,相对婴儿剂量）为（0.53%±0.13%）（95% CI：0.49%~0.58%）。结论：妊娠期高血压产妇产后继续服用拉贝洛尔,受哺婴儿理论剂量和相对剂量均低于风险限,安全性较高,可在服药3~4 h后到下次服药周期前按需哺乳。     

甲硝唑在孕妇和乳妇中的临床药理研究

本文对甲硝唑在各期妊娠妇女中的组织穿透性在哺乳期妇女乳汁中的分泌进行了研究。结果表明，甲硝唑易穿过血胎盘屏障，进入各组织体液中。孕妇及乳妇接受单次静滴甲硝唑５００ｍｇ后，绒膜、蜕膜、胎儿、胎盘、脐带和羊水等组织、体液中的平均药物浓度可为同期母血浓度的２９～５３％，脐血为８９％。乳汁中药物浓度可与同期母血相当，给药后１ｈ为７．８５ｍｇ／Ｌ１２ｈ时尚可测得１．６７ｍｇ／Ｌ，乳汁药物平均半衰期为６．１７±２．１９ｈ．根据本研究结果提出在孕妇、乳妇中合理应用甲硝唑的建议。本文建立的甲硝唑组织、体液浓度高效液相色谱测定法简单、灵敏、可靠。不但适用于甲硝唑临床药理研究，还适用于甲硝吐临床血药浓度监测。     

Anticonvulsant use during lactation.

The issue of prescribing anticonvulsant drugs during lactation is clinically important, but also complex. Data for some drugs are completely lacking and for other drugs information is only available from single dose or short term studies or case reports. Moreover, limited knowledge exists about the practical impact of the drug concentrations found in breast milk and there are great methodological problems in the assessment of possible adverse drug reactions in infants. Nevertheless, based on current knowledge, some recommendations can be suggested. Treatment with carbamazepine, valproic acid (sodium valproate) and phenytoin is considered compatible with breastfeeding. Treatment with ethosuximide or phenobarbital (phenobarbitone)/primidone should most probably be regarded as potentially unsafe and close clinical monitoring of the infant is recommended if it is decided to continue breastfeeding. Occasional or short term treatment with benzodiazepines could be considered as compatible with breastfeeding, although maternal diazepam treatment has caused sedation in suckling infants after short term use. During long term use of benzodiazepines, infants should be observed for signs of sedation and poor suckling. Only very limited clinical data are available for the new generation anticonvulsant drugs and no clearcut recommendations can be made until further data are present. If it is decided to continue breast feeding during treatment with these drugs, the infant should be monitored for possible adverse effects. In general, the drug should be given in the lowest effective dose, guided by maternal serum or plasma drug concentration monitoring. If breast feeding is avoided at times of peak drug levels in milk, the exposure of the infant can be reduced to some extent. As breast milk has considerable advantages over formula milk, the benefits of continuing breast feeding should always be taken into consideration in the risk-benefit analysis.     

Sweetening Inhaled Antibiotic Treatment for Eradication of Chronic Respiratory Biofilm Infection

One impediment to breastfeeding is the lack of information on the use of many drugs during lactation, especially newer ones. The principles of drug passage into breastmilk are well established, but have often not been optimally applied prospectively. Commonly used preclinical rodent models for determining drug excretion into milk are very unreliable because of marked differences in milk composition and transporters compared to those of humans. Measurement of drug concentrations in humans remains the gold standard, but computer modeling is promising. New FDA labeling requirements present an opportunity to apply modeling to preclinical drug development in place of conventional animal testing for drug excretion into breastmilk, which should improve the use of medications in nursing mothers.

     

Drug excretion into breast milk--overview

Breastfeeding is the optimal form of infant feeding for the first months of an infant's life, and the majority of healthy women initiate breastfeeding after the birth of their infant. However, women on medication may default to formula feeding or not taking their drug therapy for fear of exposing their infant to the medication through the breast milk. Although the majority of medications are considered to be compatible with breastfeeding, cases of significant infant toxicity exist, suggesting a case by case risk assessment to be made before the mother initiates breastfeeding or drug therapy. Unfortunately, current clinical risk assessment is often compromised by the paucity of data, as studies in breastfeeding women and their infants are ethically difficult to conduct. Circumventing the ethical constraints, approaches have been proposed to estimate drug excretion into milk from physicochemical characteristics of the drug, which diffuses through the mammary gland epithelia. However, as our understanding on drug transfer mechanisms increases, it has become abundantly clear that carrier-mediated processes are involved with excretion of a number of drugs into milk. This article provides an overview of the benefits of breastfeeding, the effect of medication use during breastfeeding on maternal decisions and infant health, and factors determining infant exposure to medication through the breast milk.     

Extremely Low Excretion of Daptomycin into Breast Milk of a Nursing Mother with Methicillin-Resistant Staphylococcus aureus Pelvic Inflammatory Disease

Antibiotic treatment for pelvic inflammatory disease (PID) is often broad spectrum and targets a diverse range of vaginal flora. Treatment of PID in nursing mothers presents a particular clinical challenge because use of antimicrobials during breastfeeding poses several potential risks to infants. Excretion of drugs into breast milk can occur through different mechanisms and depends on the characteristics of both the drug and the mother. Whether daptomycin is excreted into breast milk is unknown, as is its subsequent exposure to breastfeeding infants and the associated risks. We describe a case of PID caused by methicillin-resistant Staphylococcus aureus, an uncommon pathogen in PID, in a breastfeeding mother who was successfully treated with daptomycin. Daptomycin concentrations in her breast milk were measured to determine potential exposure to her infant. These concentrations were extremely low, with an estimated milk:plasma ratio of 0.0012. Although additional confirmatory studies are needed, daptomycin may be a reasonable option in the treatment of PID caused by gram-positive organisms that are resistant to other antibiotics.     

FDA对药物临床哺乳期研究的建议

目前由于哺乳期用药的人体数据极其缺乏,对哺乳期药物治疗以及是否继续母乳喂养往往难以做出准确决策。美国食品药品管理局（FDA）于2019年5月发布了“临床哺乳期研究：研究设计考虑的因素”指导原则（草案）,对药物临床哺乳期研究的诸多方面提出了细致、具体的建议（如需要进行哺乳期研究的药物、研究类型、母乳取样方法、婴儿摄入母乳量的测量、药动学分析、婴儿剂量估算、婴儿安全数据的收集和药物对产乳量的影响等）,以期促进该方面研究,获得所需信息。中国尚无类似的指导原则,详细介绍FDA该指导原则主要内容,希望对我国开展这方面的研究工作及其监管有益,也对结合国情制定类似的指导原则有所启示。     

Using pharmacokinetics to predict the effects of pregnancy and maternal-infant transfer of drugs during lactation

Knowledge of pharmacokinetics and the use of a mechanistic-based approach can improve our ability to predict the effects of pregnancy for medications when data are limited. Despite the many physiological changes that occur during pregnancy that could theoretically affect absorption, bioavailability does not appear to be altered. Decreased albumin and alpha(1)-acid glycoprotein concentrations during pregnancy will result in decreased protein binding for highly bound drugs. For drugs metabolised by the liver, this can result in misinterpretation of total plasma concentrations of low extraction ratio drugs and overdosing of high extraction ratio drugs administered by non-oral routes. Renal clearance and the activity of the CYP isozymes, CYP3A4, 2D6 and 2C9, and uridine 5'-diphosphate glucuronosyltransferase are increased during pregnancy. In contrast, CYP1A2 and 2C19 activity is decreased. The dose of a drug an infant receives during breastfeeding is dependent on the amount excreted into the breast milk, the daily volume of milk ingested and the average plasma concentration of the mother. The lipophilicity, protein binding and ionisation properties of a drug will determine how much is excreted into the breast milk. The milk to plasma concentration ratio has large inter- and intrasubject variability and is often not known. In contrast, protein binding is usually known. An extensive literature review was done to identify case reports including infant concentrations from breast-fed infants exposed to maternal drugs. For drugs that were at least 85% protein bound, measurable concentrations of drug in the infant did not occur if there was no placental exposure immediately prior to or during delivery. Knowledge of the protein binding properties of a drug can provide a quick and easy tool to estimate exposure of an infant to medication from breastfeeding.     

Drug use during breast-feeding

The physicochemical and pharmacokinetic factors involved in transfer of drugs into breast milk are reviewed. Passage of drugs into milk can best be viewed as a two-compartment system. Various ratios of the drug concentration values in the two compartments and ratios of maternal-to-infant intake have been described. Knowledge of the limitations of these methods is necessary to properly interpret and apply the literature on drug excretion into breast milk. Factors involved in choosing a drug for a nursing mother are listed, a stepwise approach to minimizing transfer of drug to the infant is presented, and the literature on the excretion of specific drugs into milk is reviewed. Generally, drugs given to nursing mothers reach infants in much smaller amounts than drugs given to pregnant women. Decisions about nursing during drug therapy and the choice of drug therapy in a nursing mother should be based on the dosage and duration of therapy, age of the infant, quantity of milk consumed, experience with the drug in infants, degree of oral absorption of the drug by the infant, potential long-term effects, possible interference with lactation, and non-dose-related toxicities (e.g., potential allergic reactions). Too often, the mother's need for a medication is perceived as a reason to discontinue nursing. By understanding the principles of drug passage into breast milk and systematically evaluating the mother's needs, infant factors, and the data on specific drugs, clinicians can usually devise treatment plans that allow nursing while minimizing the risks to the infant.     

Alcohol and Breastfeeding

While the harmful effects of alcohol during pregnancy are well‐established, the consequences of alcohol intake during lactation have been far less examined. We reviewed available data on the prevalence of alcohol intake during lactation, the influence of alcohol on breastfeeding, the pharmacokinetics of alcohol in lactating women and nursing infants and the effects of alcohol intake on nursing infants. A systematic search was performed in PubMed from origin to May 2013, and 41 publications were included in the review. Approximately half of all lactating women in Western countries consume alcohol while breastfeeding. Alcohol intake inhibits the milk ejection reflex, causing a temporary decrease in milk yield. The alcohol concentrations in breast milk closely resemble those in maternal blood. The amount of alcohol presented to nursing infants through breast milk is approximately 5–6% of the weight‐adjusted maternal dose, and even in a theoretical case of binge drinking, the children would not be subjected to clinically relevant amounts of alcohol. Newborns metabolize alcohol at approximately half the rate of adults. Minute behavioural changes in infants exposed to alcohol‐containing milk have been reported, but the literature is contradictory. Any long‐term consequences for the children of alcohol‐abusing mothers are yet unknown, but occasional drinking while breastfeeding has not been convincingly shown to adversely affect nursing infants. In conclusion, special recommendations aimed at lactating women are not warranted. Instead, lactating women should simply follow standard recommendations on alcohol consumption.     

Valproic acid in breast milk: how much is really there?

Valproic acid (VPA) concentrations were measured by a sensitive and highly specific gas chromatographic/mass spectrometric assay in breast milk from 16 patients treated with VPA during 17 lactation periods. The range of VPA levels in 36 breast milk samples was 0.4-3.9 micrograms/ml (mean 1.9 +/- 1.2 microgram/ml). During the investigations of breast milk it was found that the concentration of total VPA in breast milk was not much higher than that of unbound VPA. These findings agree with clinical observations of infants fed with milk from VPA-treated mothers.     

Nicotine directly affects milk production in lactating mammary epithelial cells concurrently with inactivation of STAT5 and glucocorticoid receptor in vitro

Nicotine from tobacco smoke is absorbed into the bloodstream and transferred into breast milk in breastfeeding mothers. Smoking causes a decrease in breast milk volume, adverse changes to the milk composition, and a shortened lactation period. Breast milk is produced by mammary epithelial cells (MECs) in mammary glands during lactation. However, it remains unclear whether nicotine directly affects milk production in lactating MECs. To address this issue, we prepared a culture model with high milk production ability and less-permeable tight junctions (TJs) by seeding mouse MECs on a cell culture insert. Lactating MECs showed expression of α2, α3, β2, and β4 of nicotinic acetylcholine receptors. The high concentration of nicotine at 10–100 μM inhibited β-casein secretion and caused abnormal localization of TJ proteins. We subsequently investigated whether nicotine at a physiological concentration could affect lactating MECs. Nicotine at 1.0 μM directly inhibited α- and β-casein secretion in lactating MECs concurrently with inactivation of STAT5 and glucocorticoid receptor without affecting the TJ barrier. Nicotine treatment also induced MEC apoptosis concurrently with inactivation of Akt. These results support the adverse effects of nicotine on breastfeeding in smoking mothers.