RESUMO
Haemoglobin E beta thalassaemia is the commonest form of severe thalassaemia in many Asian countries, but little is known about its natural history, the reasons for clinical diversity, or its management. We studied 109 Sri Lankan patients with the disorder over 5 years. 25 patients were not receiving transfusion; transfusion was stopped with no deleterious effect in a further 37. We identified several genetic and environmental factors that might contribute to the phenotypic diversity of the disorder, including modifiers of haemoglobin F production, malaria, and age-related changes in adaptive function. Our findings suggest that haemoglobin E beta thalassaemia can be managed without transfusion in many patients, even with low haemoglobin levels. Age-related changes in the pattern of adaptation to anaemia suggest that different and more cost-effective approaches to management should be explored.
Assuntos
Hemoglobina E/genética , Talassemia beta/genética , Adolescente , Adulto , Transfusão de Sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Esplenectomia , Sri Lanka , Talassemia beta/fisiopatologia , Talassemia beta/terapiaRESUMO
Hepatic non-transferrin-bound Fe (NTBI) flux and its regulation were characterized by measuring the uptake of Fe from [59Fe]/nitrilotriacetate (NTA) complexes in control and Fe-loaded cultures of human hepatocellular carcinoma cells (HepG2). Exposure to ferric ammonium citrate (FAC) for 1 to 7 days resulted in a time- and dose-dependent increase in the rate of NTBI uptake. In contrast to previous studies showing a dependence of the rate of Fe uptake on extracellular Fe, this was positively correlated with total cellular Fe content. The Fe3+ chelating agents deferoxamine (DFO), 1,2-dimethyl-3-hydroxypyrid-4-one (CP 020) and 1,2-diethyl-3-hydroxypyrid-4-one (CP 094) prevented or diminished the increase in NTBI transport when present during Fe loading and reversed the stimulation in pre-loaded cells in relation to their abilities to decrease intracellular iron. Although saturation of the Fe uptake process was not achieved in control cells, kinetic modelling to include linear diffusion-controlled processes yielded estimated parameters of Km = 4.3 microM and Vmax = 2.6 fmol/micrograms protein/min for the underlying process. There was a significant increase in the apparent Vmax (31.2 fmol/micrograms protein per min) for NTBI uptake in Fe-loaded cells, suggesting that Fe loading increases the number of a rate-limiting carrier site for Fe. Km also increased to 15.2 microM, comparable to values reported when whole liver is perfused with FeSO4. We conclude that HepG2 cells possess a transferrin-independent mechanism of Fe accumulation that responds reversibly to a regulatory intracellular Fe pool.
Assuntos
Quelantes de Ferro/metabolismo , Ferro/metabolismo , Ferro/farmacologia , Fígado/metabolismo , Transferrina/metabolismo , Transporte Biológico/efeitos dos fármacos , Carcinoma Hepatocelular , Morte Celular/efeitos dos fármacos , Deferiprona , Desferroxamina/farmacologia , Difusão , Compostos Férricos/farmacologia , Humanos , Quelantes de Ferro/farmacologia , Radioisótopos de Ferro , Cinética , Fígado/efeitos dos fármacos , Neoplasias Hepáticas , Ácido Nitrilotriacético/metabolismo , Piridonas/farmacologia , Compostos de Amônio Quaternário/farmacologia , Células Tumorais CultivadasRESUMO
Diamond-Blackfan anemia (DBA) is a congenital pure red blood cell aplasia that often requires lifelong transfusional therapy. Autosomal dominant and recessive inheritance have both been reported, suggesting genetic heterogeneity, but most cases occur sporadically. The origin of impaired erythropoiesis is unknown. Several erythroid growth factors have been thought to have a role in the pathogenesis of DBA. However, there is neither molecular nor clinical evidence for the involvement of erythropoietin (EPO), its receptor, stem cell factor (SCF), or interleukin (IL)-3, even if the addition of SCF to IL-3 and EPO does significantly increase the growth of erythroid progenitors in in vitro cultures in most patients. In this work we evaluated the possible role of another early-acting erythroid growth factor, IL-9. We found that the addition of IL-9 to SCF, IL-3, and EPO further increases burst-forming unit-erythroid growth in in vitro cultures of those DBA patients who responded to SCF. To investigate the role of the IL-9 gene, we evaluated its segregation in 22 families with members who have DBA by using a polymorphic microsatellite located within its intron 4. Lod score analysis ruled out any statistically significant involvement of the IL-9 gene in the pathogenesis of DBA. Moreover, linkage analysis with 11 highly polymorphic markers spanning 5q31.1-q33.2 excluded this region, which is included in the major cluster of genes active in hematopoiesis of the human genome.
Assuntos
Anemia de Fanconi/patologia , Hematopoese , Interleucina-9/fisiologia , Adolescente , Criança , Mapeamento Cromossômico , Cromossomos Humanos Par 5 , Eritropoetina/administração & dosagem , Anemia de Fanconi/tratamento farmacológico , Anemia de Fanconi/genética , Feminino , Ligação Genética , Hematopoese/efeitos dos fármacos , Fatores de Crescimento de Células Hematopoéticas/farmacologia , Humanos , Lactente , Interleucina-3/administração & dosagem , Interleucina-9/genética , Masculino , Repetições de Microssatélites , Fator de Células-Tronco/administração & dosagemRESUMO
The expanding indications for transfusions in patients with sickle cell disease raise the issues of appropriate measurement of body iron burden and optimal timing of iron chelation therapy. In this study, we obtained 42 biopsy specimens from 20 patients with sickle cell disease (mean age, 15.7 years) who received transfusions. In 12 patients whose mean age was 11.3 years at the time of liver biopsy, hepatic iron concentration was measured to provide information about the rate of iron accumulation in sickle cell disease, as well as to guide the initiation of chelating therapy. Mean hepatic iron concentration after an average of 15.4 transfusions administered over 21 months was 9.4 +/- 1.2 mg/g liver, dry weight, which did not correlate significantly with determinations of serum transferrin or ferritin levels. On Initial liver biopsy, hepatic portal fibrosis was noted in 4 of 12 patients. Twenty-nine biopsies in 16 patients were performed after variable periods of treatment with deferoxamine. These 16 patients had received a mean of 38.5 transfusions over 4 years. Hepatic iron was 14.1 +/- 1.9 mg/g of liver, dry weight, Indicating poor control of body iron in many patients. Cirrhosis was reported in one of 29 and portal fibrosis in 10 biopsy specimens. Hepatic iron concentration in patients in whom fibrosis was observed varied from 8.9 to 37.7 mg/g of liver, dry weight. These data show that after 1 to 2 years of conventional transfusions, variable tissue iron concentrations and tissue damage are observed in patients with sickle cell disease. In some patients, iron chelation therapy may not be appropriate after 1 year of transfusions; in others, therapy is clearly indicated by this time to prevent tissue injury. The data also suggest that patients with sickle cell disease develop increased portal fibrosis at the thresholds previously described in young patients with thalassemia (approximately 7 mg/g of liver, dry weight).
Assuntos
Anemia Falciforme/complicações , Sobrecarga de Ferro/diagnóstico , Adolescente , Adulto , Anemia Falciforme/patologia , Anemia Falciforme/terapia , Biópsia por Agulha , Criança , Pré-Escolar , Estudos de Coortes , Desferroxamina/administração & dosagem , Desferroxamina/farmacologia , Progressão da Doença , Ferritinas/sangue , Ferritinas/efeitos dos fármacos , Humanos , Ferro/metabolismo , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/farmacologia , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/patologia , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Hepatopatias/metabolismo , Pessoa de Meia-Idade , Transferrina/metabolismo , Reação TransfusionalRESUMO
OBJECTIVE: To examine the effect of frequency of oral administration of 1,2-dimethyl-3-hydroxypyrid-4-one (L1) on urinary iron excretion. HYPOTHESIS: Sustained serum concentrations of L1 will cause more iron chelation than the same daily dose given in larger but less frequent amounts. PATIENTS AND METHODS: Ten patients with thalassemia with a mean age of 20.9 +/- 4.7 years (range, 13 to 27 years), who were receiving regular treatment with 75 to 100 mg/kg/day oral L1, received 75 mg/kg/day L1 orally in equally divided doses: every 6 hours for 3 days and every 12 hours for 3 days. The two study periods occurred 1 month apart immediately after the monthly blood transfusions. Urine was collected for two consecutive 24-hour periods during each of the different schedules. Serial blood samples were collected from six patients over a 6-hour period and analyzed for total L1 and the L1 glucuronide metabolite concentrations. RESULTS: The patient's mean hemoglobin levels (138.8 +/- 12.5 and 139.0 +/- 11.6 gm/L) and ferritin levels (2856.4 +/- 2207.8 and 2890.0 +/- 2264.4 micrograms/L) were similar during the every-6-hour and every-12-hour L1 administrations, respectively. There was significantly more urinary iron excretion when L1 was administered every 6 hours (0.59 +/- 0.29 mg/kg/day) versus every 12 hours (0.40 +/- 0.26 mg/kg/day; p = 0.0129). Calculated 24-hour area under the plasma concentration-time curve of L1 was similar during the every-6-hour (7023.9 +/- 2637.8 mg.min/L) and every-12-hour (7050.1 +/- 1668.8 mg.min/L) experiments. CONCLUSIONS: These data suggest that the sustained presence of L1 in the blood results in greater chelation of iron than that observed with larger, less frequent doses.
Assuntos
Quelantes de Ferro/metabolismo , Ferro/urina , Piridonas/administração & dosagem , Talassemia beta/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Deferiprona , Esquema de Medicação , Ferritinas/sangue , Hemoglobinas/análise , Humanos , Piridonas/farmacocinética , Piridonas/uso terapêutico , Talassemia beta/metabolismoRESUMO
Despite the successes of deferoxamine (DFO) in the treatment and prevention of iron overload, an effective orally available iron chelating drug is needed, since erratic compliance with irritating, cumbersome parenteral infusions still results in fatal iron accumulation in many patients. Disorders of increased iron absorption should also benefit from the development of safe and effective iron chelating agents. Individuals with non-transfusion-dependent thalassemia (thalassemia "intermedia"), exhibit excessive dietary iron absorption that can lead to serious iron loading by the second or third decade of life. An orally effective iron-chelating drug would have major therapeutic advantages for all these patients.
Assuntos
Terapia por Quelação , Quelantes de Ferro/administração & dosagem , Ferro , Piridonas/administração & dosagem , Talassemia beta/tratamento farmacológico , Administração Oral , Deferiprona , Humanos , Ferro/urina , Quelantes de Ferro/uso terapêutico , Artropatias/induzido quimicamente , Cooperação do Paciente , Piridonas/uso terapêuticoRESUMO
Deferoxamine is the currently available agent for the iron-chelation therapy required by Cooley's anemia patients. The difficulties associated with parenteral administration have mandated a search for alternative therapies, especially orally active iron chelators, to remove excess iron that results in damage to the liver, endocrine organs, and heart. Four orally active agents have reached clinical trials in the last decade. The agent under consideration in this paper, deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one), has shown some promise, but, according to the studies discussed here, may not provide adequate sustained control of body iron in a substantial proportion of Cooley's anemia patients.
Assuntos
Quelantes de Ferro/uso terapêutico , Piridonas/uso terapêutico , Talassemia beta/tratamento farmacológico , Ensaios Clínicos como Assunto , Deferiprona , Desferroxamina/uso terapêutico , Ferritinas/sangue , Humanos , Ferro/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Talassemia beta/metabolismoRESUMO
Pharmacological stimulation of fetal hemoglobin production is of considerable interest as an alternative approach to therapy for Cooley's anemia. While intravenous compounds have been effective in inducing short-term increases in fetal hemoglobin in a few patients, long-term elimination of transfusion requirement has not been reported. In patients with Cooley's anemia, treatment with oral sodium phenylbutyrate alone, sodium phenylbytyrate combined with hydroxyurea, and hydroxyurea alone, has augmented fetal hemoglobin production and increased total hemoglobin concentration as much as 5 g/dl over baseline eliminating transfusion requirement in two patients. Parallel declines in circulating nucleated red cell count, and concentrations of serum transform receptor and erythropoietin, are consistent with more effective erythropoiesis. Over extended periods of treatment, no induction of other fetal proteins and no adverse effects were observed. Particular disease mutations and other genetic factors may be of prime importance in determining the response to agents that induce production of fetal hemoglobin.
Assuntos
Hemoglobina Fetal/biossíntese , Globinas/genética , Fenilbutiratos/uso terapêutico , Talassemia beta/tratamento farmacológico , Adulto , Transfusão de Sangue , Criança , Feminino , Ácido Fólico/uso terapêutico , Humanos , Linhagem , Talassemia beta/sangue , Talassemia beta/genéticaRESUMO
While the parenteral iron-chelating agent desferrioxamine B has anti-malarial activity in humans, the usefulness of an orally active chelator for this indication has not been investigated previously in vivo. We conducted a prospective, double-blind, placebo-controlled, cross-over trial of deferiprone (L1; CP20; 1,2-dimethyl-3-hydroxypyridin-4-one) in 25 adult Zambians with asymptomatic Plasmodium falciparum parasitemia. Deferiprone was administered daily for three or four days in divided doses of 75 or 100 mg/kg of body weight, dosages that are effective for treating iron overload. No reduction in asexual intra-erythrocytic parasites was observed during or after deferiprone treatment. The mean peak plasma concentration of deferiprone (108.9 +/- 24.9 micromol/L) achieved was within the range demonstrated to inhibit the growth of P. falciparum in vitro, but the systemic exposure as determined by the 24-hr plasma concentration-time curve would not be predicted inhibit growth in vivo. No evidence of deferiprone-associated hematological toxicity was noted in this short-term study of these subjects, all of whom had clinical evidence of normal body iron stores. Because of the risk of neutropenia and other adverse effects with higher doses or prolonged use of the chelator, additional trials of deferiprone as a sole anti-malarial agent would not seem to be justified. In contrast, further efforts are needed to develop other orally active iron-chelating agents specifically for their anti-malarial action.
Assuntos
Quelantes de Ferro/uso terapêutico , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Piridonas/uso terapêutico , Administração Oral , Adulto , Área Sob a Curva , Estudos Cross-Over , Deferiprona , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/farmacocinética , Malária Falciparum/metabolismo , Masculino , Parasitemia/metabolismo , Estudos Prospectivos , Piridonas/administração & dosagem , Piridonas/farmacocinéticaRESUMO
The efficacy of a eutectic mixture of local anesthetics (EMLA) in alleviating the pain associated with subcutaneous needle insertion for infusion of the iron-chelating agent, deferoxamine, was examined in 12 patients with homozygous beta-thalassemia. As reported by the patient using a 100-mm visual analogue scale, the pain of insertion was rated as significantly less after application of EMLA (mean +/- SD, 1.5 +/- 2.2 mm) than the pain associated with needle insertion without EMLA (34.8 +/- 33.5 mm, P = .005). Subsequently, in a double-blind randomized trial of 10 beta-thalassemia patients, EMLA was significantly better (5.7 +/- 8.2 mm) than placebo (27.0 +/- 22.8 mm, P = .01) in reducing the pain of needle insertion for deferoxamine infusion. No adverse effects were reported with the use of EMLA cream. These results suggest that EMLA may be effective in reducing the pain associated with needle insertion for subcutaneous deferoxamine infusion in beta-thalassemia patients, which may lead to improved compliance with this irritating, prolonged therapy. The safety of EMLA use in these patients, and others receiving regular parenteral therapy, should now be examined.
Assuntos
Anestésicos Locais/farmacologia , Desferroxamina/administração & dosagem , Lidocaína/farmacologia , Dor/prevenção & controle , Prilocaína/farmacologia , Anestésicos Locais/administração & dosagem , Desferroxamina/uso terapêutico , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Injeções Subcutâneas/efeitos adversos , Lidocaína/administração & dosagem , Combinação Lidocaína e Prilocaína , Masculino , Pomadas , Medição da Dor , Projetos Piloto , Prilocaína/administração & dosagem , Fatores de Tempo , Talassemia beta/tratamento farmacológicoRESUMO
To assess the effects of deferoxamine (DFO) on the kidneys, we studied 27 patients with thalassemia major on chronic subcutaneous (s.c.) DFO therapy. In 41% of the patients glomerular filtration rate (GFR) values were above the normal range. In a previous study similar findings were reported for thalassemia patients who did not receive DFO. The subcutaneous administration of DFO was associated with a clinically significant decrease in GFR in 40% of the patients and in a mild decrease in another 40%. In all cases of severe decreases in GFR, it tended to return to baseline values upon discontinuation of DFO. There was a significant increase in urine volume during DFO therapy. These changes are consistent with our previous observation in humans and dogs receiving high dose i.v. DFO, albeit milder.
Assuntos
Desferroxamina/efeitos adversos , Rim/efeitos dos fármacos , Talassemia/tratamento farmacológico , Adolescente , Adulto , Criança , Desferroxamina/administração & dosagem , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Injeções Subcutâneas , Rim/fisiopatologia , MasculinoRESUMO
Although synthesis of adult hemoglobin (alpha 2 beta 2) is reduced or absent in both alpha and beta thalassemias, these disorders differ in their clinical significance to the fetus and neonate. alpha-Globin synthesis is observed in the yolk sac by 3 weeks of gestation and, by 9 weeks of gestation, alpha-globin represents the main alpha-like hemoglobin in the fetus. By contrast, the switch to beta-globin chain synthesis usually remains incomplete until 1 year after birth. Therefore, the clinical manifestations of homozygous beta-thalassemia may be ameliorated by sustained synthesis of fetal hemoglobin during the first 6 months of life, whereas up until 10 years ago, homozygous alpha-thalassemia was invariably associated with death in utero. More recently, reports of infants with homozygous alpha-thalassemia surviving the neonatal period have emerged, observations particularly relevant to large numbers of immigrants to North America from Southeast Asia, where alpha-thalassemia is common. Studies of patients with the beta-globin disorders thalassemia and sickle cell disease showed that the severity of both disorders is ameliorated by sustained synthesis of fetal hemoglobin into adult life. Hence, treatment for both these disorders has focused on the pharmacological manipulation of fetal hemoglobin. Studies in vitro, in animal models, and in affected patients have shown that several compounds stimulate gamma-globin synthesis and fetal hemoglobin production through a variety of proposed mechanisms. Some of the successes in human trials are outlined herein.
Assuntos
Eritropoese/fisiologia , Doenças Fetais/fisiopatologia , Feto/fisiologia , Hemoglobinopatias/fisiopatologia , Antidrepanocíticos/uso terapêutico , Doenças Fetais/diagnóstico , Doenças Fetais/terapia , Globinas/biossíntese , Hemoglobinopatias/diagnóstico , Hemoglobinopatias/terapia , Humanos , Hidroxiureia/uso terapêutico , Lactente , Recém-Nascido , Talassemia alfa/fisiopatologiaRESUMO
Plasma iron overload causes cardiac iron accumulation leading to toxicity and organ failure. In order to understand the basis of iron acquisition, we examined mechanisms of Fe3+ and Fe2+ uptake in control and iron-loaded cardiomyocyte cultures. Iron loading increased rates of Fe3+ and Fe2+ uptake, primarily by increasing Vmax. Inhibition of Fe3+ transport by impermeable Fe2+ chelators and the presence of a cell surface ferricyanide reductase activity are consistent with a role for redox cycling in Fe3+ uptake. However, flavoproteins and copper-dependent oxidases known to be required for redox-active iron transport in yeast do not appear to be involved in iron uptake by cardiac myocytes, nor do the abundant cardiac L-type Ca2+ channels. The data suggest that both redox states of iron contribute to cardiac iron accumulation in iron overload.
Assuntos
Canais de Cálcio/fisiologia , FMN Redutase , Compostos Férricos/metabolismo , Compostos Ferrosos/metabolismo , Sobrecarga de Ferro/fisiopatologia , Ferro/metabolismo , Miocárdio/metabolismo , Animais , Animais Recém-Nascidos , Transporte Biológico , Células Cultivadas , Miocárdio/citologia , NADH NADPH Oxirredutases/metabolismo , Oxirredução , Ratos , TermodinâmicaRESUMO
Adolescents with hemoglobinopathies need daily chelation therapy with drugs which are known or suspected to be teratogenic. The prevention of fetal exposure to such drugs is therefore a major task for health professionals caring for these patients. We describe a pilot program aiming to prevent pregnancy among sexually active adolescents treated with iron chelators in Toronto. Most of them had normal response to GnRH, suggesting endocrinologic fertility, and unlike the literature concerning their healthy peers, all sexually active patients in this study reported use of at least one form of contraception.
Assuntos
Comportamento do Adolescente , Educação Sexual , Comportamento Sexual , Teratogênicos , Adolescente , Anemia Falciforme/tratamento farmacológico , Comportamento Contraceptivo , Aconselhamento , Deferiprona , Desferroxamina/uso terapêutico , Feminino , Fertilidade/efeitos dos fármacos , Humanos , Quelantes de Ferro/uso terapêutico , Gravidez , Piridonas/uso terapêutico , Talassemia beta/tratamento farmacológicoRESUMO
Recently, we demonstrated that administration of the orally active iron chelating agent deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one (L1)) at 6-hour intervals results in significantly greater urinary iron excretion than that induced during administration of the drug at 12-hour intervals. That study was conducted in thalassemia patients, all of whom had received a packed red cell transfusion of 15 cc/kg. 72 hours prior to evaluation of urinary iron excretion, at a time when endogenous erythropoiesis would be expected to be at its lowest. In clinical practice however, thalassemia patients, suppression of endogenous erythropoiesis is not sustained between transfusions. We set out to determine the influence that administration of deferiprone has on urinary iron excretion at lower hemoglobin concentrations, immediately prior to transfusion. We hypothesized that hemoglobin levels will affect the ability of deferiprone to chelate iron. Ten regularly transfused patients with homozygous beta-thalassemia (HBT) aged mean +/- SD, 20.9 +/- 4.7, range 13 - 27 years, receiving long-term therapy with deferiprone, were treated with deferiprone 75 mg/kg/day, administered every 6 hours (or every 12 hours) for 72 hours immediately prior to a blood transfusion in the first month. One month later each patient received the other of the 2 dosing regimens for 72 hours immediately prior to transfusion. The deferiprone-induced 24-hour urinary iron excretion was similar during both dosing regimens; 0.56 +/- 0.45 mg/kg when L1 was given every 6 hours and 0.48 +/- 0.52 mg/kg when L1 was administered every 12 hours (p = 0.79). However, the calculated 24-hour area under the plasma concentration-time curve (AUC0-24) of deferiprone was significantly lower when deferiprone was administered at 6-hour intervals (6,762.8 +/- 1,601.6 mg*min/l), than that observed when deferiprone was administered every 12 hours (8,250.1 +/- 1,235.7 mg*min/l) (p = 0.04). The pharmacokinetics of deferiprone when administered immediately prior to transfusions are different from those following transfusions. More studies assessing total body iron excretion are needed to determine the contribution of the fecal route in iron excretion.
Assuntos
Hemoglobinas/metabolismo , Quelantes de Ferro/farmacologia , Quelantes de Ferro/farmacocinética , Piridonas/farmacologia , Piridonas/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Deferiprona , Transfusão de Eritrócitos , Meia-Vida , Humanos , Ferro/urina , Espectrofotometria Atômica , Talassemia/sangue , Talassemia/terapiaRESUMO
OBJECTIVE: Iron deposition in the anterior pituitary continues to pose a serious problem in older patients with homozygous beta-thalassemia particularly in terms of gonadal function. This study aimed to investigate whether iron loading within the pituitary correlated with endocrine function. PATIENTS: 33 patients above 15 years of age, with transfusion-dependent homozygous beta-thalassemia and iron overload were studied. All had been receiving deferoxamine since 1978. DESIGN AND MEASUREMENTS: The endocrine status of the patients was assessed on clinical examination by an endocrinologist, and by a gonadotropin releasing hormone stimulation test. MRI of the pituitary was carried out for each patient. RESULTS: Anterior pituitary function (GnRH stimulation test) correlated well with MRI results. However, no correlation was found between the MRI measurements, the GnRH stimulation test and the clinical status of the patients, as 28 out of the 33 patients achieved normal puberty. CONCLUSIONS: MRI in conjunction with a GnRH stimulation test may be useful in predicting future impairment of pituitary function; however, further studies are needed to assess the effect of chelation therapy on the iron overload in the gland.
Assuntos
Ferro/metabolismo , Ovário/fisiopatologia , Adeno-Hipófise/metabolismo , Testículo/fisiopatologia , Talassemia beta/metabolismo , Adolescente , Adulto , Feminino , Hormônio Liberador de Gonadotropina , Humanos , Hormônio Luteinizante/sangue , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Talassemia beta/genéticaRESUMO
In this study, 50 thalassemia patients were tested using dual-energy X-ray absorptiometry (DEXA) and in vivo neutron activation analysis (IVNAA) to determine their bone mineral status. Both techniques were suitable for this purpose. Lower age was found to correspond to lower liver iron content and higher bone mineral content in the normal range. Patients undergoing treatment with transfusion had higher bone mineral content. Osteopenic patients had higher hepatic iron content than those with normal bone status. In the case of DEXA, bone mineral content (BMC) divided by height cubed was found to be a better indicator of bone mineral status than the BMD usually given. Liver density as determined by DEXA correlates well with hepatic iron.
Assuntos
Densidade Óssea/fisiologia , Talassemia/fisiopatologia , Absorciometria de Fóton , Adolescente , Adulto , Envelhecimento/metabolismo , Radioisótopos de Cálcio/análise , Humanos , Ferro/metabolismo , Fígado/química , Fígado/metabolismo , Análise de Ativação de Nêutrons , Reação TransfusionalRESUMO
Recent reports have demonstrated improvement in the clinical status and hemoglobin levels with use of intravenous arginine butyrate in patients with homozygous ß-thalassemia and sickle cell disease. To allow optimalization of therapy, we conducted pharmacokinetic studies in nine patients, five with sickle cell disease and four with ß-thalassemia, treated with continuous intravenous infusion of arginine butyrate. The disappearance of the drug after discontinuation was characterized by a biphasic elimination with an initial rapid phase followed by a slower phase. Redistribution was noted in five of the patients after 11.2 ± 4.0 min. The short half life was the result of both rapid clearance rate of 93.6 ± 31.9 ml/kg/min and small Vc (0.21 ± 0.26 l/kg) and Vss (0.31 ± 0.37 l/kg). While preliminary results of the effectiveness of arginine butyrate are encouraging with a rise of γ-globin mRNA and F reticulocytes in some patients, the rapid elimination of this agent will probably limit its current use to administration by continuous infusion.
RESUMO
The most serious adverse effect of deferiprone, the first orally active iron chelator, is agranulocytosis afflicting an estimated 1.6% of patients. Among the 13 reported patients who had experienced deferiprone-induced agranulocytosis or severe neutropenia, 5 were rechallenged. We studied the onset, clinical and rechallenge course of all 5 patients in an attempt to characterise the mechanisms involved in deferiprone-induced agranulocytosis, to verify whether rechallenge in future patients is ethically justified. Deferiprone-induced agranulocytosis showed no trend of dose dependency: of all patients who had experienced agranulocytosis 23% were treated with 50 mg/kg/day, 46% with 75 to 90 mg/kg/day, and 31 % with > 90 mg/kg/day. Available data including bone marrow aspiration in some patients support the hypothesis that an early myeloid precursor is the target cell affected by deferiprone. All 5 rechallenged patients re-experienced agranulocytosis/neutropenia. The lag period to agranulocytosis/neutropenia following reinduction was significantly shorter (13.2 ± 21.7 weeks compared with 46.4 ± 14.2 weeks in the first episode; p < 0.05). All but one of the rechallenged patients re-experienced agranulocytosis or neutropenia 2 to 4 weeks following re-exposure to deferiprone, suggesting a possible immune mechanism. We found that deferiprone was oxidised in vitro by hypochlorous acid, the major neutrophil oxidant to produce a myelotoxic metabolite. This reactive species demonstrated neutrophil toxicity and a dose-dependent lymphotoxic curve. However, we found no differences in the toxicity of this reactive species to neutrophils from 2 patients with a history of deferiprone-induced agranulocytosis when compared with controls. In combination with the clinical characteristics, these results suggest a reactive metabolite-induced immune-mediated reaction. These 5 rechallenged cases ethically preclude the rechallenge of additional cases.