Therapies for acute renal failure

a renal failure and therapy technology, applied in the field of renal disease treatment methods, can solve the problems of acute renal failure, failure of other major organ systems and death, significant permanent and/or progressive damage to renal tissues, etc., to reduce the rate and/or degree of morbidity, prevent, inhibit, delay or alleviate the permanent or progressive loss of renal function, and improve survival rate

Inactive Publication Date: 2010-04-29
STRYKER CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]The treatments of the present invention are useful in reducing the rate and / or degree of morbidity in mammals in, or at risk of, acute renal failure. In addition, the treatments of the present invention are useful in preventing, inhibiting, delaying or alleviating the permanent or progressive loss of renal function which may result from acute renal failure. As such, the present invention has great value, not only for increasing survival rates, but also in preventing or delaying the need for chronic dialysis or renal replacement therapy, in preventing or delaying the development of chronic renal insufficiency or chronic renal failure, and / or for reducing the necessary frequency of chronic renal dialysis.

Problems solved by technology

Renal failure is, therefore, a life-threatening condition in which the build-up of catabolites and other toxins, and / or the development of significant imbalances in electrolytes or fluids, may lead to the failure of other major organs systems and death.
Pre-renal causes (e.g., decreased cardiac output, hypovolemia, altered vascular resistance) and post-renal causes (e.g., obstructions or constrictions of the ureters, bladder or urethra) do not involve direct damage to the kidneys but; by affecting the flow of blood to the kidneys or the flow of urine from the kidneys, may lead to significant permanent and / or progressive damage to renal tissues.
On the other hand, acute renal failure may be due to intrinsic renal causes which involve a more direct insult or injury to the kidneys, and which also may entail permanent and / or progressive damage to the nephrons or other kidney structures.
If not treated, the electrolyte and fluid imbalances (e.g., hyperkalemia, acidosis, edema) associated with acute renal failure may lead to life-threatening arrhythmia, congestive heart failure, or multiple organ system failures.

Method used

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  • Therapies for acute renal failure
  • Therapies for acute renal failure

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0061]To examine the ability of OP-1 to beneficially affect the course of renal function after an acute ischemic insult to the kidney, the effect of OP-1 on creatinine levels was examined in rats in which ischemic renal damage was induced by temporarily preventing renal blood flow. In this model system, both renal arteries are clamped for 60 minutes. OP-1 is administered into the tail vein of each rat at 0.25 μg / kg at the following four times: 10 minutes before artery clamping, and then again at each of 24, 48, and 72 hours after the ischemic injury. As shown in FIG. 1, the creatinine level of placebo-treated rats rises rapidly after injury, peaks at the 24 hour measurement, and is back to normal by the 18th day post-injury. In contrast, OP-1 treatment is associated with a creatinine level which peaks at the 24 hour measurement to a level only half that of the placebo group, after which it begins to decrease. For each of the four post-injury days on which measurements were made, the...

example 2

[0062]To study the effect of post-injury OP-1 treatment on renal function in another animal model of renal failure, rats with a single kidney were treated with OP-1 2 days after norepinephrine-induced renal damage. In the model system (further described in Conger et al., Kidney Intl. 40:21-28, 1991), each rat has a kidney removed 7 days prior to renal injury, which is induced by intra-arterial infusion of norepinephrine for 90 minutes. Two days after norepinephrine administration, OP-1 is administered intravenously at 0.25 mg / kg.

[0063]The upper table of FIG. 2 presents creatinine levels of vehicle- and OP-1 treated rats. On the fourth day after injury, the animals which had been treated with OP-1 on the second day after injury had creatinine levels which are significantly lower than the levels of the vehicle-treated controls. The data presented in the lower table of FIG. 2 shows that OP-1 treatment was also associated with improvements in renal blood flow, GFR, and urine flow as com...

example 3

[0064]Further experiments, using ischemia-reperfusion injury as a model of acute renal failure in rats, were conducted as follows:

[0065]Animal Surgical Procedures and Experimental Protocols.

[0066]Wistar male rats of 200-250 g (Pliva Breeding Laboratory, Zagreb, Croatia) were fasted for 12 h prior to surgery. After intraperitoneal administration of ketamin (20 mg / kg) anesthetic, both renal arteries were dorsally occluded for 60 minutes with microaneurysm clamps (Roboz). Vehicle buffer or OP-1 containing 20 mM sodium acetate buffer (500 μl) were administered via the tail vein. All animals were subjected to intraperitoneal administration of 1-3 ml of pre-warmed (37° C.) saline (0.9% NaCl) to compensate for any fluid loss during the surgery. Experiments were blind, and rats were terminated at different time intervals ranging from 30 min to 18 days. Blood samples (0.5 ml) were obtained from the orbital plexus at 0 h, 24 h, 48 h, and 72 h and, in some cases, at 30 min, 2 h, 8 h, and 96 h,...

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Abstract

The present invention provides methods for the treatment, and pharmaceuticals for use in the treatment, of mammalian subjects in, or at risk of, acute renal failure, or subject to, or at risk of, inflammation, neutrophil-mediated cell damage, and apoptosis resulting from tissue damage or injury. The methods involve the administration of certain proteins of the osteogenic protein/bone morphogenetic protein (OP/BMP) family within the TGF-β superfamily of proteins.

Description

FIELD OF THE INVENTION[0001]The present invention relates generally to methods of treatment for renal disease and, in particular, methods of treatment for mammals, including humans, afflicted with, or at risk of, acute renal failure. The methods involve the administration of certain proteins of the osteogenic protein / bone morphogenetic protein (OP / BMP) family within the TGF-β superfamily of proteins.BACKGROUND OF THE INVENTION[0002]The mammalian renal system serves primary roles both in the removal of catabolic waste products from the bloodstream and in the maintenance of fluid and electrolyte balances in the body. Renal failure is, therefore, a life-threatening condition in which the build-up of catabolites and other toxins, and / or the development of significant imbalances in electrolytes or fluids, may lead to the failure of other major organs systems and death. As a general matter, renal failure is classified as “acute” or “chronic” As detailed below, acute renal failure typicall...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/17A61K38/00A61P13/12A61K38/18A61P43/00
CPCA61K38/1875A61K2300/00A61P13/02A61P13/12A61P15/00A61P19/04A61P29/00A61P43/00
Inventor COHEN, CHARLES M.SAMPATH, KUBER T.VUKICEVIC, SLOBODAN
Owner STRYKER CORP
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