Embryo collection from pigs post-pseudopregnancy induced by estradiol dipropionate.

We aimed to define whether embryo collection carried out after pseudopregnancy was of similar outcome and quality as after artificial abortion. To induce pseudopregnancy, 30 gilts or sows were given 20 mg intramuscular estradiol dipropionate (EDP) 10-11 days after the onset of estrus. Ten additional pigs were inseminated artificially at natural estrus as a control group. Prostaglandin F2α (PGF2α ) was administered twice with a 24 hr interval beginning 15, 20, or 25 days after EDP-treatment (n = 10 per group) or between 23 and 39 days after artificial insemination in control pigs. Following this, all pigs were given 1,000 IU equine chorionic gonadotropin and 500 IU human chorionic gonadotropin (hCG) and then inseminated. Embryos were recovered 6 or 7 days after hCG treatment and outcome was recorded. There was no significant difference in the number of normal embryos collected from the pigs with PGF2α initiated at different time points or from the control group. Embryonic developmental stages 7 days after hCG treatment also did not differ among groups. These results indicate that the use of EDP to induce pseudopregnancy, followed by PGF2α administration to synchronize estrus for subsequent embryo harvest, is a suitable alternative to the artificial abortion method.

Effect of Topical Prostaglandin F2α Analogs on Selected Oxidative Stress Parameters in the Tear Film.

Background and Objectives: Topically administered antiglaucoma medications, especially those containing benzalkonium chloride (BAC), may cause local adverse effects and compromise ocular surface. The aim of the study was to assess the effect of topical prostaglandin F2α analogs (PGAs): preservative-free latanoprost, BAC-preserved latanoprost, preservative-free tafluprost, and BAC-preserved bimatoprost, on selected oxidative stress parameters in the tear film. Materials and Methods: The patients were divided into five groups: group C (n = 25) control group-subjects who did not use topical antiglaucoma medications, group L (n = 22)-patients using topical preservative-free latanoprost, group L+BAC (n = 25)-patients using topical BAC-preserved latanoprost, group T (n = 19)-patients using topical preservative-free tafluprost, and group B+BAC (n = 17)-patients using topical BAC-preserved bimatoprost. The oxidative stress markers in the tear film samples were evaluated: total protein (TP) concentration, advanced oxidation protein products (AOPP) content, total sulfhydryl (-SH) groups content, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as Total Oxidant Status (TOS), Total Antioxidant Response (TAR), and Oxidative Stress Index (OSI). Results: The TP concentrations in the groups L, L+BAC, and B+BAC were statistically significantly higher in comparison with group C. The SOD and CAT activities in the groups L+BAC and B+BAC were statistically significantly higher when compared to group C. As compared to group C, AOPP and TOS were statistically significantly higher in all the study groups. OSI was found to be statistically significantly higher in the groups L+BAC, T, and B+BAC in comparison with group C. Conclusion: Use of topical PGAs by the patients with ocular hypertension or primary open-angle glaucoma is associated with increased oxidative stress in the tear film which is additionally exacerbated by the presence of BAC in the formulation.

Advantages of Efficacy and Safety of Fixed-Dose Tafluprost/Timolol Combination Over Fixed-Dose Latanoprost/Timolol Combination.

PURPOSE: To compare the safety and efficacy of fixed-dose tafluprost/timolol combination (Taf/T-FDC) with those of fixed-dose latanoprost/timolol combination (Lat/T-FDC) by measuring the intraocular pressure (IOP)-lowering effect, ocular pharmacokinetics, and ocular surface toxicity. METHODS: The IOP-lowering effect of Taf/T-FDC and Lat/T-FDC in ocular normotensive monkeys was evaluated at 4 and 8 h after instillation in study A, at 12, 14, 16, and 18 h after instillation in study B, and at 24, 26, 28, and 30 h after instillation in study C. Drug penetration into the eye was evaluated by measuring the concentrations of timolol, tafluprost acid (active metabolic form of tafluprost), and latanoprost acid (active metabolic form of latanoprost) using liquid chromatography coupled with tandem mass spectrometry after single instillation of Taf/T-FDC or Lat/T-FDC to Sprague Dawley rats. Cytotoxicity following 1-30 min exposure of SV40-transformed human corneal epithelial cells to Taf/T-FDC or Lat/T-FDC was analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays. Undiluted and 10-fold diluted solutions of each FDC were evaluated. RESULTS: The IOP-lowering effect of Taf/T-FDC was almost equivalent to that of Lat/T-FDC at 4-8 h after instillation. The peak IOP reduction of Taf/T-FDC and Lat/T-FDC was observed at 8 h after instillation, and there is no difference between the two. The difference between them was observed at 24-30 h after instillation, and Taf/T-FDC demonstrated a significantly greater IOP-lowering effect than Lat/T-FDC at 24-30 h after instillation. The IOP-lowering effect of Taf/T-FDC was sustained up to 30 h after instillation, while that of Lat/T-FDC had almost disappeared at 28 h after instillation. Timolol concentrations in aqueous humor after Taf/T-FDC instillation were higher than those after Lat/T-FDC instillation (Cmax, 3870 ng/mL vs 1330 ng/mL; AUCinf, 3970 ng·h/mL vs 1250 ng·h/mL). The concentrations of tafluprost acid and latanoprost acid in aqueous humor after instillation of Taf/T-FDC and Lat/T-FDC, respectively, were similar to those after instillation of mono-preparations of tafluprost and latanoprost, respectively. The cytotoxic effect of Taf/T-FDC to the human corneal epithelial cells was significantly lower than that of Lat/T-FDC at all evaluated time points in both undiluted and 10-fold diluted FDCs. CONCLUSION: Taf/T-FDC provides increased IOP-lowering effect duration and lower potential ocular surface toxicity than Lat/T-FDC.

Pharmacokinetics, Efficacy, and Safety of the Preservative-free Fixed Combination of Tafluprost 0.0015% and Timolol 0.5% in Healthy Volunteers: A Phase I Comparison vs. the Corresponding Preservative-free Monotherapies.

PURPOSE: Plasma concentrations of tafluprost acid and timolol were compared after single (Day 1) and repeated (Day 8) instillations of once-daily tafluprost 0.0015%-timolol 0.5% preservative-free (PF) fixed-dose combination (FDC), once-daily PF tafluprost 0.0015%, and twice-daily PF timolol 0.5%. PATIENTS AND METHODS: Fifteen healthy volunteers were randomized to this double-masked, single-center, three-period cross-over study. A wash-out interval of at least 4 weeks separated each three 8-day dosing period. Blood samples were drawn on the first and last day of each dosing period, prior to the morning dose, as well as 5, 10, 15, 30, and 45 min, and 1, 1.5, 2, 4, 8, and 12 h post-dosing. Sample plasma concentrations of tafluprost acid and/or timolol were determined and maximum concentration (C max), area under the concentration-over-time curve from time zero to the last time point with a quantifiable measurement (AUC0-last), and time to maximum concentration were calculated. Intraocular pressure (IOP), adverse events, and ocular/systemic safety variables were also evaluated. RESULTS: Plasma concentrations of tafluprost acid were low, with similar levels measured subsequent to either single or repeated dosing of PF FDC and PF tafluprost. On both sampling days, concentrations peaked at 10 min after the dose, and were cleared from the blood circulation by 30 min; average C max ranged from 17 to 24 pg/mL, and AUC0-last from 3 to 5 pg*h/mL. Plasma concentrations of timolol were comparable after the first dose of PF FDC or PF timolol. Concentrations peaked at 15 min post-dose and diminished in a similar manner after 2 h; average C max was 800 pg/mL and AUC0-last 3900 pg*h/mL. As expected, PF timolol produced a higher Day 8 pre-dose timolol concentration than PF FDC (235 vs. 37 pg/mL; p < 0.001, respectively). The Day 8 post-dose changes in timolol concentrations were relative to this pre-dose difference. All study treatments were well tolerated and safe. PF FDC seemed to provide the best IOP reduction. CONCLUSIONS: PF FDC demonstrated good IOP-lowering efficacy and displayed similar pharmacokinetic characteristics to the monotherapy agents. Exposure to timolol was reduced via the halved dosing.

Benefits of Tafluprost and Timolol Fixed-Dose Combination for the Treatment of Glaucoma Are Confirmed by Studies on Experimental Animal Models.

PURPOSE: To assess the usefulness of 0.0015% tafluprost and 0.5% timolol fixed-dose combination (TT-FDC) for glaucoma, the ocular hypotensive effect of TT-FDC and concentration of tafluprost and timolol in the aqueous humor were compared with those of the concomitant administration of 0.0015% tafluprost and 0.5% timolol with or without an appropriate administration interval. METHODS: The ocular hypotensive effect was assessed by intraocular pressure (IOP) measurement in cynomolgus monkeys. Drug penetration into the aqueous humor was estimated by the concentrations of tafluprost acid (active metabolic form of tafluprost) and timolol, which were measured using liquid chromatography-tandem mass spectrometry after administration of tafluprost and timolol to Sprague Dawley rats. RESULTS: The ocular hypotensive effect of TT-FDC was equivalent to that of the concomitant administration of timolol and tafluprost at a more than 5-min interval in monkeys. However, the ocular hypotensive effect of the concomitant administration of timolol and tafluprost without an interval (-2.8 ± 0.2 mmHg at peak IOP reduction) was significantly weaker compared with TT-FDC (-4.3 ± 0.5 mmHg at peak IOP reduction, P = 0.008 vs. concomitant administration of timolol and tafluprost) in monkeys. The aqueous humor concentration of the second administered drug (tafluprost) was not affected by the dosing conditions, whereas the concentration of the first instilled drug (timolol) without the interval was lower than that with a 5-min interval (1,200 ng · h/mL vs. 1,890 ng · h/mL in AUC0-4) in rats. CONCLUSION: TT-FDC demonstrates a clear benefit by preventing efficacy loss without an appropriate interval in experimental animal models.

Tafluprost: the first preservative-free prostaglandin to treat open-angle glaucoma and ocular hypertension.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, efficacy data, and adverse effect incidence of tafluprost. DATA SOURCES: A literature search was completed using PubMed, Web of Science, and Google Scholar. Tafluprost was the primary search term. Articles published between January 2008 and April 2012 were included in this review. Additional limits placed on the searches were "human" and "English." Citations in which tafluprost appeared in the title were 36, 29, and more than 300 in PubMed, Web of Science, and Google Scholar, respectively. STUDY SELECTION AND DATA EXTRACTION: Three clinical trials were included in this review. One trial enrolled more than 500 subjects in a randomized fashion. Another also enrolled more than 500 subjects, although the study design was not randomized. The third trial evaluated the effects of tafluprost on subjects who had recently discontinued use of latanoprost, another prostaglandin that is approved to treat glaucoma and ocular hypertension. The duration of all 3 trials was 12 weeks. DATA SYNTHESIS: Tafluprost 0.0015% is the first topical prostaglandin approved by the Food and Drug Administration for treatment of open-angle glaucoma and ocular hypertension that does not contain the widely used preservative, benzalkonium chloride (BAK). Although some controversy surrounds the long-term safety of exposure to BAK, clinical trial data are inconclusive. Tafluprost, like other prostaglandin analogues, exerts its effects on prostaglandin F receptors to reduce intraocular pressure (IOP). Results from 1 trial demonstrated significant reductions in IOP when monotherapy was switched to tafluprost monotherapy. Reductions in IOP with tafluprost use were compared with those seen with use of timolol and latanoprost in 2 trials, and noninferiority was observed. Significant reductions in tear osmolarity were noted in subjects who changed from latanoprost, another prostaglandin analogue, to tafluprost therapy. Conjunctival hyperemia is the most common adverse effect seen in patients receiving drugs from this class. Many have also reported stinging, ocular pruritus, increased darkening or growth of eyelashes, and darkening of eyelids, as well as irreversible brown pigmentation of the iris. CONCLUSIONS: Clinical trial data suggest that tafluprost is as efficacious as other agents used in the management of ocular hypertension and glaucoma. Its use may be especially advantageous in people with allergies, sensitivities to preservatives, or dry or sensitive eyes.

Tafluprost: a novel prostaglandin analog for treatment of glaucoma.

OBJECTIVE: The objective of this review is to evaluate the safety and efficacy of tafluprost, a fluoroprostaglandin receptor analog, for reduction of intraocular pressure in open angle glaucoma and ocular hypertension. METHODS: A search of published literature was performed on the PubMed database using the search term "tafluprost." The literature search identified 48 publications, including clinical and preclinical studies, from 2003 to 2011. From these ressults, articles available in the English language and in full text were selected and systematically reviewed by the authors. RESULTS: Recent studies have shown that tafluprost is an effective IOP-lowering medication. Evidence based medicine also reveals that tafluprost is safe and well-tolerated. Preservative-free tafluprost is as potent as the preserved formulation, but with fewer and milder ocular surface side effects. CONCLUSION: Since its introduction in 2008, initial studies have demonstrated that preserved and preservative-free tafluprost formulations have proven efficacy and safety in the treatment of glaucoma and ocular hypertension. Larger studies with longer follow-up are needed to assess long-term safety, efficacy, and tolerability compared with other prostaglandin analogs used for treating glaucoma.

Metabolism and ocular tissue distribution of an antiglaucoma prostanoid, tafluprost, after ocular instillation to monkeys.

PURPOSE: To investigate the metabolism of a new antiglaucoma difluoroprostaglandin, tafluprost, in ocular tissues and evaluate the distribution of the parent drug and its metabolites in ocular and systemic tissues after a single ocular administration to cynomolgus monkeys (Macaca fascicularis). METHODS: A single dose of an ophthalmic solution containing 0.0005%, 0.005%, or 0.05% [(3)H]tafluprost was topically instilled (20 µL/eye) to male and/or female cynomolgus monkeys to study tissue distribution and metabolism. Blood, ocular/systemic tissues, or excreta were collected until 24 h after dosing. The radioactivity of each sample was measured by liquid scintillation counting, and metabolites were characterized by liquid chromatography-mass spectrometry. The major metabolites found in ocular tissues were intracameraly administered to monkeys to confirm their effect on intraocular pressure (IOP). RESULTS: Soon after dosing, high concentrations of drug-related radioactivity were observed in the cornea and bulbar/palpebral conjunctiva, followed by the iris, sclera, choroid with retinal pigmented epithelium, and aqueous humor. The highest concentration of radioactivity concentrations occurred in the anterior and posterior ocular tissues within 2 h after dosing. The radioactivity measured in the plasma and ocular tissues was proportional to the dose administered. The major metabolites of tafluprost identified in the ocular tissues were tafluprost acid and 1,2-dinor- and 1,2,3,4-tetaranor-tafluprost acid. The estimated concentration of tafluprost acid in the aqueous humor and ciliary body was enough to stimulate prostanoid FP-receptors. After hydrolysis to the acid form, the primary metabolic pathway of tafluprost was via ß-oxidation and, subsequently, oxidation. No metabolic reactions to the 15-carbon position were observed. Tafluprost acid was shown to significantly lower the IOP, whereas 1,2-dinor- and 1,2,3,4-tetaranor-tafluprost acid did not. CONCLUSIONS: Topically administered [(3)H]tafluprost was well absorbed into the ocular and systemic tissues of the primary nonclinical species, monkey. The amount of the pharmacologically active form, that is, tafluprost acid, was high enough to occupy the target FP receptors at the site of action. The pharmacokinetic and metabolic properties of this difluorinated prostaglandin in primates are believed to result in clinical benefits of a long-term IOP-lowering effect.

Disposition and metabolism of a novel prostanoid antiglaucoma medication, tafluprost, following ocular administration to rats.

The disposition and metabolism of tafluprost, an ester prodrug of the 15,15-difluoro-prostaglandin F(2alpha) antiglaucoma agent, have been studied in rats after ocular administration. Radioactivity was absorbed very rapidly into the eye and systemic circulation after a single ocular dose of 0.005% [(3)H]tafluprost ophthalmic solution, with maximum levels in plasma and most eye tissues occurring within 15 min. The absorption ratio of radioactivity was approximately 75%, suggesting the high availability of ocular administration of tafluprost. Approximately 10% of the dose was present in cornea at this time, and radioactivity concentrations in this tissue exceeded those in aqueous humor and iris/ciliary body throughout the 24-h study period. After repeated daily ocular doses, radioactivity levels remained greatest in cornea, followed by iris/ciliary body that replaced aqueous humor as the eye tissue containing the second highest radioactivity concentration. In female rats, radioactivity was excreted equally between urine and feces after a single ocular dose, whereas in male rats more was excreted in feces, reflecting the greater biliary excretion in males rats (50% dose) compared with females rats (33% dose). Tafluprost was extensively metabolized in the rat, such that intact prodrug was not detected in plasma, tissues, or excreta by radio-high-performance liquid chromatography. On the other hand, the active moiety, tafluprost acid, was the only noteworthy radioactive component in cornea, aqueous humor, and iris/ciliary body for at least 8 h after the ocular dose, and it was also a major plasma metabolite in early time points. The gender differences in conjugation reactions resulted in the differences in the excretion.

Corneal penetration into rabbit aqueous humor is comparable between preserved and preservative-free tafluprost.

BACKGROUND: Some studies have shown that benzalkonium chloride (BAK), a preservative used in antiglaucoma medications, can increase corneal permeability by acting as a penetration enhancer. Tafluprost is a new prostaglandin F(2)(alpha) analog in clinical use for the treatment of ocular hypertension and glaucoma. METHODS: This study evaluated the corneal penetration of preservative-free tafluprost 0.0015% eye drops and tafluprost 0.0015% eye drops preserved with 0.01% BAK into the aqueous humor of rabbits. RESULTS: After the administration of a single topical dose (30 microl), the maximum concentrations at 45 min of tafluprost acid in aqueous humor were 4.50 ng/ml for preservative-free tafluprost and 3.99 ng/ml for preserved tafluprost. The area under the concentration-time curves from 45 min to 3 h was 5.14 ng h/ml for the preservative-free formulation and 4.54 ng h/ml for the preserved formulation. CONCLUSIONS: These data indicate that BAK does not affect the corneal penetration of tafluprost into the rabbit aqueous humor.

Pharmacokinetics, efficacy and safety profiles of preserved and preservative-free tafluprost in healthy volunteers.

PURPOSE: Prostanoid F(2alpha) (PF(2alpha)) analogues are commonly used as first-line treatment of glaucoma. Tafluprost is a newly synthesized PF(2alpha) derivative and represents the first PF(2alpha) analogue with a fully preservative-free formulation. METHODS: A randomized, investigator-masked, single-centre, crossover phase I study evaluated the pharmacokinetics, efficacy and safety profiles of preserved and preservative-free tafluprost 0.0015% eyedrops in healthy volunteers. Both formulations were administered once/day for 8 days each. Plasma concentrations and, consequently, area under the curve (AUC(0-last)), maximum concentration (C(max)) and time to maximum concentration (t(max)) were determined for tafluprost acid, the biologically active metabolite. Intraocular pressure, adverse events, and ocular and systemic safety parameters were analysed. RESULTS: There were no statistically significant differences in pharmacokinetic parameters between preserved and preservative-free formulations after either single (day 1) or repeated (day 8) dosing. The mean (+/- standard deviation) results for preserved and preservative-free formulations on day 8 were, respectively: AUC(0-last) 581.1 +/- 529.9 pg/min/ml versus 431.9 +/- 457.8 pg/min/ml (p = 0.462); C(max) 31.4 +/- 19.5 pg/ml versus 26.6 +/- 18.0 pg/ml (p = 0.294), and median (range) t(max) 10 (5-15) for both. Generally, plasma concentrations of tafluprost acid were low at all time-points and were cleared rapidly from the circulatory system. There were no unexpected safety findings. The incidence of ocular hyperaemia was similar in both formulations and was of predominantly moderate severity with preserved tafluprost and mild severity with preservative-free tafluprost. CONCLUSIONS: Preservative-free tafluprost appeared to have similar pharmacokinetic properties to the preserved formulation and was generally well tolerated.

New fluoroprostaglandin F(2alpha) derivatives with prostanoid FP-receptor agonistic activity as potent ocular-hypotensive agents.

To find new prostanoid FP-receptor agonists possessing potent ocular-hypotensive effects with minimal side effects, we evaluated the agonistic activities of newly synthesized prostaglandin F(2alpha) derivatives for the prostanoid FP-receptor both in vitro and in vivo. The iris constrictions induced by the derivatives and their effects on melanin content were examined using cat isolated iris sphincters and cultured B16 melanoma cells, respectively. The effects of derivative ester forms on miosis and intraocular pressure (IOP) were evaluated in cats and cynomolgus monkeys, respectively. Of these derivatives, 6 out of 12 compounds were more potent iris constrictors, with EC(50) values of 0.6 to 9.4 nM, than a carboxylic acid of latanoprost (EC(50)=13.6 nM). A carboxylic acid of latanoprost (100 microM) significantly increased the melanin content of cultured B16 melanoma cells, but some 15,15-difluoro derivatives, such as AFP-157 and AFP-172, did not. Topically applied AFP-168, AFP-169 and AFP-175 (isopropyl ester, methyl ester and ethyl ester forms, respectively, of AFP-172) induced miosis in cats more potently than latanoprost. AFP-168 (0.0005%) reduced IOP to the same extent as 0.005% latanoprost (for at least 8 h). These findings indicate that 15,15-difluoroprostaglandin F(2alpha) derivatives, especially AFP-168, have more potent prostanoid FP-receptor agonistic activities than latanoprost. Hence, AFP-168 may be worthy of further evaluation as an ocular-hypotensive agent.

Mechanisms of blood pressure regulation by magnesium in man.

In order to determine the effect and mechanism of Mg on vascular tone, a 3-hour infusion of Mg (200 mg/h) was administered to normal subjects. The Mg infusion resulted in a drop in blood pressure (BP), a rise in renal blood flow, and an increase in urinary 6-keto-PGF1 alpha excretion. Cyclooxygenase inhibition with indomethacin and the calcium channel blocker, nifedipine, prevented these vascular effects of Mg. These data suggest that prostacyclin release via changes in Ca2+ flux may be the mechanism of Mg vasodilatory action. Since angiotensin II (AII) acts via the Ca2+ messenger system, we also studied the effects of Mg loading and dietary Mg depletion on AII responses. Mg loading blunted the rise in BP and the aldosterone-stimulating effect of AII, whereas Mg depletion significantly enhanced these AII effects. These results support the hypothesis that Mg may be an antagonist of the pressor and steroidogenic effects of AII.

Effect of phorbol ester on prostaglandin regulation of proliferation in rabbit endometrial cells.

We have proposed that two of the endogenously synthesized endometrial prostaglandins, prostaglandin F2 alpha (PGF2 alpha) and prostaglandin E1 (PGE1), play a regulatory role in growth control of the endometrium. PGF2 alpha increases DNA synthesis and PGE1 inhibits that effect. Primary cultures of rabbit endometrial cells were used here to examine the effects of the tumor-promoting, diacylglycerol mimicking, phorbol ester, 12-O-tetradecanoyl phorbol-13-acetate (TPA), on the prostaglandin control of cell proliferation. TPA treatment of these cultures results in: a decrease in control levels of proliferation and complete inhibition by TPA of PGF2 alpha stimulated DNA synthesis; a reduction in [3H]PGF2 alpha binding with short term treatment but an increase to above control binding level with long term treatment; an inhibition of the normal PGF2 alpha stimulated inositol polyphosphate synthesis; and a small increase in accumulation of PGF2 alpha in the culture media. Furthermore, in this culture system, TPA does not down regulate [3H]PGE1 binding; it does not alter the normal PGE1 stimulation of cAMP synthesis; and it has no effect on the normal endogenous PGE1 synthesis by these cultures. The above results are consistent with our previous observations that PGF2 alpha works through the intracellular messengers inositol polyphosphate/diacylglycerol whereas PGE1 works through cAMP.

Prostaglandin E2 in induction of labour: a pharmacokinetic study of dose and treatment protocols.

The absorption of administered prostaglandin E2 (PGE2) into the term uterus was analysed, by measurement of intrauterine PGE2 and PGF 2 alpha, in 137 women. Amniotic fluid was sampled after elective Caesarean section, or at rupture of the membranes, and fetal membranes were collected after delivery of the placenta. Within 2 h of administration of a PGE2 pessary (500 micrograms), a significant elevation in amniotic fluid PGE2 was detected. Exogenous PGE2 stimulated the production of intrauterine PGE2 and PGF2 alpha, causing an elevated PGE2 concentration in amniotic fluid, and increased PGF2 alpha in fetal membranes. These studies indicate that the administration of as little as 500 micrograms of PGE2 pessary, resulted in elevated intrauterine PGE2. Exogenous PGE2 (2.5 mg) administration resulted in increased concentrations of PGF2 alpha in the fetal membranes. Considerable local release of PGs was observed at the site of membrane rupture, and this influenced the method of amniotic fluid sampling used in this study.

Intact biliary excretion of gastrically administered prostaglandin F2 alpha in rats: developmental differences.

Tritium-labeled prostaglandin F2 alpha was administered via orogastric tube to bile duct-cannulated suckling and weanling rats to determine if maturational differences were present in the biliary excretion of prostaglandin F2 alpha and metabolites. Animals were killed 2 h after radioactivity administration. Characterization of radioactivity present in bile revealed age-related differences in biliary prostaglandin F2 alpha excretion. Suckling rats had a greater proportion of radioactivity migrating in chromatographic regions of greater polarity than prostaglandin F2 alpha. Compared with the weanling, a significantly greater amount of radioactivity cochromatographed with intact, unmetabolized prostaglandin F2 alpha (33.08 +/- 1.99 vs. 21.38 +/- 1.46). These results indicate that orogastrically administered prostaglandin F2 alpha can be absorbed from the gastrointestinal tract, transported to the liver, and subsequently excreted into bile and detected in an unmetabolized form in suckling and weanling rats. The enterohepatic circulation of milk-derived prostaglandin present in bile may contribute to the overall content of intestinal prostaglandins.

[Evaluation of an in vivo perfusion technic for the dental pulp in rats as validated by demonstration of the release of prostaglandins]. / Mise au point d'une technique de perfusion in vivo de la pulpe dentaire de rat validée par la mise en évidence de la libération de prostaglandines.

Many different biologically active substances contribute to the metabolism of dental pulp. Until now, release of these substances has been evaluated only by in vitro studies. The aim of this study was to establish a technique of perfusion allowing the evaluation in vivo of the secreting activity of dental pulp. In order to validate this technique, the in vivo release of prostaglandins, substances which seem to play a key role in pulpal metabolism was measured. The "push-pull" perfusion technique was used, whereby a physiological medium was made to bath the pulpal surface by aspiration. Pulp was exposed by opening an upper incisor in an anaesthetized rat. The perfusion was kept constant by means of a device composed of cannula, catheters, and micropumps which produced a flow followed by an aspiration of the liquid. Every ten minute fraction was analysed by high performance liquid chromatography. Ten minutes after the beginning of perfusion, the results showed a kinetic for PGE2 and PGF2 alpha release, characterized by a base level of 7.4 +/- 6.7 and 28.6 +/- 12.0 pg/min respectively. These were interrupted by a very high peak as compared to base level (19 times higher for PGE2 and 6.6 times for PGF2 alpha), occurring fifty minutes after trepanation. This experiment is the first attempt made in vivo and in situ, to measure biologically active substances of pulpal origin.