potassium-cyanate and Anemia--Sickle-Cell

Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of deoxyhemoglobin S or Csat, (2) evaluation of sickling in whole SS blood at various pO2s, (3) measurement of the oxygen affinity of hemoglobin and blood, and (4) examination of red cell indices and morphology. Among the 4 noncovalent agents tested, butylurea was the most potent inhibitor of gelation and sickling in vitro; however, relatively high concentrations were required compared to the covalent agents. In the latter group, bis-(3,5 dibromosalicyl)-fumarate, nitrogen mustard, and dimethyladipimidate were especially effective inhibitors of gelation and/or sickling. All of these compounds require further development before they can be considered for clinical use.

Topics: Anemia, Sickle Cell; Antisickling Agents; Aspirin; Azepines; Carbamyl Phosphate; Cyanates; Cystamine; Dimethyl Adipimidate; Drug Evaluation; Erythrocyte Indices; Glyceraldehyde; Hemoglobins; Humans; Imidoesters; Mechlorethamine; Oxygen Consumption; Phenylalanine; Pyridoxal; Solubility; Urea

Topics: Anemia, Sickle Cell; Blood Viscosity; Cyanates; Erythrocytes, Abnormal; Flow Cytometry; Genetic Carrier Screening; Humans; Lasers; Oxygen

1. The Ektacytometer, which allows quantitation of cell fluidity under known environmental conditions, has been recently modified so that cells can be exposed to any desired O2 tension during shear stress. 2. Heterozygotes (HbAS)show a pO2 vs deformability curve which varies from patient to patient in relation to the quantity of HbS. In the high viscosity medium used for this measurement, erythrocytes are normally deformable at any pO2 from 5 mmHg to normoxic conditions, at physiologic pH [7.3] and osmolarity (290 mOsm Kg-1). Modulation of the pH and osmolarity induces cell rigidity at different pO2 below 40 mmHg. 3. Homozygotes (HbSS) blood contains heterogeneous erythrocyte populations from the reticulocytes to abnormally dense cells (heterogeneity in cell volume, Hb concentration, shape, etc.). After separation by differential centrifugation, the various fractions each show a characteristic response to pO2 changes, pH, osmolarity and other parameters, which are specific to each patient and his pathological status at a given time. 4. This method was used to evaluate the activity of anti-sickling drugs. In addition, the action of such compounds on normal cells gives information on the mechanism of activity (changes in volume, in oxygen affinity, membrane properties or other--yet poorly explored--parameters). 5. This new application of the Ektacytometer may be of value for a) evaluating anti-sickling drugs and designing new therapeutic modalities, b) monitoring therapy of sickle cell patients, and c) research into the phenomenon of sickling.

Topics: Anemia, Sickle Cell; Blood Viscosity; Cyanates; Cystamine; Erythrocyte Indices; Erythrocytes, Abnormal; Heterozygote; Homozygote; Humans; Hydrogen-Ion Concentration; Oxygen; Rheology; Stress, Mechanical