In vivo formation of prostaglandin E1 and prostaglandin E2 in atopic dermatitis

The authors present the young man case who had undergone 6 months long antibiotic therapy first, than has been operated because of growing nose obstruction with bloody pus secretion. Diagnostic difficulties were responsible for diagnosis and undertaking treatment. Fulminant course of disease resulted in death of patient in the course of immunosupression therapy.     

Potent prostaglandin A1 analogs that suppress tumor cell growth through induction of p21 and reduction of cyclin E

Although the cyclopentenone prostaglandin A1 (PGA1) is known to arrest the cell cycle at the G1 phase in vitro and to suppress tumor growth in vivo, its relatively weak activity limits its usefulness in cancer chemotherapy. In an attempt to develop antitumor drugs of greater potency and conspicuous biological specificity, we synthesized novel analogs based on the structure of PGA1. Of the newly synthesized analogs, 15-epi-delta7-PGA1 methyl ester (NAG-0092), 12-iso-delta7-PGA1 methyl ester (NAG-0093), and ent-delta7-PGA1 methyl ester (NAG-0022) possess a cross-conjugated dienone structure around the five-member ring with unnatural configurations at C(12) and/or C(15) and were found to be far more potent than native PGA1 in inhibiting cell growth and causing G1 arrest in A172 human glioma cells. These three analogs induced the expression of p21 at both RNA and protein levels in a time- and dose-dependent fashion. Kinase assays with A172 cells treated with these analogs revealed that both cyclin A- and E-dependent kinase activities were markedly reduced, although cyclin D1-dependent kinase activity was unaffected. Immunoprecipitation-Western blot analysis showed that the decrease in cyclin A-dependent kinase activity was due to an increased association of p21 with cyclin A-cyclin-dependent kinase 2 complexes, whereas the decrease in cyclin E-dependent activity was due to a combined mechanism involving reduction in cyclin E protein itself and increased association of p21. Thus, these newly synthesized PGA1 analogs may prove to be powerful tools in cancer chemotherapy as well as in investigations of the structural basis of the antiproliferative activity of A series prostaglandins.     

The effects of prostaglandin E1 and tyrosine kinase inhibitors on energy status and protein synthetic ability in hepatic ischemia-reperfusion injury

AIM: Preseptal and orbital cellulitis are rare presenting features of intraocular retinoblastoma. The objectives of this study were to determine the frequency of retinoblastoma associated cellulitis, as well as to review its clinical and histopathological features. METHODS: The medical records of 292 retinoblastoma patients in the King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia were reviewed. Those indicating a history of, or presenting with, cellulitis were retrieved and their clinical, radiological, and histopathological variables were assessed. Patients with definite extraocular tumour extension on clinical or radiological examination were excluded. RESULTS: 14 patients were found to have retinoblastoma associated cellulitis (4.8%); nine had bilateral and five had unilateral retinoblastoma. Conjunctival and blood cultures were performed in 10 cases and were negative. 10 children were treated with intravenous steroids, often in conjunction with antibiotics, resulting in a prompt decrease in inflammation. Three other children were treated with antibiotics alone and one received no treatment. Computed tomographic scanning depicted large intraocular tumours occupying between 80% and 100% of the globe in each case. In eight patients, periocular inflammation was radiologically interpreted as possible extraocular extension. In one patient serial computed tomographic scanning showed a reduction in intraocular calcification over time which occurred in the presence of cellulitis, 12 patients underwent enucleation and histopathological examination revealed large necrotic, poorly differentiated tumours associated with uveal involvement and early optic nerve invasion. Focal perilimbal destruction was seen in one patient, and in another peripapillary extrascleral extension was present. 12 patients are alive with a mean follow up of 56.4 months. CONCLUSIONS: Radiological evaluation of scleral integrity may be hindered by periocular inflammatory changes. The orbital cellulitis correlated well with the presence of advanced intraocular retinoblastoma with massive necrosis and anterior chamber involvement. In the majority of patients, cellulitis was not indicative of an extension of retinoblastoma into the orbit. Intravenous steroid treatment reduced orbital inflammation, facilitating examination and subsequent enucleation.     

A double-blind, randomized, placebo-controlled trial of prostaglandin E1 in liver transplantation

A double-blind placebo-controlled trial of intravenous prostaglandin PGE1 (40 micrograms/h) was conducted in adult orthotopic liver transplant recipients. Infusion was started intraoperatively and continued for up to 21 days. Patients were followed up for 180 days postoperatively. Among 172 patients eligible for treatment in the study, 160 could be evaluated (78 PGE1; 82 placebo). Patient and graft survival were similar (PGE1: 16 deaths, 9 retransplantations [7 survivors]; controls: 15 deaths, 6 retransplantations [3 survivors]). In patients with surviving grafts, however, PGE1 administration resulted in a 23% shorter mean duration of hospitalization following transplantation (PGE1: 24.4 days; controls: 31.8 days; P = .02) and a 40% shorter length of time postoperatively in the intensive care unit (PGE1: 8.2 days; controls 13.7 days; P = .05). Reduced needs for renal support (P = .03) or surgical intervention other than retransplantation (P = .02) were also noted with PGE1 use. Further, PGE1 administration resulted in a trend toward improved survival rates in patients with mild renal impairment (preoperative serum creatinine 1.5 mg percent or greater; P = .08). Neither the incidence of acute cellular rejection nor of primary nonfunction was significantly different in the two groups. Phlebitis was the only complication that was more common during PGE1 administration, (PGE1: 9; controls: 4). These results suggest that PGE1 use in hepatic allograft recipients reduces morbidity and may result in sizable cost reductions.     

Pharmacokinetics of prostaglandin E1 and its main metabolites after intracavernous injection and short-term infusion of prostaglandin E1 in patients with erectile dysfunction

PURPOSE: Alprostadil (prostaglandin E1) is the preferred monotherapy for intracavernous injection in the diagnosis and treatment of erectile dysfunction. Our study was designed to evaluate whether there is a difference in the pharmacokinetics of prostaglandin E1 and its main metabolites after intracavernous injection or short-term intravenous infusion. In addition, we also investigated the influence of the erectile response on prostaglandin E1 kinetics after intracavernous injection. MATERIALS AND METHODS: A total of 24 patients with erectile dysfunction received, in a randomized order at an interval of 5 hours, an intracavernous injection or a 30-minute intravenous infusion of 20 microg. of alprostadil alfadex (prostaglandin E1). Venous blood samples were obtained 5 minutes before and at various times after the applications. We used highly sensitive gas chromatography/double-mass spectrometry method to measure prostaglandin E1 and its metabolites in plasma. RESULTS: We demonstrated the presence of relevant systemic blood levels of prostaglandin E1 and its metabolites immediately after intracavernous injection. We found significantly lower systemic prostaglandin E1 concentrations between 7 and 20 minutes after intracavernous injection in patients with an erectile response compared with those without. CONCLUSIONS: We found significant systemic concentrations of prostaglandin E1 and its metabolites after intracavernous injection. The systemic presence did not lead to significant changes in vital signs.     

Attenuation of ischemic liver injury by prostaglandin E1 analogue, misoprostol, and prostaglandin I2 analogue, OP-41483

Workplace AIDS training is a recent addition to many corporations' occupational health agenda. However, little is known about the objectives, content, and practices of AIDS training programs. A survey of 126 workplace AIDS trainers was conducted to determine the impact of the trainer's organizational affiliation (in-house, consultant, union, etc.) and personal motives on training program objectives, content, and practices. Results indicate that the organizational affiliation of trainers is significantly related to training objectives, topics, and practices, whereas strong personal motives for becoming an AIDS trainer is significantly associated with an emphasis on more controversial content areas and training practices. Findings are discussed in terms of applicability to other values-oriented training topics, applications to practice, and future research needs.     

Effects of hypoxia on the hemodynamic actions of prostaglandin E1

The effect of prostaglandin E1 (PGE1) on central and peripheral hemodynamics was studied in seven conscious dogs under conditions of normoxia and hypobaric hypoxia to ascertain if hypoxia attenuated the cardiovascular actions of PGE1. Silastic catheters were chronically implanted in the pulmonary artery, left atrium, and aorta. Acute hypoxia was produced in a hypobaric chamber maintained at 446 mmHg pressure (14,000 feet). PGE1 at sea level (normoxia) resulted in significant increases in heart rate, cardiac output, left ventricular stroke work and pulmonary blood volume as well as significant decreases in aortic, pulmonary arterial, and left atrial pressures. During hypobaric hypoxia, PGE1 produced essentially identical effects on all hemodynamic parameters except pulmonary blood volume and pulmonary arterial pressure where marked attenuation of PGE1 action occurred.     

Chemolipiodolization and prostaglandin E1 administration with use of hepatic arterial infusion port for the treatment of hepatocellular carcinoma and liver cirrhosis

Frequent chemolipiodolization and prostaglandin E1 (PGE1) administered through a hepatic arterial infusion port were used for treatment in 2 cases of hepatocellular carcinoma (HCC) with liver cirrhosis. Chemolipiodolization was performed every 4 weeks with 6 ml lipiodol, 3 ml Optilay and 30 mg Epirubicin or 10 mg Mytomycin C. PGE1 (10 ug) was administrated to the hepatic artery once every week after the first 7 days administration. The treatment resulted in a decrease of the AFP level, an arrest of HCC growth and a reduction in ascites with an improvement of clinical and biochemical parameters in both cases. These encouraging preliminary results show that frequent lipiodolization is effective for unresectable HCC and frequent PGE1 administration via the hepatic artery is a safe and efficient treatment for liver cirrhosis.     

A trial use of prostaglandin E1 for prevention of hepatic veno-occlusive disease after allogeneic bone marrow transplantation

We performed retrospective analysis of hepatic veno-occlusive disease (VOD) in 57 cases with leukemia after allogeneic bone marrow transplantation (BMT). Prostaglandin E1 (PGE1) was used to prevent VOD in 8 cases at a dose of 0.3 micrograms/kg/hr from day -8 to day 30. No VOD was noted in the PGE1 group, while the incidence of VOD was 8/49 (16.3%) in the non PGE1 group. In twelve patients with pretransplant liver dysfunction, VOD was noted in 0/3 in the PGE1 group and 4/9 (44.4%) in the non PGE1 group, respectively. However, prophylactic effects of PGE1 on VOD is not significant in this study, so further studies are needed to determine the efficacy of PGE1. One of 8 patients with PGE1 prophylaxis had edema and erythema on extremities, however, severe toxicity was not experienced.     

Effects of prostaglandin E1 metabolites on the induction of arterial thromboresistance

Prostaglandin (PG) E1 has been shown to induce arterial thromboresistance in experimental animals and in man. It is known to be degraded in vivo to metabolites which have comparable (13,14-dihydro-PGE1) or no (15-keto-PGE1, 15-keto-13,14-dihydro-PGE1) biological activity. It was the goal of this study to examine whether 13,14-dihydro-PGE1 and its derivatives might share biological activity in rendering the arterial wall less thrombogenic. Using a cross-perfusion technique the aorta and iliac artery surface were exposed to a donor rabbits' blood. We examined the intact endothelial lining and a surface which had been deendothelialized before by means of a Fogarty catheter. Donor animals and/or receiver animals were treated daily for 1 week with 13,14-dihydro-PGE1, PGE1, 15-keto-PGE1, 15-keto-13,14-dihydro-PGE1, or the vehicle only, respectively. From the group of the receiver animals, a subgroup of 6 animals each was treated for the same period of time with either 13,14-dihydro-PGE1, PGE1, 15-keto-PGE1, 15-keto-13,14-dihydro-PGE1, or the vehicle. Immediately after the last administration of the respective PG or solvent, native blood from a donor rabbit was circulated [30 mL/min. under in vivo flow conditions (60 Hz)] over an arterial segment of a receiver animal. Deposition of 111Indium-oxine labeled autologous platelets per surface unit was quantitatively assessed. In vitro perfusion data were morphometrically analysed. In animals pretreated with 13,14-dihydro-PGE1 the thromboresistance was almost comparable to that achieved with PGE1. In contrast, pretreatment of the donor animals (platelet) had only minor effects on the thromboresistance. The other compounds showed no effects. In vitro perfusion of human saphenous vein segments revealed PGE1 and 13,14-dihydro-PGE1 again to be of comparable potency, while 15-keto-PGE1 and 15-keto-13,14-dihydro-PGE1 were only active at concentrations being several orders of magnitude higher. Not only PGE1 but also its in vivo formed metabolite PGE0 may play an important role in inducing improvement of haemostatic balance via the vascular wall rather than the platelets. The other metabolites, however, are unlikely to exhibit an effect at biologically relevant concentrations.     

Ethical, legal and medical aspects of transplantation

Tissue and organ transplantation is a very complex interdisciplinary treatment, particularly in regard to unpaired organs, and it carries numerous risks for all participants in such an action. For the purpose of minimizing the risks to the allowed level and the preservation the humanitarian goals in medicine when performing the transplantation, professional and scientific doctrines and the respect of ethical and legal principles should be strictly observed. The paper presents the basic approaches in the estimation of justification, usefulness and certain forms of responsibility in the process of transplantation. Ethical and legal postulates which support transplantation to prevent deviation, deprivation or delinquency have also been reviewed.     

Endothelin-1 modulates calcium signaling by epidermal growth factor, alpha-thrombin, and prostaglandin E1 in UMR-106 osteoblastic cells

Local factors play an important role in the regulation of bone metabolism. The homologous and heterologous desensitization of responses to these factors may be crucial in the modulation of bone cell signaling. In this study, the effects and interactions of endothelin-1 (25 nM), alpha-thrombin (0.9 microM), epidermal growth factor (40 nM), prostaglandin E1 (5 microM), and prostaglandin F1 alpha (5 microM) were examined on calcium signaling in UMR-106 rat osteoblastic osteosarcoma cells. Intracellular calcium was measured using fluo-3 fluorescent dye. All agents elicited calcium transients at these concentrations and showed homologous desensitization to their repeated administration. Preincubation for 60 minutes with 500 microM monodansylcadaverine and 30 minutes or 24 h preincubation with 0.5 microM indomethacin did not affect homologous desensitization, suggesting that neither the internalization of receptors nor prostaglandins are involved in this event. Pretreatment for 3 minutes with 2 microM 4 beta-phorbol-12 beta, 13 alpha-dibutyrate significantly reduced the calcium elevations elicited by the first application of these compounds, whereas an inactive phorbol, 12,13-didecanoate, had no effect. Pretreatment for 4 minutes with 0.5 microM forskolin decreased the calcium signal response to PGE1 only. Pretreatment with endothelin-1 for 3 minutes significantly decreased the calcium signals elicited by epidermal growth factor and alpha-thrombin. Prior administration of endothelin-1 significantly increased prostaglandin E1-stimulated calcium transients, whereas prostaglandin F1 alpha responses were not affected. Preincubation with indomethacin did not alter any of the interactions. Responses to endothelin-1 were not significantly altered by 2-3 minutes pretreatment with the other factors, nor was there cross-desensitization among the other factors. The results could indicate that endothelin-1 has a unique and specific role in the modulation of bone cell signaling.     

Inhibition of purinergic transmission by prostaglandin E1 and E2 in the guinea-pig vas deferens: an electrophysiological study

1. The effects of prostaglandin E1 (PGE1) and E2 (PGE2) on postjunctional electrical activity in the guinea-pig vas deferens evoked by sympathetic nerve stimulation were investigated using both intracellular and focal extracellular recording techniques in vitro. 2. Bath application of PGE1 (1-100 nM) or PGE2 (0.1-100 nM) concentration-dependently inhibited the amplitudes of all excitatory junction potentials (e.j.ps) evoked during short trains of stimuli (10 stimuli at 1 Hz). Increasing the duration of nerve stimulation (100 stimuli at 1 Hz) did not overcome this inhibitory effect. At these concentrations PGE1 and PGE2 were without any apparent inhibitory effect on the amplitudes of spontaneous e.j.ps. 3. Local application of PGE1 (10-100 nM) or PGE2 (10-30 nM) markedly reduced the frequency of occurrence of excitatory junction currents (e.j.cs) evoked by trains of 20-100 stimuli at 1 to 4 Hz without changing the amplitudes of spontaneous e.j.cs or the configuration of the nerve terminal impulse. 4. In the presence of PGE1 or PGE2, raising the frequency of stimulation (from 1 to 4 Hz), increased the likelihood of e.j.c. occurrence. 5. The postjunctional electrical activity recorded in the guinea-pig vas deferens is believed to be due to ATP released from the sympathetic nerve endings. Thus the present study demonstrates that both PGE1 and PGE2 powerfully inhibit quantal ATP release in the guinea-pig vas deferens.     

Dexamethasone inhibits the pyrogenic activity of prostaglandin F2 alpha, but not prostaglandin E2

The effect of dexamethasone on prostaglandin (PG) E2- and PGF2 alpha-induced fever was studied in rats. Intracerebroventricular injection of PGE2 and PGF2 alpha (500 ng) induced increases in body temperature (maximal temperature rises of 0.97 +/- 0.13 degrees C and 0.78 +/- 0.18 degrees C, respectively, vs. vehicle 0.12 +/- 0.09 degrees C) of unrestrained rats maintained within the thermoneutral zone. PGE2-induced fever peaked earlier and the defervescence was faster when compared to the response induced by PGF2 alpha. Subcutaneous pre-administration of dexamethasone (0.5 mg/kg) did not affect PGE2-induced fever (maximal temperature rise of 1.00 +/- 0.08 degrees C), but completely prevented the pyrogenic activity of PGF2 alpha (maximal temperature rise of 0.16 +/- 0.16 degrees C). Neither PGE2- nor PGF2 alpha-induced fever was significantly altered (maximal temperature rises of 0.90 +/- 0.11 degrees C and 0.64 +/- 0.14 degrees C, respectively) by intraperitoneal administration of indomethacin (2 mg/kg). These results demonstrate for the first time that glucocorticoids, in addition to inhibiting endotoxin- and cytokine-induced fever, can also modulate the pyrogenic activity of some prostaglandins, possibly via suppression of the synthesis of corticotropin-releasing factor, indicating that multiple mechanisms may be involved in the antipyretic activity of these steroids.     

Synthesis and use of iodinated nonsteroidal antiinflammatory drug analogs as crystallographic probes of the prostaglandin H2 synthase cyclooxygenase active site

The cyclooxygenase activity of the membrane protein prostaglandin H2 synthase isoform 1 (PGHS-1) is the target of the nonsteroidal antiinflammatory drugs (NSAIDs). The X-ray crystal structures of PGHS-1 in complex with the NSAIDs flurbiprofen and bromoaspirin have been determined previously [Picot, D., et al. (1994) Nature 367, 243-249; Loll, P. J., et al. (1995) Nat. Struct. Biol. 2, 637-643]. We report here the preparation and characterization of novel potent iodinated analogs of the NSAIDs indomethacin and suprofen, as well as the refined X-ray crystal structures of their complexes with PGHS-1. The PGHS-iodosuprofen complex structure has been refined at 3.5 A to an R-value of 0.189 and shows the suprofen analog to share a common mode of binding with flurbiprofen. The PGHS-iodoindomethacin complex structure has been refined at 4.5 A to an R-value of 0.254. The low resolution of the iodoindomethacin complex structure precludes detailed modeling of drug-enzyme interactions, but the electron-dense iodine atom of the inhibitor has been unambiguously located, allowing for the placement and approximate orientation of the inhibitor in the enzyme's active site. We have modeled two equally likely binding modes for iodoindomethacin, corresponding to the two principal conformers of the inhibitor. Like flurbiprofen, iodosuprofen and iodoindomethacin bind at the end of the long channel which leads into the enzyme active site. Binding at this site presumably blocks access of substrate to Tyr-385, a residue essential for catalysis. No evidence is seen for significant protein conformational differences between the iodoindomethacin and iodosuprofen of flurbiprofen complex structures.     

Cellular and chemical mediators of type 1 hypersensitivity in calves infected with Ostertagia ostertagi: histamine, prostaglandin D2, prostaglandin E2 and leukotriene C4

Plasma histamine, prostaglandin E2 (PG) D2, PGE2, and leukotriene (LT) C4 levels were determined in 26 Holstein steers before and after natural or experimental infection with Ostertagia ostertagi. Post-infection abomasal lymph was also assayed for PGD2, PGE2, and LTC4. Histamine determinations were performed on abomasal tissue from three locations. Results showed that: (1) tissue histamine levels increased in steers with type 2 ostertagiosis, (2) lymphatic PGD2 and PGE2 levels were increased, probably as a result of macrophage activity, (3) lymphatic LTC4 levels increased in steers with type 1 ostertagiosis, and were correlated with tissue eosinophilia, and (4) plasma levels of PGD2, PGE2, LTC4 and histamine were not useful for predicting worm burdens. These findings suggest a functional role for eosinophils and mast cells in the pathophysiology of ostertagiosis, through mediation of a type 1 hypersensitivity reaction.     

Droloxifene does not blunt bone anabolic effects of prostaglandin E2, but maintains prostaglandin E2-restored bone in aged, ovariectomized rats

The authors examined 1) effects of nortriptyline (NT) on electroencephalographic (EEG) sleep measures in elderly patients with bereavement-related depression in remission under randomized, double-blind, placebo-controlled conditions, and 2) the effects of clinical remission on sleep after discontinuation of medication. Subjects were classified as responders to placebo (n = 9) or NT (n = 18) and had EEG sleep studies at three time-points: before treatment (T1), remitted on medication or placebo (T2), and remitted off medication or placebo (T3). As compared with placebo, NT was differentially associated with decreases in REM sleep time and percent and increases in REM sleep density (T2). No changes in EEG sleep measures occurred in placebo responders. REM sleep measures in NT responders reverted to T1 levels after T3, with persistence of robust clinical remission and normal subjective sleep quality. These data suggest that NT alters REM sleep, but that EEG sleep characteristics in bereavement-related depression persist into remission.     

Influence of prostaglandin E1 on cerebral mechanisms involved in the control of fluid balance

Br- has been used as a nuclear magnetic resonance (NMR) probe to study the reversible association of alpha-chymotrypsin and an Hg-labelled substrate (4-bromomercuriocinnamic acid, BrHgCin) which rapidly exchanges Br-. T1 was measured for 79Br and 81Br, using a pulse spectrometer. Values of the parameters that determine T1, Obs in aqueous solutions of KBr (pH=5.5) containing alpha-chymotrypsin and BrHgCin are reported. It is found that the rate of Br exchange is diffusion-limited and faster than the rate of reorientation of the BrHgCin-alpha-chymotrypsin complex. The rate constant for the formation of the covalent BrHgCin-alpha-chymotrypsin complex determined by this technique agrees well with previously published data. The rapid rate of Br exchange with the complex, however, is incompatible with the side chain of BrHgCin being entirely buried in a nonpolar pocket on the enzyme but compatible with the side chain being exposed to the solution. The contribution to the NMR signal from the non-covalent complex is negligible.     

The effect of low-rose prostaglandin E1 on circulation, respiration and body temperature during surgical anesthesia

We investigated the effects of low-dose prostaglandin E1 (PGE1) on circulation, respiration, and body temperature during surgical anesthesia. We studied 109 adult patients undergoing upper abdominal operations under thoracic epidural combined with inhalational anesthesia. Patients were divided into 2 groups; Control group (n = 42) and PGE1 group (n = 67). In PGE1 group, PGE1 infusion was started at the rate of 0.02 microgram.kg-1.min-1 before the induction of anesthesia and was terminated at the end of surgery. There were no differences between the groups in demographic, anesthetic and surgical characteristics. After treatment with PGE1, arterial pressure decreased slightly but significantly, resulting in lower arterial pressure in PGE1 group than in control group before the induction of anesthesia. After the induction of anesthesia, however, arterial pressure decreased significantly in both groups, and the differences in arterial pressure between the groups were not observed any more during surgery. Heart rate was not different between the groups throughout the study period. Intraoperative urine output was greater in PGE1 group than in control group. PaO2/FIO2 ratio was not different between the groups both before and during anesthesia. Rectal temperature remained slightly but significantly lower in PGE1 group throughout surgery. Rectal-to-palm temperature gradient tended to be smaller in PGE1 group 1 hour after the induction of anesthesia. Low-dose PGE1 reduced arterial pressure. However, the difference in arterial pressure between the groups was so small that the difference disappeared during surgery. Meanwhile, low-dose PGE1 increased urine output, suggesting that renal blood flow was better-maintained with PGE1. In spite of several investigations reporting an unfavorable effect of PGE1 on PaO2, low dose PGE1 did not affect PaO2 in this study. Finally low-dose PGE1 reduced core temperature, though slightly, probably through redistribution of the body heat.