Anti-inflammatory activity of polyphosphazene-based naproxen slow-release systems.

A biocompatible and biodegradable polyphosphazene bearing phenylalanine ethyl ester, imidazole and chlorine (10.7:1:2.5 molar ratio) as substituents of the phosphorus atoms of the polymer backbone was studied for the preparation of polymeric naproxen slow-release systems. Discs 2.5 cm in diameter and 0.5 mm (thin) or 0.65 mm (thick), loaded, respectively, with 20 and 13.5% naproxen, showed different drug release kinetics, the thin matrices releasing naproxen at a faster rate and for a shorter time. In-vivo studies in rats demonstrated the pharmacological efficacy of these two different delivery systems in the inhibition of acute or chronic inflammatory diseases. Subcutaneous implantation of the thin matrices in rats was found to reduce carrageenan oedema induced both 1 h and 7 days after implantation. Rats implanted with thick matrices showed a reduction in chronic inflammation caused by adjuvant arthritis. Approximately 78% inhibition of arthritic oedema was found 28 days after subcutaneous administration of the matrices whereas 28.7% inhibition was found after daily oral administration of naproxen. Blood levels of naproxen in arthritic rats after matrix implantation showed the presence of drug up to day 28. These positive results have encouraged us to study a controlled-release system suitable for use in man.

Serum retinol levels throughout 2 years of cholesterol-lowering therapy.

Some studies have reported an inverse correlation between serum cholesterol level and risk of cancer. This correlation might be due to a decrease in serum retinol, a lipid-soluble vitamin that controls cell proliferation and differentiation. We evaluated the influence of cholesterol-lowering therapy on serum retinol in 102 subjects (mean +/- SE: aged 47.1 +/- 4.1 years; body mass index, 23.8 +/- 0.6 kg/m2) with primary hypercholesterolemia treated for 2 years with different therapeutic protocols. Twenty-two subjects had been treated with diet alone, 35 with diet and fibrates, 37 with diet and hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors (statins), and eight with diet and cholestyramine. Postabsorptive serum retinol, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride levels were determined at baseline and every 3 months. Baseline TC and LDL-C were significantly lower in the diet-treated group than in other groups. No intergroup differences were found in pretreatment levels of triglycerides and serum retinol. After 2 years of treatment, TC and LDL-C serum levels were not significantly decreased in the diet-alone group, whereas they were decreased by 20% and 24%, respectively, in the gemfibrozil group, 28% and 34% in the statins group; and 21% and 27% in the cholestyramine group. In the entire population (N = 102), serum retinol was 3.46 +/- 0.08 mumol/L before therapy and 3.76 +/- 0.07 after 2 years of therapy (P < .001). Serum retinol increased in diet- and statin-treated groups, but not in fibrate- and resin-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma concentrations and pharmacokinetic parameters of nitrofenac using a simple and sensitive HPLC method.

An accurate and sensitive HPLC method has been developed for the determination of nitrofenac, a new, original diclofenac derivate showing a good tolerability and a wide anti-inflammatory profile, diclofenac, and its metabolites in plasma. This method has been applied to evaluate the pharmacokinetic parameters of the drugs, using a noncompartmental model, after the oral administration of 5 mg/kg nitrofenac to rats. Nitrofenac and the internal standard flufenamic acid were dissolved in acetonitrile, and diclofenac was dissolved in methanol. The drugs were eluted from a 5 microns LC-8 column with a mobile phase consisting of acetonitrile/water (50/50 v/v) adjusted to pH 3.3 with glacial acetic acid, at a flow rate of 2 mL/min with UV detection at 280 nm for diclofenac and 275 nm for nitrofenac. The detection limit for the drugs in plasma was 25 ng/mL. The peak concentration of nitrofenac was reached 7 h after drug administration, while with diclofenac we observed three peaks at 2, 5, and 10 h; the mean residence time and the elimination rate constant for nitrofenac were 6.18 +/- 0.09 h and 0.37 +/- 0.03 h-1 respectively, while those for diclofenac were 12.24 +/- 0.11 h and 0.11 +/- 0.04 h-1. Under our conditions, the metabolism of nitrofenac produced 23% diclofenac and other metabolites: the plasma concentrations and kinetic characteristics of diclofenac are enough to induce an anti-inflammatory activity, while the clinical importance of the other metabolites remains to be elucidated.

Modification of serum and membrane lipid composition induced by diet in patients with chronic renal failure.

Disorders of lipid metabolism during chronic renal failure (CRF) play a crucial role in the pathogenesis of early cardiovascular complication of this syndrome. In addition, some experimental evidence suggests that hyperlipidemia may accelerate progression of renal disease. We have studied 65 patients with CRF (S-creatinine 1.5-9.0 mg/dl), 52.3% of whom were hypertensive. Patients were divided in 2 groups matched for age, sex and degree of renal failure: group 1 was kept for 36 +/- 8 months on a free diet; group 2 was kept for 39 +/- 6 months on a low-protein diet with an elevated polyunsaturated/saturated fatty acid (PUFA/SFA) ratio. We found significantly higher levels of triglycerides (TG) and lower levels of esterified cholesterol in high density lipoprotein (HDL-C) in group 1 than in group 2. Patients on the diet had a lower percentage of membrane SFA and a higher percentage of PUFA than patients on free diet. Only in group 1 a direct correlation between cholesterol/phospholipid (Chol/P) ratio and age was observed; in group 2, a negative correlation between levels of PUFA and TG and between linoleic/oleic (Lin/Ol) ratio and serum Chol was shown. S-creatinine levels were directly correlated with Chol/P ratio in group 1 and indirectly with Lin/Ol ratio and PUFA in group 2. These data show that a low-protein diet, containing an elevated PUFA/SFA ratio, is able to counteract lipid abnormalities in patients with CRF and the normalization of this pattern is associated with significant improvement of membrane lipid composition and, presumably, of "functional" activity of cell membranes with a better control of supposed "renal lipoprotein toxicity".

Membrane fatty acids, glutathione-peroxidase activity, and cation transport systems of erythrocytes and malondialdehyde production by platelets in Laurence Moon Barter Biedl syndrome.

The fatty acid composition of erythrocyte membrane, the glutathione-peroxidase activity of erythrocytes and platelets, the production of malondialdehyde by platelets and the activity of the main systems of transmembrane cation transport have been studied in 5 members of a family, 2 of whom affected by Laurence-Moon-Barter-Biedl Syndrome. A remarkable increase of polyunsaturated fatty acids (particularly arachidonic acid) and of cholesterol/phospholipid molar ratio has been noted. This pattern of membrane lipids was associated to an increment of malondialdehyde production and an increase activity of glutathione-peroxidase. Serum retinol and a-tocopherol were in the normal range, whereas serum selenium was low in 3 out of 5 members. Moreover, the alteration of membrane lipids was associated to a decrease of the maximal velocity of Li-Na countertransport. We speculate that the enrichment of polyunsaturated fatty acids on the cell membranes may represent a condition favoring the lipoperoxidation and therefore the development of the retinitis pigmentosa characteristic feature of Laurence-Moon-Barter-Biedl Syndrome.

Effects of dietary fish oil on malondialdehyde production and glutathione peroxidase activity in hyperlipidaemic patients.

In 20 adult patients suffering from hyperlipidaemia we measured the lipid composition of erythrocyte membrane, the glutathione peroxidase activity in both erythrocytes and platelets, the production of malondialdehyde by platelets stimulated with thrombin, as well as the level of plasma selenium, retinol and alpha-tocopherol, before and after 8 weeks of fish oil supplementation (20 ml daily). We noted a remarkable reduction in plasma triglycerides which was associated with a significant decrease in blood pressure; moreover, we noted a reduction in the amount of arachidonic acid compensated by an increment of omega-3-fatty acid (particularly eicosapentaenoic and docosahexaenoic acids). The dietary supplementation with fish oil was associated with a significant increase in glutathione peroxidase activity in both erythrocytes and platelets. On the contrary, the production of malondialdehyde, which was originally higher than normal in hyperlipidaemics, was inhibited significantly after fish oil (p less than 0.001). Whereas no changes were observed in the concentration of plasma selenium and alpha-tocopherol, an increment of plasma retinol occurred. These data indicate that in hyperlipidaemics there is a proaggregant status; this situation may be normalized by using a dietary supplementation of fish oil; the increase of polyunsaturated fatty acids on the cell membrane, with a possible increment of the formation of lipoperoxides, induced by fish oil, is compensated by an increased activity of the scavenger enzyme glutathione peroxidase.

[Changes in the concentration of urinary homovanillic acid as a prognostic factor in patients treated for malignant melanoma]. / Variazioni di concentrazione di acido omovanilico urinario come fattore prognostico in pazienti trattati per melanoma maligno.

In 34 patients with malignant melanoma in three different stages HVA concentrations were determined. Some patients in stage 1 presented a considerable discrepancy between concentration values and values reported in other works. This group had been controlled for three years to observe the development of disease. We found three subgroups: the first with values within 4,3-6.0 mg/24 hr haven't had any recurrence; the second with values within 6.8-11.75 mg/24 hr presented lymphonodal metastasis in the lapse of six months - 1 year; in the third with values within 10-20 mg/24 hr patients died in two years for disseminated metastasis. The Authors according to the results achieved, conclude that variation of HVA concentration will be further prognostic factor.