Mcw Research Foundation, Inc.

Taisho Pharmaceutical Co., Ltd.

The Medical College of Wisconsin, Inc.

Genzyme Corporation

Amylin Pharmaceuticals, Inc.

Astrazeneca Pharmaceuticals LP

Richard J Roman

John Russell Falck

Elizabeth R Jacobs

Magdalena Alonso-Galicia

Noriyuki Miyata

William E Sweeney

Ellis D Avner

Masakazu Sato

Alain D Baron

Naoki Kojima

Kazuya Kameo

David R Hathaway

Steven R Ledbetter

David R Harder

Shigeru Okuyama

Takuya Takeda

Teisuke Takahashi

Kristopher G Maier

Hideki Tomoike

Howard J Jacob

Marcelo Nobrega

Mahesh Mistry

The present invention provides a method for preferentially reducing the proliferation of cystic epithelial cells in the kidney or bile duct in a mammal in need thereof by administering a 20-HETE synthesizing enzyme inhibitor or a 20-HETE antagonist to the mammal in an amount sufficient to preferentially reduce the proliferation of cystic epithelial cells over normal epithelial cells such as tubule epithelial cells in the kidney or bile duct. The present invention also provides a method for preventing or treating autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), ARPKD associated congenital hepatic fibrosis, ARPKD associated Caroli's disease, or cholangiocarcinoma in a mammal in need thereof by administering a 20-HETE synthesizing enzyme inhibitor or a 20-HETE antagonist to the mammal in an amount sufficient to prevent or treat the disease.

Methods of modulating cell proliferation and cyst formation in polycystic kidney and liver diseases

Medicaments that depend on a combination of SGLT 2 inhibitors and antihypertensive drugs and which are useful in the treatment of diseases involving at least hypertension or diabetes mellitus as a risk factor of cardiovascular events, as well as methods of treating the diseases are provided. Since the present invention exhibits a superior hypotensive action that cannot be attained by any single antihypertensive drugs, the conventional problems associated with the use of two or more antihypertensive drugs in order to lower the blood pressure to the desired level can be solved. In addition, the present invention shows a marked therapeutic efficacy in diabetes mellitus, a disease associated with diabetes mellitus, or complications of diabetes mellitus, in particular, diabetic nephropathy. As a further advantage, the present invention is also useful for the treatment of diseases involving lowered renal function.

Combinations of SGLT 2 inhibitors and antihypertensive drugs

A rat model of diabetic nephropathy is disclosed. In another embodiment of the invention, a method of evaluating a test compound's effect of diabetic nephropathy is disclosed. In one embodiment, this method comprises the steps of (a) exposing the test compound to the rat of claim, wherein the rat would develop progressive proteinuria and glomerulosclerosis leading to diabetic nephropathy in the absence of the test compound, and (b) comparing the rat's development of diabetic nephropathy with a control T2DN mimic rat that has not been exposed to the test compound.

Rat model of diabetic nephropathy

A method for treating cerebral vascular diseases in a human or non-human animal is disclosed. The method involves inhibiting 20-HETE synthesizing enzyme activity sufficiently to increase or prevent a decrease in cerebral blood flow in the human or non-human animal.

Use of 20-HETE synthesizing enzyme inhibitors as therapy for cerebral vascular disease

The present invention provides a fluorescent HPLC assay for detecting the presence and/or measuring the level of 20-hydroxyeicosatetraenoic acid (20-HETE) and other P-450 metabolites of arachidonic acid in a sample. P-450 metabolites of arachidonic acid are first extracted from the sample and then labeled with 2-(2,3-naphthalimino)ethyl trifluoromethanesulfonate. The labeling reaction is catalyzed by N,N-diisopropylethylamine. Next, the labeled P-450 metabolites are separated on a 4.5&times;250-mm, 5 &mgr;M particle size C18 reverse-phase HPLC column using a mobile phase of methanol:water:acetic acid (82:18:0.1, v/v/v) and an isocratic elution at a rate of about 1.3 ml per minute. Fluorescence intensities of the column eluent are monitored by a fluorescence detector. Quantitation of P-450 metabolites in a sample can be made by using an internal standard.

Fluorescent hplc assay for 20-hete and other p-450 metabolites of arachidonic acid

20-HETE agonists and antagonists are disclosed along with therapeutic applications. In a preferable form of the invention, the 20-HETE agonists are selected from the group consisting of 21-hydroxyheneicosa-5(Z), 8(Z), 11(Z), 14(Z)-tetraenoic acid, 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid and 20-, 21-dimethyl 20-HETE. Preferable 20-HETE antagonists include 5(S)-HETE, 15(S)-HETE, 19(S)-HETE, 19-hydroxynonadeca-5(Z), 8(Z), 11(Z), 14(Z)-tetraenoic acid and 20-hydroxyeicosa 6(Z), 15(Z)-dienoic acid.

20-HETE antagonists and agonists

20-HETE agonists and antagonists are disclosed along with therapeutic applications. In a preferable form of the invention, the 20-HETE agonists are selected from the group consisting of 21-hydroxyheneicosa-5(Z),8(Z),11(Z),14(Z)-tetraenoic acid, 20-hydroxyeicosa-5(Z),4(Z)-dienoic acid and 20-,21-dimethyl 20-HETE. Preferable 20-HETE antagonists include 5(S)-HETE, 15(S)-HETE, 19(S)-HETE, 19-hydroxynonadeca-5(Z),8(Z),11(Z),14(Z)-tetraenoic acid and 20-hydroxyeicosa 6(Z),15(Z)-dienoic acid.

20-Hete antagonists and agonists

20-HETE agonists and antagonists are disclosed along with therapeutic applications. In a preferable form of the invention, the 20-HETE agonists are selected from the group consisting of 21-hydroxyheneicosa-5(Z),8(Z),11(Z),14(Z)-tetraenoic acid, 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid and 20-,21-dimethyl 20-HETE. Preferable 20-HETE antagonists include 5(S)-HETE, 15(S)-HETE, 19(S)-HETE, 19-hydroxynonadeca-5(Z),8(Z),11(Z),14(Z)-tetraenoic acid and 20-hydroxyeicosa 6(Z),15(Z)-dienoic acid.

Growing community of inventors

Brookfield, WI, United States of America

Richard J Roman