Treatment of human retroviral infections with 2',3'-dideoxyinosine alone and in combination with other antiviral compounds

• US 5,026,687 A
• Filed: 01/03/1990
• Issued: 06/25/1991
• Est. Priority Date: 01/03/1990
• Status: Expired due to Term

• Current Assignee: United States Department Of Health And Human Services
• Original Assignee: United States Department Of Health And Human Services
• Inventors: Mitsuya, Hiroaki, Yarchoan, Robert, Broder, Samuel
• Primary Examiner(s): Brown, Johnnie R.
• Assistant Examiner(s): Crane, L. Eric
• Application Number:
  US07/460,490
• Time in Patent Office: 538 Days
• Field of Search: 514/45, 514/116, 536/24, 536/26
• US Class Current: 514/45
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61P 31/12 Antivirals

Abstract

A preferred method and dosages for the short and long-term treatment of human retroviral infections, or retroviral-like infections, including acquired immunodeficiency syndrome (AIDS) and other manifestations of human immunodeficiency virus (HIV) infection, with 2'"'"',3'"'"'-dideoxyinosine (ddl) are disclosed, along with a protocol for halting and restarting 2'"'"',3'"'"'-dideoxyinosine to minimize certain side effects.

Claims

1. A method for increasing the CD4 count or CD4+:

CD8+ ratio in immunodepressed patients by administration of about 1.0 mg/kg/day to about 14 mg/kg/day of 2'"'"',3'"'"'-dideoxyinosine.

2. A method of treating HIV infection which comprises administering to an HIV infected patient in need thereof about 0.4 to 25.6 mg/kg/day of 2'"'"',3'"'"'-dideoxyinosine in combination with a member selected from the group consisting of 3'"'"'-azido-2'"'"',3'"'"'-dideoxythymidine, acyclovir, gancyclovir, pentamidine and ribovirin.

3. A method of claim 2 wherein the 2'"'"',3'"'"'-dideoxyinosine is administered in combination with 3'"'"'-azido-2'"'"',3'"'"'-dideoxythymidine (AZT, zidovudine).

4. A method of claim 2 wherein the 2'"'"',3'"'"'-dideoxyinosine is administered in combination with acyclovir.

5. A method of claim 2 wherein the 2'"'"',3'"'"'-dideoxyinosine is administered in combination with gancyclovir.

6. A method of claim 2 wherein the 2'"'"',3'"'"'-dideoxyinosine is administered in combination with pentamidine.

7. A method of claim 6 wherein the pentamidine is administered in dosage of about 50 to about 400 mg.

8. A method of claim 2 wherein the 2'"'"',3'"'"'-dideoxyinosine is administered in combination with about 200 mg/day to about 1600 mg/day of ribavirin.

9. A method of administering 2'"'"',3'"'"'-dideoxyinosine to a patient infected with HIV in a manner to minimize neuropathy comprising administration of 2'"'"',3'"'"'-dideoxyinosine wherein the 2'"'"',3'"'"'-dideoxyinosine is withheld at the first indication of pain, tingling, or a loss of vibratory sense, followed by a resumption of dosing with about 0.4 to about 9.6 mg/kg/day of 2'"'"',3'"'"'-dideoxyinosine when the aforementioned symptoms and signs subside.

10. A method of administering 2'"'"',3'"'"'-dideoxyinosine to a patient infected with HIV in a manner to minimize pancreatitis comprising administration of 2'"'"',3'"'"'-dideoxyinosine in a range of about 0.4 mg/kg/day to about 14 mg/kg/day wherein:

(1) the patient'"'"'s serum triglyceride levels and/or serum amylase levels are monitored;

(2) the 2'"'"',3'"'"'-dideoxyinosine is withheld when the serum triglyceride level exceeds about 500 mg/dl or the amylase levels rise to about 150% or more of the upper limit of normal levels; and

(3) administration of 2'"'"',3'"'"'-dideoxyinosine is resumed at a dose of about 0.4 mg/kg/day to about 9.6 mg/kg/day after triglyceride or amylase levels return to about normal or baseline levels.

11. A method of administering 2'"'"',3'"'"'-dideoxyinosine to a patient infected with HIV in a manner to minimize hepatitis comprising administration of 2'"'"',3'"'"'-dideoxyinosine in a range of about 0.4 mg/kg/day to about 14 mg/kg/day wherein

(1) the patient'"'"'s hepatic transaminase levels are monitored;

(2) the 2'"'"',3'"'"'-dideoxyinosine is withheld when the transaminase levels exceed about five times the upper limit of normal; and

(3) administration of 2'"'"',3'"'"'-dideoxyinosine is resumed at a dose of about 0.4 mg/kg/day to about 9.6 mg/kg/day after the transaminase levels return to three times the upper limit of normal or lower.

12. A method of treating HIV infection which comprises administering to an HIV infected patient in need thereof 2'"'"',3'"'"'-dideoxyinosine (ddI) at a dose of about 0.4 to about 9.6 mg/kg/day.

13. The method according to claim 12, wherein said ddI is administered at a dose of about 3.2 to 9.6 mg/kg/day.

14. The method according to claim 12, wherein said ddI is administered at a dose of about 6.4 to 9.6 mg/kg/day.

15. The method according to claim 12, wherein said ddI is administered in multiple dosages per day.

16. A method of administering 2'"'"',3'"'"'-dideoxyinosine (ddI) to a patient infected with HIV in a manner to minimize treatment induced pancreatitis or other pancreatic dysfunction which comprises:

(a) administering said ddI to said patient at a dosage of about 0.4 to about 25.6 mg/kg/day;

(b) monitoring said patient for indications of an increased risk of pancreatitis or other pancreatic dysfunction;

(c) interrupting the administration of said ddI when said indications are noted; and

(d) resuming administration of said ddI at a dosage of about 0.4 to about 14 mg/kg/day when said indications subside.

17. The method according to claim 16, wherein said monitoring comprises monitoring the triglyceride levels of said patient and interrupting said administration of ddI when said triglyceride level indicates an increased risk of pancreatitis.

18. The method according to claim 16, wherein said ddI is administered at a dose of about 3.2 to about 9.6 mg/kg/day.

19. The method according to claim 16, wherein said ddI is administered in combination with a member selected from the group consisting of 3'"'"'-azido-2'"'"',3'"'"'-dideoxythymidine, acyclovir, gancyclovir, pentamidine and ribavirin.

20. A method of administering 2'"'"',3'"'"'-dideoxyinosine (ddI) to a patient infected with HIV in a manner to minimize treatment induced neuropathy which comprises:

(a) administering said ddI to said patient at a dosage of about 0.4 to about 25.6 mg/kg/day;

(b) monitoring said patient for indications of potential onset of neuropathy;

(c) interrupting the administration of said ddI when said indications are noted; and

(d) resuming administration of said ddI when said indications subside.

21. The method according to claim 20, wherein said monitoring comprises monitoring said patient for indications of pain, tingling or a loss of vibratory sense.

22. The method according to claim 20, wherein said ddI is administered at a dose of about 3.2 to about 9.6 mg/kg/day.

23. The method according to claim 20, wherein said ddI is administered in combination with a member selected from the group consisting of 3'"'"'-azido-2'"'"',3'"'"'-dideoxythymidine, acyclovir, gancyclovir, pentamidine and ribavirin.

24. A method of administering 2'"'"',3'"'"'-dideoxyinosine (ddI) to a patient infected with HIV in a manner to minimize treatment induced hepatitis which comprises:

(a) administering said ddI to said patient at a dosage of about 0.4 to about 25.6 mg/kg/day;

(b) monitoring said patient for indications of potential onset of hepatitis;

(c) interrupting the administration of said ddI when said indications are noted; and

(d) resuming administration of said ddI when said indications subside.

25. The method according to claim 24, wherein said monitoring comprises monitoring the hepatic transaminase levels of said patient and interrupting said administration of ddI when said transaminase level indicates a potential onset of hepatitis.

26. The method according to claim 24, wherein said ddI is administered at a dose of about 3.2 to about 9.6 mg/kg/day.

27. The method according to claim 24, wherein said ddI is administered in combination with a member selected from the group consisting of 3'"'"'-azido-2'"'"',3'"'"'-dideoxythymidine, acyclovir, gancyclovir, pentamidine and ribavirin.