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S Endres

Publications and source records attributed to S Endres.

At least 73 records · Page 4Linked to original sources
PubMed1996

The clinical relevance of circulating tumor necrosis factor-alpha in acute decompensated chronic heart failure without cachexia.

STUDY OBJECTIVE: To evaluate the clinical relevance of circulating tumor necrosis factor-alpha (TNF alpha) in subjects with advanced acutely decompensated congestive heart failure (CHF) and to determine the modulatory effect of clinical interventions on short-term elaboration of this cytokine. DESIGN: Prospective, case-controlled study. SETTING: Inpatient and outpatient (hospital and clinic), at regional academic medical center. PATIENT INTERVENTIONS: Plasma concentrations of TNF alpha were determined in 25 healthy, normal control subjects and in 29 noncachectic patients with advanced CHF (mean ejection fraction = 16 +/- 6%) who required hospitalization for i.v. diuretic and/or inotropic therapy despite optimization of oral medical regimens. CHF patients were divided into two groups: diuretic responsive (group A; n = 6) and diuretic resistant requiring inotropic support (group B; n = 23). Group B was randomly allocated to receive either i.v. dobutamine (n = 13) or milrinone (n = 10) for 72 h. TNF alpha levels in CHF patients were measured serially at baseline, at 6 h, at 48 h, at 72 h, and at 1-week follow-up after hospital discharge. RESULTS: Plasma TNF alpha levels at baseline in CHF patients were 4.0 +/- 1.1 pg/mL (range, 0.5 to 6.5 pg/ mL) and 2.5 +/- 0.6 pg/mL (range, 0.5 to 6.8 pg/mL) in groups A and B, respectively, which were significantly different (p < 0.002) from normal subjects (0.89 +/- 0.40 pg/mL; range, 0.5 to 9.7 pg/mL). Despite clinically successful therapy with i.v. diuretics, dobutamine, or milrinone, plasma levels of this cytokine remained unchanged. Plasma TNF alpha in CHF patients measured in recovery (1 week after hospital discharge) was 5.1 +/- 1.2 pg/mL (range, 1.0 to 9.9 pg/mL) and 3.9 +/- 0.8 pg/mL (range, 0.5 to 8.7 pg/mL) in groups A and B, respectively. CONCLUSION: These findings suggest that although noncachectic patients with chronic heart failure who suffer acute decompensation elaborate significantly higher circulating levels of TNF alpha compared with healthy control subjects, no significant reduction or alteration in circulating TNF alpha is noted in the short-term follow-up despite clinical improvement.

Acute Disease↗
PubMed1996

[n-3 fatty acids and cardiovascular diseases: update to 1996].

n-3 Fatty acids (mostly eicosapentaenoic and docosahexaenoic acid) continue to elicit research interest as dietary or pharmacological agents able to prevent or retard the progression of atherosclerosis and its clinical manifestations. Significant advances have occurred over the past five years in understanding their mechanism of action, including anti-atherogenic, anti-thrombotic and anti-arrhythmic properties. In parallel, clinical studies have continued the evaluation of these compounds in the prevention of cardiovascular disease. Recent epidemiological studies have in general confirmed the hypothesis of a relevant anti-atherogenic effect, although this has not necessarily translated into clinical benefits in selected, relatively low-risk populations. Recent negative studies in trials of restenosis prevention after coronary angioplasty have tempered the initial enthusiasm as a possible preventive strategy in this subset, although reasons for discrepancies among past trials still await conclusive explanations. A recent dietary intervention trial in post-myocardial infarction patients has renewed the interest for alpha-linolenic acid, both as the metabolic precursor of eicosapentaenoic and docosahexaenoic acid, and as a fatty acid with direct specific properties.

Animals↗
PubMed1996

Oligodeoxynucleotides enhance lipopolysaccharide-stimulated synthesis of tumor necrosis factor: dependence on phosphorothioate modification and reversal by heparin.

BACKGROUND: Specific inhibition of target proteins by antisense oligodeoxynucleotides is an extensively studied experimental approach. This technique is currently being tested in clinical trials applying phosphorothioate-modified oligonucleotides as therapeutic agents. These polyanionic molecules, however, may also exert non-antisense-mediated effects. MATERIALS AND METHODS: We examined the influence of oligonucleotides on lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF alpha) synthesis in freshly isolated human peripheral blood mononuclear cells. Oligonucleotides (18 mer) with different degrees of phosphorothioate modification were studied. RESULTS: The addition of phosphorothioate oligonucleotides (5 microM) caused amplification of TNF synthesis of up to 410% compared with the control with LPS alone. Without LPS stimulation, phosphorothioate oligonucleotides did not induce TNF production. We demonstrate that the enhancement of LPS-stimulated TNF production by phosphorothioate oligonucleotides does not rely on the intracellular presence of oligonucleotides and is not mediated by LPS contamination. Partially phosphorothioate-modified oligonucleotides and unmodified oligonucleotides did not increase TNF synthesis. High concentrations of the polyanion heparin reversed the oligonucleotide-induced enhancement of TNF synthesis. CONCLUSIONS: The data suggest that amplification of TNF synthesis may be caused by binding of the polyanionic phosphorothioate oligonucleotide to cationic sites on the cell surface. Such binding sites have been proposed for polyanionic glycoaminoglycans of the extracellular matrix, which have also been described to augment LPS-stimulated TNF synthesis. The present results are relevant to all in vitro studies attempting to influence protein synthesis in monocytes by using phosphorothioate oligonucleotides. The significance of our findings for in vivo applications of phosphorothioates in situations where there is a stimulus for TNF synthesis, such as in sepsis, should be elucidated.

Animals↗
PubMed1996

Synthesis of tumour necrosis factor-alpha in tissue culture of rat caecum: lack of suppression by phosphodiesterase inhibitors and prostanoids.

Tumour necrosis factor-alpha (TNF) plays a pivotal role in acute and chronic inflammatory processes. It has been demonstrated that TNF is a mediator in inflammatory bowel disease. In the past different pharmacological approaches have been identified to suppress TNF synthesis in lipopolysaccharide-stimulated human mononuclear cells by cAMP-elevating agents. In the present study we examine whether TNF synthesis in the colon underlies similar regulatory mechanisms as in mononuclear cells. We therefore established a short-time organ culture of rat caecum. In this model we obtained maximal TNF formation of 159 pg/ml after a 7-h incubation period, as determined by L929 bioassay. The formation of bioactive TNF was confirmed by the application of neutralizing TNF antibody in the L929 bioassay and by immunodot blot. Lipopolysaccharide and pokeweed mitogen did not further enhance TNF synthesis. In contrast, TNF production was suppressed to 25% of control by 5 micrograms/ml hydrocortisone. Unexpectedly, the specific type IV phosphodiesterase inhibitor rolipram and cicaprost, a stable prostacyclin analogue, did not achieve significant suppression of TNF synthesis in this model. The present study defines an experimental model to investigate ex vivo TNF synthesis in rat colonic tissue. Applying this model, cAMP-elevating agents are identified as poor candidates for TNF-suppressing strategies in inflamed colon.

Animals↗
PubMed1996

[Severe protracted cholestasis after general anesthesia in a patient with Alagille syndrome].

A 27-year-old female patient with partial Alagille's syndrome (hypoplasia of the intrahepatic bile ducts, typical facial dysmorphism and skeletal anomalies) developed a marked cholestasis (total bilirubin 59 mg/dl), decrease of liver synthesis tests and ascites four weeks after gynecological surgery with general anesthesia involving propofol, isoflurane and nitrous oxide. Slow recovery could be achieved under treatment with ursodeoxycholic acid, spironolactone and substitution of fat-soluble vitamins A, D, E and K. Four months after admission the ascites had disappeared, liver synthesis had increased and the total bilirubin level had dropped to 3.8 mg/dl. Since all other possible causes were excluded during the hospital stay, the prolonged episode of cholestasis in this patient is best explained by the preceding general anesthesia with propofol which is known to be metabolized in the liver and impedes hepatic cytochrome P450 and hepatic blood flow.

Adult↗
PubMed1995

Exogenous and endogenous nitric oxide attenuates tumor necrosis factor synthesis in the murine macrophage cell line RAW 264.7.

Effects of TNF on nitric oxide (NO) production have been well documented in a variety of experimental and clinical settings, as for example, in septic shock. Investigations focusing on an inverse relation of NO on TNF synthesis are rare. Previously we could demonstrate that exogenous NO-releasing agents suppress LPS-induced TNF production in human PBMC. We now investigate whether a regulatory role on TNF synthesis could also be ascribed to endogenous NO. This was studied in the murine macrophage cell line RAW 264.7, which is able to express both TNF and the inducible NO synthase. No production was determined by measuring nitrite with Griess reagents. TNF formation was quantified by L929 cytotoxicity. We found a suppression of LPS-induced TNF synthesis by the exogenous addition of NO-releasing agents in the murine cell line, as previously observed in human cells. The application of NO synthase inhibitors led to a decrease in NO production, associated with an increase in TNF synthesis. TNF production increased from a base line (stimulation with 1 microgram/ml LPS alone) of 20.8 ng/ml to 36.3 ng/ml (means of six experiments) in the presence of the NO synthase inhibitor NG-monomethyl L-arginine (100 microM). Similar results were obtained with another NO synthase inhibitor, NG-nitro L-arginine-methylester. Lack of L-arginine in the medium resulted in a threefold increase in LPS-stimulated TNF synthesis compared with medium containing the usual concentration of 1 mM L-arginine. Restitution of L-arginine but not of D-arginine reversed this increase in TNF synthesis in a dose-dependent manner. To our knowledge these results indicate for the first time a negative feedback by endogenous NO on TNF synthesis in vitro. This finding may be relevant in pathophysiologic processes in which both TNF and NO are formed and in experimental therapies aiming at changes of NO concentrations.

Animals↗
PubMed1995

Enhanced tumor necrosis factor suppression and cyclic adenosine monophosphate accumulation by combination of phosphodiesterase inhibitors and prostanoids.

We investigated cooperative effects of phosphodiesterase (PDE) inhibitors and prostanoids on cyclic adenosine monophosphate (cAMP) accumulation and tumor necrosis factor (TNF)-alpha synthesis in human peripheral blood mononuclear cells (PBMC). PDE inhibitors alone induced only a small increase in cAMP levels in lipopolysaccharide (LPS)-stimulated PBMC. Cicaprost (a stable analogue of prostacyclin) and pentoxifylline added simultaneously to LPS-stimulated PBMC (2.0 x 10(6)/ml) induced a rapid increase of cAMP to a level of 100 nM that peaked within 10 min and remained at a plateau for up to 4 h. Thus combined prostanoids and PDE inhibitors enhanced cAMP accumulation. TNF-alpha suppression in the presence of pentoxifylline and prostanoids exceeded that of either drug alone. The potency of different PDE inhibitors (theophylline, pentoxifylline, penthydroxifylline, albifylline, torbafylline, A 80 2715, amrinone and rolipram) to increase cAMP levels in combination with cicaprost was evaluated after 1 h of incubation. The dose-dependent increase of cAMP for all PDE inhibitors tested in this combined stimulation provided a useful tool for evaluating the potency of PDE inhibitors on cAMP accumulation. The effective concentration of PDE inhibitors, which raised cAMP levels to 300% of control, (EC300), correlated with the IC50 for TNF-alpha suppression (r = 0.930, p = 0.007, with theophylline excluded from the analysis). Interestingly, by contrast, the specific type IV PDE inhibitor rolipram caused only a moderate rise of accumulated cAMP in the same cells. Our data support cAMP as an essential mediator for TNF-alpha suppression by PDE inhibitors. Furthermore, an enhanced inhibiting effect on TNF-alpha production may prove therapeutically advantageous. It may occur in inflammatory and infectious diseases in vivo, since high levels of endogenous prostaglandins are liberated in these conditions.

Cells, Cultured↗
PubMed1995

The specific type IV phosphodiesterase inhibitor rolipram differentially regulates the proinflammatory mediators TNF-alpha and nitric oxide.

We compared the effect of the specific type IV phosphodiesterase inhibitor rolipram on intracellular cAMP concentration, nitric oxide (NO) and tumour necrosis factor-alpha (TNF) formation in the murine macrophage cell line RAW 264.7. We found a dose-dependent increase of nitrite accumulation in LPS-stimulated macrophages from 17.5 to 25.1 microM nitrite with rolipram, whereas TNF synthesis was suppressed to less than 30% of control. This was accompanied by an increase from 7.4 to a maximum of 10.5 nM cAMP in RAW cells incubated with rolipram. These results were confirmed with the stable cAMP analogue (S)-p-adenosine 3',5'-cyclic phosphorothioate [(S)-p-cAMPS]. These findings demonstrate that elevation of cAMP in RAW 264.7 cells by rolipram decreases TNF synthesis and increases NO formation.

Animals↗
PubMed1995

Radioimmunoassays for cyclic AMP cross-react with phosphodiesterase inhibitors and buffer components.

We addressed the issue of cross-reactivity of several commonly used phosphodiesterase inhibitors with radioimmunoassays for cyclic AMP, after we had observed a considerably high cross-reactivity with a noncommercial antibody. Theophylline, pentoxifylline, penthydroxifylline (BL 194), albifylline (HWA 138), torbafylline (HWA 448), A 80 2715, isobutyl methylxanthine, and the nonmethylxanthines amrinone and rolipram were dissolved in supplemented and boiled cell culture medium (RPMI 1640). These samples were assayed for apparent cyclic AMP in two different, commercially available radioimmunoassay kits (based on polyclonal antibodies), applying the nonacetylated protocol. Cross-reactivity was dose-dependent and nonlinear. Samples containing theophylline and amrinone exhibited the strongest cross-reactivity in assay A (NEN/DuPont): 3.0 +/- 0.5(-nM) and 2.4 +/- 1.1 (-nM) apparent cyclic AMP +/- SD at 1-nM spike, respectively. With the more sensitive assay B (Amersham), higher concentrations of apparent cyclic AMP were detected: from 7.9 +/- 0.4 nM (for albifylline) to 3.5 +/- 0.1 nM (for rolipram). Values were calculated from standard curves set up in the respective assay buffer, where culture medium controls resulted in 1.8 +/- 0.3 nM and 3.1 +/- 0.1 nM for assay A and B, respectively. The culture medium interference increased with rising cyclic AMP concentrations. Although comparatively low, this degree of cross-reactivity is relevant for in vitro experiments. Phosphodiesterase inhibitors are commonly administered at millimolar concentrations, and resulting cyclic AMP levels are often in the nanomolar range. Neglecting these findings may lead to falsely high readouts of cyclic AMP concentrations.

Buffers↗
PubMed1995

Rolipram, a specific type IV phosphodiesterase inhibitor, is a potent inhibitor of HIV-1 replication.

OBJECTIVE: To determine the effects of rolipram, a specific type IV phosphodiesterase inhibitor, on tumor necrosis factor (TNF)-alpha production and HIV-1 replication. DESIGN: TNF-alpha enhances HIV-1 replication in vitro; blocking TNF-alpha and thereby inhibiting HIV-1 replication may therefore potentially delay progression of HIV disease. Pentoxifylline is a non-specific phosphodiesterase inhibitor that blocks TNF-alpha synthesis and HIV-1 replication in vitro and has been shown in preliminary clinical studies to decrease viral replication in HIV-1-infected patients. Rolipram, which selectively inhibits the predominant phosphodiesterase isoenzyme of monocytes, inhibits lipopolysaccharide (LPS)-induced TNF-alpha with 500-fold greater potency than pentoxifylline. We, therefore, hypothesized that rolipram would be a powerful inhibitor of HIV-1 replication. METHODS: The effects of rolipram and pentoxifylline on TNF-alpha production and HIV-1 replication were determined in infected and uninfected peripheral blood mononuclear cells (PBMC), in a chronically infected promonocytic cell line (U1) and in an acutely infected monocytic cell line (BT4A3.5). TNF-alpha was determined by specific radioimmunoassay and HIV-1 replication was measured by p24 antigen and HIV-1 mRNA production. RESULTS: Rolipram inhibited TNF-alpha production in LPS- and phorbol myristate acetate (PMA)-stimulated PBMC and in PMA-stimulated U1 cells. Rolipram also inhibited HIV-1 replication in the U1 cell line, as well as in acutely infected PBMC and BT4A3.5 cells. Depending on the experimental conditions, rolipram was 10-600 times more potent, on a molar basis, than pentoxifylline. CONCLUSION: Rolipram is a potent inhibitor HIV-1 replication and therefore deserves further investigation as a potential therapeutic agent in the treatment of HIV-1-infected patients.

Cell Line↗
PubMed1995

n-3 polyunsaturated fatty acids: update 1995.

Epidemiologic and biochemical studies have suggested an anti-inflammatory effect of n-3 fatty acids. Beneficial therapeutic effects reported from small patient groups need to be confirmed in large-cohort controlled clinical trials. There is a growing number of clinical trials of n-3 fatty acid supplementation in disease. Clinical benefits have been moderate in patients with rheumatoid arthritis and with arterial hypertension. Clearly negative results have been reported during the past 2 years for patients with lupus nephritis and for patients with psoriasis or with atopic dermatitis. Such trials have now been completed. For patients with coronary artery disease following coronary angioplasty, earlier results of a large meta-analysis, could not be confirmed. For patients with IgA-nephropathy and for patients following kidney transplantation, a clear benefit was seen in patients receiving fish oil. These promising results are currently pursued in follow-up phase III clinical trials.

Animals↗
PubMed1994

n-3 fatty acids and renal diseases.

There are numerous biologic rationales for the use of n-3 fatty acids in renal diseases, including a possible increase in the renal vasodilatory capacity by a rearrangement of renal prostanoid production, a reduction in the production of proinflammatory leukotrienes, a reduction in the transcapillary escape rate of albumin, and actions limiting cyclosporine-related nephrotoxicity. Studies of animal models of renal disease, mostly of immune-renal disease, support the idea of the possible usefulness of these compounds. The most promising areas of clinical investigation include the reduction of proteinuria in some chronic glomerular diseases, the treatment of immunoglobulin A nephropathy, and the prevention of cyclosporine-induced nephrotoxicity. However, the results of larger clinical studies, some of which are ongoing, are necessary to support the use of n-3 fatty acids in human renal diseases.

Animals↗
PubMed1994

Delayed treatment with platelet activating factor receptor antagonist web 2086 attenuates pulmonary dysfunction in porcine endotoxin shock.

The triazolodiazepine WEB 2086, a specific platelet activating factor (PAF) receptor antagonist, has previously been shown to prevent pulmonary hypertension, hypoxia, and bronchoconstriction when given before bacterial lipopolysaccharide (LPS). The aim of the present study was to examine whether WEB 2086 reduced these changes even when given after the onset of LPS-induced shock. In a randomized trial LPS was given intravenously (i.v.) in a dose of 1 microgram/kg/h for 8 hours to anesthetized, ventilated pigs. Ten animals received LPS and WEB 2086, 10 mg/kg/h i.v. for 6.5 hours, beginning 1.5 hours after LPS. Ten control animals received LPS and saline. During treatment with WEB 2086, pulmonary hypertension was significantly attenuated compared with the findings in the control group. Gas exchange, airway pressure, extravascular lung water levels, intrapulmonary shunt, and cathepsin B levels in plasma showed a trend toward improvement but the group differences were not statistically significant. These data indicate that the PAF antagonist WEB 2086 can partially block pulmonary dysfunction and enzyme release from inflammatory cells when given during ongoing LPS shock in pigs, and that PAF may be an important mediator of the cardiopulmonary changes seen in septic shock.

Animals↗
PubMed1994

Amrinone suppresses the synthesis of tumor necrosis factor-alpha in human mononuclear cells.

Tumor necrosis factor-alpha (TNF) exerts a wide spectrum of biological activities and contributes to the pathophysiology of septic shock. Elevated circulating levels of TNF have also been reported in patients with severe chronic heart failure. We studied the effect of amrinone, a class III cyclic nucleotide phosphodiesterase inhibitor used in the treatment of acute heart failure, on the synthesis of TNF in vitro. Peripheral blood mononuclear cells from healthy volunteers or cells of a permanent monoblast cell line were stimulated for 20 h with bacterial lipopolysaccharide and different doses of amrinone. TNF production is suppressed in a dose-dependent manner to a minimum of 9% of controls with 1000 microM of amrinone, reaching half-maximal inhibition at 80 microM amrinone. This effect appears to be mediated via cAMP, which accumulated nearly twofold in the presence of amrinone. Suppression of TNF synthesis by therapeutically administered phosphodiesterase inhibitors such as amrinone may contribute to their beneficial effect in the treatment of heart failure.

Amrinone↗
PubMed1993

Nitric oxide-releasing agents enhance cytokine-induced tumor necrosis factor synthesis in human mononuclear cells.

In septic shock tumor necrosis factor (TNF) leads to increased nitric oxide (NO) production by induction of NO synthase. An inverse regulatory effect, the influence of NO on cytokine synthesis, has rarely been investigated. The present study assessed the influence of NO-releasing agents on TNF production from interleukin-1 alpha (IL-1 alpha)-stimulated human peripheral blood mononuclear cells (PBMC). 3-Morpholino-sydnonimine (SIN-1) enhanced IL-1 alpha-induced TNF synthesis to a maximum of 272% (mean of n = 5 donors), with 100% set as TNF production by stimulation with IL-1 alpha alone. This finding was confirmed using another NO-donor, i.e., sodium nitroprusside (SNP). The effect was specific for TNF compared to the uninfluenced synthesis of IL-1 beta. Kinetic analysis showed the most pronounced increase in TNF synthesis when SIN-1 was added during the first 60 min after IL-1 alpha addition. These data reveal an enhancing effect of NO on cytokine-induced TNF synthesis. It may contribute to the regulation of TNF synthesis in pathological processes such as microbicidal activity, tumor cell lysis or endothelium-mediated hypotension.

Humans↗