Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/193—Colony stimulating factors [CSF]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

• This invention relates to pharmaceutical compositions comprising an antiviral effective amount of DHPG, i.e. 9-(l,3-dihydroxy-2-propoxymethyl) guanine, in combination with an anti-myelosuppressive effective amount of GM-CSF, i.e. granulocyte macrophage colony stimulating factor, for use in treating patients suffering from myelosuppression and a viral infection associated with AIDS, i.e. Acquired Immune Deficiency Syndrome.
• DHPG i.e. 9-(l,3-dihydroxy-2-propoxymethyl) guanine
• GM-CSF i.e. granulocyte macrophage colony stimulating factor
• AIDS Acquired Immune Deficiency Syndrome
• HIV human immunodeficiency virus
• the major effect of the AIDS virus is the incapacitation of the immune system, particularly T4 helper cells, which is the very system designed to fight against such invaders.
• the fatal result of AIDS infection is the host defense defect that renders the body highly susceptible to opportunistic infections and neoplasms. Besides halting the AIDS virus itself. methods of treatment can be directed to lessening the effect of such opportunistic infections and neoplasms.
• Cytomegalovirus (CMV) infection eventually develops in many patients having severe HIV disease as described in Quinnan et al., JAMA 1984, 252; 72-7; and Macher et al., N. Engl. J. Med. 1983, 309: 1454.
• CMV is the most frequent cause of HIV-associated retinitis. See Glatt et al., N. Engl. J. Med. 1988, 318: 1439-48; and Georgia et al., Opthalmology 1984, 91: 1092-9.
• Granulocyte macrophage colony stimulating factor is a lymphokine that exhibits a broad spectrum of immune cell stimulation as described in Burgess and Metcalf, Blood 1980, 56 947-58.
• GM-CSF has been shown to increase .the leukocyte count in patients with the acquired immunodeficiency syndrome (Brandt e t al. , N. Engl. J. Med. 1988, 318: 869-76) and people suffering from chemotherapy-induced myelosuppression (Antman et al.. New Eng. J. Med.
• colony stimulating factors alone may be a useful treatment of patients suffering from AIDS-type disease or together with erythropoietin and/or an antiviral agent and/or interleukin-2(IL-2) (PCT Application No. 87/03204).
• one aspect of the present invention is a pharmaceutical composition comprising an antiviral effective amount of DHPG in combination with a anti-myelosuppressive effective amount of GM-CSF.
• Another aspect involves administering to a patient suffering from cytomegalovirus retinitis an antiviral effective amount of DHPG in combination with an anti- myelosuppressive effective amount of GM-CSF.
• the present invention also contemplates the use of DHPG for the preparation of a pharmaceutical composition for use in a combined therapy for treating a patient suffering from myelosuppression and a viral infection by administering DHPG in association with GM- CSF.
• the present invention further contemplates the use of GM-CSF for the preparation of a pharmaceutical composition for use in a combined therapy for treating a patient suffering from myelosuppression and a viral infection by administering GM-CSF in association with DHPG.
• the present invention still further contemplates the use of DHPG in association with GM-CSF -for the preparation of a pharmaceutical composition for treating a patient suffering from myelosuppression in association with a viral infection, said pharmaceutical composition comprising DHPG and GM-CSF together with pharmaceutical carriers therefor.
• the present invention also provides the use of DHPG in combination with GM-CSF for treating a patient suffering fro myelosuppression and a viral infection.
• the.present invention provides a process for the preparation of a pharmaceutical composition which comprises admixing DHPG and GM-CSF with pharmaceutically acceptable carriers therefor.
• kits for use in treating patients suffering from myelosuppression and a viral infection comprising a pharmaceutical package having a first container and a second container, wherein the first container comprises an antiviral effective amount of a pharmaceutical composition containing DHPG and the second container comprises an anti-myelosuppressive amount of GM-CSF pharmaceutical composition.
• DHPG [9-(l,3-Dihydroxy-2- propoxymethyl)guanine] , which is produced by Syntex Corporation, Palo Alto, California, and which may be obtained as described in U.S. Patent 4,355,032, can be administered in an amount so as to lessen the symptoms associated with cytomegalovirus retinitis. Such symptoms include production of a characteristic retinal lesion consisting of hemorrhagic exudates in a vascular pattern of distribution manifested clinically by decreased vision and/or blindness.
• DHPG is administered in an amount of from about 5.0 to about 20 mg per kilogram per day.
• the preferred administration regime is twice daily by intravenous infusion.
• the DHPG is administered in an amount of from about 7.5 to about 15 mg per kilograms per day. The amount is adjusted based upon patient tolerance manifested by decreased white blood cell count.
• GM-CSF Complementary DNAs
• cDNAs Complementary DNAs
• GM-CSF Complementary DNAs
• non-recombinant GM-CSF has been purified from various culture supernatants, e.g. U.S. Patent 4,438,032 (Mo cell line); Burgers et al., Exp. Hematol. j ⁇ :893 (1981) (mouse); Sparrow et al., Proc. Natl. Acad. Sci., "82:292 (1985) (purification and partial amino acid sequence for mouse) ; Wu et al., Exp.
• GM-CSF GM-CSF
• the GM-CSF used in the present invention will be a human GM-CSF, most preferably the GM-CSF described in Proc. Natl. Acad. Sci. USA 82:4360 (1985) , which is hereby incorporated by reference.
• GM-CSF is administered to a patient showing symptoms of CMV retinitis and who is being treated with DHPG as described above and who is experiencing a myelosuppression.
• Myleosuppression for purposes of this invention is meant to include a reduction in the white blood cell count below about 2000 per cm 3 or a granulocyte count less than about 1000 per cm 3 .
• the dosage for GM-CSF will vary according to the response observed. Generally, it is desirable to administer GM-CSF in a sufficient amount to maintain white blood cell counts from about 2000 to about 10,000 per cm 3 , preferably from "about 2000 to about 5,000 per cm 3 . A typical dosage of GM-CSF is about 3 to about 15 ⁇ g per kilogram per day intravenously or subcutaneously. Such white blood cell.levels will permit the full administration of DHPG and the prevention of further visual deterioration.
• the usual time to efficacious rises in white blood cell count is 5 to 10 days after initiation of GM- CSF therapy. If no rise in white blood cell count has occurred, dosage may be adjusted by increasing increments of 25% every four days after day 10. If white blood cell count is greater than about 20,000 per cm 3 , dosage should be decreased by 25%. Dosage should be adjusted so that white blood cell count does not exceed about 20,000 per cm 3 .
• the administration of the pharmaceutical compositions of this invention is via the subcutaneous or intravenous route.
• DHPG and GM-CSF may be given together or sequentially, whichever is deemed more appropriate by the attending clinician.
• the solutions to be administered may be reconstituted lypholized powders, particularly for GM-CSF and they may additionally contain preservatives, buffers, dispersahts etc.
• GM- CSF is reconstituted with preservative-free sterile water with the maximum concentration not to exceed 1500 micrograms per ml. and administered subcutaneously or as a continuous infusion, depending on the urgency of the situation.
• the daily dose is to be added to 50 ml of normal saline and the solution infused by mechanical pump.
• kits for use in treating patients suffering from myelosuppression and a viral infection as discussed above.
• the kits comprise a pharmaceutical package having a first container comprising a pharmaceutical composition containing an antiviral effective amount of DHPG and a second container comprising a pharmaceutical composition containing an anti-myelosuppressive amount of GM-CSF.
• the kits or packages may also contain instructions for use of the pharmaceutical composition of DHPG and of GM- CSF in accordance with the present invention.
• a 30 year old male was diagnosed as having AIDS and CMV retinitis.
• treatment with DHPG was commenced and life threatening myelosuppression was the result.
• a 100% dose of DHPG refers to a full protective dose or the recommended dose of DHPG of 15 mg per kilogram per day.
• the dosage of DHPG was maintained until changed as indicated in Table 1 below.
• Table 1 illustrates, administration of 10 mg of purified recombinant GM-CSF as described in Proc. Natl. Acad. Sci USA 82:4360 (1985) per kg by intravenous infusion drastically improved the white blood cell (WBC) count and permitted a return to a full protective dose of DHPG.
• WBC white blood cell
• Example 1 A 30 year old male was diagnosed as having AIDS and CMV retinitis. At Day 0, treatment with DHPG was commenced and a myelosuppression was the result. As the accompanying table illustrates, administration of GM-CSF, as described in Example 1, improved the white blood cell - (WBC) count and permitted a return to a full protective dose of DHPG as described in Example 1.
• WBC white blood cell -
• EXAMPLE 3 A 56 year old male was diagnosed as having AIDS and CMV retinitis. At Day 0, treatment with DHPG was commenced and a myelosuppression was the result. As the accompanying table illustrates, administration of GM-CSF, as described in Example 1, improved the white blood cell (WBC) count and permitted a return to a full protective dose of DHPG as described in Example l. Unfortunately, the patient developed thrombocytopenia during GM-CSF treatment and expired.
• WBC white blood cell

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• Health & Medical Sciences (AREA)
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• Pharmacology & Pharmacy (AREA)
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• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Immunology (AREA)
• Virology (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Epidemiology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Molecular Biology (AREA)
• Hematology (AREA)
• Diabetes (AREA)
• Ophthalmology & Optometry (AREA)
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• Gastroenterology & Hepatology (AREA)
• Tropical Medicine & Parasitology (AREA)
• AIDS & HIV (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 1989
  • 1989-11-07 AU AU45268/89A patent/AU630637B2/en not_active Ceased
  • 1989-11-07 EP EP89912836A patent/EP0446230A1/de active Pending
  • 1989-11-07 WO PCT/US1989/004872 patent/WO1990004973A1/en not_active Ceased
  • 1989-11-07 EP EP89311507A patent/EP0370656A1/de not_active Ceased
  • 1989-11-07 CA CA002002413A patent/CA2002413A1/en not_active Abandoned
  • 1989-11-07 ZA ZA898478A patent/ZA898478B/xx unknown
  • 1989-11-07 NZ NZ231304A patent/NZ231304A/en unknown
  • 1989-11-07 IL IL92234A patent/IL92234A/xx not_active IP Right Cessation
  • 1989-11-07 KR KR1019900701463A patent/KR960014097B1/ko not_active Expired - Fee Related
  • 1989-11-07 JP JP2500639A patent/JPH0651639B2/ja not_active Expired - Lifetime
  • 1989-11-08 MY MYPI89001557A patent/MY105868A/en unknown
• 1991
  • 1991-05-03 DK DK082191A patent/DK82191A/da not_active Application Discontinuation

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