U.S. patent application number 14/993079 was filed with the patent office on 2016-05-05 for hemodialysis and peritoneal dialysis solutions comprising one or more creatine compounds.
The applicant listed for this patent is CREARENE LTD.. Invention is credited to Michael Moeddel, Theo Wallimann.
Application Number | 20160120829 14/993079 |
Document ID | / |
Family ID | 42111284 |
Filed Date | 2016-05-05 |
United States Patent
Application |
20160120829 |
Kind Code |
A1 |
Moeddel; Michael ; et
al. |
May 5, 2016 |
HEMODIALYSIS AND PERITONEAL DIALYSIS SOLUTIONS COMPRISING ONE OR
MORE CREATINE COMPOUNDS
Abstract
The present invention provides a hemodialysis solution or
concentrate thereof including creatine compound(s), the use of
creatine compound(s) for preparing a dialysis solution or
concentrate thereof, a method for preparing creatine-containing
dialysis solutions and concentrates, and a method for treating
patients with dialysis dependent renal failure with creatine
compounds to provide a variety of significant health benefits and
improvement of life quality parameters for dialysis patients. This
is achieve by supporting and improving the physiological functions
of organs and cells via creatine compounds delivery to the
patients, and by protecting organs and cells of the patients from
deleterious effects of a variety of endogenous or exogenous
cellular stressors that are linked to the disease state or to the
clinical treatment modalities. Furthermore, in peritoneal dialysis
solutions creatine can be used as an osmotic agent preventing side
effects caused by high glucose supplementation.
Inventors: |
Moeddel; Michael; (Dallikon,
CH) ; Wallimann; Theo; (Bergdietikon, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CREARENE LTD. |
Nassau |
|
BS |
|
|
Family ID: |
42111284 |
Appl. No.: |
14/993079 |
Filed: |
January 11, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13263189 |
Dec 12, 2011 |
9248112 |
|
|
PCT/CH10/00065 |
Mar 10, 2010 |
|
|
|
14993079 |
|
|
|
|
Current U.S.
Class: |
514/565 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 9/08 20130101; A61K 47/02 20130101; A61K 47/26 20130101; A61P
13/12 20180101; A61K 31/197 20130101; A61K 31/198 20130101 |
International
Class: |
A61K 31/197 20060101
A61K031/197 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 6, 2009 |
EP |
09005038.6 |
Claims
1. A dialysis concentrate for treating a patient with renal
dysfunction, the concentrate comprising: at least one creatine
compound; and (ii) one or both of: (a) physiologically acceptable
ions; and (b) a physiologically acceptable buffering substance;
wherein said dialysis concentrate is formulated such that upon
water dilution a resulting physiologically acceptable dialysis
solution is obtained.
2. The dialysis concentrate according to claim 1, wherein the
physiologically acceptable buffering substance is present, and
wherein said physiologically acceptable buffering substance has a
basic pH.
3. The dialysis concentrate according to claim 1, wherein the
dialysis concentrate is essentially free of water prior to water
dilution.
4. The dialysis concentrate according to claim 1, wherein the
dialysis concentrate is formulated such that upon water dilution by
a factor of 25 to 60 by weight, the resulting physiologically
acceptable dialysis solution has a concentration equivalent to from
0.002 to 45 mM/l creatine.
5. The dialysis concentration according to claim 1, wherein the
dialysis concentrate is in dry form.
6. A dialysis concentrate for treating a patient with renal
dysfunction, the concentrate comprising: (i) at least one creatine
compound; and (ii) one or more physiologically acceptable ions
selected from the group consisting of Na-ions, K-ions, Ca-ions,
Mg-ions and Cl-ions; (iii) glucose; and (iv) optionally, a
physiologically acceptable buffering substance; wherein said
dialysis concentrate is formulated such that upon water dilution in
the presence of at least one basic physiologically acceptable
buffering substance a resulting physiologically acceptable dialysis
solution is obtained having a pH in the range of 7.1 to 7.5.
7. The dialysis concentrate according to claim 6, wherein the basic
physiologically acceptable buffering substance is present in the
dialysis concentrate.
8. The dialysis concentrate according to claim 6, wherein the basic
physiologically acceptable buffering substance is mixed with the
dialysis concentrate during water dilution.
9. The dialysis concentrate according to claim 6, wherein the
dialysis concentrate is essentially free of water prior to water
dilution.
10. The dialysis concentrate according to claim 6, wherein the
dialysis concentrate is formulated such that upon water dilution by
a factor of 25 to 60 by weight, the resulting physiologically
acceptable dialysis solution has a concentration equivalent to from
0.002 to 45 mM/l creatine.
11. The dialysis concentration according to claim 6, wherein the
dialysis concentrate is in dry form.
12. A method for treating a patient with renal dysfunction, said
method comprising: providing a dialysis solution having a
concentration equivalent to from 0.002 to 45 mM/l creatine; and
administering the dialysis solution in a physiologically effective
volume to the patient.
13. The method according to claim 12, wherein in a first step a
creatine compound is administered to the patient orally, and in a
second step the dialysis solution is administered to the patient.
Description
[0001] This application is a division of U.S. application Ser. No.
13/263,189, filed Dec. 12, 2011, now U.S. Pat. No. ______, which
was a U.S. national phase of PCT/CH2010/000065, filed Mar. 10,
2010, and claims priority to EP 09005038.6, filed Apr. 6, 2009.
[0002] The present invention relates to a hemodialysis solution and
peritoneal dialysis solution or concentrates thereof and to the use
of creatine compound(s) for preparing a dialysis solution or
concentrate thereof. Furthermore, the present invention is directed
to a method for preparing creatine-containing hemodialysis and
peritoneal dialysis solutions and concentrates. In addition, the
present invention is directed to a method for treating patients
with renal failure, who depend on dialysis treatment, to enhance
their creatine levels in cells and organs and improve their health
status.
[0003] Finally, the present invention is directed to a method for
treating peritoneal dialysis patients with high concentrations of
creatine compounds as active osmolytes, alone or in combination
with other osmotically active substances, in order to significantly
reduce the high glucose concentrations in peritoneal dialysis fluid
that eventually lead to fibrosis of the peritoneum and an induction
of diabetes-II.
BACKGROUND OF THE INVENTION
[0004] The present invention is directed to the field of creatine
supplementation and hemodialysis and/or peritoneal dialysis for
patients with renal failure, who depend on dialysis treatment.
[0005] Creatine is a natural body substance involved In numerous
physiological functions and, hence, of particular relevance for the
vertebrate organism, in particular the brain, skeletal and cardiac
muscle, where most of the creatine is located in adult mammals (120
to 150 g for a human of about 75 kg weight). Creatine and
phosphocreatine are the key substrates of the
creatine/phosphocreatine-kinase system that supplies cells with
energy. In cells creatine kinase reversibly converts
phosphocreatine (PCr) and ADP into ATP and creatine. This
reversible reaction plays a key role in the energy metabolism of
skeletal and cardiac muscle, the brain, sensory cells, e.g. retina
and inner ear, as well as sperm and other cells. The
creatine/phoshocreatine-kinase system has a dual function. It
represents an immediately available, high energy phosphate buffer
system for regenerating ATP as well as an intracellular energy
transport system or shuttle between either mitochondria or sites of
glycolysis to those places where energy is needed, e.g. at sites of
high ATPase activity (for cell locomotion, ion-pumping etc). More
specifically, the creatine system sustains the local cellular
ADP/ATP-ratio in the vicinity of ATPases and thereby ensures the
effective functioning of these ATPases. The concentration of
phospho-creatine/creatine is much higher than that of ADP/ATP, has
a lesser influence on cell metabolic regulation and replenishes ATP
upon demand. Furthermore, ATP and ADP have limited diffusion
abilities whereas creatine and phospho-creatine are readily
diffusing from either mitochondria or from regions of ATP
production by glycolysis to those places where energy and ATP is
needed.
[0006] Nutritional or supplemented Creatine is actively transported
into cells by a Creatine-Na/K-cotransporter (CrT).
[0007] In animal experiments it was demonstrated that creatine
deficit leads to functional abnormalities and histopathological
changes in muscle similar to those of patients with mitochondrial
myopathies. Creatine kinase knock-out mice (in brain and muscle)
demonstrated a significant loss of muscle power and problems
relating to muscle relaxation, due to creatine's key role in
providing the contractile apparatus and the calcium ion pumps with
energy. Also, these transgenic mice show irregular behavioral
phenotypes and histological abnormalities in muscle and brain.
Patients with genetic deficits in the creatine metabolism present
with severe neurological symptoms. For example, children with these
genetic defects show development disorders, speech delay, autism
and epilepsy. Depending on the type of genetic defect oral creatine
supplementation can reverse these abnormalities.
[0008] Creatine supplementation has been shown to elicit
significant cell protective, antioxidant and even anti-apoptotic
effects, in particular for skeletal and cardiac muscle cells, as
well as for nerve and skin cells. These effects of creatine are of
benefit for healthy people as well as patients with diverse
muscular, neuromuscular, neurological and neurodegenerative
disorders. Endogenous creatine is mainly produced in the kidney and
liver. Specifically, in the kidney guanidino-acetate is produced
from arginine and glycine and subsequently methylated by activated
methionine to methyl guanidino acetate, i.e. creatine, in the
liver.
[0009] The daily human demand for creatine is approximately 3 to 4
g, whereas the endogenous production is limited to about 1 to 2
g/day. Natural creatine is mainly available in fish and meat and to
some minor extent also in milk.
[0010] Dietary Creatine, taken up with meat and fish consumption,
or supplementation of Creatine in form of chemically pure substance
(e.g. Creatine Monohydrate or Creatine salts) has a number of
benefits and advantages for humans. Naturally, it helps for
compensating the chronic creatine deficits of vegetarians. Also, it
is an officially authorized diet supplement for athletes leading to
an enhanced cellular energy status that results in prolonged muscle
endurance, in a delay of muscle fatigue and in an accelerates
muscle recuperation.
[0011] Moreover, creatine supplementation has shown to be
beneficial in a number of muscular, neuromuscular, neurological and
neurodegenerative diseases, for example, congestive heart failure,
cardiac insufficiency, cardiac arrhythmia, muscle disuse atrophy,
gyrate atrophy, McArdle's disease, diabetic and toxic neuropathies,
peripheral nervous system diseases, dysmyelination and
demyelination diseases, motor neuron disease, traumatic nerve
injury, multiple sclerosis, mitochondrial diseases, muscular
dystrophy, amyotrophic lateral dystrophy (ALS), Morbus Huntington,
Morbus Parkinson, Charcot Marie tooth syndrome, epilepsy, stroke,
spine injuries, cranial cerebral injury, brain atrophy, cognitive
dysfunction (see EO 03/101402 A2) osteoporosis, skin disorders (see
WO 2008/073332, WO 01/00203 A1), dermatitis (see WO2009/002913),
eye disorders (see US 2009/0005450 A1), transmissible spongiform
encephalopathies (see WO 01/00212), disorders of the glucose
metabolism (see EP 0 854 712 B1).
[0012] The positive effects of creatine supplementation are
directly or indirectly based on its effect on the energy status of
cells, its ability to protect cells and its anti-apoptotic
influence.
[0013] Clinical studies have demonstrated creatine to be safe up to
extremely high doses, for example up to 20 g daily intake for
adults. Up to date no serious side effects are known.
[0014] Creatine in the form of creatine monohydrate is a white
powder that can be stored at room temperature. In acidic aqueous
solutions it displays some instability at temperatures over
60.degree. C. At neutral pH and cooled, however, it can be stored
for thirty days without losses.
[0015] When administered orally, most of the creatine passes
unchanged through the acidic stomach environment. Next to creatine
monohydrate, which is only moderately soluble in water, a number of
more soluble salts like creatine pyruvate and citrate are
commercially available. For people with severely reduced body
creatine levels, an initial loading phase with 4.times.5 g of
creatine per day during a 7-10 days period, followed by a low dose
daily intake of 3 to 6 g is generally recommended. It has been
shown that the simultaneous administration of creatine and glucose
is beneficial in order to compensate for energy losses due to
creatine phosphorylation.
[0016] Hemodialysis is used for providing an artificial replacement
for lost kidney function due to renal failure. Dialysis may be used
for patients with sudden but temporary loss of kidney function
(acute renal failure) or for patients permanently lacking kidney
function (stage 5 chronic kidney disease). When healthy, the
kidneys maintain the body's internal equilibrium of water and
minerals and remove the daily metabolic load of waste products and
toxins from the blood. As part of the endocrine system they produce
erythropoietin and 1.25-dihydroxycholecalciferol (calcitriol),
Dialysis is an imperfect treatment for replacing kidney function
because it does not correct the endocrine functions of the kidney.
It replaces the excretory function through diffusion (waste
removal) and ultrafiltration (fluid removal) of solutes. But
prolonged dialysis treatment also leads to a wash-out of valuable
body substances (minerals, vitamins and other nutrient compounds,
which are lost during the dialysis process, due to lack of
resorption by the kidneys. Therefore, dialysis patients are
creatine-depleted because endogenous creatine synthesis is hampered
in the diseased kidney and ingested creatine is washed out during
dialysis.
[0017] Hemodialysis works on the principles of (i) diffusion of
solutes and (II) ultrafiltration of fluid across a semi-permeable
membrane, On one side of the semi-permeable membrane blood flows by
and the dialysate flows by the opposite side. Small and medium-size
solutes (typically up to 25 kDa) and fluid pass through the
membrane. The counter-current flow of blood and dialysate maximizes
the concentration gradient of solutes between the blood and
dialysate, which helps to remove more urea and creatinine from the
blood. The concentrations of solutes (for example potassium,
phosphorus, and urea) are undesirably high in the blood, but low or
absent in the dialysis solution and constant replacement of the
dialysate ensures that the concentration of undesired solutes is
kept low on this side of the membrane. The dialysis solution has
levels of minerals similar to their natural concentration in
healthy blood. For another solute, bicarbonate, dialysis solution
level is regularly set at a slightly higher level than in normal
blood, to encourage diffusion of bicarbonate into the blood, to act
as a pH buffer to neutralize the metabolic acidosis that is often
experienced in these patients. The levels of the dialysate
components are typically prescribed by a nephrologist according to
the needs of the individual patient.
[0018] In hemodialysis, the patient's blood is pumped through the
blood compartment of a dialyzer exposing it through a semipermeable
membrane to the compartment of the dialysis solution and Diffusion
of solutes Is possible. The cleansed blood is then returned via the
circuit back to the body. Ultrafiltration occurs by increasing the
hydrostatic pressure across the dialyzer membrane. This is usually
done by applying a negative pressure to the dialysate compartment
of the dialyzer. This pressure gradient causes water and dissolved
solutes to move from blood to dialysate and allows the removal of
several litres of excess fluid during a typical three to five hour
treatment.
[0019] In peritoneal dialysis a sterile solution containing
minerals and glucose is run through a tube into the peritoneal
cavity, the abdominal body cavity encasing the intestines, where
the peritoneal membrane acts as a semipermeable membrane. The
dialysate is left there for a period of time to absorb waste
products and then it is drained out through the tube and discarded.
This cycle or "exchange" is normally repeated four to five times a
day (CAPD: Continuous Ambulatory Peritoneal Dialysis), and
sometimes overnight with an automated system (APD: Automated
Peritoneal Dialysis). Ultrafiltration occurs via osmosis; the
dialysis solution used contains a high concentration of glucose,
and the resulting osmotic pressure causes fluid to move from the
blood into the dialysate. The amount of ultrafiltration is directly
dependent from the level of concentration of glucose or other
osmotic active substances such as poly-sugars (eicodextrin) or
amino acids. As a result, more fluid is drained than was
instilled.
[0020] Hemofiltration is a treatment similar to hemodialysis, but
it makes use of a different principle.
[0021] The blood is pumped through a dialyzer or "hemofilter" as in
dialysis, but no dialysate is used. A pressure gradient is applied;
as a result water moves across the very permeable membrane rapidly,
"dragging" along with it many dissolved substances, importantly
ones with large molecular weights, which are cleared less well by
hemodialysis. Salts and water lost from the blood during this
process are replaced with a "substitution fluid" that is infused
into the extracorporeal circuit during the treatment.
Hemodiafiltration is a term used to describe several methods of
combining hemodialysis and hemofiltration in one process.
[0022] Due to the loss of excretory function the blood volume and
the metabolic toxic load that accumulates between dialysis
treatments regularly reaches an unhealthy range leading to an
increased number of disorders directly related to renal failure and
dialysis treatment, e.g. hypotension, hypertension, muscle cramps,
fatigue, nausea, vomiting. Furthermore, the high mechanical
(shearing forces) and immunological stress (bioincompatibility of
contact surfaces) regularly imposed on the blood and the blood
cells in the dialyzer leads to further and often chronic disorders,
e.g. hemolysis, amyloidosis, probably malnutrition and
cardiovascular morbidity and mortality. Loss of physiologically
functioning blood cells, e.g. erythrocytes and immune cells due to
mechanical and chemical stress during dialysis treatment is a major
problem for patients undergoing regular long-term dialysis
treatment.
[0023] The choice of materials for the dialyzer and an accompanying
anticoagulant treatment, including the choice of optimally composed
biocompatible dialysis fluids is often an important factor
influencing patient mortality.
Cell and Organ Protection by Creatine
Modes of Action and Plelotropic Functions of Creatine Compounds for
Cell and Organ Protection
Anti-Catabolic Effects of Creatine
[0024] It has been found out that creatine generally enhances
muscle cell proliferation and muscle cell differentiation. For
example, creatine has been shown to enhance the release of growth
hormone (GH), insulin-like growth factors (IGF-I and IGF-1), as
well as insulin itself. In addition, creatine promotes the
expression of myogenic transcription factors and positively affects
muscle cell signaling via the Akt/PKB signaling pathway. Finally,
creatine promotes the recruitment and division of muscle satellite
cells that are important for muscle build-up and repair. Since
endogenous synthesis of creatine uses a significant proportion of
the cells activated methionine in the form of S-adenosyl-methionine
(SAM), external creatine supplementation spares labile methyl
groups in the form of SAMS which then is available for protein
synthesis, cell and tissue anabolism.
[0025] All these effects contribute to the anti-catabolic effects
of creatine and lead to an improvement and/or maintenance of muscle
cells and lean body mass, as well as muscle strength and better
coordination of movement. This holds especially true in situations
of muscle-disuse by which muscle atrophy is induced. Immobilization
and muscle cell loss is indeed a general problem in dialysis
patients. creatine has been shown to prevent such
immobilization-induced muscle cell atrophy and to improve and
speed-up rehabilitation.
[0026] Therefore, by preventing catabolic events and loss of cells,
creatine supplementation also helps dialysis patients to be able to
maintain their muscle cell mass and to keep their physiological
functions, which positively affects life quality and mobility,
resulting in more independence and security for the patient. By
doing so creatine supplementation with creatine compounds delays
entrance into the disability zone, thus extending a plethora of
positive life-quality parameters for such dialysis patients.
Improvement of Cellular Energy Status of Cells and Organs.
[0027] As a consequence of creatine supplementation, cells take up
creatine that is subsequently phosphorylated by intra-cellular
creatine kinase to give high-energy-rich Phospho-Creatine (PCr). By
elevation of intra-cellular Phospho-Creatine levels, creatine
supplementation improves the cellular energy status, i.e. by
increasing the PCr/ATP energy-charge ratio and intracellular energy
trafficking via the PCr/Cr shuttle (Wallimann at al. 2007).
Creatine stimulates mitochondrial respiration and thus Improves
energy production in mitochondria.
[0028] Creatine also activates the AMP-stimulated protein kinase
(AMPK) a general energy sensor and cell stress kinase that improves
energy provision via enhancing glucose uptake and oxidation in
cells. Such energy charging of cells by Creatine compounds leads to
higher metabolic activity of cells and improved cell function.
Prevention of Mitochondrial Permeability Pore Opening, Membrane
Damage and Cell Death (Apoptosis)
[0029] Creatine prevents mitochondrial swelling and induction of
programmed cell death (apoptosis), thus rendering cells more
resistant to metabolic and environmental stress.
[0030] Creatine and even more so, Phospho-Creatine, as amphiphiles,
are able by interaction with lipid bilayers to stabilize membranes
and cells against mechanical and osmotic stress. Since these cells
are able to take up external Creatine and express creatine kinase,
some of the supplemented Creatine taken up is then converted into
Phospho-Creatine, which can invoke membrane stabilization and
protection from the intra-cellular side of the cell. These latter
facts are especially relevant for protection by Creatine,
Phospho-Creatine or other Creatine compounds of erythrocytes and of
white blood cells during the dialysis process, when both metabolic
and mechanical stress is imposed on these very cells during the
dialysis process.
[0031] Thus supplementation of dialysis fluid by a Creatine
compound leads to significant cell protection and thus to a health
benefit for dialysis patients.
Direct and Indirect Anti-Oxidant Effects of Creatine, Reduction of
Advanced Glycosylation End Products (AGE) and Anti-Aging of Cells
and Organs
[0032] Creatine has been shown to act either directly or indirectly
as an anti-oxidant to cells in vitro and in vivo and thus exert
protective effects on cells and tissues against oxidative stress
and lipid peroxidation, including lowering of TBARS
(thiobarbituric-acid reaction products); 2008).
[0033] Thus, Creatine generally protects cells in the body from
numerous stress factors. This protection is especially relevant
again for dialysis patients whose erythrocytes and white blood
cells are mechanically and oxidatively stressed during the process
of dialysis.
[0034] Therefore, Creatine compounds reduce anemia and weakening of
the immune response that are commonly observed in dialysis
patients. Creatine enhances the levels of camosin and anserin in
muscle, compounds that are involved in reducing Advanced Protein
Glycation (AGE) that is inflicted in faster cell aging. Thus,
supplementation by Creatine compounds leads to cell protection and
acts as anti-aging intervention also for dialysis patients.
Reduction of Homocysteine Levels by Creatine Supplementation
[0035] Creatine supplementation has been shown to reduce serum
levels of homocysteine, in an animal model, a significant
cardiovascular risk factor that is also generally elevated in
haemodialysis patients. Another study showed a reduction of
homocystein levels upon creatine supplementation in humans with
approximately 5 g Cr/day. With a lower daily dosage of 2 g/day, in
additionally vitamin B supplemented subjects, no such effects were
seen. It Is likely, however, that dialysis patients take profit
from supplementation of a Creatine compound at a dosage of 5 g or
more per day, with or without additional supplementation by Vitamin
B complex, by reducing homocysteine concentration in their blood
and thus lower the risk of cardiovascular and endothelial damage,
which is a serious problem in dialysis patients.
Addition of Osmotically Active Creatine Makes Possible to Reduce
Glucose Concentration in Peritoneal Fluid.
[0036] Creatine is an osmotically active substance and thus the
glucose concentration needed to obtain the osmolarity needed for
peritoneal dialysis fluids can be reduced significantly, thus
alleviating the bio-incompatibility of chronic high-glucose
exposure of the peritoneum that eventually may lead to fibrosis of
the peritoneum and Diabetes II with all its negative consequences
for health.
Other Actions of Creatine on Cells and Organs.
[0037] It is obvious to the educated reader that Creatine acts as a
pleiotropic nutritional supplement.
[0038] Therefore, it is likely that there are many more positive
effects of Creatine on cells and tissues that have not been
described yet and that are still waiting to be discovered. It is
thus self-understood that dialysis patients would eventually profit
from those effects, as well.
[0039] For a detailed review on creatine and its physiological
impact on healthy and diseased humans see the article of Theo
Wallimann, "Kreatin--warum, wann and fur wen?", Schweizer
Zeitschrift fur Emahrungsmedizin, 5/08, p. 29-40, 2008, which is
incorporated herewith by reference.
Cell Protection by Creatine Compounds Relevant for Dialysis
Patients
Protection of Residual Kidney Cell Function by Creatine
Compounds
[0040] Haemodialysis patients often still show some residual renal
function and in this case creatine, due to its cell protective and
anti-apoptotic effects, can protect renal cells and stop or delay
further degeneration and cell death in the kidney.
Protection of Blood Cells: Erythrocytes and Immune Cells by
Creatine Compounds
[0041] During the dialysis process, blood cells are subjected to
metabolic, mechanical, osmotic and oxidative and other stresses,
which can lead to loss of cell function and cell death. Thus, in
dialysis patients, creatine will energetically charge blood cells,
protect the cell against metabolic and oxidative stress and protect
its membranes against mechanical stress, thus counteracting the
loss of red blood cells, and together with erythropoietin (EPO) act
synergistically to prevent anemia, a problem commonly encountered
in haemodialysis patients. Since EPO, however, is known to cause
serious side effects, by the addition of Creatine, which protects
erythrocytes from haemolysis, less EPO is needed for treating
haemodialysis patients and thus the probability of EPO-related side
effects is lowered in haemodialysis patients by Creatine
supplementation.
[0042] In addition, white blood cells, that is, cells of the Immune
system will also be protected by creatine and Phospho-Creatine from
energy loss due to creatine depletion and by stabilizing cell
membranes will protect these cells against mechanical stress. Thus,
Creatine will maintain proper cell function and strengthen the
patient's immune system, which is of paramount importance also for
haemodialysis patients.
Protection of Muscle and Muscle Cells by Creatine Compounds
[0043] Due to its anti-catabolic effects (by increased of secretion
of growth hormone and muscle differentiation factors),
supplementation by Creatine compounds improves muscle cell mass,
muscle cell function, proliferation and differentiation and finally
overall muscle cell performance (force generation), parameters that
are all highly relevant quality of life parameters for
haemodialysis patients, who generally loose body weight, muscle
mass and muscle force.
Protection and Maintenance by Creatine Compounds of Brain and Brain
Cells From Uremic Toxins
[0044] The neuro-protective effects of Creatine compounds are well
documented (for review see Andres et al. 2008) and it is obvious
that dialysis patients are also taking advantage from brain and
nerve cell protection by creatine, resulting in lower fatigue
levels, improved memory and learning function and general
well-being.
[0045] In addition, uremic toxins are known to negatively influence
brain function and morphology, and Creatine compounds are
neuro-protective to a significant extent towards these toxins, some
of them have been demonstrated to affect Creatine synthesis und
Creatine transport in the brain, Creatine supplementation is
exerting its neuroprotective effect towards such toxins and thus
also improving brain function and life quality of dialysis
patients.
Protection and Maintenance of Bone Cells by Creatine Compounds
[0046] Creatine enhances bone cell proliferation, differentiation
and mineralization thus counteracting osteoporosis, osteomalacia
and adynamic bone disease, problems often encountered in dialysis
patients.
Anti-Aging Effects by Creatine Compounds on Cells and Organs
[0047] Supplementation by creatine compounds leads to protection of
body cells and tissues, against oxidative stress, lipid
peroxidation, advanced glycation end products (AGE's). These
protective mechanisms of Creatine are true also and important for
dialysis patients as well.
Creatine an Essential Supplement for Dialysis Patients
[0048] Dialysis Patients are generally catabolic and
energy-depleted, as well as creatine-depleted in their skeletal
muscles and in heart and other tissues and cells. The latter is due
to a reduced endogenous synthesis in the kidney of guanidino
acetate, the precursor of Creatine, as well as lower alimentary
intake of Creatine by Dialysis patients compared to healthy
meat-eaters.
[0049] Creatine in this case turns out to be an essential nutrient
for dialysis patients and externally added Creatine is absolutely
necessary for normal physiological body and organ function in these
patients.
[0050] Instead of forcing dialysis patients to consume 5-20 grams
of Creatine powder daily by oral intake, Creatine is added directly
to dialysis fluid from where it is taken up (unnoticed by the
patient) into the blood and from there via the Creatine-Transporter
into the target organs, such as muscle, brain and nervous tissue
etc. By adding Creatine to the dialysis fluid only so much Creatine
is taken up by the cells as is necessary to fill up the cellular
Creatine pools and the rest of the Creatine remains In the dialysis
fluid. The advantage of such treatment is that these patients are
not burdened by an over-load of Creatine, which may be the case, if
Creatine would be taken orally. Under the latter circumstances,
excess of orally taken Creatine has to be eliminated and may
represent a burden for the patients organism. If, however, Creatine
is supplemented into the dialysis fluid, each patient, depending on
his Creatine status, is taking up only as much Creatine as is
needed to fill his cellular Creatine pools, and no elimination of
creatine is necessary and no extra burden is inflicted on the
patients system.
Addition of Osmotically Active Creatine Allows for Significant
Reduction of the Glucose Concentration In Peritoneal Dialysis
Fluid
[0051] For peritoneal dialysis, the very high concentration of
glucose or other osmolytes that potentially have negative effects,
e.g. exposure to constantly high glucose concentration present the
peritoneal fluid significantly increases in the dialysis patients
the formation of Advanced Glycation Endproducts (AGE'S), loss of
transport function of the peritoneum and finally enhances the
chances of weight increase and of acquiring Diabetes-II. Since
Creatine is an osmotically active substance, the glucose
concentration in the dialysis fluid can be significantly lowered if
Creatine is added instead, in this case preferentially at the
highest concentration possible, e.g. up to 24-25 g of Creatine per
liter of dialysis fluid at a body temperature of 37.degree. C. By
this invention, deleterious side effects caused by high glucose
exposure of the dialysis patient to this very fluid can be reduced.
As an example Creatine concentrations near the respective
solubility limit at the requested temperatures are added for this
purpose to significantly reduce the glucose concentration but
retain the require osmolarity for peritoneal dialysis. During a
typical peritoneal dialysis set-up, the peritoneal dialysis fluid
of 2-3 liters is replaced 4-5 times, that is, between 8-15 liters
of peritoneal fluid are used per patient and treatment, such that
the patient's peritoneum is exposed to a total of 8.times.25 to
15.times.25 g less of glucose, corresponding to 200 g to 375 g less
glucose than with the regular peritoneal dialysis treatment This
reduction of glucose is highly significant.
[0052] Creatine may also be combined with other osmotically active
compounds such as betaine, amino acids, mono- or poly-sugars of
glucose or other sugar compounds, such that glucose can be even
more reduced.
[0053] This strategy has two advantages in one, first creatine is
used as osmolyte to substitute glucose and second, at the same time
the creatine needed is transported through the peritoneum and taken
up by the target organs of the patient. This combination is novel
and it makes possible that chronic ambulatory peritoneal dialysis
(CAPD) or automated peritoneal dialysis (APD), as a simpler and
cheaper option of dialysis treatment as compared to hemodialyis,
may be used for a much more prolonged period of time for the
treatment of chronic renal failure patients, compared to
conventional treatments.
Routes of Creatine Supplementation for Dialysis Patients
[0054] The routes of creatine delivery vary according to the
specific needs of patients and modalities of the clinical setting.
Creatine may be delivered via an oral, intra-peritoneal,
intra-venous route or by the hemodialysis fluid.
1) For Oral Creatine Supplementation
[0055] The specific range of oral Creatine supplementation for
dialysis patients would similar as used by athletes. The
recommended range of daily Creatine intake would be at a dosage of
1-20 g Creatine per day (as Cr-monohydrate or other Cr-containing
compounds, Cr-salts or Cr-analogs) taken orally in form of a
powder, tablets, and aqueous solution or as a suspension. The
preferred supplementation scheme would allow for 5-20 g of Creatine
or Creatine analogs per day for a loading phase period of 7-14
days, followed by a maintenance phase of 2-5 g of Creatine per day
during an unlimited time frame or as long as needed.
[0056] Oral supplementation may also be combined with
supplementation of creatine via dialysis fluid.
2) For Peritoneal and/or Haemodialysis
a) Addition of Creatine Directly to the Final Dialysis Fluid for
Peritoneal or Hemodialysis
[0057] The novelty of the present invention and its preferred
embodiment consists of the addition of Creatine (Mr 131.13
Daltons), Creatine-Monohydrate, Creatine-containing salts or
Cr-analogs directly to the final dialysis solution. The specific,
therapeutically effective range of Creatine concentrations for this
application is from 0.05 mM/l to 20 mM/l final concentration of
Creatine as Cr-monohydrate or other Cr-containing compounds
Cr-salts or Cr-analogs added in its solid form (powder) to the
final dialysis fluid, immediately before usage, to avoid the
generation of unwanted creatinine during prolonged storage of
Creatine in solution.
[0058] Creatine or Creatine-analogues are preferably to be added in
solid state (as powder) immediately before the final dialysis
solutions are made up. This has the advantage that Creatine, which
is not very stable in solution at room temperature during, longer
periods of time (weeks), Is not converted to unwanted creatinine
that otherwise would be generated by a spontaneous non-enzymatic
chemical reaction during prolonged storage of Creatine in
solution.
b) Addition of Creatine to the Dialysis Fluid Concentrate for
Peritoneal or Hemodialysis
[0059] The novelty of the present invention and its preferred
embodiment consists of the addition of Creatine (Mr 131.13 Daltons)
Creatine-Monohydrate, Creatine-containing salts or Cr-analogs to
the concentrated dialysis stock solution (concentrate). For
peritoneal dialysis this Creatine-containing concentrate is
directly diluted before usage. For haemodialysis, creatine present
in the concentrate would be continuously diluted during the course
of haemodialysis, such that the patient is constantly exposed to an
entirely physiological concentration of Creatine during the entire
dialysis treatment process. This concentration of Creatine (in the
final dialysis liquid) is in the range of 0.05 to 20 mM and thus in
the same range as reached in the serum of subjects supplemented
with a singly portion of 5-20 g of Creatine. The Creatine
concentration proposed herein together with Creatine uptake during
a 3-4 hr dialysis is sufficient to provide those cell protection
effects and health benefits for the patient that are claimed
here.
[0060] Creatine or Creatine-analogues are preferably added in solid
state (as powder) immediately before the dialysis concentrate
solutions are made up. This has the advantage that Creatine, which
is not very stable in solution at room temperature during longer
periods of time (weeks), is not converted to unwanted creatinine
that otherwise would be generated by a spontaneous non-enzymatic
chemical reaction during prolonged storage of creatine in
solution.
3) For Peritoneal Dialysis: Creatine Compounds as Osmolytes for
Peritoneal Dialysis
[0061] The Novelty of the Present Invention is that for Peritoneal
Dialysis Fluid, High Concentrations of Osmotically Active Creatine
or Creatine Compounds are Added to Substitute or Replace Glucose or
Other Osmolytes Necessary for Peritoneal Dialysis.
[0062] By addition of high concentrations of osmotically active
creatine in a peritoneal dialysis setting, 24-25 g of creatine,
creatine salts, or creatine analogues per liter are added
immediately to the final peritoneal dialysis solution at a
temperature 37.degree. C. These concentrations are near the
saturation limit of creatine the solubility of which is highly
sensitive to temperature. By this way, a maximum of osmotically
active creatine compound can be dissolved and thus the glucose
content in the peritoneal dialysis fluid can be reduced
accordingly. In this set-up creatine compounds primarily act as
osmolyte and only secondarily are taken up in a very small
proportion of the total creatine compound added.
[0063] Such a strategy, by significantly reducing glucose in the
dialysis fluid, allows in the long-term to alleviate the
potentially deleterious side effects of chronic exposure of the
peritoneum and the dialysis patient to a high glucose load, e.g.
fibrosis of the peritoneum and loss of function of peritoneal
membranes and induction of diabetes in the patients.
[0064] For peritoneal dialysis, a high concentration of creatine is
proposed herein, e.g. 24-25 g of creatine compound per liter of
dialysis fluid 37.degree. C. (up to approximately 190 mM/l) where
creatine acts in the first place as an osmolyte to replace or
reduce the high-glucose concentration. The crucial difference of
peritoneal dialysis versus hemodialysis is that in the first case,
the dialysis fluid is not in direct contact with the patients blood
system, since the peritoneal dialysis fluid is separated from the
patients blood system by the peritoneum representing a biologically
active fitter equipped with transport systems and ion pumps.
[0065] Whereas in hemodialysis the dialysis fluid is only separated
by a metabolically inert and passive diffusion membrane. Therefore,
for peritoneal dialysis, in contrast to hemodialysis where this
should be avoided, creatine compounds can be added to the
peritoneal dialysis liquid at high concentrations near saturation
at body temperature. The uptake of creatine compound by the
peritoneum then is a secondary but entirely wanted effect, as
creatine transport through the peritoneum is not passive by simple
diffusion, as in hemodialysis, but actively mediated via a specific
sodium chloride-dependent creatine transporter (CRT). Thus only a
very small fraction of the actual creatine compound, to which the
peritoneum is exposed to, is taken up via CRT.
[0066] Most importantly this CRT-mediated uptake is governed by the
actual physiological needs and requirements of the patients body
for creatine and thus no overloading by creatine compounds is
possible by peritoneal dialysis, even though an excess of creatine
may be offered in the fluid. This novel strategy to be able to
reduce, by addition of high concentrations of creatine compounds,
the exposure of the patients to very high glucose levels and at the
same time allow for physiological uptake of creatine compound
avoids the numerous unwanted potential side-effects eluded to
below.
[0067] Chang at al., Nephrol. Dial. Transplant, 17: 1978-1981
(2002) teaches that creatine monohydrate treatment alleviates
hemodialysis-associated muscle cramps (HAMC), which are assumed to
be the result of disturbances in the muscle energy metabolism,
intradialytic hypotension, excessive ultrafiltration and/or
elevation of serum creatine kinase. For this purpose ten patients
with frequent muscle cramps during hemodialysis were selected, five
for the creatine supplementation group and five for the placebo
group. To the creatine receiving group 12 g creatine monohydrate in
100 ml water were administered orally 5 minutes before starting
hemodialysis. The authors claim that there was a 60% decrease in
muscle cramps in the creatine receiving group and that serum
creatinin increased from 10.7 to 12.4 mg/dl in the four week
treatment period.
[0068] Next to the limited number of patients in each group (five
each) it should be recognized that 12 g of creatine monohydrate are
not easily solubilized at once and ingested creatine that has to be
taken up by intestinal epithelial cells will take about two to four
hours to reach maximal levels in the blood stream. Hence, the
timing of the administration of creatine five minutes before
starting dialysis is irrelevant for its alleged effect. The authors
themselves admit that further long term, large-scale studies are
mandatory to confirm the effects and safety of creatine monohydrate
supplementation in HAMC because of the small number of patients and
brief follow-up period.
[0069] US patent application 2003/0013767 A1 teaches a method of
using a creatine compound to specifically treat weight loss
associated with liver and kidney diseases and in this respect
discloses a dialysis fluid for hemodialysis containing 1.5 g
creatin/100 ml corresponding to a concentration of 114.4 mM/l. The
disadvantage of such high concentrations of creatine for
hemodialysis, however, are:
1) During hemodialysis, creatine may precipitate or crystallize in
different parts of the hemodialysis machine. 2) Such high
concentrations of creatine during hemodialysis are neither
necessary nor desired because they are far from physiological and
in fact are two orders of magnitudes higher than the concentrations
of those serum creatine concentration that are reached
post-prandial after a meal rich in fish or meat or after direct
oral creatine supplementation with 5-20 g of chemically pure
creatine. 3) A chronic overload with creatine is bound to
down-regulate endogenous creatine bio-synthesis in the body
(Guerrero and Wallimann 1998), whereas moderate creatine
supplementation, even if given long-term as proposed herein, is
not. 4) A chronic overload of a dialysis patient with creatine is a
burden for the liver if its creatine storage is exhausted by excess
creatine supply 5) A chronic overload with creatine leads to
ATP-depletion, for cellular ATP will be used for phosphorylation of
creatine taken up into the target organs to produce
phospho-creatine (PCr) 6) Creatine overload has been shown to
influence cell signaling, e.g. to activate the low-energy-sensor
and cellular stress-responding AMP-activated protein kinase (AMPK),
with potentially unknown side-effects, and 7) High oral dosage of
creatine have been shown to influence inflammatory markers and
hormone responses that may not be desired for dialysis patients
[0070] In view of the above it is the objective of the present
invention to provide new means for alleviating or avoiding
disorders and/or side effects directly or indirectly attributed to
hemodialysis treatment. Furthermore, it is the objective to provide
new medical indications and new medical compositions for creatine
supplementation.
[0071] The present invention is predicated, at least in part, by
the surprising and unexpected discovery that creatine
supplementation at very low concentrations to a hemodialysis
solution can alleviate or avoid disorders and/or side effects
directly or indirectly attributed to hemodialysis treatment, in
particular mechanical, oxidative, pro-apoptotic, metabolic and
immunological stress of the blood cells being dialyzed.
[0072] In view of this discovery and in a first aspect the present
invention provides a new (haemo)dialysis solution comprising one or
more creatine compound(s) in a concentration equivalent of 0.002 to
45 mM/l creatine, preferably of 0.05 to 40 mM/l ans most preferably
of 0.05 to 20 mM/l creatine.
[0073] The term "concentration equivalent to 0.05 to 20 mM/l
creatine" refers to a total concentration of 0.05 to 20 mM/l for
all creatine compound(s) in the dialysis solution.
[0074] The term dialysis solution as used herein is any solution
suitable for the safe treatment of renal failure by dialysis
including hemodialysis, peritoneal dialysis, hemofiltration and
hemodiafiltration. It is the solution into which the blood solutes
of small and moderate size (typically 15 to 50, preferably 20 to
35, more preferably about 25 kDa) diffuse during dialysis.
[0075] It typically comprises mineral salts and buffer substance(s)
In physiologically acceptable concentrations. Additionally, it may
comprise nutrients, e.g. glucose and amino acids, anticoagulants
such as heparin, antioxidants and other physiologically or
medically relevant compounds. Naturally, its pH and osmolality is
physiologically acceptable.
[0076] The creatine compound in the dialysis solution may be any
physiologically acceptable creatine and/or phosphocreatine
((phospho)creatine) compound, derivative, analog and/or precursor
thereof that will eventually raise the creatine and phosphocreatine
level to normal physiologically healthy concentrations In the blood
of the dialysis patient.
[0077] For example, suitable creatine compounds and derivatives are
(phospho)creatine, (phospho)cyclocreatine, homocyclocreatine,
(phospho)creatine monohydrate, (phospho)creatine salts such as
creatine -pyruvate, -lactate, -ascorbate, -acetate, -citrate,
-hydroxycitrate, -aleurate, -phytate, -mandelate, -malate,
-glycolate, -cinnamate, -salicylate, -hyluronate,
-.beta.-hydroxybutyrate, -gluconate, -choline, -carnitine,
-propionyl carnitine, -coenzyme Q10, -adenosine, -fructose,
-fructose-1,6-biphosphate, etc. Other examples are the ester of
creatine-adenosine, the acid anhydride of creatine-glutamine and
the acid anhydride of creatine pyruvate. Preferred creatine
ascorbyl derivatives for practicing the present invention are those
specifically mentioned in WO 2008/137137 A1 in claims 1 to 11,
which are hereby incorporated in their entirety by reference.
Further preferred creatine derivatives are those specifically
mentioned in WO 2007/133731 A2 in claims 1 to 11, which are hereby
incorporated in their entirety by reference, more preferably
creatine-ligand compounds, wherein the ligand is selected from the
group consisting of an aminoacid, a water-soluble vitamin,
preferably vitamin C or a vitamin B complex vitamin, preferably,
selected from the group consisting of thiamine, riboflavin,
pyridoxine, niacin, vitamin B12, folic acid, pantothenic acid,
biotin, resveratrol, omega-fatty acids, poly-unsaturated fatty
acids, linoleic acid, S-adenosine-methionine (SAM), L-carnitine,
and betaine.
[0078] Preferred creatine precursors are guanidinoacetic acid,
3-guanidinopropionic acid, guanidino benzoic acid and the
combination of the three basic building blocks of creatine glycine,
arginine and methionine as well as their physiologically acceptable
salts and derivatives. For precursors, it is noted that one or more
precursors may be necessary to form one creatine compound. Hence,
for precursors the term "in a concentration equivalent to 0.05 to
20 mM/l creatine" should be interpreted as the amount of precursors
necessary for providing to 0.05 to 20 mM/l creatine.
[0079] Creatine analogs are compounds lacking creatine structure
but mimicking its biological activity in vivo. Preferred creatine
analogs are those specifically mentioned in EP 1 719 510 A1 in
claim 2 and in claim 7 of US 2009/0005450 A1, which are hereby
incorporated in their entirety by reference.
[0080] Typically, healthy humans have a fasting concentration of
creatine compounds in the serum of about 20 to 40 .mu.M/l. Upon
consumption of creatine-containing food, like fish and meat, this
concentration transiently increases to 1 to 2 mM/l. Erythrocytes
(red blood cells) and immune cells in the blood are able to
accumulate creatine inside the cell via the creatine-transporter
(CRT) and due to the presence of creatine kinase (CK) in these
cells, some of the creatine is converted to phospho-creatine, such
that these cells contain approximately 2/3 of phospho-creatine and
1/3 of creatine. The concentration of total creatine
(phospho-creatine plus creatine) in erythrocytes is approximately
0.5 to 1 mM/l, depending on the cell age, and in white blood cells
approximately 0.75 to 1.25 mM/l.
[0081] Whereas creatine concentrations as high as feasible
(solubility limitation) are good for muscle mass maintenance, as
taught in the prior art, the concentration of creatine compound(s)
of the hemodialysis solution of the invention may be much lower
than the (phospho)creatine concentration in the blood of a healthy
human and stilt be physiologically highly effective in protecting
dialysed blood cells. This effect is due to the active uptake of
creatine and most creatine compound(s) by blood cells. As mentioned
before, under physiological conditions blood cells comprise
(phospho)creatine in a concentration about 10-50 times higher than
the concentration In the surrounding serum. Hence, creatine
compounds in the dialysis solution of the present invention will be
actively taken up by cells and thus accumulate in blood cells
providing the desired cell protective and anti-apoptotic
effects.
[0082] Therefore, in a preferred embodiment, the dialysis solution
of the invention comprises one or more creatine compound(s) in a
concentration equivalent to 0.05 to 20 mM/l creatine, 0.05 to 15
mM/l, 0.05 to 10 mM/l, preferably 0.1 to 10 mM/l, most preferably
0.1 to 5 mM/l, also preferably 0.1 to 2.0 or 0.1 to 1.0 mM/l
creatine. Additionally, it is noted that the concentration range of
creatine compounds in the dialysis solution of the present
invention may have a lower value selected from 0.001, 0.002, 0.003,
0.004, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.15, 0.2, 0.25,
0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85,
0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 mM/l and an upper
value selected from 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mM/l. All of the above
lower and upper values may be combined to ranges for concentrations
for creatine compounds suitable for a dialysis solution of the
invention and all of the options resulting therefrom are considered
as being specifically listed and fully disclosed.
[0083] Depending on the type and mode of dialysis, the extent of
renal dysfunction and other physiologically parameters, a patient
typically receives a volume of a dialysis solution in the range of
5 to 200 liters, regularly about 100 to 600 liters per treatment
session, typically 120 to 170 I within a time period of about 3 to
8 hours. Depending on treatment duration and bloodflow (100 to 400
ml/min) 18 to 192 liters blood is regularly presented to the
dialysis solution.
[0084] The skilled person is fully enabled and aware of how to
prepare, adjust, sterilize, store and utilize common dialysis
solutions. The principles of hemodialysis and the basic
requirements for preparing dialysis solutions have been known since
the late 1940s. For a more detailed discussion of hemodialysis and
hemofiltration reference is again made to Kuhlmann, Walb, Luft,
Nephrologie, 4.sup.th ed., chapter 15, 516, 2003 et seq. and to the
sales brochure "Hamodialyse; Konzentrate und Losungen fur die
Dialyse", Lieferprogramm, Fresenius Medical Care, 2008, both of
which are hereby incorporated by reference.
[0085] A common dialysis solution typically comprises the mineral
ions Na--, K--, Ca--, Mg--, Cl-- and at least one buffering
substance adjusting and buffering the pH to a physiologically
acceptable value, most commonly in the range of 7 to 7.8,
preferably to 7.1 to 7.5, more preferably to 7.2 to 7.4.
[0086] Because dialysis reduces the carbohydrate-based energy
content of the dialyzed blood and thereby depletes the patient of
energy, most dialysis solutions comprise glucose and/or some other
carbohydrate source of energy. However, in the case of the dialysis
solution of the present invention, the creatine compound(s), in
particular the phosphorcreatine compound(s) can supplement for the
lost energy. On the other hand, it is probably still beneficial to
have some carbohydrate energy source in the dialysis solution of
the present invention in order not to unbalance the glycolysis
hemostasis in the cells. Moreover, creatine compounds have been
shown to elicit pharmaceutically beneficial effects when given In
combination with dextrose (glucose) (see e.g. WO 2007/133673 A2).
Last but not least, carbohydrate energy sources like glucose In the
dialysis solution of the present invention have the advantage that
they enable blood cells to energize, i.e. phosphorylate the
creatine compounds.
[0087] In a preferred embodiment the dialysis solution of the
Invention further comprises: [0088] (i) Na--, K--, Ca--, Mg--,
Cl-ions, [0089] (ii) at least one physiologically acceptable
buffering substance, preferably selected from bicarbonate, lactate
and/or acetate, and [0090] (iii) optionally but preferably a
carbohydrate source, more preferably glucose, all of (i) to (iii)
in physiologically acceptable concentrations.
[0091] In an additional preferred embodiment the dialysis solution
of the present invention may also comprise any physiologically
acceptable additive in physiologically acceptable concentrations,
preferably additives selected from the group consisting of
water-soluble vitamins, trace elements, nutrients, preferably amino
acids.
[0092] As mentioned above creatine compounds suitable for use in
this invention are any physiologically acceptable creatine and/or
phosphocreatine compounds, derivatives, analogs and/or precursors
that will eventually raise the creatine and phosphorcreatine level
to normal physiologically healthy concentrations in the blood and
body of the dialysis patient.
[0093] In a preferred embodiment the creatine compound(s) of the
dialysis solution of the present invention is(are) selected from
the group consisting of:
(i) (phospho)creatine compounds, preferably (phospho)creatine,
(phospho)creatine monohydrate, (phospho)cyclocreatine,
homocyclocreatine, (ii) (phospho)creatine derivatives, preferably
(phospho)creatine salts, more preferably creatine -pyruvate,
-lactate, -ascorbate, -acetate, -citrate, -hydroxycitrate,
-aleurate, -phytate, -mandelate, -malate, -glycolate, -cinnamate,
-salicylate, -hyaluronate, -.beta.-hydroxybutyrate, -gluconate,
-choline, -carnitine, -propionylcarnitine, -coenzyme Q10,
-adenosine, -fructose, -fructose-1,6-biphosphate, esters of
creatine-adenosine, acid anhydrides of creatine-glutamine and
creatine pyruvate, (iii) creatine precursors , preferably
guanidinoacetic acid, 3-guanidinopropionic acid, guanidino benzoic
acid and the combination of glycine, arginine and methionine as
well as their physiologically acceptable salts and derivatives, and
(iv) creatine analogs, preferably those disclosed above by specific
reference.
[0094] In a more preferred embodiment, the creatine compound(s) of
the dialysis solution of the present invention is(are) selected
from the group consisting of (phospho)creatine compounds,
preferably (phospho)creatine, (phospho)creatine monohydrate, and
(phospho)creatine salts, preferably pyruvate, lactate, ascorbate,
acetate, citrate and hydroxycitrate.
[0095] Most of the creatine compounds will contribute to the
osmolality of the dialysis solution of the invention. It goes
without saying that the osmolality of the dialysis solution of the
Invention must be adjusted to meet physiologically acceptable
limits. Because the concentration of the creatine compounds in the
dialysis solution of the present invention is very low, much lower
than recommended for anti-catabolic effects, these creatine
concentrations will not cause any osmolaitity problems.
[0096] In a specific non-limiting and preferred embodiment, the
dialysis solution of the present invention, essentially consists
of:
a) 0.05 to 20, preferably 0.1 to 10, more preferably 0.5 to 10,
most preferably 0.1 to 5 mmol/l creatine compound(s), b) 130 to
150, preferably 135 to 145, more preferably about 138 mmol/l Na
ions, c) 0 to 10, preferably 1 to 6, more preferably 1 to 4 mmol/K
ions, d) 0,5 to 3, preferably 1 to 2, more preferably 1 to 1.25
mmol/Ca ions, e) 0 to 10, preferably 1 to 6, more preferably 1 to 4
mmol/Mg ions, f) 0 to 10, preferably 1 to 6, more preferably 1 to 4
mmol/Cl ions, and preferably comprising g) 0.2 to 3 g/l, preferably
0.5 to 2.5 g, more preferably 1 to 2 g/l glucose, as well as h) 25
to 40, preferably 28 to 35, more preferably about 32 mmol/l
bicarbonate ions, and i) 1 to 5, preferably 2 to 4, more preferably
2 to 3 mmol/l acetate ions, as physiologically acceptable buffer
substances, and j) optionally further physiologically acceptable
compounds in physiologally acceptable concentrations wherein the
theoretical osmolality of the dialysis solution is 270 to 310,
preferably 280 to 305, more preferably 285 to 300, most preferably
287 to 298 and the pH is in the range of 7.1 to 7.5, preferably 7.2
to 7.4.
[0097] Because large amounts of dialysis solutions are typically
required for hospital dialyzers, it is common in the art to produce
dry and aqueous concentrates for preparing dialysis solutions that
are manually or automatically diluted, admixed (multiple component
systems), sterilized and warmed to body temperature. in the case of
less soluble components, in particular minerals such as magnesium
and calcium, the about pH-neutral ready-to-use dialysis solutions
are often produced and stored as acidic and/or basic solutions
and/or concentrates.
[0098] In particular bicarbonate-buffered dialysis solutions tend
to precipitate carbonates at neutral to basic pH if stored over
prolonged times. Therefore, the bicarbonate component is typically
added to the dialysis solution of the dialyser only shortly before
the administration of the dialysis solution to the patient.
Standard commercial concentrates for dialysis solutions are
multiple (mostly two) part systems, usually comprising (i) a dry Or
aqueous bicarbonate concentrate in a container such as a bag or
cartridge and (ii) a dry or aqueous mineral concentrate in a
container such as a canister optionally comprising further
non-mineral components such as glucose.
[0099] The term "dialysis solution" as used herein is meant to
indicate any ready-to-use dialysis solution or component of a
dialysis solution that does not require further dilution before
administering it to a patient in need thereof. The term "dialysis
concentrate" as used herein is meant to indicate any dry or aqueous
dialysis solution component that requires at least aqueous dilution
and optionally addition of further components before becoming a
ready-to-use dialysis solution suitable for administering to a
patient in need thereof. According to the present invention the
creatine compound(s) can be present in (i) a ready-to-use dialysis
solution, but also in (ii) a dry or aqueous concentrate as a one
component dialysis system or (iii) a dry or aqueous concentrate
being part of a multi-component dialysis system for preparing a
ready-to-use dialysis solution.
[0100] In another aspect the present invention is directed to a dry
or aqueous dialysis concentrate comprising (i) at least one
creatine compound and (ii) physiologically acceptable ions and/or
at least one buffering substance(s), wherein said concentrate
results in a dialysis solution according to the invention upon
aqueous dilution and optionally addition of further substances.
[0101] (Phospho)creatine and many of the creatine compounds for use
in the present invention have a tendency to form creatinine at an
acidic pH and higher temperatures by a spontaneous non-enzymatic
reaction. Hence, it is of advantage to avoid creatinine formation
by keeping creatine compounds in dialysis solutions and dry or
aqueous concentrates of the invention at low temperatures and a
neutral to basic pH. If kept as aqueous solution, it is preferably
cooled to 2 to 5.degree. C., because the chemical stability of
creatine is enhanced and storage life of the solution is extended
in the cold. However, even under neutral and alkaline conditions,
e.g. pH 7.0 to pH 8.5, dialysis solutions and concentrates of the
invention can comprise creatine compounds without significant
creatinine formation for an acceptable time span that can be
extended by storage in the cold.
[0102] Hence, in a preferred embodiment the present invention also
relates to an acidic dialysis concentrate, comprising [0103] (i)
Na--, K--, Ca--, Mg-- and Cl-ions, [0104] (ii) at least one
creatine compound, [0105] (iii) optionally at least one
physiologically acceptable buffering substance, preferably selected
from bicarbonate, lactate and/or acetate [0106] (iv) glucose,
[0107] in concentrations providing for physiologically acceptable
concentrations and a pH in the range of 7.1 to 7.5 upon dilution
and addition of at least one basic physiologically acceptable
buffering substance, preferably selected from bicarbonate, lactate
and/or acetate.
[0108] For example, acidic dialysis concentrates according to the
invention can be prepared by adding creatine compound(s) in
physiologically acceptable amounts to suitable concentrates.
[0109] The osmolality and pH of the acidic concentrate has to be
adjusted depending on the type and amount of creatine compound(s)
added.
[0110] Because of better stability a more preferred embodiment of
the invention is directed to a basic dialysis concentrate
comprising at least one creatine compound and at least one basic
physiologically acceptable buffering substance, preferably selected
from bicarbonate, lactate and/or acetate, preferably essentially
free of magnesium and calcium. Most preferably, the basic dialysis
concentrate of the invention is a bicarbonate concentrate. Dry
concentrates have the advantage of avoiding the weight as well as
the chemical and biological disadvantages attributed to water, e.g.
instability of some components in aqueous environments, oxidation
and microorganism growth.
[0111] In a most preferred embodiment the present invention relates
to a dry dialysis concentrate of the invention, essentially free of
water, preferably consisting of at least one creatine compound and
at least one basic buffering substance, preferably selected from
the group consisting of bicarbonate, lactate and/or acetate.
[0112] Preferably a dialysis concentrate of the Invention is one
for which water dilution by a factor of 25 to 60, preferably 30 to
50, more preferably 32 to 48, most preferably 35 to 45 by weight Is
required in order to produce a dialysis solution of the invention
as described above.
[0113] In a further aspect the present invention is directed to the
use of at least one creatine compound for preparing a dialysis
solution or a dialysis concentrate of the invention. For said use
creatine compound(s) as mentioned above are suitable, preferably
creatine compound(s) selected from the group consisting of
(phospho)creatine compounds, preferably (phospho)creatine,
(phospho)creatine monohydrate, and (phospho)creatine salts,
preferably pyruvate, lactate, ascorbate, acetate, citrate and
hydroxycitrate.
[0114] In an additional aspect the present invention pertains to a
method for preparing a dialysis solution or a dialysis concentrate
of the invention, comprising the steps of admixing at least one (i)
creatine compound and (Ha) physiologically acceptable ions and/or
(iib) at least one physiologically acceptable buffering
substance.
[0115] Preferably, the invention relates to the above method
resulting in (i) a concentrate useful for preparing a dialysis
solution or (ii) a dialysis solution, said dialysis solution
essentially consisting of:
a) 0.05 to 20, preferably 0.1 to 10, more preferably 0.5 to 10,
most preferably 0.1 to 5 mmol/l creatine compound(s) b) 130 to 150,
preferably 135 to 145, more preferably about 138 mmol/l Na ions, c)
0 to 10, preferably 1 to 6, more preferably 1 to 4 mmol/K ions, d)
0.5 to 3, preferably 1 to 2, more preferably 1 to 1.25 mmol/Ca
ions, e) 0 to 10, preferably 1 to 6, more preferably 1 to 4 mmol/Mg
ions, f) 0 to 10, preferably 1 to 6, more preferably 1 to 4 mmol/Cl
ions, and preferably comprising g) 0.2 to 3 g/l, preferably 0.5 to
2.5 g, more preferably 1 to 2 g/l glucose, as well as h) 25 to 40,
preferably 28 to 35, more preferably about 32 mmol/l bicarbonate
ions, and i) 1 to 5, preferably 2 to 4, more preferably 2 to 3
mmol/l acetate ions, as physiologically acceptable buffer
substances, and j) optionally further physiologically acceptable
compounds in physiologically acceptable concentrations, wherein the
theoretical osmolality of the dialysis solution is 270 to 310,
preferably 280 to 305, more preferably 285 to 300, most preferably
287 to 298 and the pH is in the range of 7.1 to 7.5, preferably 7.2
to 7.4.
[0116] In a special embodiment a dialysis solution comprising one
or more creatine compound(s) In a concentration equivalent to 0.002
mM/l to 45 mM/l, preferably to 0.05 mM/l to 40 mM/l at 37.degree.
C. is used for hemodialysis.
[0117] Other embodiments a dialysis solution comprising one or more
creatine compound(s) in a concentration equivalent to 40 mM/l to
200 mM/l at 37.degree. C. is directed to the use for peritoneal
dialysis, wherein the creatine compounds are acting as osmolyte.
Preferably the the concentration is equivalent to 115 mM/l to 200
mM/l at 37.degree. C., most preferably to 120 mM/l to 200 mM/l at
37.degree. C.
[0118] A further embodiment is directed to the use of an
unsaturated dialysis solution comprising one or more creatine
compound(s) for peritoneal dialysis, wherein the creatine compounds
are acting as osmolyte. Said dialysis solution can further comprise
one or more organic osmolytes from the following three classes of
compounds: [0119] A) polyols, preferably inositol, myo-inositol or
sorbitol; [0120] B) methylamines, preferably choline, betaine,
carnitine (L-, D- and DL forms), n-acetyl-carnitine, L-carnitine
derivatives, phosphorylcholine, lyso-phosphorylchotine or
glycerophosphorylcholine; and [0121] C) amino acids.
[0122] A further embodiment is directed to a dialysis solution
comprising one or more creatine compound(s) in a concentration
equivalent to 40 to 200 mM/l creatine and an amount of glucose
inferior to 106 g/l, preferably inferior to 62.6 g/l and most
preferably inferior to 37.5 g/l.
[0123] Last but not least, one more aspect of the present invention
is directed to a method of treatment comprising the step of
administering a dialysis solution according to the invention in a
physiologically effective volume to a patient in need thereof, e.g.
for blood detoxification.
[0124] A further aspect of this invention Is directed to a method
for treating a patient with renal dysfunction, said method
comprising [0125] a) in a first step the oral administration of a
creatine compound; and [0126] b) in a second step the dialysis with
a creatine compound.
[0127] By "treating" is meant the slowing, interrupting, arresting
or stopping of the progression as well as the preventing of the
onset of a disease or condition associated with renal dysfunction
and/or dialysis treatment and treating does not necessarily require
the complete elimination of all disease symptoms and signs.
"Preventing" is intended to include the prophylaxis of a disease or
condition, wherein "prophylaxis" is understood to be any degree of
inhibition of the time of onset or severity of signs or symptoms of
the disease or condition, including, but not limited to, the
complete prevention of the disease or condition.
[0128] This and other objects of the present invention as well as
additional inventive features, will be apparent from the detailed
description provided herein.
[0129] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention pertains.
[0130] Preferred methods and materials are described below,
although methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the
present invention. The following example serves to illustrate
further the present invention and is not Intended to limits its
scope in any way.
EXAMPLE 1
[0131] For a clinical set-up 0.1 to 30 g of creatine (m.w. 131.13
g/mol) can be added to a dialysis concentrate of about 4.7 liters
(that is normally used for one dialysis treatment per patient per
day in a dialysis machine) to provide a final concentration of
creatine compound(s) of 0.16 to 48 mM/l in the concentrated
dialysis fluid or stock solution. For creatine the concentration of
6.4 g per liter dialysis concentrate corresponds to the maximum
solubility of creatine in water at neutral pH at a temperature of
about 5 degree Celsius. A higher concentration for creatine is not
feasible if the dialysis concentrate is to be cooled for stability
purposes without the risk of precipitation.
[0132] With a typical dialysis flux rate of 800 ml/min over a
period of 4 h--amounting to a dilution of the above concentrated
dialysis fluid during the dialysis process to a final volume of 192
liters of actual dialysis fluid (corresponding to a dilution factor
of the dialysis stock solution of about 40 fold)--the effective
creatine concentrations in the final dialysis solution will be
0.004 to 1.2 mM/l.
[0133] Because the creatine transporter protein (CrT) in the plasma
membrane has a very high affinity to creatine with a km of
approximately 25 to 30 micromolar, the mentioned concentrations of
creatine in the final dialysis solution (0.004-1.2 mM/l) are in the
range of or significantly above the km of the creatine transporter,
allowing for the efficient uptake of creatine compounds by blood
cells from the final dialysis solution.
[0134] Typically, 20 to 30 g of creatine added to 4.7 liters of
dialysis concentrate are used to give a creatine concentration of
32 mM-48 mM/l stock concentration, getting diluted in the final
dialysis solution of 0.8 to 1.2 mM/l. Because the patient's blood
is continuously in contact with these concentrations of creatine
during the entire treatment, and because the CrT is efficient in
transporting creatine into the cells, the cells are loaded with
creatine.
[0135] The above-mentioned concentrations of creatine in the final
dialysis solution of about 1 mM are considerably lower than those
proposed by prior art documents teaching creatine supplementation
for dialysis patients for maintaining and building muscle mass, but
are highly effective for cell protection. During the dialysis
process using the inventive dialysis solution with very low
creatine concentrations the patient is eventually exposed to all of
the creatine that was originally added to the concentrated dialysis
fluid. The resulting creatine concentrations are physiological,
e.g. such concentrations of creatine occur post-prandially in the
serum of a human after a good meal of meat of fish. The creatine
concentrations in the dialysis solution do not elicit any side
effects and will not lead to undesired and unhealthy
down-regulation of endogenous creatine synthesis in the
patient.
EXAMPLE 2
[0136] As a preferred practical example for direct oral Creatine
supplementation of dialysis, patients would orally ingest Creatine,
Cr-monohydrate or other Cr-containing compounds, e.g. Cr-salts or
Cr-analogs. These Creatine-containing compounds would be taken
orally in form of a powder or tablets, or as an aqueous solution or
suspension. The preferred supplementation scheme allows for 1-20 g
of Creatine or Creatine compounds per day for a loading phase
period of 7-14 days, followed by a maintenance phase of 2-5 g of
Creatine per day during unlimited time or as long as needed.
[0137] Additionally to this oral supplementation creatine was given
to the patient also by dialysis at a concentration of 2 mM/l.
EXAMPLE 3
[0138] As a preferred practical example for a clinical
haemodialysis setting, 1-30 g of Creatine are added to the
haemodialysis concentrate of 5 liters (normally used for one
haemodialysis treatment per patient per day, in a commercial
haemodialysis machine) to give a final creatine concentration of
0.08-45 mM/l in the dialysis concentrate.
[0139] With a typical dialysis flux rate of 800 ml/min over a
period of 4 hrs, amounting to a dilution of the above concentrated
dialysis fluid during the dialysis process to a final volume of 190
liters of actual dialysis fluid (corresponding to a dilution factor
of the dialysis concentrate of approximately 40 fold), the
effective creatine concentrations in the final dialysis solution
administered to the patient will be between 0.002-1.125 mM/l.
[0140] Since the Creatine Transporter Protein (CrT) in the plasma
membrane has a very high affinity to creatine with a km of
approximately 25-30 micro molar (Straumann at al. 2006), the latter
concentrations of creatine in the final dialysis liquid
(0.004-1.125 mM/l) are entirely in the range of or significantly
above the km of the Creatine transporter, such that efficient
uptake of creatine by the cells from the final dialysis liquid is
entirely guaranteed.
[0141] Typically, 20-30 g of creatine added to 5 liters of dialysis
concentrate are used to give a creatine concentration of 30 mM/l-45
mM/l. This then gets diluted in the final dialysis fluid to
0.75-1.125 mM/l. Since the patient's blood continuously sees these
concentrations of creatine during the entire treatment, and since
the CrT is efficient in transporting creatine into the cells, the
cells have the chance of fully loading up with creatine during the
3-4 hrs of each dialysis session. Thus, the range of creatine
concentration in the final dialysis fluid as proposed herein
corresponds to physiological post-prandial creatine concentrations
that are reached by oral ingestion of a single dose of 5-20 g of
creatine directly or alternatively by consuming a meal rich In
fresh fish and meat. Uptake of creatine from the dialysis liquid
during the time of haemodialysis of 3-4 hrs is sufficient to allow
for optimal uptake of creatine into the body, loading of the target
organs and cells with creatine and attaining the beneficial
physiological effects, including cell protection, of creatine for
the patients, as stated above.
[0142] Such creatine concentrations, as proposed herein, do not
have any side effects and will not lead to any down-regulation of
endogenous creatine synthesis in the body.
[0143] The concentration of creatine in the final haemodialysis
liquid of approximately 1 mM (see above) as proposed here is
significantly lower compared to that proposed by patent application
US 2003/0013767 A1 by Bessman, but are nevertheless still fully
sufficient to allow for the reported cell protection effects
described above. In our case, the patient is exposed to the total
amount of Creatine that has been added to the concentrated dialysis
fluid (1-30 g) during the entire dialysis process, After dilution
(see above), those concentrations of creatine are absolutely
physiological (approximately 1-2 mM/l), e.g. such a concentration
of creatine appears post-prandial in the serum of a human after a
good meal of meat or fish or after a single dose of creatine
supplementation with 5-20 g of Creatine orally.
[0144] The values in Bessman's patent application US 2003/0013767
A1 (15 g of Creatine per liter of final dialysis fluid are much
higher compared to those proposed herein of 20-30 g creatine
diluted in approximately 200 liters of final dialysis fluid equal
0.1-0.15 g of creatine per liter). The concentrations of creatine
known in prior art are highly non-physiological for a hemodialysis
fluid and likely to exert a high-osmotic pressure and metabolic
stress on cells.
[0145] In addition, as an unfavorable and undesired side effect,
exposure of the organism to such very high concentrations of
creatine may reduce endogenous creatine synthesis in the body,
lower cellular ATP-levels for production of phospho-creatine and
activate AMPK, influence hormonal and inflammatory parameters in
the body of dialysis patients This is definitely not the case at
the lower creatine concentrations proposed here to be used for
haemodialysis.
[0146] Finally, the high concentrations of creatine proposed in the
application US 2003/0013767 A1 by Bessman are technically
impractical, due to the rather low solubility of creatine in water
and the very large temperature-dependence of the creatine
solubility. It is a high risk that under the high-concentration
conditions proposed by the Bessman patent application US
2003/0013767 A1 of 15 g of Creatine per liter of fluid, which is at
the solubility limit of a creatine solution at 25.degree. C.,
creatine will precipitate in the dialysis fluid with all of the
very unfavorable consequences for the practicability of the
dialysis process.
EXAMPLE 4
[0147] As a preferred practical example for a chronic ambulatory
peritoneal dialysis (CAPD) or an automated peritoneal dialysis
(APD) setting, 20-24 g of creatine is added per liter of peritoneal
dialysis liquid at 37.degree. C., corresponding to a concentration
of 150-190 mM/l of creatine. These concentrations of creatine are
still below the critical solubility limits at the respective
temperatures and thus pose no problem for precipitation. At the
same time, these creatine concentrations are high enough to be
accounted for as osmotically relevant.
[0148] Therefore, the glucose concentration in standard peritoneal
dialysis fluid can be lowered accordingly. By using other creatine
compounds, e.g. creatine salts and analogs that are better soluble
in water, the concentration of creatine compounds may be set even
higher, and thus more glucose can be replaced, accordingly.
[0149] Typically, and preferably 20-24 g of creatine are added per
liter of final peritoneal dialysis liquid at 37.degree. C., leading
to a final creatine concentration of 150-190 mM/l 37.degree. C.
Using this strategy, the amount of glucose in peritoneal dialysis
solution of differing strength, e.g. containing 37.5 g/l, 62.6 g/l
or 106 g/l, can be reduced by addition of the above 24 g of
creatine/l to 13.5 g/l, 38.6 g/l or 82 g/l, respectively. This
significantly reduces the glucose load on the peritoneum with its
potential negative consequences, as stated above. In fact, since in
APD and CAPD the actual 2-3 liters of peritoneal dialysis fluid are
exchanged 4-5 times during a single dialysis session, the total
glucose sparing effect, that is, the lower exposure of the patients
peritoneum to high glucose is 4-5 times higher in absolute terms,
e.g. 5 x 24 g or 120 g of glucose, can be substituted by creatine
in one single dialysis session.
[0150] Alternatively, for peritoneal dialysis, if high-glucose
poses no problem, a total amount of creatine between 5 to maximal
20 g is added directly to the final dialysis liquid, thus
representing a similar creatine exposure reached by standard oral
creatine supplementation.
* * * * *