Method of increasing intracellular accumulation of hydrophilic anionic agents using gemfibrizol

• US 5,422,372 A
• Filed: 06/15/1993
• Issued: 06/06/1995
• Est. Priority Date: 04/10/1990
• Status: Expired due to Fees

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Neu, Harold C., Cao, Charles, Silverstein, Samuel C.
• Primary Examiner(s): Henley, III, Raymond
• Assistant Examiner(s): TRAVERS, RUSSELL S
• Application Number:
  US08/077,755
• Time in Patent Office: 721 Days
• Field of Search: 514/571
• US Class Current: 514/571
• 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 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/545 Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins, cefaclor, or cephalexine
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention provides an improved therapeutic method which comprises administering to a mammal a therapeutic agent and 5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid, or a structural analog thereof, in an amount effective to improve the efficacy of the therapeutic agent. Also provided by this invention is an improved therapeutic method which comprises administering to a mammal a therapeutic agent and 5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid, or a structural analog thereof, in an amount effective to improve the efficacy of the therapeutic agent. Further provided by this invention is a method of treating an intracellular bacterial infection which comprises contacting the infected cell with an effective amount of a therapeutic agent and with an effective amount of 5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoic acid, or a structural analog therof, effective to treat an intracellular bacterial infection. A pharmaceutical composition is further provided by this invention wherein the composition comprises a therapeutic agent and 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof, and a pharmaceutically acceptable carrier.

Claims

1. A method to enhance intracellular accumulation in mammalian cells of a hydrophilic, anionic antibiotic which cannot normally accumulate in such cells selected from the group consisting of:

beta-lactam antibiotics; and

quinolone antibiotics,

which comprises contacting the cells with the antibiotic and with 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof, in an amount effective to block transport of the antibiotic from the cells causing intracellular accumulation of the antibiotic in the cells.

2. The method of claim 1, wherein the beta-lactam antibiotic is selected from the group consisting of penicillins and cephalosporins.

3. The method of claim 1, wherein the quinolone is ciprofloxacin.

4. The method of claim 1, wherein the quinolone is norfloxacin.

5. The method of claim 1, wherein the contacting with the antibiotic and with the 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof is sequential.

6. The method of claim 1, wherein the contacting with the antibiotic and with the 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof is simultaneous.

7. An improved therapeutic method which comprises administering to a mammal an antibiotic selected from the group consisting of:

beta-lactam antibiotics; and

quinolone antibiotics,

and 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof, in an amount effective to improve the efficacy of the antibiotic.

8. The method of claim 7, wherein the mammal is a human.

9. The method of claim 7, wherein the beta-lactam antibiotic is selected from the group consisting of penicillins and cephalosporins.

10. The method of claim 7, wherein the quinolone is ciprofloxacin.

11. The method of claim 7, wherein the quinolone is norfloxacin.

12. The method of claim 7, wherein the administering of the antibiotic and the 5-(2,5 -dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof is sequential.

13. The method of claim 7, wherein the administering of the antibiotic and the 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof is simultaneous.

14. A pharmaceutical composition comprising a hydrophilic anionic antibiotic which cannot normally accumulate in mammalian cells, selected from the group consisting of:

beta-lactam antibiotics; and

quinolone antibiotics,

and 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof, and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, wherein the beta-lactam antibiotic is from the group consisting of penicillins and cephalosporins.

16. The pharmaceutical composition of claim 14, wherein the quinolone is ciprofloxacin.

17. The pharmaceutical composition of claim 14, wherein the quinolone is norfloxacin.

18. A method of treating an intracellular bacterial infection which comprises contacting the infected cell with an effective amount of an antibiotic selected from the group consisting of:

beta-lactam antibiotics; and

quinolone antibiotics,

and with an effective amount of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof, effective to treat an intracellular bacterial infection.

19. The method of claim 18, wherein the beta-lactam antibiotic is selected from the group consisting of penicillins and cephalosporins.

20. The method of claim 18, wherein the quinolone is ciprofloxacin.

21. The method of claim 18, wherein the quinolone is norfloxacin.

22. The method of claim 18, wherein the contacting with the therapeutic agent and with the 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof, is sequential.

23. The method of claim 18, wherein the contacting with the therapeutic agent and with the 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, or a structural analog thereof, is simultaneous.

24. A method of claim 18, wherein the intracellular bacterial infection is an infection by Listeria, Tuberculosis, Mycoplasma, Legionella, Leprosy, Brucella or Salmonella.