DIALYSIS WITH MONOPHOSPHORYL LIPID A

Abstract: 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: DIALYSIS WITH MONOPHOSPHORYL LIPID A Technical Field and Prior Art Chronic peritoneal dialys s 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, pending Patent Application Serial No. 435,806, filed October 21, 1982 and entitled "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 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 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 lethal ty 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 l pid A, which is substantially non toxic at effective doses in accordance with this invention. Description of the Invention In accordance with 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 preferably, in a dose which is less than that necessary to create any toxic reaction. The monophosphoryl lipid A is most desirably mixed with a peritoneal dialysis solution, preferably in a 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 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 range stated above, significant toxic symptoms are not expected.. Any desired, known peritoneal dialysis solution may be used in conjunction with this invention where solution is administered into the peritoneal cavity and thereafter withdrawn. The necessary parameters and ingredients 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, magnesium chloride, and perhaps a small amount of a potassium salt such as potassium chloride. An osmotic agent 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 by placing in a typical peritoneal dialysis solution from 1.5 - 4.25 grams of dextrose, although certain other osmotic agents have been suggested in the prior art, for example, σlycerol . It is intended that the invention of this application may be used with any peritoneal dialysis solution. A typical peritoneal dialysis solution which may be util zed in this invention may contain, per 100 ml., 1.5 to 4.25 grams of dextrose hydrous U.S.P., 500 mg. of sodium chloride U.S.P., 448 mg. 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 comrnercfally 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 50 micrograms 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 believed 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 containing ~ .5% dextrose, sold by Travenol Laboratories, Inc., was modified by the addition of 35 micrograms per ml. of monophosphoryl lipid A (sold by Ribi ImmunoChem Research, Inc.). The mixing of the materials was performed under aseptic conditions. Then, 0.5 ml. of the resulting modified peritoneal dialysis solution was peritoneally injected into each of a group of CF-1 mice. Control CF-1 mice received 0.5 ml. of the unmodified peritoneal dialysis solution. On the next day there was administered to the same CF-1 g mice, and the control mice, a peritoneal injection of 10 • epiderm s 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. Among 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 greater activity and other signs indicating 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: THAT WHICH IS CLAIMED IS: 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 l pid 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 l pid 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 -re 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. 5. The method of administering monophosphoryl lipid A into the peritoneal cavity of a patient in sufficient dose to suppress symptoms of peritonitis. 6. The method.of Claim 5 in which said monophosphoryl l pid A is administered to the peritoneal cavity while dispersed in peritoneal dialysis solution. 7. The method of Claim 6 in which the concentration of monophosphoryl l pid A in said peritoneal dialysis solution s 0.3 to 100 micrograms per ml. 8. 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 monophosphoryl lipid A per ml. of peritoneal dialysis solution.

Inventors: DULEK MARY H, PEARSON FREDERICK C, SALIT MARC G, DULEK, MARY, H., PEARSON, FREDERICK, C., SALIT, MARC, G.
Applicants: BAXTER TRAVENOL LAB, BAXTER TRAVENOL LABORATORIES, INC.
Application year: 1985
Main classification: A61M5
IPC codes: A61K31, A61M1