Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1996-04-10
1998-12-22
Nutter, Nathan M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514513, 514515, 514529, 514538, 514563, 514567, A01N 3712, A01N 3744, A61K 31195, A61K 3124
Patent
active
058520562
DESCRIPTION:
BRIEF SUMMARY
I. FIELD OF THE INVENTION
This invention relates to methods of using phenylacetic acid and its pharmaceutically acceptable derivatives to treat and prevent pathologies and to modulate cellular activities. In particular, this invention relates to A) use of phenylacetic acid and it derivatives in treatment or prevention of cancer, B) use of phenylacetic acid and its derivatives in wound healing, C) use of phenylacetic acid and its derivatives in treatment of diseases associated with interleukin-6, D) use of phenylacetic acid and its derivatives in the treatment of AIDS-associated CNS dysfunction, E) use of phenylacetic acid and its derivatives to enhance immunosurveillance, F) methods of monitoring the dosage level of phenylacetic acid and its derivatives in a patient and/or the patient response to these drugs, G) the activation of the PPAR by phenylacetic acid and its derivatives, the use of phenylacetic acid and its derivatives in combination with agents that interact with retinoid receptors and the use of phenylacetic acid and its derivatives as free radical-based radiation or chemotherapy sensitization or protective agents, H) use of phenylacetic acid and its derivatives in treatment of cancers having a multiple-drug resistant phenotype, I) phenylacetic acid and its derivatives, correlation between potency and lipophilicity, J) phenylacetic acid and its derivatives in synergistic combination with retinoic acid for the treatment and prevention of cancers such as those involving neuroblastoma cells, K) phenylacetic acid and its derivatives in synergistic combination with lovastatin for the treatment and prevention of cancers such as malignant gliomas or other CNS tumors, L) phenylacetic acid and its derivatives for the treament and prevention of cancers and other differentiation disorders such as those involving malignant melanoma or other neuroectodermal tumors, M) phenylacetic acid and its derivatives in synergistic combination with hydroxyurea (HU) for the treatment and prevention of cancers such as prostate cancer, N) phenylacetic acid and its derivatives for the treatment and prevention of cancers involving medulloblastoma and astrocytoma derived cells, O) phenylacetic acid and its derivatives in human studies relating to treatments with PA and PB, P) phenylacetic acid and its derivatives in methods of altering lipid metabolism, including reducing serum triglyerides, Q) induction of HbF by phenylacetic acid and its derivatives in malignant and nonmalignant cells, and R) methods of administering phenylacetic acid and its derivatives.
II. BACKGROUND OF THE INVENTION
Phenylacetic acid (PAA) is a protein decomposition product found throughout the phylogenetic spectrum, ranging from bacteria to man. Highly conserved in evolution, PAA may play a fundamental role in growth control and differentiation. In plants, PAA serves as a growth hormone (auxin) promoting cell proliferation and enlargement at low doses (10.sup.-5 -10.sup.-7 M), while inhibiting growth at higher concentrations. The effect on animal and human cells is less well characterized. In humans, PAA is known to conjugate glutamine with subsequent renal excretion of phenylacetylglutamine (PAG). The latter, leading to waste nitrogen excretion, has been the basis for using PAA or preferably its salt sodium phenylacetate (NaPA, also referenced herein as that active anionic meoity, phenylacetate or "PA") in the treatment of hyperammonemia associated with inborn errors of ureagenesis. Clinical experience indicates that acute or long-term treatment with high NaPA doses is well tolerated, essentially free of adverse effects, and effective in removing excess glutamine. Inherited Diseases, Vol. 6:629-633 (1989)!.
Glutamine is the major nitrogen source for nucleic acid and protein synthesis, and a substrate for energy in rapidly dividing normal and tumor cells. Compared with normal tissues, most tumors, due to decreased synthesis of glutamine along with accelerated utilization and catabolism, operate at limiting levels of glutamine availability, and cons
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Nutter Nathan M.
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