Cholestasis-induced fibrosis is reduced by interferon alpha-2a and is associated with elevated liver metalloprotease activity.

BACKGROUND/AIM: Several drugs have been tested for the treatment of hepatic cirrhosis induced by various etiologic agents. Although interferon (IFN)alpha-2a has mostly been used to treat viral hepatitis, its anti-fibrogenic properties remain to be established. METHODS: An experimental model of cholestasis-induced cirrhosis was used to test the effect of IFNalpha-2a. Cirrhosis was induced in rats via ligation of the common bile duct. IFNalpha-2a (100,000 IU/rat, s.c.) was administered daily throughout the experiment. Collagens and TIMP-1 mRNA transcripts were determined by semi-quantitative reverse transcriptase-polymerase chain reaction in liver tissue samples. Activity of metalloproteases (MMPs) was measured using gelatin (denatured collagen) as substrate and the specific size of the enzymes was estimated by zymograms. Histology was performed using Sirius red as a specific stain for collagenous material, and computer-assisted morphometric analyses were carried out. A polyclonal mouse anti-plasminogen activator inhibitor (PAI-1) antibody was used to evaluate the distribution during treatment with IFNalpha-2a. RESULTS/CONCLUSIONS: MMP-activity was up-regulated in bile duct ligated rats treated with IFNalpha-2a. MMP-activity in homogenates of total liver was minimal as compared with activity in non-parenchymal cells isolated from the same parental perfused liver, indicating a cryptic MMP activity which was completely abolished by EDTA and 1,10 phenanthroline. Three bands of gelatin degradation were detected by zymography, corresponding to 95, 75 and 65 kDa. IFNalpha-2a decreased PAI-1 immunoreactivity in liver tissue slices as well as biochemical activity in non-parenchymal cell extracts (3.3+/-0.08 vs 7.4+/-1.1 U/mg protein). Procollagen alpha1 (III) and alpha1 (IV) genes expression were also down-regulated 1.5 and 4-fold, respectively. Interestingly, TIMP-1 gene expression did not change. Functional hepatic tests: alanine aminotransferase, aspartate aminotransferase, bilirubins and alkaline phosphatase were significantly lower in IFNalpha-2a treated animals. Analysis of histology demonstrated that IFNalpha-2a promoted resolution of fibrosis and decreased bile duct proliferation.

[The stability of all-trans retinoic acid in "retinoid solutions" of "Di Bella's Cure"]. / Stabilità dell'acido all-trans retinoico nella "soluzione ai retinoidi" della "cura Di Bella".

Recently all-trans retinoic acid, an oxidation product of retinol, has become famous, since it is a component of "retinoids solution" of "Di Bella's therapy". Since all-trans retinoic acid is rapidly destroyed in the presence of light and oxidants, we verified its stability in samples of "retinoids solution" stored in conditions believed optimal (under stream of nitrogen) and we compare the obtained results with those observed in other "retinoids solution" samples daily open and close again, simulating the intake from the patient. All samples showed a decrease of all-trans retinoic acid recovery at the end of the study, with a more rapid decline in samples daily open. From our observations, we decided to indicate an expiration date of one months from the date of "solution" preparation. The patient's manipulation brings out a change in the final composition of "retinoids solution".

Endogenous beta-endorphins in hypertension: correlation with 24-hour ambulatory blood pressure.

OBJECTIVES: The aims of this study were to determine whether hypertensive patients showed increased endogenous opioid tone and to find a possible correlation between beta-endorphin levels and 24-h ambulatory blood pressure. We also investigated whether circulating beta-endorphin levels were associated with pain perception at rest. BACKGROUND: Experimental studies suggest an involvement of the endogenous opioid system in cardiovascular control mechanisms. METHODS: We determined baseline beta-endorphin plasma levels by radioimmunoassay in 81 consecutive subjects (48 hypertensive, 33 normotensive) after a 30-min rest and before 24-h ambulatory blood pressure monitoring. In 72 of 81 subjects with a dental formula suitable for the pulpar test (graded increase of test current -0 to 0.03 mA applied to three healthy teeth), pain perception was also investigated. RESULTS: Hypertensive patients showed higher beta-endorphin plasma levels than normotensive subjects (p < 0.002). Circulating endogenous opioid levels correlated with 24-h diastolic blood pressure (p < 0.01), whereas the relation with systolic pressure did not reach statistical significance. When 24-h blood pressure recordings were divided into daytime and nighttime values, and blood pressure loads (percent of measurements > or = 140 mm Hg for systolic blood pressure and > or = 90 mm Hg for diastolic pressure) were calculated, a significant correlation was found between beta-endorphin levels and diastolic pressures and load. Similarly, presampling diastolic blood pressure was significantly correlated with beta-endorphin levels. Of the 72 subjects tested, hypertensive patients showed a lower pain sensitivity than normotensive subjects. A positive correlation was found between pain threshold and circulating beta-endorphin levels (p < 0.05). CONCLUSIONS: Sustained arterial pressure is probably involved in the tonic activation of cardiovascular mechanisms linked to endogenous opioid tone. Circulating plasma endorphins may account, at least in part, for the pain perception pattern relating to blood pressure levels at rest.

Bioequivalency of three tableted gallopamil products.

A three cross-study was conducted in 12 healthy male volunteers to evaluate the relative bioavailability of three different gallopamil tablets: Product A-Galcan 25 mg, Product B-Galcan 50 mg and Product C-Procorum 50 mg. Each dose was administered as a single tablet after an overnight fast, and blood samples were obtained for 12 hours. There was no statistically significant differences among the three products for the mean area under the plasma concentration-time curves (when corrected for the different doses). The relative bioavailability of Product A and B to Product C was respectively 96.3% (ESM = 12.4%) and 103.1% (ESM = 10.2%). Statistically significant (p less than 0.05) differences were found in Tmax between Product C (1.0 hr) and both Product A (2.1 hr) and Product B (2.4 hr). A longer-lasting absorption should always diminish peak to trough fluctuations during multiple dosing and to this extent Product B has some advantage over Product C.