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

EP; Endogenous Metabolite

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]。

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]。

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]

Absorption, Distribution and Excretion
Absorbed at a rate of 0.3 mg per hour over 12 hours while the vaginal system is in place.
The major route of elimination of the products of PGE2 metabolism is the kidneys.

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Metabolism / Metabolites
Rapid metabolism of dinoprostone occurs primarily in the local tissues; any systemic absorption of the medication is cleared mainly in the maternal lungs and, secondarily, at sites such as the liver and kidneys.

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Biological Half-Life
Less than 5 minutes.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Dinoprostone (prostaglandin E2) has not been measured in human milk after exogenous administration, but it is a normal component of breastmilk in small amounts where it may help protect the infant's gastrointestinal tract.
Use of vaginal dinoprostone to induce labor appears to have a negative effect on breastfeeding. Given orally in the first few days postpartum, dinoprostone can suppress lactation. Whether postpartum vaginal or endocervical administration suppresses lactation is not known, but it should probably not be used postpartum in mothers who wish to breastfeed. By one month postpartum, the drug appears not to suppress lactation.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
A retrospective cohort study of birth records in Cardiff, Wales, UK found that the use of vaginal prostaglandins for the induction of labor resulted in an 11% decrease in the likelihood that mothers would be breastfeeding at 48 hours postpartum. The subgroup of first-time mothers had a 15% decrease.
A nonrandomized prospective study compared women who had spontaneous deliveries with those who had elective induction using dinoprostone vaginal gel. At hospital discharge, exclusive breastfeeding rates were similar between the two groups (88% and 89%). However, at 1 and 3 months postpartum, exclusive breastfeeding rates were significantly lower in mothers who had dinoprostone induction than in those who delivered spontaneously. Exclusive breastfeeding rates were 54% and 85% at 1 month and 46% and 59% at 3 months postpartum, respectively. Rates of supplemental and exclusive formula feeding were higher in the induced mothers at both time points also.
Dinoprostone has been used investigationally to inhibit postpartum lactation and engorgement by reducing serum prolactin concentrations. The effect on prolactin levels, engorgement and lactation appears to be dose and duration related. Oral dosages of 3 mg daily for 4 days or 0.5 mg three times daily were ineffective, whereas oral dosages of 8 to 12 mg over 24 to 30 hours were effective. These effects seem to be limited to the first few days postpartum; dinoprostone had no effect on serum prolactin or milk production when given to women 30 days postpartum. Compared to oral bromocriptine 2.5 mg every 12 hours for 14 days, dinoprostone 12 mg orally in divided doses over 30 hours was as effective as bromocriptine, but resulted in less rebound breast tenderness.

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Protein Binding
73%, to albumin

[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 prostaglandin F2alpha in which the hydroxy group at position 9 has been oxidised to the corresponding ketone. Prostaglandin E2 is the most common and most biologically potent of mammalian prostaglandins. It has a role as an oxytocic, a human metabolite and a mouse metabolite. It is a conjugate acid of a prostaglandin E2(1-).
Dinoprostone is a naturally occurring prostaglandin E2 (PGE2). It has important effects in labour. It also stimulates osteoblasts to release factors which stimualtes bone resorption by osteoclasts. As a prescription drug it is used as a vaginal suppository, to prepare the cervix for labour and to induce labour.
Dinoprostone is a Prostaglandin Analog.
Dinoprostone has been reported in Populus balsamifera, Populus candicans, and other organisms with data available.
Dinoprostone is a synthetic prostaglandin E2 (PGE2) analogue with smooth muscle contraction inducing property. It has been suggested that PGE2 regulates the intracellular levels of cyclic 3, 5-adenosine monophosphate (cAMP) by activating adenylate cyclase and thereby increases cellular membrane calcium ion transport. By acting directly on the myometrium, dinoprostone induces uterine and gastrointestinal smooth muscle contractions.
Prostaglandin E2 is a prostaglandin with 2 double bonds that is generated by the action of prostaglandin E synthases on prostaglandin H2. Prostaglandin E2 is a mediator of active inflammation, and has important biologic effects including potent vasodilation, smooth muscle relaxation, stimulation of osteoclast-dependent bone resorption and induction of both pain and fever. It is also used as a vaginal suppository during labor to soften the cervix and promote uterine contractions.
Prostaglandin E is a family comprised of three naturally occurring prostaglandins that are involved in the regulation of many biological functions including vasodilation, inflammation and smooth muscle cell contractility.
The most common and most biologically active of the mammalian prostaglandins. It exhibits most biological activities characteristic of prostaglandins and has been used extensively as an oxytocic agent. The compound also displays a protective effect on the intestinal mucosa.

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Drug Indication
For the termination of pregnancy during the second trimester (from the 12th through the 20th gestational week as calculated from the first day of the last normal menstrual period), as well as for evacuation of the uterine contents in the management of missed abortion or intrauterine fetal death up to 28 weeks of gestational age as calculated from the first day of the last normal menstrual period. Also used in the management of nonmetastatic gestational trophoblastic disease (benign hydatidiform mole). Other indications include improving the cervical inducibility (cervical "ripening") in pregnant women at or near term with a medical or obstetrical need for labor induction, and the management of postpartum hemorrhage.

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Mechanism of Action
Dinoprostone administered intravaginally stimulates the myometrium of the gravid uterus to contract in a manner that is similar to the contractions seen in the term uterus during labor, resulting in the evacuation of the products of conception from the uterus. It is believed that dinoprostone exerts its uterine effects via direct myometrial stimulation, but the exact mechanism of action is unkown. Other suggested mechanisms include the regulation of cellular membrane calcium transport and of intracellular concentrations of cyclic 3',5'-adenosine monophosphate. Dinoprostone also appears to produce local cervical effects including softening, effacement, and dilation. The exact mechanism of action for this effect is also unknown, but it has been suggested that this effect may be associated with collagen degradation caused by secretion of the enzyme collagenase as a partial response to locally administered dinoprostone.

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Pharmacodynamics
Dinoprostone is equivalent to prostaglandin E2 (PGE2). It stimulates labor and delivery by stimulating the uterine, and thus terminates pregnancy. Dinoprostone is also capable of stimulating the smooth muscle of the gastrointestinal tract of man. This activity may be responsible for the vomiting and/or diarrhea that is not uncommon when dinoprostone is used to terminate pregnancy.

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。