Effect of immersion in CO2-enriched water on free radical release and total antioxidant status in peripheral arterial occlusive disease.

AIM: The aim of this paper was to investigate the release of oxygen free radicals in patients with peripheral occlusive arterial disease and the effects of immersion of the legs and feet in carbon dioxide (CO(2))-enriched water. METHODS: Twenty-five patients with peripheral occlusive arterial disease (Fontaine stage II) and 15 healthy controls were treated by immersing the lower legs in either CO(2)-enriched or normal spa water. Blood samples were collected in heparinized tubes and total antioxidant status (TAS) and reactive oxygen metabolites (ROMs) were measured after five treatments a week for two weeks. RESULTS: d-ROM plasma levels decreased in patients with peripheral occlusive disease after immersion in CO(2)-enriched water (P<0.001), and in healthy controls (P<0.01), in line with a significant increase in TAS (P<0.001). CONCLUSION: CO(2)-enriched water immersion had a positive effect, reducing free radical plasma levels and raising the levels of antioxidants, suggesting an improvement in the microcirculation.

[Effect of thermal mud baths on normal, dry and seborrheic skin]. / Effetti dell'uso di un fango termale su cute normale, secca e seborroica.

PURPOSE: To investigate the curative effects of thermal water and thermal muds in various cutaneous pathologies. PATIENTS AND METHODS: Modifications of phmetry and sebometry using sulphur thermal muds in normal, dry and seborrheic skin have been studied. The three groups of patients have been submitted to a 14 day treatment with thermal muds. RESULT: The application of thermal mud normalized the value of cutaneous pH and sebometry. CONCLUSIONS: These beneficial effects are long-lasting in individuals who have a prolonged treatment with thermal muds.

Chronic toxicity of taurohyodeoxycholic acid in dogs.

Fifty-two-week oral toxicity and 24-week intramuscular toxicity of a new synthetized biliary acid, taurohyodeoxycholic acid (Io, Praxis, CAS 2958-04-5) were investigated in dogs. Taurohyodeoxycholic acid was orally administered at dose levels up to 500 mg/kg/d and i.m. administered at dose levels up to 200 mg/kg/d. No deviations from normality were observed in mortality, physical appearance and general behaviour of the treated animals. Food and water consumption and body weight gain of treated groups did not differ from those of control animals. No treatment-related changes were observed in hematology, serum biochemistry, urinalysis, organ weights and post-mortem macroscopic or histopathological examinations. No dose- or sex-related differences were observed. The no-effect dose level was estimated to be 500 mg/kg/d in the chronic oral toxicity study and 200 mg/kg/d in the intramuscular study.

Chronic toxicity of taurohyodeoxycholic acid in rats.

Fifty-two-week oral toxicity and 24-week intraperitoneal toxicity of a new synthetized biliary acid, taurohyodeoxycholic acid (Io, Praxis, CAS 2958-04-5), were investigated in rats. Taurohyodeoxycholic acid was orally administered at dose levels up to 500 mg/kg/d and intraperitoneally administered at dose levels up to 200 mg/kg/d. The treated animals showed no deviations from normality in mortality, physical appearance and general behavior. Food and water consumption and body weight gain of the treated groups did not differ from those of the control. No treatment-related changes were observed in hematology, serum biochemistry, urinalysis, organ weights and post-mortem macroscopic or histopathological examinations. No dose- or sex-related differences were observed. The no-effect dose level was estimated to be 500 mg/kg/d in the chronic oral toxicity study and 200 mg/kg/d in the intraperitoneal study.

Pharmacokinetic studies in healthy volunteers on a new gastroprotective pharmaceutic form of diclofenac.

The pharmacokinetic properties of a new gastroprotective pharmaceutical formulation of diclofenac (CAS 15307-79-6) were investigated in twelve healthy volunteers. In this new form the diclofenac is the nucleus of sequential sucralfate-covered tablets. The experimental design was an open, random, two period balanced cross-over study. All the subjects received a single oral dose of 50 mg diclofenac contained in the new formulation or in the reference enteric-coated tablets. Plasma concentrations of diclofenac were determined at 0.5, 1, 2, 4, 6, and 8 h after drug administration using HPLC method. After administration of a diclofenac-sucralfate association diclofenac was quickly absorbed and the peak plasma concentration (0.773 +/- 0.08 microgram/ml) was achieved in about 1 h. AUC(0-infinity) value was about 1.8 micrograms/ml/h and the mean elimination half-life was 1.20 +/- 0.12 h. The pharmacokinetic profile of diclofenac-sucralfate association is similar to the values reported in previous papers for enteric-coated forms; anyway an early occurrence of the peak plasma concentration was observed for the new formulation. The new diclofenac-sucralfate association shows a different rate of absorption (namely an early and greater peak plasma concentration of diclofenac) and a similar extent of absorption (AUC(0-infinity) being not statistically different) as compared to the reference enteric-coated tablets of 50 mg diclofenac. These results could be related to the delaying and protective effect of sucralfate whose action is different from the one carried by the coat of the enteric-coated tablets.

In vitro/in vivo correlation of prolonged release dosage forms containing diltiazem HCI.

Six preparations were considered: three multiple unit dosage forms (micropellets in capsules) (D, E and G) and one matrix tablet (B) were experimental prolonged release formulations, two non-disintegrating tablets (A and C) were commercial products. The in vitro dissolution behaviour of the differing formulations was investigated using the USP XXII paddle apparatus. The in vivo study was effected on a panel of 12 healthy volunteers. The two commercial tablets (A and C) showed mean dissolution time (MDT) of 1.34 and 1.44 h and td of 91 and 92 min, respectively; for prolonged release formulations (B, E, D, and G) MDT ranged between 2.28 and 4.23 h and td between 149 and 291 min. The mean residence time (MRT) was 8.68 and 6.47 h for tablets A and C, respectively; it ranged between 9.62 and 10.24 h for the multiple unit formulations E, D, and G and was 11.27 h for matrix B. Formulation B also showed the higher apparent elimination half-life t1/2 (7.12 h), while apparent t1/2 for all the other formulations were very similar, ranging between 5.04 and 5.28 h. High variability between the various formulations was found for Cmax and AUC values, and no relationships could be established with the type of formulation. An in vitro/in vivo correlation was found for all the formulations examined on the basis of analogous parameters (MDT and MRT); (r = 0.83, p < 0.05). In a few cases the Wagner-Nelson deconvolution method was applied to individual plasma level versus time curves and the corresponding absorption curves were obtained. In these cases the in vitro/in vivo correlation was tested on the basis of the comparison of the in vivo absorption curves with the in vitro dissolution profiles. This was accomplished using the 'Levy's plot' (per cent released versus per cent absorbed) approach and provided further support for the correlation found.

Chronic toxicity study on a new glucan extracted from Candida albicans in rats.

Fifty-two-week oral toxicity of a new glucan (Glucanil, Gluimmun) extracted from Candida albicans ATCC 20955 was investigated in rats. The glucan was orally administered in dose levels up to 200 mg/kg/d and was well tolerated. No deviation from normality was observed in mortality, physical appearance and general behaviour of the treated animals. Food and water consumption and body weight gain of glucan-fed groups did not differ from those of control animals. In these groups no alteration of the weight of the main organs was also observed. Hematology, blood chemistry, urinalysis and autopsy findings were within normal ranges in every group of rats treated. No sex difference was noted. In the 200 mg/kg group soft stools or diarrhoea and cecal enlargement with variable hyperplasia of the colon mucosa were observed. These symptoms are typical of exposure to substances which are absorbed incompletely in the small intestine and subjected to microbial metabolism in the cecum and colon. Diarrhoea, cecal enlargement and mucosal hyperplasia are reversible. The no-effect dose level was estimated to be 100 mg/kg/d under these conditions.

Pharmacokinetics of a sustained release formulation of pyridoxal phosphate of buflomedil after single or repeated oral doses in healthy volunteers.

The pharmacokinetics of a sustained release (SR) formulation of pyridoxal phosphate of buflomedil (Pirxane retard) has been studied after oral administration to healthy volunteers using among else a gaschromatographic dosage method. After oral administration of 400 mg of the SR formulation, pyridoxal phosphate of buflomedil has a much slower kinetics compared to the normal formulation (tmax:approx. 1.5 h) reaching the maximum plasma concentration, which was about 467 ng/ml, in about 3 h. After 24 h the concentrations were still about 1/10 (48 ng/ml) the maximum value. 24-h urinary excretion was about 21% of the administered dose. Repeated administration of the SR formulation for 7 days in single daily doses of 400 mg gave steady state plasma levels (ca. 250 ng/ml) 12 h after the administration without statistically significant variations. The plasma concentrations of the drug measured daily after reaching the steady state were similar one to the other. The tolerability was very good and no local or systemic side effects of any kind were reported.

A computer-aided simulation approach in the development of a prolonged release formulation.

Prolonged medication with diltiazem has proved advantageous in the treatment of coronary insufficiency and arterial hypertension. Consistently, a number of extended release formulations, based on different retardation mechanisms, have been proposed. In the present work two prolonged release oral formulations containing diltiazem, one intended for twice-a-day and one for once-a-day administration, were tested for in vitro behaviour; the in vitro release test had been opportunely validated using an in vitro-in vivo correlation approach. On the basis of in vitro release profiles, simulations were effected, using a computer program previously developed, in order to generate the plasma levels that could be expected on single dosing of the two formulations. The two formulations were then tested in vivo and the measured plasma profiles were compared with those predicted from in vitro data. For both formulations, a good agreement was found between the measured and the simulated plasma levels, thus demonstrating the usefulness of the simulation approach in the formulative development.

Swelling-restricted minimatrices for controlled release of drugs. Preliminary in-vivo studies.

A preliminary in-vivo study was performed on a new modified release system which contained diltiazem hydrochloride. The system consisted of swellable minimatrices that were coated with an acrylic polymeric film. The film thickness, because of its pH-dependent solubility, might represent a critical variable with regard to in-vivo release. In order to evaluate the influence of such a variable on in-vivo behaviour, two minimatrices formulations with differing film thickness were tested versus a commercial tablet. The in-vivo study, which was based on a balanced incomplete block design, involved six volunteers in two sequences. The drug was quantified in plasma by an HPLC method. Computation and statistical analysis of pharmacokinetic parameters were performed by means of SIPHARR package (Simed, F). The results show that the approach of film coating, in order to modify the release rate from minimatrices, is feasible, but it must be improved; in particular the results point to the necessity of reducing the film susceptibility to pH changes.

Bioavailability of suckable tablets of oral N-acetylcysteine in man.

The pharmacokinetics and bioavailability of suckable tablets and granules of N-acetylcysteine (NAC) have been compared after oral administration of 400 mg doses to 10 healthy volunteers. The oral bioavailability of the NAC tablets was 103%. In a multiple dosing study of the same tablets in the same subjects, a high maintenance plasma level of NAC was revealed.

Lack of effect of a single-dose of sulglicotide on the bioavailability of diclofenac.

The bioavailability of diclofenac (D) was assessed in 12 healthy volunteers treated orally with single doses of 100 mg (retard formulation) and subsequently retreated with the same dose of (D) plus sulglicotide (S) 200 mg. (D) blood levels were measured by GLC in samples collected after 1, 2, 4, 6, 8, 12, 24 h. No relevant difference was seen in (D) bioavailability after (S) administration; after 8 h plasma levels of (D) were slightly higher after (S) (p less than 0.05), but this difference can be considered incidental only. Thus, sulglicotide does not interfere with the bioavailability of diclofenac, and can be administered concurrently with the latter to prevent possible gastric injury by the antiinflammatory drug.