The General Hospital Corporation

The Brigham and Women's Hospital, Inc.

Enos Pharmaceuticals, Inc.

Michael A Moskowitz

Joseph V Bonventre

Paul L Huang

Mark C Fishman

James K Liao

Alessandro Alessandrini

Shobu Namura

Eyal S Ron

Roger L Whiting

Franklin D Collins

Michael Spedding

Brian J Alps

Seth P Finklestein

Caroline J Emmett

Christine Mary Brown

Deborah Russell

Matthias Endres

Mary Nallin Omstead

Ulrich Laufs

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

This invention relates to transgenic non-human animals comprising a disrupted endothelial nitric oxide synthase gene. These animals exhibit abnormal wound-healing properties and hypertension. This invention also relates to methods of using the transgenic animals to screen for compounds having a potential therapeutic utility for vascular endothelial disorders, such as hypertension, cerebral ischemia or stroke, atherosclerosis and wound-healing activities. Moreover, this invention also relates to methods of treating a patient suffering from hypertension and wound-healing abnormalities with the compounds identified using the transgenic animals, and methods of making the transgenic animals. A method of treating a wound using nitroglycerin is also provided.

Endothelial NOS transgenic animals and methods of use

The invention relates to the use of MEK1 inhibitors to reduce tissue damage resulting from ischemia and/or reperfusion, particularly brain damage associated with ischemia resulting from stroke. Pharmaceutical compositions, kits and perfusion fluids including MEK1 inhibitors are also provided.

Use of MEK1 inhibitors as protective agents against damage due to ischemia

Endothelial NOS knockout mice and methods of use

Use of MEK1 inhibitors as protective agents against damage due to

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.

Upregulation of Type III endothelial cell Nitric Oxide Synthase by

The present invention provides methods for treating migraine headache comprising administering an effective amount of a neurosteroid that directly or indirectly activates GABA.sub.A receptors.

Method for treating vascular headaches

The present invention provides methods for treating migraine headache. The methods useful according to the invention involve the treatment of patients who experience symptoms of migraine headache with compounds that directly or indirectly activate GABA.sub.A receptors.

Methods for the treatment of neuronal damage associated with ischemia,

A method for treatment of stroke in a patient, involving administering to the patient a nitric oxide-releasing compound. A preferred compound of the invention is L-arginine.

Treatment of stroke with nitric-oxide releasing compounds

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Belmont, MA, United States of America

Michael A Moskowitz