Claims for Patent: 5,939,455

Summary for Patent: 5,939,455

Title:	Therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives
Abstract:	This invention provides a method of augmenting the therapeutic activity of an oxyalkylene-containing compound, butyric acid, a butyric acid salt or butyric acid derivative by administering an inhibitor of .beta.-oxidation of fatty acids to a patient or to host cells. Pharmaceutical compositions are also included.
Inventor(s):	Rephaeli; Ada (North Caldwell, NJ)
Assignee:	Beacon Laboratories, Inc. (Phoenix, MD)
Application Number:	08/814,222
Patent Claims:	1. A method of augmenting the therapeutic activity of an oxyalkylene-containing compound which comprises administering to a patient or host cells an amount of an inhibitor of .beta.-oxidation of fatty acids effective to inhibit the .beta.-oxidation of said the compound, and thereby augment the therapeutic activity of said compound, wherein said compound is represented by the formula: ##STR5## wherein R is C.sub.3 to C.sub.10 alkyl, C.sub.3 to C.sub.10 alkenyl, C.sub.3 to C.sub.10 alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl, any of which can be optionally substituted with aryl, heteroaryl, halo, alkyl, alkoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, carbonyl, acylamino, carbamoyl or a combination thereof; R.sup.1 and R.sup.2 are independently H, C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, or C.sub.2 to C.sub.10 alkynyl, any of which can be optionally substituted with halo, alkoxy, amino, trifluoromethyl, aryl, heteroaryl or a combination thereof; R.sup.3 is (1) C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, C.sub.2 to C.sub.10 alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl, any of which can be optionally substituted with aryl, heteroaryl, halo, alkyl, alkoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, carbonyl, acylamino, carbamoyl or a combination thereof; (2) --ACOOR.sup.6, wherein A is aryl, heteroaryl, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.3 alkenyl, or C.sub.2 to C.sub.3 alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with one or more of hydroxy, halo, lower alkyl, alkoxy, carbonyl, thiol, lower alkylthio, aryl, heteroaryl or combination thereof, and further wherein R.sup.6 is H, alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or --CR.sup.1 R.sup.2 --O--C(O)--R; ##STR6## wherein Z is --CR.sup.9 .dbd.CR.sup.10 -- or --C.tbd.C--; R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are independently H, alkyl or alkenyl; B is aryl or heteroaryl; m and n are independently integers from 0 to 5; the sum of m and n is from 1 to 5; and p, q and r are independently integers from 0 to 2; (4) a nitrogen-containing heterocycloalkyl, heterocycloalkenyl, heteroaryl group or heteroaralkyl group, wherein the heteroaryl group and the heteroaralkyl group can have up to two additional substituents; (5) an aryl or aralkyl group having one or two nitrogen-containing substituents selected from the group consisting of amino, monoalkylamino, dialkylamino, trialkylammonium salts, acylamino, arylcarbonylamino, alkoxycarbonylamino, formamido, guanidino, ureido, sulfamyl, and alkylsulfonamido, wherein the aryl or aralkyl groups can have up to two additional substituents; (6) a C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, C.sub.3 to C.sub.10 alkynyl or C.sub.3 to C.sub.7 cycloalkyl group having one or two nitrogen-containing substituents selected from the group consisting of amino, monoalkylamino, dialkylamino, trialkylammonium salts, acylamino, arylcarbonylamino, alkoxycarbonylamino, formamido, guanidino, ureido, sulfamyl, and alkylsulfonamido; (7) C.sub.1 to C.sub.12 alkyl or C.sub.2 to C.sub.10 alkenyl substituted with from one to ten substituents selected from the group consisting of hydroxy, alkoxy, acyloxy, aroyloxy and aryloxy, and, optionally having one or more halo groups, wherein adjacent hydroxy groups, if present, can optionally be present as an acetonide; (8) --(CH.sub.2).sub.n --[O--(CH.sub.2).sub.p ].sub.m --OR.sup.11, --(CH.sub.2).sub.n -PEG-OR.sup.11, or --(CH.sub.2).sub.n -PPG-OR.sup.11 ; wherein R.sup.11 is C.sub.1 to C.sub.6 alkyl, C.sub.2 to C.sub.6 alkenyl, aryl, acyl, aroyl, alkoxycarbonyl, aminocarbonyl or --(CH.sub.2).sub.n --COOCR.sup.1 R.sup.2 --O--C(O)--R; PEG is a polyethylene glycol moiety having an average molecular weight of 200-8000; PPG is a polypropylene glycol moiety having an average molecular weight of 200-8000; p is an integer from 2 to 4; n is an integer from 1 to 5; and m is an integer from 1 to 6; (9) together with the carbonyl group to which it is attached, an acyl moiety of an inhibitor of .beta.-oxidation of fatty acids (R.sup.3 CO), wherein said first and second inhibitors are different; X is oxygen or sulfur; R.sup.4 is independently H, C.sub.1 to C.sub.6 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, --OCR.sup.1 R.sup.2 --O--C(O)--R or OR.sup.5 ; R.sup.5 is independently H, C.sub.1 to C.sub.6 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl or --CR.sup.1 R.sup.2 --O--C(O)--R; or a pharmaceutically-acceptable salt thereof. 2. The method of claim 1 wherein said oxyalkylene-containing compound is pivaloyloxymethyl butyrate or butylidine dibutyrate. 3. The method of claim 1 wherein said oxyalkylene-containing compound is mono-(butyroyloxymethyl)glutarate, bis-(butyroyloxymethyl)glutarate, mono-(1-butyroyloxyethyl)glutarate or bis-(1-butyroyloxyethyl)glutarate. 4. The method of claim 1 wherein said oxyalkylene-containing compound is cinnamoyloxymethyl butyrate, cinnamoyloxymethyl phenylacetate, cinnamoyloxymethyl 4-phenylbutyrate, 1-(cinnamoyl)oxyethyl phenylacetate, 1-(cinnamoyl)oxyethyl 4-phenylbutyrate, 3,4-dimethoxycinnamoyloxymethyl butyrate or 1-(3,4-dimethoxycinnamoyl)oxyethyl butyrate. 5. The method of claim 1 wherein said oxyalkylene-containing compound is 4-(butyramido)butyroyloxymethyl butyrate, 4-(butyramido)benzoyloxymethyl butyrate, 4-aminobenzoyloxymethyl butyrate, 4-aminobenzoyloxymethyl butyrate hydrochloride, 1-(4-aminobenzoyloxy)ethyl butyrate, 3-pyridinecarboxymethyl butyrate, 1-(3-pyridinecarboxy)ethyl butyrate or (N-methylpyridinium)-3-carboxymethyl butyrate chloride. 6. The method of claim 1 wherein said oxyalkylene-containing compound is 2-(2-methoxyethoxy)acetyloxymethyl butyrate, 2-[2-(methoxyethoxy)ethoxy]acetyloxymethyl butyrate, 1-[2-(2-methoxyethoxy)acetyl]oxyethyl butyrate or 1-{2-[2-(2-methoxyethoxy)ethoxy]acetyl}oxyethyl butyrate. 7. The method of claim 1 wherein said oxyalkylene-containing compound is .alpha.-methyl-4-(2-methylpropyl)-benzeneacetyloxymethyl butyrate, 1-{.alpha.-methyl-4(2-methylpropyl)-benzeneacetyloxy}-ethyl butyrate, 1-{.alpha.-methyl-4(2-methylpropyl)-benzeneacetyloxy}-butyl butyrate, 6-methoxy-.alpha.-methyl-2-naphthaleneacetyloxylmethyl butyrate, 1-{6-methoxy-.alpha.-methyl-2-naphthaleneacetyloxy}-ethyl butyrate or 1-{6-methoxy-.alpha.-methyl-2-naphthaleneacetyloxy}-butyl butyrate. 8. The method of claim 1 wherein said oxyalkylene-containing compound is butyroyloxymethyl diethyl phosphate, 1-(1-butyroyloxy)ethyl diethyl phosphate, mono(butyroyloxymethyl)phosphate or 1-{1-(4-phenylbutyroyloxy)ethyl} diethyl phosphate. 9. The method of claim 1 wherein said inhibitor is selected from the group consisting of ketoprofen, diflunisal, salsalate, etodolac, tolmetin, ibuprofen, naproxen, oxaprozin, salicylic acid, acetylsalicylic acid, indomethacin, flurbiprofen, diclofenac, mefenamic acid, meclofenamic acid, ketorolac, sulindac, valproic acid and 2-valproenic acid. 10. The method of claim 1 wherein said therapeutic activity is effective to treat or ameliorate cancer or other proliferative disorder. 11. The method of claim 10 wherein said therapeutic activity is effective to inhibit histone deacetylase in said patient. 12. The method of claim 10 wherein said therapeutic activity is effective to induce cellular apoptosis of cancer cells or proliferating cells of said proliferative disorder. 13. The method of claim 1 wherein said therapeutic activity is effective to cause differentiation of or block proliferation of cancerous or neoplastic cells. 14. The method of claim 1 wherein said therapeutic activity is effective to inhibit telomerase activity in cancer cells and to thereby inhibit malignant progression of said cells. 15. The method of claim 1 which further comprises administering an antiviral agent. 16. The method of claim 15 wherein said further administering is effective to treat or ameliorate a virus-associated tumor selected from the group consisting of an EBV-associated malignancy, Kaposi's sarcoma, an AIDS-related lymphoma, an hepatitis B-associated malignancy and an hepatitis C-associated malignancy. 17. The method of claim 16 wherein said EBV-associated malignancy is nasopharyngeal carcinoma or non-Hodgkin's lymphoma. 18. The method of claim 17 wherein said antiviral agent is ganciclovir, acyclovir, or famciclovir. 19. The method of claim 1 which further comprises administering a pharmaceutical agent to thereby enhance the activity of said agent, wherein said agent is selected from the group consisting of a cytokine, an interleukin, an anti-cancer agent or an anti-neoplastic agent, a chemotherapeutic agent, an antibody, a conjugated antibody, an immune stimulant, an antibiotic, a hormone antagonist or a growth stimulant. 20. The method of claim 19 wherein said antibiotic is selected from the group consisting of ganciclovir, acyclovir, and famciclovir. 21. The method of claim 19 wherein said chemotherapeutic agent is selected from the group consisting of an alkylating agent, a purine analog, a pyrimidine analog, a vinca alkaloid, a vinca-like alkaloid, etoposide, an etoposide-like drug, a corticosteroid, a nitrosourea, an antimetabolite, a platinum-based cytotoxic drug, a hormonal antagonist, an anti-androgen and an anti-estrogen. 22. The method of claim 19 wherein said cytokine is an interferon. 23. The method of claim 19 wherein said immune stimulant is Corynebacterium parvum or a sarcolectin. 24. The method of claim 19 wherein the chemotherapeutic agent is selected from the group consisting of tamoxifen, doxorubicin, L-asparaginase, dacarbazine, amascrine, procarbazine, hexamethylmelamine, mitosantrone and gemcitabine. 25. The method of claim 1 which further comprises administering a cytotoxic agent to thereby ameliorate the effects of said cytotoxic agent in a patient by inducing growth arrest of rapidly-proliferating epithelial cells or bone marrow stem cells of said patient. 26. The method of claim 25 wherein said compound is administered simultaneously with, before or after administration of said cytotoxic agent. 27. The method of claim 1 wherein said therapeutic activity is effective to modulate an immune response in said patient. 28. The method of claim 27 wherein modulation of said immune response is effective to enhance cytokine secretion, inhibit or delay apoptosis in polymorphonuclear cells, enhance polymorphonuclear cell function by augmenting hematopoietic growth factor secretion, induce expression of cell surface antigens in tumor cells, enhance progenitor cell recovery after bone marrow transplantation, or a combination thereof. 29. The method of claim 1 wherein said therapeutic activity is effective to increase hemoglobin content in blood of said patient. 30. The method of claim 1 wherein said therapeutic activity is effective to treat a blood disorder in said patient. 31. The method of claim 1 wherein said therapeutic activity is effective to treat a gastrointestinal disorder. 32. The method of claim 1 wherein said therapeutic activity is effective to treat a cutaneous ulcer. 33. The method of claim 1 wherein said therapeutic activity is effective to induce wound healing. 34. The method of claim 1 wherein said therapeutic activity is effective to modulate gene expression in a host or host cells by enhancing, augmenting or repressing expression of a gene of interest. 35. The method of claim 1 wherein said therapeutic activity is effective to enhance insulin expression in an insulin-dependent patient. 36. The method of claim 1 wherein said therapeutic activity is effective to enhance chloride channel expression in a cystic fibrosis patient. 37. The method of claim 1 wherein said therapeutic activity is effective to enhance recombinant gene expression in a recombinant host cell containing an expression system for a butyric acid-responsive gene. 38. The method of claim 37 wherein said host cells are mammalian cells, insect cells, yeast cells or bacterial cells. 39. The method of claim 1 wherein said therapeutic activity is effective to induce tolerance to an antigen. 40. The method of claim 39 wherein said antigen is a self-antigen associated with an autoimmune disease or said antigen is present on a transplanted organ or cells. 41. The method of claim 1 wherein said therapeutic activity is anti-protozoan activity. 42. The method of claim 41 wherein said anti-protozoan activity is anti-malarial, anti-cryptosporidiosis, anti-toxoplasmosis, or anti-coccidiosis activity. 43. The method of claim 41 wherein said anti-protozoan activity is effective to inhibit protozoan histone deacetylase in said patient. 44. The method of claim 1 wherein said therapeutic activity is effective to inhibit histone deacetylase in said host cells. 45. A pharmaceutical composition for augmenting the therapeutic activity of an oxyalkylene-containing compound, butyric acid, a butyric acid salt or a butyric acid derivative which comprises a therapeutically-effective amount of said compound, acid, salt or derivative and an amount of a first inhibitor of .beta.-oxidation of fatty acids effective to inhibit the .beta.-oxidation of said compound, acid, salt or derivative, and thereby augment the therapeutic activity thereof, in admixture with a pharmaceutically acceptable carrier, wherein said oxyalkylene-containing compound is represented by the formula: ##STR7## wherein R is C.sub.3 to C.sub.10 alkyl, C.sub.3 to C.sub.10 alkenyl, C.sub.3 to C.sub.10 alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl, any of which can be optionally substituted with aryl, heteroaryl, halo, alkyl, alkoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, carbonyl, acylamino, carbamoyl or a combination thereof; R.sup.1 and R.sup.2 are independently H, C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, or C.sub.2 to C.sub.10 alkynyl, any of which can be optionally substituted with halo, alkoxy, amino, trifluoromethyl, aryl, heteroaryl or a combination thereof; R.sup.3 is (1) C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, C.sub.2 to C.sub.10 alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl, any of which can be optionally substituted with aryl, heteroaryl, halo, alkyl, alkoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, carbonyl, acylamino, carbamoyl or a combination thereof; (2) --ACOOR.sup.6, wherein A is aryl, heteroaryl, C.sub.1 to C.sub.8 alkyl, C.sub.2 to C.sub.3 alkenyl, or C.sub.2 to C.sub.3 alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with one or more of hydroxy, halo, lower alkyl, alkoxy, carbonyl, thiol, lower alkylthio, aryl, heteroaryl or combination thereof, and further wherein R.sup.6 is H, alkyl, alkenyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or --CR.sup.1 R.sup.2 --O--C(O)--R; ##STR8## wherein Z is --CR.sup.9 .dbd.CR.sup.10 -- or --C.tbd.C--; R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are independently H, alkyl or alkenyl; B is aryl or heteroaryl; m and n are independently integers from 0 to 5; the sum of m and n is from 1 to 5; and p, q and r are independently integers from 0 to 2; (4) a nitrogen-containing heterocycloalkyl, heterocycloalkenyl, heteroaryl group or heteroaralkyl group, wherein the heteroaryl group and the heteroaralkyl group can have up to two additional substituents; (5) an aryl or aralkyl group having one or two nitrogen-containing substituents selected from the group consisting of amino, monoalkylamino, dialkylamino, trialkylammonium salts, acylamino, arylcarbonylamino, alkoxycarbonylamino, formamido, guanidino, ureido, sulfamyl, and alkylsulfonamido, wherein the aryl or aralkyl groups can have up to two additional substituents; (6) a C.sub.1 to C.sub.10 alkyl, C.sub.2 to C.sub.10 alkenyl, C.sub.3 to C.sub.10 alkynyl or C.sub.3 to C.sub.7 cycloalkyl group having one or two nitrogen-containing substituents selected from the group consisting of amino, monoalkylamino, dialkylamino, trialkylammonium salts, acylamino, arylcarbonylamino, alkoxycarbonylamino, formamido, guanidino, ureido, sulfamyl, and alkylsulfonamido; (7) C.sub.1 to C.sub.12 alkyl or C.sub.2 to C.sub.10 alkenyl substituted with from one to ten substituents selected from the group consisting of hydroxy, alkoxy, acyloxy, aroyloxy and aryloxy, and, optionally having one or more halo groups, wherein adjacent hydroxy groups, if present, can optionally be present as an acetonide; (8) --(CH.sub.2).sub.n --[O--(CH.sub.2).sub.p ].sub.m --OR.sup.11, --(CH.sub.2).sub.n -PEG-OH.sup.11, or --(CH.sub.2).sub.n -PPG-OR.sup.11 ; wherein R.sup.11 is C.sub.1 to C.sub.6 alkyl, C.sub.2 to C.sub.6 alkenyl, aryl, acyl, aroyl, alkoxycarbonyl, aminocarbonyl or --(CH.sub.2).sub.n --COOCR.sup.1 R.sup.2 --O--C(O)--R; PEG is a polyethylene glycol moiety having an average molecular weight of 200-8000; PPG is a polypropylene glycol moiety having an average molecular weight of 200-8000; p is an integer from 2 to 4; n is an integer from 1 to 5; and m is an integer from 1 to 6; (9) together with the carbonyl group to which it is attached, an acyl moiety of an inhibitor of .beta.-oxidation of fatty acids (R.sup.3 CO), wherein said first and second inhibitors are different; X is oxygen or sulfur; R.sup.4 is independently H, C.sub.1 to C.sub.6 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, --OCR.sup.1 R.sup.2 --O--C(O)--R or OR.sup.5 ; R.sup.5 is independently H, C.sub.1 to C.sub.6 alkyl, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl or --CR.sup.1 R.sup.2 --O--C(O)--R; or a pharmaceutically-acceptable salt thereof. 46. The composition of claim 45 wherein said oxyalkylene-containing compound is pivaloyloxymethyl butyrate or butylidine dibutyrate. 47. The composition of claim 45 wherein said oxyalkylene-containing compound is mono(butyroyloxymethyl)glutarate, bis-(butyroyloxymethyl)glutarate, mono-(1-butyroyloxyethyl)glutarate or bis-(1-butyroyloxyethyl)glutarate. 48. The composition of claim 45 wherein said oxyalkylene-containing compound is cinnamoyloxymethyl butyrate, cinnamoyloxymethyl phenylacetate, cinnamoyloxymethyl 4-phenylbutyrate, 1-(cinnamoyl)oxyethyl phenylacetate, 1-(cinnamoyl)oxyethyl 4-phenylbutyrate, 3,4-dimethoxycinnamoyloxymethyl butyrate or 1-(3,4-dimethoxycinnamoyl)oxyethyl butyrate. 49. The composition of claim 45 wherein said oxyalkylene-containing compound is 4-(butyramido)butyroyloxymethyl butyrate, 4-(butyramido)benzoyloxymethyl butyrate, 4-aminobenzoyloxymethyl butyrate, 4-aminobenzoyloxymethyl butyrate hydrochloride, 1-(4-aminobenzoyloxy)ethyl butyrate, 3-pyridinecarboxymethyl butyrate, 1-(3-pyridinecarboxy)ethyl butyrate or (N-methylpyridinium)-3-carboxymethyl butyrate chloride. 50. The composition of claim 45 wherein said oxyalkylene-containing compound is 2-(2-methoxyethoxy)acetyloxymethyl butyrate, 2-[2-(methoxyethoxy)ethoxy]acetyloxymethyl butyrate, 1-[2-(2-methoxyethoxy)acetyl]oxyethyl butyrate or 1-{2-[2-(2-methoxyethoxy)ethoxy]acetyl}oxyethyl butyrate. 51. The composition of claim 45 wherein said oxyalkylene-containing compound is .alpha.-methyl-4-(2-methylpropyl)-benzeneacetyloxymethyl butyrate, 1-{.alpha.-methyl-4(2-methylpropyl)-benzeneacetyloxy}-ethyl butyrate, 1-{.alpha.-methyl-4(2-methylpropyl)-benzeneacetyloxy}-butyl butyrate, 6-methoxy-.alpha.-methyl-2-naphthaleneacetyloxylmethyl butyrate, 1-{6-methoxy-.alpha.-methyl-2-naphthaleneacetyloxy}-ethyl butyrate or 1-{6-methoxy-.alpha.-methyl-2-naphthaleneacetyloxy}-butyl butyrate. 52. The composition of claim 45 wherein said oxyalkylene-containing compound is butyroyloxymethyl diethyl phosphate, 1-(1-butyroyloxy)ethyl diethyl phosphate, mono(butyroyloxymethyl) phosphate or 1-{1-(4-phenylbutyroyloxy)ethyl} diethyl phosphate. 53. The composition of claim 45 wherein said derivative is isobutyramide, monobutyrin, tributyrin, 2-phenylbutyric acid, 3-phenylbutyric acid, 4-phenylbutyric acid, phenylacetic acid, cinnamic acid, .alpha.-methyldihydrocinnamic acid, 3-chloropropionic acid or vinylacetic acid. 54. The composition of claim 45 wherein said butyric acid salt is a sodium, arginine or lysine salt. 55. The composition of claim 45 wherein said butyric acid salt is arginine butyrate. 56. The composition of claim 45 wherein said inhibitor is selected from the group consisting of ketoprofen, diflunisal, salsalate, etodolac, tolmetin, ibuprofen, naproxen, oxaprozin, salicylic acid, acetylsalicylic acid, indomethacin, flurbiprofen, diclofenac, mefenamic acid, meclofenamic acid, ketorolac, sulindac, valproic acid and 2-valproenic acid. 57. The composition of claim 45 which further comprises a pharmaceutical agent selected from the group consisting of a cytokine, an interleukin, an anti-cancer agent, a chemotherapeutic agent, an antibody, a conjugated antibody, an immune stimulant, an antibiotic, a hormone antagonist, a growth stimulant, an antiviral agent and a cytotoxic agent. 58. The composition of claim 57 wherein said antiviral agent is ganciclovir, acyclovir, or famciclovir. 59. The composition of claim 57 wherein said chemotherapeutic agent is selected from the group consisting of an alkylating agent, a purine analog, a pyrimidine analog, a vinca alkaloid, a vinca-like alkaloid, etoposide, an etoposide-like drug, a corticosteroid, a nitrosourea, an antimetabolite, a platinum-based cytotoxic drug, a hormonal antagonist, an anti-androgen and an anti-estrogen. 60. The composition of claim 57 wherein said cytokine is an interferon. 61. The composition of claim 57 wherein said immune stimulant is Corynebacterium parvum or a sarcolectin. 62. The composition of claim 57 wherein the chemotherapeutic agent is selected from the group consisting of tamoxifen, doxorubicin, L-asparaginase, dacarbazine, amascrine, procarbazine, hexamethylmelamine, mitosantrone and gemcitabine. 63. The composition of claim 57 wherein said cytotoxic agent induces growth arrest of rapidly-proliferating epithelial cells or bone marrow stem cells of said patient.

Details for Patent 5,939,455

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2039-02-26