Search PubMed⌕ Search

Biomedical subjects

S Charache

Publications and source records attributed to S Charache.

At least 55 records · Page 3Linked to original sources
PubMed1987

Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia.

Five patients with sickle cell anemia were treated with hydroxyurea (HU), in hopes of augmenting their production of fetal hemoglobin. Laboratory responses in two patients treated for more than 2 years were encouraging and there were suggestions of clinical improvement. Long-term HU therapy should be considered for severely affected adults with sickle cell anemia who are willing to accept what is probably a small risk of carcinogenesis. Preliminary chromosomal analysis and knowledge of the clastogenic properties of HU suggest that conception and pregnancy should be avoided. Pharmacokinetic studies will probably be necessary to adjust individual dosage schedules so that cytotoxicity is avoided. F cell responses can be seen in 2 to 3 weeks if the HU dose is optimal, but establishment of a large number of F cells in the circulation may take a month or longer.

Adult↗
PubMed1987

Increasing fetal hemoglobin production in sickle cell disease: results of clinical trials.

Five years experience using 5AZA and HU in a limited number of patients with SS disease, have resulted in the following conclusions. First, these drugs can rapidly induce increases in HbF production. Rapid increases in HbF production are not associated with reductions in overall reticulocyte levels, or reductions in late erythroid precursors, such as CFU-E. Indeed, where higher doses of these drugs are used or where the patient is unable to clear the drug rapidly, cytotoxicity is associated with reduced HbF production. These drugs not only increase the number of cells containing HbF, but also increase the MCV and the MCH of both F cells and non-F cells. Uncontrolled clinical trials suggest that the clinical severity of the disease measured by reduction in anemia and fewer vasoocclusive SS crises, may result from use of these drugs. The mechanisms by which these drugs result in increased F-cell production and increased MCH of F cells and non-F cells, may be due to their ability to reversibly block cells during their cell-cycle. This reversible blockade does not inhibit either on-going protein production or the establishment of origins of replications of DNA. Even though the mechanisms whereby the increased HbF production is not known, early clinical results seem to justify the initiation of controlled clinical trials of HU in severely affected SS patients.

Anemia, Sickle Cell↗
PubMed1987

Flow cytometric reticulocyte counting with thioflavin T in a clinical hematology laboratory.

Flow cytometric measurement of reticulocyte counts, using the cationic dye thioflavin T, was implemented in a clinical hematology laboratory. Results obtained correlated well with manual reticulocyte counts using new methylene blue, but the reproducibility of counts done with the flow cytometer was much greater than that with manual counts. The new procedure permitted a reduction in laboratory staff, but required an intensive period of training for technologists. Utilization of the cytometer required about four hours per day of machine time for 60 counts, permitting implementation of other flow cytometric assays in the clinical laboratory.

Benzothiazoles↗
PubMed1987

Pseudosickling of hemoglobin Setif.

Hemoglobin Setif produces pseudosickling of red cells in vitro; the nature of the process and the conditions that "trigger" it are unknown. Studies of red cells, hemolysates, purified hemoglobin solutions, and artificial mixtures of Hb A and Setif suggest that pseudosickling is produced by intracellular crystallization of insoluble hemoglobin. Increased tonicity of the suspending medium accentuates the process, probably by causing a rise in intracellular hemoglobin concentration. If precipitates from A/Setif mixtures are analyzed, they always contain Hb A, suggesting an unusual mechanism for the process. Despite the fact that osmolality in the renal medulla is similar to that which produces pseudosickling in vitro, carriers do not have renal dysfunction of the type found in patients with sickle cell disease.

Adult↗
PubMed1986

Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production.

Initial alterations in fetal hemoglobin (HbF) production among eight sickle cell anemia subjects treated with hydroxyurea (Hu) are summarized. Four of these subjects had been previously treated with 5-azacytidine (5-aza). All subjects treated with Hu (50 mg/kg/d for three to five days) had suppression of their total reticulocyte counts by seven days, whereas the four subjects previously treated with 5-aza (2 mg/kg/d for three to five days) had increased reticulocyte counts at day 7. The effect of Hu on increasing the number of HbF-containing reticulocytes (F reticulocytes) is extremely variable, ranging from ten-to less than onefold differences in maximal posttherapy v pretherapy levels. Recovery from marrow suppression did not result in greater than twofold increases in F reticulocyte counts. Mean day 7 F reticulocyte levels in the four subjects treated with both Hu and 5-aza were 4.1 X 10/microL and 15.4 X 10(4)/microL, respectively. Among Hu-treated subjects, increased F reticulocyte production was correlated with low serum creatinine levels and rapid removal of Hu from the plasma. Furthermore, suppression of CFU-E colony formation on day 2 of therapy with Hu was inversely correlated with maximal F reticulocyte response. We conclude that where Hu treatment results in marrow toxicity (decreased reticulocyte counts, decreased CFU-E colony formation) HbF production is less likely to increase. Those sickle cell anemia subjects with minimal renal dysfunction (serum creatinine level, greater than 1.0 mg/dL) exhibit the most cytotoxicity and least F reticulocyte response to Hu.

Anemia, Sickle Cell↗
PubMed1985

Laboratory evaluation of the Coulter "three-part electronic differential".

Comparisons were made between "electronic" white blood cell (WBC) differential counts based on nuclear volume, differential counts performed by an automated image analyzer, and conventional manual counts performed by experienced technologists in a routine laboratory setting. The correlation between methods was excellent for lymphocytes (r = 0.9) and granulocytes (r = 0.9), but none of the three methods that were tested produced good results in enumeration of mononuclear cells (r = 0.6). Approximately 85% of the samples on which differentials were requested for an inpatient population could be processed by the electronic counter. Although the electronic counter failed to flag all abnormal samples (there were 6% false negatives), the performance of technologists doing 200 cell differentials was similar. Rapidly generated "electronic differentials" might be a useful and cost-effective adjunct to inpatient hospital practice if certain suggestions were implemented.

Adult↗
PubMed1985

5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin.

The effect of 5-azacytidine on erythroid precursors and progenitors was studied in nine patients with sickle cell anemia or severe thalassemia. Each patient received the drug intravenously for 5 or 7 d. 5-Azacytidine caused a four- to sixfold increase in gamma-messenger RNA concentration in bone marrow cells of eight of the nine patients and decreased the methylation frequency of a specific cytosine residue in the gamma-globin gene promoter in all nine patients. Within 2 d of the start of drug treatment there was a rise in the percentage of reticulocytes containing fetal hemoglobin (HbF; F-reticulocytes) without a significant change in the total number of reticulocytes, which suggested that there was a direct action of 5-azacytidine on erythroid precursors. Late erythroid progenitors (CFU-E), present in bone marrow after 2 d of drug administration, formed colonies containing an increased amount of HbF as compared with control colonies. Moreover, the number of CFU-E derived colonies was not decreased at these early times, which suggested that there was a direct action of 5-azacytidine on erythroid progenitors in the absence of cytotoxicity. Exposure of normal bone marrow cells in tissue culture to 5-azacytidine for 24 h reproduced both of these effects as judged during subsequent colony formation. The combined direct effects of 5-azacytidine on both the erythroid precursor and progenitor compartments resulted in an increase in HbF synthesis that was sustained for 2-3 wk. Toxicity to bone marrow as reflected by cytoreduction was evident after treatment in some patients but was not accompanied by an increase in HbF production. A correlation was found between the effects of 5-azacytidine on bone marrow, as assessed by in vitro measurements, and the hematological response of the individual patients to drug treatment.

Adult↗
PubMed1985

5-Azacytidine increases HbF production and reduces anemia in sickle cell disease: dose-response analysis of subcutaneous and oral dosage regimens.

Varying doses of 5-azacytidine (5-aza) were given to four sickle cell individuals for 500, 200, 100, and 30 days. The percentage of fetal hemoglobin (HbF) containing reticulocytes (F reticulocytes) increased two- to five-fold within five days of 5-aza therapy in all patients, with a two- to three-fold rapid response (less than 48 hours after initial dose) in three patients. Reticulocyte suppression was not observed prior to, during, or after therapy in those patients who responded within 48 hours. Subcutaneous 5-aza was given in 35-day courses consisting of every day, every other day, or three consecutive days a week. No marrow toxicity was observed on any of the regimens. For three patients, the highest average F reticulocyte level was observed on the three consecutive day a week regimen. Oral 5-aza, given with tetrahydrouridine, produced comparable F reticulocyte response. In the two patients treated for more than 100 days, Hb levels increased to 11 to 12 and 9 g/dL, MCV and MCH increased by 25%, and lysate HbF levels peaked at 12% and 20%. Fetal erythroid characteristics (i-antigen, galactokinase activity, and G gamma/A gamma ratios) did not correlate with maximal HbF production. The frequency of vasoocclusive crises appeared to decrease in both patients followed for more than 100 days.

Administration, Oral↗
PubMed1985

Pharmacologic manipulation of fetal hemoglobin synthesis.

The ease with which HbF production can be increased in subjects with SS disease was a totally unexpected phenomena on the basis of previous models of HbF synthesis. The fact that these drugs induce rapid increases in F cell production and increase HbF per F cell and HbS in non-F cells, may be important clues as to the mechanism of the action of these drugs. It is far from clear whether either one of these agents will be eventually used as therapy for subjects with SS disease. The more recent problems with cytotoxicity illustrated by HU, and the potential carcinogenic effect of 5-aza limit our ability to perform large controlled clinical trials at this time. The observation that HbF production is increased by two agents which perturb DNA replication may be important clues in understanding not only the origins of differential gamma versus beta globin gene expression but also the mechanism by which HbF is restricted to expression in only certain cells during normal erythroid maturation.

Anemia, Sickle Cell↗
PubMed1985

Iron deficiency anemia: mitochondrial alpha-glycerophosphate dehydrogenase in guinea pig skeletal muscle.

Severe iron deficiency anemia in rats causes a decrease in the activities of iron-containing enzymes in skeletal muscle mitochondria, and subsequent diminished respiratory activity has been linked to lowered work capacity. It was suggested that loss of mitochondrial alpha-glycerophosphate dehydrogenase activity plays a particularly important role in this process and, by inference, in the clinical manifestations of iron deficiency anemia. This view may be ill founded, inasmuch as other pathways with potentially greater activity are capable of transporting reducing equivalents from the cytosol into the mitochondria in mammalian skeletal muscle. In our experiments, iron deficiency anemia of a severity on the order of that in humans was produced in guinea pigs. Mitochondria from skeletal muscles of test animals exhibited respiration rates diminished by 24% to 36% compared with control mitochondria in the presence of several substrates. However, differences in respiration were not observed with alpha-glycerophosphate as substrate, nor were there differences in alpha-glycerophosphate dehydrogenase enzyme activity between mitochondria from iron-deficient and control animals. Although cytochrome oxidase activity and muscle mitochondrial protein content were the same in both groups of guinea pigs, cytochrome and flavoprotein concentrations were lower in mitochondria from iron-deficient animals and there was a preferential loss of cytochrome c + c1. Iron deficiency anemia in guinea pigs thus results in impaired oxygen metabolism in skeletal muscle mitochondria that is associated with a general decrease in the concentrations of iron-containing electron transport chain components as well as with an alteration in chain stoichiometry.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Hypochromic↗
PubMed1985

A clinical trial of three-part electronic differential white blood cell counts.

Three-part white blood cell differential counts (diffs), performed during electrical impedance counting of blood cells, can accurately classify lymphocytes, granulocytes, and mononuclear cells in 85% of specimens, with an error rate not exceeding that of conventional diffs. To assess the clinical utility of the new test, we tried it for three months on a medical unit. Conventional diffs were no better than three-part diffs or total white blood cell counts in signaling clinical changes, and the same decisions would have been made in 78% of instances if only three-part diffs were available. The three-part diff is as reliable a clinical index for monitoring most inpatients as the conventional diff or white blood cell count. Although its use could effect significant cost savings, acceptance of the new test seems unlikely unless enforced by administrative flat.

Clinical Trials as Topic↗