The hyperalgesic effects of prostacyclin and prostaglandin E2.

Hyperalgesia induced in rat paws or dog knee joints by prostacyclin (PGI2) and prostaglandin E2 was measured by a modification of the Randall-Selitto method (1) or by the degree of incapacitation (2). In both species PGI2 induced an immediate hyperalgesic effect but the effect of PGE2 had a longer latency. Low doses of PGI2 caused a short lasting effect but PGE2, large doses of PGI2 or successive administration of small doses of PGI2 caused a long lasting effect. It is suggested that prostacyclin mediates rat paw hyperalgesia induced by carrageenin. The long lasting hyperalgesic effect of PGE2 and high doses of PGI2 is possibly an indirect effect caused by stimulation of a sensory nerve sensitising mechanism.     

Comparison of the effects of prostacyclin (PGI2), prostaglandin E1 and D2 on platelet aggregation in different species

The activity of prostacyclin (PGI₂), PGE₁ or PGD₂ as inhibitors of platelet aggregation in plasma from human, dog, rabbit, rat, sheep and horse was investigated. Prostacyclin was the most potent inhibitor in all species. PGD₂ was a weak inhibitor in dog, rabbit and rat plasma whereas PGE₁ and prostacyclin were highly active. Theophylline or dipyridamole potentiated the inhibition of human platelet aggregation by prostacyclin, PGE₁ or PGD₂. Compound N-0164 abolished the inhibition by PGD₂ of human platelet aggregation but did not inhibit the effects of PGE₁ or prostacyclin. The results suggest that prostacyclin and PGE₁ act on similar sites on platelets which are distinct from those for PGD₂.     

Molecular conformation of prostaglandin E2

The crystal and molecular structure of prostaglandin E₂ (PGE₂) has been determined by X-ray diffraction. The compound crystallizes in the triclinic space group P1 with Z = 1 and , , , α = 87.347°, β = 94.042°, and γ = 91.010°. Gauche-gauche interactions appear in both side chains. The efficient molecular packing and hydrogen bonding network appears to stabilize the observed molecular conformation.     

Prostanoids and hemostasis in chickens: Anti-aggregating activity of the prostaglandins E1 and E2, but not of prostacyclin and prostaglandin D2

Aggregation of chicken thrombocytes was studied in whole blood using an electronic aggregometer. Serotonin (5-hydroxytryptamine, 5HT), arachidonic acid (AA) and collagen, but not adenosinediphosphate (ADP) induced aggregation. Prostaglandin (PG) endoperoxides were essential for arachidonic acid-induced aggregation, but were not involved in 5HT-induced aggregation, as indicated by inhibitory studies with indomethacin. Similar experiments indicated that biosynthesis of endogenous PG endoperoxides contributed to the aggregation induced by low concentrations of collagen, but was of little importance when high collagen doses were employed. PGE₁ and PGE₂ could abolish all types of aggregation studied, whereas prostacyclin (PGI₂) and PGD₂ were without any anti-aggregatory activity at 1 μg/ml. Between 1 and 100 ng/ml PGE₁ and PGE₂ inhibited arachidonic acid- and 5HT-induced aggregation dose-dependently.The lack of any hemostatic function of PGI₂ in chickens was also indicated by the absence of biosynthesis of endogenous PGI₂ in chicken aorta. PGI₂ was assessed as anti-aggregating activity, released by aortic fragments stirred in rabbit platelet rich plasma. Still, the presence of chicken aortic tissue i chicken whole blood inhibited 5HT-, but not arachidonic acid-induced aggregation. This inhibition was not affected by pretreatment of the aortic fragments with indomethacin or pargyline.     

Labour induction using buccal prostaglandin E2

Prostaglandins may remain in the circulation for some two hours after oral therapy and any resultant hypertonus may be difficult to treat in these circumstances. Buccal administration based on the concept that tablets could be discarded should this occur, has been evaluated in 30 patients. Effective uterine stimulation occured in 90% of subjects receiving a dose of 1mg hourly. No hypertonus occured but two patients had a prolonged contraction on a single occasion during labour. The fact that the tablets dissolve rapidly and in addition produce an unpleasant taste with a high incidence of nausea and vomiting, indicates buccal prostaglandins do not have advantages over alternative methods of oxytocic administration.     

Stimulation of bone formation by prostaglandin E2

We examined the effect of prostaglandin E₂ (PGE₂), in the presence or absence of cortisol, on bone formation in 21-day fetal rat calvaria maintained in organ culture for 24 to 96 h. [³H]Thymidine and [³H] proline incorporation were used to assess DNA and collagen synthesis, respectively. Changes in dry weight and DNA content were assessed after 96 h.PGE₂ (10⁻⁷ M) stimulated both DNA and collagen synthesis in calvaria. The effect on DNA synthesis was early (24 h), transient and limited to the periosteum. Collagen synthesis was stimulated at a later time (96 h), predominantly in the central bone. Cortisol (10⁻⁷ M) inhibited DNA and collagen synthesis. The addition of PGE₂ reversed the inhibitory effects of cortisol on DNA synthesis and content and increased collage synthesis in central bone to levels above control untreated cultures.We conclude that PGE₂ has stimulatory effects on bone formation and can reverse the inhibitory effects of cortisol. Hence the effects of cortisol may be mediated in part by their ability to reduce the endogenous production of prostaglandins.     

The metabolism of prostaglandin E2 in perinatal rabbit lungs

The inactivation of prostaglandin E₂ (PGE₂) was studied in isolated perfused lungs of fetal and neonatal rabbits. 200 nmol of ¹⁴C-PGE₂ was infused into the pulmonary circulation and the metabolites of PGE₂ were analysed from the nonrecirculating perfusion effluent. The amount of the main metabolite, 13,14-dihydro-15-keto-PGE₂, increased significantly between the 28th and 30th day of fetal life, remained relatively constant at the time of birth and increased again between 1st and 7th postnatal day. In contrast the amount of 15-keto-PGE₂ remained relatively stable during the studied period. The activity of NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase (15-OH-PGDH) was determined from the 100.000 g supernatant fraction of fetal, neonatal and maternal rabbit lungs using ¹⁴C-PGE₂ (20 μM) as the substrate. In the lungs of late fetal rabbits the activity of 15-OH-PGDH was significantly higher compared to the early postnatal period. Maternal rabbit lungs possessed, however, very high activities compared to the studied perinatal lungs. The results show, that the activity of the pulmonary 15-OH-PGDH is high already during the late fetal period. The inactivation of PGE₂ in isolated perfused lungs seems, however, to increase during the last prenatal days. Thus it seems possible that the uptake mechanism could be the rate limiting step in the metabolism of PGE₂ in rabbit lungs during the perinatal period.     

The effect of prostaglandin E2 on duodenal ulcer healing

Oral prostaglandin E₂ (PGE₂) has specific protective effects so called cytoprotection on the gastrointestinal mucosa that are independent of the acid secretion. This has recently been documented in man. A clinical study was performed to test whether this mucosal reinforcing property also could be used to accelerate duodenal ulcer healing. Twenty-eight patients with endoscopically confirmed duodenal ulcers were randomized to treatment with PGE₂ 0.5 mg three times daily and 1 mg at night or to placebo under double-blind conditions during a four week period. To reduce antacid consumption a fluid placebo antacid was given regularly. An active antacid could be used for pain relief. Healing rate was assessed with repeated endoscopies after 2 and 4 weeks. The treatment groups were comparable with respect to age, duration of ulcer history and present ulcer symptoms, smoking habits, family history, gastric acid secretory rate and number of patients with blood group 0. There was a slight difference in sex distribution. 2 mg PGE₂ did not reduce pentagastrin-stimulated acid secretion in five of the patients. After the treatment significantly more in the PGE₂-group ( , 86%) had healed than in the placebo-group . There was no difference in pain relief between PGE₂ and placebo-treated. The antacid consumption was very low in both PGE₂ and placebo-treated. No significant side effects or changes in laboratory test-results were recorded. It is suggested that the cytoprotective effect of PGE₂ can be used to accelerate healing of duodenal ulcer.     

Effect of gestational age on pulmonary metabolism of prostaglandin E1 & E2

The fetus and prematurely delivered newborn lamb have high concentrations of circulating PGE₂ that may play a hormonal role, particularly in maintaining the patency of the ductus arteriosus. We studied the ability of the isolated, perfused lung from immature (100 ± 150 days) lamb fetuses to metabolize PGE₂ as a function of PGE₂ concentration in the perfusate. After an intra-arterial infusion of ³H-PGE₂ and ¹⁴C-inulin (to act as a marker of extracellular space), the bulk of the ¹⁴C-inulin was rapidly cleared through the isolated lung and the majority of the ³H activity appeared after the ¹⁴C activity had fallen to negligible values. The ³H activity that was retained longer in the lung was primarily associated with the 15-keto prostaglandin E₂ and 15-keto-13,14 dihydro prostaglandin E₂ metabolites. Lungs from immature fetal lambs metabolized 25% less PGE₂ than did lungs from animals near term. This is consistent with our prior observation that premature lambs have decreased plasma clearance rates (in vivo) and elevated circulating concentrations of PGE₂ when compared with term newborn lambs.     

Plasma endotoxin and concentrations of stable metabolites of prostacyclin, thromboxane A2, and prostaglandin E2 in postpartum dairy cows

The presence of endotoxin in plasma and patterns of stable metabolites of prostacyclin (PC), thromoxane A₂ (TXA₂) and prostaglandin E₂ (PGE₂) were determined during the first postpartum estrous cycles in sixteen dairy cows. These included 8 cows with uterine infections which exhibited shortened luteal phases (SC) and 8 cows which had normal luteal phases (NC) after the first post partum ovulations. Endotoxin was consistently detected in all SC cows during the abbreviated estrous cycles while plasma samples of NC cows were free of endotoxin. Plasma concentrations of TXA₂ metabolite was higher in SC cows (p<0.05) (1785–3452 pg/ml) compared to NC cows (723–1240 pg/ml). Similarly, plasma concentrations of PC metabolite was higher in SC cows (p<0.07) (423–1847 pg/ml) compared to NC cows (159–325 pg/ml). In contrast, plasma concentrations of PGE₂ metabolite was higher in NC cows (p<0.05) (850–2219 pg/ml) compared to SC cows (455–628 pg/ml). The results of this study suggest that postpartum uterine infections mediate the release of prostaglandins from the uteri by means of the endotoxin and endotoxin appears to stimulate selectively the production of PC and TXA₂ favoring early demise of corpora lutea formed after first postpartum ovulations in dairy cows.     

Bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E1

We evaluated in a double-blind study the bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E₁ (PGE₁-carbinol), described recently as a nonirritant bronchodilator in animals. Fifteen asthmatic patients received by inhalation single doses of 1, 10, and 30 μg PGE₁-carbinol, 55 μg PGE₂, and placebo (10% ethanol in normal saline, which was also used as diluent for the PGs). Such pulmonary function tests as forced expiratory volume in 1 second, forced vital capacity, and maximal expiratory flow were monitored during 2 hours following inhalation of each compound. 10 and 30 μg PGE₁-carbinol produced significant but short-acting bronchodilation, similar to that caused by 55 μg PGE₂. One-third of the patients reported mild cough and throat irritation during and shortly after inhalation of 30 μg PGE₁-carbinol or 55 μg PGE₂. Placebo and 1 μg PGE₁-carbinol produced minimal side effects, but neither agent caused bronchodilation. In an adjunctive, unblinded trial, the same patients received 400 μg fenoterol. Fenoterol caused greater bronchodilation 15 and 30 minutes after inhalation than did the PGs in the double-blind study.     

The preparation and characterization of prostaglandin E1 antiserum

Antiserum against PGE₁ was raised in rabbits following immunization with prostaglandin-thyroglobulin conjugates. The antiserum exhibits 22% cross reactivity with PGE₂ but little or no apparent cross reaction with PGE₁ metabolites or heterologous prostaglandins. The data indicate some limitations in the use of this antiserum for the measurement of PGE₁ in biologic samples.     

Termination of pregnancy with prostaglandin E2 methyl ester

Prostaglandin E₂ methyl ester was several times more potent than PGE₂ (free acid) in stimulating the human uterus at mid-pregnancy, when administered by the intra-amniotic, extra-amniotic and intravaginal routes. At effective abortifacient dosage, however, the frequency and intensity of gastrointestinal, central nervous and cardiovascular side effects were high. This precluded further clinical trials with the compound. It is suggested that rapid entry of the drug into the systemic circulation takes place.     

Phosphatidylethanolamide derivatives of prostaglandins E1 and E2

Prostaglandins E₁ (PGE₁) and E₂ (PGE₂) have been coupled with the amine group of phosphatidylethanolamine (PE) by means of dicyclohexylcarbodiimide. These complexes basically mimic the relaxant and contractile effects of the corresponding free prostaglandins (PGs) on various smooth muscle preparations, but exhibit a delayed onset of action and a lower affinity for the PG receptors. The complexes are comparable with the free, parent PGs, in their intrinsic activities. The same holds true for the effects on blood pressure and on the motility of the uterus . The PGE₂-PE complex is hydrolysed to release obviously free PGE₂ by cell-free homogenates prepared from various tissues, but not by blood plasma. The PGE₂-PE complex is immunologically indistinguishable from the free PGE₂.     

Teratological studies with prostaglandin E2 in chick embryos

Prostaglandin E₂ (20–100 μg) was lethal to a relatively high percentage of chick embryos when administered at 48 hours incubation; no such effect was observed after 72 hours incubation. A relatively high incidence of abnormal embryos, which increased with the dose-levels of prostaglandin, was induced at both 48 and 72 hours incubation compared to the controls. However, this difference was statistically significant only in embryos treated with 100 μg prostaglandin at 48 hours incubation. The embryos showed no signs of growth retardation.     

Serum relaxin levels in prostaglandin E2 induced abortions

Relaxin, a peptide hormone produced only by the corpus luteum of pregnancy, can be used as a marker of luteal function in human pregnancy. Serum immunoreactive relaxin levels were measured serially in six women having second trimester abortions induced with intravaginal prostaglandin E2 (PGE₂) suppositories. All patients aborted within 17 hours of the first suppository. No significant changes were detectable in serum relaxin levels in any of the patients. It is concluded that PGE₂ does not interfere with the corpus luteum's ability to secrete relaxin in the second trimester of human pregnancy.     

The effects of 11-methyl 16,16 dimethyl prostaglandin E2 on canine gastric acid secretion

11-Methyl 16,16 Dimethyl Prostaglandin E₂ (TM-PGE₂) at peak effectiveness inhibited acid output stimulated submaximally by histamine in the dog by 95 and 84% when administered by the intravenous and oral routes, respectively. Inhibition of secretion was maintained for hours following intravenous administration while with the oral route, secretory inhibition was still present at the end of two hours after administration of the drug. The degree of inhibition of acid secretion caused by TM-PGE₂, its duration of action and the lack of side effects observed following administration of this drug makes it a suitable compound for evaluation as an anti-secretory agent in man.     

Antiabsorptive effects of 16, 16 dimethyl prostaglandin E2 and isolated rat colon

Ulcerative colitis is distinguished by abundant prostaglandin E₂ (PGE₂) in the stools and by severe diarrhea. To determine whether luminal PGE₂ alters normal colonic absorption, Na⁺ and Cl⁻transport across isolated rat proximal colon were studied before and after 16, 16 dimethyl PGE₂ (dmPGE₂) addition to flux chambers. Luminal administration of dmPGE₂ significantly reduced the net mucosal to serosal fluxes of Na⁺ and Cl⁻. These antiabsorptive tive effects of dmPGE₂ on Na⁺ and Cl⁻ active transport were reflected by a reduced metabolic rate of colonic tissue slices incubated with dmPGE₂. Addition of dmPGE₂ significantly reduced oxidation of glucose by the colon. Structurally, dmPGE₂ reduced the length of colonic mucosal microvilli, thereby decreasing absorptive surface area. These results suggest that PGE₂ released into the colonic lumen of patients with ulcerative colitis exerts antiabsorptive effects on the colon and in this way contributes to the associated diarrhea.     

Endocervical prostaglandin E2 gel for preinduction cervical softening

A single, endocervical application of a new commercial preparation of prostaglandin E₂ (PGE₂) gel, 0.5 mg of PGE₂ in 2.5 ml (3g), was evaluated for preinduction cervical softening. Safety and efficacy were assessed in a comparison with a 2.0 mg PGE₂ vaginal tablet and placebo in normal nulliparous women at term, with low Bishop scores. Treatment was administered in randomized, double blind fashion. Overall success, defined as a progression in Bishop score of at least 3 points within 12 hours, was achieved in 22/40 (55 %) of the gel group, 15/41 (37 %) in the tablet treated women, and 8/40 (20 %) in those receiving placebo. Od interest was the observation that of women with very unfavorable induction features (Bishop score 0–2), the cervical gel treatment resulted in a 6/8 (75 %) success rate compared with 2/13 (15 %) success for the vaginal tablet and 0/7 (0 %) for placebo. In as much as a very low incidence of side effects accompanied this treatment scheme, expanded multi-center testing is recommended.