Bencyclane as an anti-sickling agent

A vasodilating Ca²⁺ channel blocker, bencyclane, was used in 18 patients with homozygous sickle cell anaemia (SCD) to test the possible anti-sickling effect. With bencylane intervention the Na⁺-K⁺ ATPase activity increased from 256±29 to 331±37 nmol Pi/mg protein/h ( P <0.0001) and the Ca²⁺-Mg²⁺ ATPase level increased from 172±12 to 222±44 nmol Pi/mg protein/h ( P <0.0001). The intracytoplasmic Ca²⁺ concentration reduced from 3.5±0.6 to 2.7±0.25 μmol/l ( P <0.0001). The patient's blood contained fewer irreversibly sickled cells (ISCs) (a reduction from 21.4% to 14.4%) ( P <0.05). At the same time MCHC of the erythrocytes decreased from 34.5 to 33.0 g/dl ( P <0.05). Bencyclane appears to be a promising anti-sickling agent that can be used orally in SCD.     

The pronase resistance of cholesterol-nucleating glycoproteins in human bile

BACKGROUND & AIMS: Many putative pronucleating proteins have been isolated from the biliary concanavalin A (con A)-binding fraction. The pronase resistance of the overall nucleating-promoting activity was almost never taken into consideration. The aim of this study was to identify the major pronase-resistant con A-binding glycoproteins. METHODS: Pronase-treated and -untreated con A-binding glycoproteins were separated on a Superose 12 gel permeation column (Pharmacia, Uppsala, Sweden) and tested in a crystal growth assay. Proteins were identified by amino-terminal sequencing. RESULTS: Con A-binding pronucleating activity eluted in two peaks on the Superose column. This activity was unaltered after pronase treatment. Activity peak I contained too little protein to allow amino-terminal sequencing. In activity peak II, the major pronase-resistant con A-binding glycoproteins were identified as alpha 1-antitrypsin and alpha 1- antichymotrypsin. The 130-kilodalton nucleation promoter was identified as aminopeptidase N, but the full pronase resistance of this protein, reported earlier, was not confirmed. Immunoabsorptive removal of alpha 1-antitrypsin and alpha 1-antichymotrypsin and immunopurification showed that only alpha 1-antichymotrypsin had pronucleating activity. CONCLUSIONS: The pronase resistance of the nucleating-promoting activity of the con A-binding glycoprotein fraction was confirmed. An important part of this activity could be attributed to alpha 1- antichymotrypsin. It is an acute-phase protein, as are many other pronucleating proteins, which might indicate a general mechanism of action in gallstone formation. (Gastroenterology 1996 Jun;110(6):1926-35)     

Successful Treatment of Bone Marrow Failure in Gaucher's Disease with Low-dose Modified Glucocerebrosidase

We report the beneficial effects of enzyme replacement therapywith mannose-terminated human glucocerebrosidase (‘Ceredase’)in a patient suffering from transfusion-dependent bone marrowfailure due to Gaucher's disease. Treatment with low-dose enzymeinfusions, given twice weekly, rapidly reversed the haematopoieticfailure and incapacitating skeletal disease. It appears likelythat prior splenectomy favourably influenced the response tothis therapy.     

Synergistic inhibition of platelet activation by plasmin and prostaglandin I2

Endothelial cell prostacyclin (PGI2) inhibits platelet activation by raising platelet cyclic AMP. Previously, platelet activation was also shown to be blocked by plasmin formed by endothelium-derived tissue plasminogen activator (TPA). We have now studied interactions between PGI2 and plasmin in the control of platelet function. PGI2 and plasmin cause synergistic inhibition of thrombin- and ADP-induced aggregation of washed platelets. Inhibition by PGI2 is similarly potentiated by TPA added to platelet-rich plasma to generate plasmin. Thrombin-stimulated rise in platelet cytosolic Ca2+, measured by fura2 fluorescence, and thromboxane A2 formation, measured by radioimmunoassay (RIA), are likewise synergistically inhibited by PGI2 and plasmin. Plasmin neither increases nor potentiates PGI2-stimulated increases in platelet cyclic AMP. Thus, PGI2 and plasmin cause synergistic inhibition of platelet activation by both cyclic AMP-dependent and independent mechanisms. This interaction between two different endothelium-derived products may play an important role in localizing the hemostatic plug to a site of vascular injury by preventing further thrombin-mediated accrual of platelets.