PubMed Health⌕ Search

Biomedical subjects

S Charache

Publications and source records attributed to S Charache.

At least 19 recordsLinked to original sources
PubMed1995

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. The trial was stopped after a mean follow-up of 21 months. RESULTS: Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P < 0.001). The median times to the first crisis (3.0 vs. 1.5 months, P = 0.01) and the second crisis (8.8 vs. 4.6 months, P < 0.001) were longer with hydroxyurea treatment. Fewer patients assigned to hydroxyurea had chest syndrome (25 vs. 51, P < 0.001), and fewer underwent transfusions (48 vs. 73, P = 0.001). At the end of the study, the doses of hydroxyurea ranged from 0 to 35 mg per kilogram of body weight per day. Treatment with hydroxyurea did not cause any important adverse effects. CONCLUSIONS: Hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in some adults with three or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects of hydroxyurea do not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia is uncertain.

Adult↗
PubMed1995

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. An estimated 1.8 medical technologists could be assigned to other tasks; however, because of the equipment's high cost, in a laboratory processing 1,000 samples per day, 4.6 years would be needed before any actual cost savings were experienced.

Efficiency↗
PubMed1994

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. All subjects received their initial therapy of 9 to 13 g/m2/day as 0.5-g tablets of sodium 4-phenylbutyrate as inpatients. All subjects showed a rapid increase in the percentage of F-reticulocytes (pretreatment, 1% to 20%; posttreatment, 10% to 44%). Four subjects were treated only 11 to 25 days as inpatients. Two of these four subjects failed to respond to the outpatient component because of their inability to maintain an intake of 30 to 40 tablets per day. One subject (C) developed a rash at day 10 and discontinued treatment at day 14. Another subject (B) was transfused for a painful crisis on day 25. Subject A, treated for 179 days, has an increased percentage of F cells, from 54% to 77%, and increased HbF levels, from 10.6% to 18%. Subject F, treated for 154 days, has an increased percentage of F cells, from 59% to 73%, and an increased percentage of HbF, from 10.4% to 16%. All subjects showed some increase in weight. Subject A developed mild transient ankle edema. Myelotoxicity was not seen in any treated patient. Oral administration of sodium 4-phenylbutyrate rapidly increases F-cell production in sickle cell disease.

Administration, Oral↗
PubMed1994

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. These risks are explicitly stated in our consent forms. A significant number of patients who are asked to enroll refuse to enter the study. This refusal is probably because of individual variations in perception of risk and personal inconvenience, as well as differences in perception of personal benefit. We have a few hints as to which patients are more likely to produce increased amounts of fetal hemoglobin, but our findings do not indicate which patients are most likely to show a good clinical response. RESULTS: Our study group decided not to treat patients under 18 years of age with hydroxyurea until clinical efficacy of the drug is proved in adults. We have criteria for selecting patients for entry into our ongoing study, but the criteria are based more on study design than on an estimate of present or future severity of the manifestations of sickle cell disease. CONCLUSIONS: Features of our previous study and results of the present trial may be helpful in defining indications for bone marrow transplantation in children with sickle cell disease.

Anemia, Sickle Cell↗
PubMed1993

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. The goal of the study is to determine if hydroxyurea can decrease the incidence of painful crises by 50%. Results of this study are not expected before the end of 1993.

Anemia, Sickle Cell↗
PubMed1992

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). Among 32 patients, last HbF levels were 1.9% to 26.3% (mean, 14.9%) with increases in HbF over initial values of 1.4% to 20.2% (mean, 11.2%). The most significant predictors of last HbF were last plasma hydroxyurea level, initial white blood count and initial HbF concentration. Last HbF was not related to beta globin haplotype or alpha globin gene number. No serious toxicity was encountered. Clinically significant bone marrow depression was avoided, and chromosome abnormalities after 2 years of treatment were no greater than those observed before treatment. The period of observation has been too short to evaluate the risk of carcinogenesis. Patient's red cells developed striking macrocytosis. Median red cell Hb concentrations did not change. Hb concentrations increased, on average 1.2 g/dL, but serum erythropoietin levels increased. Patients' body weights increased, and some returned to work or school, but no conclusions regarding therapeutic efficacy could be drawn from this uncontrolled open-label study.

Adult↗
PubMed1992

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). The white blood cell count, the platelet count, and the absolute immature neutrophil count and immature/total neutrophil ratio were useful to assess the severity of current clinical events. The white blood cell count was superior to the differential count for following trends in patients' conditions. Information regarding nuclear immaturity derived from automated counts and the cost and slowness of the manual differential count are good indications for decreased use of conventional counts, increased use of certain features of the automated differential, or both, in neonatal intensive care units.

Automation↗
PubMed1992

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.

Anemia, Sickle Cell↗
PubMed1991

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. After 24 hr, about 80% of the cells in 290 mOsm sodium chloride buffer contained polymer which appeared as short rods compared to greater than 99% containing polymer at 450 mOsm. Similar proportions of cells were morphologically sickled. Deformability of erythrocytes with 40% hemoglobin Setif incubated in 290 mOsm buffer at 37 degrees C decreased to 80% of normal by 210 min but in 450 mOsm decreased to 50% after only 30 min as measured by the ektacytometer. However, at 4 degrees C deformability remained normal even in 450 mOsm buffer. The solubility of gelled hemolysate containing 40% hemoglobin Setif was 24 g/dl and 21 g/dl at 290 and 459 mOsm buffer respectively. The gel persisted at 4 degrees C with a solubility of 26 g/dl, but melted when dialyzed into sodium phosphate or potassium phosphate buffer. These data suggest that hemoglobin polymerization, reduced deformability, and sickling of hemoglobin Setif-containing erythrocytes are related to reduced hemoglobin solubility. The rate and extent of intracellular polymerization in vitro are considerably reduced (as in the case of sickle trait) compared with erythrocytes from individuals with sickle cell anemia. Hence, the slower kinetics of hemoglobin aggregation in hemoglobin Setif-containing cells provide an alternate system for studying hemoglobin polymerization and abnormal rheology.

Anemia, Sickle Cell↗
PubMed1991

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. It is very tempting to consider treating them with hydroxyurea, because the drug is available in any pharmacy, but it is equally important to consider whether the treatment would accomplish any more than treating the physician's own sense of futility, or making the patient feel that "something was being done." If hydroxyurea were as safe as folic acid, treatment for these purposes would be reasonable. It is not, but its use may still be appropriate (although illegal unless used under an Investigational New Drug Agreement, because its use for this purpose is not approved by the FDA). Whether or not it is legal, prescription of hydroxyurea for patients with sickle cell anemia would be ethical or proper only if the potential risks, the variability of the Hb F response, and the lack of proof of clinical efficacy were clearly explained to potential recipients.

Anemia, Sickle Cell↗
PubMed1990

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. Three of these patients were subsequently treated with daily doses of oral hydroxyurea. After the optimal dose was determined, erythropoietin was then given along with hydroxyurea for four weeks. Treatment with erythropoietin, either alone or in combination with hydroxyurea, had no significant effect on the percentage of hemoglobin F-containing reticulocytes (F reticulocytes) or red cells (F cells). In contrast, hydroxyurea treatment was associated with a 3-to-25-fold increase in F reticulocytes, a 1.6-to-7-fold increase in F cells, and a 2.3-to-16-fold increase in the percentage of hemoglobin F. In all three patients given hydroxyurea, treatment with this drug was associated with reduced hemolysis, shown by decreases in serum bilirubin and lactic dehydrogenase and prolongation of red-cell survival. Hydroxyurea treatment also resulted in a decrease in the percentage of irreversibly sickled cells and sickling at partial oxygen saturation, an increase in oxygen affinity and total red-cell cation content, and a reduction in potassium-chloride cotransport. All three patients had a decrease in the number of pain crises. CONCLUSIONS: This study confirms that hydroxyurea therapy increases hemoglobin F production and provides objective evidence that hydroxyurea reduces the rate of hemolysis and intracellular polymerization of hemoglobin S. In contrast, recombinant human erythropoietin, whether alone or in combination with hydroxyurea, offers no measurable benefit.

Administration, Oral↗
PubMed1990

Fetal hemoglobin, sickling, and sickle cell disease.

Increased numbers of F cells and large amounts of Hb F/F cell appear to produce clinical benefit in rare variants of sickle cell disease and probably in more commonly encountered patients. Fetal hemoglobin interferes with polymerization of Hb S in vitro, but laboratory studies carried out with homogeneous hemoglobin solutions are inadequate models of events in vivo, because RBCs are heterogeneous in their MCHC and Hb F content. Studies of hemoglobin switching in sheep, in tissue culture, and then in baboons led to use of 5-azacytidine for induction of increased Hb F synthesis in SS patients. Drug trials were successful but the theory that led to them was not. An alternate theory, not without flaws, led to the use of hydroxyurea. Chronic administration of the drug can lead to very impressive increases in Hb F synthesis and apparent clinical benefit. It is not clear that such clinical benefit is real rather than a placebo effect. Nor is it entirely clear that all of the effect of hydroxyurea can be related to increased production of F cells and increased F/F cell. Controlled clinical trials and studies of the properties of RBCs from treated patients may answer those questions. It is also likely that they will not only raise still other questions but probably show that our current understanding of the biology and treatment of sickle cell disease is far from complete.

Adolescent↗
PubMed1990

Delayed intracranial hemorrhage following cerebral infarction in sickle cell anemia.

Clinical and necropsy findings in 11 patients with sickle cell anemia (SS) indicate that intracranial hemorrhage (IH) is a delayed sequela of the same vasculopathy that causes cerebral infarction during childhood. Evidence of prior cerebral infarction during childhood included hemiparesis, seizures, an episode of coma, or mental retardation. Computerized tomography (CT) scans showed cerebral infarcts with lucent areas and dilated ventricles or cerebral atrophy. CT or magnetic resonance imaging (MRI) scans after the intracranial hemorrhage demonstrated intraventricular or intracerebral hemorrhages. Angiography or autopsy in seven patients showed widespread vascular occlusion and narrowing of arterial vessels. Moyamoya with internal carotid artery occlusion was identified in two cases. At the time of the IH, three patients were being treated with prophylactic transfusion regimens. We hypothesize that the central nervous system vasculopathy progresses over time and that arterial narrowing in both large and small vessels secondary to endothelial hyperplasia is followed by neovascularization and hemorrhage. Recognition of this pattern of delayed intracranial hemorrhage following cerebral infarction should encourage more intensive evaluation aimed at developing rational interventional therapy prior to a terminal intracranial hemorrhage.

Adolescent↗