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.     

Prostaglandin metabolite levels during cervical ripening with a controlled-release hydrogel polymer prostaglandin E2 pessary

Prostaglandin E and F metabolite (PGEM and PGFM) concentrations in peripheral plasma were assayed following the vaginal administration of a controlled release hydrogel polymer pessary designed to release 0.6 mg PGE2 per hour in vivo. A linear relationship between calculated PGE2 release from the pessary and PGEM levels was observed with a correlation coefficient of 0.78. A significant rise in PGEM levels occurred two hours following pessary administration, with significantly higher PGEM levels in patients delivering within the eight hour observation period compared with those delivering later. PGFM levels increased more slowly. The results suggest that PGE2 released by the pessary crosses the vaginal epithelium and may stimulate endogenous prostaglandin production. The controlled rise of metabolites in association with the polymer pessary suggest that it should provide greater control in labour induction than other vehicles we have studied, but this should be confirmed by clinical trials.     

Comparative study of a two dose schedule of PGE2 3 mg pessary and 1700 micrograms film for induction of labour in nulliparae with poor cervical score

Efficacy of a two dose schedule of 3 mg pessary or 1700 micrograms film of PGE2 for induction of labour was compared in nulliparae with poor cervical score. Patient characteristics in the two groups (43 in 3 mg and 40 in 1700 micrograms group) were comparable in age, period of gestation, indications for induction of labour and in their initial cervical score. The number of patients who started labour with a two dose schedule 4 hours apart were similar in each group. The improvement of cervical score, length of labour, mode of delivery and the neonatal outcome were not different in the two groups. There was no advantage of using a film preparation over that in the form of a pessary and the use of 3 mg dose did not give significantly better results compared with the 1700 micrograms dose, in terms of obstetric or neonatal outcome.     

Prospective study of different methods and routes of administration of prostaglandin E2 to improve the unripe cervix.

Methods of vaginal and extra-amniotic prostaglandin administration to achieve ripening of the cervix as a preliminary to induction of labour are described. Three groups of twenty patients with unfavourable induction features were studied, each receiving prostaglandin E2 the evening prior to planned induction. One group received PGE2 500 micrograms suspended in a viscous medium extra-amniotically. One group received PGE2 3 mg suspended in a viscous medium into the vaginal vault. A third group received a 3 mg PGE2 vaginal pessary to the posterior fornix. Improvement in cervical status at time of induction occurred in all groups but no single group had a significant advantage when regarding mean improvement, the induction-delivery interval or the number of patients in whom labour began before formal induction. However, with regard to relative cost, ease of preparation and storage, as well as patient and medical staff convenience, Prostaglandin E2 in pessary form is a superior form of administration.     

Physical polymer matrices based on affinity interactions between peptides and polysaccharides

A rapidly forming polymer matrix with affinity-based controlled release properties was developed based upon interactions between heparin-binding peptides and heparin. Dynamic mechanical testing of 10% (w/v) compositions consisting of a 3:1 molar ratio of poly(ethylene glycol)-co-peptide (approximately 18,000 g/mol) to heparin (approximately 18,000 g/mol) revealed a viscoelastic profile similar to that of concentrated, large molecular weight polymer solutions and melts. In addition, the biopolymer mixtures recovered quickly following thermal denaturation and mechanical insult. These gel-like materials were able to sequester exogenous heparin-binding peptides and could release these peptides over several days at rates dependent on relative heparin affinity. The initial release rates ranged from 3.3% per hour for a peptide with low heparin affinity to 0.025% per hour for a peptide with strong heparin affinity. By altering the affinity of peptides to heparin, a series of peptides can be developed to yield a range of release profiles useful for controlled in vivo delivery of therapeutics.     

Oxytocin induces PGE2 release from bovine cervical mucosa in vivo

Oxytocin receptor (OTR) concentrations in bovine cervical mucosa rise steeply a few days before estrus to high concentrations and fall rapidly after estrus. To study the physiological role of these OTR, the effect of OT on the release of PGE, from the cervical mucosa of periestrous cows in vivo was determined by inserting bags made of dialysis tubing containing isooncotic saline solution in the endocervix for two 2-h periods, a fresh bag for each period. During the first period no treatment was given, during the second period OT (100 IU) or saline was injected i.m. PGE2 content in the second bag was significantly greater in OT-treated cows than in saline-treated cows. In a second experiment cervical resistance to stretch, achieved by distention of a balloon inside the cervical canal, was measured in periestrous cows before and 10 h after i.m. injection of OT, or endocervical application of 2.5mg PGE1 in a jelly, or the inactive jelly. A significant reduction in the resistance was achieved with both OT and PGE1; in the doses given the effect of PGE1 was longer lasting than that of OT.     

Effects of crude and pure cholera toxin on prostaglandin.

Investigations were made into the effects of crude and pure preparations of cholera toxin on the release of prostaglandin-like substances (PLS) from rabbit ileum. Perfusion of ileal loops in vivo with buffer containing crude toxin was followed by a release of PLS into the perfusate, in amounts up to 37.5 ng/30 min (PGE2 equivalents). In contrast, no detectable PLS was released when ileal loops were perfused with pure toxin. Similarly, pieces of ileum opened longitudinally released PLS in amounts up to 107 ng PGE2/g tissue when incubated with crude toxin for 1-4 hr, but no release of PLS was detected in the presence of pure toxin under comparable conditions. Treatment of rabbits with indomethacin, 1.6 mg/kg p.o., had no effect on the accumulation of fluid in ileal sacs injected with crude or pure cholera toxin. These results support the view that prostaglandins do not play an essential role in the action of cholera toxin.     

Development of a vaginal gel containing 9-deoxo-16,16-dimethyl-9-methylene PGE2 for cervical dilatation and pregnancy termination

A stable hydrophilic gel for vaginal administration containing 9-deoxo-16,16-dimethyl-9-methylene PGE2 (9-methylene PGE2) was developed and its clinical usefulness for preoperative cervical dilatation and for termination of first and second trimester pregnancy evaluated in 521 pregnant patients admitted to the hospital for therapeutic abortion. Following vaginal administration of 3 mg of 9-methylene PGE2 gel a peak plasma level of between 3.5 and 10 ng/ml was found 3 to 6 hours following treatment. The "bioavailability" of the drug was in the order of 25-30%. 9-methylene PGE2 was found to be equally effective as 1 mg Cervagem for preoperative cervical dilatation. With a pretreatment period of 3 hours side effects were rare with both compounds. If the pretreatment period was extended to 12 hours the degree of cervical dilatation, but also the frequency of side effects increased significantly. Repeated administration of 9-methylene PGE2 was found to be effective (96% complete abortion) in terminating very early pregnancy provided the total dose was 10 mg or more. During second trimester the minimum effective dose was 4.5 mg of the compound repeated every fourth hour. The results of the present study have shown that with the new gel formulation the amount of 9-methylene PGE2 needed to terminate first and second trimester pregnancy was approximately ten times less in comparison with the previously used lipid base suppositories. The treatment was also associated with a low frequency of side effects.     

Sustained release implants of chloroquine phosphate for possible use in chemoprophylaxis of malaria

Implants of chloroquine phosphate (CQP) using biodegradable polymer, gelatin (G) and cross-linked gelatin (CLG) were prepared and evaluated to assess their physicochemical properties and in vitro release profile. The mechanism and kinetics of release were studied to correlate the release phenomenon with the formulation parameters. Out of many batches of the implants investigated, the implant prepared with 20% gelatin at 2:1 drug polymer ratio, 10% crosslinking agent and 2% plasticizer (Batch J) was found to provide optimum release behavior conforming to the requirements of a long term implant for a week. In vivo studies conducted on albino rats showed consistent therapeutic blood level over a period of 7 days. Mean residence time (MRT) of the drug released in the body, calculated as the ratio of the area under the first moment curve (AUMC) to area under concentration time curve (AUC) was 72 hr for implant against 2.42 hr for subcutaneous injection.     

The systemic absorption from the vagina of prostaglandin E2 administered for the induction of labour

The absorption rates of PGE2 released from tablets, gel and pessary bases inserted into the vagina for the induction of labour in a total of 27 patients have been measured by means of serial plasma 15-keto-PGE2 levels. The results are discussed with a view to obtaining both the optimum dose of PGE2 and vehicle of release.     

Analysis of food stimulation of gastrin release in dogs by a panel of inhibitors

The release of gastrin into the serum of five conscious gastric fistula dogs after a meat meal was monitored for 2 hours. Neither the rate of increase in serum gastrin nor the 2 hour cumulative integrated gastrin response was changed by administration of small doses of somatostatin tetradecapeptide (0.5 microgram/kg.hr IV for 2 hr), 16-16 dimethyl prostaglandin E2 (0.25 microgram/kg.hr IV for 2 hr or 1 microgram/kg intragastrically), or bethanechol (20 micrograms/kg.hr IV for 2 hr). Acidification of the food in the antrum to pH 1.2 to 1.4 eliminated serum gastrin release in response to food. In control studies, serum gastrin levels were not altered by IV administration of saline for 2 hr with no food or when a plate of food was held just out of the dogs' reach (teasing). Food-stimulated gastrin release was contrasted with that stimulated by bombesin under identical laboratory conditions [17]. In each case, antral acidification, somatostatin, prostaglandin E2 and bethanechol affected bombesin-stimulated gastrin release differently from that stimulated by food. We conclude that food and bombesin release gastrin by different pathways.     

Aspirin dose-dependently reduces alcohol-induced birth defects and prostaglandin E levels in mice.

The purpose of the present study was threefold. The first purpose was to determine if aspirin (ASA) decreases alcohol-induced birth defects in mice in a dose-dependent fashion. The second purpose was to see if the antagonism of alcohol-induced birth defects afforded by ASA pretreatment was related to dose-dependent decreases in prostaglandin E (PGE) levels in uterine/embryo tissue. The third purpose was to determine if ASA pretreatment altered maternal blood alcohol level. In experiments 1 and 2, pregnant C57BL/6J mice were administered ASA (0, 18.75, 37.5, 75, 150, or 300 mg/kg) on gestation day 10. One hour following the subcutaneous injection of ASA, mice received alcohol (5.8 g/kg) or an isocaloric sucrose solution intragastrically. In experiment 1 the incidence of birth defects was assessed in fetuses delivered by caesarean section on gestation day 19. In experiment 2 uterine/embryo tissue samples were collected on gestation day 10 1 hr following alcohol intubation for subsequent PGE analysis. In experiment 3 blood samples were taken at five time points following alcohol intubation from separate groups of alcohol-treated pregnant mice pretreated with 150 mg/kg ASA or vehicle. The results from the three experiments indicated that 1) ASA dose-dependently reduced the frequency of alcohol-induced birth defects in fetuses examined at gestation day 19, (2) ASA decreased the levels of PGE in gestation day 10 uterine/embryo tissue in a similar dose-dependent fashion, and 3) ASA pretreatment did not significantly influence maternal blood alcohol levels. These results provide additional support for the hypothesis that PGs may play an important role in mediating the teratogenic actions of alcohol.     

Prostaglandin formation in bacteria.

We report here that intact Gram positive and Gram negative bacteria, in the presence of exogenous arachidonic acid, produce and release PGE2 and PGF2 alpha into the medium as measured by radioimmunoassay. The seven bacterial strains so far studied release 6.5-50.9 ng PGE2 and less than 0.02-0.51 ng PGF2 alpha per mg bacterial protein during a 1 hour incubation, quantities of the same order of magnitude as those observed in mammalian systems. PGE2 and PGF2 alpha formation in bacteria are inhibited by indomethacin.     

Growth hormone-releasing factor (GRF) stimulates PGE2 production in rat anterior pituitary. Evidence for a PGE2 involvement in GRF-induced GH release

Rat anterior pituitaries were incubated over a 3-h period. Both PGE2 and GH were increased by GRF in a concentration-related manner (ED50: 3.5 nM and 6.5 nM, respectively). A significant correlation (r = 0.88, n = 127) was observed between GH and PGE2 release over the range of GRF concentrations tested. Among the five prostanoids analyzed, only PGE2 was selectively increased. Somatostatin lowered GH release, without any effect on PGE2 production. Indomethacin (Id) and Aspirin reduced significantly PGE2 synthesis and GRF-induced GH release. The inhibitory effect of Id was counteracted by addition of PGE2 to the medium. GRF and PGE2, at maximal concentrations, had a partial additive effect on GH release. The increase in PGE2 production and the reduced GH release in the presence of cyclooxygenase inhibitors suggest that PGE2 is involved in GRF-induced GH release.     

Prostaglandin release from preparations used vaginally for the induction of labour

The release and absorption profiles from the vagina of PGE2 in different vehicles used for cervical ripening and labour induction have been studied observing changes in concentrations of PGE metabolite (PGEM) and PGF metabolite (PGFM). In all groups a rise in PGEM concentration occurred over the 6 hour observation time but with wide variation. The profiles obtained differed markedly between the preparations under investigation correlating with the uterine contractions generated. PGFM generally showed little change. The model used could be explored further to enable modification of the vehicles used for PGE2 incorporation to achieve improved clinical results.     

Clinical evaluation of endocervical prostaglandin E2-triacetin-gel for preinduction cervical softening in pregnant women at term

In an open randomized clinical trial 100 pregnant women with low Bishop Scores at term were treated either with intracervical Prostaglandin (PG) E2 (0.5 mg in 2.5 ml triacetin-gel) 12 hours before labor induction with intravenous oxytocin or with oxytocin infusion alone. In 46 of the 50 pretreated patients (92%) the Bishop Score progressed at least 3 points, in four cases only 2 points. The mean Bishop score in the untreated patients increased insignificantly. After PGE2-gel administration 16 patients delivered during the 12 hour interval compared to 3 in the group without pretreatment. The first induction attempt was successful in 14 (64%) of the 22 patients that were left to be induced after cervical softening and in 26 (57%) of the 47 women without cervical priming. The Cesarean section rate was 10% (n = 5) in the PGE2-gel group and 12% (n = 6) in the control group. Dosage of oxytocin required for labor induction was significantly lower after cervical softening. No serious fetal or maternal side effects were observed after PGE2 pretreatment.     

Design and in vitro and in vivo evaluation of mucoadhesive microcapsules of glipizide for oral controlled release: A technical note

Conclussion  Thus, large spherical microcapsules with a coat consisting of alginate and a mucoadhesive polymer (sodium CMC, methylcellulose, Carbopol, or HPMC) could be prepared by an orifice-ionic gelation process. The microcapsules exhibited good mucoadhesive properties in an in vitro test. Glipizide release from these mucoadhesive microcapsules was slow and extended over longer periods of time and depended on composition of the coat. Drug release was diffusion controlled and followed zero-order kinetics after a lag, period of 1 hour. In the in vivo evaluation, alginate-Carbopol microcapsules could sustain the hypoglycemic effect of glipizide over a 14-hour period. These mucoadhesive microcapsules are, thus, suitable for oral controlled release of glipizide.     

Induction of prostaglandin E release from macrophages by colchicine

Rat peritoneal macrophages released high amounts of prostaglandin E (PGE) when treated in vitro with 10(-7) to 10(-4) M colchicine. PGE production occurred after a lag period of 4 hr and proceeded at a constant rate for more than 24 hr. Lymphocytes could not be stimulated to PGE release by colchicine. Disaggregation of microtubules appeared to be an essential event, since lumicolchicine was inactive and addition of heavy water (D2O) abolished colchicine-induced PGE formation. Cytochalasin B (5 microgram/ ml) did not interfere with PGE production by colchicine during the initial 12 hr, but thereafter it gave rise to an activity capable of degrading or converting newly synthesized PGE. Although details of the mechanisms by which colchicine in association with disrupted microtubules may induce PGE release remain unclear, these observations suggest that components of the cytoskeleton may efficiently influence the biosynthesis of prostaglandins.     

Effect of PGE1 on PGF2 alpha-induced luteolysis in nonbred ewes

Fifty-six ewes were used to study the effects of PGE1 or PGE2 plus PGF2 alpha given into the perivascular space of the ovarian vascular pedicle on luteal function of nonbred ewes. All ewes receiving PGF2 alpha had reduced levels of plasma progesterone and unoccupied receptors for LH at 24 hr after treatment regardless even if they received PGE1 or PGE2 concomitantly. Levels of plasma progesterone in ewes receiving only PGF2 apha were reduced further at 48 hour. Plasma progesterone and unoccupied receptors for LH of ewes receiving PGE2 + PGF2 alpha were maintained at 48 hr at levels seen at 24 hr after treatment, while progesterone in ewes receiving PGE1 + PGF2 alpha at 48 hr returned to levels seen in controls at 48 hr and unoccupied receptors for LH were three fold greater than controls.     

Assessment of a two dose scheme of PGE2 gel for preinduction cervical softening

A single dose technique of endocervically administered 0.5 mg PGE2 triacetin gel has been reliably effective for preinduction cervical softening. This study examined the value of a 2 times 0.25 mg dosing scheme over a 12 hour period and compared it with the single dose method. It was concluded that there was no advantage in the two dose scheme and given the potential for contamination or inadvertent rupture of the membranes with more frequent dosing, the single application remains the procedure of choice.