Adenosine A1R-specific antagonist SLV329 and demonstrated its long-term safety and efficacy in an animal model of cirrhosis

Chronic SLV329 treatment starting at an early stage of liver cirrhosis prevented the decrease of creatinine clearance. Further studies will have to evaluate, whether SLV329 or other A1R antagonists are clinically beneficial at different stages of liver cirrhosis, either as an add-on to aldosterone antagonists or in combination with loop diuretics. Bound radioactivity was measured by Ruxolitinib scintillation counting using a liquid scintillation cocktail. Enzyme assays were carried out as follows: after incubation of SLV329 with an enzyme preparation and its radioactive substrate, radioactivity of the enzyme product was measured by scintillation counting using a liquid scintillation cocktail. Testing was done at a 3-log concentration range around a predetermined half-maximally inhibitory concentration for the respective assay. The highest concentration tested for primes was 10 mM in receptor binding and 100 mM for enzyme assays. If no significant receptor binding or enzyme inhibition was detected at those concentrations SLV329 was considered to be inactive. Results were calculated as percentage of control values or for receptor binding assays as percentage of total ligand binding and that of nonspecific binding per concentration of SLV329. From the concentration-displacement curves IC50 values were determined by nonlinear regression analysis using Hill equation curve fitting. Antifungal chemotherapy is required to control the disease. The conventional treatment of PCM is based on sulfonamides, amphotericin B and azole derivates. Extended periods of therapy are usually required to warrant a good clinical response and avoid relapses. But, the prolonged time of drugs administration causes frequent self-exclusion of the patient from treatment. The introduction of azoles marked an advance in the treatment of fungal diseases, PCM among them. Azoles act on ergosterol biosynthesis at the C-14-demethylation stage, and the resulting ergosterol depletion and accumulation of 14-methylated sterols interferes with the functions of ergosterol as a membrane component, altering the normal permeability and fluidity of the fungal membrane. Imidazoles and triazoles have been extensively used for the treatment of PCM and have proven effective for clinical purposes, showing fewer side effects than amphotericin B. The above mentioned antifungal antibiotics have drawbacks such as long time of medication, severe renal side effects, unresponsiveness of some patients to the treatments and high cost. Therefore, the search for new and more effective strategies to conventional chemotherapy for P. brasiliensis and other fungal pathogenic species, with fewer or no side effects, continues. Because of the search for these new alternatives for PCM treatment, several candidate antigen molecules and its mechanisms of protection against P. brasiliensis are being studied.