Oxytocin is rapidly removed from the plasma by the liver and kidney. The enzyme oxytocinase is largely responsible for the metabolism and regulation of oxytocin levels in pregnancy and only a small percentage of the neurohormone is excreted in the urine unchanged. Oxytocinase activity increases throughout pregnancy and peaks in the plasma, placenta and uterus near term. The placenta is a key source of oxytocinase during gestation and produces increasing amounts of the enzyme in response to increasing levels of oxytocin produced by the mother. Oxytocinase activity is also expressed in mammary glands, heart, kidney, and the small intestine. Lower levels of activity can be found in the brain, spleen, liver, skeletal muscle, testes, and colon. The level of oxytocin degradation is negligible in non-pregnant women, men, and cord blood.
来源:DrugBank
代谢
催产素酶，一种在怀孕早期产生的循环酶，也能够使多肽失活。
Oxytocinase, a circulating enzyme produced early in pregnancy, is also capable of inactivating the polypeptide.
来源:Hazardous Substances Data Bank (HSDB)
代谢
在怀孕期间... "催产素酶" ...能够通过切断1-半胱氨酸到2-酪氨酸的肽键来使催产素失活。
During pregnancy ... "oxytocinase" ... is capable of inactivating oxytocin by cleavage of the 1-cysteine to 2-tyrosine peptide bond.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
◉ Summary of Use during Lactation:Oxytocin is an essential lactation hormone released during breastfeeding that causes milk ejection and appears to have calming effect on the mother. Administration of exogenous oxytocin to mothers having difficulty in breastfeeding has not been clearly shown to have a beneficial effect on lactation success or in the treatment of breast engorgement. It might be of benefit in women who have lost the neuronal connection between the breast and hypothalamus. Effects on the infant are unlikely when given during breastfeeding.
Numerous studies suggest that oxytocin given during labor can negatively affect breastfeeding, possibly by reducing sucking behavior in the newborn in a dose-dependent manner, or by decreasing postpartum oxytocin release although study methodology and consistency has varied considerably. This effect might be most important during the initiation of breastfeeding, but may not persist after lactation is established. One study found that only oxytocin in conjunction with epidural analgesia reduced breastfeeding, but not oxytocin alone. Another study found that all rhythmic reflexes, the antigravity reflex, and total primitive neonatal reflexes were inhibited by intrapartum oxytocin administration, unrelated to dose, which could adversely affect breastfeeding. Some evidence exists that peripartum oxytocin administration might increase the risk of postpartum depression.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Nasal spray. Intranasal oxytocin is reportedly used by some midwives in Switzerland as a galactogogue. It has been used as part of regimens used by adoptive mothers who wish to breastfeed.
A small study found no difference in symptoms between subcutaneous oxytocin 2.5 international units daily and placebo after 3 days of treatment for breast engorgement.
An early randomized, placebo-controlled trial used oxytocin nasal spray in the mothers of newborns, but lactation management fell far short of what is considered acceptable nowadays. The study found that the spray might be useful in decreasing breast engorgement slightly in the mothers of fullterm infants, but no difference was found in the average infant weight loss between birth and day 4 in the oxytocin and placebo groups.
Two similarly designed trials studied oxytocin nasal spray in mothers of preterm newborns who were pumping milk for their infants. The first studied mothers of infants born before 38 weeks and used a total of 3 units of intranasal oxytocin (Syntocinon-Sandoz, 40 units/mL) before pumping each breast for10 minutes a breast pump four times daily. Among primiparous mothers, milk production during days 2 to 5 days postpartum was 1964 mL in those who used oxytocin and 510 mL in those who received placebo spray. Because of the large and statistically significant effect of oxytocin among primiparous women, the trial was stopped after only 8 primiparous mothers had been studied. No statistically significant difference was found between oxytocin and placebo among 4 multiparous women who were attempting to breastfeed for the first time. The paper did not report giving the mothers any instructions in lactation technique.
Fifty-one mothers who delivered an infant of less than 35 weeks gestation were studied. Twenty-seven mothers used 4 units of intranasal oxytocin (Syntocinon-Novartis, 40 units/mL), and 24 mothers received an identical placebo spray before pumping with a breast pump. All mothers were given instructions on using hand massage before pumping and advised to pump every 3 hours. No difference in milk production over the first 5 days postpartum was found between mothers who received oxytocin (median 667 mL) and placebo (median 530 mL), although women receiving oxytocin produced slightly more milk on day 2 of the study. Parity had no effect in this study.
Several factors might explain the differences in findings between the studies. Because of the great interpatient variability in milk production documented in the recent study and the small number of patients in the first study, the finding in the earlier study may have been due to chance. A 50% higher dose of oxytocin was used in the first study, which may have caused a greater effect. Another plausible explanation is the good lactation support given to mothers in the recent larger study that seemed to be lacking in the early study.
Two case reports indicate that oxytocin nasal spray may facilitate letdown in tetraplegic women who have lost the neuronal connection between the nipple and the hypothalamus.
During labor. A study of mothers who received oxytocin during labor found that on the second day postpartum, oxytocin infusion decreased endogenous oxytocin levels dose-dependently. Epidural analgesia in combination with oxytocin infusion influenced endogenous oxytocin levels negatively. Oxytocin infusion also increased serum prolactin.
Logistic regression of data from 585 mothers who had epidural analgesia during labor found that mothers who had received exogenous oxytocin had a 3.3 times greater risk of delayed onset of lactation than women who did not.
An observational study of 20 primiparous women found that those who were exclusively breastfeeding at 3 months (63%) had received a lower dose of oxytocin during labor (mean total dosage 1363 milliIunits) than those who were not exclusively breastfeeding (mean total dosage 3088 milliIunits). This result was attributed to an inhibitory effect on neonatal sucking by the infant caused by oxytocin.
A small, nonrandomized cohort study found that the newborn infants whose mothers received synthetic oxytocin to induce or maintain labor had a decreased level of prefeeding organization one hour after birth.
A retrospective cohort study in Spain compared breastfeeding outcomes between mothers who received oxytocin during labor (n = 189) and mothers who did not, including those who delivered via elective Cesarean section (n = 127). Mothers who received oxytocin during the first and second stages of labor had a 45% increased risk of bottle feeding and a 129% increased risk of breastfeeding discontinuation by 3 months of age. Effects were most pronounced in women under 27 years of age.
A small prospective study in California compared women who received an epidural infusion of fentanyl and ropivacaine to mothers who did not receive an epidermal during labor. All mothers had normal vaginal deliveries and their infants had 1 uninterrupted hour of skin-to-skin contact immediately postpartum. The study found inverse relationships between the amount of fentanyl and the amount of oxytocin received during labor and the time of the first suckling. Because women who received more fentanyl also tended to receive more oxytocin, the study could not clearly separate the effects of the two drugs.
A small prospective cohort study in Spain followed mothers by telephone postpartum to determine their breastfeeding status. Mothers who had received oxytocin during labor were breastfeeding at a similar rate as those who had not at 1, 3 and 6 months postpartum.
A nonblinded, nonrandomized study compared breastfeeding among the infants of mothers who received oxytocin during delivery (n = 70) and those who did not (n = 90) in two Iranian hospitals. Mothers were primiparous and infants were full term. Infant breastfeeding behavior was assessed to be either successful or unsuccessful within 2 hours of delivery. Infants whose mothers received oxytocin were judged to successfully breastfeed 48.6% compared to 82.2% among the infants of mothers who did not receive oxytocin. Use of opiate pain relievers in the two groups was not stated.
A retrospective cohort study compared breastfeeding results between women who did and did not receive oxytocin during labor. After correcting for confounding factors, the study found that exogenous oxytocin impaired breastfeeding during the first hour postpartum, but not at 3 months postpartum. High pregestational body mass index was the best predictor of an impaired third month's postpartum breastfeeding.
A retrospective case-control study conducted in two hospitals in central Iran compared breastfeeding behaviors in the first 2 hours postdelivery by infants of 4 groups of primiparous women with healthy, full-term singleton births who had vaginal deliveries. The groups were those who received no medications during labor, those who received oxytocin plus scopolamine, those who received oxytocin plus meperidine, and those who received oxytocin, scopolamine and meperidine. The infants in the no medication group performed better than those in all other groups, and the oxytocin plus scopolamine group performed better than the groups that had received meperidine.
A prospective cohort study in Spain found no relationship between oxytocin dose during labor or postpartum with the duration of breastfeeding. However, elective cesarean section without oxytocin resulted in the greatest risk of stopping exclusive breastfeeding.
An observational study in Sweden compared nursing behaviors of the infants of mothers who received intravenous oxytocin or intramuscular oxytocin with or without receiving epidural analgesia with sufentanil and bupivacaine. Infants of mothers who received oxytocin infusions alone during labor breastfed as well as those of mothers who had no interventions during labor. Mothers who received oxytocin plus epidural analgesia had reduced breastfeeding behaviors and more weight loss at 2 days postpartum than those who did not receive epidural analgesia. The mothers of infants who breastfed well had greater variability in serum oxytocin than those whose infants did not breastfeed well.
A study examined the effects of low, medium and high doses of intrapartum synthetic oxytocin administered to that in mothers who received no oxytocin. A dose-related decrease in several infant breastfeeding behaviors and the number of exclusive nursing bouts at 24, 48 and 72 hours was found, but there was no difference in the rate of exclusive breastfeeding at 3 months postpartum.
Oxytocin is administered parenterally and is fully bioavailable. It takes approximately 40 minutes for oxytocin to reach steady-state concentrations in the plasma after parenteral administration.
The enzyme oxytocinase is largely responsible for the metabolism and regulation of oxytocin levels in pregnancy; only a small percentage of the neurohormone is excreted in the urine unchanged.
来源:DrugBank
吸收、分配和排泄
清除
在一项观察了10名接受催产素引产的女性的研究中，平均代谢清除率为7.87毫升/分钟。
In a study that observed 10 women who were given oxytocin to induce labor, the mean metabolic clearance rate was 7.87 mL/min.
Oxytocin is destroyed by chymotrypsin in the GI tract. Uterine response occurs almost immediately and subsides within 1 hour following iv administration of oxytocin. Following im injection of the drug, uterine response occurs within 3-5 minutes and persists for 2-3 hours. Following intranasal application of 10-20 units of oxytocin (nasal preparations are no longer commercially available in the US), contractions of myoepithelial tissue surrounding the alveoli of the breasts begin within a few minutes and continue for 20 minutes; iv oxytocin produces the same effect with a dose of 100-200 milliunits.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
像血管升压素一样，催产素分布在细胞外液中。少量催产素可能会到达胎儿循环。
Like vasopressin, oxytocin is distributed throughout the extracellular fluid. Small amounts of oxytocin probably reach the fetal circulation.
[EN] HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF STRESS-RELATED CONDITIONS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES POUR LE TRAITEMENT D'ÉTATS LIÉS AU STRESS
申请人：OTSUKA PHARMA CO LTD
公开号：WO2010137738A1
公开（公告）日：2010-12-02
The present invention provides a novel heterocyclic compound. A heterocyclic compound represented by general formula (1) wherein, R1 and R2, each independently represent hydrogen; a phenyl lower alkyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group and the like on a benzene ring and/or a lower alkyl group; or a cyclo C3-C8 alkyl lower alkyl group; or the like; R3 represents a lower alkynyl group or the like; R4 represents a phenyl group that may have a substituent(s) selected from the group consisting of a 1,3,4-oxadiazolyl group that may have e.g., halogen or a heterocyclic group selected from pyridyl group and the like; the heterocyclic group may have at least one substituent(s) selected from a lower alkoxy group and the like or a salt thereof.
[EN] ORAL FORMULATIONS OF PYRROLIDINE DERIVATIVES<br/>[FR] FORMULATIONS ORALES DE DÉRIVÉS DE PYRROLIDINE
申请人：OBSEVA SA
公开号：WO2015091365A1
公开（公告）日：2015-06-25
The present invention relates to solid oral formulations comprising a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2'-methyl-1,1'-biphenyl-4-yl)carbonyl]pyrrolidin-3-one- O-methyloxime, and/or an active metabolite thereof, and the use of said formulations in the treatment and/or prevention of preterm labor, premature birth, dysmenorrhea and embryo implantation failure due to uterine contractions. The present invention is furthermore related to processes for their preparation.
[EN] ALANINE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE<br/>[FR] MODULATEURS DE PROTÉOLYSE À BASE D'ALANINE ET PROCÉDÉS D'UTILISATION ASSOCIÉS
申请人：ARVINAS INC
公开号：WO2017011590A1
公开（公告）日：2017-01-19
The description relates to inhibitors of Apoptosis Proteins (TAPs) binding compounds, including Afunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the IAP E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
[EN] DERIVATIVES OF 1-[(CYCLOPENTYL OR 2-PYRROLIDINYL)CARBONYLAMINOMETHYL]-4-(1,3-THIAZOL-5-YL) BENZENE WHICH ARE USEFUL FOR THE TREATMENT OF PROLIFERATIVE, AUTOIMMUNE OR INFLAMMATORY DISEASES<br/>[FR] DÉRIVÉS DE 1-[(CYCLOPENTYL OU 2-PYRROLIDINYL)CARBONYLAMINOMÉTHYL]-4-(1,3-THIAZOL-5-YL)-BENZÈNE QUI SONT UTILES POUR LE TRAITEMENT DE MALADIES PROLIFÉRATIVES, AUTO-IMMUNES OU INFLAMMATOIRES
申请人：UNIV DUNDEE
公开号：WO2016146985A1
公开（公告）日：2016-09-22
There is provided novel small molecule E3 ubiquitin ligase protein binding ligand compounds, having utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for the preparation thereof, and use in medicine. There is particularly provided PROTACs which bind to a protein within the bromo- and Extra-terminal (BET) family of proteins, and especially to PROTACs including novel small molecule E3 ubiquitin ligase protein binding ligand compounds which selectively induce degradation of the BRD4 protein within the bromodomain of the BET family of proteins.
[EN] COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF BROMODOMAIN-CONTAINING PROTEINS<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LA DÉGRADATION CIBLÉE DE PROTÉINES CONTENANT UN BROMODOMAINE
申请人：ARVINAS INC
公开号：WO2017030814A1
公开（公告）日：2017-02-23
The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.
