Cornell Research Foundation Inc.

The Medical College of Wisconsin, Inc.

University of Texas System

Other

Duke University

Massachusetts Institute of Technology

Owen W Griffith

Steven S Gross

Robert G Kilbourn

Jonathan S Stamler

Krishnaswamy Narayanan

Henry S Friedman

Roberto Levi

Darell D Bigner

Brian J Day

Benjamin M Gaston

Ramesh Babu Boga

Dennis C Mynarcik

Gordon F Fairclough, Jr

Ernest B Campbell

Deborah L Jenkins

Mammals are treated for infections or for conditions associated with pathologically proliferating mammalian cell growth by administration of a manipulator of nitrosative stress to selectively kill or reduce the growth of the microbes or helminths causing the infection or of host cells infected with the microbes or of the pathologically proliferating mammalian cells. Novel agents include &#x3b1;-alkyl-S-alkyl-homocysteine sulfoximines wherein the &#x3b1;-alkyl contains 2 to 8 carbon atoms, and the S-alkyl contains 1 to 10 carbon atoms. Mammals in need of increased nitrosative stress defenses are treated, e.g., humans at risk for a stroke because of having had a transient ischemic attack, are treated. Treatments to increase nitrosative stress defenses include repeated administrations of low doses of manipullators of nitrosative stress so that subject treated has increased tolerance to nitrosative stress. Mammals are treated for protozoal infections by systemic administration of L-buthionine-S-sulfoximine and agent that increases nirtrosative stress.

Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically proliferating cells or to upregulate nitrosative stress defenses

Asthma is ameliorated, and mild or moderate asthma is prevented from progressing to more severe asthma by administering agents which prevent and/or accommodate for S-nitrosothiol breakdown.

Treating asthma by preventing and/or accomodating S-nitrosothiol breakdown

Mammals are treated for infections or for conditions associated with pathologically proliferating mammalian cell growth by administration of a manipulator of nitrosative stress to selectively kill or reduce the growth of the microbes or helminths causing the infection or of host cells infected with the microbes or of the pathologically proliferating mammalian cells. Novel agents include &agr;-alkyl-S-alkyl-homocysteine sulfoxmines wherein the &agr;-alkyl contains 2 to 8 carbon atoms, and the S-alkyl contains 1 to 10 carbon atoms. Mammals in need of increased nitrosative stress defenses are treated, e.g., humans at risk for a stroke because of having had a transient ischemic attack, are treated. Treatments to increase nitrosative stress defenses include repeated administrations of low doses of manipulators of nitrosative stress so that the subject treated has increased tolerance to nitrosative stress. Mammals are treated for protozoal infections by systemic administration of L-buthionine-S-sulfoximine and agent that increases nitrosative stress.

Mammals are treated for infections or for conditions associated with pathologically proliferating mammalian cell growth (for example, certain cancers, restenosis, benign prostatic hypertrophy) by administration of a manipulator of nitrosative stress to selectively kill or reduce the growth of the microbes or helminths causing the infection or of host cells infected with the microbes or of the pathologically proliferating mammalian cells. Novel agents include &agr;-alkyl-S-alkyl-homocysteine sulfoximines wherein the &agr;-alkyl contains 2 to 8 carbon atoms, and the S-alkyl- contains 1 to 10 carbon atoms. In another invention herein, mammals in need of increased nitrosative stress defenses are treated, e.g., humans at risk for a stroke because of having had a transient ischemic attack, are treated. Treatments to increase nitrosative stress defenses include, for example, repeated administrations of low doses of manipulators of nitrosative stress so that the subject treated has increased tolerance to nitrosative stress. In still another invention, mammals are treated for protozoal infections by systemic administration of L-buthionine-S-sulfoximine and agent that increases nitrosative stress.

Manipulating nitrosative stress to upregulate nitrosative stress defenses

Paraquat has been found to accept electrons from nitric oxide synthase (NOS) whereupon the reduced paraquat generates toxic O,and prevents NOS from giving electrons to arginine and thereby inhibits NO production. This is generalized for compounds with a redox potential greater than nitric oxide synthase. The compounds inhibit nitric oxide synthase and kill cells including NOS by generating O,and also by depriving the cells of the NO which they need. Applications include treating paraquat-induced injury and pathologically proliferating cells (tumors, restenosis benign prostatic hypertrophy, pulmonary hypertension, infective pathogens).

Treatments based on discovery that nitric oxide synthase is a paraquat diaphorase

Mammals are treated for infection or for conditions associated with pathologically proliferating mammalian cell growth (for example, certain cancers, restenosis, benign prostatic hypertrophy) by administration of a manipulator of nitrosative stress to selectively kill or reduce the growth of the microbes or helminths causing the infection or of host cells infected with the microbes or of the pathologically proliferating mammalian cells. Novel agents include &agr;-alkyl-S-alkyl-homocysteine sulfoximines wherein the &agr;-alkyl contains 2 to 8 carbon atoms, and the S-alkyl- contains 1 to 10 carbon atoms. In another invention herein, mammals in need of increased nitrosative stress defenses are treated, e.g., humans at risk for a stroke because of having had a transient ischemic attack, are treated. Treatments to increase nitrosative stress defenses include, for example, repeated administrations of low doses of manipulators of nitrosative stress so that the subject treated has increased tolerance to nitrosative stress. In still another invention, mammals are treated for protozoal infections by systemic administration of L-buthionine-S-sulfoximine and agent that increases nitrosative stress.

Manipulating nitrosative stress to kill pathologic microbes, pathologic helminths and pathologically, proliferating cells or to upregulate nitrosative stress defenses

Selective and irreversible inhibitors of neuronal isoform of nitric oxide synthase catalyzed production of nitric oxide are L-ornithine or L-lysine derivatives having the formula ##STR1## wherein Q is H or (CH.sub.2).sub.r CH.sub.3 where r ranges from 0 to 15, x is 1 or 2, R' is CH.sub.2 or C(H) (CH.sub.2).sub.y CH.sub.3 where y ranges from 0 to 5, R' is CH.sub.2 or C(H) (CH.sub.2).sub.z CH.sub.3 where z ranges from 0 to 5, R is H or (CH.sub.2).sub.s CH.sub.3 where s ranges from 0 to 5, with none or only one of R, R' and R' providing an alkyl substituent on ornithine or lysine moiety, R.sup.III is OH or is an alkoxy group of 1 to 6 carbon atoms or is an amino acid or peptide attached in amide linkage through its free .alpha.-amino group, and R.sup.IV is --H or an acyl group of 1 to 6 carbon atoms or is an amino acid or peptide attached in amide linkage through its free .alpha.-carboxylate group, and mixtures thereof with corresponding D-isomers. A preferred compound is N.sup.5 -(1-imino-3-butenyl)-L-ornithine. The compounds are useful for treatment of migraine headaches, stroke, pain due to stimulation of nNOS-containing neurons including chronic visceral pain, drug addiction, Parkinson's disease, schizophrenia, and epilepsy.

L-N.sup.5 -(1-imino-3-alkenyl) ornithine and related compounds and use

Mammals are treated for infections or for conditions associated with pathologically proliferating mammalian cell growth (for example, certain cancers, restenosis, benign prostatic hypertrophy) by administration of a manipulator of nitrosative stress to selectively kill or reduce the growth of the microbes or helminths causing the infection or of host cells infected with the microbes or of the pathologically proliferating mammalian cells. Novel agents include .alpha.-alkyl-S-alkyl-homocysteine sulfoximines wherein the .alpha.-alkyl contains 2 to 8 carbon atoms, and the S-alkyl-contains 1 to 10 carbon atoms. In another invention herein, mammals in need of increased nitrosative stress defenses are treated, e.g., humans at risk for a stroke because of having had a transient ischemic attack, are treated. Treatments to increase nitrosative stress defenses include, for example, repeated administrations of low doses of manipulators of nitrosative stress so that the subject treated has increased tolerance to nitrosative stress. In still another invention, mammals are treated for protozoal infections by systemic administration of L-buthionine-S-sulfoximine and agent that increases nitrosative stress.

Manipulating nitrosative stress to kill pathologic microbes, pathologic

The present invention involves a method for prophylaxis or treatment of an animal for systemic hypotension induced by endotoxin and/or a biological response modifier such as the cytokines, IFN, TNF, IL-1 or IL-2 and the like. The method involves administering, preferably intravascularly, a therapeutically effective amount of dobutamine and an inhibitor of nitric oxide formation from arginine.

Method of use of cardiotonic drugs and inhibitors of nitric oxide

A method for prophylaxis or treatment of an animal for systemic hypotension induced by internal nitrogen oxide production. The method involves administering a therapeutically effective amount of certain arginine derivatives to inhibit nitrogen oxide formation from arginine. Preferably N.sup.G -substituted arginine or an N.sup.G,N.sup.G -disubstituted arginine (having at least one hydrogen on a terminal guanidino amino group replaced by another atomic species) is administered to an animal possibly developing or already having such induced systemic hypotension. The arginine derivatives are preferably of the L configuration and include pharmaceutically acceptable addition salts. Prophylaxis or treatment of systemic hypotension in a patient which has been induced by chemotherapeutic treatment with biologic response modifiers such as tumor necrosis factor or interleukin-2 may be accomplished. Treatment of an animal for systemic hypotension induced by endotoxin, i.e., septic shock may also be accomplished by treatment with the arginine derivatives.

Argine antagonists for inhibition of systemic hypotension associated

Administration of argininosuccinate synthetase activity reducing agents, e.g., argininosuccinate synthetase induction blocking agents (e.g., antibiotics that bind to DNA sequences present in the upstream regulatory region of the argininosuccinate synthetase gene, such as mithramycin) and argininosuccinate synthetase inhibitors (e.g., L-citrulline antagonists such as methyl citrulline and L-aspartate antagonists such as D-aspartate) is useful to prevent or treat sepsis or cytokine-induced systemic hypotension, is useful in the treatment of sepsis or cytokine-induced systemic hypotension to restore vascular sensitivity to the effects of .alpha..sub.1 -adrenergic agonists, and is useful to suppress an immune response, e.g., in treating inflammation. In one embodiment, certain argininosuccinate synthetase activity reducing agents are used together with arginine antagonists to treat sepsis or cytokine induced hypotension.

Preventing conversion of citrulline to argininosuccinate to limit

L-amino acid oxidase is utilized to reduce the plasma level of large neutral amino acids to allow the opportunity of increased large neutral amino acid drug transport across the blood brain barrier. Preferably anti L-amino acid oxidase antibody is administered intermediate to the L-amino acid oxidase and large neutral amino acid drug administrations to deplete L-amino acid oxidase activity once the L-amino acid oxidase has caused the large neutral amino acid drug transport improving level plasma reduction of large neutral amino acids thereby to reduce or eliminate degrading of large neutral amino acid drugs by L-amino acid oxidase. The large neutral amino acid drugs include levodopa, melphalan, L-DON, azaserine, acivicin, L-alanosine and 3-(phosphonomethyl)phenylalanines. For treatment of brain tumors, the drug administration is preferably preceded by the administration of a large neutral amino acid glutathione depleting agent, e.g., L-buthionine-SR-sulfoximine. L-Amino acid oxidase is also utilized to enhance the transport of large neutral amino acid glutathione depleting agent across the blood brain barrier as an adjunct to radiation therapy of brain tumors.

Enhancing delivery of large neutral amino acid drugs

Inhibitors of nitric oxide formation from arginine useful for treating hypotension, inflammation, stroke and to restore vascular contractile sensitivity to the effects of .alpha..sub.1 adrenergic agonists are physiologically active compounds including N.sup..delta. -substituted ornithine or N.sup..epsilon. -substituted lysine moieties or monoalkyl carbon-substituted N.sup..delta. -substituted ornithine or N.sup..epsilon. -substituted lysine moieties, having the formula ##STR1## wherein R is (CH.sub.2).sub.y CH.sub.3 or H, R' is CH.sub.2 or C(H)(CH.sub.2).sub.y CH.sub.3, and R' is CH.sub.2 or C(H)(CH.sub.2).sub.y CH.sub.3, with y ranging from 0 to 5, and x is 0 or 1 and wherein none or only one of R, R' and R' provides an alkyl substituent on ornithine or lysine moiety, and wherein Q is a heme binding moiety and/or a sulfur-containing binding moiety and Q' is --NH.sub.2 when there is a double bond between the omega carbon and Q and Q' is .dbd.NH when there is a single bond between the omega carbon and Q, and physiologically acceptable acid addition salts thereof.

Heme binding compounds and use thereof

An anti-hypotensive formulation comprising an essentially arginine-free or low arginine (less than about 0.1%, most preferably, about 0.01%) containing mixture of amino acids is provided. The invention in particular embodiments of the anti-hypotensive formulation includes ornithine, citrulline or both. A method for prophylaxis and treatment of systemic hypotension in an animal is provided. Most particularly, a method for treating hypotension caused by nitric oxide synthesis through administering a low or essentially arginine-free parenteral formulation to an animal, so as to reduce or eliminate nitric oxide synthesis is described. A method for treating an animal in septic shock is also disclosed, comprising administering to the animal an anti-hypotensive formulation comprising a mixture of amino acids, which is essentially arginine free.

Growing community of inventors

Milwaukee, WI, United States of America

Owen W Griffith