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Collagenase in lung tissue
Thiazinamium-methylsulfate;
a drug with anticholinergic and antihistaminic properties; its use in chronic generalised obstructive lung disease L. E. VAN BORK (J. H. G. JONKM~N. N. G. M. ORIE and R. DE zEEI!W) (Groningen, Netherlands) Thiazinamium-methylsulfate (Multergan) is a drug with anticholinergic and antihistaminic properties which has been much used for assessment of the degree of reversibility of bronchial obstruction and for therapy of some forms of generalised chronic obstructive lung disease. Intramuscular injection of thiazinamium induces considerable bronchodilatation; but after oral administration inconsistent results are obtained. This is probably the result of its high water solubility: it is absorbed rapidly and completely from the muscle and passes poorly through the lipoid-pore gastrointestinal epithelial membrane. The present study concerns the bio-availibility of the drug in various doses and various ways of administration. Plasma concentration, at a nanogram level, lung function (VC and FEV,) and heart rate were presented in relation to dose and time. A good relation exists between dosage and plasma concentration after intramuscular injection. After oral administration the plasma level is also proportional to the dose, but individual variations are considerable. The improvement of lung function is proportional to the plasma-concentration when a distinct reversible bronchial obstruction exists. For therapeutic oral use considerable individual differences in dosage are required, depending on the rate of passage through the gastrointestinal mucosa and biotransformation in the liver. There is a close relation between plasma concentration and heart rate.
Collagenase in Lung Tissue C. FRANKEN (Leiden, Netherlands) The occurrence of panlobular emphysema in patients with a,-antitrypsin deficiency suggests that the presence of this serum protein protects the lung from the development of emphysema. Besides trypsin it also inhibits elastase and collagenase. After the discovery by Lazarus (1968) of a collagenase occurring in human PMN leucocytes, which was confirmed by us, it seemed useful to look for the presence of collagenase in lung tissue. This seems highly probable since during growth production and degradation of collagen takes place. It is possible that the absence of the inhibiting oc,-antitrypsin in patients with this deficiency disturbs the balance in such a way that degradation prevails. We therefore isolated from the lungs of young rats lysosomes, a cell fraction which contains protein-splitting enzymes: collagenase activity was not found directly in this fraction, even after activation with trypsin, which in cell cultures turns the inactive pro-collagenase into an active enzyme. Only after raising the salt concentration of the lysosomes to 1 molar and passing the membranes was activity found in the filtrate. In solution over XM 300 and XM 100 ultrafiltration the supernatant, collagen was found, which makes it likely that the enzyme was bound in a complex form to collagen during the homogenisation of the lung. Poiyacrylamide gel electrophoresis showed the degradation of the collagen in solution at neutral pH. Both EDTA and cysteine as well as human and rat serum inhibited the reaction. DFP and the soya bean trypsin inhibitor had no effect. Heparin seemed to promote the activity. In the homogenate no PMN leucocytes and only a few macrophages were present.
Classification of Bronchial Asthma H. DEENSTRA (Utrecht, Netherlands) Recent immunological research has led to a better classification of asthma than the traditional distinction between intrinsic and extrinsic asthma. After a short discussion of the aspecific humoral
a drug with anticholinergic and antihistaminic properties; its use in chronic generalised obstructive lung disease L. E. VAN BORK (J. H. G. JONKM~N. N. G. M. ORIE and R. DE zEEI!W) (Groningen, Netherlands) Thiazinamium-methylsulfate (Multergan) is a drug with anticholinergic and antihistaminic properties which has been much used for assessment of the degree of reversibility of bronchial obstruction and for therapy of some forms of generalised chronic obstructive lung disease. Intramuscular injection of thiazinamium induces considerable bronchodilatation; but after oral administration inconsistent results are obtained. This is probably the result of its high water solubility: it is absorbed rapidly and completely from the muscle and passes poorly through the lipoid-pore gastrointestinal epithelial membrane. The present study concerns the bio-availibility of the drug in various doses and various ways of administration. Plasma concentration, at a nanogram level, lung function (VC and FEV,) and heart rate were presented in relation to dose and time. A good relation exists between dosage and plasma concentration after intramuscular injection. After oral administration the plasma level is also proportional to the dose, but individual variations are considerable. The improvement of lung function is proportional to the plasma-concentration when a distinct reversible bronchial obstruction exists. For therapeutic oral use considerable individual differences in dosage are required, depending on the rate of passage through the gastrointestinal mucosa and biotransformation in the liver. There is a close relation between plasma concentration and heart rate.
Collagenase in Lung Tissue C. FRANKEN (Leiden, Netherlands) The occurrence of panlobular emphysema in patients with a,-antitrypsin deficiency suggests that the presence of this serum protein protects the lung from the development of emphysema. Besides trypsin it also inhibits elastase and collagenase. After the discovery by Lazarus (1968) of a collagenase occurring in human PMN leucocytes, which was confirmed by us, it seemed useful to look for the presence of collagenase in lung tissue. This seems highly probable since during growth production and degradation of collagen takes place. It is possible that the absence of the inhibiting oc,-antitrypsin in patients with this deficiency disturbs the balance in such a way that degradation prevails. We therefore isolated from the lungs of young rats lysosomes, a cell fraction which contains protein-splitting enzymes: collagenase activity was not found directly in this fraction, even after activation with trypsin, which in cell cultures turns the inactive pro-collagenase into an active enzyme. Only after raising the salt concentration of the lysosomes to 1 molar and passing the membranes was activity found in the filtrate. In solution over XM 300 and XM 100 ultrafiltration the supernatant, collagen was found, which makes it likely that the enzyme was bound in a complex form to collagen during the homogenisation of the lung. Poiyacrylamide gel electrophoresis showed the degradation of the collagen in solution at neutral pH. Both EDTA and cysteine as well as human and rat serum inhibited the reaction. DFP and the soya bean trypsin inhibitor had no effect. Heparin seemed to promote the activity. In the homogenate no PMN leucocytes and only a few macrophages were present.
Classification of Bronchial Asthma H. DEENSTRA (Utrecht, Netherlands) Recent immunological research has led to a better classification of asthma than the traditional distinction between intrinsic and extrinsic asthma. After a short discussion of the aspecific humoral