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At least 19 recordsLinked to original sources
PubMed1977

Stability of prostaglandin E1 and dinoprostone (prostaglandin E2) under strongly acidic and basic conditions.

The stability of prostaglandin E1 and dinoprostone was investigated at the extremes of the pH range (less than or equal to 3 and greater than or equal to 10) in the sequence prostaglandin E leads to prostaglandin A leads to prostaglandin B. The degradation rate is first order with hydrogen-ion and hydroxide-ion concentrations. Separation and analysis of the E prostaglandins were accomplished by TLC and UV spectrophotometry. At the lowest pH values and at elevated or low temperatures, significant amounts of 15-epiprostaglandin E were present. Apparent activation energies for the total dinoprostone loss, calculated from elevated temperature data, were 21 kcal/mole in the strongly acidic region and about 18 kcal/mole at pH 3. Corresponding studies in the alkaline region led to a derived arrhenius activation energy of 15 kcal/mole with the appearance of significant amounts of 8-isoprostaglandin E. This difference in activation energies may reflect the different mechanisms operant at high and low pH values.

Chromatography, Thin Layer↗
PubMed1979

Prostaglandin prodrugs. I: Stabilization of dinoprostone (prostaglandin E2) in solid state through formation of crystalline C1-phenyl esters.

Dinoprostone para-substituted phenyl esters were synthesized in attempt to improve the solid-state stability of the parent prostaglandin. A phenol series covering a wide melting-point range was employed, and a linear relationship was observed between the phenol melting points and the resulting prostaglandin C1-ester melting points. The crystalline esters showed improved solid-state stability over the parent compound, and many esters were biologically active.

Animals↗
PubMed1977

Nucleophilic addition of bisulfite ion to prostaglandins E2 and A2: implication in aqueous stability.

Evidence is presented to indicate that the bisulfite ion (HSO3-) adds across the C-9 carbonyl group of dinoprostone (prostaglandin E2) and across the delta 10,11- bond of prostaglandin A2. At room temperature, the apparent equilibrium constant, determined by phase solubility analysis, circular dichroism, UV spectroscopy, and partitioning, for the formation of the bisulfite adduct of dinoprostone is about 7.5 M-1 at neutral pH. From this result and a free energy relationship reported in the literature for the thermodynamics of nucleophilic addition to carbonyl groups, it is concluded that the chemical reactivity of the C-9 carbonyl group of dinoprostone is not high enough to improve aqueous stability through reversible one-step nucleophilic reactions. However, from a series of kinetic experiments, it is concluded that the equilibrium is extremely favorable for the formation of the bisulfite adduct of prostaglandin A2 over pH 4-8 at room temperature. The second-order rate constant for the attack of sulfite ion (SO3 2-) to prostaglandin A2 is 1.75 sec-1 M-1.

Chemical Phenomena↗
PubMed1979

Prostaglandin prodrugs. II: New method for synthesizing prostaglandin C1-aliphatic esters.

A new method for synthesizing C1-aliphatic esters of dinoprost and dinoprostone without using hydroxyl protective groups is described. Reaction of the prostaglandin with an alkyl halide in the presence of the sterically hindered amine N,N-diisopropylethylamine proceeds smoothly to give C1-esters in various solvents at ambient or slightly elevated temperatures. Polar solvents were strongly catalytic, and even the hindered tert-butyl esters were synthesized by employing solvents such as dimethylformamide or dimethyl sulfoxide. Biological evaluation in the hamster antifertility assay showed that some esters maintained high bioactivity.

Animals↗
PubMed1979

Proposed metabolic dysfunctions in diabetic microthromboses and microangiopathy.

This report describes, at least in part, the role of prostaglandin and cyclic nucleotide metabolism in the etiology of the vascular disease associated with diabetes mellitus. Alterations in this metabolism seem associated with induction of platelet aggregation leads to microthromboses leads to microangiopathy sequences that are subtle but inexorable over a long period of time. Prostaglandins are generally elevated in blood from patients having frank signs of diabetic retinopathy when compared with nondiabetic subjects. Prostaglandin concentration remained elevated in diabetic retinopathy patients receiving indomethacin. We formed, therefore, the working hypothesis--yet to be fully tested either in patients or animal models with and without indomethacin treatment--that the increased prostacyclin (synthesized by endothelial microsomes) and cyclic-AMP production, both of which favor prevention of platelet aggregation, accompany the increased concentration of one or more of the prostaglandin E and F compounds. Concurrently, there may be an accompanying reduction of thromboxane A2 (synthesized by platelet microsomes) and cyclic-GMP (both of which favor platelet aggregation) production in the diabetic patients. The elevated prostaglandin in the diabetic patients not receiving indomethacin could possibly be directed toward slowing but not preventing the progression of the complex disease process in diabetes.

Alprostadil↗
PubMed1977

Elective induction of labor conducted under lumbar epidural block. II. Labor induction by amniotomy and intravenous prostaglandin.

Labor was electively induced at term in 117 clinically normal nulliparae and parous women by combining low amniotomy with intravenous administration of prostaglandin F2 alpha (n = 64) or prostaglandin E2 (n = 53). Analgesia was obtained by continuous lumbar epidural block with bupivacaine. The procedure was very effective in producing vaginal delivery within 24 h after prostaglandin infusion (n = 115), but it was accompanied by an extremely high incidence of uterine hypertonus. Tentative explanations for the transient uterine hyperstimulation are a direct stimulatory effect of the local anesthetic on the contractility of the myometrial fiber and/or a temporarily higher amount of circulating oxytocic compound reaching the myometrium due to local vasodilatation as a result of sympathetic nerve blockade. In some cases uterine hypertonus was associated with slowing of the basal fetal heart rate and, when severe, with the appearance of late deceleration patterns and fetal acidosis. In other cases the fetal heart rate deceleration is explained by the toxic effect of bupivacaine on the myocard. Since both the myometrial hyperactivity and the FHR alterations were temporary, fetal biochemical parameters were unaffected at completion of the first stage of labor. Because with intravenous prostaglandin uterine hyperstimulation is more difficult to avoid and regional analgesia further increases the hazard of both hypertonus and fetal heart rate deceleration, the combined application of an intravenous prostaglandin and continuous epidural analgesia should not be introduced into obstetrical practice.

Adult↗
PubMed1979

Synthesis of tritium-labeled N-acetyl PGE2 carboxamide (CP-27,987).

The preparation of N-acetyl PGE2 carboxamide (CP-27,987) regioselectively labeled at C-18 and C-19 with tritium is described. The overall radiochemical yield was 8.0% at a specific activity of 0.49 Ci/mmole. The synthesis employed is applicable to the preparation of tritium labeled natural prostaglandins and a variety of analogs.

Chemical Phenomena↗
PubMed1979

Metabolism of N-acetyl PGE2 carboxamide in the rat.

After intratracheal administration to rats, the bronchodilator N-acetyl PGE2 carboxamide was converted rapidly to PGE2 and 13,14-dihydro-15-keto-PGE2, the major plasma metabolite. Oxidation of the N-acetyl carboxamide by prostaglandin dehydrogenase and hydrolysis of the imide bond were demonstrated in vitro.

Animals↗
PubMed1979

Receptor binding in various tissues of PGE2, PGF2 alpha and sulprostone, a novel PGE2-derivative.

Sulprostone is a tissue-specific PGE2-derivative with high abortifacient activity in various species including man. The dissociation constant KD of the receptor binding of this compound was compared with PGE2 and PGF2 alpha in various tissue preparations of different species. A structure-binding relationship was developed from competition curves after a logit/log transformation. It is demonstrated that the relative affinities of Sulprostone, PGE2 and PGF2 alpha remain essentially constant in all the tissues investigated. It is concluded that the tissue-specificity of Sulprostone cannot be ascribed to structural differences of the receptor molecule.

Animals↗
PubMed1977

Debilitating interaction of adrenalectomy and intrahypothalamic implants of prostaglandin E2 upon open-field activity levels and sexual receptivity in estrogen-primed ovariectomized rats.

A group of estrogen-primed, ovariectomized rats was adrenalectomized and tested for sexual receptivity following hypothalamic implantations of PGE2. The combination of PGE2 and adrenalectomy led to severe debilitation as manifested by greatly reduced open-field activity scores and inhibition of estrogen and progesterone induced sexual receptivity. Neither exogenous progesterone nor corticosterone was able to restore these behaviors to normal levels. A mechanism involving PGE2 and adrenalectomy-induced transient ischemia was discussed as a possible cause of the debilitation.

Adrenalectomy↗
PubMed1979

The use of immobilized ligands and [125I]protein a for immunoassays of thromboxane B2, prostaglandin D2, 13,14-dihydro-prostaglandin E2, 5,6-dihydro-prostaglandin I2, 6-keto-prostaglandin F1 alpha, 15-hydroxy-9 alpha, 11 alpha(epoxymethano)prosta-5,13-dienoic acid and 15-hydroxy-11 alpha,9 alpha(epoxymethano)prosta-5,13-dienoic acid.

Immunoassays were developed for quantitative determination of thromboxane B2, prostaglandin D2, 13,14-dihydro-prostaglandin E2, 5,6-dihydro-prostaglandin I2, 6-keto-prostaglandin F1 alpha, 15-hydroxy-9 alpha, 11 alpha (epoxymethano) prosta-5, 13-dienoic acid and 15-hydroxy-11 alpha, 9 alpha (epoxymethano) prosta-5,13-dienoic acid. Ligands immobilized by covalent linkage to a solid support, bound homologous rabbit antibodies. [125I] Protein A was used to measure the bound IgG antibody. Increments of homologous and heterologous fluid-phase ligand completed with solid-phase ligand for antibody and resulted in decreasing amounts of bound [125I]-Protein A. The serologic specificity for each immune system was determined. Immunoassays for thromboxane B2, 6-keto-prostaglandin F1 alpha, and 5,6-dihydro-prostaglandin I2 were used to identify their respective homologous ligands that were separated by normal phase and reversed phase high pressure liquid chromatography.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1979

Bronchodilator activity in vivo and in vitro of four 13,14-didehydro-PGE2 analogues.

The bronchodilator activity of four analogues of PGE2: 13,14-didehydro-PGE2 (I), 20-methyl-13,14-didehydro-PGE2 (II), 16 S-methyl-13,14-didehydro-PGE2 (III) and 16 R-methyl-13,14-didehydro-PGE2 (IV) was studied in vivo and in vitro. The potency of III and IV when administered by aerosol to conscious guinea pigs was four times that of PGE2 in protecting against histamine-induced convulsion; I and II were less active. Compound III administered by aerosol to anaesthetized guinea pigs was six times more potent than PGE2 in protecting against i.v. histamine-induced increase of intractracheal pressure and the effect was longer-lasting. All the compounds caused relaxation of carbachol-induced tone in isolated guinea pig tracheal strips.

Anesthesia↗
PubMed1978

Cellular aspects of conjunctival inflammation induced by the synergistic action of histamine and prostaglandins.

Histamine or prostaglandin (PG) E1 or E2 administered to rabbits topically alone in high doses produced conjunctival vasodilation associated with little or no edema while their mixture at lower concentrations produced conjunctival vasodilation associated with profound edema. Sections of tissues treated with the mixture of histamine and PGE1 or PGE2 showed widespread epithelial and subepithelial inflammatory cellular infiltration. Conjunctival smears from eyes treated with the histamine/PG mixture contained small lymphocytes and polymorphonuclear leukocytes, including eosinophilic and occasionally basophilic cells. Differential staining of the polymorphs demonstrated both eosinophils and pseudoeosinophils. Histological examination of the conjunctival smears and sections of the lids obtained from eyes treated with either histamine or PGE1 or PGE2 alone did not show any detectable increase of inflammatory cells when compared to normal controls. The clinical and histological results indicate that the synergistic effect of histamine with PGs of the E-type in the conjunctiva produces an inflammatory response similar to that seen in various clinical forms of human allergic conjunctivitis. Such a response could not be produced by histamine or PGE1 or PGE2 alone even at much higher doses than in the mixture. The data indicate that an interplay of several different mediators may be crucial in the conjunctival response in allergy.

Alprostadil↗
PubMed2026

Identification of CD55 as a downstream factor of EP4 receptor signaling in colorectal cancer cells.

Prostaglandin E2 (PGE2) signaling through the E-type prostanoid 4 (EP4) receptor has been implicated in the pathophysiology of colorectal cancer (CRC). We herein identified decay-accelerating factor, also known as CD55, as a novel CRC-associated downstream factor of the EP4 receptor. The integration of transcriptomic profiling of PGE2-stimulated HCA-7 human colon cancer cells with analyses of cancer genomic databases predicted CD55 as a potential EP4 receptor-regulated target. Inhibitor-based experiments showed the induction of CD55 after a PGE2 stimulation required the EP4 receptor and Gi protein in HCA-7 cells, whereas protein kinase A signaling was dispensable. In combination with a toxicogenomic database analysis, p38 mitogen-activated protein kinase (MAPK) was identified as the predominant effector connecting the EP4 receptor to CD55 upregulation. A single-cell RNA-seq re-analysis of human CRC tissues revealed CD55 upregulation and p38 MAPK-related gene set enrichment in epithelial cells expressing the EP4 receptor, suggesting that this induction mechanism may operate in a subset of epithelial cells in clinical specimens. Collectively, these results delineate a PGE2/EP4 receptor/Gi protein/p38 MAPK signaling axis that induces CD55 expression in HCA-7 cells and epithelial tumor cells, provide new mechanistic clues for understanding the regulation of complement regulatory molecule CD55 expression by prostaglandin signaling.

Humans↗
PubMed1979

Efficacy and acceptability of intravenously administered sulprostone, a tissue-selective prostaglandin-E2 derivative, for induction of first-trimester abortion.

The abortifacient effect of a new tissue-selective prostaglandin E2-derivative, sulprostone, administered intravenously, has been investigated in 166 women in the the first trimester of pregnancy. Four different dose schedules (1.7 mcg/min for 5 or 10 hour--total dose 500 mcg or 1000 mcg, 2.8 mcg/min and 4.1 mcg/min for 6 hours--total dose 1000 mcg and 1500 mcg) have been evaluated. No absolute failures occurred and no severe complications or side-effects were recorded. Best results (high abortifacient efficacy and low systemic side-effects) were obtained by infusing 1000 mcg sulprostone in appr. 10 h. Our study indicates that sulprostone appears to have a high degree of acceptability.

Abortifacient Agents↗
PubMed1979

The mechanism of prostaglandin action on the early pregnant human uterus.

To extend observations in 11 weeks pregnant patients the mechanism of prostaglandin (PG) action has been examined in 6 weeks pregnant women (LMP). In 10 gravidas menstrual induction was attempted with a single slow release vaginal suppository containing 3000 microgram (155)-methyl PGF2 alpha methyl ester (U-36,384). In 10 additional gravidas menstruation was provoked by the intramuscular injection of 500 microgram 16-phenoxy-omega-tetranor PGE2 methyl sulfonylamide (Sulproston) at 4 hour intervals, totalling 1250 +/- 154 microgram. The PGF2 alpha and PGE2-analogues provoked similar changes in hormone levels and uterine function, sequentially measured by radioimmunoassays and the recording of intrauterine pressure. However, the effects of the intramuscular regimen developed earlier. Both treatments successfully terminated early pregnancy with clinical symptoms of menstruation if they irreversible compromised the conceptus within 12 hours. However, while both formulations represent advances in postconceptional therapy, only further modifications may closely approximate the "ideal" method of non-surgical menstrual induction.

Abortion, Induced↗