Liquid purification or separation – Processes – Liquid/liquid solvent or colloidal extraction or diffusing...
Reexamination Certificate
1996-12-31
2004-02-10
Ungar, Susan (Department: 1642)
Liquid purification or separation
Processes
Liquid/liquid solvent or colloidal extraction or diffusing...
C210S646000, C424S603000, C424S646000, C424S647000, C604S007000, C604S027000, C604S029000
Reexamination Certificate
active
06689275
ABSTRACT:
TECHNICAL FIELD
The present invention relates to hemodialysis and more particularly to methods of supplementing dialysate solutions for the treatment of iron deficiency in diaylsis patients.
BACKGROUND OF THE INVENTION
Patients with chronic renal failure suffer from anemia due to impaired production of erythropoietin [Erslev, 1991]. Clinical manifestations of chronic renal failure improve as uremia and volume overload were corrected by dialysis. However, anemia due to lack of erythropoieatin becomes a major limiting factor in the functional well being of end stage renal disease patients.
Molecular cloning of the erythropoietin gene in 1985 [Jacobs et al., 1985] led to commercial production of recombinant erythropoietin, which was a major advance in the treatment of renal anemia [Erslev, 1991; Levin, 1992]. Erythropoietin therapy functions by stimulating red cell production and thereby iron utilization. With the use of erythropoietin therapy, transfusions are avoided in most chronic dialysis patients. However, accelerated iron utilization coupled with small but unavoidable loss of extra corporeal blood with hemodialysis and increased gastrointestinal losses of iron lead to iron deficiency in almost all patients on long term maintenance dialysis.
Other factors that may contribute to an iron deficient state are restricted renal diet which may be deficient in iron, and iron absorption may be impaired by uremia per se. Administration of additional medication such as phosphate binders with food may also impair iron absorption. Therefore, iron deficiency has become a major problem in the maintenance of hemodialysis patients treated with erythropoietin.
Van Wyck et al., 1989, have suggested that all renal patients with low to normal iron stores should prophylactically receive iron. Iron supplementation is accomplished most conveniently by the oral administration of iron one to three times a day.
A problem exists because oral iron is often not tolerated due to gastrointestinal side effects. Practical problems such as noncompliance, impaired absorption when taken with meals, and other factors are further combined with the problem of tolerating oral iron. It is also ineffective due to impaired iron absorption. Macdougall et al., 1989, also found a retarded response to recombinant human erythropoietin in hemodialysis patients on oral iron, which was corrected once, iron was given intravenously. Schaefer and Schaefer, 1995, have recently demonstrated that only intravenous but not oral iron guarantees adequate marrow iron supply during the correction phase of recombinant erythropoietin therapy.
In Europe, iron is available for intravenous administration as iron dextran, iron saccharate and iron gluconate. In the United States, only iron dextran is approved for intravenous use and is widely used for this purpose in dialysis patients. However, there are controversies with regard to the dosage and frequency of injection.
On the one hand, intravenous iron therapy has several advantages over oral administration. Intravenous therapy overcomes both compliance problems and the low-gastrointestinal tolerance often observed in patients on oral therapy. Schaefer and Schaefer, 1992, reported a 47% reduction in erythropoietin dose, when intravenous iron was given to iron deficient hemodialysis patients previously treated with oral iron. On the other hand, intravenous iron therapy does have risks and disadvantages. Anaphylactoid reactions have been reported in patients [Hamstra et al., 1980; Kumpf et al., 1990]. Therefor, a test dose must be administered when parenteral iron therapy is first prescribed. Intravenous iron therapy can also cause hypotension, loin and epigastric pain during dialysis which may be severe enough to stop the treatment. Further, the intravenous drug is expensive and requires pharmacy and nursing time for administration.
In view of the above, neither the oral nor intravenous iron therapy route is ideal and alternative routes of iron administration are desirable for dialysis patients.
Infusion of iron during dialysis appears similar to an intravenous infusion, albeit at a slower rate. However, iron is known to be toxic when administered parenterally in its mineral form. The toxic effects may arise from precipitation of iron in the blood, producing multiple pulmonary and sometimes systemic emboli. Symptoms resembling that of fat embolism occur. Irritation of the gastrointestinal tract gives rise to diarrhea and vomiting. Also, depression of the central nervous system can lead to coma and death [Health et al., 1982].
Very few noncolloidal iron compounds are suitable for intravenous administration. In the last five years, at least two groups of researchers have, administrated ferric gluconate sodium intravenously for the treatment of iron deficiency in chronic hemodialysis patients [Pascual et al., 1992; Allegra et al., 1981]. In these and various other studies, solubility, bioavailability and toxicity of various ferric compounds were shown to be different.
Recent studies have shown that polyphpsphate compounds are possible candidates for intracellular iron transport [Konopka et al., 1981; Pollack et al., 1985]. Among these polyphosphate compounds, pyrophosphate has been shown to be the most effective agent in triggering iron removal from transferrins [Pollack et al., 1977; Morgan, 1979; Carver et al., 1978]. Pyrophosphate has also been shown to enhance iron transfer from transferrin to ferritin [Konopka et al., 1980]. It also promotes iron exchange between transferrin molecules [Morgan, 1977]. It further facilitates delivery of iron to isolated rat liver mitochondria [Nilson, et al., 1984].
The U.S. Pat. No. 4,756,838 to Veltman, issued Jul. 12, 1988, discloses a dry, free flowing, stable readily soluble, noncaking, particulate soluble products which are readily soluble in water and are useful for preparing solutions for use in hemodialysis. The patent discloses the fact that currently used dialysis procedures do not ordinarily take into account those materials in blood that are protein bound. Examples are iron, zinc, copper, and cobalt. The patent states that it is an object of the invention to make such materials as an integral part of dry dialysate products. However, no specific disclosure is made on how to make the iron available through the hemodialysis. No direction is given towards a noncolloidal iron compound as opposed to any other iron compound or mineral iron.
Ferric pyrophosphate has been used for iron fortification of food and for oral treatment of iron deficiency anemia [Javaid et al., 1991]. Ferric pyrophosphate has also been used for supplying iron to eukaryotic and bacterial cells, grown in culture [Byrd et al., 1991]. Toxic effects of ferric pyrophosphate have been studied by Mauer and coworkers in an animal model [Maurer et al., 1990]. This study showed an LD
50
slightly higher than 325 mg of ferric pyrophosphate per kilogram or approximately 35 milligrams of iron per kilogram body weight. The effective dose for replacing iron losses in hemodialysis patients is estimated to be 0.2 to 0.3 milligrams iron per kilogram per dialysis session. Therefore, the safety factor (ratio of LD
50
to effective dose) is over 100.
Studies with another metal pyrophosphate complex, stannous pyrophosphate have reported immediate toxic effects. Since ferric ion forms a stronger complex to pyrophosphate than do stannous ion or calcium ion, [Harken et al., 1981; Sillen et al., 1964], hypocalcemia is not a known side affect of ferric pyrophosphate administration.
In view of the above, it is desirable to administer iron to a large proportion of dialysis patients by adding a soluble, non-colloidal iron compound to dialysis solutions, in order to replace ongoing losses of iron or to treat iron deficiency.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a method of administering iron in dialysis patients by
Davis Minh-Tam
Drinker Biddle & Reath LLP
Ungar Susan
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