The hypothesis that chelation of free iron, by decreasing reactive oxygen species (ROS), might mimic hypoxia and stimulate the carotid body was tested. We used the iron chelators, desferrioxamine (DFO, 200-400 microM) initially, and later ciclopirox olamine (CPX, 2.5-5.0 microM), on rat carotid body in vitro and measured chemosensory activity and [Ca2+]i in isolated cultured glomus cell clusters during normoxia and hypoxia. Although acute treatment of DFO might not penetrate the cell, and extracellular DFO would not influence these activities whereas CPX significantly increased chemosensory activities as well as increased [Ca2+]i in normoxia. We concluded that chelation of extracellular free iron did not alter ROS formation and oxygen sensing. Chelation of intracellular free iron and, therefore, a decrease in intracellular ROS appears to influence oxygen sensing in the carotid body. 相似文献
BACKGROUND: According to the recommendations proposed at The Consensus Conferenceon Diagnosis and Treatment of Aluminium Overload in End-StageRenal Failure Patients, Paris, 1992 low-dose desferrioxamine(DFO) treatment was applied for the first time in 41 acutelyaluminium-intoxicated patients. METHODS AND RESULTS: DFO-related neurological/ophthalmological side-effects wereobserved in nine of 11 patients with a post-DFO serum aluminiumlevel >300 µg/litre and in two patients of 30 belowthis level after a single administration of a 5-mg/kg dose ofthe chelator in the conventional way (i.e. the last hour ofa dialysis session). They were no longer observed after introducingan alternative DFO administration schedule (i.e. administrationof the chelator 5 h prior to the start of a haemodialysis session;group I: n=14). A significant decrease in the serum aluminiumlevels as well as in the post-DFO serum aluminium increment(sAl) was observed during the first 6 months' course of low-doseDFO treatment in group I as well as group II (which consistedof patients receiving DFO in the conventional way; n=27). Low-doseDFO treatment was accompanied by a significant increase in themean ±SD serum iPTH levels (group I: 174±245 upto 286±285 ng/litre; group II: 206±272 up to 409±424ng/litre; P<0.005) and the mean corpuscular volume (groupI: 80±6.4 up to 85±3.7 fL, P<0.005; group II:76±5.0 up to 87±4.3 fL, P<0.0001). Serum ferritinlevels significantly decreased in both groups. No further side-effectswere observed during the DFO course. Patients in which DFO treatmentcould be stopped (i.e. subjects in which both serum aluminiumand sAl were below 50 µg/litre at two successive occasions)before the end of the 6-months' treatment course had a significantlygreate residual diuresis (700±682 ml/min vs 84±109ml/24 h). Also, residual diuresis was found to protect againstaluminium intoxication as reflected by the values noted in groupI versus those in group II. CONCLUSIONS: The 5-mg/kg DFO treatment provides a safe and adequate therapyfor aluminium overload. In severely aluminium-intoxicated patientspresenting post-DFO serum aluminium levels above 300 µg/litreDFO should be given once weekly 5 h prior to high-extractiondialysis ensuring (i) maximal chelation of aluminium (ii) limitedexposure to circulating aluminoxamine levels, and (iii) adequateremoval of the latter compound. Finally, the necessity for abetter communication between the local water distribution companiesand the dialysis centres is a major lesson that can be drawnfrom this dramatic intoxication. 相似文献
Background: To compare the efficacy and safety of desferrioxamine (DFO), deferiprone (DFP), deferasirox (DFX) and silymarin in patients with either thalassemia or sickle cell disorder through network meta-analysis.
Methods: Electronic databases were searched for appropriate randomized clinical trials comparing iron chelators in patients with iron overload. Random effects model was used to generate direct, indirect and mixed treatment comparison pooled estimates for the following outcomes: serum ferritin, liver iron concentration (LIC), changes in serum ferritin, mortality, urine iron excretion, adverse events, neutropenia, agranulocytosis and number of patients withdrawing the chelating therapy.
Results: Thirty-two clinical trials were included in the meta-analysis. DFX/DFO was associated with better serum ferritin levels compared to DFO, DFX, DFO/Silymarin and DFP/DFO. DFX/DFO also lower LIC significantly compared to DFO. DFP/DFO was associated with higher LVEF, low risk of adverse events and reduced end of serum ferritin compared to DFO. Combination of silymarin with either DFP or DFX was observed with reduced end of treatment serum ferritin compared to using either of the drugs alone. DFP was observed with better effects in sickle cell disease. The strength of evidence was very low for most of the comparisons.
Conclusion: Relative estimates between the individual iron chelators have been established. However, this evidence should be considered preliminary and may change with the results of future head-to-head clinical trials. 相似文献
We investigated the pharmacokinetics of desferrioxamine and its chelated compounds aluminoxamine and ferrioxamine in normal volunteers and haemodialysis patients with and without iron overload. Desferrioxamine was administered in a single dose of 30 mg per kg body-weight was a 30-min infusion to five healthy volunteers and to 20 haemodialysis patients (five patients without haemosiderosis and 15 patients with haemosiderosis). The interdialytic half-life of ferrioxamine was 2.2 h in normal volunteers, 13.3 h in dialysis patients without haemosiderosis, and 24.6 h in patients with haemosiderosis. There was no interdialytic elimination of aluminoxamine. In a second study, seven dialysis patients received 5, 10, and 20 mg per kg body-weight desferrioxamine in a random order with a time interval of 2 weeks. The peak serum concentrations after these doses were 4.1 +/- 2.9, 6.4 +/- 2.9, and 10.7 +/- 7.1 mumol/l for ferrioxamine and 2.8 +/- 1.5, 3.1 +/- 1.5, and 4.2 +/- 1.7 mumol/l for aluminoxamine. Thus, a 4-fold increase in desferrioxamine dosage resulted in a 2.7-fold increase in peak ferrioxamine levels and in only a 1.5-fold increase in peak aluminoxamine levels. We conclude that dialysis patients, especially those with haemosiderosis, are exposed to persistently elevated ferrioxamine levels. Weekly doses of 5-10 mg/kg of desferrioxamine would be sufficient for aluminium chelation therapy. 相似文献
Iron enhances the production of the highly reactive and toxic hydroxyl radical, thus stimulating oxidative damage. Iron has been associated with a number of oxidative injury-dependent, age-related conditions and diseases. Indeed, oxidative injury is a major factor of (accelerated) ageing. This commentary reviews part of the existing literature on iron's deleterious effects, particularly in the context of ischemia-reperfusion injury and cardiovascular, brain and muscle diseases as well as skin ageing. Furthermore, the advantages of iron chelation are presented. Indeed, iron chelation or deprivation has been shown to act as a potent anti-oxidant in a variety of animal models of human diseases, preventing oxidative stress to tissues and organs. Iron chelators favor successful ageing in general, and when applied topically, successful skin ageing. It has also been proposed that gender-related differences in iron status are responsible for the increased longevity of women as compared to men. Despite this evidence, the role of iron in ageing and the possibilities of pharmacologically targeting iron have remained essentially unexplored. Iron thus appears as the "malignant spirit" in successful ageing. 相似文献
This study on serum ferritin levels ind urinary iron excretion after 12h subcutaneous infusion of desferrioxamine in 10 thalassemia intermedia patients shows that even nontransfusion-dependent patients may have positive iron balance resulting in iron overload from 5 years of age. However, the iron overload found in these patients appears to be much lower than in age matched patients with transfusion-dependent thalassemia major. Iron overload increases with advancing age, as shown by increasing serum ferritin levels and desferrioxamine-induced urinary iron elimination. After a six month trial of 12h continuous subcutaneous desferrioxamine administration there was a significant decline in serum ferritin levels.From this study it seems that iron chelation is indicated in thalassemia intermedia patients over 5 years of age in order to prevent iron accumulation. However, the appropriate treatment schedule should be tailored to the individual needs of each patients, established by close monitoring of serum ferritin levels and desferrioxamine-induced urinary iron elimination.This work was supported in part by grants from Assessorato Igiene e Sanità Regione Autonoma della Sardegna, N.I.H. grant number 5 R01 HL-24173-02, C.N.R. subprogetto finalizzato Malattie Ereditarie dell'Eritrocita contract number 80-02252.83 相似文献
Four patients suffering from porphyria cutanea tarda received intramuscularly 10-15 g per month of desferrioxamine for periods ranging between 21 and 50 months. Porphyrin excretion was serially analyzed during this treatment. Desferrioxamine administration did not induce remission of the disease, which was subsequently achieved after treatment either with phlebotomies or chloroquine. Therefore, chronic intramuscular administration of desferrioxamine alone is ineffective in porphyria cutanea tarda. 相似文献