Claims for Patent: 6,221,893

Summary for Patent: 6,221,893

Title:	Administration of histamine for therapeutic purposes
Abstract:	Methods for obtaining beneficial stable levels of circulating histamine are disclosed for use in methods for enhancing natural killer cell cytotoxicity. In such methods, a beneficial level of circulating histamine is attained and an agent whose ability to enhance natural killer cell cytotoxicity is augmented by histamine is administered. Alternatively, stable beneficial levels of circulating histamine can be attained in subjects receiving chemotherapy or antiviral treatment. The invention may also be employed in treatments combining histamine, agents which enhance natural killer cell cytotoxicity, and chemotherapeutic agents. Optimization of the delivery of histamine and substances which induce the release of endogenous histamine are also disclosed.
Inventor(s):	Hellstrand; Kristoffer (Goeborg, SE), Hermodsson; Svante (Molndal, SE), Gehlsen; Kurt R. (Carlsbad, CA)
Assignee:	Maxim Pharmaceuticals, Inc. (N/A)
Application Number:	08/767,338
Patent Claims:	1. A method of augmenting the activity of an agent which enhances cytotoxicity of cytotoxic effector cells comprising: a) administering a pharmaceutically acceptable form of histamine such that a stable blood histamine concentration sufficient to augment the cytotoxicity enhancing effect of said agent is achieved, wherein said histamine is delivered over a period of time not less than one and not greater than thirty minutes; and b) administering a beneficial amount of said agent, wherein the cytotoxicity enhancing effects of said agent are augmented. 2. A method of treating a subject having a malignancy with histamine and a second beneficial agent wherein the activity of said second beneficial agent is augmented by histamine comprising: a) administering a pharmaceutically acceptable form of histamine such that a stable beneficial blood histamine level is achieved, wherein said histamine is delivered over a period of time not less than one and not greater than thirty minutes; and b) administering said second beneficial agent. 3. A method of enhancing the cytotoxic activity of cytotoxic effector cells comprising: a) measuring blood histamine levels in a subject to determine whether the cytotoxic activity of said subject's cytotoxic effector cells could be enhanced by increasing the levels of blood histamine in said subject; b) administering a pharmaceutically acceptable form of histamine to a subject for whom said measuring step indicated that the cytotoxic activity of said subject's cytotoxic effector cells could be enhanced by increasing said subject's blood histamine levels, such that stable beneficial levels of blood histamine are achieved, wherein said histamine is delivered over a period of time not less than one and not geater than thirty minutes; and c) administering a second agent to said subject having beneficial levels of blood histamine, such that the cytotoxic activity of said subject's cytotoxic effector cells is enhanced. 4. A method of treating a malignancy comprising: a) treating a subject having a malignancy with a chemotherapeutic agent; and b) maintaining a beneficial stable level of circulating blood histamine by administering a pharmaceutically acceptable form of histamine in a dose sufficient to attain said beneficial stable levels of circulating blood histamine, wherein said dose is delivered over a period of time not less than one and not greater than thirty minutes. 5. A method of administering to a patient a therapeutically effective amount of a substance selected from the group consisting of histamine, histamine dihydrochloride, histamine phosphate, histamine salts, histamine esters, histamine congeners, histamine prodrugs, serotonin, 5HT agonists and H.sub.2 receptor agonists, wherein said therapeutically effective amount is delivered over a period of time not less than one and not greater than thirty minutes. 6. The method of claim 5, wherein said therapeutically effective amount is delivered over a period of time not less than five and not greater than twenty minutes. 7. The method of claim 5, wherein said therapeutically effective amount is about 0.4 to 10 mg/day. 8. The method of claim 5, wherein said therapeutically effective amount is about 2.0 mg/day. 9. The method of claim 5, wherein said administration occurs once to four times per day. 10. The method of claim 5, wherein said administration occurs twice per day. 11. The method of claim 5, wherein said therapeutically effective amount is delivered at a rate of about 0.025 to 0.2 mg/minute. 12. The method of claim 5, wherein said administration is selected from the group consisting of subcutaneous, intravenous, intramuscular, intraocular, oral, and transdermal. 13. The method of claim 12, whereby said transdermal administration is achieved through use of a transdermal patch. 14. The method of claim 5, wherein said therapeutically effective amount is delivered by means of a controlled release mechanism. 15. The method of claim 14, wherein said controlled release mechanism is selected from the group consisting of polymers, gels, microspheres, liposomes, tablets, capsules, pumps, syringes, ocular inserts, transdermal formulations, hydrophilic gums, microcapsules, and colloidal drug delivery systems. 16. A method for treating a patient in need of a therapeutic dosage of histamine, comprising the step of administering an amount of a substance which induces the release of an effective therapeutic amount of endogenous histamine, wherein said substance is delivered over a period of time such that said effective therapeutic amound of endogenous histamine is released in not less than one and not greater than thirty minutes. 17. The method of claim 16, wherein said substance is selected from the group consisting of retinoic acid or a retinoid. 18. The method of claim 16, wherein said substance is IL-3. 19. The method of claim 16, wherein said substance is an ingestible allergen. 20. The method of claim 16, wherein said patient is suffering from a neoplastic disease. 21. The method of claim 16, wherein said administration is selected from the group consisting of oral, intravenous, intramuscular, and subcutaneous. 22. The method of claim 16, wherein said effective amount is sufficient to induce a release of about 0.05 to about 0.2 mg/min endogenous histamine. 23. The method of claim 16, wherein said administering occurs from once to four times per day.

Details for Patent 6,221,893

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Alk-abello, Inc.	HISTATROL	positive skin test control-histamine	Injection	103754	09/29/1950		2016-05-14
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	03/13/1924		2016-05-14