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B A Peskar

Publications and source records attributed to B A Peskar.

At least 145 records · Page 8Linked to original sources
PubMed1986

The effects of acidic and nonacidic pyrazoles on arachidonic acid metabolism in mouse peritoneal macrophages.

The effects of acidic and nonacidic pyrazole derivatives and their metabolites on arachidonic acid metabolism have been investigated in mouse peritoneal macrophages stimulated with the calcium ionophore A 23 187 (10(-6) Mol/l). In the group of the acidic compounds with anti-inflammatory properties, phenylbutazone and butyl malonic acid mono (1-phenylhydrazide), the hydrolysis product of mofebutazone, inhibited prostaglandin production in a dose-dependent manner (10(-4)-10(-6) Mol/l). In contrast, mofebutazone itself and its hydroxylation product, 4-OH-mofebutazone, failed to show any activity. Similarly, in the case of bumadizone, an anti-inflammatory drug structurally related to phenylbutazone, no inhibitory effect on prostaglandin release was found either. The nonacidic pyrazole derivatives with antipyretic and anti-inflammatory activity, antipyrine, isopropylaminophenazone, as well as metamizol and its active metabolites 4-methylaminophenazone and 4-aminophenazone, also inhibited prostaglandin release dose-dependently. This was found to be paralleled by an increased leukotriene C4 production. Neither of the main excretory metabolites of metamizol, acetyl- and formylaminophenazone, showed any effect. The concentration levels at which the nonacidic compounds affected arachidonic acid metabolism (approx. 10(-4) Mol/l) were high enough to elicit anti-inflammatory effects. They were far higher, though, than the plasma levels producing antipyretic and analgesic effects that are reached after therapeutic doses.

Aminopyrine↗
PubMed1986

Effect of anti-inflammatory and analgesic pyrazoles on arachidonic acid metabolism in isolated heart and gastric mucosa preparations.

The effects of acidic and nonacidic pyrazoles on the release of arachidonic acid-derived mediators from isolated perfused anaphylactic guinea pig hearts as well as rat and human gastric mucosa were investigated. High concentrations of the acidic drugs phenylbutazone and oxyphenbutazone as well as of the nonacidic metabolites of metamizol, i.e. 4-methylaminoantipyrine and 4-aminoantipyrine, inhibited the release of the cyclo-oxygenase products of arachidonic acid metabolism, TXB2 and 6-keto-PGF1 alpha, and simultaneously increased the release of LTC4-like immunoreactivity in hearts. By contrast, comparatively high concentrations of the metamizol metabolites 4-formylaminoantipyrine and 4-acetylaminoantipyrine were without effect. The comparable effects of acidic and nonacidic pyrazoles on eicosanoid release from anaphylactic hearts support the concept that hypersensitivity reactions to NSAIDs are related to their effect on arachidonic acid metabolism. The anti-inflammatory effects of phenylbutazone and oxyphenbutazone and of high concentrations of metamizol seem to be correlated with the inhibition of cyclo-oxygenase. On the other hand, lower concentrations of metamizol, which have analgesic and anti-pyretic effects, only marginally inhibit cardiac cyclo-oxygenase. It remains to be investigated whether the partial inhibition of the synthesis of PGI2, a major hyperalgesiccyclo-oxygenase product of arachidonic acid metabolism, at lower concentrations of the active metamizol metabolites contributes to the analgesic effect of metamizol. The acidic NSAID mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) had no effect on the cardiac release of arachidonic acid-derived cyclo-oxygenase and lipoxygenase products. The anti-inflammatory effect of these compounds requires further investigation. In isolated gastric mucosa, the active metabolite of metamizol 4-methylaminoantipyrine was found to inhibit fatty acid cyclo-oxygenase dose-dependently. Pharmacokinetic differences due to the nonacidic structure of metamizol and its metabolites as compared to acidic NSAIDs may be responsible for the fact that metamizol is better tolerated than e.g. indomethacin. In rat experiments, phenylbutazone was found to inhibit gastric mucosal cyclo-oxygenase like indomethacin. On the other hand, mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) did not affect gastric mucosal synthesis of 6-keto-PGF1 alpha. This lack of effect on gastric mucosal cyclo-oxygenase seems to be correlated with the considerably lower gastric toxicity of mofebutazone as compared to phenylbutazone.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Allergic and pseudoallergic reactions to non-narcotic analgesics.

Pulmonary side effects are relatively rarely observed with analgesics and anti-inflammatory drugs. However, some patients react to the ingestion of such drugs with bronchoconstriction and asthmatic attacks. In only a small percentage of these patients is a true allergic mechanism underlying the pulmonary reaction to the drugs. In most of the patients the basis for the pulmonary side effects is pseudoallergic. The molecular mechanism of pseudoallergy is not completely understood. However, several hypotheses have been put forward, such as drug-induced stimulation of kinin receptors, activation of the complement system or interference with eicosanoid biosynthesis. The last hypothesis is attractive, since it could explain the similar sensitivity of such patients to drugs which are completely different chemically. It is not known, however, if the crucial drug effect on arachidonic acid metabolism is inhibition of synthesis of a bronchodilator eicosanoid such as prostaglandin E2 or increased synthesis of bronchoconstrictor eicosanoids such as leukotrienes.

Analgesics↗
PubMed1985

[Defects in the prostaglandin system. IV. Inborn, nonfamilial plasma factor deficiency].

On routine screening of 143 newborn infants, complete plasma factor deficiency was discovered in 4 cases. All the relatives, however, exhibited normal plasma factor activity. Up to now all 4 babies are healthy. Long-term follow up should clarify whether an inborn plasma factor deficiency might predispose to diseases accompanied by haemostatic imbalance.

Biological Assay↗
PubMed1985

[Defects in the prostaglandin system. V. Inherited (?) disorder of prostacyclin degradation in the plasma (Wien-Döbling defect)].

The case report is presented of a woman of child-bearing age who developed myocardial infarction. An extremely shortened in vitro half-life of PGI2 in plasma was detected in this patient. This new familial defect "Wien-Döbling", in the prostaglandin system might affect an essential coregulator of haemostatic balance in man. It is not known whether this short half-life of PGI2 in vitro is due to accelerated degradation or a failure in stabilization of this biologically active compound.

Adult↗
PubMed1985

[Accelerated degradation of prostacyclin in diabetic plasma--a further factor in the impairment of hemostatic balance?].

Prostacyclin is degraded in human plasma in vitro with an average half-life of 10 minutes. The degradation in plasma of patients suffering from type II diabetes mellitus is significantly enhanced. However, the inactivation of prostacyclin in plasma in patients with clinical manifestations of atherosclerosis, such as peripheral vascular disease, is unchanged. Methodological studies reveal that storage of plasma at various temperatures up to investigation, repeated freezing and thawing, as well as the addition of thromboxane-synthetase inhibitors do not exert any effect on plasmatic degradation of PGI2. In addition, no differences are found in plasmatic degradation in diabetics in accordance with the mode of treatment. The presence of a factor in human plasma in diabetics capable of increasing PGI2 degradation or the loss of a possible stabilizer could be one further important parameter, amongst others responsible for the development of either macro- or microangiopathy in diabetes mellitus.

Aged↗
PubMed1985

Monoclonal antibodies against E- and F-type prostaglandins. High specificity and sensitivity in conventional radioimmunoassays.

Polyclonal antisera against prostaglandins (PGs) are widely used for the assessment of the biological role of these mediators, but even the most specific contain antibodies against the major metabolites and degradation products of the haptens employed. To overcome this inherent problem we produced monoclonal antibodies (mAs) against PGE2, PGF2 alpha and 6-keto-PGF1 alpha using the somatic cell hybridization technique. The mAs against 6-keto-PGF1 alpha and PGF2 alpha proved to be highly specific, but allowed only for moderate detection limits (1-2 ng) in conventional fluid phase radioimmunoassays (RIAs). One of the mAs against PGE2 permitted a 100-fold improvement in the detection limit while being almost devoid of cross-reactivity with metabolites and other structurally related PGs. These results show that highly specific mAs against PGs can be produced to improve the available RIA technique for PG quantification.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

The prostacyclin synthesis stimulating plasma factor is unchanged during acute angina pectoris.

Earlier studies have demonstrated that the levels of prostacyclin synthesis stimulating plasma factor are changed during various clinical situations thus leading to disturbances in hemostatic balance. Therefore, we studied the plasma factor in 20 patients undergoing acute anginal attacks in order to see whether there is any influence or a timedependent change after the event. The patients were subdivided into males or females as well as into those with or without maturity onset diabetes and who were smokers or no-smokers. As in-vitro test systems the rat abdominal aorta, human coronary artery and cultured endothelial and smooth muscle cells obtained from minipigs were used. Our findings demonstrate that incubating the different tissue samples in plasma leads to a significant increase of prostacyclin formation or of its stable breakdown 6-oxo-PGF1 respectively, in comparison to buffer control incubation. However, in none of the groups was a change observed during an anginal attack or in rate 60 and 120 minutes thereafter. These findings suggest that the prostacyclin synthesis stimulating plasma factor is not involved in hemostatic dysregulation, which has been observed to occur during and immediately after a coronary anginal attack.

Adult↗
PubMed1985

Pharmacological modification of leukotriene release and coronary constrictor effect in cardiac anaphylaxis.

The modification of anaphylactic release of leukotriene (LT) C4-like immunoreactivity from isolated guinea pig hearts and of LT-induced coronary constriction by the muscarinic receptor against methacholine and by various exogenous prostaglandins (PG) was investigated. The vasodilators PGI2 and PGE2 as well as the vasoconstrictors PGD2, PGF2alpha, and 11,9-epoxymethano-PGH2, a PG endoperoxide analogue with biological properties similar to thromboxane (TX) A2, inhibited the anaphylactic coronary constriction without affecting release of LTC4-like immunoreactivity. On the other hand, the increased anaphylactic LT release in the presence of methacholine was not paralleled by more pronounced coronary constriction after challenge. The results suggest that the coronary constrictor effect of endogenous LT is modified by the drugs used by direct vascular effects and/or effects on other anaphylactic mediators.

Anaphylaxis↗
PubMed1985

Modulation of eicosanoid release from anaphylactic guinea-pig heart with 5-benzoyl-a-methyl-2-thiophene acetic acid (tiaprofenic acid).

The effects of infusion of the non-steroidal anti-inflammatory drugs (NSAID), tiaprofenic acid (2.2 micrograms/min or 10.0 micrograms/min) and indomethacin (1.0 microgram/min) on the release of leukotriene (LT) C4-like immunoreactivity, thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1 alpha from isolated perfused anaphylactic guinea-pig hearts were investigated. Tiaprofenic acid at both concentrations used significantly inhibited anaphylactic release of TXB2 and 6-keto-PGF1 alpha as did indomethacin (1.0 microgram/min) which was, however, about ten times more potent in this respect. Release of immunoreactive LTC4-like material was not influenced by the lower concentration of tiaprofenic acid used (2.2 micrograms/min), but significantly enhanced by the higher concentration (10.0 micrograms/min). Thus, the effect of tiaprofenic acid on eicosanoid release by the anaphylactic heart is very similar to that of indomethacin without any differential inhibition of TXB2 or 6-keto-PGF1 alpha formation.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Modulation by drugs of leukotriene and prostaglandin production from mouse peritoneal macrophages.

Leukotriene and prostaglandin production by mouse peritoneal macrophages was investigated. It could be shown that the tumour promoter 12-O-tetradecanoylphorbol-13-acetate, despite initiating the release of prostaglandin E2, had little effect on the release of leukotriene C4-like immunoreactivity. The divalent cation ionophore A 23187 at concentrations between 10(-6) and 10(-8) mol/l initiated prostaglandin as well as leukotriene release. This prostaglandin and leukotriene release could be modulated by drugs. Non-steroidal anti-inflammatory drugs inhibited prostaglandin release but enhanced leukotriene production. The experimental compound BW 755C inhibited prostaglandin and leukotriene production, whereas the antithrombotic compound nafazatrom inhibited the production of leukotriene C4-like immunoreactivity but enhanced the prostaglandin E2 production. Nordihydroguaiaretic acid inhibited prostaglandin and leukotriene production. The results show that the metabolism of arachidonic acid in macrophages via the cyclooxygenase or the lipoxygenase pathway is dependent on the stimulus applied. Both pathways can be inhibited conjointly or selectively by drugs. The experimental system described may be used for assessing the potency of drugs to inhibit the lipoxygenase and the cyclooxygenase pathway of arachidonic acid metabolism.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Release and vasoconstrictor effect of leukotriene C-like immunoreactive material in the anaphylactic guinea-pig mesenteric vascular bed.

Antigen challenge of sensitized isolated guinea-pig mesentery perfused under constant pressure resulted in a significant flow reduction, which was paralleled by the release of leukotriene (LT)C4-like immunoreactivity into the perfusates. The lipoxygenase inhibitor quercetin inhibited the release of immunoreactive LTC4 and simultaneously abolished the antigen-induced mesenteric flow reduction. Mesenteric flow reduction was also observed after injection of exogenous LTC4. The results demonstrate that LTC4 is a constrictor of the mesenteric vascular bed and that endogenous LTC4-like immunoreactive material is a mediator of anaphylactic vasoconstriction in the guinea-pig mesentery.

Anaphylaxis↗
PubMed1984

Local release of histamine, prostaglandin F2 alpha and thromboxane B2 into the tracheal lumen and its influence on airways reactivity.

The influence of tracheal lavage with ascaris extract (AE) on airway response to acetylcholine (ACH) and histamine (Hi) was investigated in a series of 24 dogs. AE administered to a restricted area of the trachea resulted in a release of various mediators such as Hi, prostaglandin F2 alpha (PGF2 alpha, measured as the metabolite 15-keto-13, 14-dihydro-PGF2 alpha) and thromboxane B2 (TXB2) into the tracheal lumen. This differed from H2O administration which resulted in no increased release of these mediators. The relatively small concentrations of these substances measured in arterial plasma argue for the role of these mediators on a local basis. On the other hand, tracheal lavage with allergen induced changes in airway response to ACH and Hi aerosols which was not observed after tracheal lavage with water. An interaction between this allergen-induced mediator release into the trachea and peripheral airways reactivity could be demonstrated.

Acetylcholine↗
PubMed1984

Formation of leukotriene C4-like material by rat brain tissue.

Pieces of rat brain incubated in oxygenated Tyrode solution were stimulated with the divalent cation ionophore A 23187. Incubation media were assayed for leukotriene (LT) C4-like immunoreactivity as well as for prostaglandin (PG) D2, 6-keto-PGF1 alpha and thromboxane (TX) B2 using specific and sensitive radioimmunoassays. Spontaneous release of the cyclooxygenase products but only of trace amounts of LTC4-like immunoreactivity was detected. Stimulation with ionophore A 23187 increased the level of cyclooxygenase products and to a smaller extent the level of LTC4-like immunoreactivity. Inhibition of cyclooxygenase by indomethacin was paralleled by a significantly increased release of LTC4-like material under basal conditions as well as in the presence of ionophore A 23187. On the other hand, the synthesis of LTC4-like material was significantly decreased by the lipoxygenase inhibitors quercetin and nordihydroguaiaretic acid. The presence of LT-like material in rat brain incubates was confirmed by bioassay. The capacity of brain tissue to synthesize LT-like material may be important for cerebral blood flow as well as cellular functions in the central nervous system.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Molecular mechanisms of the gastric toxicity of antirheumatic drugs.

Gastric toxicity of non-steroidal antiinflammatory drugs has been suggested to be due to inhibition of prostaglandin synthesis. Proquazone, which is less ulcerogenic than indomethacin, however, is a more potent inhibitor of gastric mucosal prostaglandin synthesis than indomethacin in vitro and equally effective in vivo. These results indicate that additional factors such as pharmacokinetic properties contribute to the gastric toxicity of non-steroidal antiinflammatory drugs. Furthermore, lipoxygenase products of arachidonic acid metabolism might modulate the effects of inhibition of prostaglandin synthesis by non-steroidal antiinflammatory drugs. Using a radioimmunoassay for leukotriene C4 the capacity of ovalbumin-sensitized guinea pig gastric mucosa to release leukotriene C4-like immunoreactivity after antigenic challenge has been demonstrated.

Adult↗