Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-11-06
2002-07-09
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S004300, C514S021800, C514S866000
Reexamination Certificate
active
06417164
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates,to medicine, and, more particularly, to amylin agonists and methods for the treatment of Type II diabetes mellitus by administering an amylin agonist.
BACKGROUND
Publications and other materials including patents and patent applications used to illuminate the specification are hereby incorporated by reference.
Amylin
Amylin is a 37 amino acid protein hormone. It was isolated, purified and chemically characterized as the major component of amyloid deposits in the islets of pancreases of human Type II diabetics (Cooper et al.,
Proc. Natl. Acad. Sci., USA
84:8628-8632 (1987)). The amylin molecule has two important post-translational modifications: the C-terminus is amidated, and the cysteines in positions 2 and 7 are cross-linked to form an N-terminal loop. Amylin is the subject of United Kingdom patent application Serial No. 8709871, filed Apr. 27, 1987, and corresponding U.S. Pat. No. 5,367,052, issued Nov. 22, 1994.
Amylin is a member of a family of related peptides which include CGRP and calcitonin (Rink et al.,
Trends Pharmacol. Sci
. 14:113-118 (1993)). Amylin is primarily synthesized in pancreatic beta cells and is secreted in response to nutrient stimuli such as glucose and arginine. Moore et al.,
Biochem. Biophys. Res. Commun
. 179:1-9 (1991); Kanatsuka et al.,
FEBS Lett
. 259:199-201 (1989); Ogawa et al.,
J. Clin. Invest
. 85:973-976 (1990); Gedulin et al.,
Biochem. Biophys. Res. Commun
. 180:782-789 (1991).
In normal humans, fasting amylin levels from 1 to 10 pM and post-prandial levels of 5 to 20 pM have been reported (e.g., Hartter et al.,
Diabetologia
34:52-54 (1991); Sanke et al.,
Diabetologia
34:129-13:2 (1991)); Koda et al.,
The Lancet
339:1179-1180 (1992)). In obese, insulin-resistant individuals, however, post-food amylin levels can go higher, reaching up to about 50 pM, for example. For comparison, the values for fasting and post-prandial insulin are 20 to 50 pM, and 100 to 300 pM respectively in healthy people, with perhaps 3- to 4-fold higher levels in insulin-resistant people. In Type 1 diabetes, where beta-cells are destroyed, amylin levels are at or below the levels of detection and do not rise in response to glucose (Koda et al.,
The Lancet
339:1179-1180 (1992)). In normal mice and rats, basal amylin levels have been reported from 30 to 100 pM, while values up to 600 pM have been measured in certain insulin-resistant, diabetic strains of rodents (e.g., Huang et al.,
Hypertension
19:I-101-I-109 (1991)); Gill et al.,
Life Sciences
48:703-710 (1991).
The first discovered action of amylin was the reduction of insulin-stimulated incorporation of glucose into glycogen in rat skeletal muscle (Leighton et al.,
Nature
335:632-635 (1988));
the muscle was made “insulin-resistant”. Subsequent work with rat soleus muscle ex-vivo and in vitro has indicated that amylin reduces glycogen-synthase activity, promotes conversion of glycogen phosphorylase from the inactive b form to the active a form, promotes net loss of glycogen (in the presence or absence of insulin), increases glucose-6-phosphate levels, and can increase lactate output (see, e.g., Deems et al.,
Biochem. Biophys. Res. Commun
. 181:116-120 (1991)); Young et al.,
FEBS Letts
. 281:149-151 (1991)).
It is believed that amylin acts through receptors present in plasma membranes. Beaumont et al.,
Mol. Pharmacol
. 44:493-497 (1993). Amylin receptors and their use in various methods for screening and assaying for amylin agonist and antagonist compounds are described in U.S. Pat. No. 5,264,372, issued Nov. 23, 1993.
The biological actions of amylin relating to fuel metabolism are discussed in Young et al.,
J. Cell. Biochem
. 555:12-18 (1994). While amylin has marked effects on hepatic fuel metabolism in vivo, there is no general agreement as to what amylin actions are seen in isolated hepatocytes or perfused liver. The available data do not support the idea that amylin promotes hepatic glycogenolysis, i.e., it does not act like glucagon (e.g., Stephens, et al.,
Diabetes
40:395-400 (1991)); Gomez-Foix et al.,
Biochem J
. 276:607-610 (1991)). It has been suggested that amylin may act on the liver to promote conversion of lactate to glycogen and to enhance the amount of glucose able to be liberated by glucagon (see Roden et al.,
Diabetologia
35:116-120 (1992)). Thus, amylin could act there as an anabolic partner to insulin in liver, in contrast to its catabolic action in muscle.
In fat cells, contrary to its action in muscle, amylin has no detectable actions on insulin-stimulated glucose uptake, incorporation of glucose into triglyceride, CO
2
production (Cooper et al.,
Proc. Natl. Acad. Sci
. 85:7763-7766 (1988)) epinephrine-stimulated lipolysis, or insulin-inhibition of lipolysis (Lupien and Young,
Diabetes Nutrition and Metabolism—Clinical and Experimental
, Vol. 6(1), pages 13-18 (1993)). Amylin thus exerts tissue-specific effects, with direct action on skeletal muscle, marked indirect (via supply of substrate) and perhaps direct effects on liver, while adipocytes appear “blind” to the presence or absence of amylin. No direct effects of amylin on kidney tissue have been reported.
It has also been reported that amylin can have marked effects on secretion of insulin. In isolated islets (Ohsawa et al.,
Biochem. Biophys. Res. Commun
. 160:961-967 (1989)), in the perfused pancreas (Silvestre et al.,
Reg. Pept
. 31:23-31 (1991)), and in the intact rat (Young et al.,
Mol. Cell. Endocrinol
. 84:R1-R5 (1992)), various experiments indicate that amylin down-regulates insulin secretion. The perfused pancreas experiments point to selective down-regulation of the secretary response to glucose with sparing of the response to arginine. Other workers, however, have been unable to detect effects of amylin on isolated beta cells, on isolated islets, or in the whole animal (see Broderick et al.,
Biochem. Biophys. Res. Commun
. 177:932-938 (1991) and references therein).
A striking effect of amylin in rodents at pharmacological dosages in vivo is stimulation of a sharp rise in plasma lactate, followed by a rise in plasma glucose (Young et al.,
FEBS Letts
. 281:149-151 (1991)). Evidence indicates that the increased lactate provides substrate for glucose production and that amylin actions can occur independent of changes in insulin or glucagon. In “glucose clamp” experiments, amylin infusions cause “insulin resistance”, both by reducing peripheral glucose disposal, and by limiting insulin-mediated suppression of hepatic glucose output (e.g., Frontoni et al.,
Diabetes
40:568-573 (1991)); Koopmans et al.,
Diabetologia
34:218-224 (1991)).
It has been shown that amylin. agonists can slow gastric emptying (Young et al.,
Diabetologia
(June 1995, in press), and is believed to contribute to their ability to reduce post-prandial hyperglycemia (Moyses and Kolterman,
Drugs of the Future
(May 1995). Methods for reducing gastric motility and slowing gastric emptying comprising the administration of an amylin agonist (including amylin) are the subject of U.S. patent application Ser. No. 08/118,381, filed Sep. 7, 1993, and U.S. patent application Ser. No. 08/302,069, filed Sep. 7, 1994 (and corresponding PCT application, Publication No. WO 95/07098, published Mar. 16, 1995).
Non-metabolic actions of amylin include vasodilator effects which may be mediated by interaction with CGRP vascular receptors. (Brain et al.,
Eur. J. Pharmacol
. 183:2221 (1990). It has also been reported that amylin markedly increases plasma renin activity in intact rats when given subcutaneously in a manner that avoids any disturbance of blood pressure. Methods for treating renin-related disorders with amylin antagonists are described in U.S. Pat. No. 5,376,638, issued Dec. 27, 1994.
Injected into the brain, amylin has been reported to suppress food intake (e.g., Chance et al.,
Brain Res
. 539:352-354 (1991)), an action shared with CGRP and calcitonin. The effective concentrations at the cells that mediate this action are not known. Amylin has also been reported to have effects b
Kolterman Orville G.
Mullane John F.
Thompson Robert G.
Amylin Pharmaceuticals Inc.
Duft Bradford J.
Low Christopher S. F.
McGeehan Lisa M.
Mohamed Abdel A.
LandOfFree
Treatment of type II diabetes mellitus with amylin agonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Treatment of type II diabetes mellitus with amylin agonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Treatment of type II diabetes mellitus with amylin agonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2837623