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.     

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

11-Methyl 16,16 Dimethyl Prostaglandin E₂ (TM-PGE) was administered orally to man in dosages of 2.5, 5, 7.5 and 10 μg/kg. Maximal inhibition of basal secretion was 52 and 78% and submaximal histamine-stimulated secretion 45 and 70% for volume and acid output, respectively. Secretory inhibition was observed for approximately two hours after ingestion of the drug. No effect was observed on serum gastrin levels. Side effects occurred with equal frequency in the placebo and drug groups. TM-PGE is well tolerated and inhibits both basal and submaximal histamine-stimulated acid secretion in man. Further evaluation may prove it to be helpful in the clinical treatment of acid hypersecretory states and peptic ulcer disease.     

Effect of PGI2, PGE2 and 6-keto PGF1α on canine gastric blood flow and acid secretion

Prostaglandins (PG)I₂, PGE₂ and 6-keto PGF₁α were infused directly into the gastric arterial supply at 10⁻⁹, 10⁻⁸ and 10⁻⁷ g/kg/min during an intra-gastric artery pentagastrin infusion in anesthetized dogs. 6-keto PGF₁α was also infused at 10⁻⁶ g/kg/min. Gastric arterial blood flow was measured continuously with a non-cannulating electromagnetic flow probe and gastric acid collected directly from the stomach. PGI₂ and PGE₂ produced similar dose-dependent increases in blood flow with an increase of more than four-fold at the highest dose. Both PGs inhibited acid output over this dose range with PGE₂ having 10 times the potency of PGI₂. 6-keto PGF₁α was at least 1000 times less active than PGI₂ or PGE₂ at increasing blood flow and failed to inhibit acid output even at 10⁻⁶ g/kg/min.     

Use of vaginal prostaglandin-E2 suppositories in septic abortion

A case report of successful clinical use of prostaglandin-E₂ vaginal suppositories to terminate a septic abortion is reported. A new indication for such therapy is suggested.     

Hepatic protection by 16,16-dimethyl prostaglandin E2 (DMPG) against acute aflatoxin B1-induced injury in the rat

Studies were conducted to assess the possible protective action of 16,16-dimethyl prostaglandin E₂ (DMPG) against acute aflatoxin B₁ (AFB₁) induced hepatic injury in the rat. Evaluation of liver damage of histopathologic techniques and clinical chemistry indicated that hepatic necrosis was ameliorated by treatment with DMPG even though binding of radiolabeled (3H)-AFB₁ to hepatic DNA was unaffected by this prostaglandin. However, DMPG did not protect rats against AFB₁-induced mortality. These data suggest that hepatic protection by DMPG was due to mechanisms other than an interference with the activation or hepatic binding of AFB₁.     

Structure and function of gastric corpus mucosa in suckling rats after treatment with 16,16-dimethyl prostaglandin E2

Suckling rats were treated every 8 h by intragastric instillation of 16,16-dimethyl prostaglandin E₂ (PG) from postnatal day 7 to 11. As compared to saline control treatment, PG increased the thickness of antral and corpus mucosa, the volume density of parietal cells, the mean individual parietal cell volume and pentagastrin-stimulated acid secretion at the end of the treatment. Plasma gastrin and corticosterone levels were depressed by PG while plasma thyroxine levels were unchanged. These structural and functional changes suggest PG-induced accelerated maturation of gastric mucosa.     

The effect of orally administered prostaglandins A1, A2 and 15 Epi-A2 on human gastric acid secretion

Prostaglandins A₁, A₂ and 15 Epi-A₂ were administered orally to human male volunteers. Prostaglandin A₁ and 15 Epi-A₂ did not consistently affect gastric acid secretion either in terms of the pH values within individual tests or in respect of comparative control test data. Prostaglandin A₂ administration resulted in a transient inhibition of secretion in all 6 subjects tested, with the pH rising above 6 in every case.It is concluded that none of these compounds is likely to have therapeutic application to the peptic ulceration problem.     

Changes in thymidine uptake in the gastrointestinal tract of the rat following treatment with 16,16-dimethyl prostaglandin E2

Thymidine uptake in the organs of the gastrointestinal tract of the rat was studied to determine if cell synthesis was involved in the increases in weight of the stomach, small intestine and colon which result from treatment with 16,16-dimethyl prostaglandin E₂ (16,16-dimethyl PGE₂). Animals were treated for 2 days with 16,16-dimethyl PGE₂. They were injected with the ³H-thymidine, sacrificed and the organs of interest were removed. The total amount of tritium in the stomach, duodenum, jejunum, ileum, and colon was determined.Thymidine uptake was significantly increased in the duodenum (1.50 times), jejunum (1.53 times), and colon (1.40 times) but not in the stomach and ileum. The increases were dose related in the duodenum and jejunum. The colon showed a similar dose response pattern but the changes with dose did not reach significance.These results confirm and extend a previous report that 16,16-dimethyl PGE₂ increased thymidine uptake in the duodenum but not the stomach (1). This is different from gastrin which has been shown by others to increase thymidine uptake in the stomach, duodenum, ileum and colon (2,3).     

Effect of prostaglandin 16,16 dimethyl E2 methyl ester on the pregnant human uterus

The oxytocic properties of prostaglandin 16,16 dimethyl E₂ methyl ester were investigated during the second trimester of pregnancy. As an abortifacient, this compound compared unfavorably to the 15 methyl analogs of prostaglandin E₂, with a lower rate of effectiveness and a relatively high incidence of side effects.     

Prostaglandin E1 or E2 (PGE1, PGE2) prevents premature luteolysis induced by progesterone given early in the estrous cycle in ewes

The objective of this study was to determine whether prostaglandin E₁ (PGE₁) or prostaglandin E₂ (PGE₂) prevents premature luteolysis in ewes when progesterone is given during the first 6 days of the estrous cycle. Progesterone (3 mg in oil, im) given twice daily from Days 1 to 6 (estrus = Day 0) in ewes decreased (P < 0.05) luteal weights on Day 10 postestrus. Plasma progesterone concentrations differed (P < 0.05) among the treatment groups; toward the end of the experimental period, concentrations in jugular venous blood decreased (P < 0.05) compared with the other treatment groups. Plasma progesterone concentrations in ewes receiving PGE₁ or PGE₁ + progesterone were greater (P < 0.05) than in vehicle controls or in ewes receiving PGE₂ or PGE₂ or PGE₂ + progesterone. Chronic intrauterine treatment with PGE₁ or PGE₂ prevented (P < 0.05) decreases in plasma progesterone concentrations, luteal weights, and the proportion of luteal unoccupied and occupied LH receptors on Day 10 postestrus in ewes given exogenous progesterone, but did not affect (P > 0.05) concentrations of PGF_2α in inferior vena cava blood. Progesterone given on Days 1 to 6 in ewes advanced (P < 0.05) increases in PGF_2α in inferior vena cava blood. We concluded that PGE₁ or PGE₂ prevented progesterone-induced premature luteolysis by suppressing loss of luteal LH receptors (both unoccupied and occupied).     

Studies on the mechanism of the protective action of 16,16-dimethyl PGE2 in carbon tetrachloride induced acute hepatic injury in the rat

We have previously demonstrated the partial protection of the rat liver by 16,16-dmPGE₂ (DMPG) against a number of hepatotoxins including carbon tetrachloride (CCl₄). However, it has not been determined whether hepatoprotection by DMPG represents a true “cytoprotective” action or if merely accomplished through inhibition of CCl₄ metabolism to reactive, toxic trichoromethyl (CCl₃·) free radicals. This report details a series of experiments in which the effects of DMPG on CCl₄ metabolism was evaluated in the rat.These data indicate that pretreatment with DMPG may reduce the hepatic concentration of the toxic CCl₃· free radicals in CCl₄ poisoned rats. Evidence is presented which suggests that this reduction in binding may have been due to a decrease in the rate of CCl₄ metabolism. However, DMPG did not affect the hepatic concentration of total microsomal cytochrome P450, the necessary enzyme in this metabolic process. On the other hand, free radical spin trapping experiments indicate that the rate of free radical formation from CCl₄ was slowed by treatment. Also, indirect evidence suggests that the metabolism of another cytochrome P450 substrate, phenobarbital, was slowed in DMPG treated rats. We conclude that the rate of CCl₄ metabolism may be reduced by pretreatment with DMPG. Furthermore, some measure of hepatic protection might be expected to occur as a result of the reduction in the rate of CCl₄ metabolism. However, we are unable to determine if this action was solely responsible for the observed hepatic protection.     

Antihypertensive activity of 16,16-dimethyl-oxa-alkyl-prostaglandins of the PGA2, PGE2 and trans-Δ 2-11-deoxy-PGE1 series: Structure-activity relationships

Utilizing Corey's synthesis, a variety of prostaglandins (PGs) with a modified ω-side chain were prepared. The 16,16-dimethyl-oxa-alkyl analogues of PGA₂ had potent antihypertensive activity. HR 466 (16,16-dimethyl-18-oxa-PGA₂), the best compound out of this series was active for 5–6 hours after oral administration of 0,1 mg/kg to conscious renal hypertensive dogs. The corresponding analogues of PGE₂ were also potent antihypertensive compounds, but were much more spasmogenic. Structural variations within the trans-Δ2-11-deoxy-PGE₁-series, in both side chains, gave HR 601 (trans-Δ2-15α-acetoxy-16,16-dimethyl-18-oxa-11-deoxy-PGE₁-methylester) which was orally active in the hypertensive dog with similar activity to HR 466.     

Effect of prostaglandins A1, A2, B1, B2, E2 and F2α on human umbilical cord vessels

The effect of six naturally occurring prostaglandins on isolated umbilical arteries and veins has been studied. All six prostaglandins had a constricting effect on the umbilical vessels. On the umbilical artery preparations the potencies in decreasing order were A₂>B₂>F_2α>B₁>E₂>A₁. Prostaglandin B₂ was more potent than PGA₂ on the umbilical vein. Polyphloretin phosphate (PPP) antagonised the constricting effect of all six prostaglandins without altering responses to 5-hydroxytryptamine.     

Synthesis of thromboxane A2 by non-aggregating dog platelets challenged with arachidonic acid or with prostaglandin H2

Dog platelets challenged with arachidonic acid fail to aggregate but synthesize a substance which aggregates rabbit and human platelets, this aggregation being suppressed by dibutyryl cyclic AMP. The aggregating substance contracts strips of rabbit aorta and of coeliac and mesenteric arteries, is soluble in diethyl ether, has a half-life of about 40 seconds at 37°C and of 100 seconds at 22°C. Its generation is blocked by various inhibitors of prostaglandin biosynthesis. The thromboxane A₂ synthetase inhibitor imidazole and its analogue benzimidazolamine also suppress generation of vessel contracting activity in incubates of dog platelets and prostaglandin H₂. Since dog platelets also transform prostaglandin H₂ into thromboxane A₂ their failure to aggregate, when stimulated by arachidonic acid or by prostaglandin H₂, is not due to lack of thromboxane synthesizing ability.     

A dose-response comparison of PGA2, PGE1 and PGE2 using the phenylephrine-stimulated perfused oviduct of the rabbit

The phenylephrine-stimulated perfused oviduct of the rabbit was evaluated as a model for studying the activity of prostaglandins that produce inhibition of the oviducal smooth muscle. Elevation of the normal “tone” of the oviduct by perfusing phenylephrine through the lumen permitted quantitation of the responses to PGA₂, PGE₁ and PGE₂ by measuring the magnitude of the inhibitory response produced by the agents. PGE₂ was relatively more potent, efficacious and specific for the oviduct than PGA₂ or PGE₁. It was concluded that the model was suitable for comparative dose-response studies of PGA₂, PGE₁ and PGE₂ and their analogs.     

Presence of prostaglandins E2 and A2 in canine gastric secretions

The presence of prostaglandins (PGs) was determined in gastric juice obtained from 3 conscious dogs, provided with a chronic gastric fistula. Outputs of acid (mequiv min^?1) and PGs (pg min^?1) were measured in gastric secretions stimulated by pentagastrin (100 or 200 ng kg^?1min^?1). Prostaglandin activity was estimated, after extraction and thin layer chromatography, by radioimmuno-assay of the PGB formed by treatment with alkali. Tritiated PGs were added to gastric juice for the purpose of correcting for PGs recovery. Using this method, the minimum mass of PGB which could be satisfactorily distinguished from zero was 25 pg. Prostaglandins A₂ and E₂ were present in pentagastrin-activated gastric secretions and averaged (mean ± SE, n = 8) 200.7 ± 18.1 and 260.1 ± 18.0 pg min^?1 respectively. The identity of PGA₂ and PGE₂ was confirmed by gas liquid chromatography combined with mass spectrometry. The amount of PGE₂ converted to PGA₂ during extraction, separation and conversion procedures was estimated from the amount of [³H] PGA₂ found when only [³H] PGE₂ had been added to a sample of gastric juice and averaged 14.5% ± 2.0. Our preliminary results support the possibility that PGE₂ and PGA₂ may be of physiological importance in the regulation of canine gastric secretions.     

Actions of prostacyclin (PGI2) and its product, 6-oxo-PGF1α on the rat gastric mucosa in vivo and in vitro

The effects of prostacyclin (PGI₂) and its breakdown product 6-oxo-PGF_1α on various aspects of gastric function were investigated in the rat. PGI₂ increased mucosal blood flow when infused intravenously. PGI₂ was a more potent inhibitor of gastric acid secretion in vivo than PGE₂. Like PGE₂, PGI₂ inhibited acid secretion from the rat stomach in vitro. PGI₂ had comparable activity to PGE₂ in inhibiting indomethacin-induced gastric erosions. Thus prostacyclin shares several of the activities of PGE₂, and may be involved in the regulation of gastric mucosal function.     

Effect of methylated prostaglandin E2 analogue on insulin secretion in man

Previous studies of the effect of E series prostaglandins /PGs/ on insulin secretion gave conflicting results in animals and little information in man. This study was designed to determine the effect of methylated PGE₂ analogue /15/S/-15-methyl PGE₂ methyl ester/, given orally, intraduodenally or intravenously, on insulin secretion, both under basal conditions and in response to intraduodenal or intravenous administration of glucose in 22 male volunteers. Methylated PGE₂ kept basal serum insulin level unchanged, but significantly reduced insulin response by 15 ± 6 μU/ml to intravenous glucose pulse injection /0.1 g/kg/ or by 45 ± 11 μU/ml to intraduodenal glucose infusion /0.5 g/kg-hr/. Blood glucose level was unaffected in tests with intraduodenal methylated PGE₂, but in tests with intravenous administration it was significantly reduced. These studies demonstrate that methylated PGE₂ analogue given orally, intraduodenally or intravenously results in a potent suppression of insulin response to glucose challenge.     

The concurrent in vitro and in vivo release of PGE2 from controlled-release hydrogel polymer pessary for cervical ripening

Twenty five patients booked for induction of labour, at 38 weeks or more gestation, were administered a controlled release vaginal polymer pressary containing 10mg prostaglandin E₂(PGE₂), designed to release 0.6mg per hour in vivo. The release profile from the polymer was linear throughout the eight hour observation period with a correlation coefficient of 0.81, and regression slope of 0.93 mg/hr. with 95% confidence intervals of 0.63mg/hr. to 1.23 mg/hr. This compared with a concomitatnt release profile in vitro which was uniform with time for the first five hours, but then continued at a decreasing rate with a correlation coefficient of 0.98. The relationship between PGE₂ release and cervical score change was linear, with a correlation coefficient of 0.65. The results show that PGE₂ release from the pessary in vivo is predictable, and suggest that the controlled release pessary offers the advantages of greater control of cervical ripening than alternative vehicles currently available.     

Effect of MgSO4 and K2SO4 on somatic embryo differentiation in Theobroma cacao L.

Somatic embryogenesis in cacao is difficult and this species is considered as recalcitrant. Therefore, reformulation of culture media might be a breakthrough to improve its somatic embryogenesis. In cacao, acquisition of somatic embryogenesis competence involves three main stages: induction of primary callus, induction of secondary callus and embryo development. Screening for MgSO₄ and K₂SO₄ concentrations for somatic embryo differentiation was conducted on three genotypes (Sca6, IMC67 and C151-61) at the three stages. The effect of these two salts in culture media appears to be most efficient at the embryo development stage. At this stage, high MgSO₄ (24 mM) and K₂SO₄ (71.568 mM) in the culture media induced direct somatic embryos on staminodes and petals of the Sca6 and IMC67 genotypes. Media supplemented with 6.0 mM and 12.0 mM MgSO₄ enabled high responsive of explants and produced high proportion of embryos. The positive effect of MgSO₄ and K₂SO₄ on the acquisition of embryogenesis competence was further tested on seven cacao genotypes reputed as non embryogenic: SNK12, ICS40, POR, IMC67, PA121, SNK64 and SNK10. All these genotypes were able to produce somatic embryos depending on the MgSO₄ concentration. Thus, our results showed that the recalcitrance of cacao to somatic embryo differentiation can be overcome by screening for the suitable MgSO₄ or K₂SO₄ concentration. Studies of the influence of different K⁺/Mg²⁺ ratios (at normal sulphate concentration) on somatic embryo differentiation revealed that sulphate supply was the main factor promoting responsive explants and the proportion of embryos. Cysteine synthase isoforms showed patterns related to morphogenetic structures sustaining that sulphur supply and its assimilation improve somatic embryogenesis in cacao.