| 摘要 |
Use of ionic form of potassium (K) or magnesium (Mg) or a compound leading to increased concentration of ionic Mg or K for promoting F actin formation by shifting equilibrium between G and F actin in manufacture of medicament for preventing/treating a disease induced by excess of G actin or DNA, or for treating diseases of the respiratory tract e.g. pulmonary disease characterized by presence of viscous mucus. Use of ionic form of potassium (K) or magnesium (Mg) or a compound leading to increased concentration of ionic Mg or K for promoting F actin formation by shifting equilibrium between G and F actin: (a) in manufacture of medicament for: (i) preventing or treating a disease induced by excess of G actin or DNA; or (ii) for treating disease of respiratory tract e.g., pulmonary disease characterized by presence of viscous mucus; and (b) in medicament for preventing or treating disease induced by autoimmune response against DNA. Independent claims are also included for: (1) a pharmaceutical composition (I) for the treatment of pulmonary disease characterized by viscous mucus comprising a compound able to promote F actin formation by shifting equilibrium between G and F actin and a DNA degrading enzyme, in respective proportions such as to provide a synergistic effect in the reduction of mucus viscosity, as a combined preparation for simultaneous, separate or sequential use; and (2) an in vitrodiagnostic tool to characterize mucus secretions from patients suffering from disease associated with viscous mucus. ACTIVITY : Antiinflammatory; Immunosuppressive; Dermatological. MECHANISM OF ACTION : Reduces inhibition of DNAse I activity; Reduces viscoelasticity of mucus; Promotes F actin formation by shifting equilibrium between G actin and F actin. Viscosity of DNA and DNA/actin solution was measured with a calibrated capillary viscosimeter equipped with an automated apparatus. The capillary viscosimeter was placed in a water bath(20+-0.05[deg]C) and the outflow times (t in s) were determined automatically. The viscosity of the solutions was related to t by an equation as given in the specification. The effect of Mg 2>+>and K +>ions on the activity of DNAse (measured as decrease in viscosity) was determined by changing the Mg 2>+>and K +>concentration in a standardized DNA digest. DNA (salmon sperm DNA) was digested (10 Microl/ml rhDNAse I, 2,3 mg/ml DNA, 70 mM NaCl and 3 mM CaCl 2, pH 7) in order to determine the change in viscosity of the DNA solution. The results showed that viscosity rapidly dropped to a value near 1 mm 2>/s. Also the effect of K +>and Mg 2>+>ions on DNA degradation (decrease in viscosity) measured in the presence of rabbit skeletal actin prepared according to Spudich et al., J. Biol. Chem. (1971) 246:4866-4871(6.4 Microg/ml rhDNAse I, 1.5 mg DNA/ml and 1.1 mg actin/ml 70 mM NaCl, 3 mM CaCl 2, 0.35 mM ATP, 3.2 mM TRIS/HCl, 0.13 mM dithiothreitol (DTT), and 0.006% NaN 3, pH 7), K +>and Mg 2>+>were supplied as K 2HPO 4and MgCl 2respectively. The viscosity of the DNA/actin solutions at different time points after the addition of rhDNase I showed that the highest DNAse activity at high levels of Mg 2>+>and K +>. |
