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At least 649 records · Page 36Linked to original sources
PubMed1983

Reduction of myocardial infarction and dysrhythmic activity by nafazatrom in the conscious rat.

The effects of nafazatrom (30 and 100 mg/kg b.i.d.) on myocardial lesions caused by coronary artery ligation were determined in rats. The treatment lasted ten days preceding and twenty days following the cardiac insult, and its effects were compared with the effects of oral 1% Tylose suspension as drug vehicle. Nafazatrom reduced the number of extrasystoles and the duration of ventricular tachycardia and fibrillation occurring in the early (0-10 min) and late phases (2-4 h) of cardiac arrhythmias observed in the controls. Pretreatment with nafazatrom reduced the size of the ultimate infarct by 36 and 48 percent (P less than 0.05), and by 28 and 39% (P less than 0.05) with post-ligature nafazatrom treatment.

Animals↗
PubMed1984

Beneficial effects of nafazatrom on ischemic reperfused myocardium.

The effect of nafazatrom, a new antithrombotic agent, was studied in a canine model of regional myocardial ischemia. Nafazatrom was administered 1 mg/kg intravenously every 6 h for 48 h. After 24 h of drug or placebo administration, animals underwent 90 min of occlusion of the proximal left circumflex coronary artery followed by gradual reperfusion over a period of 30 min. Twenty-four hours later, the animals were sacrificed and infarct size was determined by histochemical staining with triphenyltetrazolium chloride. Nafazatrom-treated animals had a significant reduction in infarct size expressed as a percent of the anatomical area at risk for infarction: 21 +/- 5% in the treated group vs. 41 +/- 5% in the control group (X +/- S.E.M., P less than 0.05). Histological examination confirmed the gross results of postmortem histochemical staining. Salvage of ischemically jeopardized tissue appeared to be unrelated to myocardial oxygen demand as there were no hemodynamic differences between groups. The beneficial effects of nafazatrom are presumably related to a limitation of autolytic processes on the heart during and after ischemia as a result of the drug's ability to inhibit lipoxygenase and to prevent the enzymatic degradation of prostacyclin.

Animals↗
PubMed1985

Failure of nafazatrom to reduce infarct size and arrhythmias in a porcine model of acute coronary occlusion.

The effects of nafazatrom (10 mg/kg, b.i.d., orally for 2 days preoperatively; 10 mg/kg, intraduodenally, 30 min before coronary occlusion) on hemodynamics and arrhythmias were assessed in a group of drug-treated anesthetized pigs and compared with the effects in animals that received the drug vehicle and were treated identically. Infarct size (triphenyl-tetrazolium method) of the left anterior descending coronary artery was 24.4 +/- 2.4% of the left ventricle in nafazatrom-treated hearts after 2 h of occlusion and 26.2 +/- 3.2% in control hearts. Blood pressure, heart rate, left ventricular systolic and end-diastolic pressure, cardiac output and stroke volume were not different between the groups during cardiac insult. There were no differences in the number of premature ventricular contractions, arrhythmia and tachycardia, and ventricular fibrillation. It is concluded that short-term administration of the 5-lipoxygenase inhibitor nafazatrom had no effect on infarction, hemodynamics or arrhythmias in the acutely ischemic porcine myocardium.

Animals↗
PubMed1986

Enhancement of canine coronary collateral flow by nafazatrom.

The ability of oral nafazatrom treatment (10 mg/kg) 2 h preceding occlusion of the left anterior descending coronary artery for 6 h to limit expansion of myocardial injury was studied in anaesthetized canine hearts. Collateral blood flow was obtained with a load line analysis, employing aortic pressure, post-stenotic coronary pressure, and retrograde coronary flow from the occluded vessel. Contractile changes in the subendocardial ischemic perfused muscles were measured with ultrasonic techniques. Infarct size was determined post-mortem by a biochemical staining method and excision of necrosis. Post-stenotic coronary pressure was slightly below aortic pressure in both groups before coronary occlusion, and fell to 29 and 27% of aortic pressure in vehicle- and drug-treated hearts, respectively, after the insult. Retrograde flow was 2.4 +/- 0.6 vs. 4.1 +/- 0.7 ml/min in tylose- or nafazatrom-treated hearts. Collateral flow amounted to 1.5 +/- 0.06 vs. 2.5 +/- 0.04 ml/min in controls and drug-protected hearts. Contractility (dP/dtmax) and the %-segment shortening were greater in the ischaemic myocardium after nafazatrom treatment. Infarct size was 38 +/- 5.2 vs. 17 +/- 3.4 g/100 g left ventricle in the vehicle controls and nafazatrom group, respectively. Nafazatrom reduced infarct size by 46%. Besides other mechanisms, this was due to improved %-segment shortening and increased periinfarction collateral blood supply to jeopardized but viable myocardium. The drug may be of value in ischaemic heart disease as shown by the enhanced regional myocardial perfusion and improved contractility.

Animals↗
PubMed1986

Nafazatrom, an arachidonate metabolism inhibitor, decreases prolactin and GH release.

Nafazatrom, an inhibitor of arachidonate metabolism by the lipoxygenase enzymes, decreases basal prolactin and growth hormone release in a concentration-dependent manner without significantly affecting the synthesis of either hormone. It is required that nafazatrom be incubated with pituitary cells for approximately 2 h for this effect to become evident; the blockade increases in magnitude for up to 4 h. Nafazatrom blocks the increase in prolactin release caused by the releasing factors TRH and angiotensin II and the increase in prolactin and growth hormone release due to the calcium channel activator maitotoxin. These data suggest that the lipoxygenase products of arachidonate metabolism may be important mediators in basal and secretagogue-induced release of prolactin and growth hormone.

Animals↗
PubMed1987

Defined test reagents for the diagnosis of drug-induced allergy. Antibody-dependent skin reactions towards pyrazolinone and pyrazolidinedione derivatives in the guinea pig.

Chemically defined haptenic reagents and haptenic conjugates were synthesized for use in clinical skin testing. One series of reagents was based on the 1-phenyl-2,3-dimethyl-3-pyrazolin-5-one structure, a second series on 1,2-diphenyl-pyrazolidine-3,5-dione. Haptens were connected via flexible spacer molecules which insert considerable distances between haptenic moieties and carriers. The skin test reagents were hexavalent conjugates prepared from the bis-penta-L-lysine carrier 'PAL'. The methodological details exemplify the application of N-hydroxysuccinimide activated ester derivatives for the preparation of peptidic conjugates. Rabbit and guinea-pig antisera against the haptens were obtained by immunization with human serum albumin conjugates. Efficacy and cross-reactivity relationships were assessed by guinea pig PCA and by testing actively immunized guinea pigs. A striking lack of cross-reactivity was found between pyrazolinone and pyrazolidinedione haptenic reagents in all test systems. On the other hand, the elicitation of homologous anaphylaxis was highly effective with the PAL conjugates. The data presented and discussed provide a basis for the evaluation of clinical tests performed in order to define drug-induced allergic reactions. They are relevant for immediate-type skin reactions as well as for serological methods.

Animals↗
PubMed1982

Inhibition of arterial thrombosis and platelet function by nafazatrom.

Nafazatrom (1-[2-(naphthyloxy) ethyl]3-methyl-2-pyrayolin-5-one) has been shown to be a potent antithrombotic agent in experimental animals, but its mode of action is unknown. In this study, we examined its antithrombotic effect on arterial and venous thrombosis, vessel wall prostacyclin synthesis, and platelet aggregation in vivo and ex vivo in the rabbit. We found that arterial but not venous thrombus formation was significantly inhibited with low doses of nafazatrom. This antithrombotic effect was associated with a normalization of reduced platelet survival. Nafazatrom had no effect on basal or stimulated prostacyclin production but inhibited ADP- and collagen-induced platelet aggregation in vivo and ex vivo. This platelet effect was associated with a reduction in platelet thromboxane B2 release and an inhibition of irreversible ADP-induced platelet aggregation.

Adenosine Diphosphate↗
PubMed1983

The relationship between dose, pharmacokinetics, plasma-concentrations and antithrombotic effects of nafazatrom.

Nafazatrom is rapidly and almost completely absorbed after oral administration. However, the plasma levels of unchanged nafazatrom are very low, suggesting an extensive biotransformation during a first passage through the liver. The concentrations of nafazatrom in the plasma therefore, may only reflect indirectly the effective concentration at the receptor site. Concentrations, half-life and distribution of nafazatrom between aqueous and liquid compartments suggest that the cellular membrane may be the site of action.

Administration, Oral↗
PubMed1984

Ultrastructural observations of an electron dense amorphous layer on selectively damaged endothelial cells, a possible trigger of thrombogenesis in vivo, and its inhibition by nafazatrom.

Platelet aggregation can be induced by intravascular excitation of fluoresceinisothiocyanate-dextran. Cheek pouches of untreated hamsters and of nafazatrom recipients were excised before and after exposure to the exciting light for 1, 4, 6, 10 and 25 minutes and examined electron microscopically. The first observable ultrastructural change was a swelling of endothelial cells. Polymorphonuclear leukocytes began to transmigrate into the interstitium. After 4 minutes, amorphous, optically dense substances appeared on endothelial surfaces. Only on these which platelets later became adherent. Thrombi grew until vessels were occluded. The thrombi were formed by the amorphous structure, degranulated platelets and unaffected red blood cells and leukocytes. No fibrin strands were observed. Pretreatment with 100 micrograms/kg b.w. nafazatrom, a potent antithrombotic agent which stimulates endothelial release of prostacyclin, totally abolished the occurrence of the observed amorphous epiendothelial structure as well as the occurrence of platelet thrombi.

Animals↗
PubMed1988

Investigations on the role of arachidonic acid metabolism pathways in the antithrombotic activity of nafazatrom and molsidomine.

The activity of nafazatrom and molsidomine, two antithrombotic drugs claimed to increase prostacycline level, was investigated in an electrically-induced carotid thrombosis model in the conscious rat. Both nafazatrom (5 mg/kg, i.v.) and molsidomine significantly delayed thrombus formation, an activity that was shared by prostacyclin (100 ng/kg/min, i.v.). Acetylsalicylic acid, at a dosage devoided of antithrombotic activity (100 mg/kg, i.v.) abolished the effect of nafazatrom but not of molsidomine. These results indicate that a cyclooxygenase-dependent compound (prostacyclin ?) play a major role in the antithrombotic effect of nafazatrom but not of molsidomine. Moreover, since compounds inhibiting the lipoxygenase pathway, i.e., BW755c (10 and 25 mg/kg, i.v.) and nordihydroguaiaretic acid (10 and 25 mg/kg, i.v.) were unable to show any antithrombotic effect, the activity of molsidomine can unlikely be due to its lipoxygenase inhibitory property.

Animals↗
PubMed1985

Regulation of prostaglandin production by osteoblast-rich calvarial cells.

The effect of various factors upon prostaglandin (PG) production by the osteoblast was examined using osteoblast-rich populations of cells prepared from newborn rat calvaria. Bradykinin and serum, and to a lesser extent, thrombin, were all shown to stimulate PGE2 and 6-keto-PGF1 alpha (the hydration product of PGI2) secretion by the osteoblastic cells. Several inhibitors of prostanoid synthesis, dexamethasone, indomethacin, dazoxiben and nafazatrom, were tested for their effects on the calvarial cells. All inhibited PGE2 and PGI2 (the major arachidonic acid metabolites of these cells) production with half-maximal inhibition by all four substances occurring at approximately 10(-7) M. For dazoxiben and nafazatrom, this was in contrast to published results from experiments in vivo which have indicated that the compounds stimulated PGI2 production. Finally, since the osteoblast is responsive to bone-resorbing hormones, these were tested. Only epidermal growth factor (EGF) was shown to modify PG production. At early times EGF stimulated PGE2 release, however, the predominant effect of the growth factor was an inhibition of both PGE2 and PGI2 production by the osteoblastic cells. The present results suggest that the bone-resorbing hormones do not act to cause an increase in PG by the osteoblast and that any increase in PG production by these cells may be in response to vascular agents.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Evidence for a dual pathway in platelet activating factor-induced aggregation of rat polymorphonuclear leucocytes.

The purpose of this study was to determine the role, if any, of Leukotriene B4 (LTB4) in Platelet Activating Factor (PAF)-induced aggregation of rat polymorphonuclear leucocytes (PMNs). Exposure of rat PMNs to 10(-7) M PAF resulted in the release of 4.5 +/- 0.7 ng/10(7) cells of LTB4 measured by radioimmunoassay. However, the maximum aggregation of PMNs achieved by exposure to LTB4 (10(-7)M) was only 50% of that produced by maximally aggregating concentrations of PAF (10(-7)M). 5-Lipoxygenase inhibitors, BW755c and Nafazatrom at concentrations that completely abolished LTB4 synthesis inhibited the aggregation induced by PAF only by 40% and 50% respectively. Furthermore, desensitisation experiments revealed that the aggregatory response of PMNs to PAF was only partially refractory to prior treatment with LTB4 whereas the aggregatory response to LTB4 was completely refractory to prior treatment with PAF. These results suggest that PAF-induced aggregation of rat PMNs is in part mediated by LTB4 and in part directly by an as yet unidentified mechanism.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1987

Biosynthesis, characterization and inhibition of leukotriene B4 in human whole blood.

We have evaluated the biosynthesis, characterization and inhibition of Leukotriene (LT) B4 in unstimulated and in A23187-stimulated human whole blood. LTB4 was assayed by radioimmunoassay (RIA) both in unextracted serum and after extraction and thin-layer chromatography (TLC). Unstimulated human whole blood allowed to clot at 37 degrees C for 60 min produced only trace amounts of LTB4 (0.16 +/- 0.05 ng/ml, mean +/- SD, n = 3). LTB4-like immunoreactivity (ir-LTB4) detectable in unstimulated serum samples was largely overestimated by direct RIA, most likely because of interfering substance(s) unrelated to cyclooxygenase or lipoxygenase activity. Incubation of human whole blood with A23187 (2-10 microM) resulted in a concentration-dependent stimulation of LTB4 production. At 10 microM A23187, ir-LTB4 was 18 +/- 2.4 ng/ml (mean +/- SEM, n = 28). In A23187-stimulated serum samples, LTB4 concentrations measured by direct RIA correlated in a statistically significant fashion with those measured after extraction and TLC. Nafazatrom added in vitro caused a dose-dependent inhibition of A23187-stimulated ir-LTB4 production with an IC50 of 17 microM.

Aspirin↗