Cost-effectiveness of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) demonstrated the efficacy of hydroxyurea in reducing the rate of painful crises compared to placebo. We used resource utilization data collected in the MSH to determine the cost-effectiveness of hydroxyurea. The MSH was a randomized, placebo-controlled double-blind clinical trial involving 299 patients at 21 sites.

Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults.

In a randomized, placebo-controlled clinical trial, treatment with hydroxyurea (HU) reduced crisis rates in adult patients with severe sickle cell anemia. No serious acute toxicity was seen, but the safety of long-term therapy could not be evaluated. The rationale for the use of HU was based on its ability to increase fetal hemoglobin (HbF) synthesis and the inhibitory effect of HbF on polymerization of sickle cell hemoglobin.

Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea.

Hydroxyurea (HU) can increase fetal hemoglobin (HbF) in sickle cell anemia (HbSS). To identify determinants of the HbF response, we studied 150 HU-treated patients grouped by quartiles of change in HbF from baseline to 2 years. Half of the HU-assigned patients had long-term increments in HbF.

Experimental therapy.

Bone marrow transplantation, hydroxyurea therapy in children and in patients with sickling disorders other than sickle cell anemia, and prophylactic transfusion for prevention of stroke in children are currently being evaluated as treatments for patients with sickle cell disease. Long-term complications of each of these treatments are incompletely understood. Attempts to inhibit sickling by lowering intracellular hemoglobin concentration are still in progress.

Eye disease in sickling disorders.

When treating patients with sickling disorders, hematologists and oncologists should know those eye lesions that require referral to an ophthalmologist, those that should lead to referral, and those that rarely are associated with decreased vision. Hyphema in any patient whose red cells contain hemoglobin S falls into the first category. Retinal neovascularization (proliferative retinopathy) and its consequence vitreous hemorrhage fall into the second.

Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia.

Painful crises in patients with sickle cell anemia are caused by vaso-occlusion and infarction. Occlusion of blood vessels depends on (at least) their diameter, the deformability of red cells, and the adhesion of blood cells to endothelium. Deoxygenated sickle cells are rigid because they contain linear polymers of hemoglobin S (Hb S); polymerization is highly concentration dependent, and dilution of Hb S by a nonsickling hemoglobin such as fetal hemoglobin (Hb F) would be expected to lead ultimately to a decrease in the frequency of painful crises.

Treatment of sickling disorders.

Sudden death in military recruits with sickle cell trait appears to be related to hyperthermia and its consequences and can probably be prevented by use of sensible precautions and heightened awareness of the risk. Sickle cell disease can be treated by decreasing the proportion of sickle cells through transfusion; indications and pathophysiology of such transfusions are beginning to become clear. Sickle cell disease can be prevented if erythrocytes can be prevented from sickling.

Design of the multicenter study of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia is a randomized double-blind placebo-controlled trial to test whether hydroxyurea can reduce the rate of painful crises in adult patients who have at least three painful crises per year. The sample size of 299 patients yields at least 90% power to detect a 50% or greater reduction in crisis rate. Dosage starts at 15 mg/kg/day and is titrated to the patient's maximum tolerated dose up to 35 mg/kg/day.

Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia.

Background: In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises.

Methods: In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year.

Robotics in the hematology laboratory. An evaluation of the productivity of the Sysmex HS-330.

The productivity of a robotic hematology system (Sysmex HS-330) was compared with that of existing automated, semi-automated, and manual systems (Coulter Counter-Model STKS; Sysmex R-1000 reticulocyte counter. Geometric Data Miniprep slide maker, respectively) in the clinical hematology laboratory of a large hospital. On average, for a batch of 50 samples, the HS-330 performed a blood count with a 5-part differential, a reticulocyte count, and prepare a blood smear 23 minutes faster than could trained technologists using existing equipment.

Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate.

Intravenous arginine butyrate has been shown to increase fetal hemoglobin (HbF) in sickle cell and thalassemia patients. Recently, we observed that sodium 4-phenylbutyrate, a drug administered orally to treat urea cycle disorders, increases HbF production in nonanemic children and adults. We treated six subjects with sickle cell disease over a period of 14 to 179 days.

Experimental therapy of sickle cell disease. Use of hydroxyurea.

Purpose: Therapy of sickle cell disease with hydroxyurea is experimental.

Patients And Methods: We have begun a randomized blinded clinical trial to determine its clinical utility. The efficacy of this drug is unproved and its risks, which include mutagenesis, teratogenesis and carcinogenesis, are poorly understood.

Pharmacological modification of hemoglobin F expression in sickle cell anemia: an update on hydroxyurea studies.

The most studied pharmacological intervention in sickle cell anemia aiming at elevating HbF expression is the use of hydroxyurea. At the present time the experience has been that after 1 year of treatment with maximum tolerated doses (MTD) all patients showed increases of percent HbF, with a mean of 15% HbF, without apparent side effects besides the reversible ones observed during the process of attaining the MTD. The question of efficacy is presently being investigated by a multicenter placebo controlled double blind clinical trial that involves more than 20 sites.

Hydroxyurea induction of fetal hemoglobin synthesis in sickle-cell disease.

In the past 8 years, it has become apparent that some cytotoxic drugs that interfere with DNA replication can reprogram erythroid progenitors to switch from adult hemoglobin to fetal hemoglobin (HbF) production. Hydroxyurea has now been shown to substantially increase HbF in patients with sickle cell anemia. Since HbF interferes with sickle hemoglobin polymerization, hydroxyurea may become an important therapeutic agent for patients with sickle cell anemia.

Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia.

Patients with sickle cell anemia were treated with daily doses of hydroxyurea, to assess pharmacokinetics, toxicity, and increase in fetal hemoglobin (Hb) production in response to the drug. Plasma hydroxyurea clearances were not a useful guide to maximum tolerated doses of the drug. The mean daily single oral dose that could be maintained for at least 16 weeks was 21 mg/kg (range, 10 to 35 mg/kg).

Accuracy and utility of differential white blood cell count in the neonatal intensive care unit.

The clinical utility of the complete blood cell count (including the differential white blood cell count) as a means to follow the course of infants in a neonatal intensive care unit was assessed. Utility was judged for three purposes: (1) predicting the onset of clinically unrecognized disease, (2) assessing the severity of current disease, and (3) following a trend during treatment. Neither conventional nor automated differential counts were useful for surveillance (predicting the onset of clinically unrecognized disease).

Hydroxyurea as treatment for sickle cell anemia.

Hydroxyurea may be the most promising drug suggested thus far as a treatment for patients with sickle cell anemia, but its safety and efficacy remain unproved, and it probably will not be evaluable for several years. It is not "the answer" for the disease, it seems likely that crises will not be eliminated by treatment, and at this time its use should be reserved for seriously affected adult patients who can participate in a controlled clinical trial. Every hematologist, internist, or pediatrician sees a few patients who are so severely afflicted by sickle cell anemia that their lives seem totally blighted.

Hemoglobin aggregation and pseudosickling in vitro of hemoglobin Setif-containing erythrocytes.

Erythrocytes from individuals heterozygous for hemoglobin Setif (alpha 94 Asp----Tyr) sickle in vitro without deoxygenation when incubated in chloride buffer due to hemoglobin aggregation. We now report quantitative studies of hemoglobin polymerization and deformability in these cells. Hemoglobin polymer gradually increased in intact cells during a 24 h incubation period at 24 degrees C.

Treatment of sickle cell anemia with hydroxyurea and erythropoietin.

Background: Hydroxyurea increases the production of fetal hemoglobin (hemoglobin F) in patients with sickle cell anemia and therefore has the potential for alleviating both the hemolytic and vaso-occlusive manifestations of the disease. There is preliminary evidence that recombinant human erythropoietin may also increase hemoglobin F production.

Methods And Results: We treated five patients with sickle cell disease with escalating doses of intravenous erythropoietin for eight weeks.