Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Using tissue cell culture to make a protein or polypeptide
Reexamination Certificate
2000-06-09
2003-03-18
Ulm, John (Department: 1647)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Using tissue cell culture to make a protein or polypeptide
C435S070100, C514S002600, C514S016700, C514S015800, C514S014800, C514S013800, C530S300000, C530S326000, C530S328000, C530S329000
Reexamination Certificate
active
06534290
ABSTRACT:
Novel growth peptides derived from protein factors having molecular weights of about 22 and 45 kDa stimulate mitogenic activity of epithelial, but not fibroblastic cells, in particular, kidney epithelial cells.
Acute renal failure is a serious disease associated with high mortality for which no “real: treatment currently exists. Acute renal failure is defined as the abrupt disruption of previously normal kidney function. It is caused by a wide variety of mechanisms, including circulatory failure (shock), vascular blockade, glomerulonephritis, and obstruction to urine flow. In addition it can occur following surgery, trauma, sepsis, or with certain medications, particularly antibiotics and anticancer agents.
In 1985 some 140,000 Americans were hospitalized with acute renal failure (see 1990 Long Range Plan). The average cost of treatment associated with these cases was over $9000. Based on the growth in the disease over the past several yeas and normal inflation, it was estimated that currently some 240,000 patients develop acute renal failure annually at a cost of over $10,000 per patient. That translated to a staggering total cost to the U.S. healthcare system of almost $2.5 billion per year.
TABLE 1
AVERAGE COST PER HOSPITAL DISCHARGE FOR KIDNEY
AND UROLOGIC DISEASES, UNITED STATES, 1985
1
Average
Number of
Cost per
Discharges
Discharge
1.
Acute renal failure
139,134
$9,329
2.
Chronic renal failure
395,066
9,249
3.
Kidney disease of diabetes mellitus
96,731
6,819
4.
Kidney cancer
47,384
6,145
5.
Hypertensive renal disease
182,625
6,796
6.
Other intrinsic/systemic diseases
79,683
5,061
7.
Bladder cancer
125,108
4,758
8.
Impotence
30,452
4,344
9.
Prostate cancer
246,201
3,791
10.
Testicular cancer
14,219
3,711
11.
Benign prostatic hyperplasia
482,348
3,649
12.
Polycystic kidney disease
44,156
3,213
13.
Glomerulonephritis
79,531
3,135
14.
Bladder disorders
342,211
3,064
15.
Urinary stone disease
453,018
2,920
16.
Urinary tract infection
1,583,309
2,549
17.
Incontinence
162,574
2,547
18.
Hematuria
173,495
2,375
19.
Prostatitus
108,024
2,010
20.
Obstructive uropathy
2
397,074
1,842
21.
Other genitourinary infections
147,215
1,339
22.
Preeclampsia
139,000
1,025
23.
Testicular dysfunction
7,019
950
1
Includes payments to physicians.
2
Includes vesicoureteral reflux.
SOURCES: National Center for Health Statistics: National Hospital Discharge Survey, 1985 (all listed diagnoses). Department of Veterans Affairs, for year ending September 30, 1986 (first-listed diagnoses) (unpublished). Health Care Financing Administration, Medicare provider analyses and review data, 1985 (unpublished).
As can be seen in Table 1 from the Plan, kidney disease contributes to major medical costs in the United States, so factors reducing time to recovery, are beneficial to society.
Equally significant, is the fact that the number of cases of acute renal failure is growing at a rate of 9% per year (NIH, 1995) and this high rate of growth is expected to continue. A reason given for this rise in the incidence of renal failure is that “sicker” patients with a high risk of renal failure are surviving longer.
1. Older patients, who have a significantly higher incidence of acute renal failure (e.g., patients over 65 are 5 times more likely to be hospitalized for acute renal failure than those ages 45 to 64) are now surviving serious medical incidents (e.g., heart attack, stroke) as well as complicated surgery. Improved hospital intensive care units with more sophisticated monitoring and life support systems also aid in keeping “sicker” patients alive. In addition improved therapeutic agents for treating cancer and life-threatening infections are often nephrotoxic.
2. Neonates, who have an extremely high risk of kidney failure are also surviving at shorter terms and at significantly lower birth weights. Such infants formerly had difficulties overcoming severe lung and heart problems, but these problems can now be successfully treated with improved drugs and techniques, particularly in specialized neonatal intensive care units.
Because these advances in treatment modalities are expected to continue and even accelerate, it is likely that the number of cases of acute renal failure will continue to increase, perhaps at an even faster rate.
At the present time no real “cure” exists for acute renal failure. The current method of treatment is to “rest” the kidney by performing dialysis to correct metabolic imbalances and wait for kidney function to return spontaneously.
Dialysis is a technique in which impurities and toxins from the blood, that are normally cleared through the kidneys are artificially removed through an extra-corporeal circuit and filter (hemodialysis) or through the peritoneal membrane. By removing such impurities the life threatening metabolic imbalances resulting from kidney failure can be corrected and the patient stabilized.
Mortality rates resulting from a patient's developing acute renal failure are extremely high. A recent study (Levy et al., 1996) that analyzed the effect of acute renal failure on patient mortality cites such rates as ranging from 42% to 88% based on 18 previously published reports. These rates have remained essentially unchanged since the early 1950's. In the 1996 study itself the mortality rate for hospitalized patients who developed acute renal failure was 5 times higher compared to similar patients without renal failure (34% vs. 7%).
A key finding of this study is that “acute renal failure appears to increase the risk of developing severe non-renal complications that lead to death and should not be regarded as a treatable complication of serious illness.” Thus it appears that the rapid reversal of acute renal failure can significantly reduce the risk of mortality in patients who also frequently have complicated clinical courses by preventing the development of severe and often fatal non-renal complications.
It has long been known that the kidney is one of the few human organs that has an ability to repair itself after injury. Even in cases where the kidney has been irreversibly damaged, and there is extensive necrosis of kidney cells, strong evidence exists that some new cell growth occurs.
It has been proposed that growth factors are a therapeutic approach to stimulate or augment the regenerative process in the injured kidney and thereby reduce the severity and shorten the course of acute renal failure. The use of growth factors as a treatment for acute renal failure was first proposed by Toback (1984). However, finding suitable growth factors proved difficult. The rationale for this strategy was subsequently expanded after several specific growth factor proteins where identified (Mendley and Toback, 1989; Toback 1992 a and b). However, no factors have yet been confirmed as useful in treating humans.
Growth factors acting in vivo to stimulate proliferation and migration of noninjured tubular cells in the kidney, and possibly to facilitate recovery of sublethally-injured cells as well, would be beneficial. A specific growth factor could be used in combination with sufficient nutrients, calories, and dialytic therapy to increase survival of patients with renal problems. For example, administration of growth factors could (1) increase positive outcomes in patients with cadaveric renal transplants, a situation in which acute renal failure is associated with increased rejection, (2) shorten the duration of acute renal failure which would increase patient survival, and (3) reduce the number of days required for hemodialysis treatment during the renal failure syndrome.
Autocrine growth factors are produced locally by the same cells on which they act. They appear to be produced in response to a stimulating event such as cell injury. Moreover, they are produced in extremely small quantities and may exist at detectable levels for only a short time. Consequently, they have been quite difficult to isolate and identify.
Two other types of growth factors—paracrine and endocrine—both appear to have some role in stimulating kidney cell growth:—Paracine factors act on adjacent
Toback F. Gary
Walsh-Reitz Margaret M.
Arch Development Corp.
Barnes & Thornburg
Chernyshev Olga N.
Martin Alice O.
Ulm John
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