CA2102234C - Peritoneal dialysis composition and method usable during and after peritonitis - Google Patents
Peritoneal dialysis composition and method usable during and after peritonitis Download PDFInfo
- Publication number
- CA2102234C CA2102234C CA002102234A CA2102234A CA2102234C CA 2102234 C CA2102234 C CA 2102234C CA 002102234 A CA002102234 A CA 002102234A CA 2102234 A CA2102234 A CA 2102234A CA 2102234 C CA2102234 C CA 2102234C
- Authority
- CA
- Canada
- Prior art keywords
- peritoneal
- peritonitis
- solution
- amino acids
- tryptophan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
- A61K38/446—Superoxide dismutase (1.15)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/28—Peritoneal dialysis ; Other peritoneal treatment, e.g. oxygenation
- A61M1/287—Dialysates therefor
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- External Artificial Organs (AREA)
- Medicinal Preparation (AREA)
Abstract
Peritoneal dialysis solutions are specially formulated for use during and immediately after an episode of peritonitis. The solutions include one or more additives to minimize the injury and physiological effects that peritonitis can cause. One additive is a mixture of amino acids sufficient to maintain a positive nitrogen balance, at least one of the amino acids being present in a dipeptide form. Another additive is a compound that scavenges free radicals generated by peritoneal macrophages activated by the peritonitis. Another additive is chondroitin sulfate that changes the permeability of the peritoneal membrane during subsequent dialysis using solutions free of chondroitin sulfate. Another additive is the degradation products of hyaluronic acid to enhance the regeneration of the pritoneal mesothelium without fibrosis.
Description
.i i UNf./cs Peritoneal dialysis composition and method usable during and after peritonitis.
Field of the Invention The invention generally relates to peritone-al dialysis solutions, especially those used in the practice of continuous ambulatory peritoneal dialysis, or CAPD.
Backaround of the Invention Peritoneal dialysis periodically infuses sterile aqueous solution into the peritoneal cavity.
Diffusion exchange takes place between the solution and the bloodstream across the natural body membranes.
The.diffusion removes the waste products that the kid-neys normally excrete. The waste products typically consist of solutes like sodium and chloride ions, and the other compounds normally excreted through the kid-neys like as urea, creatinine, and water. The diffu-sion of water across the peritoneal membrane during dialysis is called ultrafiltration.
The inflammation of the peritoneum, called _ _:... a S.r1. UHrvtl :~ .
WO 93/14796 PCT/ U592/0.09767.-~' peritonitis, is an undesired complication of peritoneal dialysis. The inflammation may lead to loss of mesothelial cells and the excessive growth of fibrous connective tissue in the peritoneum membrane, called fibrosis. These reactions can lead to the loss of ultrafiltration during dialysis.
In addition, peritonitis may lead to in-creased protein loss in the patient, with the patient not feeling well enough to eat to replace this loss.
To make up for the reduction in normal ultrafiltration rates, peritoneal dialysis patients experiencing peritonitis often 'receive hypertonic dialysis solutions, typically containing glucose as an osmotic solute. However, the use of hypertonic solu-tions for these purposes may be counterproductive.
Due to their low pH, high osmolarity, and the presence of glucose, the solutions may inhibit the necessary regeneration of inesothelial cells. They also may lead to the growth of fibroblasts, causing fibrosis.
To enhance the patient's anabolic state and replace protein loss experienced during peritonitis, conventional dialysis solutions also may include mix-tures of nutritionally essential amino acids (like methionine, tryptophan, and isoleucine) and nutrition-ally non-essential amino acids (like glycine and ala-nine). However, the presence of these amino acids may be counterproductive, too. Many of these amino acids can inhibit the proliferation of inesothelial cells.
Therefore, there is a need for peritoneal dialysis solutions that can be used during and immedi-ately =after peritonitis without potentially counterproductive effects. The solutions would promote the replacement of mesothelial cells, minimize the formation of fibroblasts, and counter the atten-dant loss of ultrafiltration that peritonitis often :a.l.UFri~c WO 93/14796 P(.'T/US92/00972 causes.
Summary of the Invention The invention provides improved peritoneal dialysis solutions that can be used during and after episodes of peritonitis to protect the patient against the inflammatory reactions of peritonitis, fibrosis,.
and the loss of ultrafiltratibn. The invention also provides improved peritoneal dialysis solutions that can be used after episodes of peritonitis to at least partially restore ultrafiltration characteristics lost due to peritonitis.
One aspect of the invention provides perito-neal dialysis solutions that.maintain a positive ni-trogen balance during peritonitis without significant-' ly inhibiting the proliferation of mesothelial cells.
This aspect of the invention replaces at least some individual amino acids in the dialysis solution with amino acids in their dipeptide form.
The inventors have discovered that certain amino acids stunt the proliferation of mesothelial cells. By using these amino acids in their dipeptide form instead, significant improvements in the proliferatioh of inesothelial cells occur. In a preferred embodiment, at least some amino acids like methionine, tryptophan, or isoleucine appear in their dipeptide form (for example, glycine-tryptophan) to achieve this beneficial effect.
The inclusion in a peritoneal dialysis solu-tion of amino acids in dipeptide form with other es-sential and non-essential amino acids enhances the anabolic state of the patient suffering peritonitis.
In addition, the solution does not unduly inhibit the regeneration of mesothelial cells that is necessary to the patient's healing process.
Another aspect of the invention supplements .+iv;r~<, ~
peritoneal dialysis so=lution with compounds that act as scavengers of free radicals present within the peritoneal cavity. The inventors have discovered that the free radicals released by peritoneal cells during peritonitis can injure mesothelial and endothelial cells and may otherwise case disfunction of the peri-toneal membrane. The presence in a peritoneal dialy-sis solution of compounds that scavenge these free radicals decreases the injury that the peritoneum might otherwise suffer during peritonitis. In a pre-ferred embodiment, the scavengers are vitamin E, procysteine, superoxide dismutase, or chondroitin sul-fate.
The inventors have also discovered that use of a dialysis solution containing chondroitin sulfate also beneficially changes the permeability of the peritoneal membrane during subsequent dialysis using conventional solutions. Chondroitin sulfate enhances the subsequent ultrafiltration characteristics of the peritoneal membrane using conventional dialysis solu-tion. It also decreases the absorption of glucose and transperitoneal loss of proteins with no change in urea diffusion. Chondroitin sulfate therefore serves not only as a free radical scavenger to minimize cel-lular injury caused by inflammation during peritoni-tis, but it can be used after an episode of peritoni-tis to at least partially restore loss of ultrafiltra-tion characteristics caused by peritonitis.
Another aspect of the invention includes the degradation products of hyaluronic acid as an additive to.a peritoneal dialysis solution to enhance the re-generation of the peritoneal mesothelium without fi-brosis. The inventors believe that these degradation products, principally oligosaccarides, will increase the proliferation of endothelial cells without affect-ing fibroblasts growth.
Used alone or in combination, these additive compounds make possible the formulation of peritoneal dialysis solutions specifically tailored for use during and immediately after the development of peritonitis.
These additive compounds, used alone or in combination in peritoneal dialysis solutions, can enhance the regeneration of mesothelial cells and prevent the growth of fibroblasts. They can improve the nutritional status of the patient during peritonitis. They can actively decrease the degree of damage occurring during inflammation of the peritoneal membrane. They can restore the peritoneal membrane to its pro-peritonitis condition.
In accordance with an aspect of the present invention, there is provided a peritoneal dialysis solution comprising:
physiological salts in concentrations sufficient to affect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane into the solution, and a mixture of amino acids sufficient to contribute to protein synthesis and a positive nitrogen balance, wherein tryptophan is present in a glycine-tryptophan form.
In accordance with another aspect of the present invention, there is provided a peritoneal dialysis solution for use during an episode of peritonitis comprising:
physiological salts in concentrations sufficient to affect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane into the solution, a mixture of amino acids sufficient to maintain a positive nitrogen balance, at least one of the amino acids being present in a dipeptide form, and -5a-at least one additive compound selected from the group consisting of:
at least one compound to scavenge free radicals generated by activated peritoneal macrophages during peritonitis, and the degradation products of hyaluronic acid to enhance the regeneration of the peritoneal mesothelium without fibrosis.
In accordance with another aspect of the present invention, there is provided a use, as a peritoneal dialysis agent, of a solution, comprising physiological salts concentrations sufficient to effect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane into solution, and a mixture of amino acids sufficient to contribute to maintain a positive nitrogen balance, at least one of the amino acids being present in a dipeptide form, in combination with at least one additional additive selected from the group consisting of:
at least one compound that scavenges free radicals generated by peritoneal macrophages activated by peritonitis, chondroitin sulfate in a concentration sufficient to change the permeability of the peritoneal membrane during subsequent dialysis using solutions free of chondroitin sulfate, and the degradation products of hyaluronic acid to enhance the regeneration of the peritoneal mesothelium without fibrosis.
In accordance with another aspect of the present invention, there is provided a use of a solution, comprising physiological salts in concentrations sufficient to effect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane -5b-into the solution, as a peritoneal dialysis agent in combination with a mixture of amino acids sufficient to maintain a positive nitrogen balance, wherein tryptophan is present in a glycine-tryptophan form.
The many features and the advantages of the invention will become even more apparent after reading the following detailed description, associated drawings, and claims.
Brief Description of the Drawings Fig. 1 is a chart showing the mean value in 86Rb uptake by human mesothelial cells (HMC) through different pathways after being cultured for 7 days in medium with high concentrations (90 mM) of glucose, glycerol, and mannitol, expressed as a % of control where the HMC were cultured in normotonic medium; and Fig. 2 is a graph showing the accumulation of a6Rb during 72 hours in HMC exposed to different high glucose concentrations, expressed as a % of control where the HMC were cultured in normotonic medium.
Description of the Preferred Embodiments After an episode of peritonitis, the CAPD
patient typically receives a hypertonic peritoneal dialysis solution containing glucose. The intent is to counteract the loss of ultrafiltration that fre-; =;~
quently occurs during peritonitis.
However, hypertonic peritoneal dialysis so-lutions with glucose may actually interfere with the regeneration of mesothelial cells and thereby inter-fere with the patient's recovery from the inflammatory effects of peritonitis. Such solutions also may en-courage the growth fibroblasts and could contribute to peritoneal fibrosis.
The inventors have experimentally determined that potassium (measured with its analog 86Rb) enters human mesothelial cells (HMC) through three different pathways:
(1) through an active channel that the glu-coside ouabain blocks in a dose dependent way, which corresponds to the activity of the Na-K-ATPase pump in plasmalemma;
(2) through another active channel that the diuretic drug furosemide blocks in a dose dependent way, but that is not blocked by ouabain; and (3) through a passive channel that neither ouabain or furosemide b.lock.
The inventors have also experimentally determined that about 60% of 86Rb transport occurs through active Channel (1), the Na-K-ATPase pump;
about 29% through active Channel (2); and about 11%
through passive Channel (3).
As the following Example demonstrates, expo-sure of HMC to hyperosmolal medium modifies the trans-port of 86Rb into the cells through all three pathways.
This study evaluated the mechanisms regulat-ing transport of potassium from the extracellular space into HMC in in vitro culture.
HMC were isolated from omentum following the 35. method described in Van Bronswwijk et al., "Cytotoxic .~ 7 ~~ C~ n -=, ~ .
L i1 ~~ ;d ei 'lll Effects of Commercial Continuous Ambulatory Peritoneal Dialysis (CAPD) Fluids and of Bacterial Exoproducts on Human Mesothelial Cells in Vitro," Perit Dial Intern, 1989 (9): 197-202.
The HMC were seeded into 75 cm2 culture flasks and grown to confluency. Then, the HMC were harvested with trypsin-EDTA solution and seeded into 96-well culture plates and there again grown to confluency. The study used the confluent mesothelial monolayers cultured in the 96-well plates.
HMC were incubated in the culture medium for 7 days with various osmotic solutions (90 mM and more of glucose or glvicerol or inannitol). After :ncuba-tion, potassium analog 86Rb was added to the medium.
The uptake of 86Rb by HMC was measured and compared with the uptake in control HMC not exposed to osmotic solutes (the control HMC having been cultured in a normotonic medium).
As Fig. 1 shows, transport through the pas-sive Channel (3) increases in HMC exposed chronically (over 7 days) to high concentration of all the osmotic solutes (90 mM). Mannitol also stimulated active transport through Channel (1), but glucose and glycer-ol both decreased Channel (1) transport. All solutes decreased active transport through Channel (2) as well.
As Fig. 2 shows, the intracellular accumula-tion of 86Rb in HMC exposed for 72 hours to increased concentrations of glucose diminished proportionally to the glucose concentration, compared to the accumula-tion in the control HMC.
The study demonstrates that chronic exposure of HMC to high glucose concentration (90 mM) decrea,ses the activity of the Na-K-ATPase pump (i.e., Channel (1)), which is the main pump responsible for l { , .:: 1 N..{, U {JrJ :~ 'y WO 93/14796 PCT/US92/00972 intracellular potassium accumulation. The activity of"
Channel (2) also decreases as a result to exposure of HMC to high glucose concentration.
In effect, this decreased capacity of HMC to take up potassium results in diminished accumulation of potassium in HMC. This may, in turn, cause cellu-lar disfunction like those associated with diabetic disorders resulting from reduced Na-K-ATPase activity.
See Greene et al., "Sorbitol, Phosphoinodsitides and Sodium - Potassium - ATPase in the Pathogenesis of Diabetic Complications," N Encil J Med 1987; 316: 599-606; and Yorek et al., "The Effect of Increased Glu-cose Levels on Na-K Pump Activity in Cultured Neuro-blastoma Cells," J Neurochem 1988; 51:605-610. HMC
potassium depletion also may produce severe metabolic abnormalities such as deranged protein synthesis. See Lubin, "Intracellular Potassium and Control of Protein Synthesis," e~d Proc 1964; 23: 994-997.
High concentration of glycerol, but not man-nitol, produces the same effect as glucose. This sug-gests that the decrease in Na-K-ATPase pump activity depends upon the metabolism of the osmotic solute in-side the cell, since both mannitol influx and metabo-lism in HMC are probably small.
The study also shows that chronic exposure of HMC to all osmotic solutes increases the passive permeability (via Channel (3) ) of the plasmalemma to 86Rb. This may be due to a "washout" of structural components of the plasmalemma, causing increased leak-age'and loss of intracellular metabolic substrates.
This, too, can lead to cellular disfunction.
Thus, increased extracellular tonicity due to high glucose concentration may cause HMC potassium loss both through diminished active influx, mostly by reduced Na-K-ATPase activity, and through an outflux a ~t'' c~ r~ , I,=re ~ ,~ V N ~d U Z
of ion-rich water ("wash-out") from the cells due to a negative osmotic gradient. Also see Moreno et al., "Increase in Serum Potassium Resulting from the Admin-istration of Hypertonic Mannitol and Other Solutions,"
J Tab Clin Med 1969; 73: 291-294.
The presence of these disfunctions does not promote the regeneration of inesothelial cells necessary to the healing process during and after a peritonitis episode.
The peritoneal.dialysis solutions that em-body the features of the invention are specially for-mulated for patients for use during and immediately after episodes of peritonitis. The solutions prono*_e the healing process to avoid or at least minimize the' injury and adverse physiological effects of peritoni-tis upon the dialysis regime of the patient.
Like conventional peritoneal dialysis solu-tions, the solutions that embody the features of the invention include:
(1) physiological salts such as sodium chloride, calcium chloride and sodium acetate in ap-propriate concentrations to maintain a normal electro-lyte profile. Typical concentrations are from 116 to 140 mEq/liter of sodium; 0 to 6 mEq/liter of calcium, and 100 to 144 mEq/liter of chloride.
(2) lactate or bicarbonate in appropri-ate concentrations to maintain a physiologically tol-erable pH of between about 5 to about 7.4. Typical concentrations are from 30 to 45=mEq/liter of lactate;
and (3) glycerol or glucose polymers at a concentration (at least 0.5 percent by weight) suffi-cient. to generate the necessary osmotic pressure to remove water from the patient through ultrafiltration.
According to the invention, the solutions )~f ?~".-(~ i~F.N~.1 contain one or more of the following additives:
Field of the Invention The invention generally relates to peritone-al dialysis solutions, especially those used in the practice of continuous ambulatory peritoneal dialysis, or CAPD.
Backaround of the Invention Peritoneal dialysis periodically infuses sterile aqueous solution into the peritoneal cavity.
Diffusion exchange takes place between the solution and the bloodstream across the natural body membranes.
The.diffusion removes the waste products that the kid-neys normally excrete. The waste products typically consist of solutes like sodium and chloride ions, and the other compounds normally excreted through the kid-neys like as urea, creatinine, and water. The diffu-sion of water across the peritoneal membrane during dialysis is called ultrafiltration.
The inflammation of the peritoneum, called _ _:... a S.r1. UHrvtl :~ .
WO 93/14796 PCT/ U592/0.09767.-~' peritonitis, is an undesired complication of peritoneal dialysis. The inflammation may lead to loss of mesothelial cells and the excessive growth of fibrous connective tissue in the peritoneum membrane, called fibrosis. These reactions can lead to the loss of ultrafiltration during dialysis.
In addition, peritonitis may lead to in-creased protein loss in the patient, with the patient not feeling well enough to eat to replace this loss.
To make up for the reduction in normal ultrafiltration rates, peritoneal dialysis patients experiencing peritonitis often 'receive hypertonic dialysis solutions, typically containing glucose as an osmotic solute. However, the use of hypertonic solu-tions for these purposes may be counterproductive.
Due to their low pH, high osmolarity, and the presence of glucose, the solutions may inhibit the necessary regeneration of inesothelial cells. They also may lead to the growth of fibroblasts, causing fibrosis.
To enhance the patient's anabolic state and replace protein loss experienced during peritonitis, conventional dialysis solutions also may include mix-tures of nutritionally essential amino acids (like methionine, tryptophan, and isoleucine) and nutrition-ally non-essential amino acids (like glycine and ala-nine). However, the presence of these amino acids may be counterproductive, too. Many of these amino acids can inhibit the proliferation of inesothelial cells.
Therefore, there is a need for peritoneal dialysis solutions that can be used during and immedi-ately =after peritonitis without potentially counterproductive effects. The solutions would promote the replacement of mesothelial cells, minimize the formation of fibroblasts, and counter the atten-dant loss of ultrafiltration that peritonitis often :a.l.UFri~c WO 93/14796 P(.'T/US92/00972 causes.
Summary of the Invention The invention provides improved peritoneal dialysis solutions that can be used during and after episodes of peritonitis to protect the patient against the inflammatory reactions of peritonitis, fibrosis,.
and the loss of ultrafiltratibn. The invention also provides improved peritoneal dialysis solutions that can be used after episodes of peritonitis to at least partially restore ultrafiltration characteristics lost due to peritonitis.
One aspect of the invention provides perito-neal dialysis solutions that.maintain a positive ni-trogen balance during peritonitis without significant-' ly inhibiting the proliferation of mesothelial cells.
This aspect of the invention replaces at least some individual amino acids in the dialysis solution with amino acids in their dipeptide form.
The inventors have discovered that certain amino acids stunt the proliferation of mesothelial cells. By using these amino acids in their dipeptide form instead, significant improvements in the proliferatioh of inesothelial cells occur. In a preferred embodiment, at least some amino acids like methionine, tryptophan, or isoleucine appear in their dipeptide form (for example, glycine-tryptophan) to achieve this beneficial effect.
The inclusion in a peritoneal dialysis solu-tion of amino acids in dipeptide form with other es-sential and non-essential amino acids enhances the anabolic state of the patient suffering peritonitis.
In addition, the solution does not unduly inhibit the regeneration of mesothelial cells that is necessary to the patient's healing process.
Another aspect of the invention supplements .+iv;r~<, ~
peritoneal dialysis so=lution with compounds that act as scavengers of free radicals present within the peritoneal cavity. The inventors have discovered that the free radicals released by peritoneal cells during peritonitis can injure mesothelial and endothelial cells and may otherwise case disfunction of the peri-toneal membrane. The presence in a peritoneal dialy-sis solution of compounds that scavenge these free radicals decreases the injury that the peritoneum might otherwise suffer during peritonitis. In a pre-ferred embodiment, the scavengers are vitamin E, procysteine, superoxide dismutase, or chondroitin sul-fate.
The inventors have also discovered that use of a dialysis solution containing chondroitin sulfate also beneficially changes the permeability of the peritoneal membrane during subsequent dialysis using conventional solutions. Chondroitin sulfate enhances the subsequent ultrafiltration characteristics of the peritoneal membrane using conventional dialysis solu-tion. It also decreases the absorption of glucose and transperitoneal loss of proteins with no change in urea diffusion. Chondroitin sulfate therefore serves not only as a free radical scavenger to minimize cel-lular injury caused by inflammation during peritoni-tis, but it can be used after an episode of peritoni-tis to at least partially restore loss of ultrafiltra-tion characteristics caused by peritonitis.
Another aspect of the invention includes the degradation products of hyaluronic acid as an additive to.a peritoneal dialysis solution to enhance the re-generation of the peritoneal mesothelium without fi-brosis. The inventors believe that these degradation products, principally oligosaccarides, will increase the proliferation of endothelial cells without affect-ing fibroblasts growth.
Used alone or in combination, these additive compounds make possible the formulation of peritoneal dialysis solutions specifically tailored for use during and immediately after the development of peritonitis.
These additive compounds, used alone or in combination in peritoneal dialysis solutions, can enhance the regeneration of mesothelial cells and prevent the growth of fibroblasts. They can improve the nutritional status of the patient during peritonitis. They can actively decrease the degree of damage occurring during inflammation of the peritoneal membrane. They can restore the peritoneal membrane to its pro-peritonitis condition.
In accordance with an aspect of the present invention, there is provided a peritoneal dialysis solution comprising:
physiological salts in concentrations sufficient to affect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane into the solution, and a mixture of amino acids sufficient to contribute to protein synthesis and a positive nitrogen balance, wherein tryptophan is present in a glycine-tryptophan form.
In accordance with another aspect of the present invention, there is provided a peritoneal dialysis solution for use during an episode of peritonitis comprising:
physiological salts in concentrations sufficient to affect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane into the solution, a mixture of amino acids sufficient to maintain a positive nitrogen balance, at least one of the amino acids being present in a dipeptide form, and -5a-at least one additive compound selected from the group consisting of:
at least one compound to scavenge free radicals generated by activated peritoneal macrophages during peritonitis, and the degradation products of hyaluronic acid to enhance the regeneration of the peritoneal mesothelium without fibrosis.
In accordance with another aspect of the present invention, there is provided a use, as a peritoneal dialysis agent, of a solution, comprising physiological salts concentrations sufficient to effect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane into solution, and a mixture of amino acids sufficient to contribute to maintain a positive nitrogen balance, at least one of the amino acids being present in a dipeptide form, in combination with at least one additional additive selected from the group consisting of:
at least one compound that scavenges free radicals generated by peritoneal macrophages activated by peritonitis, chondroitin sulfate in a concentration sufficient to change the permeability of the peritoneal membrane during subsequent dialysis using solutions free of chondroitin sulfate, and the degradation products of hyaluronic acid to enhance the regeneration of the peritoneal mesothelium without fibrosis.
In accordance with another aspect of the present invention, there is provided a use of a solution, comprising physiological salts in concentrations sufficient to effect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane -5b-into the solution, as a peritoneal dialysis agent in combination with a mixture of amino acids sufficient to maintain a positive nitrogen balance, wherein tryptophan is present in a glycine-tryptophan form.
The many features and the advantages of the invention will become even more apparent after reading the following detailed description, associated drawings, and claims.
Brief Description of the Drawings Fig. 1 is a chart showing the mean value in 86Rb uptake by human mesothelial cells (HMC) through different pathways after being cultured for 7 days in medium with high concentrations (90 mM) of glucose, glycerol, and mannitol, expressed as a % of control where the HMC were cultured in normotonic medium; and Fig. 2 is a graph showing the accumulation of a6Rb during 72 hours in HMC exposed to different high glucose concentrations, expressed as a % of control where the HMC were cultured in normotonic medium.
Description of the Preferred Embodiments After an episode of peritonitis, the CAPD
patient typically receives a hypertonic peritoneal dialysis solution containing glucose. The intent is to counteract the loss of ultrafiltration that fre-; =;~
quently occurs during peritonitis.
However, hypertonic peritoneal dialysis so-lutions with glucose may actually interfere with the regeneration of mesothelial cells and thereby inter-fere with the patient's recovery from the inflammatory effects of peritonitis. Such solutions also may en-courage the growth fibroblasts and could contribute to peritoneal fibrosis.
The inventors have experimentally determined that potassium (measured with its analog 86Rb) enters human mesothelial cells (HMC) through three different pathways:
(1) through an active channel that the glu-coside ouabain blocks in a dose dependent way, which corresponds to the activity of the Na-K-ATPase pump in plasmalemma;
(2) through another active channel that the diuretic drug furosemide blocks in a dose dependent way, but that is not blocked by ouabain; and (3) through a passive channel that neither ouabain or furosemide b.lock.
The inventors have also experimentally determined that about 60% of 86Rb transport occurs through active Channel (1), the Na-K-ATPase pump;
about 29% through active Channel (2); and about 11%
through passive Channel (3).
As the following Example demonstrates, expo-sure of HMC to hyperosmolal medium modifies the trans-port of 86Rb into the cells through all three pathways.
This study evaluated the mechanisms regulat-ing transport of potassium from the extracellular space into HMC in in vitro culture.
HMC were isolated from omentum following the 35. method described in Van Bronswwijk et al., "Cytotoxic .~ 7 ~~ C~ n -=, ~ .
L i1 ~~ ;d ei 'lll Effects of Commercial Continuous Ambulatory Peritoneal Dialysis (CAPD) Fluids and of Bacterial Exoproducts on Human Mesothelial Cells in Vitro," Perit Dial Intern, 1989 (9): 197-202.
The HMC were seeded into 75 cm2 culture flasks and grown to confluency. Then, the HMC were harvested with trypsin-EDTA solution and seeded into 96-well culture plates and there again grown to confluency. The study used the confluent mesothelial monolayers cultured in the 96-well plates.
HMC were incubated in the culture medium for 7 days with various osmotic solutions (90 mM and more of glucose or glvicerol or inannitol). After :ncuba-tion, potassium analog 86Rb was added to the medium.
The uptake of 86Rb by HMC was measured and compared with the uptake in control HMC not exposed to osmotic solutes (the control HMC having been cultured in a normotonic medium).
As Fig. 1 shows, transport through the pas-sive Channel (3) increases in HMC exposed chronically (over 7 days) to high concentration of all the osmotic solutes (90 mM). Mannitol also stimulated active transport through Channel (1), but glucose and glycer-ol both decreased Channel (1) transport. All solutes decreased active transport through Channel (2) as well.
As Fig. 2 shows, the intracellular accumula-tion of 86Rb in HMC exposed for 72 hours to increased concentrations of glucose diminished proportionally to the glucose concentration, compared to the accumula-tion in the control HMC.
The study demonstrates that chronic exposure of HMC to high glucose concentration (90 mM) decrea,ses the activity of the Na-K-ATPase pump (i.e., Channel (1)), which is the main pump responsible for l { , .:: 1 N..{, U {JrJ :~ 'y WO 93/14796 PCT/US92/00972 intracellular potassium accumulation. The activity of"
Channel (2) also decreases as a result to exposure of HMC to high glucose concentration.
In effect, this decreased capacity of HMC to take up potassium results in diminished accumulation of potassium in HMC. This may, in turn, cause cellu-lar disfunction like those associated with diabetic disorders resulting from reduced Na-K-ATPase activity.
See Greene et al., "Sorbitol, Phosphoinodsitides and Sodium - Potassium - ATPase in the Pathogenesis of Diabetic Complications," N Encil J Med 1987; 316: 599-606; and Yorek et al., "The Effect of Increased Glu-cose Levels on Na-K Pump Activity in Cultured Neuro-blastoma Cells," J Neurochem 1988; 51:605-610. HMC
potassium depletion also may produce severe metabolic abnormalities such as deranged protein synthesis. See Lubin, "Intracellular Potassium and Control of Protein Synthesis," e~d Proc 1964; 23: 994-997.
High concentration of glycerol, but not man-nitol, produces the same effect as glucose. This sug-gests that the decrease in Na-K-ATPase pump activity depends upon the metabolism of the osmotic solute in-side the cell, since both mannitol influx and metabo-lism in HMC are probably small.
The study also shows that chronic exposure of HMC to all osmotic solutes increases the passive permeability (via Channel (3) ) of the plasmalemma to 86Rb. This may be due to a "washout" of structural components of the plasmalemma, causing increased leak-age'and loss of intracellular metabolic substrates.
This, too, can lead to cellular disfunction.
Thus, increased extracellular tonicity due to high glucose concentration may cause HMC potassium loss both through diminished active influx, mostly by reduced Na-K-ATPase activity, and through an outflux a ~t'' c~ r~ , I,=re ~ ,~ V N ~d U Z
of ion-rich water ("wash-out") from the cells due to a negative osmotic gradient. Also see Moreno et al., "Increase in Serum Potassium Resulting from the Admin-istration of Hypertonic Mannitol and Other Solutions,"
J Tab Clin Med 1969; 73: 291-294.
The presence of these disfunctions does not promote the regeneration of inesothelial cells necessary to the healing process during and after a peritonitis episode.
The peritoneal.dialysis solutions that em-body the features of the invention are specially for-mulated for patients for use during and immediately after episodes of peritonitis. The solutions prono*_e the healing process to avoid or at least minimize the' injury and adverse physiological effects of peritoni-tis upon the dialysis regime of the patient.
Like conventional peritoneal dialysis solu-tions, the solutions that embody the features of the invention include:
(1) physiological salts such as sodium chloride, calcium chloride and sodium acetate in ap-propriate concentrations to maintain a normal electro-lyte profile. Typical concentrations are from 116 to 140 mEq/liter of sodium; 0 to 6 mEq/liter of calcium, and 100 to 144 mEq/liter of chloride.
(2) lactate or bicarbonate in appropri-ate concentrations to maintain a physiologically tol-erable pH of between about 5 to about 7.4. Typical concentrations are from 30 to 45=mEq/liter of lactate;
and (3) glycerol or glucose polymers at a concentration (at least 0.5 percent by weight) suffi-cient. to generate the necessary osmotic pressure to remove water from the patient through ultrafiltration.
According to the invention, the solutions )~f ?~".-(~ i~F.N~.1 contain one or more of the following additives:
(4) a mixture of essential and non'-es-sential amino acids to serve as a source of supplemen-tal nitrogen for the support of protein synthesis for the patient and to counterbalance the protein that the patient loses because of peritonitis. According to this aspect of the invention, at least some of these amino acids are present in their dipeptide form to promote the proliferation of mesothelial cells lost .10 during peritonitis.
(5) a compound that scavenges free radicals produced by peritoneal cells that causes peroxidation of the peritoneum;
(6) chondroitin sulphate to restore at least a portion of transperitoneal transport lost due to peritonitis;
(7) compounds consisting of the degra-dation products of hyaluronic acid to enhance the re-generation of the peritoneal mesothelium without fi-2.0 brosis.
The following sections describe the benefits associated with each Additive (4) to (7).
AMINO ACID ADDITIVE (4) A preferred embodiment of the amino acid additive (4) comprises, based on one liter of solution, about 0.1 to 10 mM each of the nutritionally essential amino acids methionine, tryptophan, isoleucine, valine, leucine, lysine, histidine, threo-nine, and phenylalanine, at least some of which are present in their dipeptide form. When present as dipeptides, these amino acids do not inhibit mesothelial cell proliferation as much as they do when present as individual amino acids.
The most preferred embodiment includes at least tryptophan in its dipeptide form (glycine-tryp-,~. 31 4 tophan, or gly-trp), as the individual amino acid tryptophan inhibits mesothelial cell proliferation more than an other individual amino acid.
The mixture also includes about 0.1 to 10 mM
each of arginine, alanine, proline, glycine, serine, tyrosine, cysteine (cystine), and other individual, nutritionally non-essential amino acids as required to maintain a positive nitrogen balance in the patient.
The following Example illustrates the benefits of using amino acids in a dialysis solution, of which certain are in their dipeptide form.
This study evaluated the toxicity of a mix-ture of essential and non-essential amino acids on the proliferation of HMC in conditions simulating perito-neal dialysis.
HMC prepared as described in Example 1 were exposed to essential and nonessential amino acids.
Adverse effects were measured in terms of the impact upon cell proliferation (as measured by incorporation of 3H-thymidine) and the release of LDH from cell cy-toplasm.
All the amino acids evaluated inhibited the proliferation of HMC when present. Tryptophan exhib-ited the most inhibition effect.
When HMC are exposed to tryptophan in a con-centration of 5 mM for 24 hours, their proliferation is reduced by 82%, compared to the proliferation of control HMC cells not exposed to tryptophan. After 24 hours of exposure, tryptophan (5 mM) also increased the leakage of LDH from the mesothelial monolayer HMC
by 740%, compared to the control HMC cells.
In contrast, after 24 hours of exposure to dipeptide tryptophan (gly-trp) in concentration of 5 mM, proliferation of HMC decreased by only 30% and LDH
sJ .L l1 i: r.. c~ ~.
WO 93/14796 PCT/US92/00972 ; m' release increased by only 180%, compared to the control HMC cells.
In another experiment, growing HMC were ex-posed to two mixtures each having a high concentration of amino acids (1.1%). One amino acid mixture con-tained tryptophan. The other amino acid mixture con-tained gly-trp instead of tryptophan. The concent-ration of both amino acid mixtures was progressively decreased by dilution down to 0.22% in 6 hours. The HMC were incubated for 18 additional hours in media with the low (0.22%) concentration.
The mixture of amino acids containing tryp-tophan reduced 3H-thymidine incorporation by 30%, corn-pared to the control HMC not exposed to any amino acid i5 mixture. The mixture of amino acids in which the gly-trp replaced the tryptophan reduced 3H-thymidine in-corporation by only 17%. The inclusion of the dipep-tide form of the amino acid in the mixture reduced the undesired effect by about 50%.
FREE RADICALS SCAVENGER ADDITIVE (5) Peritonitis activates peritoneal macrophages (as proved by others). The activation of the macrophages leads to the increased generation of free radicals. The inventors believe that the increased generation of free radicals causes peritoneal peroxidation.
According to this aspect of the invention, the use of compounds that scavenge free radicals in peritoneal dialysis solutions minimizes or alleviates peritoneal peroxidation during episodes of peritonitis.
The inventors have also shown that the increased presence of free radicals also injures meso-thelial cells in the peritoneum. The free radicals N .L V N if QJ '~
WO 93/14796 PC'I'/US92/00972 probably also injure endothelial cells, too. The free radicals can depolymerize hyalurbnic acid and/or col-lagen in interstitium, causing disfunction of the peritoneal membrane.
According to this aspect of the invention, these undesired effects of peritonitis also can be minimized or lessened by supplementing the dialysis solution with free radical scavengers.
In one experiment, exposure to normal saline in the peritoneal cavities of rats for over 6 days increased peroxidation of the peritoneal membrane, as measured by the concentration of malondialdehyde in the animal's omentum: 8.12+/-0.51 uM/100 ug tissue (n=7) in controls not infused with saline, compared to 11.36+/-1.07 uM/100 ug tissue (n=12) in rats infused with saline. In another experiment, one group of rats (n=22) was infused over 6 days with saline sup-plemented with vitamin E(0.1 go). Another control group of rats (n=18) was infused over 6 days with sa-line alone. In rats.infused with the vitamin E-sup-plemented saline, the concentration of malondialdehyde in the omentum (and therefore the severity of perito-neal peroxidation) was lower (4.53+/-0.30 uM/100 ug tissue) than in the rats infused with saline alone (9.38+/-0.90 uM/100 ug tissue).
In other jn vitro experiments, free radicals generated by an xanthine-xanthine oxidase system were observed to injure mesothelial cells. The injury was prevented by using vitamin E(0.1 % to 1.0 %) and chondroitin sulphate (0.1 %).
In another experiment, the xanthine-xanthine oxidase system was added to dialysis solution (2.5%
dextrose). The solution was infused into the peritoneal cavities of rats. The increased presence of the free radicals generated by the infused oxidase system caused loss of ultrafiltration and increased glucose absorption, the same physiological effects observed. during ep=_sodes of peritonitis. This result further links the __ncreased presence of free radicals to the inflammatory effects and injury of peritonitis.
The addition of free radical scavenger vitamin E (0.01%) reduced or totally reversed the adverse effects caused by the free radicals generated by the xanthine-xanthine oxidase system. The free radicai scavenger would have the same beneficial effect in the increased presence of the free radicals during peritonitis.
In a preferred embodiment, the scavengers are selected from the qroup consisting of vitamin E, procysteine, superoxide dismutase, and chondroitiri sulfate and are present in concentrations of about 0.01 to 0.5 g%.
TRANSPORT RESTORATION ADDITIVE (6) Peritonitis can adversely alter peritoneal transport, leading '--o a reduction of ultrafiltration.
According to this aspect of the invention, the peritoneal dialysis solution includes chondroitin sulphate.to change or restore transperitoneal transport after an episode of peritonitis.
Saline sl.zpplemented with chondroitin sulphate (0.2. g%) was infused into the peritoneal cavity of rats over a period of six days. Then, conventional 2.5%
Dianeal peritoneal dialysis solution (sold by Baxter Healthcare Corporation, Deerfield, Illinois) was infused into the peritonea:l cavities of the rats.
The chronic exposure to the chondroitin sul-phate modified the permeability of the peritoneal mem-brane during the subsequent dialysis with conventional dialysis solution. The net ultrafiltration measured after a dwell period of four hours was more than the ultrafiltration measured before exposure to the chondroitin sulphate. Also, absorption of glucose from the dialysate and transperitoneal loss cf pro-teins decreased, with no change in urea diffusion, when compared to these same transport parameters mea-sured before chronic exposure to the chondroitin sul-phate.
This Example illustrates the benefits of using chondroitin sulphate in a dialysis solution to restore transperitoneal transport after an episode of peritonitis.
In a preferred embodiment, the chondroitin sulphate is present in a concentration of about 0.01 to 0.5 g%.
REGENERATION ADDITIVE (7) Wound healing during fetal life is charac-terized by healing without fibrosis or scar formation.
It is believed that this healing process is at least partly mediated by the high concentration of hyaluron-ic acid in a fetal wound extramural matrix. By increasing the concentrations of hyaluronic acid in the extracellular fluids of adults, the healing of wounds without fibrosis is enhanced.
Other studies have shown that the hyaluronic acid is not responsible by itself. It is believed that its degradation products (oligosaccharides) that are the active agents in promoting fibrosis-free wound healing. In in vitro experiments, oligosaccharides products of the degradation of hyaluronic acid in-crease the proliferation of endothelial cells without effect on fibroblasts growth.
According to this aspect of the invention, 9 4) =~ ~ ~ . ]
~.I 1. ~ ~I M t, peritoneal dialysis solution includes degradation products of hyaluronic acid to enhance the regeneration of the peritoneal mesothelium without fibrosis.
The dialysis solutions containing one or more of the additives (4) to (7), when sterile, may be used as the peritoneal dialysis solution in a conven-tional CAPD procedure, using the techniques and equip-ment developed and sold by the Baxter Healthcare Cor-poration, Deerfield, Illinois.
The above description and Examples are for illustrative purposes only. They are not intended to limit the scope of the inventions, as defined i:. the following claims.
The following sections describe the benefits associated with each Additive (4) to (7).
AMINO ACID ADDITIVE (4) A preferred embodiment of the amino acid additive (4) comprises, based on one liter of solution, about 0.1 to 10 mM each of the nutritionally essential amino acids methionine, tryptophan, isoleucine, valine, leucine, lysine, histidine, threo-nine, and phenylalanine, at least some of which are present in their dipeptide form. When present as dipeptides, these amino acids do not inhibit mesothelial cell proliferation as much as they do when present as individual amino acids.
The most preferred embodiment includes at least tryptophan in its dipeptide form (glycine-tryp-,~. 31 4 tophan, or gly-trp), as the individual amino acid tryptophan inhibits mesothelial cell proliferation more than an other individual amino acid.
The mixture also includes about 0.1 to 10 mM
each of arginine, alanine, proline, glycine, serine, tyrosine, cysteine (cystine), and other individual, nutritionally non-essential amino acids as required to maintain a positive nitrogen balance in the patient.
The following Example illustrates the benefits of using amino acids in a dialysis solution, of which certain are in their dipeptide form.
This study evaluated the toxicity of a mix-ture of essential and non-essential amino acids on the proliferation of HMC in conditions simulating perito-neal dialysis.
HMC prepared as described in Example 1 were exposed to essential and nonessential amino acids.
Adverse effects were measured in terms of the impact upon cell proliferation (as measured by incorporation of 3H-thymidine) and the release of LDH from cell cy-toplasm.
All the amino acids evaluated inhibited the proliferation of HMC when present. Tryptophan exhib-ited the most inhibition effect.
When HMC are exposed to tryptophan in a con-centration of 5 mM for 24 hours, their proliferation is reduced by 82%, compared to the proliferation of control HMC cells not exposed to tryptophan. After 24 hours of exposure, tryptophan (5 mM) also increased the leakage of LDH from the mesothelial monolayer HMC
by 740%, compared to the control HMC cells.
In contrast, after 24 hours of exposure to dipeptide tryptophan (gly-trp) in concentration of 5 mM, proliferation of HMC decreased by only 30% and LDH
sJ .L l1 i: r.. c~ ~.
WO 93/14796 PCT/US92/00972 ; m' release increased by only 180%, compared to the control HMC cells.
In another experiment, growing HMC were ex-posed to two mixtures each having a high concentration of amino acids (1.1%). One amino acid mixture con-tained tryptophan. The other amino acid mixture con-tained gly-trp instead of tryptophan. The concent-ration of both amino acid mixtures was progressively decreased by dilution down to 0.22% in 6 hours. The HMC were incubated for 18 additional hours in media with the low (0.22%) concentration.
The mixture of amino acids containing tryp-tophan reduced 3H-thymidine incorporation by 30%, corn-pared to the control HMC not exposed to any amino acid i5 mixture. The mixture of amino acids in which the gly-trp replaced the tryptophan reduced 3H-thymidine in-corporation by only 17%. The inclusion of the dipep-tide form of the amino acid in the mixture reduced the undesired effect by about 50%.
FREE RADICALS SCAVENGER ADDITIVE (5) Peritonitis activates peritoneal macrophages (as proved by others). The activation of the macrophages leads to the increased generation of free radicals. The inventors believe that the increased generation of free radicals causes peritoneal peroxidation.
According to this aspect of the invention, the use of compounds that scavenge free radicals in peritoneal dialysis solutions minimizes or alleviates peritoneal peroxidation during episodes of peritonitis.
The inventors have also shown that the increased presence of free radicals also injures meso-thelial cells in the peritoneum. The free radicals N .L V N if QJ '~
WO 93/14796 PC'I'/US92/00972 probably also injure endothelial cells, too. The free radicals can depolymerize hyalurbnic acid and/or col-lagen in interstitium, causing disfunction of the peritoneal membrane.
According to this aspect of the invention, these undesired effects of peritonitis also can be minimized or lessened by supplementing the dialysis solution with free radical scavengers.
In one experiment, exposure to normal saline in the peritoneal cavities of rats for over 6 days increased peroxidation of the peritoneal membrane, as measured by the concentration of malondialdehyde in the animal's omentum: 8.12+/-0.51 uM/100 ug tissue (n=7) in controls not infused with saline, compared to 11.36+/-1.07 uM/100 ug tissue (n=12) in rats infused with saline. In another experiment, one group of rats (n=22) was infused over 6 days with saline sup-plemented with vitamin E(0.1 go). Another control group of rats (n=18) was infused over 6 days with sa-line alone. In rats.infused with the vitamin E-sup-plemented saline, the concentration of malondialdehyde in the omentum (and therefore the severity of perito-neal peroxidation) was lower (4.53+/-0.30 uM/100 ug tissue) than in the rats infused with saline alone (9.38+/-0.90 uM/100 ug tissue).
In other jn vitro experiments, free radicals generated by an xanthine-xanthine oxidase system were observed to injure mesothelial cells. The injury was prevented by using vitamin E(0.1 % to 1.0 %) and chondroitin sulphate (0.1 %).
In another experiment, the xanthine-xanthine oxidase system was added to dialysis solution (2.5%
dextrose). The solution was infused into the peritoneal cavities of rats. The increased presence of the free radicals generated by the infused oxidase system caused loss of ultrafiltration and increased glucose absorption, the same physiological effects observed. during ep=_sodes of peritonitis. This result further links the __ncreased presence of free radicals to the inflammatory effects and injury of peritonitis.
The addition of free radical scavenger vitamin E (0.01%) reduced or totally reversed the adverse effects caused by the free radicals generated by the xanthine-xanthine oxidase system. The free radicai scavenger would have the same beneficial effect in the increased presence of the free radicals during peritonitis.
In a preferred embodiment, the scavengers are selected from the qroup consisting of vitamin E, procysteine, superoxide dismutase, and chondroitiri sulfate and are present in concentrations of about 0.01 to 0.5 g%.
TRANSPORT RESTORATION ADDITIVE (6) Peritonitis can adversely alter peritoneal transport, leading '--o a reduction of ultrafiltration.
According to this aspect of the invention, the peritoneal dialysis solution includes chondroitin sulphate.to change or restore transperitoneal transport after an episode of peritonitis.
Saline sl.zpplemented with chondroitin sulphate (0.2. g%) was infused into the peritoneal cavity of rats over a period of six days. Then, conventional 2.5%
Dianeal peritoneal dialysis solution (sold by Baxter Healthcare Corporation, Deerfield, Illinois) was infused into the peritonea:l cavities of the rats.
The chronic exposure to the chondroitin sul-phate modified the permeability of the peritoneal mem-brane during the subsequent dialysis with conventional dialysis solution. The net ultrafiltration measured after a dwell period of four hours was more than the ultrafiltration measured before exposure to the chondroitin sulphate. Also, absorption of glucose from the dialysate and transperitoneal loss cf pro-teins decreased, with no change in urea diffusion, when compared to these same transport parameters mea-sured before chronic exposure to the chondroitin sul-phate.
This Example illustrates the benefits of using chondroitin sulphate in a dialysis solution to restore transperitoneal transport after an episode of peritonitis.
In a preferred embodiment, the chondroitin sulphate is present in a concentration of about 0.01 to 0.5 g%.
REGENERATION ADDITIVE (7) Wound healing during fetal life is charac-terized by healing without fibrosis or scar formation.
It is believed that this healing process is at least partly mediated by the high concentration of hyaluron-ic acid in a fetal wound extramural matrix. By increasing the concentrations of hyaluronic acid in the extracellular fluids of adults, the healing of wounds without fibrosis is enhanced.
Other studies have shown that the hyaluronic acid is not responsible by itself. It is believed that its degradation products (oligosaccharides) that are the active agents in promoting fibrosis-free wound healing. In in vitro experiments, oligosaccharides products of the degradation of hyaluronic acid in-crease the proliferation of endothelial cells without effect on fibroblasts growth.
According to this aspect of the invention, 9 4) =~ ~ ~ . ]
~.I 1. ~ ~I M t, peritoneal dialysis solution includes degradation products of hyaluronic acid to enhance the regeneration of the peritoneal mesothelium without fibrosis.
The dialysis solutions containing one or more of the additives (4) to (7), when sterile, may be used as the peritoneal dialysis solution in a conven-tional CAPD procedure, using the techniques and equip-ment developed and sold by the Baxter Healthcare Cor-poration, Deerfield, Illinois.
The above description and Examples are for illustrative purposes only. They are not intended to limit the scope of the inventions, as defined i:. the following claims.
Claims (9)
1. A peritoneal dialysis solution comprising:
physiological salts in concentrations sufficient to affect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane into the solution, and a mixture of amino acids sufficient to contribute to protein synthesis and a positive nitrogen balance, wherein tryptophan is present in a glycine-tryptophan form.
physiological salts in concentrations sufficient to affect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane into the solution, and a mixture of amino acids sufficient to contribute to protein synthesis and a positive nitrogen balance, wherein tryptophan is present in a glycine-tryptophan form.
2. A solution according to claim 1, wherein the mixture of amino acids includes at least one amino acid selected from the group consisting of arginine, alanine, proline, glycine, serine, tyrosine, and cysteine.
3. A solution according to claim 1, wherein the mixture of amino acids includes at least one amino acid selected from the group consisting of valine, leucine, lysine, isoleucine, methionine, histidine, threonine, and phenylalanine, at least one of the selected amino acid being in its dipeptide form.
4. A solution according to claim 3, wherein the amino acid in dipeptide form is present in concentration of about 2 mM to about 10 mM, based upon liter of solution.
5. A solution according to any one of claims 1 to 4 and further including an osmotic solute in concentrations sufficient to create an osmotic pressure to effect the removal of water by diffusion from the patient's blood across the peritoneal membrane into the solution.
6. A solution according to claim 5, wherein the osmotic solute is selected from the group consisting of glucose and glycerol.
7. A use of a solution, comprising physiological salts in concentrations sufficient to effect the removal of solutes by diffusion from the patient's blood across the peritoneal membrane into the solution, as a peritoneal dialysis agent in combination with a mixture of amino acids sufficient to maintain a positive nitrogen balance, wherein tryptophan is present in a glycine-tryptophan form.
8. The use according to claim 7, further including an osmotic solute in concentrations sufficient to create an osmotic pressure to effect the removal of water by diffusion from the patient's blood across the peritoneal membrane into the solution.
9. The use according to Claim 8, wherein the osmotic solute is selected from glucose and glycerol.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002626680A CA2626680A1 (en) | 1992-02-04 | 1992-02-04 | Peritoneal dialysis composition and method usable during and after peritonitis |
| CA002102234A CA2102234C (en) | 1992-02-04 | 1992-02-04 | Peritoneal dialysis composition and method usable during and after peritonitis |
| PCT/US1992/000972 WO1993014796A1 (en) | 1992-02-04 | 1992-02-04 | Peritoneal dialysis composition and method usable during and after peritonitis |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002102234A CA2102234C (en) | 1992-02-04 | 1992-02-04 | Peritoneal dialysis composition and method usable during and after peritonitis |
| PCT/US1992/000972 WO1993014796A1 (en) | 1992-02-04 | 1992-02-04 | Peritoneal dialysis composition and method usable during and after peritonitis |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002626680A Division CA2626680A1 (en) | 1992-02-04 | 1992-02-04 | Peritoneal dialysis composition and method usable during and after peritonitis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2102234A1 CA2102234A1 (en) | 1993-08-05 |
| CA2102234C true CA2102234C (en) | 2008-11-18 |
Family
ID=25676468
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002102234A Expired - Fee Related CA2102234C (en) | 1992-02-04 | 1992-02-04 | Peritoneal dialysis composition and method usable during and after peritonitis |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA2102234C (en) |
| WO (1) | WO1993014796A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0325292D0 (en) * | 2003-10-29 | 2003-12-03 | Wivenhoe Technology Ltd | Treatment of sugar solutions |
| US20100286085A1 (en) | 2007-10-01 | 2010-11-11 | Seikagaku Corporation | Novel chondroitin sulfate having decreased molecular weight and use thereof |
| RU2465810C1 (en) * | 2011-10-26 | 2012-11-10 | Государственное учреждение здравоохранения Научно-исследовательский институт скорой помощи имени Н.В. Склифосовского Департамента здравоохранения г. Москвы | Method for choosing surgical approach in peritonitis on basis of diagnostic videolaparoscopy |
| ITMI20120896A1 (en) | 2012-05-23 | 2013-11-24 | Bongulielmi Reto | CONDROITIN FOR USE IN MEDICINE |
| RU2770281C1 (en) * | 2021-10-26 | 2022-04-15 | Государственное бюджетное учреждение здравоохранения города Москвы «Научно-исследовательский институт скорой помощи им. Н.В. Склифосовского Департамента здравоохранения города Москвы» (ГБУЗ "НИИ СП ИМ. Н.В.СКЛИФОСОВСКОГО ДЗМ") | Method for selecting the surgical treatment tactics for different appendicular peritonitis |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2041377B (en) * | 1979-01-22 | 1983-09-28 | Woodroof Lab Inc | Bio compatible and blood compatible materials and methods |
| US4339433A (en) * | 1981-01-09 | 1982-07-13 | Baxter Travenol Laboratories, Inc. | Additives for peritoneal dialysis solutions |
| US4574085A (en) * | 1981-05-15 | 1986-03-04 | Baxter Travenol Laboratories, Inc. | Method for using dialysis solution containing glycerol |
| US4761237A (en) * | 1981-07-10 | 1988-08-02 | Baxter Travenol Laboratories, Inc. | Peritoneal dialysis solution containing carbohydrate polymers |
| US4886789A (en) * | 1983-01-12 | 1989-12-12 | M. L. Laboratories Plc | Peritoneal dialysis and compositions for use therein |
| US4863907A (en) * | 1984-06-29 | 1989-09-05 | Seikagaku Kogyo Co., Ltd. | Crosslinked glycosaminoglycans and their use |
| JPS61247466A (en) * | 1985-04-25 | 1986-11-04 | テルモ株式会社 | Dialytic solution for abdominal membrane dialysis |
| EP0218900B1 (en) * | 1985-09-10 | 1992-01-22 | Research Corporation Technologies, Inc. | Osmotic agents for peritoneal dialysis |
| US4976683A (en) * | 1986-06-20 | 1990-12-11 | Abbott Laboratories | Peritoneal dialysis method |
-
1992
- 1992-02-04 WO PCT/US1992/000972 patent/WO1993014796A1/en active Application Filing
- 1992-02-04 CA CA002102234A patent/CA2102234C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993014796A1 (en) | 1993-08-05 |
| CA2102234A1 (en) | 1993-08-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5597805A (en) | Peritoneal dialysis solutions | |
| US5092838A (en) | Histidine buffered peritoneal dialysis solution | |
| US5629025A (en) | Low sodium peritoneal dialysis solution | |
| KR100478181B1 (en) | Drugs for relieving carbonyl stress and peritoneal dialysates | |
| EP0958832B1 (en) | Albumin containing peritoneal dialysis fluid | |
| EP1753437B1 (en) | Bicarbonate-based peritoneal dialysis solutions | |
| EP1585531B1 (en) | Biocompatible dialysis fluids containing icodextrins | |
| Hanning et al. | Effectiveness and nutritional consequences of amino acid-based vs glucose-based dialysis solutions in infants and children receiving CAPD | |
| US20030232093A1 (en) | Stable bicarbonate-based solution in a single container | |
| JPS61247466A (en) | Dialytic solution for abdominal membrane dialysis | |
| CA2102234C (en) | Peritoneal dialysis composition and method usable during and after peritonitis | |
| JPH10505322A (en) | Dialysate containing casein-derived peptide as osmotic agent and bicarbonate ion as buffer | |
| JP2000038348A (en) | Albumin-containing peritoneal dialysis solution | |
| JP2006305345A (en) | Drug for relieving carbonyl stress state and peritoneal dialysate | |
| CA2626680A1 (en) | Peritoneal dialysis composition and method usable during and after peritonitis | |
| US11964087B2 (en) | Peritoneal dialysis solution | |
| Gokal | Peritoneal dialysis solutions: nutritional aspects | |
| Gokal | New peritoneal dialysis solutions | |
| Gennari | Comparative physiology of acetate and bicarbonate alkalinization | |
| William et al. | New perspectives in peritoneal dialysis fluids | |
| WO2004014355A1 (en) | A peritoneal dialysis solution comprising a pyruvate | |
| Krediet | Long-term peritoneal dialysis-impact of peritoneal membrane changes and newer solutions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |