Summary. Among the various potential antisickling agents tested, hydroxyurea (HU) has been the most effective compound used for the treatment of patients with sickle cell disease (SCD). Although HU is effective in many patients, not all patients respond to this drug. In addition, some patients reveal adverse effects, including myelosuppression. In an attempt to find other effective agents with less adverse effects, we investigated the antisickling effect of NIPRISAN (Nix-0699). We found that Nix-0699, an ethanol/water extract from indigenous plants, has a strong antisickling effect. The concentration of Nix-0699 required to inhibit 50% of erythrocyte sickling was about 0AE05 mg/ml. As for the kinetics of polymerization, addition of 0AE05 lg/ml Nix-0699 caused a sixfold prolongation of the delay time prior to deoxy-Hb S polymerization when compared with that of untreated Hb S samples. The solubility of deoxy-Hb S significantly increased upon treatment with Nix-0699. Analysis of the effect of Nix-0699 on the Hb S oxygen affinity indicated that the drug slightly shifted the oxygendissociation curve of Hb S toward the left without any apparent change in the Hill coefficient. These results suggest that the antisickling properties of Nix-0699 may involve direct interaction with Hb molecules. Incubation of red blood cell (RBC) suspensions with various concentrations of Nix-0699 did not dehydrate RBCs, cause haemolysis, increase the amount of denatured Hb, nor form met-Hb. In view of the outcome of this study, Nix-0699 may be a promising option for the treatment of patients with SCD.

Summary. The substitution of glutamic acid by valine at the sixth position of the beta-globins of haemoglobin S (Hb S) causes a drastic reduction in the solubility of the deoxy form of Hb S. Under hypoxic conditions, deoxy-Hb S molecules polymerize inside the cells, forming rigid, sickled cells. We studied the effect of Niprisan (Nix-0699), a naturally occurring antisickling agent, on the survival of transgenic (Tg) sickle mice under severe acute hypoxic conditions (60 min). Before hypoxia exposure, the mice were treated by gavage once daily for 7 d with 0 mg/kg (n ¼ 10), 10 mg/kg (n ¼ 5), 50 mg/kg (n ¼ 5), 300 mg/kg (n ¼ 4) or 500 mg/kg (n ¼ 5) of Nix-0699. The mean survival times of the untreated and treated mice were 10, 25, 39, 55 or 60 min respectively. The percentage of sickled cells in the venous blood of the treated mice was lower than that in control mice and was dose dependent. Histological examination of the lungs of the control mice showed entrapment of massive numbers of sickled cells in the alveolar capillaries, although the degree of such entrapment decreased with the increased dose of Nix-0699. Nix-0699 may be a promising option for the treatment and management of patients with sickle cell disease.

In the present study, energy expenditure (EE) and rates of whole-body protein, glucose, and lipid metabolism were assessed in 8 African American sickle cell disease (SCD) patients and in 6 healthy African American control subjects during the infusion of amino acids, glucose, and lipid. Wholebody protein, glucose, and lipid kinetics were estimated by using L-[1-13 C]leucine, D-[6,6-2 H 2 ]glucose, and [ 2 H 5 ]glycerol, respectively. After a 2-h tracer equilibration period and a 0.5-h basal period, nutrients were administered intravenously for 3 h with 16% of the energy as protein, 52% as carbohydrate, and 32% as fat. Breath and blood were collected during the last 30 min of nutrient infusion and EE was measured by indirect calorimetry. EE was 14% greater (P ≤ 0.05) in SCD patients [145.0 ± 3.5 kJ · kg fat-free mass (FFM). Whole-body protein breakdown (4.4 ± 0.4 compared with 3.1 ± 0.1 mg · kg FFM Ϫ1 · min Ϫ1 , P ≤ 0.05) and protein synthesis (4.6 ± 0.4 compared with 3.2 ± 0.1 g · kg FFM Ϫ1 · min Ϫ1 , P ≤ 0.05) were 42% and 44% greater, respectively, in the SCD patients than in control subjects, but whole-body amino acid oxidation (0.90 ± 0.05 compared with 1.03 ± 0.09 mg · kg FFM Ϫ1 · min Ϫ1 ) was not significantly different between the 2 groups. Wholebody glucose and lipid kinetics did not differ significantly between the groups. EE increased in SCD patients during exogenous nutrient availability, and the additional energy required for the accelerated rates of whole-body protein breakdown and synthesis made a significant contribution to the increase in EE. These metabolic aberrations may increase the dietary energy and protein requirements of SCD patients.

Basal rates of whole body protein, glucose, and lipid metabolism and resting energy expenditure (REE) were measured in eight African-American sickle cell disease (SCD) patients and in six African-American controls. Catheters were placed 1) in an antecubital vein for stable isotope infusion and 2) in a heated hand vein for arterialized venous blood. Breath and blood were collected during the last 30 min of the 2.5-h study, and REE was measured by indirect calorimetry. REE [128 ± 5 vs. 111 ± 1 kJ ⋅ kg fat-free mass (FFM)−1 ⋅ day−1; P < 0.05 vs. controls] was 15% greater in the SCD patients. Whole body protein breakdown (5.0 ± 0.3 vs. 3.8 ± 0.2 mg ⋅ kg FFM−1 ⋅ min−1; P < 0.05 vs. controls) and protein synthesis (4.4 ± 0.3 vs. 3.2 ± 0.2 mg ⋅ kg FFM−1 ⋅ min−1; P< 0.05 vs. controls) were 32 and 38% greater, respectively, in the SCD patients, but whole body amino acid oxidation was similar (0.58 ± 0.03 vs. 0.66 ± 0.03 mg ⋅ kg FFM−1 ⋅ min−1). Measures of whole body glucose and lipid metabolism were not significantly different between the groups. The additional energy required for the greater rates of whole body protein breakdown and synthesis caused by SCD contributes significantly to the observed increase in REE, suggesting that dietary energy and protein requirements are enhanced in SCD patients.

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