Prevention by alpha-tocopherol and rutin of glutathione and ATP depletion induced by oxidized LDL in cultured endothelial cells.

1. Oxidized low density lipoproteins (LDL) are thought to play an important role in atherogenesis. Mildly oxidized LDL are cytotoxic to cultured endothelial cells. Toxic doses of oxidized LDL promote the peroxidation of cellular lipids (beginning at 6 h and being maximal after 12 h of pulse with oxidized LDL) and glutathione and ATP depletion (beginning after 15 h of pulse and evolving concurrently with the cytotoxicity). 2. Antioxidants from 3 different classes (rutin, ascorbic acid and alpha-tocopherol) were compared as to their ability to inhibit the cytotoxic effect of oxidized LDL to endothelial cells. 3. Effective concentrations of alpha-tocopherol inhibited cellular lipid peroxidation, glutathione and ATP depletion and the cytotoxic effect. 4. Ascorbic acid was less effective than alpha-tocopherol and rutin, and exhibited a dose-dependent biphasic effect in the presence of oxidized LDL. 5. Effective concentrations of rutin inhibited glutathione and ATP depletion as well as cytotoxicity, but did not block cellular lipid peroxidation. This suggests that the glutathione and ATP depletion is directly correlated to the cytotoxicity of oxidized LDL, whereas cellular lipid peroxidation is probably not directly the cause of cellular damage leading to cell death. 6. The association of antioxidants of 3 different classes allowed the suppression of the biphasic effect of ascorbic acid and increased the efficacy of the protective effect. The potential consequences for prevention of the pathogenic role of oxidized LDL in endothelial injury are discussed.

alpha-Tocopherol, ascorbic acid, and rutin inhibit synergistically the copper-promoted LDL oxidation and the cytotoxicity of oxidized LDL to cultured endothelial cells.

Low-density lipoproteins (LDL) mildly oxidized by copper ions or UV radiations exhibit a cytotoxic effect to cultured endothelial cells. Rutin, a polyphenolic flavonoid, ascorbic acid, and alpha-tocopherol were able to inhibit the peroxidation of LDL and their subsequent cytotoxicity. The mixture of the three compounds (rutin/ascorbic acid/alpha-tocopherol, 4/4/1) exhibited a supra-additive antioxidant effect. The inhibition of the cytotoxic effect was well correlated with that of TBARS formation. Another important conclusion is that these antioxidants were able to prevent directly at the cellular level the cytotoxic effect of oxidized LDL, since cells preincubated with them were protected against the cytotoxic effect of previously oxidized LDL. The protective effect of antioxidants was limited because of their own toxicity. The antioxidant mixture permitted a maximal cytoprotective effect with relatively lower concentrations to be obtained and the cytotoxicity of high concentrations to be avoided. In conclusion, rutin, ascorbic acid, and alpha-tocopherol constitute two lines of defense in protecting cells against injury owing to oxidation of LDL (1) at the LDL level, by inhibiting the LDL oxidation and the subsequent cytotoxicity, and (2) at the cellular level, by protecting the cells directly, i.e., by increasing their resistance against the cytotoxic effect of oxidized LDL.

[Ovulation inhibition with medrogestone administered on the 4th through the 24th day of the cycle]. / Inhibition de l'ovulation par la médrogestone administrée du 4e au 24e jour du cycle.

Medrogestone (M) is a derivative of 17 methylprogesterone (P) used for P insufficiency at oral doses of 5 to 15 mg/day (D). We studied the ability of M to inhibit cyclic pituitary-ovarian activity when given at a dose of 10 mg/d from D4 to D24. Ten healthy Caucasian females, aged from 21 to 33, volunteered for an open 2 consecutive cycle study (cycle 1 = control, cycle 2 = M). At inclusion mean (+/- SD) cycle length was 28.6 +/- 1.9 D. Plasma LH, FSH, E2, P, were measured daily from D10 to D20 and at D22, 24, 26. During cycle 1, every subject showed an ovulatory pattern with mid cycle E2 peak (151-400 pg/ml), LH peak (12-59 mUI/ml) and luteal P rise (9.4-22.8 ng/ml). Under M ovulatory surges were suppressed in each of the 10 subjects and P remained below 0.8 ng/ml. These data show that in addition to its known progestomimetic effect, M is a potent ovulation inhibitor when given from D4 to D24 of the cycle.

Pharmacodynamics and pharmacokinetics of Veliten (rutine, alpha-tocopherol and ascorbic acid) in patients with chronic venous insufficiency.

The aim of this study was to evaluate the pharmacodynamics and pharmacokinetics of a single oral dose of Veliten in 12 patients affected by chronic venous insufficiency. In particular, the pharmacokinetics of two components of Veliten, namely rutine and alpha-tocopherol, were considered, while with respect to pharmacodynamics, studies were made of venous function, haemocoagulative and fibrinolytic balance, and haemorheological parameters. Correlation between such changes and plasma drug levels was also evaluated. We found a significant increase of venous tone, venous capacity and venous distension after drug intake, as well as a significant activation of fibrinolysis (globally evaluated with euglobulin lysis time), related to a slight increase of plasminogen tissue activator. These changes appeared concomitantly with maximal plasma levels of rutine. We did not find any modifications of coagulative and haemorheological parameters.

[Progestagens and bones]. / Progestatifs et os.

Gestagens when administered alone to menopausal women, (19 nortestosterone or progesterone derivatives) suppress loss of mineral content. But often a slight bone loss is observed, in contrast to the effect of oestrogenotherapy. 19 norpregnane derivatives seems to protect against bone loss. Progestagen may enhance bone formation without decreasing bone resorption. Administered together with oestrogens, gestagens have demonstrated either a decrease in biochemical estimates of bone loss or a radiologically positive effect. Progestogens alone in premenopausal women have various effects. In the case of contraception by injectable MPA the bone mass tend to decline as a result of hypoestrogenism. In summary gestagens seem to have on bone mass a rather favourable effect, which nevertheless is weaker than that of oestrogen.

Pharmacokinetics and metabolism of nilutamide in the isolated rat lung.

Nilutamide (N) is a potent antiandrogen used in the treatment of diffuse carcinoma of the prostate. The drug has been implicated in a few instances of pneumonitis in man. The present studies were carried out to examine N disposition in the isolated perfused lung (IPL) from rats. Both recirculating and single-pass IPL were used. Recirculation was run for 60 min at concentrations of N ranging between 12 and 120 microM (+1 mu Ci [14C]N). Single-pass perfusions were run for 30 min (uptake, 10 min; efflux, 20 min) at inflowing concentrations ranging from 12 to 480 microM (+1 mu Ci [14C]N). Nilutamide was concentrated in the recirculating IPL, and tissue to medium ratio (T/M) ranged between 6.6 and 4.2, depending on the inflowing concentration of N (Cin). High performance liquid chromatography analysis of extracts of 60-min lung homogenates demonstrated the primary amino metabolite of N in addition to the parent compound. This indicated reduction of the nitro moiety of N by lung tissues. At 60 min and Cin = 40 microM, 17.6 +/- 4.7% of the radioactivity present in lung was accounted for by the metabolite. Perfusate samples contained low to undetectable amounts of the metabolite. No metabolism of N was detected in single-pass IPL, possibly because of the shorter duration of experiments. Amount of N taken up in lung and T/M were similar to those found in recirculating preparations. Uptake of N in the single-pass IPL was proportional to N concentration up to 480 microM.(ABSTRACT TRUNCATED AT 250 WORDS)