Search

Background Reperfusion therapy by primary coronary angioplasty has been shown to be beneficial for patients who present themselves up to 12h after the onset of symptoms. However, the relationship between outcome and ischaemic time for patients who present relatively late after the onset of symptoms is still uncertain. The aim of this study was to investigate differences in patient character-istics, left ventricular function and clinical outcome among early (

Smoking has either a beneficial or harmful effect on the course and recurrence of ulcerative colitis and Crohn's disease respectively. Transdermal application of nicotine had similar effects in ulcerative colitis and therefore was considered to be an effective basic drug which could be further developed in the search for new compounds in the treatment of acute exacerbations of corticosteroid resistant ulcerative colitis. In this communication the short-term use of nicotine in ulcerative colitis is reviewed.

We developed an in vitro organ bath method to measure permeability and contractility simultaneously in murine intestinal segments. To investigate whether permeability and contractility are correlated and influenced by mucosal damage owing to inflammation, BALB/c mice were exposed to a 10% dextran sulphate sodium (DSS) solution for 8 days to induce colitis. The effect of pharmacologically induced smooth muscle relaxation and contraction on permeability was tested in vitro. Regional permeability differences were observed in both control and 10% DSS-treated mice. Distal colon segments were less permeable to 3H-mannitol and 14C-PEG 400 molecules compared with proximal colon and ileum. Intestinal permeability in control vs. 10% DSS mice was not altered, although histologic inflammation score and IFN-gamma pro-inflammatory cytokine levels were significantly increased in proximal and distal colon. IL-1beta levels were enhanced in these proximal and distal segments, but not significantly different from controls. Any effect of pharmacologically induced contractility on intestinal permeability could not be observed. In conclusion, intestinal permeability and contractility are not correlated in this model of experimentally induced colitis in mice. Although simultaneous measurement in a physiological set-up is possible, this method has to be further validated.

Abnormal levels of pulmonary eicosanoids have been reported in infants with persistent pulmonary hypertension (PPH) and congenital diaphragmatic hernia (CDH). We hypothesized that a dysbalance of vasoconstrictive and vasodilatory eicosanoids is involved in PPH in CDH patients. The levels of several eicosanoids in lung homogenates and in bronchoalveolar lavage fluid of controls and rats with CDH were measured after caesarean section or spontaneous birth. In controls the concentration of the stable metabolite of prostacyclin (6-keto-PGF1α), thromboxane A2(TxB2), prostaglandin E2(PGE2), and leukotriene B4(LTB4) decreased after spontaneous birth. CDH pups showed respiratory insufficiency directly after birth. Their lungs had higher levels of 6- keto-PGF1α, reflecting the pulmonary vasodilator prostacyclin (PGI2), than those of controls. We conclude that in CDH abnormal lung eicosanoid levels are present perinatally. The elevated levels of 6-keto-PGF1αin CDH may reflect a compensation mechanism for increased vascular resistance.

The observed effects after ozone exposure strongly depend on ozone concentration and exposure time. We hypothesized that depending on the O3exposure protocol, mainly either an oxidant damage or an inflammation will determine the O3toxicity. We compared two different ozone exposure protocols: an acute exposure (3 ppm 2 h) for studying the oxidant damage and an exposure (1 ppm 12 h) where an inflammatory component is also probably involved. We measured LDH activity and protein and albumin exudation as markers for cellular damage. After the acute exposure an increase in LDH activity was measured and after exposure to 1 ppm ozone for 12 h the exudation of protein and albumin was also enhanced. The histological examinations showed a neutrophilic inflammatory response only after exposure to 1 ppm ozone for 12 h. The acute exposure protocol resulted in an increased release of PGE2, PGD2, PGF2αand 6-ketoPGF1αwhereas exposure to 1 ppm ozone for 12 h led to an additional release of LTB4. No effects were measured on the release of TxB2and LTC4/D4/E4. These changed amounts of eicosanoids will probably contribute to the ozone-induced lung function changes.

Purpose: Microvascular obstruction (MVO) after primary percutaneous coronary intervention (PPCI) for acute myocardial infarction is a known parameter for impaired functional recovery. This study explored the relationship between MVO, regional infarct transmurality and detailed segmental systolic and diastolic function using CMR strain analysis. Methods: CMR was performed 3-7 days after PPCI and at 4 months follow-up in 33 patients, using cine imaging, single breath-hold tagging (retrospective CSPAMM sequence, TR 42ms) and late gadolinium enhancement (LGE). Peak circumferential strain (PCS), peak systolic and diastolic circumferential strain rate (PSCSR/PDCSR), and absolute systolic wall thickening (SWT) were calculated in a 16-segment model. Results: Mean LVEF was 47±10% at baseline and 54±10% at follow up. Infarct size (% LV mass) was 18±10% at baseline and 13±9% at follow up. 273 segments were non-infarcted and 255 were infarcted; infarcted segments were stratified into four groups according to the amount of enhancement: 75% (n=48) enhancement. Infarcted segments had impaired systolic function (2±2mm vs. 4±2mm, p

1. The antimigraine drug, sumatriptan, contracts the human coronary artery and, in some patients, elicits chest symptoms (e.g. pressure and pain), particularly after subcutaneous administration. We studied the effects of the thromboxane A2 (TxA2) analogue, U46619 and endothelin-1 on contractile responses to sumatriptan in the human isolated coronary artery as well as the role of endogenously produced TxA2 and endothelin-1 in contractions evoked by sumatriptan. 2. In the presence of U46619 (1 and 3 nM), mean concentration-response curves to sumatriptan in the human coronary artery were shifted vertically due to the initial contraction by U46619, but when this initial contraction was subtracted from the response to sumatriptan, no significant augmentation was observed. However, analysis of the degree of augmentation in individual arterial segments revealed that the augmentation was variable and related inversely to the Emax of sumatriptan in the absence of U46619 (r = 0.78 and 0.81 for 1 and 3 nM, respectively; P < 0.05). 3. Treatment with the TxA2 receptor antagonist, SQ30741 (100 nM), or incubation of vessel segments with aspirin (10 microM), significantly reduced responses to sumatriptan; in aspirin-treated vessel segments, SQ30741 failed to decrease further the contractions to sumatriptan. The decrease in Emax of sumatriptan by both SQ30741 and aspirin correlated significantly with the Emax of sumatriptan without SQ30741 (r = 0.74; P < 0.01) or aspirin (r = 0.94; P < 0.01). In aspirin-treated vessel segments, responses to sumatriptan were significantly augmented in the presence of U46619 (3 nM; P < 0.05). 4. The specificity of SQ30741 was demonstrated by its ability to antagonize coronary artery contractions to U46619 (pA2: 7.54 +/- 0.30), but not endothelin-1. Similarly, incubation with aspirin (10 microM) did not affect contractile responses to endothelin-1, but significantly reduced TxA2 production in coronary artery segments as judged by a decrease in thromboxane B2 (TxB2) from 4.77 +/- 0.98 to 1.38 +/- 0.36 ng g-1 2 h-1. 5. Endothelin-1 (1 nM) did not significantly augment contractions to sumatriptan; there was also no relationship between the degree of augmentation and the control Emax of sumatriptan in the absence of endothelin-1. Furthermore, unlike SQ30741 or aspirin, a high concentration (100 nM) of the non-selective ETA/ETB receptor antagonist, SB 209670, failed to affect contractile responses to sumatriptan. However, SB 209670 potently antagonized coronary artery contractions induced by endothelin-1 with a pA2 of 8.84 +/- 0.32. 6. Compared to control vascular segments, endothelial denudation did not reduce TxA2 production (with endothelium = 2.56 +/- 1.38 vs. without endothelium = 12.32 +/- 4.94 ng TxB2 g-1 2 h-1), suggesting that the production of TxA2 is not confined to the endothelium. The sumatriptan-induced contractions were also unaffected by endothelial denudation. 7. The results of the present study suggest that endogenously produced TxA2 enhances contractions to sumatriptan in the human isolated coronary artery. Such a mechanism may play a role in causing chest symptoms after sumatriptan by potentiating coronary vascular contraction by sumatriptan in vivo.

Ulcerative colitis (UC) is predominantly a disease of non-smokers and treatment with transdermal nicotine improves symptoms in UC patients, whereas smoking seems to have a deleterious effect in patients with Crohn's disease (CD). In CD the cytokine profile is of a dominant TH1 (T helper 1) pattern whereas in UC the TH2 pattern predominates. To find an explanation for the beneficial effect of nicotine in UC and the deteriorative effect in CD we studied the in-vivo effect of nicotine on the interleukin 2 (IL-2), IL-10 and tumour necrosis factor alpha (TNF alpha) production by human cells.Eleven healthy male non-smokers were included in this study. The volunteers applied nicotine patches with a regulated release of 5 mg (day 1 and 2), 10 mg (day 3 and 4) and 15 mg (day 5, 6 and 7) nicotine per day.Heart rate and blood pressure were recorded, nicotine and cotinine concentrations in plasma measured before and after 2, 4 and 7 days of treatment. Non-adherent mononuclear cells (NAC) were isolated from peripheral blood obtained from the subjects before and after 7 days of treatment. The NAC were cultured in the absence or presence of phytohemagglutinin for 48 h. Total amount of IL-2, IL-10 and TNF alpha formed were measured in the supernatants using specific ELISAs.Treatment with nicotine caused a significant inhibition of IL-10 production by NAC. In contrast, nicotine patch treatment had no effect on the production of IL-2 and TNF alpha.Nicotine in vivo has an inhibitory effect on TH2 cell function as measured by inhibition of IL-10 production, but does not appear to have any effect on TH1 cell function.

The comparative efficacy of thrombolytic drugs and primary angioplasty for acute myocardial infarction have recently been studied, but long-term follow-up data have not yet been reported. We conducted a randomized trial involving 301 patients with acute myocardial infarction; 152 patients were randomized to primary angioplasty and 149 to intravenous streptokinase. Left ventricular function was assessed with a radionuclide technique both at hospital discharge and at the end of the follow-up period. Follow-up data were collected after a mean (+/-SD) of 31 +/- 9 months. Total medical costs were calculated. At the end of the follow-up period, 5% of the angioplasty patients had died from a cardiac cause compared to 11% of the patients randomized to intravenous streptokinase, P = 0.031. Cardiac death or a non-fatal reinfarction occurred in 7% of angioplasty patients compared to 28% of streptokinase patients, P < 0.001. There was a sustained benefit of angioplasty compared to streptokinase on left ventricular function. The total medical costs in the two groups were similar. Coronary anatomy (patency and single or multivessel disease), infarct location and previous myocardial infarction were important determinants of clinical outcome and costs. After 31 +/- 9 months of follow-up, primary angioplasty compared to intravenous streptokinase results in a lower rate of cardiac death and reinfarction, a better left ventricular ejection fraction, and no increase in total medical costs.

Inflammation following an infection induces a range of nonspecific symptoms of sickness in animals and humans. The cytokine interleukin-1 (IL- 1) mediates many of the brain-mediated symptoms of sickness. Binding sites for IL-1 have been found in mouse brain, but not in the brains of rats. This raises questions as to the involvement of these neuronally localized IL-1 binding sites in the induction of sickness symptoms. Based on observations of IL-1 receptor mRNA in close vicinity to the vasculature in the mouse and rat brain, we studied the possibility that endothelial cells in the rat brain exhibit IL-1 receptors to transduce information to the brain. Ligand binding studies reveal that cultured endothelial cells of adult rat brain exhibit specific binding sites for rat IL-1β. Polymerase chain reaction experiments demonstrated that mRNA of the type I but not that of the type II IL-1 receptor is present in rat brain endothelial cells. Incubation of these endothelial cells with recombinant rat IL-1β showed a dose-dependent increase in interleukin-6, prostaglandin E2, and prostacyclin secretion. Intravenous administration of rat IL-1β to adult rats enhanced prostaglandin E2 immunoreactivity in endothelial cells of the brain microvasculature. These results indicate that functional type I IL-1 receptors are present on endothelial cells of adult rat brain. We postulate that circulating IL-1 can be translated by brain endothelial cells into other signals such as interleukin-6 or prostaglandins that have access to the brain and induce sickness symptoms.

Background : The purpose of this study was to evaluate catheterization laboratory events and angiographic findings in patients randomly assigned to undergo primary coronary angioplasty or to receive intravenous streptokinase for acute myocardial infarction. Methods: We analysed angiographic data in 301 patients with acute myocardial infarction, randomly assigned to undergo primary coronary angioplasty without antecedent thrombolytic therapy or to receive intravenous streptokinase therapy. Follow-up coronary angiography was preferably performed after 3 months. AII angiograms were analysed with a quantitative coronary analysis system. Results: Of the 152 patients assigned to angioplasty treatment, 140 underwent this procedure with a success rate of 97%. The residual diameter stenosis of the infarct-related vessel immediately after angioplasty was 27 ± 15% and there were major events in 14% of the patients in the catheterization laboratory. At follow-up angiography after a mean interval of 92 days in the angioplasty assigned patients, a diameter stenosis of 35 ± 22% was observed in this group. The restenosis rate was 28% and the reocclusion rate 5%. A Thrombolysis in Myocardial Infarction (TIMI) grade 2 flow immediately after angioplasty was predictive for reocclusion at follow-up (P= θ0.001). In the streptokinase assigned patients (149) the infarct-related vessel was patent at follow-up angiography after a mean of 22 days in 66% of the patients with a mean residual diameter stenosis of 77 ± 20%. Conclusion: Primary coronary angioplasty is a highly effective and safe reperfusion modality for patients with acute myocardial infarction. However, TIMI grade 2 flow through the infarct-related vessel immediately after angioplasty is a predictor of reocclusion.

The capacity of rat cerebral endothelial cells (RCEC) to form eicosanoids was determined after incubation with l4C-labelled arachidonic acid. Prostaglandin E2 (PGE2) was the main metabolite formed by RCEC and was responsible for 54% of the total amount of eicosanoids produced. In contrast, in primary cultures of rat aorta endothelial cells, 32% of the amount of prostaglandins was 6-keto-PGF1α). RCEC treated with 50 ng/ml LPS for 24 h responded with an augmented PGE2 synthesis and 6-keto-PGF1α of 3.4-fold and 2.2-fold, respectively. Cultures treated with IL-1β (50 ng/ml) for 3 h showed a stimulation of the release of PGE2 and 6-keto-PGFα of 2.5- and 4.5-fold, respectively, and 2.0-fold and 2.3-fold, respectively, after IL-6 (50 ng/ml) incubation for 3 h. PGE2 is the main eicosanoid formed by RCEC in response to inflammatory agents, suggesting an important role of the cerebral endothelial cells in the transduction of an inflammatory response in the central nervous system.

We examined the in vivo effect of nicotine on the synthesis of (pro)inflammatory mediators by mouse colonic mucosa. The synthesis of lipid mediators such as the prostanoids prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2, the 5-lipoxygenase products leukotriene B4 and leukotriene C4 and the platelet activating factor was not affected, whereas the synthesis of the pro-inflammatory cytokines interleukin-1 beta and tumor necrosis factor alpha was completely abolished. The beneficial effects of smoking and nicotine in ulcerative colitis could be attributed to this inhibition.

The levels of the eicosanoids leukotriene B4, prostaglandin E2, prostacycline and thromboxane B2, the cytokines interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha and soluble intercellular adhesion molecule 1 were measured in ascites and plasma samples of patients with liver cirrhosis (53), peritoneal cancer (26) and spontaneous bacterial peritonitis (10) to assess their value as a possible diagnostic and prognostic parameter in the course of the disease. Soluble intercellular adhesion molecule 1, of the eicosanoids prostaglandin E2 and leukotriene B4, and the protein concentration in ascites were all significantly elevated in ascites of patients with peritoneal cancer in comparison to ascites of patients with liver cirrhosis. In ascites of patients with spontaneous bacterial infection interleukin-6 concentration was significantly elevated and the protein concentration was significantly lower in comparison to the other two groups. None of these parameters, however, seems to be of practical use as a diagnostic parameter, as there is an overlap between all the levels of these mediators in ascites of liver cirrhosis, peritoneal cancer and spontaneous bacterial peritonitis group. Soluble intercellular adhesion molecule 1 levels were much higher in plasma than in ascites, in contrast to interleukin-6 levels which were much higher in ascites than in plasma. Soluble intercellular adhesion molecule 1 in ascites correlated with soluble intercellular adhesion molecule 1 in plasma (r = 0.6926, P = 0.0001). Soluble intercellular adhesion molecule 1, interleukin-6 and the number of polymorphonuclear cells in peritoneal fluid correlated during episodes of infection in patients with a peritonitis. For this reason soluble intercellular adhesion molecule 1 and interleukin-6 could be of prognostic value for patients with peritonitis.

The production of interleukin-5 and eosinophil cationic protein (ECP) in the nasal cavity was examined in 24 patients with rhinitis who were allergic to the house dust mite. During a double-blind placebo-controlled cross-over study, fluticasone propionate aqueous nasal spray (200 micrograms) was administered twice daily for 2 weeks. After four basal nasal lavages provocation with house dust mite extract was performed and nasal lavages were collected every hour for 9.5 h. Interleukin-5 was present in detectable amounts in nasal lavages from patients allergic to house dust mite. Nasal challenge with house dust mite extract caused immediate nasal symptoms and increased levels of interleukin-5. Between 3.5 and 8.5 h after the challenge symptoms recurred and interleukin-5 levels increased, reflecting a late phase reaction. Eosinophil cationic protein, a marker of activated eosinophils, was released between 6.5 and 9.5 h after challenge. Treatment with fluticasone propionate (as an aqueous nasal spray) significantly decreased the evoked interleukin-5 and ECP levels in the late phase reaction. This response was correlated with an improved symptom score. This could indicate that the number and activity of eosinophils are increased during the late phase allergic reaction, a response that is inhibited by corticosteroids.

The object of this study was to establish whether different pro- and anti-inflammatory mediators were formed in colonic tissue from experimental colitis depending on the course of the disease. Concentrations of mediators of inflammation were examined in colonic tissue in dextran induced colitis in mice. Initial inflammation was produced by 5 days treatment of 10% dextran sodium sulfate (DSS) in drinking water, followed by a further 9 day period of 2% DSS in an attempt to produce a milder chronic inflammation. The degree of inflammation was scored by a standardized macroscopic and histological examination. Initially, a 60% maximum inflammation score was observed at day 4. At this time inflammation was associated with the release of interleukin-lβ (IL-1β) and tumour necrosis factor-α (TNFα), whereas both prostaglandins 6kPGF1αand PGE2and nitric oxide (NO) markedly decreased. Then a 25% inflammation score was reached which coincided with an increased production of platelet-activating factor (PAF). No significant changes were observed in leukotriene B4and C4formation. In conclusion, pro-inflammatory cytokines IL-1β and TNFα are considered to be primary mediators, whereas PAF, eicosanoids and NO may reflect secondary mediators in experimental colitis.

To examine the interactions between the main pro-inflammatory cytokines and eicosanoids produced by human inflammatory cells, human peritoneal macrophages (hp-M phi) were isolated from ascitic fluid of patients with portal hypertension. Interactions between interleukin-1 beta (IL-1 beta), IL-6, tumor necrosis factor alpha (TNF-alpha), leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) were studied by addition or inhibition of several cytokines and eicosanoids: human recombinant IL-1 beta (hrIL-1 beta) addition, LTB4 addition and 5-lipoxygenase inhibition (6-hydroxy-2-(4-sulfamoylbenzylamino)-4,5,7-trimethylbenzothiaz ole hydrochloride (E6080)), PGE2 addition and cyclooxygenase inhibition (indomethacin). In hp-M phi hrIL-1 beta stimulated the LTB4 production, while the PGE2 production was inhibited. HrIL-1 beta had no significant effect on IL-6 production in hp-M phi. LTB4 did not regulate IL-1 beta and IL-6 production. Increasing PGE2 down regulated the TNF-alpha production, but did not effect the IL-1 beta and IL-6 production.

Ascites is a readily available source of human macrophages (M phi), which can be used to study M phi functions in vitro. We characterized the mediators of inflammation produced by human peritoneal M phi (hp-M phi) obtained from patients with portal hypertension and ascites. The production of the cytokines interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) was found to be lipopolysaccharide (LPS) concentration dependent (0-10 micrograms/ml) with a maximal production at 10 micrograms/ml and also dependent on the time of exposure to the stimulus (0-36 h). IL-1 beta, IL-6 and TNF-alpha production after LPS administration reached a plateau at 24 h. In vitro stimulation for 24 h with LPS does not influence the eicosanoid production from endogenous arachidonate. 13 min of exposure of the cells to the calcium ionophore A23187 gives a significant increase in eicosanoid production from both exogenous and endogenous arachidonate. The main eicosanoids produced are the 5-lipoxgenase products LTB4 and 5-hydroxyeicosatetraenoic acid (HETE). The increase in production of the other eicosanoids is not significant. The eicosanoid production depends on the stimulus concentration. The optimal A23187 concentration is 1 microM. Oxygen radical production was measured in the M phi by a flowcytometric method. The fluorescence intensity of phorbol 12-myristate 13-acetate stimulated and dihydro-rhodamine 123 loaded hp-M phi increases significantly after 15 min. We conclude that LPS stimulation of hp-M phi from liver disease results in similar production of IL-1 beta, IL-6 and TNF-alpha, but that the profile of the eicosanoid production of these M phi stimulated with LPS and A23187 differs from M phi of other origin and species.

This study was performed to determine the selectivity of the 5-lipoxygenase inhibitor 6-Hydroxy-2- (4-sulfamoylbenzylamino)-4,5,7-trimethylbenzothiazole hydrochloride (E6080) on the in vitro eicosanoid metabolism in human peritoneal cells of patients with ascites. The IC50 for E6080 on the formation of the 5-lipoxygenase products LTB4 and 5-HETE was respectively 3.7 μM and 1.7 μM. The production of the other lipoxygenase (8-, 12-, 15-HETE) and cyclooxygenase products (HHT, 6kPGF1 α, TXB2, PGF2 α, PGE2 and PGD2) were not significantly inhibited in the dose range we have studied (0.3 μM–30 μM). E6080 is specific and equipotent to most of the known potent 5-lipoxygenase inhibitors.

This study was performed to determine whether 15-HETE, which is the major metabolite of arachidonic acid (AA) in inflamed and normal human colonic tissue, has pro- or anti-inflammatory properties. To investigate these effects, 15-HETE (100 micrograms/kg/day) was administered rectally to mice with colitis induced by dextran sodium sulphate (DSS). Colons were removed and examined macroscopically and histologically and specimens were incubated with [14C]-AA and stimulated with A23187. Exogenous eicosanoids were separated by HPLC; the endogenously formed mediators were measured by radioimmunoassay. DSS produced a marked diffuse inflammatory response in the colon, associated with a raised inflammation score (mean 7.6 vs. < 0.5) and a significant increase in endogenously formed metabolites PGE2, LTB4 and 12-HETE. 15-HETE treatment resulted in a slight decrease in inflammation score (6.4 vs. 7.6) and a slight, but not significant, decrease in endogenous LTB4.

Acetic acid induced colitis in rats was used to investigate the effects of malotilate, a drug which has been shown to inhibit 5-1ipoxygenase in human macrophages, the malotilate derivate ZY16268 and the flavenoid ZY16369 on the eicosanoid production and the colonic morphology in inflammatory bowel disease. Acetic acid produced an acute inflammatory response in the colon, associated with a markedly raised inflammation score (15.8 vs. < 0.5), based on a seven-scaled scoring system which includes observation of haemorrhage, submucosal oedema, cellular infiltration, goblet cell depletion, loss of architecture, crypt abscesses and serosal involvement, of which every item was subdivided as mild, moderate and severe. Incubation of colonic mucosa from rats treated with arachidonic acid and stimulated with A23187 showed an increase of the cyclooxygenase product 12-hydroxy-heptadecatrienoic acid (HHT) and the 12-1ipoxygenase product (12-HETE) and a decrease in the formation of 6-keto-prostaglandin F1α(6kPGF1α) in comparison with normal rat mucosa. Malotilate, ZY16268 and ZY16369 all resulted in a decrease in HHT, leukotriene B4(LTB4)-like compounds and 12-hydroxyeicosaenoic acid (12-HETE) production. None of the tested compounds significantly reduced the colonic damage by acetic acid although the formation of 12-HETE was proportional to the histologically obtained inflammation score. There were marked differences in eicosanoid formation patterns between rat and human mucosa, both normal and inflamed. In view of the hyperacute nature of the mucosal damage and the marked differences in eicosanoid production, acetic acid induced colitis in rats is probably not a suitable model of ulcerative colitis in humans.

Considerable evidence has accumulated to suggest that intracerebroventricular administration of enkephalinase inhibitors, which do not penetrate the blood-brain barrier, significantly attenuates opioid withdrawal syndrome. Therefore, the aim of this study was to examine the effect of intraperitoneal (i.p.) administration of orally active enkephalinase inhibitors, acetorphan (2.5-20 mg kg-1) and SCH 34826 (15-120 mg kg-1). These drugs significantly decreased the severity of the naloxone precipitated withdrawal syndrome in morphine dependent rats and mice. It therefore appears that these orally active enkephalinase inhibitors are promising tools in studying modulation of opioid dependence phenomena.

To evaluate indicators of inflammatory changes in the airways of young smokers we have measured the levels of several eicosanoids in bronchoalveolar lavage (BAL) fluid of 18 female smokers (age 33 +/- 2 years) and 9 female non-smokers (age 29 +/- 2 years) who were hospitalized for treatment not related to any pulmonary disease. In each BAL specimen the following eicosanoids were determined by radioimmunoassay: prostaglandin (PG) E2; PGF2 alpha; 9 alpha, 11 beta-PGF2, a metabolite of PGD2; 6-keto PGF1 alpha, a metabolite of prostacyclin; thromboxane (Tx) B2, a metabolite of TxA2; the 5-lipoxygenase products 5-hydroxy-eicosa-tetraenoic acid (HETE), leukotriene (LT) B4 and LTC4; the 12-lipoxygenase product 12-HETE; and the 15-lipoxygenase product 15-HETE. The concentrations of the cyclooxygenase products (pg ml-1) in the BAL fluid of the non-smokers were: PGE2 15.4 +/- 1.9, PGF2 alpha 7.6 +/- 1.0, 9 alpha, 11 beta-PGF2 8.7 +/- 1.8, TxB2 8.8 +/- 1.3, and 6-keto PGF1 alpha only 1.5 +/- 0.8. The concentration of the lipoxygenase products were: 15-HETE 781 +/- 200, 12-HETE 193 +/- 33, 5-HETE 14.0 +/- 3.1, LTC4 9.5 +/- 3.1, LTB4 6.2 +/- 1.4. BAL fluid from smokers contained two- to three-fold higher levels of TxB2 and PGF2 alpha (P less than 0.05). The levels of TxB2 and PGF2 alpha were positively correlated to the number of package years (rs = 0.55 and rs = 0.65, P less than 0.02). The concentrations of 5-, 12- and 15-HETE tended to be higher in BAL fluid from smokers, but this was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study the question was addressed whether cAMP mediated drugs induce a differential reduction of branches of the arachidonic acid metabolism rather than a global reduction of eicosanoid synthesis. The isolated lungs of actively sensitized rats were employed to study prostaglandin and leukotriene release in the presence and absence of the cAMP mediated drugs theophylline, milrinone, sulmazole, isobutyl-methylxanthine and salbutamol. The release of eicosanoids as measured by RIA was predominantly basal and continuous, with a mild antigen induced stimulation only for TXB2and the leukotrienes. All drugs reduced eicosanoid release globally. It is concluded that cAMP mediated drugs interfere with arachidonic acid metabolism at a site proximal to the branching into lipoxygenase and cyclo-oxygenase pathways.

Pieces of tumor tissue were implanted subcutaneously in the right flank of BN female rats. After 3, 7, 10, 12, 14 and 17 days the lungs were lavaged and the alveolar macrophages collected. The cells were activated with the calcium ionophore A23187 and the formation of thromboxane B2 (TxB2), leukotriene B4 (LTB4) and 12-hydroxyeicosatetraenoic acid (12-HETE) determined. The formation of TxB2 decreased considerably until day 7. Thereafter, no changes occurred. The formation of LTB4 increased after the tumor implantation until day 10 and remained stable for the rest of the period, 12-HETE formation was approximately similar, with a decrease at day 12 but continued to increase after day 14. These results suggest that during tumor growth an inhibition of the cyclo-oxygenase or thromboxane synthase occurs and an activation of the C5- and C12-lipoxygenases of the alveolar macrophages.

We examined the role of platelet activating factor in dextran induced colitis in mice. The release of pro-inflammatory platelet activating factor by colonic mucosa after the application of prednisolone was markedly decreased, unaffected after treatment with the platelet activating factor receptor antagonist BN52021 and significantly increased after treatment with 5-amino-salicylic acid and diclofenac. This increase of platelet activating factor could be responsible for the harmful effects often seen after treatment with specific cyclooxygenase inhibitors during inflammation.