CA1257203A - Dialysis with monophosphoryl lipid a - Google Patents
Dialysis with monophosphoryl lipid aInfo
- Publication number
- CA1257203A CA1257203A CA000482739A CA482739A CA1257203A CA 1257203 A CA1257203 A CA 1257203A CA 000482739 A CA000482739 A CA 000482739A CA 482739 A CA482739 A CA 482739A CA 1257203 A CA1257203 A CA 1257203A
- Authority
- CA
- Canada
- Prior art keywords
- peritoneal dialysis
- dialysis solution
- peritoneal
- monophosphoryl lipid
- solution
- 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
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- 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
Abstract
ABSTRACT OF DISCLOSURE
Monophosphoryl lipid A is placed into the peritoneal cavity of a patient, typically by addition to peritoneal dialysis solution, in sufficient dose to suppress symptoms of peritonitis.
Monophosphoryl lipid A is placed into the peritoneal cavity of a patient, typically by addition to peritoneal dialysis solution, in sufficient dose to suppress symptoms of peritonitis.
Description
7~()3 DIALYSIS WITH MONOPHOSPHORYL LIPID A
Technical Field and Prior Art Chronic peritoneal dialysis has been a highly successful means for the treatment of patients with end stage renal failure. Dialysis solution is passed into the peritoneal cavity and allowed to dwell, typically for a period of hours, while it engages in dialysis across the membranes of the peritoneal cavity for removal of metabolic waste products. The dialysis solution is then removed from the peritoneal cavity, and, in the case of continuous ambulatory peritoneal dialysis, promptly replaced with another quantity of fresh dialysis solution.
One significant drawback to the various forms of peritoneal dialysis is that patients who engage in it may be subject to peritonitis. While it has been found that peritonitis can be handled with antibiotics, it is potentially among the most serious of infections, due to the sensitivity of the peritoneal cavity to infection.
In accordance with this invention, a technique is proposed for the suppression of peritonitis and its symptoms, particularly that peritonitis which takes place in patients who undergo peritoneal dialysis.
Keane et al, Canadian Patent No. 1,219,212, issued 25 March 17, 1987 and en~itled "Opsonins in Peritoneal Dialysis" teaches the use of opsonins such as immunoglobulin G in peritoneal dialysis solution to suppress peritonitis.
In the article by Edgar Ribi in the Journal of ~0 Biological Response Modifiers, Volume 3 (1): 1-9 (1984), the material monophosphoryl lipid A is described, along with a method of its preparation. The material is commercially available from Ribi ImmunoChem Research, Inc. of Hamilton, Montana.
Monophosphoryl lipid A (also called detoxified endotoxin) is a chemically modified component of bacterial endotoxin, a component of the outer cell wall of gram-negative bacteria. Bacterial endotoxin is an extremely toxic material to humans, comprising a )3 ketodeoxyoctanate and diphosphoryl lipid A, which is a phosphorylated glucosamine disaccharide unit with ester-and amide-linked long-chain fatty acids. As taught in the Ribi article, the ketodeoxyoctanate moiety can be selectively removed under mildly acidic conditions of pH 4.5. The resulting diphosphoryl lipid A fraction, however, retains the full toxicity of the parent endotoxin, as determined by lethality in chick embryos. However, further treatment of the diphosphoryl lipid A with dilute hydrochloric acid results in selective removal of the phosphate group at the reducing end of the glucosamine disaccharide unit, to form monophosphoryl lipid A, which is substantially non toxic at effective doses in accordance with this invention.
Description of the Invention In accordance with an aspect of this invention, monophosphoryl lipid A may be administered to the peritoneal cavity of a patient in sufficient dose to suppress symptoms of peritonitis, and also, most
Technical Field and Prior Art Chronic peritoneal dialysis has been a highly successful means for the treatment of patients with end stage renal failure. Dialysis solution is passed into the peritoneal cavity and allowed to dwell, typically for a period of hours, while it engages in dialysis across the membranes of the peritoneal cavity for removal of metabolic waste products. The dialysis solution is then removed from the peritoneal cavity, and, in the case of continuous ambulatory peritoneal dialysis, promptly replaced with another quantity of fresh dialysis solution.
One significant drawback to the various forms of peritoneal dialysis is that patients who engage in it may be subject to peritonitis. While it has been found that peritonitis can be handled with antibiotics, it is potentially among the most serious of infections, due to the sensitivity of the peritoneal cavity to infection.
In accordance with this invention, a technique is proposed for the suppression of peritonitis and its symptoms, particularly that peritonitis which takes place in patients who undergo peritoneal dialysis.
Keane et al, Canadian Patent No. 1,219,212, issued 25 March 17, 1987 and en~itled "Opsonins in Peritoneal Dialysis" teaches the use of opsonins such as immunoglobulin G in peritoneal dialysis solution to suppress peritonitis.
In the article by Edgar Ribi in the Journal of ~0 Biological Response Modifiers, Volume 3 (1): 1-9 (1984), the material monophosphoryl lipid A is described, along with a method of its preparation. The material is commercially available from Ribi ImmunoChem Research, Inc. of Hamilton, Montana.
Monophosphoryl lipid A (also called detoxified endotoxin) is a chemically modified component of bacterial endotoxin, a component of the outer cell wall of gram-negative bacteria. Bacterial endotoxin is an extremely toxic material to humans, comprising a )3 ketodeoxyoctanate and diphosphoryl lipid A, which is a phosphorylated glucosamine disaccharide unit with ester-and amide-linked long-chain fatty acids. As taught in the Ribi article, the ketodeoxyoctanate moiety can be selectively removed under mildly acidic conditions of pH 4.5. The resulting diphosphoryl lipid A fraction, however, retains the full toxicity of the parent endotoxin, as determined by lethality in chick embryos. However, further treatment of the diphosphoryl lipid A with dilute hydrochloric acid results in selective removal of the phosphate group at the reducing end of the glucosamine disaccharide unit, to form monophosphoryl lipid A, which is substantially non toxic at effective doses in accordance with this invention.
Description of the Invention In accordance with an aspect of this invention, monophosphoryl lipid A may be administered to the peritoneal cavity of a patient in sufficient dose to suppress symptoms of peritonitis, and also, most
2~ preferably, in a dose which is less than that necessary to create any toxic reaction.
Other aspects of this invention are as follows:
In peritoneal dialysis solution which comprises a water solution of physiologically tolerable pH, having physiological salts and an osmotic agent, each in safe and effective concentrations to effect peritoneal dialysis when placed in the peritoneal cavity of a patient, the improvement comprising, in combination:
monophosphoryl lipid A dispersed in said peritoneal ~0 dialysis solution in sufficient concentration to suppress symptoms of peritonitis when inserted into the peritoneal cavity in a peritoneal dialysis procedure.
The method of performing peritoneal dialysis on a patient by administering peritoneal dialysis solution to the peritoneal cavity of a patient, and thereafter withdrawing said solution from the peritoneal cavity, the improvement comprising: using a peritoneal dialysis solution which contains from 0.5 to 50 micrograms of i .~
2a ~ 7203 monophosphoryl lipid A per ml. of peritoneal dialysis solution.
The monophosphoryl lipid A is most desirably mixed with a peritoneal dialysis solution, preferably in a S concentration of 0.3 - 100 micrograms. of monophosphoryl lipid A per ml. of peritoneal dialysis solution. A
conventional peritoneal dialysis procedure then may be performed, making use of such modified peritoneal dialysis solution, and making use of any desired mode 2( ~0 ~5 ,, .
b 72~3 of peritoneal dialysis, for example, continuous ambulatory peritoneal dialysis or continuous cycling peritoneal dialysis.
It has been found that the presence of monophosphoryl lipid A in the peritoneal cavity results in strong suppression of peritonitis and, when used in the concentration ran~e stated above, significant toxic symptoms are not expected..
Any desired, known peritoneal dialysis solut~on may be used in con~iunction with this invention where solution is administered into the peritoneal cavity and thereafter withdrawn. The necessary parameters and inqredients for peritoneal dialysis solutions are well known, and those skilled in the art are capable of formulating without difficulty any of a large variety of peritoneal dialysis solutions. It is easily calculable what concentrations of solute may be used in peritoneal dialysis solutions. It is also well known and generally predictable which solutes may be used in peritoneal dialysis solutions and which may not.
Typically, as is well known, each peritoneal dialysis solution should contain physiological salts, for example, mixtures of salts such as sodium chloride, sodium lactate, calcium chloride, ma~nesium chloride, and perhaps a small amount of a potassium salt such as potassium chloride. An osmotic a~ent is also typically present in peritoneal dialysis solution, to cause ultrafiltration to take place through the patient's peritoneal cavity for removal of water from the patient. This is currently done hy placing in a typical peritoneal dialysis solution from 1.5 4.25 gra~s of dextrose, althouah certain other osmotic a~ents have been suggested in the prior art, for example, glycerol. It is intended that the invention of this application may be used with any peritoneal dialysis solution.
-4- ~ 203 A typical peritoneal dialysis solution which may be utilized in this invention may contain, per 100 ml., 1.5 to 4.~5 grams of dextrose hydrous U.S.P., 500 mg. of sodium chloride U.S.P., 448 ma. of sodium lactate, 25.7 mg. of calcium chloride U.S.P., and 5.08 mg. of magnesium chloride U.S.P.. The pH may preferably be about 5.5, as is conventional in current commercially available peritoneal dialysis solutions. Broadly, the pH may range from about pH 5 to 7.
In accordance with this invention, preferably from 0.5 to 5~ micronrams of lyophilized monophosphoryl lipid A may be added per ml. of peritoneal dialysis solution, typically under aseptic conditions. Thereafter, the peritoneal dialysis procedure may take place in entirely conventional manner. The improved peritoneal dialysis solution of this invention exhibits a strong prophylactic or preventative effect against peritonitis in patients, who otherwise would exhibit susceptibility toward that disease. The improved peritoneal dialysis solution of this invention is also helieved to exhibit a significant curative effect against peritonitis which already exists at the initial administration of the solution of this invention. However, it is preferred to make use of the solution of this invention to prevent peritonitis, rather than to attempt to cure it exclusively through the use of peritoneal dialysis solution as herein modified.
Example Dianeal~ peritoneal dialysis solution containinq 1.5%
dextrose, sold by Travenol Laboratories, Inc., was modified by the addition of 35 micrograms per ml. of monophosphoryl lipid A
(sold by Ribi Im~unoChem Research, Inc.). The mixing of the materials was performed under aseptic conditions. Then, 0.5 ml.
-5- ~ 203 of the resultin~ modified peritoneal dialysis solution was peritoneally injected into each of a group of CF-l mice. Control CF-l mice received 0.5 ml. of the unmodified peritoneal dialysis solution.
On the next day there was administered to the same CF-l mice, and the control mice, a peritoneal injection of 10 s.
epidermis bacteria.
The mice were then monitored for three days and deaths noted.
Of the control mice which had not received monophosphoryl lipid A, two out of twenty survived over three days. The two survivors were quite debilitated and inactive at the end of the three day period, although surviving.
Amon~ the mice treated as above with monophosphoryl lipid A, fifteen out of nineteen mice survived the three day period. Furthermore, most of the survivors exhibited far ~reater activity and other signs indicatin~ significantly better health, when compared with the control animals.
Accordingly, it was concluded that the improved peritoneal dialysis solution of this invention exhibits a strong capability to suppress peritonitis against a major bacterial challenge.
The above has been offered for illustrative purposes only, and is not intended to limit the scope of the invention of this application, which is as defined in the claims below.
Other aspects of this invention are as follows:
In peritoneal dialysis solution which comprises a water solution of physiologically tolerable pH, having physiological salts and an osmotic agent, each in safe and effective concentrations to effect peritoneal dialysis when placed in the peritoneal cavity of a patient, the improvement comprising, in combination:
monophosphoryl lipid A dispersed in said peritoneal ~0 dialysis solution in sufficient concentration to suppress symptoms of peritonitis when inserted into the peritoneal cavity in a peritoneal dialysis procedure.
The method of performing peritoneal dialysis on a patient by administering peritoneal dialysis solution to the peritoneal cavity of a patient, and thereafter withdrawing said solution from the peritoneal cavity, the improvement comprising: using a peritoneal dialysis solution which contains from 0.5 to 50 micrograms of i .~
2a ~ 7203 monophosphoryl lipid A per ml. of peritoneal dialysis solution.
The monophosphoryl lipid A is most desirably mixed with a peritoneal dialysis solution, preferably in a S concentration of 0.3 - 100 micrograms. of monophosphoryl lipid A per ml. of peritoneal dialysis solution. A
conventional peritoneal dialysis procedure then may be performed, making use of such modified peritoneal dialysis solution, and making use of any desired mode 2( ~0 ~5 ,, .
b 72~3 of peritoneal dialysis, for example, continuous ambulatory peritoneal dialysis or continuous cycling peritoneal dialysis.
It has been found that the presence of monophosphoryl lipid A in the peritoneal cavity results in strong suppression of peritonitis and, when used in the concentration ran~e stated above, significant toxic symptoms are not expected..
Any desired, known peritoneal dialysis solut~on may be used in con~iunction with this invention where solution is administered into the peritoneal cavity and thereafter withdrawn. The necessary parameters and inqredients for peritoneal dialysis solutions are well known, and those skilled in the art are capable of formulating without difficulty any of a large variety of peritoneal dialysis solutions. It is easily calculable what concentrations of solute may be used in peritoneal dialysis solutions. It is also well known and generally predictable which solutes may be used in peritoneal dialysis solutions and which may not.
Typically, as is well known, each peritoneal dialysis solution should contain physiological salts, for example, mixtures of salts such as sodium chloride, sodium lactate, calcium chloride, ma~nesium chloride, and perhaps a small amount of a potassium salt such as potassium chloride. An osmotic a~ent is also typically present in peritoneal dialysis solution, to cause ultrafiltration to take place through the patient's peritoneal cavity for removal of water from the patient. This is currently done hy placing in a typical peritoneal dialysis solution from 1.5 4.25 gra~s of dextrose, althouah certain other osmotic a~ents have been suggested in the prior art, for example, glycerol. It is intended that the invention of this application may be used with any peritoneal dialysis solution.
-4- ~ 203 A typical peritoneal dialysis solution which may be utilized in this invention may contain, per 100 ml., 1.5 to 4.~5 grams of dextrose hydrous U.S.P., 500 mg. of sodium chloride U.S.P., 448 ma. of sodium lactate, 25.7 mg. of calcium chloride U.S.P., and 5.08 mg. of magnesium chloride U.S.P.. The pH may preferably be about 5.5, as is conventional in current commercially available peritoneal dialysis solutions. Broadly, the pH may range from about pH 5 to 7.
In accordance with this invention, preferably from 0.5 to 5~ micronrams of lyophilized monophosphoryl lipid A may be added per ml. of peritoneal dialysis solution, typically under aseptic conditions. Thereafter, the peritoneal dialysis procedure may take place in entirely conventional manner. The improved peritoneal dialysis solution of this invention exhibits a strong prophylactic or preventative effect against peritonitis in patients, who otherwise would exhibit susceptibility toward that disease. The improved peritoneal dialysis solution of this invention is also helieved to exhibit a significant curative effect against peritonitis which already exists at the initial administration of the solution of this invention. However, it is preferred to make use of the solution of this invention to prevent peritonitis, rather than to attempt to cure it exclusively through the use of peritoneal dialysis solution as herein modified.
Example Dianeal~ peritoneal dialysis solution containinq 1.5%
dextrose, sold by Travenol Laboratories, Inc., was modified by the addition of 35 micrograms per ml. of monophosphoryl lipid A
(sold by Ribi Im~unoChem Research, Inc.). The mixing of the materials was performed under aseptic conditions. Then, 0.5 ml.
-5- ~ 203 of the resultin~ modified peritoneal dialysis solution was peritoneally injected into each of a group of CF-l mice. Control CF-l mice received 0.5 ml. of the unmodified peritoneal dialysis solution.
On the next day there was administered to the same CF-l mice, and the control mice, a peritoneal injection of 10 s.
epidermis bacteria.
The mice were then monitored for three days and deaths noted.
Of the control mice which had not received monophosphoryl lipid A, two out of twenty survived over three days. The two survivors were quite debilitated and inactive at the end of the three day period, although surviving.
Amon~ the mice treated as above with monophosphoryl lipid A, fifteen out of nineteen mice survived the three day period. Furthermore, most of the survivors exhibited far ~reater activity and other signs indicatin~ significantly better health, when compared with the control animals.
Accordingly, it was concluded that the improved peritoneal dialysis solution of this invention exhibits a strong capability to suppress peritonitis against a major bacterial challenge.
The above has been offered for illustrative purposes only, and is not intended to limit the scope of the invention of this application, which is as defined in the claims below.
Claims (4)
1. In peritoneal dialysis solution which comprises a water solution of physiologically tolerable pH, having physiological salts and an osmotic agent, each in safe and effective concentrations to effect peritoneal dialysis when placed in the peritoneal cavity of a patent, the improvement comprising, in combination:
monophosphoryl lipid A dispersed in said peritoneal dialysis solution in sufficient concentration to suppress symptoms of peritonitis when inserted into the peritoneal cavity in a peritoneal dialysis procedure.
monophosphoryl lipid A dispersed in said peritoneal dialysis solution in sufficient concentration to suppress symptoms of peritonitis when inserted into the peritoneal cavity in a peritoneal dialysis procedure.
2. The peritoneal dialysis solution of Claim 1 in which 0.3 to 100 micrograms of monophosphoryl lipid A are present per ml. of peritoneal dialysis solution.
3. The peritoneal dialysis solution of Claim 2 in which from 0.5 to 50 micrograms per ml. of monophosphoryl lipid A are present per ml. of peritoneal dialysis solution.
4. The peritoneal dialysis solution of Claim 1 having a pH of about 5.5 and containing, per 100 ml.
of solution, from 1.5 to 4.25 grams of dextrose, and sodium chloride, sodium lactate, calcium chloride, and magnesium chloride in physiological concentrations.
of solution, from 1.5 to 4.25 grams of dextrose, and sodium chloride, sodium lactate, calcium chloride, and magnesium chloride in physiological concentrations.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61541284A | 1984-05-30 | 1984-05-30 | |
| US615,412 | 1984-05-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1257203A true CA1257203A (en) | 1989-07-11 |
Family
ID=24465263
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000482739A Expired CA1257203A (en) | 1984-05-30 | 1985-05-29 | Dialysis with monophosphoryl lipid a |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0183773A4 (en) |
| JP (1) | JPS61502234A (en) |
| CA (1) | CA1257203A (en) |
| WO (1) | WO1985005555A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4976683A (en) * | 1986-06-20 | 1990-12-11 | Abbott Laboratories | Peritoneal dialysis method |
| WO2000042994A2 (en) * | 1999-01-21 | 2000-07-27 | North Shore-Long Island Jewish Research Institute | Inhibition of bacterial dissemination |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4148877A (en) * | 1975-12-29 | 1979-04-10 | Choay S. A. | Fraction capable of inducing in vivo a resistance to bacterial infections, process for obtaining said fraction from bacteria and drugs containing said fraction |
| US4335716A (en) * | 1979-02-12 | 1982-06-22 | University Of Utah Research Foundation | Composition and method for prevention and treatment of dialysis induced peritonitis |
-
1985
- 1985-05-09 WO PCT/US1985/000842 patent/WO1985005555A1/en not_active Application Discontinuation
- 1985-05-09 JP JP60502363A patent/JPS61502234A/en active Pending
- 1985-05-09 EP EP19850902767 patent/EP0183773A4/en not_active Withdrawn
- 1985-05-29 CA CA000482739A patent/CA1257203A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| WO1985005555A1 (en) | 1985-12-19 |
| JPS61502234A (en) | 1986-10-09 |
| EP0183773A1 (en) | 1986-06-11 |
| EP0183773A4 (en) | 1988-06-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2322236B1 (en) | Bicarbonate-based solutions for dialysis therapies | |
| US5906978A (en) | Method for iron delivery to a patient by transfer from dialysate | |
| EP0456806B1 (en) | Histidine buffered peritoneal dialysis solution | |
| Yolken et al. | Acute fluoride poisoning | |
| US4906616A (en) | Hydrolyzed sodium casein compositions for dialysis procedures | |
| EP0078832A1 (en) | Dialysis solution containing glycerol. | |
| KR101338766B1 (en) | Peritoneal dialysis fluid | |
| JP3676362B2 (en) | Improved peritoneal dialysis fluid containing polypeptides. | |
| Murphy et al. | A case of poisoning with mercuric chloride | |
| CA1257203A (en) | Dialysis with monophosphoryl lipid a | |
| JP2000038348A (en) | Albumin-containing peritoneal dialysis solution | |
| Finnegan et al. | Overwhelming post-splenectomy infection with group B Streptococcus | |
| SE448882B (en) | PROCEDURE FOR THE EXTRACTION OF MYELOPEROXIDAS AND PHARMACEUTICAL COMPOSITION CONTAINING THE ENZYME | |
| CA1219212A (en) | Opsonins in peritoneal dialysis | |
| Ringoir et al. | Phagocytic function in the uremic patient | |
| KR20020031404A (en) | Blood plasma replacement solution | |
| Page, PF, Kallmeyer, JC & Malherbe | Modification of Britton's technique for the treatment of intractable cirrhotic ascites | |
| Berman et al. | Hemodialysis-associated infections: treatment with cephapirin | |
| JPS6251616A (en) | Glucide transfusion agent | |
| JPS59501983A (en) | Opsonins in peritoneal dialysis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |