Serum and urine kinetics of rosaprostol in volunteers.

The kinetics of rosaprostol (9-hydroxy-19,20-bis-norprostanoic acid, Rosal) and of its metabolite (3-(2-n-hexyl-5-hydroxy-cyclopentyl)propionic acid) has been determined in plasma and in urine of 10 healthy volunteers after oral administration of 500 mg of rosaprostol. The peak of rosaprostol (of 524 ng/ml) appears at 4 h, whereas that of the metabolite (of 503 ng/ml) appears earlier (2 h); therefore the relationship between the two substances does not follow the precursor-successor relationship in plasma and a compartmental model has been used to fit the data. In this model the biotransformation process occurs before entering the central compartment (first-pass effect). The mean half-life of rosaprostol is equal to about 5 h and that of the metabolite is equal to 3 h. All of rosaprostol is biotransformed and only the metabolite is partially eliminated by the urine. The urinary excretion of the metabolite represents only a small fraction of the administered dose. The urinary clearance of the metabolite is equal to 5.3 l/h. The volume of distribution of both substances is equal to 21.2 l.

Influence of urapidil on in vitro platelet response to adrenaline and other aggregating agents.

The effects of hypotensive drug urapidil on human platelet functions were investigated. Urapidil failed to evidence direct aggregating properties or potentiating effects. Furthermore, drug high concentrations inhibited the platelet response to ADP, PAF, collagen, adrenaline and bovine thrombin, and influenced the platelet release reaction induced by ADP and PAF. Data indicate that urapidil possesses negligible agonistic effects on human platelet alpha 2-adrenoceptors and interferes at high concentrations with the platelet activation, as evidenced for other anti-aggregating compounds.

Effects of a synthetic prostanoid, rosaprostol, on the changes of gastric acidity and digestive disorders induced by NSAID.

In 24 subjects without upper gastrointestinal lesions, gastric pH was measured from 30 min before until 90 min after the administration of diclofenac sodium (50 mg), piroxicam (20 mg), or 500 mg acetylsalicylic acid. In all these cases a drop of gastric pH was recorded, which started with all the drugs 15 min after their administration and lasted throughout the recording. Pre-treatment with rosaprostol (2 g given 30 min before the start of the trial) prevented the drop in pH. Twenty subjects with chronic joint diseases were divided into two groups in a cross-over double-blind randomized experimental design. One group received piroxicam (20 mg) + rosaprostol (2 g) daily; the other group was treated with piroxicam 20 mg + placebo. The patients were clinically reviewed every week in a month and questioned about their symptoms. Statistical analysis demonstrated that patients with articular diseases treated with NSAIDs + rosaprostol exhibited a frequency and severity of symptoms lower than those recorded in subjects receiving NSAIDs + placebo. Rosaprostol was found to be capable of antagonizing the variations of gastric acid output induced by the oral administration of NSAIDs, and to prevent and treat the occurrence of digestive disorders when given in combination with NSAIDs. These effects result from the action of rosaprostol on the mucosal barrier, and this cytoprotective action is confirmed by the present study with continuous measurements of gastric pH.

Short- and long-term treatment with rosaprostol of patients with gastritis.

Therapy with rosaprostol was applied in 25 patients with gastritis, namely 11 cases for about 30 days and 14 for 60 days, without further gastro-protective treatments. The drug induced an early complete disappearance of subjective and objective symptoms, already at the end of the first ten days of treatment, whereas the endoscopic and the histological findings revealed a highly significant improvement at the end of the treatment, with normalization in nearly all the cases. The drug was well tolerated, and did not induce diarrhoea nor change haemodynamic parameters. These highly significant results emphasize the efficacy and safety of the drug.

Silybin inhibition of human T-lymphocyte activation.

Silybin, a 3-oxyflavone occurring in the thistle Silybum marianum, displays a dose-dependent inhibition of in-vitro lymphocyte blastogenesis induced by lectins (phytohaemagglutinin, Concanavalin A and pokeweed) and by anti-CD3 monoclonal antibody. The drug has no effect on cell viability and spontaneous 3H-thymidine incorporation, suggesting that the inhibitory activity is not due to aspecific toxicity. Since all the T-cell responses investigated require cell-membrane-associated events, the effect of silybin is probably at the level of the cell membrane, as for other flavonoids. Addition of CuSO4 prevents the inhibitory activity of silybin on PHA-induced proliferative response, indicating that the drug could exert its activity also by virtue of a chelation mechanism.

Modulation of human polymorphonuclear leukocyte function by the flavonoid silybin.

The effect in vitro of the naturally occurring flavonoid silybin on human polymorphonuclear leukocyte (PMN) functions has been studied. Preincubation of PMNs for 10 min at 37 degrees C with silybin inhibited, in a dose-dependent way, the luminol-enhanced chemiluminescence (CL) generated by stimulated cells without affecting the non-enhanced CL or superoxide anion production evaluated by the cytochrome C reduction assay. No significant effect of silybin on PMN phagocytic or chemotactic activities were found. Silybin did not absorb light at the wavelength of luminol-enhanced CL and was not toxic to PMNs at the concentrations used. Catalase, a scavenger of H2O2, inhibited luminol-enhanced CL to a similar degree as silybin; moreover, when incubated together with PMNs, silybin and catalase did not produce an additive inhibition of CL. On the contrary, the simultaneous addition of silybin and sodium azide, an inhibitor of myeloperoxidase, further increased inhibition over that seen with azide alone. These results suggest that inhibition of H2O2 may be the mechanism by which silybin inhibits the luminol-enhanced CL generated by stimulated PMNs. Such results indicate a possible anti-inflammatory activity for silybin even if their clinical relevance remains to be elucidated.

Drug modulation of superoxide anion production from human neutrophils.

The effects of drugs on the production of superoxide anion from neutrophils stimulated by N-formylmethionyl-leucyl-phenylalanine (FMLP) were examined. Drugs acting on specific receptors, such as beta-adrenergic agonists (e.g. fenoterol, salbutamol) inhibited FMLP-evoked superoxide in a dose-dependent fashion. The order of activity: isoprenaline greater than fenoterol greater than salbutamol is the same as that found by assaying their effects on lysosomal enzyme release. Superoxide production from human neutrophils can also be affected in different manners, such as by a scavenging mechanism. A new non-steroidal anti-inflammatory drug, imidazole 2-hydroxybenzoate, by forming complexes with copper, displayed a significant superoxide dismutase activity which would contribute to explain its anti-inflammatory effect in vivo.