University of Florida Research Foundation, Incorporated

Other

University of North Texas

Pharmatec Gmbh

Apollo Genetics

James W Simpkins

Katherine D Gordon

Pattie S Green

Laszlo Prokai

Katalin Prokai

Robert J Leonard

Kelly E Gridley

Nicholas S Bodor

Neeraj Agarwal

Jean Bishop

Douglas F Covey

Meharvan Singh

Kerry S Estes

Warren C Stern

Wesley R Anderson, Jr

The subject invention provides a mechanism by which steroidal quinol compounds confer beneficial ophthalmic effects. The subject compounds possess a lipophilic-hydrophilic balance for transcorneal penetration and are readily reduced into parent phenolic A-ring steroid compounds to provide protection or treatment against various ocular symptoms and disorders. The compounds according to the subject invention appear to be highly advantageous as prodrugs to provide protection and/or treatment against ocular disorders. These prodrugs confer lipid solubility optimal for transocorneal penetration and are readily converted to endogenous reducing agents into active phenolic A-ring steroid compounds. To the extent that these prodrugs have reduced feminizing effects and systemic toxicity, they would be expected to be quite advantageous for protecting or treating the eye against ocular disorders such as cataract or glaucoma without undesired (systemic) side effects).

Prodrugs for use as ophthalmic agents

The present invention relates to novel estrogen-related steroidal quinols and their use as drugs for estrogen replacement therapy. The quinols of the present invention provide improved physicochemical properties, increased bioavailability, and improved distribution into tissues, bone, in the cardiovascular system, and in the CNS (central nervous system) with only a slight estrogenic action or no estrogenic action in the uterus. The compounds are suitable for the production of pharmaceutical agents for use in numerous indications (for example, estrogen replacement therapy, prevention and treatment of osteoporosis).

Steroidal quinols and their use for estrogen replacement therapy

The present invention relates to novel estrogen-related steroidal quinols and their use as prodrugs for phenolic estrogens and estrogen analogs. The quinols of the present invention provide improved physicochemical properties, increased bioavailability, and improved distribution into tissues and penetration across the blood-brain barrier when compared to phenolic estrogens and estrogen analogs.

Steroidal quinols and their use for antioxidant therapy

The present invention in various embodiments provides methods of treating stroke and conferring protection on a population of cells associated with ischemia in a subject following an ischemic event, comprising: (a) providing an estrogen compound; and (b) administering the effective amount of the compound over a course that includes at least one dose within a time that is effectively proximate to the ischemic event, so as to confer protection on the population of cells. Novel methods are provided for the delivery of an estrogen compound. Examples of ischemic events treatable according to the invention are cerebrovascular disease or stroke, subarachnoid subhemorrhage, myocardial infarct, surgery and trauma. A method of treating ischemic damage utilizing hormones that are non-sex hormones is also provided. A method of treating stroke with ent-17&bgr;-estradiol, and a method of synthesis, and compounds produced from the synthesis are provided.

Methods of prevention and treatment of ischemic damage

The present invention provides methods of conferring protection on a population of cells associated with ischemia in a subject following an ischemic event, comprising: (a) providing an estrogen compound; and (b) administering the effective amount of the compound over a course that includes at least one dose within a time that is effectively proximate to the ischemic event, so as to confer protection on the population of cells. Novel methods are provided for the delivery of an estrogen compound. Examples of ischemic events treatable according to the invention are cerebrovascular disease or stroke, subarachnoid subhemorrhage, myocardial infarct, surgery and trauma. A method of treating ischemic damage utilizing non-sex hormones is also provided.

The present invention provides methods of conferring protection on a population of cells associated with ischemia in a subject following an ischemic event, comprising: (a) providing an estrogen compound; and (b) administering the effective amount of the compound over a course that includes at least one dose within a time that is effectively proximate to the ischemic event, so as to confer protection on the population of cells. Novel methods are provided for the intravenous administration of an estrogen compound. Examples of ischemic events treatable according to the invention are cerebrovascular disease or stroke, subarachnoid subhemorrhage, myocardial infarct, surgery and trauma. A method of treating ischemic damage utilizing non-sex hormones is also provided.

The invention comprises methods for conferring a cytoprotective effect on a population of cells, such as providing a polycyclic phenolic compound in a physiologically acceptable formulation, and administering the formulation in an effective dose to the population of cells.

Cytoprotective effect of polycyclic phenolic compounds

A method is provided for preserving tissues during removal, storage and implantation into a subject by enhancing cell viability in a population of graft cells during the transplantation procedure. The method includes selecting an effective dose of a polycylic phenolic compound in a physiologically acceptable formulation and exposing at least the population of graft cells to the formulation containing the compound within a time that is effectively proximate to the transplantation procedure so as to confer cytoprotection on the population of graft cells.

Preservation of tissue during removal storage and implantation

A method is provided for conferring neuroprotection on a population of cells in a subject, the method including providing a polycyclic compound having a terminal phenolic group in a structure containing at least a second ring, the compound having a molecular weight of less than 1000 Daltons, the compound not including estrogen compounds including estrogen agonists. The compound may be administered in an effective dose to the population of cells so as to confer neuroprotection. Methods are further provided for treating a neurodegenerative disease in a subject that include providing an effective dose of a formulation containing the compound and administering the dose to the subject.

Neuroprotective effects of polycyclic phenolic compounds

Androgens and their derivates and analogs, such as anabolic agents, are characterized by at least one substituent or substituent grouping with radical trapping properties. These compounds are used as androgen or anabolic agent substitutes or therapeutical agents for treating androgen defficiency; for treating benign prostate hypertrophy and prostate carcinome, in particular with a testosterone-based compound; for treating osteoporosis, in particular post-menopausal osteoporosis in women, preferably associated with estrogen and/or gestagens; for treating brain oedema induced by vasculary or ischemic troubles, subarachnoidal bleeding, ischemic shock and cerebral insult; for treating asthma in its various forms, for treating Alzheimer's disease, Parkinson's disease; for organ transplants; and for treating androgen-dependent and non androgen-dependent malign neoplasia

Testosterone compounds and use for the protection of neurons

The present invention concerns methods and compositions for enhancing the cytoprotective effects of polycyclic phenolic compounds through the synergistic interaction with anti-oxidants.

Methods and compositions to enhance the cytoprotective effects of

The present invention is directed to a method of conferring protection on a population of cells associated with an ischemic focus, in subject, comprising:

Methods of treatment of ischemic damage

This application relates to the use of non-estrogen compounds having a terminal phenol group in a four-ring cyclopentanophenanthrene compound structure for conferring neuroprotection to cells and for the treatment of neurodegenerative diseases.

A method is provided for conferring a cytoprotective effect on a population of cells in a male of female subject which includes providing an estrogen compound having insubstantial sex related activity in a pharmaceutical formulation and administering the formulation in an effective dose to a population of cells to confer cytoprotection. The method further includes administering the estrogen compound so as to confer a cytoprotective effect in a subject so as to retard adverse effects of osteoporosis in a male or female subject.

Growing community of inventors

Gainesville, FL, United States of America

James W Simpkins