Dermatologic adverse events of protease inhibitor-based combination therapy in patients with chronic hepatitis C.

BACKGROUND: Combination therapy with pegylated interferon, ribavirin and a first-generation NS3/4A protease inhibitor, telaprevir or boceprevir, is the new strategy for treatment of genotype 1 chronic hepatitis C virus infection. This combination improves therapeutic efficacy but it also increases the risk of adverse events. OBJECTIVE: The aim of the study was to analyze frequency and severity of dermatological adverse events during protease inhibitor-based therapy and to evaluate the risk factors for their development. PATIENTS AND METHODS: This is a retrospective study of 109 patients with genotype 1 chronic hepatitis C treated with boceprevir (n=33) or telaprevir (n=76) based triple therapy. A logistic regression for relationship between clinical, demographic and laboratory factors and cutaneous adverse events was performed. RESULTS: Dermatological adverse events (skin rash, pruritus, anorectal paresthesia) occurred in both treatments (boceprevir and telaprevir) with similar frequency: 28% in telaprevir and 21% in boceprevir. In patients treated with telaprevir, men were more predisposed to develop skin rashes compared to women (OR 4,1 p=0,014) and age above 45 years was associated with occurrence of pruritus in men (OR 8,16 p=0,014). Being a female, coexistence of autoimmune thyroiditis and advanced liver fibrosis were independent factors predisposing to development of anorectal paresthesia (OR 4,13 p=0,041, OR 4,25 p=0,029, OR 4,54 p=0,018 respectively) in this group. In patients treated with boceprevir, coexistence of autoimmune thyroiditis predisposed to skin rashes (OR 10,22 p=0,017) and being a female predisposed to pruritus (OR11,2 p=0,033). The adverse events occurred after a mean time of 8,6 (range 1-24) weeks after initiation of therapy. CONCLUSIONS: In patients with chronic hepatitis C who received the triple therapy, the anorectal paresthesias were observed only in patients treated with telaprevir. The predisposing factors for this adverse event were: female gender and advanced liver fibrosis. The risk factors for other dermatological adverse were: 1) being a male over 45 years, for skin rashes and pruritus (for telaprevir), 2) coexistence of autoimmune thyroiditis for skin rashes (for boceprevir), 3) being a female, for pruritus (for boceprevir).

Effect of ghrelin on activities of some lysosomal hydrolases in rabbits.

OBJECTIVES: Observing the changes of activity of some lysosomal enzymes in blood serum of female rabbits subjected to injection of 10 microg of ghrelin/kg of body weight. METHODS: In the blood serum the activity of cathepsins D and L, alanine aminopeptidase, acid phosphatase, lysosomal lipase and lysosomal esterase was determined. RESULTS: As a result of ghrelin injection the activity of all the enzymes examined in blood serum increased markedly. CONCLUSION: Changes of lysosomal enzymes activities in the blood serum caused by the effects of ghrelin should be regarded as the response of the lysosomal system.

Further structural analysis of GnRH complexes with metal ions.

MALDI-TOF mass spectrometry, 1H NMR spectrometry, the continuous variation method and molecular modeling by MM3 calculation confirmed our earlier studies showing that gonadotropin-releasing hormone (GnRH) forms complex with copper(II) ion with the binding ratio 1:1. The copper(II) complex formed at physiological pH has a square planar configuration and GnRH complexes with nickel(II) and cobalt(II) ions are less stable than that of copper(II).

Insulin-induced changes of proteolytic activity of the lysosomal enzymes.

OBJECTIVES: Changes in the activity of alanine aminopeptidase, leucine aminopeptidase and cathepsins D and L in the liver and kidney of male and female of mice, injected with 0.4 IU/kg b.w. insulin for 4 and 8 days. METHODS: The homogenates of the liver and kidney were taken for examination. The activity of alanine aminopeptidase, leucine aminopeptidase and cathepsins D and L has been determined according to [1] method. RESULTS: The activity of alanine aminopeptidase, leucine aminopeptidase, cathepsins D and L in the liver and kidney of male and female of mice decreased in effect of insulin injections for 4 and 8 days. CONCLUSION: The changes of enzyme activities showed a stimulating effect of the insulin injection on the labilization of lysosomal membranes. The range of the reaction remained in a relationship with the kind of the organ, the type of enzyme, time over which insulin introduced operates in the organism, and with the sex.

Effect of hydrocortisone on the activity of some lysosomal enzymes in mice.

OBJECTIVES: Changes in the activity of cathepsin D and L, alanine aminopeptidase, leucine aminopeptidase, N-acetyl-beta-glucosaminidase, lysosomal arylesterase and lysosomal lipase in the liver and kidney of unselected and selected mice, subjected to 7.5 mg/kg b.w. of hydrocortisone injection for 4 and 8 days. METHODS: The homogenates of the liver and kidney were subjected to differentiated centrifuging and determination of studied enzymes. RESULTS: Injection of hydrocortisone caused an increase in the activity of all investigated lysosomal enzymes in the liver and kidney of mice. CONCLUSION: The reactions of selected mice were stronger in comparison with unselected ones. The highest increase in the activity investigated enzymes was observed after 8 days of hydrocortisone injection.