The Brigham and Women's Hospital, Inc.

The United States of America, As Represented by the Secretary, Department of Health and Human Services

The General Hospital Corporation

Enos Pharmaceuticals, Inc.

James K Liao

Michael A Moskowitz

Eyal S Ron

Darryl C Zeldin

William W Chin

Matthias Endres

Mary Nallin Omstead

Ulrich Laufs

Epoxyeicosatrienoic acids (EETs) are products of cytocrome P450 epoxygenases that have vasodilatory properties similar to endotheilum-derived hyperpolarizing factor (EDHF). The cytochrome P450 isoform CYP2J2 was cloned and identified as a source of EETs in human endothelial cells. Physiological concentrations of EETs or overexpression of CYP2J2 decreased cytolcine-induced endothelial cell adhesion molecule expression and prevented subsequent leukocyte adhesion to the vascular wall by a mechanism involving inhibition of transcription factor NF-&#x3ba;B and I&#x3ba;B kinase (IKK). The inhibitory effects of EETs were independent of their membrane hyporpolarizing effects suggesting that these molecules play an important non-vasodilatory role in vascular inflammation.

Anti-inflammatory actions of cytochrome P450 expoxygenase-derived eicosanoids

A method and compositions are provided for increased cerebral bioavailability of blood-born compositions by administering the composition of interest while increasing brain NO levels. This increase in NO levels may be accomplished by stimulating increased production of NO by eNOS, especially by administering L-arginine, by administering agents that increase NO levels independent of ecNOS, or by any combination of these methods. As NO is increased, cerebral blood flow is consequently increased, and drugs in the blood stream are carried along with the increased flow into brain tissue. By increased flow, the site of action will be exposed to more drug molecules. By stimulating increased NO production, administration of drugs that are not easily introduced to the brain may be facilitated and/or the serum concentration necessary to achieve desired physiologic effects may be reduced.

Increasing cerebral bioavailability of drugs

A use for agents that disrupt actin cytoskeletal organization is provided. In the instant invention, agents that disrupt actin cytoskeletal organization are found to upregulate endothelial cell Nitric Oxide Synthase activity. As a result, agents that disrupt actin cytoskeletal organization are useful in treating or preventing conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase. Such conditions include hypoxia-induced conditions. Subjects thought to benefit mostly from such treatments include nonhyperlipidemics and nonhypercholesterolemics, but not necessarily exclude hyperlipidemics and hypercholesterolemics.

Upregulation of type III endothelial cell nitric oxide synthase by agents that disrupt actin cytoskeletal organization

This invention provides new methods and compounds for controlling the intracellular and physiological effects of steroid hormones, including but not limited to estrogen, through modulation of the interaction of such hormone receptors with phosphatidylinositol-3 kinase. Compounds and methods for controlling the activation of endotbelial nitric oxide synthase are also disclosed.

Methods of identifying a compound which modulates the non-transcriptional non-map-kinase induced effects of steroid hormones

A use for agents that disrupt actin cytoskeletal organization is provided. In the instant invention, agents that disrupt actin cytoskeletal organization are found to upregulate endothelial cell Nitric Oxide Synthase activity. As a result, agents that disrupt actin cytoskeletal organization are useful in treating or preventing conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase. Such conditions include pulmonary hypertension, ischemic stroke, impotence, heart failure, hypoxia-induced conditions, insulin deficiency, progressive renal disease, gastric or esophageal motility syndrome, etc. Subjects thought to benefit mostly from such treatments include nonhyperlipidemics and nonhypercholesterolemics, but not necessarily exclude hyperlipidemics and hypercholesterolemics.

A use for rho GTPase function inhibitors is provided. In the instant invention, rho GTPase function inhibitors are found to upregulate endothelial cell Nitric Oxide Synthase activity. As a result, rho GTPase function inhibitors are useful in treating or preventing conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase. Such conditions include pulmonary hypertension, ischemic stroke, impotence, heart failure, hypoxia-induced conditions, insulin deficiency, progressive renal disease, gastric or esophageal motility syndrome, etc. Subjects thought to benefit mostly from such treatments include nonhyperlipidemics and nonhypercholesterolemics, but do not necessarily exclude hyperlipidemics and hypercholesterolemics.

Upregulation of Type III endothelial cell nitric oxide synthase by rho GTPase function inhibitors

A new use for HMG-CoA reductase inhibitors is provided. In the instant invention, HMG-CoA reductase inhibitors are found to upregulate endothelial cell Nitric Oxide Synthase activity through a mechanism other than preventing the formation of oxidative-LDL. As a result, HMG-CoA reductase inhibitors are useful in treating or preventing conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase. Such conditions include pulmonary hypertension, ischemic stroke, impotence, heart failure, hypoxia-induced conditions, insulin deficiency, progressive renal disease, gastric or esophageal motility syndrome, etc. Subjects thought to benefit mostly from such treatments include nonhyperlipidemics and nonhypercholesterolemics, but not necessarily exclude hyperlipidemics and hypercholesterolemics.

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Weston, MA, United States of America

James K Liao