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
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.

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Adverse Effects
The most common side effects of prostaglandin E2 concern its impact on gastrointestinal smooth muscle. The suppository correlates with the most severe side effects, with two-thirds of patients experiencing vomiting, two-fifths experiencing diarrhea, and one-third experiencing nausea. Other adverse effects include temperature elevation in half of the patients, headache in one-tenth, and shivering and chills in one-tenth. Anti-emetics and anti-diarrheal medications may be necessary before and during the drug administration to counteract these side effects.
The insert and gel have a less than one percent incidence of gastrointestinal symptoms. However, studies have shown that they have links to a higher chance of uterine hyperstimulation with and without fetal distress (greater than 2%) versus placebo (under1%). Additionally, they also have an increased chance of fetal distress without uterine hyperstimulation (over 2%) versus placebo (1%). There were also associated fetal heart rate changes, with and without distress. In all of these cases, removal of the product resulted in a return to normal, though one case did require treatment with tocolytics.

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5280360 rat LD50 oral 500 mg/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY); GASTROINTESTINAL: HYPERMOTILITY, DIARRHEA; SKIN AND APPENDAGES (SKIN): HAIR: OTHER Oyo Yakuri. Pharmacometrics., 8(787), 1974
5280360 rat LD50 subcutaneous 31600 ug/kg GASTROINTESTINAL: HYPERMOTILITY, DIARRHEA; SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE; SKIN AND APPENDAGES (SKIN): HAIR: OTHER Oyo Yakuri. Pharmacometrics., 8(787), 1974
5280360 rat LD50 intravenous 59500 ug/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY); GASTROINTESTINAL: HYPERMOTILITY, DIARRHEA; SKIN AND APPENDAGES (SKIN): HAIR: OTHER Oyo Yakuri. Pharmacometrics., 8(787), 1974
5280360 mouse LD50 oral 750 mg/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY); GASTROINTESTINAL: HYPERMOTILITY, DIARRHEA; SKIN AND APPENDAGES (SKIN): HAIR: OTHER Oyo Yakuri. Pharmacometrics., 8(787), 1974
5280360 mouse LD50 subcutaneous 19700 ug/kg GASTROINTESTINAL: HYPERMOTILITY, DIARRHEA; SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC 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 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.

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PGE2 is a cyclooxygenase-derived lipid mediator with dual immunomodulatory roles: 1) Induces suppressor T cells that potently inhibit IL-2-driven T cell activation; 2) Temporarily suppresses macrophage phagocytic function.
Acts as a selective renal vasodilator at low doses, 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.)