EP; Endogenous Metabolite

In a combination of irradiation and non-irradiated T solutions, PGE2 suppresses the generation of IL2. PGE2 (0.1–10 μM) inhibits the synthesis of IL2 in a dose-dependent manner. PGE2 functions by preventing cell activation during its induction phase. The synthesis of factors IL-2 and PHA in scaffolded cells can be induced by pre-scaffolding T-scaffolds with PGE2 [1].

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PGE2 (10⁻⁷ M) inhibited IL-2 production in phytohemagglutinin/phorbol myristate acetate-stimulated human peripheral blood mononuclear cells (PBMCs) by inducing suppressor T lymphocytes.
Suppressor T cells generated by PGE2 treatment suppressed IL-2 production in fresh PBMC cultures by 70-90% when co-cultured at 1:4 ratio.
The suppression was specific to IL-2 and required direct cell contact. [1]

In rats, intraperitoneal PGE2 (1 mg/kg) reduced phagocytosis of fluorescent microbeads by peritoneal macrophages by 50%, with decreased number of microbeads per macrophage.
Phagocytic inhibition peaked at 30 minutes post-administration and persisted for 2 hours. [2]
Renal arterial infusion of PGE2 (0.01–0.3 μg/kg/min) in pentobarbital-anesthetized rats increased renal blood flow by 25-40% in a dose-dependent manner.
Lower doses (≤0.1 μg/kg/min) selectively dilated renal vasculature without systemic blood pressure changes. [3]

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PGE2 (0.1 mg/k, ia) increases renal blood flow. PGE2 produces biphasic changes in renal vascular resistance, with vasodilation starting at 0.01 mg/min and reaching a maximum at approximately 3 mg/min, while at the highest dose used (20 mg/min), PGE2 induces renal vasoconstriction [ 3]. PGE2 (0.3 μg/k, ip) significantly reduces the number of peritoneal macrophages exposed to methacrylate microbeads in vivo [2].

IL-2 suppression assay: Human PBMCs cultured with mitogens ± PGE2 (10⁻⁹–10⁻⁶ M). IL-2 activity measured by CTLL cell proliferation.
Suppressor T cell induction: T cells isolated from PGE2-treated cultures and added to fresh PBMCs to assess IL-2 suppression. [1]

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In vitro and in vivo experiments indicate that the production of interleukin 2 (IL 2) by T lymphocytes is critical for the development of the effector phase of immunity. Complex cellular interactions are involved for the induction of IL 2 production. We have shown in a previous study that in humans monocytes can transmit opposite signals to the IL 2-producing cells. In addition to the positive signal delivered through the release of interleukin 1, human monocytes can deliver a negative signal through the release of prostaglandin E2 (PGE2). This monokine, known to activate suppressor mechanisms in several systems, was shown to inhibit IL 2 production. The data presented in this paper show that this PGE2-dependent inhibition is strictly dependent upon the presence of radiosensitive T cells in the culture, suggesting that PGE2 induces the activation of suppressor T cells modulating IL 2 production. Kinetics experiments indicate that these suppressor cells are radiosensitive during their induction phase but become radioresistant after 18 hr of incubation in the presence of PGE2. Successful in vitro induction of suppressor cells by incubation of enriched T cells with PGE2 was decisive for the analysis of the phenomenon. The induced suppressors were capable of inhibiting IL 2 production by fresh autologous T cells as well as inhibiting PHA proliferative response by these cells. A quantitative evaluation of IL 2 receptors on PGE2-treated cells has indicated that this absorption capacity was similar to the capacity of PBL known to express a low number of IL 2 receptors, thus excluding a suppression via absorption or competition for IL 2. No detectable killing of IL 2-producing cells by PGE2-induced suppressors was observed. The OKT4 and OKT8 phenotype of suppressor cells was examined. T cells were purified at two stages of differentiation before or after induction by PGE2 in vitro treatment. We conclude from these experiments that PGE2 activates suppressor cells among precursors segregating predominantly with the OKT8 subset and fewer cells with the OKT4 subset. After differentiation, however, the suppressor cells segregate with the OKT8 subset only. Such results were obtained by using positive selection (cellular affinity columns) and negative selection (monoclonal antibodies plus complement)[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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.09 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.09 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.09 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)