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Iron overload from repeated transfusions of RBCs in long-term hemodialysis patients is a problem of increasing clinical significance. We report on the prevalence of and diagnostic criteria for identification of hemodialysis patients with iron overload. In 150 unselected hemodialysis patients, 62 (41%) had ferritin levels greater than 2,000 ng/mL (normal = 10 to 360 ng/mL). In 16 of these patients, accurate transfusion histories were obtained and ferritin levels correlated with calculated transfusional iron burden (r = 0.553, P less than .05). These patients could be divided into two distinct groups on the basis of their response to a single dose (2 g, IV) of deferoxamine: "high" responders had twice the level of feroxamine (the chelated product of deferoxamine and iron) of the "low" responders (P less than .001). High responders also had significantly higher prevalence of the "hemochromatosis" alleles A3, B7, and B14 than a large group of dialysis patients awaiting transplantation (71% v 37%, P less than .001). In two patients with iron overload and clinically significant bone disease, bone histology revealed prominent iron staining at the calcification front. We conclude that transfusional iron overload is a significant clinical problem in long-term hemodialysis patients, that may also be associated with bone pathology.
The potential neuroleptic alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol HCl (BMY 14802-1) was tested for its effects on mesotelencephalic dopamine (DA) neurons in albino rats. BMY 14802-1 increased DA turnover in DA terminal regions, increased nigral DA neuronal impulse flow and blocked the behavioral stimulation and inhibition of DA neuronal impulse flow caused by DA agonists. BMY 14802-1 also increased tyrosine hydroxylase activity in vivo but did not directly affect tyrosine hydroxylase activity in vitro. In contrast to these findings, BMY 14802-1 did not cause catalepsy at any dose and reversed catalepsy produced by haloperidol. BMY 14802-1 did not block DA autoreceptors on either DA neuron soma/dendrites or on striatal nerve terminals, as assessed by inhibition of DA neuronal impulse flow by microiontophoresed DA and by inhibition of tyrosine hydroxylase activity by apomorphine, respectively. BMY 14802-1 had very low affinity for striatal D-2 receptors (IC50 greater than 10(-5) M) as determined by displacement of [3H]spiperone binding in vitro. Finally, BMY 14802-1 increased impulse flow of nigral DA neurons after pretreatment with haloperidol but had no effect on impulse flow when microiontophoresed directly onto DA neurons. It is concluded that BMY 14802-1 blocked DA-mediated effects in the mesostriatal and mesocortical/limbic systems through a non-DA receptor mechanism. BMY 14802-1 has potential as a neuroleptic with little indication of extrapyramidal motor effects.
Masking effects are a common feature of daily rhythmicity in invertebrates; and, particularly with respect to activity/rest cycles in arthropods and mollusks, there are numerous examples of masking in response to external environmental stimuli. Internal masking, in which endogenous processes modulate circadian patterns, has also been documented in a few species. In general, however, because of the absence of appropriate experimental investigations on masking, the functional significance (in an ecological sense) of masking effects is not understood.
We evaluated the kinetics and efficacy of deferoxamine (DFO) therapy in iron-overloaded hemodialysis patients. Concentrations of DFO and its chelated product, feroxamine (Fx), were assessed following single-dose DFO administration in twelve patients, and during chronic therapy over one year's time in eight, similarly iron-overloaded dialysis patients. A functional assay which relies on measurements of iron and iron binding capacity for the determination of Fx and DFO, respectively, was corroborated with liquid chromatographic techniques. Half-life measurements were also corroborated with tracer doses of 14C-DFO and 59Fe-feroxamine. Intradialytic DFO half-life (2.3 +/- 1.1 h) was considerably less than interdialytic half-life (26 +/- 1 hr). Unbound DFO was found to persist throughout the interdialytic period. Calculation of the percent saturation of the DFO dose indicated that only 30% of a given dose is chelated. The amount of iron removed dialytically was approximately 13.1 +/- 2.7 mg per dialysis session. Chronic DFO administration was also shown to enhance gastrointestinal iron excretion threefold. However, ferritin levels decreased by only 25% after one year of thrice-weekly DFO therapy. We conclude that DFO therapy for iron-overloaded hemodialysis patients is optimized by its administration interdialytically, and results in slow removal of iron, via both dialytic and gastrointestinal routes.
The in vivo pharmacokinetics and the biodistribution of superparamagnetic iron-oxide particles (AMI25, Advanced Magnetics, Cambridge, MA) were investigated in anesthetized rats. Four different dose concentrations, ranging from 49.8 to 408.9 mumol of Fe (or 2.78-22.84 mg Fe) per kilogram, radiolabeled with 6.0 microCi of 59Fe-AMI25 were injected intravenously into 18 rats. The radioactivity cleared from the circulation with a fast component with a half-life of approximately 10 minutes and a slower component with a half-life of 92 minutes. Both half-lives were independent of the injected dose (ID) in the range of 105.4-408.9 mumol (5.89-22.84 mg) Fe/kg. The relative uptake in the liver, spleen, and kidneys was 57%, 2.9%, and 2.0% of the ID, respectively. At a dose of 52.1 mumol (2.91 mg) of Fe/kg, the relative concentration of iron significantly increased in the liver and decreased in the blood. Within the kidney, autoradiography showed that the iron was selectively taken up by the cortex. In the kidney, a concentration of 0.23 mumol (0.013 mg) Fe/g resulted in a 30% reduction in image intensity in a single echo magnetic resonance image obtained using a spin-echo sequence and an echo time of 70 ms.
Five long-term hemodialysis patients with clinical iron overload were treated with 300 U/kg of recombinant human erythropoietin (rHuEPO) intravenously (IV) after each hemodialysis. The patients were phlebotomized after each hemodialysis at any time the predialysis hematocrit was 35% or greater. Over a period of 1 year, the average phlebotomy rate varied from 0.5 to 1.1 U/wk with a mean phlebotomy rate of 45.8 +/- 5.6 U/yr (range, 27 to 57 U). The mean serum ferritin decreased from 8,412 +/- 1,599 micrograms/L (ng/mL) to 3,007 +/- 1,129 micrograms/L (ng/mL), and the mean iron removal over this period was 9.5 g. Liver iron deposition, as measured by density on computed tomographic (CT) scan, improved, while skin color lightened significantly. Patients tolerated phlebotomy with no major symptoms or complications and exhibited no change in the hemogram or serum chemistries. In patients with severe iron overload, changes in serum ferritin with erythropoietin treatment alone may not reflect true change in iron burden. Use of high-dose erythropoietin and phlebotomy is an effective and safe (at least for 1 year) method of reducing iron overload in long-term hemodialysis patients.