U.S. patent application number 10/958630 was filed with the patent office on 2005-07-07 for method for iron delivery to a patient by transfer from dialysate.
Invention is credited to Ash, Stephen R..
Application Number | 20050148663 10/958630 |
Document ID | / |
Family ID | 26697806 |
Filed Date | 2005-07-07 |
United States Patent
Application |
20050148663 |
Kind Code |
A1 |
Ash, Stephen R. |
July 7, 2005 |
Method for iron delivery to a patient by transfer from
dialysate
Abstract
The invention relates to methods and compositions for delivering
iron to an iron-deficient patient, more particularly, to methods
whereby an iron complex comprising divalent or trivalent ionic iron
complexed with one or more low molecular weight anions is
administered to a patient by transfer from dialysate. A complex
selected according to the invention is non-polymeric; soluble in an
aqueous medium; chemically stable, thereby preventing the
dissociation of iron ions from the anions under conditions
according to the invention; and can be well absorbed into blood and
the living body. Also provided are dialysate compositions including
therein an iron complex selected according to the invention, and
dialysate concentrates which may be diluted to yield an inventive
dialysate composition.
Inventors: |
Ash, Stephen R.; (Lafayette,
IN) |
Correspondence
Address: |
WOODARD, EMHARDT, MORIARTY, MCNETT & HENRY LLP
BANK ONE CENTER/TOWER
111 MONUMENT CIRCLE, SUITE 3700
INDIANAPOLIS
IN
46204-5137
US
|
Family ID: |
26697806 |
Appl. No.: |
10/958630 |
Filed: |
October 5, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10958630 |
Oct 5, 2004 |
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09143143 |
Aug 28, 1998 |
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6841172 |
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09143143 |
Aug 28, 1998 |
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08869331 |
Jun 5, 1997 |
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5906978 |
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60023926 |
Aug 14, 1996 |
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Current U.S.
Class: |
514/502 |
Current CPC
Class: |
A61K 33/26 20130101;
A61M 1/1654 20130101; A61M 1/287 20130101; Y10S 514/814
20130101 |
Class at
Publication: |
514/502 |
International
Class: |
A61K 031/295 |
Claims
1-23. (canceled)
24. An aqueous composition, comprising: water; a plurality of
electrolytes dissolved in the water, the electrolytes having a
concentration in the water of from about 256.4 mEq/L to about 324.5
mEq/L, and the electrolytes proportioned for dialysis of a patient;
and an iron complex dissolved in the water, the complex comprising
one or more divalent or trivalent iron ions and one or more anions
and having a molecular weight of less than about 50,000, the iron
complex having a concentration in the water to provide an iron
concentration of from about 1 to about 250 .mu.g/dl.
25. The composition in accordance with claim 24, further comprising
glucose dissolved in the water.
26. The composition in accordance with claim 24, wherein said
plurality of electrolytes comprises a plurality of members selected
from the group consisting of sodium ions, chloride ions and acetate
ions.
27. The composition in accordance with claim 24, wherein said
plurality of electrolytes comprises a plurality of members selected
from the group consisting of magnesium ions, potassium ions, sodium
ions, chloride ions, acetate ions and bicarbonate ions.
28. The composition in accordance with claim 24, further comprising
calcium ions dissolved in the water.
29. The composition in accordance with claim 24, further comprising
a member selected from the group consisting of dextrose, a sorbent
and a surfactant dissolved or dispersed in the water.
30. A method for making an aqueous composition useful as a
dialysate, comprising, dissolving into water (i) a plurality of
electrolytes in an amount effective to provide an electrolyte
concentration in the water of from about 256.4 mEq/L to about 324.5
mEq/L, the electrolytes proportioned for dialysis of a patient and
(ii) an iron complex comprising one or more divalent or trivalent
iron ions and one or more anions and having a molecular weight of
less than about 50,000 in an amount effective to provide an iron
concentration in the water of from about 1 to about 250 .mu.g/dl,
to provide an aqueous composition.
31. The method in accordance with claim 30, further comprising
dissolving glucose in the water.
32. The method in accordance with claim 30, wherein the plurality
of electrolytes comprises a plurality of members selected from the
group consisting of sodium ions, chloride ions and acetate
ions.
33. The method in accordance with claim 30, wherein the plurality
of electrolytes comprises a plurality of members selected from the
group consisting of magnesium ions, potassium ions, sodium ions,
chloride ions, acetate ions and bicarbonate ions.
34. The method in accordance with claim 30, further comprising
dissolving calcium ions into the water.
35. The method in accordance with claim 30, further comprising
introducing into the water a member selected from the group
consisting of dextrose, a sorbent and a surfactant.
36. A method for making an aqueous composition useful as a
dialysate, comprising: providing a first aqueous solution of
electrolytes, the electrolytes having a concentration in the
solution of from about 256.4 mEq/L to about 324.5 mEq/L and the
electrolytes being proportioned for dialysis of a patient; and
introducing into the first solution an iron complex comprising one
or more divalent or trivalent iron ions and one or more anions and
having a molecular weight of less than about 50,000, to provide a
second aqueous solution useful as a dialysate, the second aqueous
solution having an iron concentration of from about 1 to about 250
.mu.g/dl.
37. The method in accordance with claim 36, wherein the complex is
introduced in a predetermined amount, the amount being selected
based upon the iron needs of a given patient.
38. An aqueous composition, comprising: water; a plurality of
electrolytes dissolved in the water; and an iron complex dissolved
in the water, the complex comprising one or more divalent or
trivalent iron ions and one or more anions and having a molecular
weight of less than about 50,000; wherein the electrolytes and the
iron complex have concentrations in the water whereby the
composition is effective for dilution to provide a dialysate having
an electrolyte concentration of from about 256.4 mEq/L to about
324.5 mEq/L and an iron concentration of from about 1 to about 250
.mu.g/dl.
39. The composition in accordance with claim 38, further comprising
glucose dissolved in the water.
40. The composition in accordance with claim 38, wherein said
plurality of electrolytes comprises a plurality of members selected
from the group consisting of sodium ions, chloride ions and acetate
ions.
41. The composition in accordance with claim 38, wherein said
plurality of electrolytes comprises a plurality of members selected
from the group consisting of magnesium ions, potassium ions, sodium
ions, chloride ions, acetate ions and bicarbonate ions.
42. The composition in accordance with claim 38, further comprising
calcium ions dissolved in the water.
43. The composition in accordance with claim 38, further comprising
a member selected from the group consisting of dextrose, a sorbent
and a surfactant dissolved or dispersed in the water.
44. The composition in accordance with claim 38, wherein the
electrolytes have a concentration in the water of from about 7692
mEq/L to about 12,980 mEq/L.
45. A method for making an aqueous composition useful as a
dialysate concentrate, comprising, dissolving into water (i) a
plurality of electrolytes and (ii) an iron complex comprising one
or more divalent or trivalent iron ions and one or more anions and
having a molecular weight of less than about 50,000, to provide an
aqueous composition; wherein the electrolytes and the iron complex
have concentrations in the water whereby the composition is
effective for dilution to provide a dialysate having an electrolyte
concentration of from about 256.4 mEq/L to about 324.5 mEq/L and an
iron concentration of from about 1 to about 250 .mu.g/dl.
46. The method in accordance with claim 45, wherein the
electrolytes have a concentration in the water of from about 7692
mEq/L to about 12,980 mEq/L and wherein the iron complex has a
concentration in the water effective to provide an iron
concentration in the water of from about 0.03 to about 10
mg/dl.
47. The method in accordance with claim 45, further comprising
dissolving glucose in the water.
48. The method in accordance with claim 45, wherein the plurality
of electrolytes comprises a plurality of members selected from the
group consisting of sodium ions, chloride ions and acetate
ions.
49. The method in accordance with claim 45, wherein the plurality
of electrolytes comprises a plurality of members selected from the
group consisting of magnesium ions, potassium ions, sodium ions,
chloride ions, acetate ions and bicarbonate ions.
50. The method in accordance with claim 45, further comprising
dissolving calcium ions into the water.
51. The method in accordance with claim 45, further comprising
introducing into the water a member selected from the group
consisting of dextrose, a sorbent and a surfactant.
52. A method for making an aqueous composition useful as a
dialysate concentrate, comprising: providing a first aqueous
solution of electrolytes, the electrolytes having a concentration
in the solution of from about 7692 mEq/L to about 12,980 mEq/L; and
introducing into the first solution an iron complex comprising one
or more divalent or trivalent iron ions and one or more anions and
having a molecular weight of less than about 50,000, to provide a
second aqueous solution useful as a dialysate concentrate, the
second aqueous solution having an iron concentration of from about
0.03 to about 10 mg/dl.
53. An aqueous composition, comprising: water; a plurality of
electrolytes dissolved in the water, the electrolytes proportioned
for dialysis of a patient; and an iron complex dissolved in the
water, the complex comprising one or more divalent or trivalent
iron ions and one or more anions and having a molecular weight of
less than about 50,000, the iron complex having a concentration in
the water to provide an iron concentration of from about 1 to about
250 .mu.g/dl.
54. The aqueous composition in accordance with claim 53, wherein
the aqueous composition is substantially hypertonic.
55. The aqueous composition in accordance with claim 53, wherein
the electrolytes are proportioned to prevent excessive ion removal
from a patient's blood during dialysis of the blood with the
composition.
56. The aqueous composition in accordance with claim 53, wherein
the iron complex comprises ferrous gluconate.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to methods and compositions for
efficiently delivering iron to a patient. More particularly, the
present invention is concerned with dialysates and dialysate
concentrates, and methods for delivering to a patient via dialysis
a composition comprising ionic iron complexed with one or more
anions. An iron complex selected according to the invention is
non-polymeric; soluble in an aqueous medium; chemically stable,
thereby preventing the dissociation of iron ions from the anions
under conditions according to the invention; and can be well
absorbed by blood and the living body.
[0003] 2. Description of Related Art
[0004] Iron is a metal which is an essential requirement for tissue
growth in humans and many animals. Therefore, an adequate supply of
iron is critical to their survival and well-being. Although there
is normally an ample amount of iron in the diet, the level of
absorption of iron from food is generally low and, therefore, the
supply of iron to the body can easily become critical under a
variety of conditions. For example, iron is a necessary in
ingredient in the production of red blood cells, and a lack of iron
may quickly lead to anemia. Iron deficiency anemia is commonly
encountered, for example, in pregnancy and may also present a
problem in the newly born. Moreover, in certain pathological
conditions there is a maldistribution of body iron leading to a
state of chronic anemia. This is seen in chronic diseases such as
rheumatoid arthritis, certain haemolytic diseases and cancer.
[0005] Anemia is also uniformly present in patients with end stage
renal disease (ESRD). The major cause of this anemia is the
deficient production of erythropoeietin hormone (EPO) by the native
kidneys. EPO stimulates the bone marrow to produce red cells, and
when EPO is deficient, patients invariably become anemic. To
counter the anemia of ESRD patients, recombinant EPO (which is very
expensive) may be administered subcutaneously or intravenously.
Recombinant EPO can effectively increase the hematocrit of patients
with adequate iron stores, but the increased rate of production of
new red cells quickly depletes body iron stores and, when this
occurs, EPO becomes completely ineffective. As such, the delivery
of iron to an ESRD patient is critical to his or her treatment.
Methods in the prior art for delivering iron to a patient, such as
an ESRD patient, have proven largely impractical and
unsatisfactory, and there is a great need for improved methods of
iron delivery.
[0006] It is well known that iron is very difficult to assimilate
into the cells of a living organism and when an iron deficiency
exists, oral iron supplements in relatively large doses are
commonly administered wherein the iron may be in a wide variety of
forms, i.e., usually as various organic and inorganic salts. Iron
compositions which have been previously administered orally
include, for example, ferrous gluconate, ferrous citrate, ferrous
sulfate, ferrous fumarate and ferric-polysaccharide complexes. As a
specific example of a condition where oral iron delivery is common,
ESRD patients are typically directed to take oral iron tablets when
EPO is started, as discussed above.
[0007] Oral iron-administration, however, has several
disadvantages. Patient noncompliance, gastrointestinal side
effects, interactions with other oral medications and very poor
absorption in ESRD patients markedly limit its effectiveness. For
example, patients often stop taking these medications because of
side effects associated therewith, such as constipation and gastric
irritation. Additionally, these oral iron preparations cause a
patient's stools to turn black, thereby making it difficult for
caregivers to detect gastrointestinal bleeding during iron therapy.
It is believed that these problems are all related to the
administration of relatively high dosage levels of oral compounds
due to the low level of iron uptake by the body, and these high
doses are thought to also cause siderosis of the gut wall.
[0008] To overcome the above-described problems with oral delivery
of iron, a great deal of effort has been directed to developing
iron delivery methods wherein iron-containing compositions are
delivered parenterally, either by intravenous or intramuscular
injection. In this regard, it is currently widely believed that
compositions used for non-oral iron administration must be in
macromolecular form. This mindset is based upon the belief that the
use of macromolecules eliminates the problem of osmolarity in the
case of intramuscular injection, and, in the case of intravenous
injection, the belief that macromolecular compositions are required
to ensure that free iron is not introduced into the blood. Since
iron is slowly freed from such macromolecules by the action of
metabolism, and then bound by transferrin in the blood as it slowly
becomes available, administration of iron in macromolecular forms
is presently thought to be the only viable option with respect to
intravenous administration techniques.
[0009] With respect to intravenous administration, iron-dextran
(INFED.RTM.), which may be obtained from Schein Pharmaceuticals,
Phoenix, Ariz., is commonly administered intravenously to ESRD
patients to increase iron stores, with about 100-200 mg injected
each successive dialysis until about 1000 mg are administered. Iron
dextran is a macromolecule having a high average molecular weight
ranging generally between about 100,000 and about 200,000. However,
iron dextran occasionally causes severe allergic reactions, fever
and rashes during injection and must therefore be administered
slowly and after a small test dose. Ferric gluconate is another
macromolecular iron complex for intravenous administration, and is
relatively free of symptoms. However, each of these intravenous
iron preparations is very expensive and requires a great deal of
time and skill for administration. The large expense related to
these intravenous preparations is associated in part with the
necessity for sterilization of the injectant. Additionally,
intravenous administration requires venous access, which is
available during hemodialysis, but not commonly available in
peritoneal dialysis patients. Finally, only about half of iron in
iron dextran is bio-available after intravenous injection for red
cell production. The fate of the rest is unknown.
[0010] With respect to intramuscular injection, iron dextrins and
iron dextrans may be administered intramuscularly; however, as a
result of their high molecular weights, absorption in the human or
animal body is incomplete. Furthermore, the administration of these
compositions intramuscularly is painful and often results in an
undesirable discoloration at the injection site. Alternatively,
U.S. Pat. No. 3,686,397 to Muller teaches an iron preparation for
intramuscular injection which comprises a nonionic complex of
trivalent iron supplied a ferric hydroxide with a complex forming
agent consisting of sorbitol, gluconic acid and certain
oligosaccharides (polyglucoses) in certain proportions and amounts.
Other macromolecular iron preparations which may be administered
via intramuscular injection are taught in U.S. Pat. No. 5,177,068
to Callingham et al., U.S. Pat. No. 5,063,205 to Peters et al.,
U.S. Pat. No. 4,834,983 to Hider et al. and U.S. Pat. No. 4,167,564
to Jenson. Many preparations, such as that taught in the Jenson
patent, may be administered parenterally either by intramuscular or
intravenous injection.
[0011] Recently, it has been proposed that iron may be administered
to a mammal by intraperitoneal delivery of macromolecular iron
dextran. It has been found that only about half of the iron
delivered intraperitoneally in this form is bioavailable, passing
to the blood and then to the reticulo-endothelial system and bone
marrow, where it is incorporated into red cells. It appears that
about 50% of the iron dextran is stored permanently in the body and
is not avaialable for red cell production. There is evidence that
macrophages near the peritoneum pick up iron-dextran and store it
within themselves, creating an abnormal physical condition which
could lead to abnormal membrane changes in the peritoneum.
[0012] In light of this background, there is a great need in the
art for improved methods for delivering iron to a patient. The
present invention addresses the problems in the prior art by
providing methods and compositions for delivering iron by transfer
of a low molecular weight (non-polymeric) iron complex from
dialysate. Inventive methods are surprisingly effective in light of
conventional thought, which teaches that complexes selected
according to the invention do not have sufficient solubility to be
useful in this manner. Further, it is widely believed that soluble
iron complexes are unacceptable iron delivery agents, this belief
being based upon a fear of the toxicity of free iron in blood.
[0013] The present inventor has discovered that iron complex
compositions selected in accordance with the invention are tightly
complexed and are highly soluble, and can thereby be safely
administered to a patient using dialysis with minimal staff effort
and very little risk. This high solubility also advantageously
allows an inventive complex to be included in dialysate
concentrates, which are described in greater detail herein. For
hemodialysis applications, the iron can be added to a dialysate or
a concentrate, just as other solutes, in "clean" form and need not
be sterilized. For peritoneal applications, the iron composition
can be sterilized.
SUMMARY OF THE INVENTION
[0014] The present invention provides methods and compositions for
delivering iron to an iron-deficient patient. More particularly,
the invention relates to delivering to a patient via dialysis a
composition comprising ionic iron complexed with one or more
anions, wherein the complex is non-polymeric; soluble in an aqueous
medium; chemically stable, thereby preventing the dissociation of
iron ions from the anions under conditions according to the
invention; and can be well absorbed by blood and the living
body.
[0015] According to one specific aspect of the invention, there is
provided a method for performing dialysis with a complex of one or
more divalent or trivalent iron ions and one or more anions, the
complex having a molecular weight of less than about 50,000 and
preferably being non-polymeric. This method of delivering iron to a
patient comprises providing an aqueous dialysate having the complex
dissolved therein, and dialyzing a patient with the dialysate to
increase the level of iron in the patient's blood. Inventive
methods achieve this advantageous result without introducing free
iron into the blood. A preferred anion according to one aspect of
the invention is an organic anion.
[0016] According to another aspect of the invention, there is
provided a method for delivering iron to blood which comprises
passing blood against a first side of a membrane and passing
against a second side of the membrane an aqueous solution having
dissolved therein an iron complex comprising one or more iron ions
and one or more anions, the complex having a molecular weight of
less than about 12,000; wherein the membrane is permeable to the
complex and wherein the complex is delivered to the blood.
[0017] According to another aspect of the invention, there is
provided a method for increasing the level of iron in a patient's
blood by introducing a dialysate into a patient's peritoneal
cavity, the dialysate comprising a non-polymeric complex of one or
more divalent or trivalent iron ions and one or more anions, the
complex having a molecular weight of less than about 50,000.
[0018] In another aspect of the invention, there is provided a
dialysate composition having dissolved therein sodium, magnesium,
calcium, potassium, chloride, acetate, bicarbonate and an iron
complex having a molecular weight of less than about 50,000. An
inventive dialysate comprises from about 130 to about 150 mEq/L
sodium, from about 0.4 to about 1.5 mEq/L magnesium, from about 2
to about 4 mEq/L calcium, from about 1 to about 4 mEq/L potassium,
from about 90 to about 120 mEq/L chloride, from about 3 to about 5
mEq/L acetate, from about 30 to about 40 mEq/L bicarbonate and from
about 1 to about 250 .mu.g/100 ml of iron as an iron complex having
a molecular weight of less than about 50,000. Also provided is a
dialysate concentrate, prepared for subsequent dilution to a
suitable concentration for use as a dialysate, preferably having a
concentration about 30 to about 40 times greater than the
concentration of the desired dialysate.
[0019] It is an object of the present invention to provide improved
methods for administering iron to a patient, especially a patient
suffering from chronic anemia and end stage renal disease.
[0020] Another object of the invention is to provide methods
whereby conventional hemodialysis techniques may be used to deliver
iron to a patient without the need to sterilize the iron-containing
composition prior to administration.
[0021] It is also an object of the invention to provide methods for
delivering iron to peritoneal dialysis patients by providing a
dialysate which includes sterile non-polymeric iron complexes
according to the invention.
[0022] Additionally, it is an object of the invention to provide
dialysate compositions which may be advantageously used to deliver
iron to a patient by a wide variety of dialysis techniques and
concentrates thereof.
[0023] Further objects, features, and advantages of the present
invention shall become apparent from the detailed drawings and
descriptions provided herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Although the characteristic features of this invention will
be particularly pointed out in the claims, the invention may be
better understood by referring to the following descriptions taken
in connection with the accompanying drawings forming a part
hereof.
[0025] FIG. 1 is a plot of iron concentration (.mu.g/dl) in plasma
versus elapsed time in minutes in the experiment described in
Example 1. The horizontal line at 234 .mu.g/dl represents the
capacity by transferrin in plasma to bind soluble iron, and the
horizontal line at 125 .mu.g/dl represents the concentration of
iron in the dialysate described in Example 1.
[0026] FIG. 2 is a plot of absorbance of plasma at 420 and 585 nm
versus elapsed time in minutes, obtained as described in Example
2.
[0027] FIG. 3 is a plot of optical absorbance of ferrous gluconate
at high concentration (100 mg/dl) versus wavelength (nm), taken for
the blood-leak detector experiment described in Example 3.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0028] For the purposes of promoting an understanding of the
principles of the invention, reference will now be made to the
preferred embodiments and specific language will be used to
describe the same. It will nevertheless be understood that no
limitation of the scope of the invention is thereby intended. Any
alterations and further modifications in the described invention,
and any further applications of the principles of the invention as
described herein are contemplated as would normally occur to one
skilled in the art to which the invention relates.
[0029] The present invention overcomes problems in the prior art
associated with delivering iron to a patient. Iron delivery
according to the invention is accomplished by providing a dialysate
composition comprising a iron complex which is soluble in an
aqueous medium and delivering the complex to a patient using
conventional dialysis techniques. An "iron complex," as used
herein, is intended to designate a composition comprising one or
more iron ions complexed with one or more suitable anions and
having a molecular weight of less than about 50,000. Inventive iron
complexes are preferably non-polymeric.
[0030] This invention, therefore, relates to surprisingly
efficacious methods for delivering iron by providing a dialysate,
the dialysate advantageously being prepared either by on-site
preparation or by diluting a pre-made dialysate concentrate and the
dialysate having dissolved therein, among otter solutes, a low
molecular weight non-polymeric iron complex; and dialyzing a
patient therewith using one of a wide variety of dialysis
techniques. Inventive methods are useful for delivering iron to a
patient in readily-available form and, since iron complexes
according to the invention are relatively tightly bound, they may
advantageously be delivered to a patient without risk of
introducing free iron into the blood. It is contemplated that
various compositions, compositional ratios, procedures, and
processes described in connection with the present invention could
be altered or substituted as would occur to those skilled in the
art without departing from the spirit of the invention. It is
believed that inventive methods may advantageously be used in
conjunction with dialysis techniques currently in wide use, as well
as improvements thereof, and with dialysis techniques yet to be
developed. It is anticipated that the present invention may find
particularly advantageous use in hemodialysis procedures and
intraperitoneal dialysis procedures.
[0031] With regard to specific examples of dialysis techniques, it
is well known that conventional hemodialysis procedures may be
performed in free-standing treatment centers, although they may
also be provided in a hospital or performed by the patient at home.
Conventional hemodialysis circuits have two fluid pathways: the
blood circuitry and the dialysate circuitry. The blood circuitry
conventionally comprises a 15-gauge needle for access to the
circulation (usually through an arteriovenous fistula created in
the patient's forearm), lengths of plasticized polyvinyl chloride
tubing (including a special segment adapted to fit into a
peristaltic blood pump), the hemodialyzer itself, a bubble trap and
an open mesh screen filter, various ports for sampling or pressure
measurements at the blood outlet, and a return cannula. Access to
the circulation may alternatively be made at a single access point
using a double-lumen catheter. Components of the blood side circuit
are supplied in sterile and nonpyrogenic condition. The dialysate
side typically comprises a machine capable of (1) proportioning out
glucose and electrolyte concentrates with water to provide a
dialysate of appropriate composition; (2) pulling dialysate past a
restrictor valve and through the hemodialyzer at subatmospheric
pressure; and (3) monitoring temperature, pressures, and flow
rates.
[0032] During treatment the patient's blood is typically
anticoagulated with heparin. Typical blood flow rates are about
200-350 ml/min and dialysate flow rates are usually set at about
500 ml/min. A dialysate volume of about 120-200 liters is typically
used per dialysis treatment. Simple techniques have been developed
to prime the blood side with sterile saline prior to use and to
return to the patient nearly all the blood contained in the
extracorporeal circuit after treatment. Whereas most mass transport
occurs by diffusion, circuits are typically operated with a
pressure on the blood side, which may be 100-500 mmHg higher than
on the dialysate side. This provides an opportunity to remove 2-4
liters of fluid along with solutes in a single treatment. Higher
rates of fluid removal are technically possible but physiologically
unacceptable. Hemodialyzers must be designed with high enough
hydraulic permeabilities to provide adequate fluid removal at low
transmembrane pressure but not so high that excessive water removal
will occur in the upper pressure range.
[0033] Although other geometries may be employed, one preferred
hemodialyzer format is a "hollow fiber" hemodialyzer about 25 cm in
length and 5 cm in diameter, resembling the design of a shell and
tube heat exchanger. Blood enters this type of hemodialyzer at an
inlet manifold, is distributed to a parallel bundle of capillary
tubes (typically potted together with polyurethane), and exits at a
collection manifold. Dialysate flows countercurrent in an external
chamber. The shell is typically made of an acrylate or
polycarbonate resin. Devices typically contain about 6000-10,000
capillaries, each with an inner diameter of about 200-250 microns
and a dry wall thickness as low as about 10 microns. The total
membrane surface area in commercial dialyzers typically varies from
about 0.5 to about 1.5 m.sup.2, and units can be mass-produced at a
relatively low cost.
[0034] Although a specific hemodialysis set-up is described in
detail above, it is well understood that a wide variety of
hemodialysis devices may be advantageously used in accordance with
the invention. Examples of alternate hemodialysis devices and
methods suitable for use according to the invention are set forth
in U.S. Pat. No. 5,277,820 to Ash; U.S. Pat. No. 4,661,246 to Ash;
U.S. Pat. No. 4,581,141 to Ash; U.S. Pat. No. 4,348,283 to Ash;
U.S. Pat. No. 4,071,444 to Ash et al.; U.S. Pat. No. 3,734,851 to
Matsumura; U.S. Pat. No. 4,897,189 to Greenwood et al.; U.S. Pat.
No. 4,267,041 to Schael; U.S. Pat. No. 4,118,314 to Yoshida; U.S.
Pat. No. 3,989,625 to Mason; and U.S. Pat. No. 3,962,075 to
Fialkoff et al. These patents are hereby incorporated herein by
reference.
[0035] In a hemodialysis treatment, as discussed above, blood is
removed from the body, propelled through a closed system of
membranes, and returned to the body, while on the other side of the
membranes is an aqueous dialysis fluid. These membranes are
semipermeable, allowing small molecules to pass through, but
retaining larger molecules such as proteins, as well as cellular
blood elements. Uremic substances, being small molecules, will pass
through the membranes as long as the concentration of these
substances is kept low in the dialysis fluid, or dialysate, on the
other side of the membrane. The aqueous medium so used must be
prior treated to remove trace elements (which would otherwise pass
back across the membrane into the blood), must be supplemented with
electrolytes and glucose, and must then be warmed to blood
temperature. The electrolytes are added to the dialysate so as to
prevent excessive ion removal (i.e., Mg.sup.++, K.sup.+, Na.sup.+,
Cl.sup.- and HCO.sub.3.sup.-). Calcium ions should also be in
slight excess in the dialysate so as to cause addition of calcium
to the patient's blood, as the total body calcium in kidney failure
patients is often low, leading to stimulation of parathyroid
hormone, which is detrimental to the patient's health.
[0036] In one preferred aspect of the present invention, a
non-polymeric iron complex is used according to the invention in
conventional extracorporeal hemodialysis techniques by providing a
dialysate, for example, as described above, having the iron complex
dissolved therein to a predetermined concentration. An iron complex
to be dissolved into dialysate for hemodialysis must be "clean,"
but need not be sterile, as is the case for other solutes in a
dialysate. This provides a substantial advantage over prior methods
of iron delivery to a patient by intramuscular or intravenous
injection, both of which necessitate that the iron preparation be
sterilized prior to injection. The dialysate, having a clean iron
complex dissolved therein will deliver the iron complex to the
blood during dialysis by diffusion, at a rate automatically
responding to the blood plasma concentration, just as the
concentrations of other solutes (such as, for example, sodium,
potassium, glucose, bicarbonate, magnesium, calcium and chloride)
are adjusted in dialysate to assure proper plasma levels in a
patient. In the case of inventive iron complexes, however, it
appears that blood proteins are binding the complex, thereby
removing the complex from the plasma and maintaining a
concentration gradient between the dialysate and the blood. Basis
for this theory is found in Example 1 and FIG. 1, where it is shown
that the total amount of ferrous gluconate transferred to blood is
higher than that expected based upon simple concentration gradient
analysis. Thus, transfer of an inventive iron complex to the blood
will continue until the level of free iron complex in the plasma
reaches the same concentration as the iron complex dissolved in
dialysate.
[0037] Turning now to an alternate dialysis technique, another type
of dialysis with which inventive methods may be advantageously used
is continuous ambulatory peritoneal dialysis (CAPD), also referred
to herein interchangeably as "peritoneal dialysis" or
"intraperitoneal dialysis." In this type of dialysis, approximately
2 liters of a sterile, nonpyrogenic, and hypertonic solution of
glucose and electrolytes are instilled via gravity flow into the
peritoneal cavity of a patient through an indwelling catheter,
typically 4 times per day. Intraperitoneal fluid partially
equilibrates with solutes in the plasma, and plasma water is
ultrafiltered due to osmotic gradients. After about 4-5 hours,
except at night where the exchange is lengthened to about 9-11
hours to accommodate sleep, the peritoneal fluid is drained and the
process repeated. Patients may perform the exchanges themselves in
about 20-30 minutes, for example at home or in the work
environment, after a training cycle which usually lasts about 1-2
weeks. Alternatively, automated peritoneal dialysis (APD) may be
used, in which case about 10-15 liters of dialysate are
automatically exchanged overnight and 2 liters remain in the
peritoneal cavity during the day for a "long dwell" exchange.
[0038] Access to the peritoneum is usually via a double-cuff
Tenckhoff catheter, essentially a 50-100 cm length of silicone
tubing with side holes at the internal end, a dacron mesh flange at
the skin line, and connector fittings at the end of the exposed
end. A wide variety of variations exist, however, and may
advantageously be used in accordance with the invention. Most are
implanted in a routine surgical procedure requiring about hour and
are allowed to heal for about 1-2 weeks prior to routine clinical
use. Sterile and nonpyrogenic fluid is commonly supplied in 2 liter
containers fabricated from dioctyl phthalate plasticized polyvinyl
chloride. The formulation is essentially potassium-free lactated
Ringers to which has been added from about 15-42.5 grams/liter of
glucose (dextrose monohydrate). The solution is buffered to a pH of
about 5.1-5.5, since the glucose would caramelize during
autoclaving at higher pH levels.
[0039] Several different exchange protocols may be used in a
peritoneal dialysis procedure. In one conventional design, the
patient simply rolls up the empty bag after instillation and then
drains into the same bag following exchange. The bag filled with
drain fluid is disconnected and a fresh bag is reconnected.
Patients are trained to use aseptic technique to perform the
connect and disconnect. Many aids have been developed to assist in
minimizing breaches of sterility including enclosed
ultraviolet-sterilized chambers and heat splicers. More recent
approaches, known as the "o" set and "Y" set or more generically as
"flush before fill" disconnect, invoke more complex tubing sets to
allow the administration set to be flushed (often with antiseptic)
prior to instillation of dialysate and generally permit the patient
to disconnect the empty bag during the dwell phase. Initial reports
of the success of these protocols in reducing peritonitis' were
regarded with skepticism, but improvement over earlier systems has
now been documented in well-designed and carefully controlled
clinical trials.
[0040] Iron complexes selected in accordance with the invention may
also be administered to a patient from dialysate intraperitoneally,
for example, as described above. While dialysates used for
intraperitoneal dialysis must be sterilized prior to use, this
aspect of the invention also provides an excellent manner in which
to introduce iron complexes into a patient's blood in an
advantageous form. In intraperitoneal dialysis techniques, just as
in hemodialysis techniques, a smaller iron complex will move more
readily from the dialysate into the patient's blood than will a
larger complex.
[0041] While the term "dialysate" is used interchangeably in
various contexts, for instance, with respect to hemodialysis and
with respect to peritoneal dialysis, it is readily understood by a
skilled artisan that a variety of solutes and concentrations of
solutes may be used with respect to various dialysis techniques,
and also may vary with respect to the particular needs of a given
patient. Because an iron complex selected for use according to the
invention is absent in native blood, its presence in dialysate
results in diffusion from the dialysate into the blood. This
diffusion is augmented in preferred aspects of the invention by the
apparent binding of the iron complex to plasma proteins.
[0042] It should be pointed out that the term "complex" may have
alternate meanings in various contexts in the related art and,
therefore, clarification of its meaning for purposes of describing
the invention is in order. At one level, the term "complex" may be
used to describe the association between two or more ions to form a
relatively low molecular weight non-polymeric composition which
exists singly under a given set of conditions. This type of complex
may be referred to as a "primary complex," and this is the manner
in which the term is to be used herein. As such, the term "primary
complex" is used interchangeably herein with the term "complex" for
purposes of describing the invention. An alternate manner in which
this term is used in the related field is to describe the
association or agglomeration of a plurality of primary complexes
into a large macromolecule, or "secondary complex." For purposes of
simplicity, these agglomerates are referred to herein as
macromolecules, and are not considered "complexes" as the term is
used to describe the invention.
[0043] As an example of the above distinction, ferrous gluconate is
a composition comprising divalent iron ions and gluconate anions. A
divalent iron ion and two gluconate anions form a primary complex
of relatively low molecular weight (about 450 Daltons) and primary
complexes of this type do not become agglomerated into
macromolecules when dissolved into an aqueous medium. Ferrous
gluconate, therefore, is a composition which falls within the scope
of the term "complex" herein. Ferric gluconate, however, does not
exist as such a complex because primary complexes of trivalent iron
ions and gluconate anions agglomerate together to form very large
macromolecules (commonly having a molecular weight of between about
100,000 and 600,000 Daltons). As such, iron complexes according to
the invention are identified by selecting a combination of one or
more iron ions (either divalent or trivalent) and one or more
anions which interact to form primary complexes, but do become
agglomerated into macromolecules.
[0044] As such, the present invention provides dialysate
compositions, and methods of using them, which comprise a primary
iron complex of one or more divalent or trivalent iron ions and one
or more anions described herein; which does not become associated
or agglomerated to form a macromolecule; which is soluble in an
aqueous medium; and which has a molecular size and,
correspondingly, a molecular weight, which imparts advantageous
properties with respect to diffusion of the complex through a
dialysis membrane.
[0045] With respect to solubility, the solubility of a given iron
complex according to the present invention must be such that the
concentration of the complex in a dialysate solution may be
achieved which enables the desired level of iron delivery to the
patient. While conventional belief in the relevant field is that
complexes of the invention would not be sufficiently soluble in an
aqueous medium to find advantageous use, the present inventor has
discovered that preferred inventive complexes are highly
soluble.
[0046] The particular concentration of iron complex to be dissolved
in a dialysate according to the present invention is dependent upon
the amount of iron desired to be transferred to the patient's
blood. For example, the amount of iron desired to be transferred in
the case of an anemic patient is associated with the known blood
building requirements of the patient. In other words, to determine
the desired concentration of the iron complex in the dialysate, it
is first calculated how much iron the patient needs for building
blood cells. The complex will transfer to the patient at a
controlled, definable rate, since the iron complex does not exist
naturally in the blood. As is readily understood by one skilled in
the art, a higher concentration of iron complex would be needed in
peritoneal dialysis techniques than that which would be needed in
extracorporeal hemodialysis techniques due to differing rates of
diffusion with respect to the respective membranes and due to the
lower daily volume of dialysate used in peritoneal dialysis.
Preferred concentrations in a given situation may be readily
determined by a skilled artisan with minimal experimentation.
[0047] In a preferred aspect of the invention, iron complexes
selected for use are sufficiently soluble in aqueous media to be
advantageously included in a wide variety of formulations to make
dialysate concentrates. As used herein, the term "concentrate" is
intended to designate a solution wherein the solutes are dissolved
therein at concentrations much greater (commonly about 30-40 times
greater) than a desired dialysate concentrate. A dialysate
concentrate, therefore, has a volume 0-40 times less than the
actual dialysate and may therefore be pre-mixed and advantageously
shipped and handled much more readily. At the location of a
dialysis procedure, a concentrate is diluted to the proper volume,
commonly in the dialysis instrument itself, thereby providing a
dialysate having suitable solute concentrations for the particular
use.
[0048] The high concentration of solutes in a dialysate concentrate
results in a reduced amount of water which is available to dissolve
additional solutes. Therefore, the most preferred iron complexes
used in accordance with the invention are highly soluble. The use
in the art of dialysate concentrates is apparently an additional
factor which has engendered the belief that iron complexes, such as
those selected in accordance with the invention, do not have
sufficient solubility to be used as described herein. In
contravention of this belief, the present inventor has discovered,
for example, that ferrous gluconate is stably soluble in such a
concentrate at levels over 8 grams per 100 ml (dl), thus providing
an iron concentration of about 1 gram per 100 ml. As is readily
ascertainable by one skilled in the art, this would result in an
iron concentration in dialysate of approximately 30 mg (30,000
.mu.g) per 100 ml after a 35:1 dilution.
[0049] An iron complex contemplated for use according to the
present invention comprises one or more divalent or trivalent iron
ions relatively tightly bound to one or more anions to form a low
molecular weight iron complex. As used herein, "relatively tightly
bound" is intended to mean that the iron ion or ions and the anion
or anions will not readily become dissociated under conditions-of
the present invention to yield free iron ions. The anion may be a
natural or a synthetic molecule and may be either organic or
inorganic, so long as it forms a primary complex with divalent or
trivalent iron ions according to the present invention, but does
not ultimately become associated into a macromolecule and so long
as the anion is biocompatible. It is important that the iron ion
and the anion remain tightly bound under relevant conditions
because an overabundance of free iron ions in a dialysate and, as a
result, in a patient's blood, may cause hemolysis and, if extreme,
may cause death.
[0050] The anion of an iron complex selected in accordance with the
invention is preferably a multi-polar anion, including for example
a divalent or trivalent anion (e.g. di- or tricarboxylic acids
(preferably aliphatic) having up to about 10 carbon atoms,
optionally also substituted with one or more polar groups such as
hydroxyl groups); or a monovalent anion which has additional polar
substituents (such as hydroxyl groups) and which is readily
complexed with iron ions, such as monohydroxycarboxylic or
polyhydroxycarboxylic acids, typically having up to about 10 carbon
atoms, especially aliphatic acids of this type such as gluconic
acid. It is contemplated that suitable anions for iron complexes of
the invention include, for example, gluconate, sulfate, fumarate,
citrate and succinate. It is not intended, however, that this list
be limiting, and it is within the purview of a skilled artisan to
identify anions which form suitable iron complexes for advantageous
use according to the invention.
[0051] The term "low molecular weight iron complex" is intended to
designate an iron complex having a size useful for passing through
dialysis membranes. As such, iron complexes selected according to
the invention preferably have a molecular weight of less than about
50,000 and are preferably non-polymeric. This designation is
intended to distinguish iron complexes selected according to the
invention from large polymeric compositions and compositions in
which primary complexes have become associated with one another to
form macromolecules, as discussed above. This molecular weight
limitation ensures that iron complexes used according to the
present invention are of a size which will pass a wide variety of
dialysis membranes used in a wide variety of dialysis methods. It
is readily understood by a skilled artisan that many iron complexes
selected according to the invention may be advantageously used in
both hemodialysis techniques and in intraperitoneal dialysis
techniques. Some iron complexes, however, such as those having a
molecular weight greater than about 12,000, may not diffuse through
many membranes used in hemodialysis to a suitable degree, but may
nevertheless be advantageously used in intraperitoneal dialysis
techniques.
[0052] With regard to intraperitoneal dialysis, it is expected that
an iron complex having a molecular weight greater than about 50,000
will not be transported to the patient's blood. In a preferred
aspect of the invention, therefore, the iron complex to be used for
intraperitoneal dialysis has a molecular weight of less than about
50,000, preferably less than about 25,000, more preferably less
than about 12,000 and most preferably less than about 5000.
[0053] With regard to extracorporeal hemodialysis methods, it is
preferred that the iron complex have a molecular weight of less
than about 12,000. More preferably, the iron complex has a
molecular weight of less than about 5,000 and most preferably less
than about 2,500. It is to be understood that the lower the
molecular weight of the iron complex and, correspondingly, the
smaller the iron complex, the faster the iron complex may be
incorporated into a patient's blood.
[0054] Complexes selected for use according to the invention may be
identified, therefore, by their molecular weight, by their degree
of solubility in an aqueous medium and by their ability to remain
tightly complexed under conditions of the invention. In this
regard, a useful way to determine whether an iron-containing
composition falls within the scope of the invention, is to
introduce it into water and, using techniques well known to those
skilled in the art, to test levels of solubility and to determine
whether the complex becomes dissociated in solution.
[0055] According to another aspect of the invention, there is
provided a dialysate composition having dissolved therein sodium,
magnesium, calcium, potassium, chloride, acetate, bicarbonate and
an iron complex having a molecular weight of less than about
50,000. In certain preferred embodiments of the invention, the
dialysate may also optionally include dextrose, a sorbent and/or a
surfactant. Preferably, the dialysate composition comprises from
about 130 to about 150 mEq/L sodium, from about 0.4 to about 1.5
mEq/L magnesium, from about 2 to about 4 mEq/L calcium, from about
1 to about 4 mEq/L potassium, from about 90 to about 120 mEq/L
chloride, from about 3 to about 5 mEq/L acetate, from about 30 to
about 40 mEq/L bicarbonate and from about 1 to about 250 .mu.g/dl
iron as an iron complex having a molecular weight of less than
about 50,000.
[0056] As discussed above, in the field of dialysate preparation,
it is common for dialysates to be prepared at the site of dialysis,
immediately before or simultaneously with the dialysis procedure,
by diluting a pre-made "dialysate concentrate" having dissolved
therein the desired solutes at a very high concentration. In this
regard, dialysate concentrates, which are also considered to be a
part of the present invention, are typically prepared such that the
solutes have concentrations about 30-40 times greater than the
desired concentration in the actual dialysate fluid, e.g. the
preferred concentrations given above. The present inventor has
discovered that certain iron complexes of the invention, such as,
for example, ferrous gluconate, have excellent solubility and may
find advantageous use in the preparation of dialysate
concentrates.
[0057] In this respect, in another aspect of the invention, there
is provided a dialysate concentrate comprising sodium, magnesium,
calcium, potassium, chloride, acetate, bicarbonate and an iron
complex having a molecular weight of less than about 50,000. In
certain preferred embodiments of the invention, the concentrate may
also optionally include dextrose, a sorbent and/or a surfactant. As
stated above, the concentrate may then be diluted to the desired
dalysate concentration, preferably in the dialysis apparatus
itself, and the ratio of concentrate to diluent combined in the
dilution apparatus may be carefully controlled to achieve the
desired concentrations of materials dissolved in the dialysate.
More preferably, the concentrate comprises the above compositions
at concentrations from about 35 to about 45 times more concentrated
than the desired dialysate concentration, even more preferably
between about 34 and about 38 times more concentrated and, most
preferably from about 35 to about 37 times more concentrated.
[0058] In a preferred aspect of the invention, the iron complex
which is dissolved into a dialysate or a dialysate concentrate is
ferrous gluconate. Ferrous gluconate is commercially available from
Fluka Chemical Corporation, Chemika--Biochemika, 980 South Second
Street, Ronkonkoma, New York, N.Y. 11779-7238. Ferrous gluconate
has been found by the present inventor to be extremely soluble and
to readily diffuse into blood through a dialysis membrane during
conventional hemodialysis techniques. In this iron complex, two
gluconate anions are tightly complexed with a ferrous ion in the
presence of water.
[0059] Furthermore, as is demonstrated in Example 1, ferrous
gluconate surprisingly transfers into blood from dialysate in an
amount substantially higher than that expected based upon the level
of transferrin in the blood. Normally, it is expected that blood
plasma is able to bind no more iron than that held by transferrin,
which is the main iron binding protein in the blood. However, in
the experiment set forth in Example 1, a ferrous gluconate
concentration (125 .mu./dl) was purposely provided in the dialysate
which was less than the transferrin iron binding capacity (225
.mu.g/dl) in the blood. As is shown in FIG. 1, after only a few
minutes of hemodialysis, the transferrin iron level of the blood
was reached, and the percent saturation of this iron protein was
100%. Nevertheless, the iron level in the plasma continued to rise
over the next half hour or more of dialysis to a level in the
plasma which was several times higher than the fully saturated
transferrin level, and also much higher than the level of iron in
the dialysate (125 .mu.g/dl).
[0060] While it is not intended that the present invention be
limited by any mechanism by which it achieves it advantageous
result, it appears that ferrous gluconate complexes are bound by
another protein in the blood. The mechanism by which this occurs is
not known; however, it is evident that the invention enables the
delivery of iron complexes from dialysate into blood to much higher
levels than previously considered possible. Furthermore, since this
iron complex does not become dissolved in blood plasma, there
should be much less threat of toxicity caused by increasing free
iron levels in the blood. While this result was achieved by
delivering ferrous gluconate to blood from dialysate, it is
expected that a wide variety of compositions having similar
characteristics to ferrous gluconate would show similar results
according to the present invention.
[0061] The invention will be further described with reference to
the following specific Examples and associated Figures. It will be
understood that these Examples are illustrative and not restrictive
in nature.
EXAMPLE ONE
Transfer of Ferrous Gluconate into Blood
[0062] A two liter volume of bovine blood (hematocrit adjusted from
49 to 40 with saline) which had been stored with heparin
anticoagulation for 24 hours was dialyzed using a PAN membrane
dialyzer. The volume was maintained at 2 liters throughout the
experiment by adding saline. The dialyzer type was FILTRAL 12 and
the PAN membranes used had an intrinsic negative charge and,
therefore, tended to bind positively charged molecules. The
dialysate was created from 20 liters of purified (deionized) water
with acetate concentrate (Dial Medical Supply Concentrate Solution
for Acetate Dialysate) in a 1:34 dilution with water and 10 mg/L
ferrous gluconate (1 mg/dl containing 125 .mu.g/dl iron).
[0063] A sample of the blood was taken prior to dialysis of the
blood and tested for iron content. The iron content of the
pre-dialysis blood was 110 .mu.g/dl and the transferrin iron
binding capacity was 225 .mu.g/dl. Dialysis was then started using
the following equipment and conditions:
1 Blood Pump: Minipump Renal Systems at 300 ml/min (setting 323,
1/4") Dialysate Pump: Travenol at 500 ml/min (setting approximately
92) Bath for Dialysate: 37.degree. C.
[0064] The circuit was primed with dialysate, prepared as described
above, pumps were adjusted for proper flow, and then the blood side
was drained of dialysate by pulling the Blood In tube out of the
dialysis bath and allowing air to fill this side.
[0065] Assays were performed to determine plasma iron
concentrations at 0, 5, 10, 20 and 30 minutes. A plot of iron
concentration in plasma versus elapsed time of this experiment is
provided in FIG. 1. Though the iron content of the dialysate was
only 125 .mu.g/dl, it was found that a continued transfer of iron
into the blood proceeded until the plasma level reached nearly 500
.mu.g/dl after 30 minutes. This transfer indicates an avidity of
plasma for the iron complex, even higher than the iron binding
capacity of transferrin.
[0066] Based upon these results, it is concluded that if the
initial rate of iron transfer to the plasma is continued according
to this experiment for a period of 180 minutes, approximately 4 mg
of iron would be transferred to the plasma. Therefore, to transfer
15 mg of iron to the patient during dialysis, the iron
concentration in the dialysate would need to be increased
four-fold. As such, increasing the dialysate concentration of
ferrous gluconate to 4 mg/dl (with iron concentration of 0.5
.mu.g/dl) will result in transfer of 15 mg of iron per dialysis
treatment.
EXAMPLE TWO
Monitoring of Hemolysis in Experimental Dialysis
[0067] To determine whether the method of Example 1 would cause
hemolysis (lysis of red blood cells with the liberation of
hemoglobin), absorbance data at 420 and 585 nm was collected for
the plasma at various stages of the experiment described in Example
1. These data are provided in FIG. 2. The increase in absorbance
indicates that some degree of hemolysis occurred during the
experiment; however, this level is not higher than that of similar
experiments conducted without iron in the dialysate.
EXAMPLE THREE
Effect on Blood-Leak Detection Systems
[0068] To determine whether the presence of ferrous gluconate in
the dialysate would interfere with blood-leak detection systems
used in hemodialysis procedures, optical absorbance data for
ferrous gluconate at high concentrations were obtained. These data
are provided in FIG. 3. From the plot of FIG. 3, it is apparent
that iron can be added to the dialysate without interfering with
the detection of hemoglobin in dialysate by blood-leak detectors
using optical absorbance at either 420 nm or 585 nm.
[0069] While the invention has been described in detail in the
foregoing description, the same is to be considered as illustrative
and not restrictive in character, it being understood that only the
preferred embodiments have been described and that all changes and
modifications that come within the spirit of the invention are
desired to be protected.
* * * * *