Role of prostaglandin E2 in bronchoconstriction-triggered cough response in guinea pigs.

A feature of cough variant asthma is a heightened cough response to bronchoconstriction. The mediators of this response are unknown. This study was designed to elucidate the role of lipid mediators in bronchoconstriction-triggered cough response in an experimental animal model. We examined the influence of bronchoconstriction on cell components and mediators including prostaglandin E2 (PGE2) in bronchoalveolar lavage fluid (BALF). We studied the cough response to bronchoconstriction (CRB) by measuring the correlation between the increase in enhanced pause (Penh), an index of bronchoconstriction, and cough counts induced by methacholine (Mch) inhalation in conscious guinea pigs. We then examined the effects of intraperitoneal pretreatment with 16, 16-dimethyl-prostaglandin E2 (dm-PGE2) on CRB and cough counts. The total number of cells and cell components in the BALF were not influenced by bronchoconstriction. While levels of PGE2, prostaglandin I2, and cysteinyl leukotrienes were significantly increased, levels of prostaglandin D2, thromboxane B2, and substance P in the BALF were not. Dm-PGE2 significantly decreased the Mch-induced increase in Penh. Following bronchoconstriction by additional Mch inhalation, dm-PGE2 produced an increase in CRB and cough counts in a dose-dependent manner. Additionally, the heightened CRB following dm-PGE2 treatment was suppressed by pretreatment with PGE2 receptor (E-prostanoid EP) -1 and EP-3 antagonists in a dose-dependent manner, but not by EP-2 and EP-4 antagonists. The EP-1 antagonist also decreased cough counts. These results suggest that PGE2 acts as an exacerbating factor for bronchoconstriction-triggered cough. EP1 and EP3 may provide new therapeutic targets for cough variant asthma.

Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles.

The incidence of obesity, which is recognized by the American Medical Association as a disease, has nearly doubled since 1980, and obesity-related comorbidities have become a major threat to human health. Given that adipose tissue expansion and transformation require active growth of new blood vasculature, angiogenesis offers a potential target for the treatment of obesity-associated disorders. Here we construct two peptide-functionalized nanoparticle (NP) platforms to deliver either Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) activator rosiglitazone (Rosi) or prostaglandin E2 analog (16,16-dimethyl PGE2) to adipose tissue vasculature. These NPs were engineered through self-assembly of a biodegradable triblock polymer composed of end-to-end linkages between poly(lactic-coglycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) and an endothelial-targeted peptide. In this system, released Rosi promotes both transformation of white adipose tissue (WAT) into brown-like adipose tissue and angiogenesis, which facilitates the homing of targeted NPs to adipose angiogenic vessels, thereby amplifying their delivery. We show that i.v. administration of these NPs can target WAT vasculature, stimulate the angiogenesis that is required for the transformation of adipose tissue, and transform WAT into brown-like adipose tissue, by the up-regulation of angiogenesis and brown adipose tissue markers. In a diet-induced obese mouse model, these angiogenesis-targeted NPs have inhibited body weight gain and modulated several serological markers including cholesterol, triglyceride, and insulin, compared with the control group. These findings suggest that angiogenesis-targeting moieties with angiogenic stimulator-loaded NPs could be incorporated into effective therapeutic regimens for clinical treatment of obesity and other metabolic diseases.

16,16-Dimethyl prostaglandin E2 efficacy on prevention and protection from bleomycin-induced lung injury and fibrosis.

In this study, we evaluated the protective effect and therapeutic potential of the prostaglandin E(2) (PGE(2)) synthetic analog 16,16-dimethyl-PGE(2) (dmPGE(2)) in the animal model of pulmonary fibrosis induced by bleomycin. Mice subjected to intratracheal administration of bleomycin (1 mg/kg) received a dmPGE(2) dose of 30 microg/kg/day by continuous subcutaneous infusion. Bronchoalveolar lavage (BAL); immunohistochemical analysis for IL-1, TNF-alpha, and nitrotyrosine; measurement of fluid content in lung; myeloperoxidase activity assay; and lung histology were performed 1 week later. Lung histology and Sircol assay for collagen deposition were performed 3 weeks after treatments. Changes of body weight and survival rate were also evaluated at 1 and 3 weeks. Compared with bleomycin-treated mice, dmPGE(2) co-treated mice exhibited a reduced degree of body weight loss and mortality rate as well as of lung damage and inflammation, as shown by the significant reduction of: (1) lung infiltration by leukocytes; (2) myeloperoxidase activity; (3) IL-1, TNF-alpha, and nitrotyrosine immunostaining; (4) lung edema; and (5) histologic evidence of lung injury and collagen deposition. In a separate set of experiments, dmPGE(2) treatment was started 3 days after bleomycin administration, and the evaluation of lung damage and inflammation was assessed 4 days later. Importantly, delayed administration of dmPGE(2) also was able to protect from inflammation and lung injury induced by bleomycin. These results, indicating that dmPGE(2) is able to prevent and to reduce bleomycin-induced lung injury through its regulatory and anti-inflammatory properties, encourage further research to find new options for the treatment of pulmonary fibrosis.

Comparison of prostaglandin and cimetidine in protection of isolated gastric glands against indomethacin injury.

Prostaglandins can protect the in vivo gastric mucosa against necrosis produced by a variety noxious agents. Cimetidine has also been shown to have protective properties in humans and in some models of experimental injury. Whether prostaglandins or cimetidine may protect gastric mucosal cells directly in the absence of systemic factors remains controversial. In the present study, the potential protective actions of prostaglandin and cimetidine against indomethacin injury were assessed in isolated rat gastric glands. Gastric glands were pre-incubated in oxygenated medium with either placebo, 16,16 dimethyl prostaglandin E(2) (dm PGE(2)) or cimetidine and incubated at 37 degrees C in medium containing 0.5 mg/ml of indomethacin for 2, 4 and 6 hrs. Cell injury and protection was assessed by the Fast Green exclusion test (viability test), leakage of lactate dehydrogenase (LDH) into the medium, and by scanning and transmission electron microscopy. In addition, the generation of PGE(2) by the gland cells was determined using RIA assay. Indomethacin by itself significantly reduced the viability of gastric glands, increased LDH release into the medium and produced prominent ultrastructural damage. In contrast to cimetidine, co-incubation of gastric glands with dm PGE(2) added to indomethacin, significantly reduced indomethacin-induced injury, increased the number of viable cells, reduced LDH leakage and diminished the extent of ultrastructural damage. The dose of indomethacin (5 microg/ml) which significantly inhibited the generation of PGE(2) (up to 90% inhibition) had no effect on cell viability nor LDH release. We conclude that 1) exogenous PGE2 exerts a potent protective activity in vitro which is independent on neural, vascular and hormonal factors; 2) inhibition of endogenous PGs may not the primary mechanism in the deleterious action of indomethacin against damage to gastric glandular cells and 3) indomethacin can exert a direct cytotoxic effect on the mucosal cells in gastric glands.

Role of ATP-sensitive potassium channels in prostaglandin-mediated gastroprotection in the rat.

This study compares the involvement of ATP-sensitive potassium (K(ATP)) channels and prostaglandins in various forms of gastroprotection in the rat. Instillation of 1 ml of 70% ethanol induced severe gastric mucosal damage (lesion index 39 +/- 0.8), which was substantially but not maximally reduced by oral pretreatment with 16,16-dimethyl-prostaglandin (PG) E(2) (75 ng/kg), 20% ethanol (1 ml), sodium salicylate (15 mg/kg), the metal salt lithium chloride (7 mg/kg), the sulfhydryl-blocking agent diethylmaleate (5 mg/kg), and the thiol dimercaprol (10 mg/kg). Administration of indomethacin (20 mg/kg) increased gastric mucosal damage induced by 70% ethanol (lesion index 45 +/- 0.8) and significantly reduced the protective effect of 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The blocker of K(ATP) channels glibenclamide (5-10 mg/kg) significantly antagonized the protective effect of 16,16-dimethyl-PGE(2), 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The inhibition of protection induced by glibenclamide was reversed by pretreatment with the K(ATP) channel activator cromakalim (0.3-0.5 mg/kg). In conclusion, our results indicate a role of K(ATP) channels in the gastroprotective effect of 16,16-dimethyl-PGE(2) and of the other agents tested. Since the protection afforded by these agents is additionally indomethacin-sensitive, it is suggested that under these conditions endogenous prostaglandins act as activators of K(ATP) channels, and this mechanism, at least in part, mediates gastroprotection.

Secretion of the trefoil factor TFF3 from the isolated vascularly perfused rat colon.

The trefoil factor TFF3 is a peptide predominantly produced by mucus-secreting cells in the small and large intestines. It has been implicated in intestinal protection and repair. The mechanisms that govern TFF3 secretion are poorly understood. The aim of this study was, therefore, to evaluate the influence of neurotransmitters, hormonal peptides and mediators of inflammation on the release of TFF3. For this purpose, an isolated vascularly perfused rat colon preparation was used. After a bolus administration of 1 ml isotonic saline into the lumen, TFF3 secretion was induced by a 30-min intra-arterial infusion of the compounds to be tested. TFF3 was evaluated in the luminal effluent using a newly developed radioimmunoassay. TFF3 was barely detected in crude luminal samples. In contrast, dithiothreitol (DTT) treatment of the effluent revealed TFF3 immunoreactivity, which amounted to about 0.3 pmol min(-1) cm(-1) in the basal state. Gel chromatography of DTT-treated luminal samples revealed a single peak that co-eluted with the monomeric form of TFF3. TFF3 was not detected in the portal effluent. Bethanechol (10(-6)-10(-4) M), vasoactive intestinal peptide (VIP, 10(-8)-10(-7) M) or bombesin (10(-8)-10(-7) M) induced a dose-dependent release of TFF3. In contrast, substance P evoked a modest release of TFF3, whereas calcitonin gene-related peptide (CGRP), somatostatin, neurotensin or peptide YY (PYY) did not modify TFF3 secretion. The degranulator compound bromolasalocid, 16,16-dimethyl PGE2 (dmPGE2) or interleukin-1-beta (IL-1-beta) also evoked a marked release of TFF3. In conclusion, TFF3 in the colonic effluent is present in a complex. This association presumably involves a disulfide bond. Additionally, the present results suggest a role for enteric nervous system and resident immune cells in mediation of colonic TFF3 secretion.

A multicentre randomized comparative clinical trial of 200 mg RU486 (mifepristone) single dose followed by either 5 mg 9-methylene PGE(2) gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of early pregnancy within 28 days of missed menstrual period. ICMR Task Force Study. Indian Council of Medical Research.

A multicentre, randomized, comparative clinical trial of 200 mg RU486 (Mifepristone) followed 48 h later by either 5 mg 9-methylene PGE(2) vaginal gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of pregnancy within 28 days of the missed period, was carried out through the Indian Council of Medical Research's (ICMR) network of Human Reproduction Research Centres (HRRCs). A total of 893 subjects were assessed regarding their therapeutic responses to the two different treatment groups. The results indicated a success rate of 84.6% among 453 women treated with RU486 followed by 9 methylene PGE(2) vaginal gel, that was not significantly different from the success rate of 87.7% observed in 440 women treated with RU486 followed by oral PGE(1). The majority of study subjects (90%) started bleeding within 72 h. About 26% of the subjects had started bleeding before the administration of any prostaglandin. The average duration of bleeding in all the subjects was about 7 days. No life threatening side effects were observed among the subjects in two treatment groups. Gastro-intestinal complaints were reported more often by women treated with oral PGE(1) as compared to those treated with 9-methylene vaginal PGE(2) gel; nausea occurred in 25.7% and 19.2%, vomiting in 6.8% and 4.6%, and diarrhoea in 4.8% and 0.9% of the subjects in the 2 treatment groups, respectively. Fever higher than 38 degrees C and severe abdominal pain were reported by 4.2% and 5.0% of all subjects treated, respectively. Intravenous infusion of glucose and saline was required by 6 subjects in each treatment of the prostaglandin treated groups. Blood transfusion was required in 2 subjects, one in each treatment group, for profuse bleeding.

Topical prostaglandin E2 protects isolated gastric mucosa against acidified taurocholate-, but not ethanol- or aspirin-induced injury.

This study investigates whether topical prostaglandins protect isolated gastric mucosa against injury provoked by acidified "barrier-breaking" agents. Intracellular pH (pHi), apical cell membrane potential (Vcm) and intraepithelial resistances in isolated Necturus antral mucosa were measured using double-barreled liquid sensor microelectrodes. Topical PGE, treatment protected the antral mucosa against acidified taurocholate-induced injury, reducing significantly (P<0.05) intracellular acidification (pHi from 7.39+/-0.05 to 7.08+/-0.08 vs. from 7.30+/-0.02 to 6.62+/-0.15), and opposing significantly the changes in Vcm (hyperpolarization followed by depolarization), and completely abolishing the decrease in transmembrane resistance (Rt from 702+/-37 to 723+/-39 Ohms x cm2 vs. from 721+/-34 to 270+/-105 Ohms x cm2). Also the ratio of apical and basolateral membrane resistances (Ra/Rb) remained at a significantly higher level in PGE2-treated tissues. In contrast, PGE2 treatment had no protective influence on the changes of the respective parameters in acidified ethanol or acetylsalicylic acid injured mucosas. Topical prostaglandin E2 protects isolated gastric mucosa against acidified taurocholate, but not against ethanol- or acetylsalicylic acid-induced injury.

Early abortion by mifepristone (RU 486) followed by vaginal gel (meteneprost) versus oral (misoprostol) prostaglandin.

The present study was conducted to compare the therapeutic regimens of low-dose mifepristone (200 mg) plus vaginal meteneprost versus oral misoprostol in terms of efficacy and safety for medical termination of early pregnancy. A randomized clinical trial was conducted by the Department of Obstetrics and Gynecology at the All India Institute of Medical Sciences, New Delhi. A total of 101 subjects were enrolled within 56 days of amenorrhea. A single dose of 200 mg of mifepristone (RU 486) was given and, 48 hr later, prostaglandin was administered as either 5 mg of 9 methylene PGE2 vaginal gel, meteneprost (classified as group I) or 600 microg of oral PGE1 derivative misoprostol (classified as group II). In group I, 50 subjects and in group II, 51 subjects were treated with the respective schedule. The success rate with mifepristone + misoprostol (group II) was 88.63% which was significantly higher than that with mifepristone + meteneprost (group I) which was 82% (p < 0.05). The average duration of bleeding in cases with complete abortion was 8.95+/-5.67 and 9.77+/-6.51 in group I and II, respectively. There were no serious side-effects. Only one subject in group I (2%) required blood transfusion for heavy bleeding. This study indicated that oral prostaglandin after a low dose of mifepristone (200 mg) could be developed into an effective method to terminate early pregnancy. Oral administration of both drugs would be a more convenient, feasible, private and acceptable regimen.

Absorption, retention and urinary excretion of chromium-51 in rats pretreated with indomethacin and dosed with dimethylprostaglandin E2, misoprostol or prostacyclin.

Drug-nutrient interactions affecting chromium were investigated in this study. Rats were injected with indomethacin to reduce endogenous prostaglandin synthesis and dosed with prostaglandin analogues or prostacyclin. Effects on absorption, tissue distribution and urinary excretion of 51Cr from 51CrCl3 were evaluated using a 2 x 4 factorial experimental design. Forty-eight adult male rats were food deprived for 12 h and then injected intraperitoneally with indomethacin (5 mg/kg body wt) or placebo. Thirty minutes later, rats were intubated and dosed with one of four treatments: a prostaglandin E1 analogue (misoprostol) at 50 microg/kg body wt; a prostaglandin E2 analogue (16,16-dimethylprostaglandin E2) at 7.5 microg/kg body wt; prostacyclin at 20 microg/kg body wt; or control (7.64 mmol/L Tween-80 suspended in 0.15 mol/L NaCl containing 0.48 mol/L ethanol). Immediately after intubation, rats were dosed with 3.7 mBq of 51CrCl3 by micropipette. Blood was collected from the tail at intervals after 51Cr dosing. Six hours after dosing, 51Cr rats were exsanguinated by cardiac puncture. Indomethacin, an inhibitor of prostaglandin synthesis, significantly increased (P < 0.05) 51Cr in blood at all time periods tested except at 15 min. In tissues, indomethacin significantly increased 51Cr retention. Urinary 51Cr excretion at 6 h was higher (P < 0.05) in indomethacin-pretreated rats than in control rats. Administration of indomethacin, which blocks prostaglandin synthesis, enhanced 51Cr absorption, whereas dosing with 16,16-dimethylprostaglandin E2 decreased 51Cr absorption.

Analysis of 16,16-dimethylprostaglandin E2-induced diarrhea in cecectomized rats.

The 16,16-dimethylprostaglandin E2 (dmPGE2)-induced diarrhea was analyzed in cecectomized rats prepared by resecting the cecum and its vasculature without disturbing the ileocecal junction. dmPGE2 (0.1-1.0 mg/kg, p.o.) dose-dependently increased the number of defecation episodes and induced a soft and watery stool in cecectomized rats. At 0.3 mg/kg, the diarrhea-inducing effects of dmPGE2 were more pronounced in cecectomized than in control rats. When given i.p., dmPGE2 (0.3 mg/kg) induced a watery stool in cecectomized and control rats with the same efficacy, although these effects were short-lasting as compared to oral administration. Castor oil (4 ml/kg, p.o.) also induced diarrhea, but did not produce a watery stool in cecectomized rats. There were no differences between cecectomized and control rats in basal small intestinal transits or in dmPGE2 (0.3 mg/kg, p.o.)-induced enhancements. Moreover, the basal and dmPGE2-induced jejunal net fluid transfers were the same in cecectomized and in control rats. On the other hand, the enhanced secretion of colonic fluid by dmPGE2, given intraluminally, was only half of that in control rats, whereas the colonic transit-enhancing effect of dmPGE2 in cecectomized rats was more pronounced than in control rats at 15 but not at 30 min after its administration. The basal colonic fluid contents and transits were the same in cecectomized and in control rats. Loperamide and morphine (0.1 and 1.0 mg/kg, s.c.) inhibited the dmPGE2 (0.3 mg/kg, p.o.)-induced diarrhea in cecectomized rats. N-methyllevallorphan (5 mg/kg, s.c.) completely antagonized the inhibitory effect of loperamide and partly antagonized the effect of morphine. These results suggest that oral administration of dmPGE2 induces a more pronounced secretory diarrhea in cecectomized than in control rats, probably due to the lack of the reservoir function of the cecum in the operated animals. This secretory diarrhea model is suitable for evaluating the antidiarrheal activity of drugs.

A multicentre clinical trial with RU 486 followed by 9-methylene-PGE2 vaginal gel for termination of early pregnancy: a dose-finding study. Indian Council of Medical Research Task Force on Hormonal Contraception.

A dose-finding study was carried out with two different doses of RU 486 (200mg or 600mg) each in combination with two doses of 9-methylene-PGE2 gel (3mg or 5mg) for termination of pregnancy between 7 to 28 days after missed menstrual period. It was observed that the success rates with 200mg RU 486 followed by 5mg 9-methylene-PGE2 gel were 94.5% and 89.6% in women with 7-14 days and 15-28 days of missed menstrual period, respectively. These rates were similar to those observed with 600mg RU 486 given along with 3mg or 5mg 9- methylene-PGE2 gel and were significantly higher than those observed with 200mg RU 486 given along with 3mg 9-methylene-PGE2 gel. All subjects except four started bleeding following the treatment. The average duration of bleeding in subjects with successful outcome (complete abortion) ranged between 7.0 to 11.8 days in the four different treatment schedules. There were no serious side effects with any of the treatment schedules; only one subject required transfusion of one unit of blood for heavy bleeding. The immediate and delayed complication rates were similar with the four treatment schedules.

Topical or systemic 16, 16 dm prostaglandin E2 or WR-2721 (WR-1065) protects mice from alopecia after fractionated irradiation.

Our previous studies in mice demonstrated that systemic or topical 16,16 dm PGE2 protected against single dose radiation-induced hair loss. We have now investigated prostaglandin, or WR-2721, protection against murine alopecia produced by varying doses and schedules of fractionated radiation. On days one to eight after hair was plucked from the thighs of B6D2F1 mice, groups of 6 animals each were given daily exposures of 4.0 or 4.5 Gy for 5 days; 2.5, 3.5, 4.5 or 5.5 Gy for 10 days; or 2 Gy for 15 days. One hour before irradiation each mouse received 10 microgram 16,16 dm PGE2, either by subcutaneous injection into the neck or topical application, 8 mg WR-2721 by injection, or 0.3 mg WR-1065 by topical application. Three weeks later counts of regrowing hairs were recorded from excised skin samples. For the radioprotectors used, hair regrowth was increased 25-100% in the various radiation groups in comparison to irradiated-only control sites. In some studies with the radioprotector given systemically, WR-2721 afforded slightly greater radioprotection than 16,16 dm PGE2. The two compounds were essentially equally radioprotective in the topical application studies. Since both systemic and topical applications of the agents tested enhanced hair regrowth following radiation, we conclude that clinical use of these compounds may provide some protection of hair follicles, and perhaps other tissues, lying within a radiation therapy field.

Subcutaneous or topical administration of 16,16 dimethyl prostaglandin E2 protects from radiation-induced alopecia in mice.

Alopecia, a common sequel of radiation treatment of brain tumors, increases patient stress to the extent that refusal of treatment may occur. The expectation that loss of hair will be prevented, or that regrowth will occur, is extremely important to patients. To investigate prostaglandin-induced radiation protection against alopecia, the hair of B6D2F1 male mice was plucked from the right thigh and surrounding area to induce anagen. Fourteen days later, mice were injected subcutaneously in the neck with 10 micrograms 16,16 dm PGE2 in 0.2 ml of vehicle, or with the vehicle alone. In another group of previously plucked mice, 16,16 dm PGE2 in the same concentration, or the vehicle was applied topically. One hour later, graded single doses from 6.5 to 12.5 Gy 137Cs gamma irradiation were given to groups of six animals. On day 21 post-plucking, all animals were killed and a portion of the irradiated site was excised. The average hair counts per field in irradiated animals were 85 +/- 4 (6.5 Gy), 25 +/- 5 (8.5 Gy), and 5.5 +/- 0.7 (10 Gy). Animals receiving the prostaglandin systemically had values of 60 +/- 10 (6.5 Gy), 54 +/- 3 (8.5 Gy), 66 +/- 6 (10 Gy), and 30.1 +/- 8 (12.5 Gy). Topical application of the prostaglandin resulted in protection that yielded 52 +/- 3 (8.5 Gy), 34 +/- 4 (10 Gy), and 3.2 +/- 0.9 (12.5 Gy) hairs per field. Both systemic and topical application of 16,16 dm PGE2 protected from some degree of radiation-induced alopecia, which supports the conclusion that prostaglandins may be useful in the protection of hair follicles in patients treated with radiation for brain tumors.

The effect of dopamine in a model of biliary acute hemorrhagic pancreatitis.

Perfusion of the main pancreatic duct in cats with a dilute solution of bile salts increases ductal permeability. Subsequent perfusion of a permeable duct with activated pancreatic enzymes results in acute edematous pancreatitis. Simultaneous infusion of 16-16 dimethyl-PgE2 converts edematous pancreatitis to acute hemorrhagic pancreatitis (AHP). AHP may be associated with a reduction in pancreatic blood flow; it is certainly associated with increases in microvascular permeability. Low dose dopamine is a splanchnic vasodilator and may also reduce pancreatic microvascular permeability through beta agonist effects. In these studies, we investigated the effect of dopamine in an established feline model of biliary AHP. We also studied its effect on blood flow in both normal pancreas and after induction of AHP. We found that dopamine significantly reduced the degree of pancreatic inflammation, even when administered up to 12 h after onset of biliary AHP. However, the drug had no significant effect on blood flow either in normal pancreas or in the gland affected by hemorrhagic pancreatitis. We concluded that the effect of dopamine was most likely due to its ability to reduce pancreatic microvascular permeability.

A study of the time course of conversion of edematous to hemorrhagic pancreatitis.

We studied the conversion of acute edematous pancreatitis (AEP) to acute hemorrhagic pancreatitis (AHP) in an experimental model in cats. In the model, 16,16 dimethyl PgE2 effects this conversion by increasing microvascular permeability. First, we induced AEP in cats and then gave PgE2 at increasing intervals after the induction of AEP to see how long an interval would still allow conversion. In 6 groups of cats, PgE2 was administered for 2 h, starting at 2, 4, 6, 8, 10, or 12 h after the creation of AEP. Twelve h later, the cats were sacrificed and the pancreases were graded for inflammation and hemorrhage. Significant pancreatic hemorrhage did not occur when the PgE2 was administered at 12 h compared to 2 h. Next, we determined that PgE2 still retained its ability to increase pancreatic vascular permeability when administered 12 h after the creation of AEP. This was done by perfusing a marker molecule through the MPD (fluorescein isothiocyanate labeled dextran: FITC-D, mol wt 20,000) and then finding it in portal venous blood (PVB). The presence of FITC-D in PVB signified increased vascular permeability, since normally none was present. We concluded that conversion of AEP to AHP was possible during the first 12 h after induction of AEP. Lack of conversion at 12 h was not caused by a lack of vascular reactivity at that time.

The use of antiprogestin (RU 486) for termination of second trimester pregnancy.

Pretreatment with laminaria tent is often used in prostaglandin-induced second-trimester abortion to increase efficacy and shorten induction-to-abortion time. In the present study, two alternatives to soften the cervix and dilate the cervical canal, the antiprogestin RU 486 and intra-cervical application of PGE2, were studied. The study included 71 women requesting legal abortion in the 15th to 23rd week of pregnancy who were treated with repeated vaginal applications of 9-methylene PGE2 in a hydrophilic gel (5 mg every 4th hour) following pretreatment with 200 mg of RU 486 and/or intracervical administration of 0.5 mg of PGE2 gel. The mean interval from start of vaginal prostaglandin treatment to abortion was 13.2 h after intracervical PG-treatment, 10.0 h after antiprogestin and 6.6 h after the combined pretreatment. Patients who received pretreatment with RU 486 alone or in combination with intracervical PGE2 experienced the lowest frequency of episodes of vomiting. Of these two pretreatment alternatives, RU 486 alone has the advantage of a shorter hospital stay. It can be concluded that vaginal administration of 9-methylene PGE2 after pretreatment with RU 486 was a highly effective, safe and rapid procedure for termination of mid-trimester pregnancy, was well tolerated by the patients and was associated with few side effects.

Termination of early pregnancy through a combination of the antiprogestin and prostaglandin analogue.

Termination of early pregnancy (less than 49 days of amenorrhea) was induced in 75 patients with the combination of the antigestagen mifepristone and a prostaglandin analogue, meteneprost. After 48 h a single oral dose of 600 mg of mifepristone was followed by a 10 mg meteneprost vaginal pessary. Pregnancy was confirmed by clinical and ultrasound examinations and plasma HCG assessment. Complete abortion occurred in 72 patients (96%) and the three others required a surgical uterine aspiration. Bleeding continued for 4 to 12 days (mean = 8). Uterine pain and side effects occurred during the 3 h following the use of prostaglandin. Only minor analgesic were required in 30 patients. The combination of mifepristone and meteneprost is a safe and effective method to terminate an early pregnancy.

PIP: Termination of early pregnancy (49 days of amenorrhea) was induced in 75 patients with the combination of the antigestagen mifepristone and a prostaglandin (PG) analogue, meteneprost. After 48 hours, a single oral dose of 600 mg mifepristone was followed by a 10 mg meteneprost vaginal pessary. Pregnancy was confirmed by clinical and ultrasound examinations and plasma hCG assessment. Complete abortion occurred in 72 patients (96%) and the 3 others required a surgical uterine aspiration. Bleeding continued for 4-12 days (mean=8). Uterine pain and side effects occurred during the 3 hours following the use of PG; only minor analgesics were required in 30 patients. The combination of mifepristone and meteneprost is a safe and effective method of terminating and early pregnancy.

Prostaglandin E2 inhibits in vitro and in vivo lymphocyte responses in allogeneic transplantation.

Prostaglandin E2 (PGE2) has been shown to a clear role in the suppression of immune responses after burn and trauma injury. This probably results from inhibition of interleukin-2 production. This study examined the effects of PGE2 in vivo on the survival of solid-organ allografts and in vitro on the rat allogeneic mixed lymphocyte response. Administration of 16,16-dimethyl prostaglandin E2 (DMPGE2), a stable analogue of PGE2, significantly prolonged the survival of heterotopic cardiac allografts from ACI to LBN rats: 10.4 +/- 1.7 days versus 5.7 +/- 1.1 days (mean +/- standard error of the mean) (p less than or equal to 0.001). In 1 animal, DMPGE2 apparently led to the induction of long-term tolerance. Mixed lymphocyte cultures using splenocytes from naive LBN and ACI rats to which DMPGE2 was added showed a dose-dependent suppression of the mixed lymphocyte response with concentrations as low as 1 x 10(-7) mol/L. Splenocytes harvested from treated animals with functioning but histologically rejecting hearts demonstrated a marked decrease in mixed lymphocyte response to donor (ACI) stimulators compared with naive LBN controls (3,804 +/- 603 versus 27,395 +/- 2,668 cpm, n = 4), but maintained a normal response to third-party (Wistar Furth) stimulators. We conclude that DMPGE2 suppressed solid-organ allograft rejection, inhibited the allogeneic mixed lymphocyte response, and induced donor-specific in vitro hyporesponsiveness.