Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-10-18
2003-03-25
Gitomer, Ralph (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C604S029000
Reexamination Certificate
active
06537976
ABSTRACT:
FIELD OF THE INVENTION
This invention generally relates to methods and compositions for hemodialysis and peritoneal dialysis. In particular, the invention relates to the use of a dialysate solution comprising at least one vitamin to improve the nutritional status of a dialysis patient.
BACKGROUND OF THE INVENTION
A. Dialysis
Dialysis provides a method for supplementing or replacing renal function in patients with renal failure. Therefore, dialysis helps maintain homeostasis in patients with end stage kidney failure. Dialysis is defined as the movement of solute and water through a semipermeable membrane which separates the patient's blood from the dialysate solution. The semipermeable membrane can either be the peritoneal membrane in peritoneal dialysis patients or an artificial dialyzer membrane in hemodialysis patients. Molecules transfer across this semipermeable membrane by the processes of diffusion and convection. In hemodialysis, the patient's blood is passed through an artificial kidney dialysis machine. A membrane in the machine acts as an artificial kidney for cleansing the blood. Because it is an extracorporeal system that requires special machinery, there are certain inherent disadvantages with hemodialysis.
To overcome the disadvantages associated with hemodialysis, peritoneal dialysis was developed. Peritoneal dialysis utilizes the patient's own peritoneum as a semi-permeable membrane. The peritoneum is the membranous lining of the body cavity that due to the large number of blood vessels and capillaries, is capable of acting as a natural semi-permeable membrane. In peritoneal dialysis, a dialysis solution is introduced into the peritoneal cavity utilizing a catheter. After a sufficient period of time, an exchange of solutes between the dialysate and the blood is achieved. Fluid removal is achieved by providing a suitable osmotic gradient from the blood to the dialysate to permit water outflow from the blood. The dialysis solution is then simply drained from the body cavity through the catheter.
Modern hemodialysis machines utilize a sophisticated proportioning system to mix concentrated sodium bicarbonate solution with an acid concentrate solution (containing NaCl, KCl, CaCl
2,
Na-Acetate, and glucose) and purified water. For example in the widely used Fresenius system, the ratio of acid:bicarbonate:water:total is 1:1.23:32.77:35. Therefore, 1 part of the concentrated bicarbonate solution is mixed with 27.5 parts of the other (acid+water), to make the final dialysate. Concentrated bicarbonate solution is either prepared from powder in the dialysis facility or is supplied by the manufacturer as a ready-made sterile solution. In making the bicarbonate concentrate, purified water is pumped from the water source by a pipe into a large tank. Sodium bicarbonate is supplied as a powder packaged in plastic bags and the contents of each bag are mixed with purified water in the tank, to make 25 gallons (94.6 liters) of bicarbonate solution. After thorough mixing with a stirrer the concentrated solution is dispensed into 20 liter plastic receptacles, that are capped. The non-sterile concentrate is used within 24 hr of its preparation. In dialysis practice bicarbonate concentrate is usually prepared in 25-50 gallon quantities.
Various other compounds, in addition to salts, buffers, and carbohydrates, may be added to dialysate solutions. U.S. Pat. No. 5,230,996 discloses methods and compositions for the treatment and prevention of cardiovascular disease in which ascorbate, binding inhibitors, and antioxidants are added to a hemodialysis solution. U.S. Pat. No. 5,597,805 discloses the addition of dipeptides and free radical scavengers such as vitamin E, procysteine, superoxide dismutase, and chondroitan sulfate to peritoneal dialysis solutions for use during and immediately after an episode of peritonitis. Vitamin C is added to the dialysate solution in some centers in order to neutralize chloramine and prevent hemolytic anemia (Kjellstrand et al. (1974),
Nephron
13:427-433), but high levels of ascorbic acid in the dialysate may predispose to oxalemia and vascular disease.
B. Vitamin Deficiencies in Dialysis Patients
Patients with chronic renal failure are at an increased risk for multiple vitamin deficiencies. Vitamin intake is often decreased in uremic patients because of anorexia and reduced food intake. Also, the diets prescribed for these patients frequently contain less than the recommended daily allowances for certain water soluble vitamins. The metabolism of folate and pyridoxine is abnormal in renal failure and many drugs have been reported to impair the metabolism and pharmacology of vitamins.
Furthermore, water soluble vitamins are removed by dialysis. In hemodialysis, some of the factors that may influence the degree of loss of a specific vitamin are the size of the vitamin molecule in relation to the pore size of the dialysis membrane, the number of pores, the blood and dialysate flow rate, the duration of dialysis, the aging of the reused membrane, and the specific dialysis fluid composition. In addition, vitamins that are bound to large protein molecules are less likely to pass across the dialysis membrane. In peritoneal dialysis the peritoneum of the patient serves as the dialysis membrane and absorption plays a role in nutrient exchange. Factors influencing the flux of vitamins in peritoneal dialysis include the molalities of the different dialysates, which can affect the activity of specific exchange processes in the peritoneum, and peritonitis or sclerosis of the membrane.
C. Vitamin Supplementation in Dialysis Patients
While fat soluble vitamins are known to accumulate in uremia, deficiencies of water soluble vitamins have been reported in dialysis patients. The prescription of oral water-soluble vitamins is, therefore, a routine practice in many dialysis units.
Among the ten major dialysis centers in Australia for example, Allman reported that an oral supplement of thiamin, riboflavin, pyridoxine, ascorbic acid and nicotinamide was given in all, and folic acid was given in eight of the ten centers (Allman et al. (1989),
Medical Journal of Australia
150:130-33).
On the other hand, the need for routine vitamin supplementation in dialysis patients has been questioned by some practitioners, based on the facts that hemodialysis patients are no longer on severely restricted diets, that dialysate losses may be lower than previously believed, and that recent studies in patients receiving systematic supplementation showed excessively high vitamin levels. In one study, forty-three chronic hemodialysis patients not prescribed biotin, riboflavin, or vitamin B
12
supplements were found to maintain normal serum levels of these vitamins for period of one year (Descombes et al. (1993),
Kidney International
43:1319-28). Furthermore, despite the water solubility of thiamine, riboflavin, pantothenic acid and biotin, these compounds are frequently maintained in the normal range in chronic dialysis patients. It has been postulated that the losses of these vitamins into the dialysate might be offset by the reduction in renal catabolism or urine loss in these patients. Some clinicians therefore believe that no systematic supplement is indicated for biotin, riboflavin, or vitamin B
12
in maintenance hemodialysis patents. However, vitamin supplementation with ascorbic acid, pyridoxine, and folic acid is needed to correct vitamin deficiencies; and despite an absence of true thiamine deficiency, thiamine supplementation is needed to restore erythrocyte transketolase activity in chronic dialysis patients.
D. Carnitine Deficiencies in Dialysis Patients
Carnitine is an amino acid derivative which is essential for the transport of long-chain fatty acids across the mitochondria, where fatty acids are oxidized to provide energy for muscle and other cells. Signs of carnitine deficiency include muscle weakness, cardiac dysfunction, hypoglycemia, and changes in lipid profile such as elevated triglycerides. Carnitine is water soluble and not highly bound to any
Drinker Biddle & Reath LLP
Gitomer Ralph
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