Oxymetholone treatment for sickle cell anemia

Seven patients with sickle cell anemia were treated with oxymetholone for at least 2 mo. Markedly increased basal rates of hemolysis and erythropoiesis were confirmed. The urinary erythropoietin excretion was either normal or lower than expected for the red cell mass, and an expanded blood volume was due primarily to an increased plasma volume. After androgen therapy, six patients demonstrated more than a fivefold increase in urinary erythropoietin, with an increase in red cell mass ranging from 17%-75% above the control value. All showed a decline in serum iron level to the 25-75 mug/100 ml range within 4 wk after the start of therapy. Less marked changes followed lower oxymetholone doses. Reversible hepatic toxicity, with a serum bilirubin concentration exceeding 50 mg/100 ml, occurred in one patient. Androgenic hormone therapy may be useful for selected adult patients with sickle cell disease when severe anemia contributes to disease morbidity.     

Acute childhood bacterial meningitis in Luanda, Angola

Incidence, morbidity and mortality of bacterial meningitis in developing countries are manifold greater than those in the industrialized world. We reviewed retrospectively children with meningitis treated in the paediatric hospital of Luanda in 2004. Among the 555 children, median age 11.0 months, the leading agents were Haemophilus influenzae type b (Hib), pneumococcus, and meningococcus in 60%, 24%, and 10%, respectively. The median length of illness before admission was 7 d. 65% had convulsed. Altered level of consciousness was observed in 61% and blood haemoglobin lower than 8 g/dl in 36% of cases. Case fatality was 35% and, of survivors, 24% were left with severe neurological sequelae. Blood transfusion appeared beneficial since fatality of children with and without transfusion was 23% versus 39% (p=0.003). While awaiting large-scale vaccinations, tools to improve the prognosis of meningitis in Angola comprise generating better awareness to reduce the delay, better fluid treatment and monitoring and active use of blood transfusions.     

A prophylactic transfusion program for children with sickle cell anemia complicated by CNS infarction

CNS infarction is a devastating complication in sickle cell anemia. Episodes are frequently repetitive and often result in permanent neurologic abnormalities. In an attempt to prevent such recurences a periodic transfusion program was begun at the Children's Hospital of Michigan in 1969. Twenty-one children currently on the program receive buffy-coat poor transfusions on an out-patient basis every 3 weeks. Of 15 who have been on the program for periods of from 9 months to 5 ¾ years, none have had progression of neurologic abnormalities, and several have had definite improvement in neurologic function. One child who was not brought in regularly had recurrent CNS infarction. The only recognized complication has been one instance of serum hepatitis. While such a transfusion of neurologic abnormalities resulting from recurrent CNS infarction in sickle cell anemia.     

Vanillin, a potential agent for the treatment of sickle cell anemia

Vanillin, a food additive, has been evaluated as a potential agent to treat sickle cell anemia. Earlier studies indicated that vanillin had moderate antisickling activity when compared with other aldehydes. We have determined by high performance liquid chromatography that vanillin reacts covalently with sickle hemoglobin (HbS) both in solution and in intact red blood cells. Hemoscan oxygen equilibrium curves show a dose-dependent left shift, particularly at low oxygen tensions. Rheologic evaluation (pO2 scan Ektacytometry) of vanillin-reacted HbS erythrocytes shows a dose-dependent inhibition of deoxygenation-induced cell sickling. Ektacytometry also suggests that vanillin may have a direct inhibitory effect on HbS polymer formation. Vanillin has no adverse effects on cell ion or water content. X-ray crystallographic studies with deoxyhemoglobin (HbA)-vanillin demonstrate that vanillin binds near His 103 alpha, Cys 104 alpha, and Gln 131 beta in the central water cavity. A secondary binding site is located between His 116 beta and His 117 beta. His 116 beta has been implicated as a polymer contact residue. Oxygen equilibrium, ektacytometry, and x-ray studies indicate that vanillin may be acting to decrease HbS polymerization by a dual mechanism of action; allosteric modulation to a high-affinity HbS molecule and by stereospecific inhibition of T state HbS polymerization. Because vanillin is a food additive on the GRAS (generally regarded as safe) list, and because it has little or no adverse effects at high dosages in animals, vanillin is a candidate for further evaluation as an agent for the treatment of sickle cell disease.     

Oral analgesia for treatment of painful crisis in sickle cell anemia

A therapeutic plan that emphasized oral narcotic analgesia was instituted for the treatment of painful crisis of sickle cell anemia. Of the 100 adult sickle cell syndrome patients registered at North Central Bronx Hospital, 15 were identified as using the emergency department facilities three or more times per year. This "frequent user" patient population was tracked in their hospital and drug usage patterns during the first full year of the oral protocol and compared to their own patterns during the year prior to the protocol. The patients used the ED at the same rate but their frequency of admissions to the hospital dropped by 75%. The oral program produced a significant fall in the amount of narcotics dispensed in the ED (P less than .01).     

Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ(0)), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 10(9)/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.     

Hydroxyurea treatment of sickle cell anemia in hospital-based practices

In a published randomized clinical trial, hydroxyurea (HU) improved clinical outcomes in patients with sickle cell anemia (SCA). The mean treatment duration of that trial was 21 months. Here we attempt to determine whether the benefits associated with HU therapy of SCA have led also to successful patient acceptance of HU treatment in community practices, and whether successful clinical outcomes persist beyond 2 years. This is an observational retrospective chart study of the computerized medical records of 60 men and women with SCA who had HU treatment for at least 3 months and who were treated at teaching hospital subspecialty clinics in Baltimore, Maryland, and Washington, D.C. Thirty had remained on therapy for at least 24 months. Admissions declined in this group by 30% (P = 0.04). Declines were seen also in transfusion requirements (-58%, P = 0.07). In 17 of these 30 patients, at least 48 months of follow-up records were available. Fourteen of these remained on therapy the entire period, with similar and sustained reductions in admissions and transfusions. We conclude that hydroxyurea therapy of SCA applied in community settings leads to declining admissions and transfusion rates in many individuals for 4 years or more.     

Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal.     

Screening and follow-up of children exposed to tuberculosis cases, Luanda, Angola

This prospective study enrolled children aged < 5 years with reported contact with adult tuberculosis (TB) patients in Angola. The study sample consisted of 124 children: 70 (56.5%) were active TB cases, 22 (17.7%) had latent TB infection (LTBI) and 32 (25.8%) were TB-exposed; 14 (20%) were human immunodeficiency virus positive. After 6 months of follow-up, 31.8% of the LTBI cases had evolved to active TB and 9.4% of the non-infected children had developed active TB. The strategy of simultaneous chest X-ray and TB skin test used in this study was effective; despite this protocol, however, 31.8% LTBI children developed active TB.     

Newborn screening shows a high incidence of sickle cell anemia in Central India

There is limited data on the incidence of sickle cell anemia in Central India; we therefore conducted a study to estimate the incidence of this disease in Central India. Mothers who delivered a live baby at the Government Medical College, Nagpur, India were screened for the presence of the sickle cell hemoglobin {Hb S: [β6 (A3) Glu→Val, GAG>GTG]} using the solubility test within 48 hours of delivery. Infants of mothers who showed the presence of Hb S then underwent Hb analysis by high performance liquid chromatography (HPLC). A total of 8243 mothers was screened, 1178 of whom were positive. One thousand, one hundred and sixty-two infants of mothers with a positive solubility test underwent Hb analysis by HPLC; 530 infants were normal, while 536 were heterozygous for Hb S (sickle cell trait), 88 babies were homozygous for Hb S (sickle cell anemia), while another eight babies had other Hb abnormalities. The incidence of sickle cell anemia was highest in the Scheduled caste group (1:50). We concluded that the incidence of sickle cell anemia is high in central India.     

Provoked priapism in sickle cell anemia

Two patients with sickle cell anemia are reported who developed relative impotence after repeated episodes of priapism. They learned that excessive ethanol ingestion produced an erection and utilized this mechanism to satisfy sexual partners. Hospitalization and transfusion therapy were required for repeated episodes of priapism. Extensive interviews were required in order to learn the sequence of events. This synergistic relationship between ethanol and priapism should be sought in patients with repeated hospitalizations for this complication of sickle cell anemia because it is preventable with appropriate counseling.     

Myocardial infarction in sickle cell anemia

A review of the electrocardiograms (ECG) of 108 patients with sickle cell anemia found only 3 with patterns consistent with myocardial infarction. Two of the 3 patients with ECG infarct patterns had postmortem examination confirmation of the infarction. These two patients had no significant coronary atherosclerosis nor did the other six autopsied patients in the present series. Literature reports of postmortem examinations on patients with sickle cell anemia confirm the scarcity of coronary atherosclerosis and myocardial infarction in these patients. Forty of the 108 ECGs showed signs of left ventricular hypertrophy and 20 others had nondiagnostic ST and T wave abnormalities. Nine showed first degree AV block and four right bundle branch block.