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Biomedical subjects

B A Peskar

Publications and source records attributed to B A Peskar.

At least 55 records · Page 3Linked to original sources
PubMed1994

Pharmacokinetics of vasoactive substances administered into the human corpus cavernosum.

The pharmacokinetics of vasoactive substances injected into the corpus cavernosum for the treatment of erectile dysfunction have not been investigated to date. We measured the local intracavernous and peripheral venous concentration curves of papaverine and prostaglandin E1, and its primary metabolite 15-keto-13,14-dihydro-prostaglandin E1 in an intra-individual comparison after intracavernous injection. Papaverine was measured with high performance liquid chromatography and prostaglandin E1 was measured with a specially adapted radioimmunoassay. The results demonstrate that papaverine is slowly draining into the systemic circulation, showing slightly elevated levels in the peripheral blood 30 and 60 minutes after injection. Prostaglandin E1 shows a much faster decrease in local concentrations with no measurable increase in the periphery, probably due to the short half-time after lung passage. Measurement of the primary metabolite proves a local degradation of prostaglandin E1 in the corpus cavernosum into the biologically inactive 15-keto-13,14-dihydro-prostaglandin E1, which also shows a slight increase in the peripheral circulation due to the longer half-time of approximately 8 minutes. The data provide good explanation for the clinical finding of a markedly decreased incidence of priapism with the use of prostaglandin E1, which can be shown to be locally metabolized, compared to papaverine, which is retained in the corpus cavernosum in cases of nonvenogenic impotence.

Alprostadil↗
PubMed1994

Effects on platelet functions and pharmacokinetics of azapropazone and ketorolac tromethamine given as single parenteral doses.

The biosynthesis of thromboxane (TX) B2 and immunoreactive prostaglandin (PG) F2 alpha in clotting whole blood ex vivo as well as collagen-induced platelet aggregation were determined before and up to 72 h after intravenous injection of 600 mg azapropazone 2H2O and intramuscular injection of 30 mg ketorolac tromethamine in six healthy subjects. The drug doses were selected on the basis of comparable analgesic activity (maximal recommended analgesic dose). Both platelet aggregation and prostanoid biosynthesis were inhibited by racketorolac to a significantly greater extent and for a longer period of time than by azapropazone. Correlations between serum concentrations and the inhibitory effects on TXB2 biosynthesis were observed for both drugs. Using the sigmoidal Emax model the mean serum concentration of azapropazone inhibiting platelet TXB2 generation by 50% (EC50) was found to be 98.1 +/- 41.9 (s.d.) micrograms ml-1, a value 1000 times higher than that for rac-ketorolac. The moderate inhibition of platelet function by azapropazone as compared with rac-ketorolac might be an advantage with regard to its use as a post-operative analgesic.

Adult↗
PubMed1993

Effect of prostaglandin (PG) E1 and its initial metabolites on neutrophil-induced inhibition of human platelet aggregation.

We have investigated the effects of PGE1, 15-keto-PGE1, 15-keto-13,14-dihydro-PGE1 and 13,14-dihydro-PGE1 on inhibition of human platelet aggregation by rat peritoneal neutrophils (RPN) and human polymorphonuclear neutrophils (PMN). Both RPN and PMN are known to synthesize nitric oxide (NO). In the presence of a threshold concentration of RPN or PMN the inhibitory effects of PGE1 and 13,14-dihydro-PGE1 on thrombin- or collagen-induced platelet aggregation were significantly increased as compared to the absence of cells, while 15-keto-PGE1 and 15-keto-13,14-dihydro-PGE1 were inactive. Oxyhemoglobin (oxy-Hb) abolished the synergistic effect of RPN and either PGE1 or 13,14-dihydro-PGE1 on thrombin-induced platelet aggregation, but under the experimental conditions used had much less effect on inhibition of collagen-induced aggregation. Potentiation of the antiaggregatory effect of PGE1 and 13,14-dihydro-PGE1 by NO might contribute to the therapeutic efficacy of exogenous PGE1. This view is supported by the fact that plasma levels of PGE1 and its active metabolite in patients receiving infusions of PGE1 for treatment of peripheral arterial occlusive disease are in the order of magnitude acting synergistically with neutrophil-derived NO, while direct inhibition of platelet aggregation requires considerably higher concentrations of PGE1 and 13,14-dihydro-PGE1.

Alprostadil↗
PubMed1993

In vitro release of prostaglandins and leukotrienes from synovial tissue, cartilage, and bone in degenerative joint diseases.

OBJECTIVE: To determine the major source of eicosanoid release in arthritic joint tissues and to examine the modulation of this release by indomethacin and diclofenac. METHODS: Release of prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, leukotriene B4 (LTB4), and LTC4 was measured in supernatants of synovial tissue, cartilage, and bone incubates from patients with osteoarthritis, active rheumatoid arthritis (RA), inactive RA, and pseudogout. Radioimmunoassay (RIA) was used to determine the levels of the eicosanoids. RESULTS: Addition of the divalent cation ionophore A23187 resulted in significant release of all eicosanoids measured from synovial tissue, but not from cartilage, cortical bone, or cancellous bone. PG release was significantly inhibited by the addition of indomethacin or diclofenac at either 10(-5) moles/liter or 10(-7) moles/liter. The amount of LTC4 released from cartilage and bone was only slightly above the detection limit of the RIA, whereas large amounts were released from synovial tissue. Neither indomethacin nor diclofenac had an effect on LTC4 release. LTC4 release from synovial tissue of patients with inactive RA was significantly decreased in comparison with the levels from synovial tissue of patients with the other joint diseases. There was no significant difference in PG release among patients in the various disease groups. CONCLUSION: Synovial tissue appears to be the major source of eicosanoids in synovial fluid. Indomethacin and diclofenac inhibit the release of PG, but not LT, from various joint tissues.

Arthritis↗
PubMed1993

Transient ventilatory responses to endotoxin infusion in the cat are mediated by thromboxane A2.

We tested the hypothesis that ventilatory responses to endotoxin infusion in the anesthetized cat are mediated by thromboxane A2 (TxA2). Intravenous infusion of endotoxin (1.6 mg/kg of E. coli, strain 05:B55, delivered over 1 min) in six cats elicited increases in right ventricular blood pressure (Prv) and a transient systemic hypotension. These hemodynamic changes were accompanied by an abrupt apnea, followed by a transient period of rapid, shallow breathing, Cardiorespiratory changes coincided with large increases (> 10-fold) in the plasma concentration of TxB2, the stable metabolite of TxA2. These effects and the release of TxA2 did not occur if endotoxin was infused a second time into the same animal. In addition, animals that were pretreated with either indomethacin (n = 3; 3.0 mg/kg) or the TxA2 receptor antagonist, daltroban, (n = 4; 7.5 mg/kg) exhibited no change in Prv, arterial blood pressure, or respiration when given equivalent doses of endotoxin. We conclude that the release of TxA2 is responsible for the early pulmonary hypertension and rapid, shallow breathing observed during endotoxin infusion in the anesthetized cat. These TxA2-mediated responses are severe but transient in nature.

Animals↗
PubMed1993

Gastro-protective effects by extracts of Petasites hybridus: the role of inhibition of peptido-leukotriene synthesis.

Extracts from Petasites hybridus are in therapeutic use for more than 2000 years. They have been claimed to improve gastrointestinal pain, lung-diseases such as asthma and cough, as well as spasms of the urogenital-tract. We have investigated these claims in animal models of gastro-intestinal ulcers and confirmed that alcoholic extracts of Petasites hybridus block the ethanol-induced gastric damage and reduce small intestinal ulcerations induced in rats by indomethacin. Searching for a possible mode of action, we found that ethanolic extracts of Petasites hybridus inhibit the peptido-leukotriene biosynthesis in mouse peritoneal macrophages but leave prostaglandin biosynthesis unimpaired. We conclude that the active principle could be useful in the treatment of gastro-intestinal human diseases and that Petasites hybridus may contribute to the inhibition of calcium-dependent processes such as leukotriene biosynthesis.

Animals↗
PubMed1993

Selectin-P-mediated adherence of platelets to neutrophils is regulated by prostanoids and nitric oxide.

The expression of Selectin-P was measured in terms of formation of "rosettes" by human gel-filtrated thrombin (30-50 mU)-stimulated platelets on the surface of isolated homologous neutrophilic leucocytes (PMNs) according to Jungi (1986). The monoclonal anti-Selectin-P antibody completely prevented the formation of "rosettes", proving the specificity of Selectin-P-mediated adhesion. The Selectin-P-mediated adhesion of platelets to PMNs was inhibited by both iloprost (ILO) (IC50 = 5.0 nM) and sodium nitroprusside (NaNP) (IC50 = 0.93 microM); thus ILO is ca. 180 times more potent an inhibitor of "rosette" formation than NaNP. The NOS-inhibitors L-NO2Arg (10-30 microM) and L-MetArg (3-30 microM) each suppressed the adhesion, while at lower and higher concentrations these NOS-inhibitors did not influence rosette formation. L-Arginine (up to 1 mM) was not able to influence significantly the Selectin-P-mediated adhesion of platelets to PMNs. The COX inhibitor aspirin (10-30 microM) promoted the adhesion. We conclude that the Selectin-P-mediated adhesion of platelets to PMNs is inhibited by both ILO and NaNP, whereas endogenous prostanoids and nitric oxide seem to exert an antagonist effect on the adhesion of platelets to PMNs.

Antigens, CD↗
PubMed1992

13,14-Dihydro-prostaglandin E1 decreases low-density lipoprotein influx into rabbit aorta.

The effect of 4-week daily administration of 13,14-dihydro-prostaglandin E1 (13,14-DH-PGE1; 2 micrograms/kg) on LDL influx into the rabbit aortic wall was examined versus the effect of the same dose of PGE1 and sham-treatment in 108 male animals fed an 1% cholesterol supplemented diet. Treatment was started after de-endothelialization of the abdominal aorta with a Fogarty catheter. After the 1-month treatment period the animals were injected with 10 microCi 125I-low-density lipoprotein (LDL; 0.5 mg protein/ml). Uptake of the radiolabelled LDL was measured in morphologically verified endothelialized, re-endothelialized and de-endothelialized abdominal aortic segments. The LDL influx into the aorta was significantly (P less than 0.001) lower in 13,14-DH-PGE1- and PGE1-treated rabbits than in the controls. This reduction was most pronounced in re- and de-endothelialized segments. No significant difference between effect of PGE1 and of its biologically active derivative, 13,14-DH-PGE1, on arterial LDL entry was found. These data demonstrate a comparable beneficial effect of 13,14-DH-PGE1 and PGE1 on vascular wall lipid metabolism by decreasing LDL entry into the aortic wall in vivo.

Alprostadil↗
PubMed1992

Release of endothelin in the oleic acid-induced respiratory distress syndrome in rats.

Rats injected intravenously with oleic acid developed pulmonary edema leading to hypoxia and hypercarbia. These changes were accompanied by an increase in immunoreactive endothelin (ir-ET) in plasma as early as 15 min after injection. At 45 min after injection plasma levels peaked at 114 +/- 19 pg/ml plasma (n = 8) and reached basal levels again after 240 min. In contrast, much larger amounts of ir-ET were found in the bronchoalveolar lavage fluid, with a peak at 120 min (2878 +/- 258 pg/lung, n = 7) preceding the maximum hypoxia observed at 180 min. In both plasma and bronchoalveolar lavage fluid samples ir-ET was characterized by reverse-phase HPLC as a mixture consisting mainly of ET-1 and smaller amounts of big ET-1, ET-2 and ET-3. In light of the biological effects of ET, the data suggest that these peptides might be of pathophysiological significance in this model of adult respiratory distress syndrome.

Animals↗
PubMed1992

Effect of 3-morpholinosydnonimine (SIN-1), NG-nitro-L-arginine (NNA) and NG-monomethyl-L-arginine (NMMA) on isolated anaphylactic guinea-pig hearts.

In isolated perfused ovalbumin-sensitized guinea-pig hearts modulating effects of nitric oxide (NO) on cardiac function and eicosanoid release were investigated. While the NO-donor SIN-1 exhibited a protective effect during cardiac anaphylaxis, inhibition of NO biosynthesis by NNA or NMMA aggravated anaphylactic changes of cardiac functions. Exogenous and endogenous NO seems to functionally antagonize the effects of vasoconstrictor mediators released during the anaphylactic reaction. In addition, inhibition of cysteinyl-leukotriene (cys-LT) release could contribute to the protective effect of SIN-1 observed.

Anaphylaxis↗
PubMed1992

Release of eicosanoids and endothelin in an experimental model of adult respiratory distress syndrome.

In an experimental model of adult respiratory distress syndrome (ARDS) we have investigated the release of several vasoactive mediators since the rapid and severe increase in pulmonary arterial pressure is known to be a key feature in this condition. Intravenous injection of oleic acid (OA) into rats resulted in the development of a syndrome similar to ARDS characterized by severe hypoxia. As early as 15 min after OA injection elevated levels of 11-deoxy-15-keto-13,14-dihydro-11,16-cyclo-prostaglandin (PG) E2 (DKH2-cyclo-PGE2) as an indicator of endogenous PGE2 formation could be observed. Similarly, elevated levels of cysteinyl-leukotrienes (LT), determined as immunoreactive (ir) LTE4, and ir-endothelin (ET) could be detected. These mediators were found to be elevated in plasma samples for at least 3 h. In addition, rather large amounts of ir-ET could be detected in bronchoalveolar lavage (BAL) fluid samples between 1 h and 3 h. Thus, it seems possible that cysteinyl-LT and peptides of the ET family, both known for their vasoactivity, might be involved in the pathophysiological process of ARDS.

Animals↗
PubMed1992

Effect of 3-morpholinosydnonimine (SIN-1) and NG-nitro-L-arginine (NNA) on isolated perfused anaphylactic guinea-pig hearts.

The modulating effects of exogenous and endogenous nitric oxide (NO) on the cardiac anaphylactic reaction and eicosanoid release were investigated in isolated perfused sensitized guinea-pig hearts using 3-morpholinosydnonimine (SIN-1), the active metabolite of molsidomine, as NO-donor and NG-nitro-L-arginine (NNA) as an inhibitor of NO biosynthesis. Infusion of SIN-1 (final concentrations in the perfusates 0.3 or 1.0 mmol/l) elevated coronary flow under basal conditions as well as during cardiac anaphylaxis, while NNA (0.1 mmol/l) decreased basal coronary flow and aggravated the anaphylactic coronary constriction. Both drugs did not modify the characteristic biphasic profile of the coronary constriction after antigen challenge with an initial more severe phase followed by a less pronounced long-lasting flow reduction. Neither SIN-1 nor NNA affected spontaneous heart rate. However, while NNA tended to prolong the duration of antigen-induced arrhythmias, SIN-1 (1 mmol/l) had an inhibitory effect. This protection might be related to the increased coronary flow in the presence of SIN-1. SIN-1 inhibited anaphylactic release of cysteinyl-leukotrienes (LT) and 6-keto-prostaglandin (PG) F1 alpha, but did not influence thromboxane (TX) B2 release. On the other hand, NNA (0.1 mmol/l) inhibited anaphylactic release of TXB2, but had only marginal effects on the release of cysteinyl-LT and 6-keto-PGF1 alpha. The results suggest that exogenous and endogenous NO functionally antagonize the effects of vasoconstrictor mediators released after antigen challenge. Additional effects of high concentrations of SIN-1 and NNA on antigen-induced eicosanoid release could modulate the vascular actions of these drugs during cardiac anaphylaxis.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Effect of prostaglandin E2 and 3-morpholinosydnonimine (SIN-1) on arachidonic acid metabolism in fMLP-stimulated rat neutrophils and on thrombin-induced human platelet aggregation.

The effects of prostaglandin (PG) E2 and the nitric oxide (NO) donor SIN-1 on leukotriene (LT) release from formyl-methionyl-leucyl-phenylalanine (fMLP) (100 nM)-stimulated rat peritoneal neutrophils (RPN) and on thrombin-induced aggregation of washed human platelets were investigated. Both PGE2 (1-100 nM) and SIN-1 (30-300 microM) inhibited release of LTB4 and cysteinyl-LT from RPN in a concentration-dependent manner. The combined effects of PGE2 and SIN-1 were not greater than expected by summation. On the other hand, the inhibitory effect of SIN-1 (0.5 or 1.0 microM) on platelet aggregation was potentiated by PGE2 (0.3-5 microM) in a concentration-dependent manner, while PGE2 alone in the concentrations used had only marginal effects. The results suggest differential regulation of platelet and leukocyte functions by the mediators PGE2 and NO, which could be relevant for various physiological and pathophysiological conditions.

Animals↗
PubMed1992

Synergism between PGE1-metabolites(13,14-dihydro-prostaglandin E1, 15-keto prostaglandin E1, 15-keto-13,14-dihydro-prostaglandin E1) and nitric oxide (NO) on platelet aggregation.

A synergistic antiplatelet effect between prostaglandins (PG), cAMP-stimulators and nitric oxide (NO), a cGMP-stimulator, has already been described. Data on a synergism between NO and the metabolites of PGE1, however, are lacking so far. We therefore tested the antiplatelet activity of the metabolites of PGE1 alone and their synergism with NO on human platelets of 8 healthy volunteers in vitro. 13,14-DH-PGE1 (ID 50 = 10.8 ng/ml platelet rich plasma (PRP)) was the only PGE1 metabolite inhibiting the ADP-induced platelet aggregation, its efficacy being 76.4% of the parent compound PGE1 (ID 50 = 8.25 ng/ml PRP). NO (ID 50 = 0.52 microM) also inhibited platelet aggregation. The combined addition of 13,14-dihydro-prostaglandin E1 (13,14-DH-PGE1) and NO caused an additive effect. The other PGE1-metabolites tested, 15-keto prostaglandin (15-K-PGE1) (ID 50 = 16.2. micrograms/ml PRP) and 15-keto-13,14-dihydro-prostaglandin(15-K-13,14-DH-PGE1) (ID 50 = 14.8 micrograms/ml PRP), neither had any relevant antiaggregatory capacity themselves nor a synergistic effect with NO. These findings could be of clinical relevance as a NO-synergism may occur not only with therapeutically administered PGE1 but also with its biologically active metabolite 13,14-DH-PGE1.

Adult↗
PubMed1991

Aspirin-like drugs, ethanol-induced rat gastric injury and mucosal eicosanoid release.

The effect of oral administration of various non-steroidal antiinflammatory drugs on ethanol-induced rat gastric injury and mucosal release of leukotriene C4, 6-keto-prostaglandin F1 alpha and 15-hydroxy-5,8,11,13-eicosatetraenoic acid was investigated. It was found that besides sodium salicylate and high doses of aspirin, other salicylate-type drugs, such as diflunisal, 4-aminosalicylic acid, 2,4-dihydroxybenzoic acid and methyl salicylate, and several non-acidic compounds, such as proquazone, benzydamine and paracetamol, were gastroprotective. All these drugs inhibited ex vivo leukotriene C4 formation by ethanol-stimulated gastric mucosa. However, naproxen, lonazolac, ibuprofen, gentisic acid and 5-aminosalicylic acid also inhibited leukotriene C4 formation, but were not protective. Gastroprotection was independent of 6-keto-prostaglandin F1 alpha formation. Both protective and non-protective drugs inhibited the ethanol-stimulated, but not the basal, release of 15-hydroxy-5,8,11,13-eicosatetraenoic acid. The results indicate that the differential effects of various non-steroidal antiinflammatory drugs on gastroprotection against ethanol are not correlated with specific effects on mucosal cyclooxygenase, 5-lipoxygenase or 15-lipoxygenase activity.

6-Ketoprostaglandin F1 alpha↗