A correlation between endogenous hemin and pro-oxidant activity was revealed in serum of beta-thalassemia/hemoglobin E disease (beta-thal/Hb E), which is the most common prevalent type of thalassemia in Thailand. The technique of low temperature electron spin resonance spectroscopy was used for characterization and quantification of high spin ferric heme, which had been identified as hemin (iron (III)-protoporphyrin IX). Hemin was present at levels ranging from 50 to 280 microM in serum of beta-thal/Hb E but not detectable in serum of non-thalassemia. Pro-oxidant activity in serum of beta-thal/Hb E was demonstrated by luminol-mediated chemiluminescence, a sensitive method for screening of free radical generation in vitro. In the presence of H2O2, the chemiluminescence intensity (CL) was about 20 fold enhanced in serum of beta-thal/Hb E, indicating its extensive pro-oxidant activity. The CL showed a good correlation with serum heroin, r = 0.778 (p < 0.001), while the correlations with total serum iron and serum ferritin were 0.260 (p = 0.259) and 0.519 (p = 0.004), respectively. Our finding suggested that serum hemin readily catalyzed free radical reactions and it may contribute a major pro-oxidant in blood circulation of beta-thal/Hb E.
Summary. A double-blind, crossover, placebo-controlled study of the effect of vitamin E on platelet functions was performed on nine splenectomized and 16 non-splenectomized b-thalassaemia/haemoglobin E (b-thalassaemia/ HbE) patients. The patients were supplemented with a daily dose of vitamin E (525 IU) for 3 months. The functions of platelets were assessed by adenosine diphosphate (ADP)-induced platelet aggregation and adenosine triphosphate release. Plasma a-tocopherol, plasma thiobarbituric reactive substances (TBARs) and serum ferritin levels represented patients' antioxidant status, lipid peroxidation status and iron status respectively. Before experimentation, all patients had low plasma a-tocopherol levels. The splenectomized patients showed severe iron overload iron, had higher plasma TBAR levels and their platelets were more reactive to ADP than those of non-splenectomized patients. Three months of daily vitamin E supplementation resulted in a significant increase in plasma a-tocopherol levels and reduction in plasma TBAR levels in all patients. Serum ferritin levels of the patients were not altered; however, vitamin E reduced the platelet reactivity of the splenectomized patients towards normal levels. The influence of vitamin E on platelet reactivity may result in delaying hypoxaemia and pulmonary occlusion that commonly occurs in splenectomized b-thalassaemia/HbE patients.Keywords: vitamin E, platelet hyperactivity, lipid peroxidation, oxidative stress, splenectomized b-thalassaemia/ HbE patients.Compound heterozygous b-thalassaemia/haemoglobin E (b-thalassaemia/HbE) is one of the common types of thalassaemia in south-east Asia. The degree of severity of illness of these patients ranges from a state with no complication to one resembling severe b-thalassaemia. They are diagnosed as thalassaemia intermedia and only occasionally receive packed red cells. Certain patients acquire transfusion dependence because of hypersplenism, and revert to non-transfusion dependence after splenectomy. The predominant disorder of haemostasis in b-thalassaemia/HbE patients, especially after splenectomy, is a hypercoagulable state leading to vascular occlusion (Sonakul & Fucharoen, 1992).About 50% of splenectomized b-thalassaemia/HbE patients show arterial hypoxaemia. Chronic pulmonary vessel occlusion is a frequent finding at autopsy in these patients. This pathological condition is associated with evidence of pulmonary hypertension, right ventricular hypertrophy and cor pulmonale (Sonakul & Fucharoen, 1992). It has thus been proposed that hypoxaemia could be a consequence of pulmonary arterial occlusion. However, there was a minor abnormality in the clotting system and treatment of the patients with aspirin has shown encouraging results (Wasi et al, 1982). In addition, the majority of the splenectomized thalassaemic patients exhibited thrombocytosis, and platelet hyperaggregation in response to most platelet agonists, e.g. adenosine diphosphate (ADP), adrenaline and collagen (Isarangkura et al, 1987;Chantharaksri et al...
Both iron and splenectomy status have significant effects on the pharmacokinetics and iron chelation efficacy of deferiprone. A greater degree of iron overload in splenectomized patients results in alterations in pharmacokinetic parameters (the C(max) and AUC) of deferiprone glucuronide and deferiprone-chelated iron, as well as a significant increase in UIE.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • UGT1A6 has been proposed as the predominant isoform responsible for the glucuronidation of deferiprone. • UGT1A6*2 allele has been associated with the altered enzyme activity. WHAT THIS STUDY ADDS • There is no statistically significant effect of UGT1A6 genotype on the single‐dose pharmacokinetics of deferiprone in healthy volunteers. • Gender influences serum pharmacokinetics of deferiprone. • Body iron stores reflected by serum ferritin levels may have an influence on the extent of extravascular deferiprone distribution. AIMS To examine the effects of UGT1A6 polymorphisms on the pharmacokinetics of deferiprone in healthy volunteers. METHODS Twenty‐two healthy volunteers were enrolled and grouped according to UGT1A6 genotype. After an overnight fast, the subjects received a single oral dose of 25 mg kg−1 deferiprone. Blood samples were collected at 0, 15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min after dosing. Urine output was collected at 0, 0–2, 2–4, 4–8, 8–12 and 12–24 h. Deferiprone (L1) and deferiprone‐glucuronide (L1G) concentrations in serum and urine were determined using a validated high‐performance liquid chromatography method. UGT1A6 genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism analysis. RESULTS No statistically significant differences in any pharmacokinetic parameters of either deferiprone or deferiprone‐glucuronide among the genotype groups were noted. Likewise, there were no statistically significant differences in 24‐h urinary deferiprone and deferiprone‐glucuronide excretion among the genotype groups. Significant differences between men and women were found in AUC0–∞, Vd/F, and CL/F of deferiprone. Gender differences in 24‐h urinary deferiprone and its metabolite excretion, however, failed to reach statistical significance. The Vd/F of deferiprone was found to correlate significantly with serum ferritin (rs = 0.665; P = 0.001). CONCLUSION The studied single nucleotide polymorphisms in UGT1A6 do not appear to exert statistically significant effects on the single‐dose pharmacokinetics of deferiprone. Gender appears to influence the serum pharmacokinetics of deferiprone, but not urinary excretion of deferiprone and its metabolite. Body iron stores may have an influence on the extent of extravascular deferiprone distribution.
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