Unlike other classic NSAIDs, some fenamates given at therapeutic concentrations, have been shown to inhibit, both in vitro and in vivo, the 5-lipoxygenase pathway of arachidonic acid cascade as well as the synthesis of cyclooxygenase products. This dual inhibitory property might represent an improvement in anti-inflammatory therapy. The aim of this work was to characterize the effect of morniflumate, administered at therapeutic dosages to normal human volunteers, on leukotriene B4 (LTB4) and thromboxane (TXB2) synthesis, both in purified PMNs and in whole blood. PMNs, isolated two hours after a single oral administration of morniflumate and at steady-state condition, fully retain their capacity to release LTB4 and TXB2. Since intracellular concentrations of the drug were undetectable, in spite of its elevated concentrations in platelet poor plasma, the results obtained using PMNs suggest a drug loss during the cells purification procedure. In whole blood experiments, morniflumate reduced blood LTB4 synthesis induced by Ca-ionophore A23187 Bx approximately 50%, both after single dose and at steady state; the degree of inhibition showed a pattern similar to the plasma levels of the bioactive metabolite of morniflumate (M1). The inhibition of serum TXB2 levels was higher than 85%. Hence, morniflumate is capable of reducing arachidonic acid metabolism acting both on cyclooxygenase and 5-lipoxygenase. This characteristic might provide a better approach in anti-inflammatory therapy.

No abstract

The mechanism of action and the pharmacological effects of the new furoxan derivative, CHF 2363 (4‐ethoxy‐3‐phenylsulphonylfuroxan), were investigated. Pre‐incubation of CHF 2363 with human platelet‐rich plasma produced a concentration‐dependent inhibition of the platelet aggregation induced by collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). The test compound was about 5 times more potent than sodium nitroprusside. 3‐Isobutyl‐1‐methyl‐xanthine (IBMX) potentiated the antiaggregating effect of CHF 2363. CHF 2363 was a potent inhibitor of rubbed endothelium rabbit aortic ring contraction induced by noradrenaline. Comparison of IC50 values showed that CHF 2363 was as potent as glyceryl trinitrate (GTN). Increasing concentrations of CHF 2363 elevated platelet guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) levels. Adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels were unaffected. Oxyhaemoglobin reduced all the pharmacological actions of the test compound. Moreover, CHF 2363 concentration‐dependently released nitric oxide (NO) in platelet‐rich plasma. The NO release was correlated to its ability to increase platelet cyclic GMP levels. After exposure of rat aortic strips to supramaximal concentrations of GTN (550 μm), the vasorelaxant activity of CHF 2363 did not change, although that of GTN decreased about 55 fold. It has been concluded that the new furoxan derivative CHF 2363 exerts a potent antiaggregating and vasorelaxant activity via NO release and increase of cyclic GMP levels. No in vitro cross tolerance between GTN and CHF 2363 was observed.

No abstract

Attenuation of neuroendocrine activation may be beneficial in congestive heart failure. Sympathetic nervous system overactivity can be reduced by receptors blockade or by reducing norepinephrine (NE) spillover. This study evaluated and compared the effects of a DA2-dopaminergic receptor/alpha2-adrenoceptor agonist (CHF-1024) and a beta1-adrenoreceptor antagonist in terms of hemodynamics, ventricular remodeling, beta-adrenergic drive, and cardiac fibrosis after myocardial infarction (MI) in rats. MI was induced by left coronary artery ligation in 213 rats, whereas 12 were left unoperated on. After 2 months, the operated-on animals were treated for 1 more month with CHF-1024 at either 0.33 mg/kg/day (low dose) or 1 mg/kg/day (high dose) or with metoprolol (10 mg/kg/day), delivered through implanted osmotic minipumps. Plasma concentration and urinary excretion of NE were measured before the rats were killed. Hemodynamic variables were measured and morphometric analysis was done on the diastole-arrested hearts to quantify left ventricular remodeling and interstitial collagen density. Metoprolol treatment tended to normalize LV end-diastolic pressure (LVEDP). CHF-1024 at either dose, and metoprolol, significantly reduced collagen deposition in LV of infarcted animals (from 8.8 +/- 0.5% LV area in vehicle-treated rats to 6.6 +/- 0.2% or 6.4 +/- 0.2% after the low or high dose of CHF-1024, respectively; p < 0.05). Similarly, CHF-1024 at either dose reduced the plasma concentration of NE (from 224 +/- 53 pg/ml to 60 +/- 7 pg/ml or 87 +/- 13 pg/ml; p < 0.05) and urinary excretion of NE in rats with MI, whereas beta-blockade did not affect these variables. In conclusion, CHF-1024 infused for 1 month to rats with LV dysfunction reduced heart rate, NE spillover, and collagen deposition, without unwanted effects, only appearing at the higher dose. Effective beta-blockade with metoprotol reduced LVEDP with no effects on heart function. Neither DA2/alpha2 stimulation nor beta-blockade altered LV remodeling after coronary artery ligation.