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Introduction: Discussion of the relevance of suitable experimental models for the effective translation of drug effects to clinical inflammatory diseases has a long history. Much emphasis is placed these days on genetically transformed mice, which may have developmental drawbacks. But are established models redundant?, Findings: Drawn from personal experience, examples are provided of the success of tinkering with technology in the context of inflammation. These include the use of specific dietary deficiency conditions, the development of new applications for established drugs and the introduction of a variety of readouts to assess outcome in studies on established disease models. Such approaches have been used to demonstrate inflammation-modulating effects of prostaglandin E, in the development of ebselen, for the introduction of immunomodulatory macrolide drugs and in new approaches to the therapy of multiple sclerosis., Conclusion: Fine tuning of experimental approaches and evaluation technologies can often still provide innovative, clinically relevant insights into the potential beneficial effects of drugs and pharmacological agents.

People with diabetes are more prone to Staphylococcus aureus skin infection than healthy individuals. Control of S. aureus infection depends on dendritic cell (DC)-induced T-helper 17 (Th17)-mediated neutrophil recruitment and bacterial clearance. DC ingestion of infected apoptotic cells (IACs) drive prostaglandin E 2 (PGE 2 ) secretion to generate Th17 cells. We speculated that hyperglycemia inhibits skin DC migration to the lymph nodes and impairs the Th17 differentiation that accounts for poor skin host defense in diabetic mice. Diabetic mice showed increased skin lesion size and bacterial load and decreased PGE 2 secretion and Th17 cells compared with nondiabetic mice after methicillin-resistant S. aureus (MRSA) infection. Bone marrow-derived DCs (BMDCs) cultured in high glucose (25 mmol/L) exhibited decreased Ptges mRNA expression, PGE 2 production, lower CCR7-dependent DC migration, and diminished maturation after recognition of MRSA-IACs than BMDCs cultured in low glucose (5 mmol/L). Similar events were observed in DCs from diabetic mice infected with MRSA. Topical treatment of diabetic mice with the PGE analog misoprostol improved host defense against MRSA skin infection by restoring DC migration to draining lymph nodes, Th17 differentiation, and increased antimicrobial peptide expression. These findings identify a novel mechanism involved in poor skin host defense in diabetes and propose a targeted strategy to restore skin host defense in diabetes., (© 2016 by the American Diabetes Association.)

Aims: Prostanoids are indicated in the treatment of peripheral arterial disease (PAD). Available trials suggest that these compounds could reduce the symptoms of intermittent claudication, even though the quality of studies is poor. The present meta-analysis is aimed at verifying the effects of prostanoids on amputation rate and ulcer healing in patients with lower limb PAD., Materials and Methods: The review protocol was published on http://www.crd.york.ac.uk/prospero (CRD42015020258). A comprehensive search for published and unpublished trials comparing iloprost, alprostadil, prostaglandin-E1, epoprostenol, or taprostene with placebo/no therapy on amputation rate in patients with PAD and ulcer healing rate in patients with concomitant foot ulcers. Mantel-Haenzel odds ratio (MH-OR) was calculated with random effect models for the chosen endpoints., Results: A total of 18 trials, enrolling 3,077 and 2,763 patients in the prostanoid and comparator groups, respectively were included in the analysis. Only 11 and 10 of those trials reported data on total and major amputations, respectively. Prostanoids were associated with a significantly lower risk of major (MH-OR [95% confidence interval] was 0.77 [0.63; 0.93], p=0.007), but not total, amputations. Healing rate (available only in 7 trials) was not significantly augmented by prostanoid treatment., Conclusions: Available data are not sufficient to support an extensive use of prostanoids in patients with critical limb ischemia, as an adjunct to revascularization or as an alternative to major amputation in cases which cannot undergo revascularization., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To localize different prostaglandin E(2) receptors in rat retinas of varying age, deduce how they are affected by acute stress insult, and determine whether the negative effect of ischemia/reperfusion is attenuated by the EP2 agonist butaprost., Methods: Ischemia was induced by the elevation of intraocular pressure. Butaprost was injected intravitreally immediately after ischemia. Standard methods were used for recording of electroretinograms (ERGs) and processing of immunohistochemistry. Extracts of whole retinas were analyzed for specific proteins by Western blotting or by RT-PCR for defined mRNAs., Results: The localization of different EP receptor types is similar in retinas of all aged rats. However, differences exist in the monomer/dimer ratios in retinas of different age. Acute stress insult (48 hours after ischemia) affects the ratio of monomer/dimer of all EP receptor types and increases EP2 and EP3 immunoreactivities in Müller cells of the adult retina. Ischemia and 5 to 7 days of reperfusion to the retina caused the normal ERG and the localization of nNOS and ChAT immunoreactivities to be affected. Certain proteins and mRNAs were lowered in content, whereas other proteins and mRNAs were upregulated. In addition, specific optic nerve proteins were drastically reduced. Most of these changes induced by ischemia/reperfusion were significantly blunted by butaprost., Conclusions: All subtypes of EP receptors exist primarily in the inner retina at different ages, but their monomer/dimer ratios vary. Stress affects the monomer/dimer ratio and EP2 and EP3 immunoreactivities in Müller cells. Butaprost injected intravitreally significantly blunts the detrimental influence of ischemia/reperfusion to the retina.

Background: There is no known preventive agent against nonsteroidal anti-inflammatory drug (NSAID) induced small-intestinal injury., Objective: To evaluate by capsule endoscopy whether coadministration of prostaglandin (PG) can prevent small-intestinal damage induced by short-term NSAID treatment., Design: Single-blind, randomized, controlled trial., Setting: All procedures were performed at Nippon Medical School., Subjects: Thirty-four healthy male volunteers., Methods: All subjects were randomly assigned to 2 groups: an NSAID-control group, who underwent NSAID (diclofenac sodium, 25 mg 3 times daily) and omeprazole (20 mg once daily) treatment, and an NSAID-PG group, who received PG (misoprostol, 200 microg 3 times daily) in addition to the same NSAID-omeprazole treatment. Eligible subjects, 15 per group, underwent capsule endoscopy before and 14 days after treatment., Main Outcome Measurements: The number of mucosal breaks at capsule endoscopy., Results: NSAID treatment significantly increased the mean (SD) number of mucosal breaks per subject, from a basal level of 0.1 +/- 0.3 up to 2.9 +/- 6.3 lesions in the NSAID-control group (P = .012). In contrast, there was no significant change in the mean number of mucosal breaks before and after PG cotreatment (P = 0.42). Thus, the mean number of posttreatment mucosal breaks per subject was significantly higher in the NSAID-control group than in the NSAID-PG group (P = .028). There was a significant increase in the percentage of subjects in the NSAID-control group, with at least 1 mucosal break after treatment (from 6.7% to 53.3%), whereas there was no change in the incidence of mucosal breaks in the NSAID-PG group, which remained at 13.3%. (P = .002)., Limitations: Single-center, open-label study., Conclusions: PG cotherapy reduced the incidence of small-intestinal lesions induced by a 2-week administration of diclofenac sodium.

Pharmacological approaches to the treatment of ARDS are reviewed. Future treatments should be targeted at elements of the pathological process that produce specific clinical problems.

Unlabelled: IV prostaglandin E1 improves clinical symptoms in patients with spinal canal stenosis. In the present study, we assessed the effects of OP-1206 alpha-CD, an orally active prostaglandin E1 analog, on walking dysfunction in the rat neuropathic intermittent claudication model. To induce spinal stenosis, two pieces of silicon rubber were placed in the lumbar (L4-6) epidural space in rats. Postsurgical walking function was measured using a treadmill apparatus. Spinal cord blood flow (SCBF) and skin blood flow (SKBF) were measured using a laser-Doppler flowmeter. OP-1206 alpha-CD was administered orally bid for 11 days from postoperative Day 3. In Control nontreated rats, a significant walking dysfunction was observed from Day 1 after the induction of spinal stenosis and persisted for 14 days when compared with the Sham-Operated group. On postoperative Day 15, SCBF revealed a significant reduction in the territory of spinal stenosis, although SKBF was not affected. OP-1206 alpha-CD significantly improved walking dysfunction on postoperative Days 5 (300 microg/kg), 7 (150 and 300 microg/kg), and 14 (150 and 300 microg/kg) when compared with the Vehicle-Treated group. On postoperative Day 15, the decrease in SCBF was significantly (150 and 300 microg/kg) improved by OP-1206 alpha-CD treatment, albeit SKBF remained unaffected. These data show that oral treatment with OP-1206 alpha-CD is effective in improving walking dysfunction induced by spinal canal stenosis, and this therapeutic effect is likely mediated by improved SCBF at the territory of spinal stenosis., Implications: Intermittent motor dysfunction is a clinical symptom associated with partial spinal compression. The present study provides evidence that oral treatment with the prostaglandin E1 analog (OP-1206 alpha-CD) is effective in improving motor dysfunction and spinal cord blood flow in rats with spinal compression.

Objective: To evaluate which vasoactive agents have synergistic effects on the cavernosal smooth muscles of rabbits and rats when the agents are combined with sildenafil., Materials and Methods: Relaxation responses of cavernosal smooth muscle to single agents (phentolamine, moxisylyte, sodium nitroprusside, forskolin, vasoactive intestinal peptide, VIP, papaverine and sildenafil) in the rabbit, and prostaglandin-E1 and sildenafil in the rat, and to combinations of each agent plus sildenafil, were assessed in vitro. The response to sildenafil of the rabbit strips with and without incubation with l-arginine (1 mmol/L) for 20 min was also evaluated. The effective concentrations for a half-maximal response of single agents and combination solutions were compared., Results: All single agents induced concentration-dependent relaxation of the rabbit and rat cavernosal smooth muscles. There was significant synergism on rabbit cavernosal smooth muscle when the sildenafil was combined with forskolin, sodium nitroprusside, VIP or phentolamine. There was also significant synergism with sildenafil plus prostaglandin-E1 in rat cavernosal muscles. There were no synergistic effects of combinations of sildenafil plus moxisylyte, papaverine or l-arginine., Conclusions: These results suggest potentially effective combined therapies of sildenafil and intraurethral or intracavernosal prostaglandin-E1, intracavernosal forskolin or VIP, or oral phentolamine for patients with erectile dysfunction who have no success after monotherapy with these agents.

The diagnosis and treatment of chronic glomerulonephritis (CGN) have come to be based on apparent manifestations of the disease. It is most important that the disease be identified early in its course depending on the stage of bodily adaptational processes in CGN patients. A study into adaptational reactions of the organism was made together with ways for correction thereof using medicamentous and nonmedicamentous modes of treatment. As a result of the examination conducted and treatments administered there have been secured certain regularities showing a clear relation to the type of bodily unspecific adaptational reaction and clinical manifestations of the affliction.

The aim of the retrospective analysis is to estimate the results of PGE treatment/or cervical ripening with Bishop score < or = 4--effectiveness and safety. The research includes 60 patients with different induction indications. The comparative analysis has been carried out between 2 groups of patients with premature ruptiere of the ammotic membranes. The first group includes 22 patients treated only with Pg; and the second one includes 18 patients treated only with....

The authors have examined 48 patients aged 17-70 years with erectile disorders. In 15 cases sexual adaptation was achieved after teaching them autoinjections. Pharmacological aid with PGE1 (Edex, Caverject) proved effective for sexual adaptation of patients with erectile disorders. In case of well adjusted dose and strict compliance of the autoinjection regimen the number of complications was minimal. In 50-70-year-olds PGE1 do not cause systemic complications due to pharmacokinetics and endogenic nature of PGE1. This prostaglandin is highly effective in some forms of psychogenic erectile dysfunction especially in expecting failure. For such patients 1 or 2 autoinjections of minimal dose are enough to correct erection.

Prostaglandin E1 (PGE1) is commonly used in therapy for obstructive diseases, including ischemic retinopathy, in which pathogenetic reactive oxygen intermediates are responsible. However, the mechanism(s) of PGE1 in reducing tissue damage is still unclear. Adult T-cell leukemia-derived factor/human thioredoxin (ADF) is induced by oxidative stresses and has protective activity against oxidative cellular injury. To evaluate the possible involvement of ADF in the tissue-protective effect of PGE1, we analyzed ADF expression immunohistochemically using a rat transient retinal ischemia model. Rats were treated orally with 300 micrograms/kg/day OP-1206 alpha-cyclodextrin clathrate (OP-1206), a stable PGE1 analogue, for 14 days after photodynamic retinal vascular thrombosis by rose Bengal. Rats without any OP-1206 treatment were used as controls. In the OP-1206-treated rats, minimal retinal atrophy due to ischemia/reperfusion was observed histologically up to 14 days, whereas in the non-treated rats the inner layer of the retina became markedly atrophic. In parallel with the histological change, after 14 days following thrombosis ADF immunoreactivity was preserved on retinal pigment epithelial cells in the OP-1206-treated rats, whereas it was diminished in the non-treated rats. These findings suggest an important role for ADF in the OP-1206-dependent suppression of retinal tissue damage caused by oxidative insult.

A multicentre trial was conducted to evaluate whether a combination regimen of a 600 mg dose of the antiprogestogen, mifepristone, followed 48 h later by a 1 mg vaginal suppository of the prostaglandin analogue, gemeprost, could be an effective pharmacological method for menstrual regulation. A total of 228 women with menstrual delay of < or = 11 days were studied in nine centres; 35 of the women (15%) received the treatment without having been pregnant as determined by human chorionic gonadotrophin measurements performed retrospectively. The mifepristone-gemeprost regimen induced vaginal bleeding in all of the pregnant women and in all but two of the non-pregnant women, and a complete abortion in all but four of the 193 pregnant subjects. The four failures included one incomplete and two missed abortions and one continuing live pregnancy. Most women reported lower abdominal pain during the first few hours after gemeprost administration but few, if any, other side-effects were observed. Most non-pregnant women described the induced vaginal bleeding to be comparable with--albeit somewhat longer than--a normal menstruation. In pregnant women the duration of the bleeding was on average longer, and the amount greater, than normal menstruation, but haemoglobin concentrations in these women as well as in the non-pregnant subjects were not affected. The overall success rate (97.4%; 95% confidence interval: 94.4-99.0%) of the regimen employed in this pilot trial strongly suggests that the combination of an antiprogestogen followed by a suitable prostaglandin is potentially useful for menstrual regulation and probably also as a late luteal, once-a-month contraceptive.(ABSTRACT TRUNCATED AT 250 WORDS)

Therapeutic attempts with anti-fibrotic drugs are still at an experimental stage. The clinical efficacies of most agents listed in Table II have not been proved. Some potential agents, such as colchicine, analogues of PGE, gamma-interferon, inhibitors of prolyl hydroxylase, malotilate, and PUL, must be further evaluated in controlled clinical trials. In addition, almost all anti-fibrotic agents, except HOE 077, are neither liver-nor fibrosis-specific. Some site-directed (targeted) drug delivery systems, drug-loaded vesicle carrier systems, like liposomes and erythrocyte ghosts, which selectively affect the extracellular matrix-producing cells, may improve efficacy and reduce adverse effects if they can be carriers for anti-fibrotic agents. Developments in biochemistry, immunohistochemistry, and molecular biology have considerably advanced our understanding of pathogenic mechanisms of hepatic fibrosis. With the development of available pathologic and serologic markers for ongoing fibrogenesis, experimental and clinical anti-fibrotic trials have become more active. Some therapeutic strategies have chosen targets for interference in collagen metabolism. In vivo inhibition of Ito cell activation has been a focus for the anti-fibrotic studies (70). In the present review an update of pharmacologic intervention in the process of metabolic pathways of collagen, the main extracellular matrices in both interstitium and basement membrane, has been summarized. Several drugs or biochemical agents that act on different steps of collagen synthesis, crosslinking, and breakdown are listed and discussed briefly. Moreover, agents that inhibit other matrix components are also involved in the review.(ABSTRACT TRUNCATED AT 250 WORDS)

The end point in peptic ulcer disease is a crater in the mucosa. The cause of gastric ulcers seems to be the breakdown of defensive factors, which then allows damage from endogenous and/or exogenous aggressive factors. Aggressive factors are more important in duodenal ulcer formation. Treatment options discussed herein have similar clinical effectiveness, and all have better results than placebo. Selection of a specific agent should be individualized. Helicobacter pylori infection has been implicated in both gastric and duodenal ulcer formation, and use of triple-drug therapy to eradicate or suppress the organism has decreased recurrence rates when maintenance therapy is not used. However, first-line treatment in acute peptic ulcer disease remains the use of antacids, sucralfate (Carafate), or histamine2 receptor antagonists. This approach to therapy is inexpensive, safe, and effective.

A comparison of the subjectively measured cervical dilatation and the dilatation measured objectively with a force-sensing instrument connected to metal dilators was made in two studies of cervical treatment prior to first trimester abortion. It was concluded that the subjective method is a sensitive and accurate method of measuring cervical dilatation but does not allow for comparison between different studies where an objective method of measurement should be used.

The aminothiols exemplified by WR-2721 are effective radioprotectors; however, their toxicity associated with hypotension, nausea, and emesis has limited their development for applications to medicine or in harzardous radiation environments. There is a need for new radioprotectors that have fewer toxic side effects when given alone or combined with reduced amounts of thiols. A variety of prostaglandins (PGs) have been shown to be radioprotective agents and some appear to have fewer toxic side effects than the aminothiols. Iloprost, a stable PGI, analog protects the clonogenic epithelial cells of intestinal crypts but does not protect epithelial cells of the villi. In contrast, an E-series omega chain diene analog designated SC-44932 protects epithelial cells of both crypts and villi. When the two are combined, protection of the crypts is additive and the villi are protected to the same degree as when SC-44932 is given alone. Since radioprotection for some PGs has been shown to be dependent upon receptors, we suggest that the pattern of radioprotection seen with these two analogs depend on the location of the respective receptors or on the ability of differentiated villus cells to respond to PGs. By studying different analogs, we hope to identify mechanisms associated with PG-induced radioprotection and to identify the most protective PG analogs for applications of radioprotection.

The effect of vaginal administration of a PgE1 analogue to terminate missed abortion and fetal death in utero was evaluated in 62 women with gestation ranging from the 13th to the 37th week. Abortion occurred in 85.4% of women with missed abortion and in 86% of women with fetal death. In both groups, the mean induction time was less than 12 h. The incidence of side effects, primarily gastrointestinal symptoms, was infrequent.

An oral prostaglandin E1 (PGE1) analogue, OP-1206.alpha-CD, was given to rats with streptozocin (STZ)-induced diabetes to examine the therapeutic effects of OP-1206 on short-term and long-term diabetic neuropathy and its action mechanism with special reference to nerve Na(+)-K(+)-ATPase activity. In the short-term experiment, OP-1206 was administered daily to diabetic rats in 3- and 30-mg/kg doses for 4 wk from the day of STZ injection. In the long-term study, 10 micrograms/kg OP-1206 was also given daily for 8 wk from 7 mo after induction of diabetes. The compound improved decreased sciatic motor nerve conduction velocity in both short-term and long-term diabetic rats. The nerve Na(+)-K(+)-ATPase activity of diabetic rats, reduced by 40% compared with controls, was reversed to the level of controls in both experiments, whereas weight loss and hyperglycemia were unchanged, and neither nerve sorbitol accumulation nor myo-inositol depletion was corrected. In a morphometric analysis of myelinated nerve fibers (MNFs) in long-term diabetes, the mean diameter of the largest 10% of MNFs was significantly reduced in untreated diabetic compared with control rats, but OP-1206 completely reversed this reduction. The results suggest that OP-1206 ameliorates a decrease in nerve Na(+)-K(+)-ATPase activity without any effect on nerve myo-inositol level and that the compound may be not only a potent therapeutic agent for the treatment of diabetic neuropathy but also a useful research tool to investigate the mechanism of nerve Na(+)-K(+)-ATPase activity regulation.

Enprostil is a synthetic prostaglandin E2 analogue with gastric antisecretory and mucosal protective properties. We compared the effects of enprostil and ranitidine on the healing of gastric ulcers and the subsequent relapse rates over 6 months. Patients (N = 156) were recruited for a double-blind study from 12 centers in Europe; 71 were randomly assigned to oral treatment with 35 micrograms enprostil twice daily and 85 to 150 mg ranitidine twice daily for up to 8 weeks. Both groups were of similar demography; their healing rates were also similar. Cumulative intent-to-treat healing rates were at 4 weeks enprostil 48%, ranitidine 41%: at 6 weeks enprostil 65%, ranitidine 68%; and at 8 weeks enprostil 72%, ranitidine 80%. Of those patients who met all protocol criteria and completed treatment, and were endoscoped at the prescribed times, healing rates were at 4 weeks enprostil 55%, ranitidine 54%, at 6 weeks enprostil 75%, ranitidine 84%; and at 8 weeks enprostil 80%, ranitidine 90%. Relief of pain was rapid and similar in both groups. The incidence of adverse events was low and similar in the two groups. The treatment-free relapse rate at 6 months was enprostil 64%, ranitidine 49%; the median times to relapse were 169 and 203 days, respectively. Enprostil and ranitidine appear to be equally effective in healing gastric ulcers.

In a randomised, double-blind trial, 75 women received either placebo or a 1-mg gemeprost (Cervagem) pessary for cervical dilatation prior to gynecological procedures which require mechanical dilatation of the cervix. No significant difference was seen between gemeprost and placebo with respect to preoperative cervical dilatation. The incidence of vaginal bleeding and adverse effects was similar in each group.

Ornoprostil, a methyl derivative of PGE1 developed in Japan, was tested for its effect on gastric mucosal damage caused by ethanol in human subjects. Sixteen healthy volunteers were given either ornoprostil or a placebo, followed by 20 ml of 70% ethanol instilled into the gastric antral mucosa. Fifteen minutes later, visible mucosal lesions were evaluated endoscopically. The biopsy specimens were obtained from mucosa that had been exposed to ethanol but looked normal. The specimens were assessed by light microscopy and scanning electron microscopy. The gross mucosal damage demonstrated endoscopically was significantly less (p less than 0.05) in the subjects receiving ornoprostil than those receiving placebo. Hyperemia and hemorrhage in the mucosa were also significantly less (p less than 0.05) in the subjects given ornoprostil pretreatment. Ornoprostil, however, failed to prevent the disruption of surface epithelial cells as assessed by scanning electron microscopy. These data suggest that ornoprostil protects gastric mucosa against damage caused by concentrated ethanol.

The effect of gastric emptying of two doses (35 and 70 micrograms) of enprostil given orally was evaluated in eight patients with endoscopically confirmed duodenal ulcer. Gastric emptying of a radiolabelled solid meal was assessed with the use of a gamma camera. Enprostil dose-dependently accelerated gastric emptying of solids; the gastric emptying index, Ix, increased from 1.62 +/- 0.38 min-1.10(-2) after placebo to 2.77 +/- 0.56 min-1.10(-2) after 35 micrograms enprostil (p less than 0.05 versus placebo) and to 3.65 +/- 0.64 min-1.10(-2) after 70 micrograms enprostil (p less than 0.005 versus placebo). The fraction of the radiolabelled food retained in the stomach at the end of the gastric emptying examination (that is, after 90 min) amounted to 50.5 +/- 6.9% after placebo, 35.2 +/- 7.4% after 35 micrograms enprostil, and 24.1 +/- 8.4% after 70 micrograms enprostil. It is concluded that enprostil elicits a significant speeding up of solid-phase gastric emptying in duodenal ulcer patients.

Administration of a long-acting prostaglandin E, 16,16-dimethyl-PGE (dPGE), to rats improves their survival of bacterial peritonitis. We examined the mechanism of this protective effect with reference to its interaction with the release of cachectin (TNF). Sixty rats received saline, 20 micrograms/kg dPGE, or 80 micrograms/kg dPGE 12 hr prior to endotoxin and continuing for 48 hr. Survival rates for the saline, 20 micrograms/kg dPGE, and 80 micrograms/kg dPGE groups were 0, 40, and 85%, respectively. Forty rats received saline or 80 micrograms/kg dPGE, with the initial dose being 3 hr following endotoxin challenge and continuing for 48 hr. Survival rates for both groups were 0%. Sixty rats received saline or 80 micrograms/kg dPGE at 12 and 1 hr prior to endotoxin. Two hours after challenge, they were sacrificed and plasma TNF levels were assayed. The plasma TNF level in saline-treated rats was 22.72 +/- 0.83 ng/ml and in the dPGE-treated group, 16.03 +/- 1.13 ng/ml (P less than 0.001).

Gastric ulcers in children are often seen as a result of an imbalance between nocive factors and the resistance of the mucosa. Glanzmann's thromboastenia is a defect in platelet aggregation and its nature may be associated to local factors which precipitate or perpetuate bleeding. Prostaglandins are hormones of local action which inhibit the secretion of acid and therefore protect the mucosa. We report a case of an 18 year old male youngster with Glanzmann's thromboastenia and a gastric ulcer previously unsuccessfully treated with cimetidine, aluminum hydroxide solution, ranitidine, sucralfate and later controlled with PGE2. In sum, the usefulness of the cytoprotecting effects of the prostaglandins are successfully evaluated in a young man with platelet aggregation abnormalities.

The influence of 16,16-dimethyl prostaglandin E2 (16,16-dm PGE2; an agent used for the prevention of stress ulcer after hepatectomy of the cirrhotic liver) on liver regeneration after hepatectomy was studied in rats. The following results were obtained. Ulceration after the stress of 6 h of water immersion was markedly suppressed in rats treated with 30 r/kg of 16,16-dmPGE2 as compared with the untreated controls. In animals that received hepatectomy alone, the gastric pH and gastric mucosal blood flow showed significant reduction from the preoperative levels. In animals that received hepatectomy plus 16,16-dmPGE2 treatment the postoperative reduction in the gastric pH and gastric mucosal blood flow was suppressed, suggesting the effectiveness of 16,16-dmPGE2 treatment in the prevention of stress ulcer after hepatectomy of the cirrhotic liver. The 3H-thymidine uptake percentage and thymidine activity 24 h after hepatectomy and the DNA content 30 h after hepatectomy were significantly higher in animals treated with 16,16-dmPGE2 than in the untreated controls. In animals that were treated intraperitoneally with 50 mg/kg of indomethacin 6 h before hepatectomy the mitotic index 30 h after hepatectomy was markedly lower than that in untreated controls. This indomethacin-induced reduction in the mitotic index tended to be normalized by treatment with 16,16-dmPGE2. These results suggest that 16,16-dmPGE2 treatment effectively prevents stress ulcer and favorably affects hepatic regeneration after hepatectomy of the cirrhotic liver.

We evaluated the effects of 16,16-dimethyl prostaglandin E2 (dm-PGE2), with and without syngeneic bone marrow transplantation (BMT) on the survival and hematopoietic recovery of mice given 14-20 Gy total body irradiation (TBI). Survival of mice given combined dm-PGE2 and BMT was improved significantly over that of mice given either treatment alone. The 30-day survival after 14, 15, 16 or 18 Gy TBI for combined treatment was 97, 90, 20 or 10 percent, respectively. The corresponding 30-day survival rates for mice given BMT alone were 69, 60, 7 or 0 percent, respectively. For dm-PGE2 alone, 30-day survival was 63, 20, 10 or 0 percent, respectively. Deaths in both dm-PGE2 treated groups generally occurred after day 10 whereas deaths in the BMT group occurred before day 10. All irradiated controls were dead on or before day 10; after larger doses, deaths clustered around day 5. After 20 Gy TBI, all mice in all groups were dead by day 7. Studies of white blood cell recovery 1-9 days after 14 Gy TBI showed improvement with BMT, whereas dm-PGE2 did not enhance recovery. Nucleated cells per humerus, spleen weight, and spleen iron uptake (erythropoiesis) were also improved by BMT but not dm-PGE2.

Three randomized, placebo-controlled multiclinic trials involving arbaprostil dosages of (a) 10 micrograms; (b) 25 micrograms; and (c) 10, 25, or 50 micrograms orally for 4 wk in patients older than 18 yr with rheumatoid arthritis or osteoarthritis who had endoscopically documented nonsteroidal antiinflammatory drug-associated gastric mucosal damage were conducted in the United States. All patients continued taking the nonsteroidal antiinflammatory drugs and were reendoscoped after 4 wk of therapy. Success at that time was defined as complete resolution of all gastric mucosal damage. Six hundred fifty-eight patients were enrolled in the three trials. Significantly more patients experienced healing in the arbaprostil treatment groups in all trials compared with those who received placebo. The healing rates in the various trials were 68% and 32% (10 micrograms vs. placebo; p = 0.007); 77% and 23% (25 micrograms vs. placebo; p less than 0.001); and 52%, 46%, 35%, and 16% (50, 25, and 10 micrograms vs. placebo; p less than 0.001, less than 0.001, and 0.002, respectively). Diarrhea, mostly of a mild nature, was the only arbaprostil-associated side effect and was found with the 25- and 50-microgram dosages (33% and 59%, respectively). No exacerbation of arthritis signs or symptoms was found. Arbaprostil at doses with varying effects on gastric acid secretion (25 and 50 micrograms) was documented in these trials to be an effective and safe agent for healing gastric mucosal damage associated with aspirin or other nonsteroidal antiinflammatory drugs in patients with either rheumatoid arthritis or osteoarthritis without adversely affecting joint symptomatology.

This study was performed to assess the effects of misoprostol, a synthetic prostaglandin E1 analog, on cerulein-induced pancreatitis. Per group of 10 each, male Wistar rats received either cerulein (2.5 micrograms/kg/h subcutaneously), cerulein and misoprostol (500 micrograms/kg intraperitoneally at 0 and 4 h), or saline. Rats were killed 6 h after the first injection. Misoprostol treatment significantly reduced interstitial edema and acinar cell lesions induced by hyperstimulation. Pancreatic amylase and chymotrypsin contents were increased by cerulein and returned towards control levels in the misoprostol-treated group. The lysosomal volume density and the pancreatic beta-D-glucuronidase activity were significantly increased after hyperstimulation. The two parameters were significantly reduced by misoprostol. A protective effect of misoprostol against lesions induced by cerulein hyperstimulation would be a consequence of a lysosomal stabilizating effect.

In a double-blind, multicentre study 77 patients with benign gastric ulcer were randomly allocated to treatment with either enprostil 35 micrograms bd or pirenzepine 50 mg bd. After four weeks of treatment 13/26 (50 per cent) of evaluable enprostil-treated patients and 9/30 (30 per cent) of evaluable pirenzepine-treated patients were healed. Corresponding healing figures after eight weeks were 20/25 (80 per cent) and 25/31 (81 per cent). Both drugs rapidly reduced the severity of ulcer pain and the need for antacid use. No statistically significant differences were detected between the treatments with respect to healing rate or symptom control. Adverse events were reported by eight patients taking enprostil and by 17 patients taking pirenzepine. Two patients withdrew from each treatment group because of adverse events. None of these was serious. In conclusion, enprostil and pirenzepine were equally effective in healing gastric ulcers and no statistically significant differences in safety and efficacy were detected. There was a tendency for earlier healing and fewer side effects in the enprostil-treated patients.

The effect of enprostil and the somatostatin analogue SMS 201 995 on the growth of a clonal variant of the human gastric adenocarcinoma cell line, MKN45, was studied. The derived cell line grew twice as fast as MKN45 when grown as a xenograft line in nude mice. However, it did not respond trophically to gastrin either in vitro or in vivo (unlike MKN45) although it possessed the same number of gastrin receptors as the parental line. Gastrin production by the cell line during in vitro culture was twice that of MKN45; thus, the cell line was denoted MKN45G. When MKN45G was grown as xenografts in nude mice (n = 10/group), enprostil (20 micrograms/kg/day) significantly inhibited tumour growth when administered continuously by an osmotic mini-pump from day 1 to day 7 of a 20-day experiment, and induced tumour regression when administered from day 7 to day 14. Enprostil reduced postprandial serum gastrin levels when administered from day 7 to day 14 and prevented gastrin release by MKN45 in vitro. SMS 201 995 at doses of 25 and 240 micrograms/kg/day induced tumour regression when administered from day 1 to day 7 and the former dose reduced post-prandial serum gastrin levels at day 5. Gastrin release by MKN45G was not affected by SMS 201 995 in vitro, thus its effect may not be mediated directly via gastrin, requiring interaction between other hormones or growth factors in the in vivo situation.

In a double-blind cross-over randomized study adjunct therapy with ranitidine (2 x 150 mg) was compared with enprostil (2 x 35 micrograms) in eight adult cystic fibrosis (CF) patients receiving a fixed dose of enteric-coated microsphere capsules of pancreatin (Pancrease). The study consisted of two consecutive 14-day treatment periods. All patients kept a fixed daily fat intake during the last 5 days of each treatment period and performed 72-h faecal collections during the last 3 days of each treatment period. Gastrointestinal complaints were scored at the end of each treatment period. During treatment with ranitidine there was less faecal fat excretion (18.9% versus 25.1%; NS), less faecal weight (263 versus 303 g/day; NS), and a lower gastrointestinal complaints score (5.3 versus 3.1; P less than 0.05) compared with the treatment with enprostil. One patient dropped out during the treatment period with enprostil because of very severe diarrhoea and abdominal discomfort. We conclude from this study that adjunct therapy with ranitidine has significantly less side effects and may give a better reduction of faecal fat excretion and daily faecal weight in CF.

The effects of TY-10957, a stable PGI2 derivative, on gastroduodenal lesions and secretory responses were examined in rats and compared with those of ornoprostil, a PGE1 derivative. Orally administered TY-10957 dose dependently prevented gastric lesions induced by ethanol/HC1 (60% ethanol in 150 mM HCl) and duodenal ulcers induced by mepirizole (200 mg/kg); a significant effect was obtained at 3 micrograms/kg or greater in the former and at 300 micrograms/kg in the latter. Intraduodenally administered TY-10957 had minimal effects on gastric acid secretion, and at the highest dose (300 micrograms/kg) both the basal acid output and that stimulated by histamine (20 mg/kg) were significantly reduced by about 40%. TY-10957 (30-300 micrograms/kg s.c.) produced a marked increase of alkaline secretion in both stomach and duodenum of anesthetized rats, and these effects were significant at 30 micrograms/kg in the stomach and at 100 micrograms/kg in the duodenum. On the other hand, ornoprostil produced a potent and significant inhibition against ethanol/HCl-induced lesions (greater than 1 microgram/kg), but had no effect on mepirizole-induced duodenal ulcers. This PGE1 derivative had no influence on both basal and stimulated acid secretion and did not significantly affect alkaline secretion even at 100 micrograms/kg. These results suggest that TY-10957 has a protective action on both gastric and duodenal mucosa. The mechanism of duodenal antiulcer effect may involve both inhibition of acid and stimulation of alkaline secretion, while the gastroprotective action of this agent may be attributed to other factors.

The expectation that prostaglandin analogues would improve the ulcer healing abilities of other agents by combining mucosal protection with decreased acid secretion has been proved unwarranted. The ulcer healing capabilities of these drugs reflect their antisecretory potency. A role for these drugs in ulcer healing is questionable but their use has been advocated most strongly to prevent ulceration developing during treatment with non-steroidal anti-inflammatory drugs. While some evidence supports this role, an important clinical benefit of reducing complication rates has yet to be demonstrated.

Milligram-range doses of E2 prostaglandins have long been used to induce labor or abortion in the second and third trimesters of pregnancy. Enprostil, a synthetic dehydroprostaglandin E2 structural analogue, is administered in microgram doses for the treatment of acute duodenal ulcer and acute gastric ulcer. This study examined the effect of the ulcer-healing dose and twice the ulcer-healing dose upon women in the first trimester of pregnancy. Two hundred and seven women who had requested legal abortion in the first trimester participated in two randomized, double-blind, placebo-controlled, parallel studies. They received two doses of enprostil 35 micrograms (the recommended dose for the treatment of duodenal and gastric ulcer) (n = 51), 70 micrograms (twice the recommended dose) (n = 53), or placebo (n = 103) 12 h apart. No drug-induced abortions occurred in any of the first-trimester pregnancies. Vaginal bleeding occurred in 4% of volunteers receiving the lower dose and 4% receiving the higher dose of enprostil. Vaginal bleeding occurred in up to 2% of volunteers on placebo. Although not recommended for pregnant women, if enprostil is given inadvertently to pregnant women with ulcers, it is unlikely to endanger the pregnancy during the first trimester.

Enprostil, a synthetic PGE2, has been shown to have an inhibitory effect on gastric acid secretion, a mucoprotective effect and a postprandial lowering effect on gastrin. A double blind randomized study was performed in 80 patients, in order to evaluate the efficacy and safety enprostil (35 mu b.i.d) as compared to cimetidine (400 mg b.i.d) in duodenal ulcer. Healing rates after two, four and six weeks of treatment, as based on endoscopic evaluation, were 35, 72 and 83 p. 100 for enprostil and 45, 73 and 83 p. 100 for cimetidine, respectively. There were no significant differences between treatment groups. The time to relief of nighttime and daytime ulcer pain and antacid consumption were similar in the two groups. The patient's overall subjective assessment was better in the cimetidine group, but this was not confirmed by physicians' opinions. Diarrhea was observed in 7 p. 100 of patients treated by enprostil compared with 5 p. 100 for patients treated by cimetidine. One enprostil treated patient withdrew from the trial prematurely because of abdominal pain. This study demonstrates the efficacy and safety of enprostil in the treatment of active duodenal ulcer at the dosage of 35 micrograms twice daily.

The efficacy of intravenously administered prostaglandin E2 (PGE2) compared to that of intravenously administered 16-phenoxy-17,18,19,20 tetranor prostaglandin E2 methyl sulfonylamide (SHB 286) for termination of fetal death in utero was evaluated in 20 pregnant women from 14 to 38 weeks' gestation. Ten subjects received 1 microgram of PGE2 per minute intravenously. This rate of infusion was doubled at hourly intervals up to 8 microgram per minute. Ten subjects received 0.25 microgram of SHB 286 per minute. This rate of infusion was doubled at hourly intervals up to 2 microgram per minute. It appears that the dosage schedules of PGE2 and SHB 286 were equally effective in inducing labor. Cumulative expulsion rates and mean induction times were similar in both groups. Rates of emesis were low in both groups. Either fever greater than 38.0 degrees C, or shivering, or phlebitis at the site of infusion was observed in three patients treated with PGE2 but in no patient receiving SHB 286.

Prostaglandin E1 was used to treat five infants with d-transposition of the great arteries and intact ventricular septum who had persistent severe hypoxemia after the creation of an interatrial communication. Three infants had a dramatic improvement in systemic arterial oxygen saturation associated with dilation of the ductus arteriosus; in two of the three cases urgent surgery was avoided. Two infants had no clinical evidence of increased ductal shunting and no improvement in oxygen saturation. A trial of prostaglandin E1 is recommended for treatment of severe hypoxemia in infants with d-transposition of the great arteries with intact ventricular septum if the presence of a large atrial septal defect is established.

The authors have used suppositories containing 1 mg of an analogue of PGE1 in 117 cases. The indication was fetal abnormality or fetal disease in 85 cases, fetal death in utero in 24 cases and very premature rupture of the membranes in 8 cases. The pessaries have a number of advantages over the techniques that were employed previously; intra-amniotic injection and intra-cervical perfusion of PGF2. The method is very efficacious: 98.3% successes. There was no failure in the series of intra-uterine fetal deaths. Placing the pessaries in the posterior vaginal fornix is easy and the technique does not consist of any manipulation. Not having to put any laminary tents in and no early rupture of the membranes has made it possible to avoid infection except in 1.7% of cases. The incidence of heavy bleeding was exceptionally low: 0.8%. As far as the dangers of rupture of the uterus or of tears in the cervix, this was minimal. Picking cases for correct indications, using doses adapted to each patient and careful observation by a team who are used to dealing with terminations of pregnancy and their techniques should lower the risk. The time spent in hospital is lessened: on an average 3 days. The fetus that is expelled is never macerated, which is important in order to be able to find out all the facts necessary to give good genetic counselling to a couple who have been profoundly traumatised.(ABSTRACT TRUNCATED AT 250 WORDS)