Progress does not just come in giant leaps: adapting techniques for the study of inflammation to novel applications.

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.

Topical Prostaglandin E Analog Restores Defective Dendritic Cell-Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice.

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 E2 (PGE2) 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 PGE2 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, PGE2 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.

Prostanoids in patients with peripheral arterial disease: A meta-analysis of placebo-controlled randomized clinical trials.

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.

Expression of prostaglandin PGE2 receptors under conditions of aging and stress and the protective effect of the EP2 agonist butaprost on retinal ischemia.

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.

Prevention of nonsteroidal anti-inflammatory drug-induced small-intestinal injury by prostaglandin: a pilot randomized controlled trial evaluated by capsule endoscopy.

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.

The pulmonary physician in critical care - part 9: non-ventilatory strategies in ARDS.

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.

The effects of OP-1206 alpha-CD on walking dysfunction in the rat neuropathic intermittent claudication model.

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.

[Role of physiological adaptation in the development of renal inflammatory disease]. / Rol' adaptatsionnykh reaktsii v razvitii vospalitel'nykh zabolevanii pochek.

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.

Synergistic effects of sildenafil on relaxation of rabbit and rat cavernosal smooth muscles when combined with various vasoactive agents.

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.

Dolor lumbar de origen neopláscio. Diagnóstico y tratamiento conservador / No disponible

Realizamos una revisión de las principales causas de dolor lumbar de origen neoplásico, diferenciando el debido a invasión ósea o neural. Entre las diferentes causas de invasión ósea destacar el mieloma múltiple, el osteoma osteoide y el originado por metástasis. En invasión neural: por carcinomatosis meningea, la plexopatía lumbosacra y a tener en cuenta el tan temido síndrome de compresión espinal. Una vez confirmado el diagnóstico, el tratamiento debe ser multidisciplinario, conjuntamente con oncólogos y radioterapeutas (AU)

A revision of the main causes of lumbar neoplasic pain has been carried out. The pain may be attributed to bone or nerve invasion. Among the different causes of bone invasion multiple myeloma, osteoid osteoma and metastases must be considered regarding neural invasion the main causes are meningeal carcinomatosis lumbosacral plexopaty and the espinal compression syndrome. Once the diagnosis is confirmed treatment must be multidisciplinary carried out by the pain unit, oncologist and radiotherapists (AU)

[Retrospective analysis (1996-1998) of the treatment results with PgE2 (3 mg) of pregnant women with induced birth indications because of unsatisfactory cervix condition]. / Retrospektiven analiz ot prilozhenieto na PgE2 (3 mg) pri nezadovolitelno s'stoianie na matochnata shiika pri bremenni s indikatsii za induktsiia na razhdaneto (1996-1998).

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....

Controle neuroendócrino da contraçäo uterina / The neuroendocrine control of uterine contraction

Os autores apresentam uma revisäo acerca da contratilidade da musculatura lisa uterina. Foram abordados os aspectos relacionados ao controle neural, hormonal e à atuaçäo de outras substâncias envolvidas no mecanismo de contraçäo da mesma. Dentre estas substâncias foi descrita a atuaçäo do Misoprostol, um análogo de prostaglandina sintetizado laboratorialmente, que exerce potente atividade contrátil sobre a rferida musculatura

[A trial of the use pf prostaglandin E1 (Edex, Caverject) for the diagnosis and treatment of erectile dysfunction]. / Opyt primeneniia prostaglandina E1 (edeks, kaverdzhekt) dlia diagnostiki i lecheniia érektil'noi disfunktsii.

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.

Analysis of localization of adult T-cell leukemia-derived factor in the transient ischemic rat retina after treatment with OP-1206 alpha-CD, a prostaglandin E1 analogue.

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.