Prostaglandin E2 (Dinoprostone)   中文名称: 前列腺素

EP; Endogenous Metabolite

PGE2（10⁻⁷ M）通过诱导抑制性 T 淋巴细胞，抑制植物血凝素/佛波酯刺激的人外周血单核细胞（PBMC）中 IL-2 的产生。
PGE2 诱导的抑制性 T 细胞以 1:4 比例与新鲜 PBMC 共培养时，可抑制 70-90% 的 IL-2 生成。
该抑制作用具有 IL-2 特异性且需要细胞直接接触。 [1]

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在辐射和未辐射 T 溶液的组合中，PGE2 抑制 IL2 的产生。 PGE2 (0.1–10 μM) 以剂量依赖性方式抑制 IL2 的合成。 PGE2 通过在诱导阶段阻止细胞激活来发挥作用。通过使用 PGE2 预先搭建 T 型支架，可以诱导支架细胞中因子 IL-2 和 PHA 的合成 [1]。

大鼠腹腔注射 PGE2（1 mg/kg）使腹腔巨噬细胞对荧光微珠的吞噬作用降低 50%，每个巨噬细胞吞噬的微珠数量减少。
给药后 30 分钟吞噬抑制达峰值，持续 2 小时。 [2]
戊巴比妥麻醉大鼠肾动脉输注 PGE2（0.01–0.3 μg/kg/min），肾血流量呈剂量依赖性增加 25-40%。
低剂量（≤0.1 μg/kg/min）选择性扩张肾血管而不影响全身血压。 [3]

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PGE2 (0.1 mg/k, ia) 增加肾血流量。 PGE2 使肾血管阻力产生双相变化，血管舒张从 0.01 mg/min 开始，在大约 3 mg/min 时达到最大值，而在使用的最高剂量 (20 mg/min) 下，PGE2 会诱导肾血管收缩 [3]。 PGE2 (0.3 μg/k, ip) 显着减少体内暴露于甲基丙烯酸酯微珠的腹膜巨噬细胞数量 [2]。

IL-2 抑制实验：PBMC 与丝裂原 ± PGE2（10⁻⁹–10⁻⁶ M）共培养，通过 CTLL 细胞增殖法检测 IL-2 活性。
抑制性 T 细胞诱导：从 PGE2 处理组分离 T 细胞，加入新鲜 PBMC 评估 IL-2 抑制能力。 [1]

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体外和体内实验表明，T淋巴细胞产生白细胞介素2（IL-2）对免疫效应期的发展至关重要。诱导IL-2的产生涉及复杂的细胞相互作用。我们在之前的一项研究中表明，在人类中，单核细胞可以向产生IL-2的细胞传递相反的信号。除了通过释放白细胞介素1传递阳性信号外，人单核细胞还可以通过释放前列腺素E2（PGE2）传递阴性信号。这种单因子已知在几个系统中激活抑制机制，已被证明可以抑制IL-2的产生。本文提供的数据表明，这种PGE2依赖性抑制严格依赖于培养物中放射敏感性T细胞的存在，表明PGE2诱导抑制性T细胞的激活，调节IL-2的产生。动力学实验表明，这些抑制细胞在诱导阶段对辐射敏感，但在PGE2存在下孵育18小时后变得对辐射有抗性。通过将富集的T细胞与PGE2孵育成功体外诱导抑制细胞对于分析这一现象具有决定性意义。诱导的抑制剂能够抑制新鲜自体T细胞产生IL-2，并抑制这些细胞的PHA增殖反应。PGE2处理细胞上IL-2受体的定量评估表明，这种吸收能力与已知表达少量IL-2受体的PBL的能力相似，因此排除了通过吸收或竞争IL-2的抑制。没有观察到PGE2诱导的抑制剂对IL-2产生细胞的可检测到的杀伤作用。检测抑制细胞的OKT4和OKT8表型。在PGE2体外处理诱导之前或之后的两个分化阶段纯化T细胞。我们从这些实验中得出结论，PGE2激活了前体细胞中的抑制细胞，这些前体细胞主要与OKT8亚群分离，与OKT4亚群分离的细胞较少。然而，分化后，抑制细胞仅与OKT8亚群分离。这些结果是通过使用阳性选择（细胞亲和柱）和阴性选择（单克隆抗体加补体）获得的[1]。

Several studies have suggested that prostaglandin E2 (PGE2) might influence the phagocytic activity of macrophage cells. The present study was designed to examine the in vivo effects of PGE2, the prostaglandin synthesis inhibitor meclofenamate, the prostaglandin precursor arachidonic acid, and the biologically inactive fatty acid 11,14,17-eicosatrienoic acid on phagocytosis by peritoneal macrophage cells in the rat. Following 3 days of treatment with either agent, fluorescent methacrylate microbeads were injected intraperitoneally into all rats. Peritoneal exudates were harvested after administration of the microbeads and the percent phagocytosis determined in macrophage cells using a fluorescence-activated cell sorter (FACS II). The administration of PGE2 was associated with a significant decrease in the percentage of peritoneal macrophages ingesting the fluorescent methacrylate microbeads. In contrast, treatment with arachidonic acid or 11,14,17-eicosatrienoic acid significantly enhanced the percentage of phagocytic macrophage cells. A significant increase in the number of macrophages undergoing phagocytosis of the methacrylate microbeads was also observed in rats treated with meclofenamate. This later observation, taken together with the inhibitory effect induced by PGE2 on macrophage phagocytosis, points to a potential modulator role of PGE2 on the phagocytic activity of macrophages. These data also suggest that arachidonic acid might influence macrophage phagocytosis by a mechanism independent of PGE2[2].

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1 The effect of intra-aortic administration (i.a.) of prostaglandin E2 (PGE2) on renal blood flow was studied in the rat anaesthetized with pentobarbitone. Renal blood flow was assessed in two ways, either by use of an electromagnetic flow probe or by measurement of the renal clearance of p-aminohippurate (PAH). 2 PGE2 (0.1 microgram/min, i.a.) increased renal blood flow measured by either method. However, PAH clearance overestimated the degree of vasodilatation compared to that obtained using the flow meter. The possibility that PGE2 or a metabolite may increase PAH extraction by the kidney was considered. 3 The sensitivity of the rat to the renal vasodilator actions of PGE2 was enhanced by using a flank retro-peritoneal approach from which to insert the flow probe, rather than a mid-line abdominal incision. 4 Dose-response curves demonstrate that under the conditions used, PGE2 produced a biphasic change in renal vascular resistance, vasodilatation started at 0.01 microgram/min and was maximal at about 3 micrograms/min, while at the highest dose used (20 micrograms/min) PGE2 induced renal vasoconstriction. 5 The results indicate that contrary to previous reports, the rat does not exhibit an important species difference in the response of its renal vasculature to PGE2. Therefore, physiological and pathophysiological roles which have previously been attributed to vasoconstriction produced by PGE2 synthesized in the kidney may now have to be considered.[3]

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Phagocytosis model: Rats injected intraperitoneally with PGE2 (1 mg/kg in saline) 30 min before fluorescent microbead administration. Peritoneal macrophages harvested after 30 min for phagocytosis quantification.
Renal hemodynamics: Anesthetized rats received intra-renal arterial infusion of PGE2 (0.01–0.3 μg/kg/min in saline-ethanol vehicle). Renal blood flow monitored via electromagnetic flow probe. [2][3]

Absorption, Distribution and Excretion
After placement via the vaginal delivery system, it is absorbed at a rate of 0.3 mg per hour over 12 hours. The primary route of excretion for PGE2 metabolites is the kidneys. Metabolism/Metabolites The rapid metabolism of dinoprost primarily occurs in local tissues; any systemically absorbed drug is primarily cleared from the mother's lungs, followed by the liver and kidneys. Biological Half-Life Less than 5 minutes.

Effects During Pregnancy and Lactation
◉ Overview of Lactation Use
Dinoprostone (prostaglandin E2) has not been detected in human milk following exogenous administration, but small amounts are a normal component of breast milk and may help protect the infant's gastrointestinal tract.
Dinoprostone administered vaginally appears to have a negative impact on breastfeeding. Oral administration of dinoprostone in the first few days postpartum suppresses lactation. It is unclear whether vaginal or intracervical administration postpartum suppresses lactation, but dinoprostone may not be recommended postpartum for mothers who wish to breastfeed. One month postpartum, the drug does not appear to suppress lactation.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
A retrospective cohort study of birth records from Cardiff, Wales, UK, found that vaginal prostaglandin induction of labor resulted in an 11% lower likelihood of breastfeeding within 48 hours postpartum. The reduction was 15% in the primiparous subgroup. A non-randomized prospective study compared women who delivered vaginally and those who underwent selective induction of labor using dinoprostone vaginal gel. At discharge, exclusive breastfeeding rates were similar in both groups (88% and 89%, respectively). However, at 1 and 3 months postpartum, the exclusive breastfeeding rate was significantly lower in mothers who underwent labor with dinoprostone than in mothers who delivered vaginally. Exclusive breastfeeding rates were 54% and 85% at 1 month postpartum, and 46% and 59% at 3 months. At both time points, the supplemental and exclusive formula feeding rates were also higher in the induction group. Dinoprostone has been used in research to suppress postpartum lactation and breast engorgement, with its mechanism of action being a reduction in serum prolactin concentration. Effects on prolactin levels, breast engorgement, and lactation appear to be dose- and duration-dependent. Oral administration of 3 mg daily for 4 consecutive days, or 0.5 mg three times daily, was ineffective; however, oral administration of 8 to 12 mg over 24 to 30 hours was effective. These effects appear to be limited to the first few days postpartum; when dinoprostone was administered to women 30 days postpartum, it had no effect on serum prolactin or milk production. Oral administration of 12 mg dinoprostone divided into 30-hour doses was comparable in efficacy to bromocriptine 2.5 mg every 12 hours for 14 days, but with a lower incidence of breast rebound tenderness. Protein binding rate: 73%, bound to albumin. Adverse reactions: The most common side effect of prostaglandin E2 is its effect on gastrointestinal smooth muscle. Suppositories were associated with the most serious side effects; vomiting occurred in two-thirds of patients, diarrhea in two-fifths, and nausea in one-third. Other adverse reactions included: fever in half of patients, headache in one-tenth, and chills in one-tenth. To combat these side effects, antiemetics and antidiarrheals may be necessary before and during administration. The incidence of gastrointestinal symptoms with the implant and gel is less than 1%. However, studies have shown that they are associated with a higher risk of uterine hyperstimulation compared to placebo (less than 1%), regardless of fetal distress (greater than 2%). Furthermore, they are also associated with a higher risk of fetal distress compared to placebo (1%), but without uterine hyperstimulation (greater than 2%). Changes in fetal heart rate were also observed, regardless of fetal distress. In all these cases, the condition returned to normal upon discontinuation of the product, except for one case requiring treatment with a tocolytic.

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5280360trattLD50toralt500 mg/kgt Behavior: Somnolence (reduced overall activity); Gastrointestinal tract: Hypermotility, diarrhea; Skin and appendages (skin): Hair: Other tOyo Yakuri. Pharmacometrics., 8(787), 1974
5280360trattLD50tsubcutaneoust31600 ug/kgt Gastrointestinal tract: Hypermotility, diarrhea; Skin and appendages (skin): Dermatitis, other: Post-exposure; Skin and appendages (skin): Hair: Other tOyo Yakuri. Pharmacometrics., 8(787), 1974
5280360trattLD50tintravenoust59500 ug/kgt Behavior: Somnolence (inhibited overall activity); Gastrointestinal tract: Hypermotility, diarrhea; Skin and appendages (skin): Hair: Other
Oyo Oyo Yakuri. Pharmacometrics., 8(787), 1974
5280360tmousetLD50tsubcutaneoust750 mg/kgt Behavior: Somnolence (overall activity inhibition); Gastrointestinal tract: Hypermotility, diarrhea; Skin and appendages (skin): Hair: Other
Oyo Yakuri. Pharmacometrics., 8(787), 1974
5280360tmousetLD50tsubcutaneoust19700 ug/kgt Gastrointestinal tract: Hypermotility, diarrhea; Skin and appendages (skin): Other Dermatitis: Post-exposure; Skin and appendages (skin): Hair: Other. Oyo Yakuri. Pharmacometrics., 8(787), 1974

[1]. The mechanisms of inhibition of human IL 2 production. II. PGE2 induction of suppressor T lymphocytes. J Immunol. 1984 Apr;132(4):1851-7.

[2]. In vivo effects of prostaglandin E2 and arachidonic acid on phagocytosis of fluorescent methacrylate microbeads by rat peritoneal macrophages. J Histochem Cytochem. 1982 May;30(5):466-70.

[3]. Renal vasodilator activity of prostaglandin E2 in the rat anaesthetized with pentobarbitone. Br J Pharmacol. 1982 May;76(1):131-7.

Prostaglandin E2 is a derivative of prostaglandin F2α, with its 9-hydroxyl group oxidized to the corresponding ketone group. Prostaglandin E2 is the most common and biologically active prostaglandin in mammals. It has oxytocin effects and is a metabolite in humans and mice. It is the conjugate acid of prostaglandin E2(1-). Dinoprostone is a naturally occurring prostaglandin E2 (PGE2). It plays an important role in childbirth. It can also stimulate osteoblasts to release factors, thereby stimulating osteoclasts to carry out bone resorption. As a prescription drug, dinoprostone is used in the form of vaginal suppositories for preparing for and inducing labor. Dinoprostone is a prostaglandin analog. Dinoprostone has been reported to exist in balsam poplar, white poplar, and other organisms with relevant data. Dinoprostone is a synthetic prostaglandin E2 (PGE2) analog with smooth muscle contraction-inducing effects. Studies have shown that PGE2 regulates intracellular cyclic adenosine monophosphate (cAMP) levels by activating adenylate cyclase, thereby increasing calcium ion transport across cell membranes. Dinoprostone acts directly on the myometrium, inducing uterine and gastrointestinal smooth muscle contractions. Prostaglandin E2 is a prostaglandin containing two double bonds, produced by prostaglandin E synthase acting on prostaglandin H2. Prostaglandin E2 is an inflammatory mediator with important biological effects, including potent vasodilation, smooth muscle relaxation, stimulation of osteoclast-dependent bone resorption, and induction of pain and fever. It is also commonly used as a vaginal suppository during labor to soften the cervix and promote uterine contractions. Prostaglandin E is a family of three naturally occurring prostaglandins involved in regulating various biological functions, including vasodilation, inflammation, and smooth muscle cell contraction. It is the most common and biologically active prostaglandin in mammals. It possesses most of the biological activities of prostaglandins and is widely used as an oxytocin. This compound also has a protective effect on the intestinal mucosa. Drug Indications For termination of pregnancy in the second trimester (12 to 20 weeks of gestation from the first day of the last normal menstrual period), and for the removal of uterine contents in cases of missed abortion or intrauterine fetal death (within 28 weeks of gestation, calculated from the first day of the last normal menstrual period). Also used to treat non-metastatic trophoblastic disease of pregnancy (benign hydatidiform mole). Other indications include improving cervical induction (cervical “ripening”) in women in late or near term pregnancy who require induction for medical or obstetric reasons, and for the management of postpartum hemorrhage. Mechanism of Action Intravaginal administration of dinoprostone stimulates contractions of the myometrium of the pregnant uterus, similar to uterine contractions during term delivery, thereby expelling the pregnancy tissue. It is believed that dinoprostone exerts its uterine effect by directly stimulating the myometrium, but the exact mechanism of action remains unclear. Other hypothesized mechanisms include regulation of cell membrane calcium transport and intracellular cyclic adenosine monophosphate (cAMP) concentrations. Dinoprost appears to also produce local cervical effects, including softening, cervical canal obliteration, and cervical dilation. The exact mechanism of this effect is unclear, but studies suggest it may be related to collagen degradation caused by collagenase secretion following topical application of dinoprost.

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Pharmacodynamics
Dinoprost is equivalent to prostaglandin E2 (PGE2). It terminates pregnancy by stimulating the uterus to promote labor. Dinoprost also stimulates smooth muscle in the human gastrointestinal tract. This effect may be the cause of the vomiting and/or diarrhea commonly seen when using dinoprost to terminate pregnancy.

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PGE2 is a cyclooxygenase-derived lipid mediator with dual immunomodulatory effects: 1) inducing suppressor T cells and effectively inhibiting IL-2-driven T cell activation; 2) temporarily inhibiting macrophage phagocytosis.
At low doses, it can act as a selective renal vasodilator, potentially modulating renal perfusion without systemic effects. [1][2][3]

C20H32O5

352.4651

352.224

C, 68.15; H, 9.15; O, 22.70

363-24-6

53697-17-9 (sodium);363-24-6 (free acid);

5280360

White to off-white solid powder

1.1±0.1 g/cm3

530.1±50.0 °C at 760 mmHg

66-68 °C

288.5±26.6 °C

0.0±3.2 mmHg at 25°C

1.561

1.88

94.83

3

5

12

25

469

4

O([H])[C@]1([H])C([H])([H])C([C@]([H])(C([H])([H])/C(/[H])=C(/[H])\C([H])([H])C([H])([H])C([H])([H])C(=O)O[H])[C@@]1([H])/C(/[H])=C(\[H])/[C@]([H])(C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])O[H])=O

XEYBRNLFEZDVAW-ARSRFYASSA-N

InChI=1S/C20H32O5/c1-2-3-6-9-15(21)12-13-17-16(18(22)14-19(17)23)10-7-4-5-8-11-20(24)25/h4,7,12-13,15-17,19,21,23H,2-3,5-6,8-11,14H2,1H3,(H,24,25)/b7-4-,13-12+/t15-,16+,17+,19+/m0/s1

(Z)-7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-en-1-yl)-5-oxocyclopentyl)hept-5-enoic acid

Dinoprostone; Prostenone; Prostin; U 12062; U12062; U-12062; trade names: PGE2, Cervidil, Propess; PGE2; 363-24-6; Prostin E2; Prepidil; Cervidil; Minprostin E2;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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 (~283.71 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.09 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (7.09 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (7.09 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。