Efficacy of zinc therapy in prevention of crisis in sickle cell anemia: a double blind, randomized controlled clinical trial. Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Reduction of painful vaso-occlusive crisis of sickle cell anaemia by tinzaparin in a double-blind randomized trial. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. Effect of zinc supplementation on incidence of infections and hospital admissions in sickle cell disease (SCD). A randomized controlled trial of the effect of zinc as adjuvant therapy in children 2-35 mo of age with severe or nonsevere pneumonia in Bhaktapur, Nepal. [Preliminary results of a multicenter randomized study on the treatment of acute promyelocytic leukemias].
145 patients were recruited in the trial while 130 completed it. Patients were randomized to receive zinc sulphate capsules. 220 mgm three times a day or identical placebo. Major outcome variable was 'Sickle cell crisis'. After a follow up of 1.5 years, the mean number of episodes of crisis was 2.46 +/- 1.04 in the intervention group and 5.29 +/- 2.58 in the control group (p < 0.025; 95% CI for difference between groups: 1.98, 3.42). Mean duration of hospital stay was 4.3 +/- 2.2 days in the intervention group and 3.9 +/- 1.6 days in the control group. The difference was not significant (p > 0.05). There was a significant reduction of the mean number of infective episodes and associated morbidity in patients with sickle cell anaemia. Red blood cell (RBC) hydration is regulated in part by the Ca(2+) -activated K(+) efflux (Gardos) channel. Senicapoc selectively blocks potassium efflux through the Gardos channel, reducing RBC dehydration and haemolysis, and increasing haemoglobin levels in sickle cell disease (SCD). This randomized, placebo-controlled trial was designed to determine the safety and clinical efficacy of senicapoc in SCD patients. One hundred and forty-five patients were randomized to receive senicapoc and 144 patients to receive placebo for 52 weeks. Consistent with a previous study, patients in the senicapoc group had significantly increased haematocrit, haemoglobin, and decreased numbers of both dense erythrocytes and reticulocytes when compared to the placebo group. The unblinded Data Monitoring Committee terminated this study early due to a lack of efficacy when it determined that, despite improvements in anaemia and haemolysis, no significant improvement in the rate of sickle cell painful crises was observed in patients treated with senicapoc compared to those on placebo (0·38 vs. 0·31, respectively). Comparisons of the times to first, second and third crises between the senicapoc and placebo groups were not statistically significant. Nausea and urinary tract infections occurred more frequently in the senicapoc group than placebo. Serious adverse events were similar in the two groups.
                © 2011 Blackwell Publishing Ltd. Senicapoc, a novel Gardos channel inhibitor, limits solute and water loss, thereby preserving sickle red blood cell (RBC) hydration. Because hemoglobin S polymerization is profoundly influenced by intracellular hemoglobin concentration, senicapoc could improve sickle RBC survival. In a 12-week, multicenter, phase 2, randomized, double-blind, dose-finding study, we evaluated senicapoc's safety and its effect on hemoglobin level and markers of RBC hemolysis in sickle cell anemia patients. The patients were randomized into 3 treatment arms: placebo; low-dose (6 mg/day) senicapoc; and high-dose (10 mg/day) senicapoc. For the primary efficacy end point (change in hemoglobin level from baseline), the mean response to high-dose senicapoc treatment exceeded placebo (6.8 g/L [0.68 g/dL] vs 0.1 g/L [0.01 g/dL], P < .001). Treatment with high-dose senicapoc also produced significant decreases in such secondary end points as percentage of dense RBCs (-2.41 vs -0.08, P < .001); reticulocytes (-4.12 vs -0.46, P < .001); lactate dehydrogenase (-121 U/L vs -15 U/L, P = .002); and indirect bilirubin (-1.18 mg/dL vs 0.12 mg/dL, P < .001). Finally, senicapoc was safe and well tolerated. The increased hemoglobin concentration and concomitant decrease in the total number of reticulocytes and various markers of RBC destruction following senicapoc administration suggests a possible increase in the survival of sickle RBCs. This study is registered at http://clinicaltrials.gov as NCT00040677. A randomized double-blind clinical trial was performed to test the safety and efficacy of a low-molecular-weight heparin, tinzaparin (Innohep), for the management of acute painful vasoocclusive crisis characteristic of sickle cell anemia (SCA). We studied 253 patients with acute painful crisis but with no other complications of SCA, randomized to treatment or control groups. In the treatment group, 127 patients received tinzaparin at 175 IU/kg, subcutaneous once daily, along with supportive care including morphine analgesia; in the control group, 126 patients received placebo and the same supportive care. The maximal experimental treatment period was seven days. Analysis revealed a statistically significant reduction in number of days with the severest pain score, overall duration of painful crisis, and duration of hospitalization (p < 0.05 for each comparison of tinzaparin vs. placebo). The decline in pain intensity was sharper for tinzaparin-treated patients, and complications consisted of two minor bleeding events that were reported and treated by cessation of tinzaparin. This investigation demonstrated that tinzaparin, administered at its approved treatment regimen, reduced the severity and duration of acute crisis of SCA. 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.
                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.
                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.
                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. Children with sickle cell anemia have an increased susceptibility to bacterial infections, especially to those caused by Streptococcus pneumoniae. We therefore conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial to test whether the regular, daily administration of oral penicillin would reduce the incidence of documented septicemia due to S.pneumoniae in children with sickle cell anemia who were under the age of three years at the time of entry. The children were randomly assigned to receive either 125 mg of penicillin V potassium (105 children) or placebo (110 children) twice daily. The trial was terminated 8 months early, after an average of 15 months of follow-up, when an 84 percent reduction in the incidence of infection was observed in the group treated with penicillin, as compared with the group given placebo (13 of 110 patients vs. 2 of 105; P = 0.0025), with no deaths from pneumococcal septicemia occurring in the penicillin group but three deaths from the infection occurring in the placebo group. On the basis of these results, we conclude that children should be screened in the neonatal period for sickle cell hemoglobinopathy and that those with sickle cell anemia should receive prophylactic therapy with oral penicillin by four months of age to decrease the morbidity and mortality associated with pneumococcal septicemia. Zinc deficiency is a common nutritional problem in adult sickle-cell disease (SCD) patients. Hyperzincuria and increased requirement of zinc due to continued hemolysis in SCD are probable bases for zinc deficiency in these patients. Zinc deficiency affects adversely T-helper1 (TH1) functions and cell mediated immunity and interleukin (IL)-2 production is decreased in zinc deficient subjects. We hypothesized that zinc supplementation will improve T-helper1 function and decrease incidence of infections in patients with SCD. We tested this hypothesis in 32 SCD subjects who were divided in three groups (Grs A, B, and C). Grs A (n = 11) and B (n = 10) were zinc deficient based on cellular zinc criteria and Gr C (n = 11) were zinc sufficient. Gr A subjects were observed for 1 year (baseline), following which they received zinc acetate (50 to 75 mg of elemental zinc orally daily) for 3 years. Gr B subjects were observed for 1 year (baseline), following which they received placebo for 1 year and then switched to zinc supplementation (50 to 75 mg of elemental zinc orally daily) for 2 years. Gr C subjects did not receive any intervention inasmuch as they were zinc sufficient. Prolonged zinc supplementation resulted in an increase in lymphocyte and granulocyte zinc (P = 0.0001), and an increase in interleukin-2 production (P = 0.0001), decreased incidence of documented bacteriologically positive infections (P = 0.0026), decreased number of hospitalizations and decreased number of vaso-occlusive pain crisis (P = 0.0001). The predominant pathogens isolated were staphylococci and streptococci involving the respiratory tract and aerobic gram-negative bacteria, particularly Escherichia coli, involving the urinary tract. Further confirmation of our observations will require prospective studies of zinc supplementation in a larger number of SCD patients.
                Copyright 1999 Wiley-Liss, Inc. Pneumonia is a leading cause of illness and death in young children. Interventions to improve case management of pneumonia are needed.
                Our objective was to measure the effect of zinc supplementation in children with pneumonia in a population in which zinc deficiency is common.
                In a double-blind, placebo-controlled clinical trial, children aged 2-35 mo with severe (n = 149) or nonsevere (n = 2479) pneumonia defined according to criteria established by the World Health Organization were randomly assigned to receive zinc (10 mg for children aged 2-11 mo, 20 mg for children aged > or =12 mo) or placebo daily for 14 d as an adjuvant to antibiotics. The primary outcomes were treatment failure, defined as a need for change in antibiotics or hospitalization, and time to recovery from pneumonia.
                One of 5 children did not respond adequately to antibiotic treatment; the odds ratios between zinc and placebo groups for treatment failure were 0.95 (95% CI: 0.78, 1.2) for nonsevere pneumonia and 0.97 (95% CI: 0.42, 2.2) for severe pneumonia. There was no difference in time to recovery between zinc and placebo groups for nonsevere (median: 2 d; hazard ratio: 1.0; 95% CI: 0.96, 1.1) or severe (median: 4 d; hazard ratio: 1.1; 95% CI: 0.79, 1.5) pneumonia. Regurgitation or vomiting < or =15 min after supplementation was observed more frequently among children in the zinc group than among those in the placebo group during the supplementation period (37% compared with 13%; odds ratio: 0.25; 95% CI: 0.20, 0.30).
                Adjuvant treatment with zinc neither reduced the risk of treatment failure nor accelerated recovery in episodes of nonsevere or severe pneumonia. This trial was registered at clinicaltrials.gov as NCT00148733. To study efficacy of maintenance therapy of patients with acute promyelocytic leukemia (APL) in the APL treatment Russian multicenter trial.
                The trial was made with participation of 18 hematological departments of clinics in Russia. A total of 68 APL patients entered the trial. The maintenance therapy consisted of 5-day courses of cytostatic drugs which alternated or did not alternate with 5-day courses of ATRA. Cytogenetic tests were made in 31 patients, t(15;17) was detected in 26 of them. Molecular examination conducted in 28 patients discovered chimeric transcript PML/RARa in 26 of them. Of 20 patients examined in Hematological Research Center, 7 (35%) had a bcr 1/2 variant of the transcript PML/RARa, 13 (65%)--bcr 3 variant.
                65 patients were eligible for assessment. A complete remission was achieved in 90% cases. No resistance was observed. In follow-up within 30 months the recurrence rate was similar on both treatments. The results of the induction therapy and survival in patients with different variants of the transcripts were also similar. Overall 2.5 year survival for all the patients was 77%, recurrence-free--80%. The survival analysis in patients with leukocytosis higher and lower 10 x 10(9)/l found no statistical differences by the survival. Patients with hyperleukocytosis had higher early lethality than patients with leukocytes under 10 x 10(9)/l (25% vs 5.3%, p = 0.03).
                The APL 06.01 protocol showed high efficacy of the relevant maintenance which provides a complete molecular remission in the majority of patients with probable recurrence-free 2.5 year survival 80%.
While the results of zinc for reducing sickle-related crises are encouraging, larger and longer-term multicenter studies are needed to evaluate the effectiveness of this therapy for people with sickle cell disease.
While the Phase II and the prematurely terminated phase III studies of senicapoc showed that the drug improved red cell survival (depending on dose), this did not lead to fewer painful crises.