Disease relevance of Bay-g 6575

• The development of hypersensitivity-type pulmonary granulomas in mice was dramatically suppressed by inhibitors with anti-LO activity (nordihydroguairetic acid (NDGA), nafazatrom, and BW755c) in a dose-dependent manner, while indomethacin, which is primarily CO-selective, had no significant effect [1].
• Nafazatrom in treatment of thrombotic thrombocytopenic purpura [2].
• Nafazatrom in thrombocytopenic purpura [3].
• Nafazatrom also reduced the incidence of accompanying arrhythmias [4].
• Nafazatrom-induced myocardial salvage was not associated with any hemodynamic changes; moreover, it was independent of platelets, since thrombocytopenia did not prevent nafazatrom from exerting a protective effect [4].

High impact information on Bay-g 6575

• In vitro exposure of exponentially growing B16 amelanotic cells to nafazatrom (1 microgram/ml for 72 hr) in culture did not change their ability to adhere to endothelial cell monolayers [5].
• The reduction in metastatic lesions was not accompanied by changes in primary tumor growth, and up to 1 microgram nafazatrom/ml did not inhibit tumor cell proliferation in vitro [5].
• Administration of either Bay g 6575 or dipyridamole alone had no effect on platelet aggregation in vitro, but combined administration resulted in a striking and prolonged inhibition of A.D.P.-induced platelet aggregation [6].
• Ingestion of 1.2 g Bay g 6575 daily for 1 week by six healthy volunteers had no effect on blood-coagulation, fibrinolysis, or platelet aggregation in vitro, but it seemed to inhibit platelet aggregation in vivo (shown by a smaller reduction in the platelet aggregate ratio after venous occlusion) [6].
• Nafazatrom-induced salvage of ischemic myocardium in anesthetized dogs is mediated through inhibition of neutrophil function [4].

Chemical compound and disease context of Bay-g 6575

• 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 [7].
• Of all modulators of thromboxane and prostacyclin biosynthesis, nafazatrom was found to exhibit promising results for the treatment of advanced breast cancer, although its use in the routine therapy is questionable at this stage [8].
• The in-vivo effects of the new antithrombotic compound nafazatrom on experimental thrombosis of the left circumflex coronary artery, on hemodynamics and on ultimate infarct size were studied in pentobarbital-anesthetized, open-chest dogs [9].
• Studies have documented that neutrophil depletion or suppression of neutrophil function (ibuprofen, nafazatrom, BW 755C, or more recently with prostacyclin or iloprost) results in a significant salvage of myocardial tissue that is subjected to a period of regional ischemia followed by reperfusion [10].

Biological context of Bay-g 6575

• In addition, nafazatrom causes an elevation in the levels of 6-keto-prostaglandin F1 alpha, the non-enzymatic hydrolysis product of prostacyclin (PGI2) biosynthesized from arachidonic acid by ram seminal vesicle microsomes [11].
• The pronounced anti-fibrillatory effect of nafazatrom during reperfusion of the ischaemic myocardium may be related to the ability of this drug to elevate prostacyclin concentrations in the coronary circulation [12].
• Nafazatrom did not affect peripheral haemodynamics but during drug vehicle treatment and LAD occlusion systemic blood pressure, left ventricular pressure and dP/dtmax decreased while filling pressure, heart rate, and the S-T segments of the ECG increased [13].
• Compared to placebo, nafazatrom did not significantly increase exercise tolerance time or exercise-induced symptoms [14].
• Oral nafazatrom is ineffective as a 5-lipoxygenase inhibitor in man, probably because of poor bioavailability after administration [15].

Anatomical context of Bay-g 6575

• Thus, the ability of nafazatrom to inhibit neutrophil function in vitro and cell infiltration in vivo may underly its myocardial-protective effects [4].
• Measurements of the neutrophil-specific myeloperoxidase enzyme in ischemic myocardium indicate that the smaller infarct size in dogs treated with nafazatrom is accompanied by diminished leukocyte infiltration [4].
• Platelet survival and function in animals with prosthetic mitral valve: the effect of nafazatrom [16].
• However, the incidence of VF resulting from release of a 40-min coronary artery occlusion was markedly reduced (from 88% in the controls to 14% in the nafazatrom group) [12].
• Nafazatrom: in-vitro assessment of radiation and drug activity against animal and human cell lines [17].

Associations of Bay-g 6575 with other chemical compounds

• In contrast, nafazatrom (0.4-37.5 microM) did not substantially influence platelet aggregation or the platelet metabolism of arachidonic acid [4].
• Inhibition of leukotriene B4 formation in human neutrophils after oral nafazatrom (Bay g 6575) [18].
• Administration of placebo or nafazatrom before the exercise stress test did not significantly influence any of the coagulation or platelet function parameters or plasma concentrations of thromboxane B2 and 6-keto-PGF1 alpha [14].
• 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 [19].
• These results indicate that a cyclooxygenase-dependent compound (prostacyclin ?) play a major role in the antithrombotic effect of nafazatrom but not of molsidomine [20].

Gene context of Bay-g 6575

• The lipoxygenase inhibitor nafazatrom inhibits stimulated prolactin secretion in cultured rat lactotrophs (GH4C1 cells) [21].
• Nafazatrom also inhibited catabolism by 15-OH PGDH of [3H]PGI2-ME to [3H]6,15-diketo-PGF1 alpha ME [22].
• These findings suggest that nafazatrom may act as a reducing cofactor for the hydroperoxidase involved in the cyclooxygenase- and lipoxygenase-pathways of arachidonic acid metabolism [23].
• The ease of oxidation of nafazatrom makes it ideally suited to act as an antioxidant [24].
• Nafazatrom also inhibits, in a dose-dependent way, the calmodulin-dependent phosphodiesterase activity [25].

Analytical, diagnostic and therapeutic context of Bay-g 6575

• Treated animals (n = 9) received nafazatrom, a potent lipoxygenase inhibitor, 10 mg.kg-1 orally 4 h before occlusion followed by intravenous boluses of 1.5 mg.kg-1 and 0.5 mg.kg-1 5 min before occlusion and 1 min before reperfusion respectively [26].
• The effect of oral nafazatrom (Bay g6575, 2 X 3 g) or placebo on inhaled antigen challenge was assessed in a double-blind study [15].
• Determination of nafazatrom in body fluids by high-performance thin-layer chromatography with post-chromatographic derivatization [27].
• The effects of nafazatrom (30 and 100 mg/kg b.i.d.) on myocardial lesions caused by coronary artery ligation were determined in rats [28].
• Pulse radiolysis and electron spin resonance experiments have been performed on the antithrombotic and antimetastatic agent, nafazatrom [24].

References