Selective beta-glucuronidase inhibitors as a treatment for side effects of camptothecin antineoplastic agents
View Patent ↗Compounds, compositions and methods are provided that comprise selective β-glucuronidase inhibitors for both aerobic and anaerobic bacteria, especially enteric bacteria normally associated with the gastrointestinal tract. The compounds, compositions and methods can be for inhibiting bacterial β-glucuronidases and for improving efficacy of camptothecin-derived antineoplastic agents or glucuronidase-substrate agents or compounds by attenuating the side effects caused by reactivation by bacterial β-glucuronidases of glucuronidated metabolites of camptothecin-derived antineoplastic agents or glucuronidase-substrate agents or compounds.
1. A composition comprising at least one compound having selective β-glucuronidase inhibitor activity, the compound selected from the group consisting of
and a pharmaceutically acceptable carrier, wherein the at least one compound having selective β-glucuronidase inhibitor activity is present at a concentration from about 1 nM to about 1 mM.
2. A composition comprising at least one compound having selective β-glucuronidase inhibitor activity, the compound selected from the group consisting of
wherein said compound is administered prior to, concurrently with, or after the administration of at least one camptothecin-derived antineoplastic agent.
3. The composition of claim 2 , wherein the at least one camptothecin-derived antineoplastic agent is selected from the group consisting of camptothecin, diflomotecan, exatecan, gimatecan, irinotecan, karenitecin, lurtotecan, rubitecan, silatecan and topotecan.
4. The composition of claim 2 , wherein the at least one compound having selective β-glucuronidase inhibitor activity is present at a concentration from about 1 nM to about 1 mM.
5. A method for selectively inhibiting bacterial β-glucuronidases, the method comprising administering to a subject in need thereof an effective amount of at least one compound having selective β-glucuronidase inhibitor activity, the compound selected from the group consisting of
6. The method of claim 5 , wherein the at least one compound having selective β-glucuronidase inhibitor activity is present at a concentration from about 1 nM to about 1 mM.
7. The method of claim 5 , wherein the bacterial β-glucuronidases are enteric bacterial β-glucuronidases.
8. The method of claim 7 , wherein the bacteria are selected from the group consisting of a Bacteroides sp., Bifidobacterium sp., Catenabacterium sp., Clostridium sp., Corynebacterium sp., Enterococcus faecalis , Enterobacteriaceae, Lactobacillus sp., Peptostreptococcus sp., Propionibacterium sp., Proteus sp., Mycobacterium sp., Pseudomonas sp., Staphylococcus sp. and Streptococcus sp.
9. A method for improving camptothecin-derived antineoplastic agent efficiency, the method comprising administering to a subject prior to, concurrently with, or after administration of a camptothecin-derived antineoplastic agent a therapeutically effective amount of at least one compound having selective β-glucuronidase inhibitor activity, the compound selected from the group consisting of
10. The method of claim 9 , wherein the camptothecin-derived antineoplastic agent is selected from the group consisting of camptothecin, diflomotecan, exatecan, gimatecan, irinotecan, karenitecin, lurtotecan, rubitecan, silatecan and topotecan.
11. The method of claim 10 , wherein the camptothecin-derived antineoplastic agent is irinotecan.
12. A method for alleviating gastrointestinal distress associated with chemotherapy, the method comprising
a) administering to an animal an anti-cancer effective amount of a chemotherapeutic agent, and
b) administering to the same animal at least one compound having selective β-glucuronidase inhibitor activity, the compound selected from the group consisting of
13. The method of claim 12 , wherein the chemotherapeutic active agent is a camptothecin-derived antineoplastic agent.
14. A method for improving the efficiency of a glucuronidase-substrate agent or compound, the method comprising administering to a subject prior to, concurrently with or after administration of said glucuronidase-substrate agent or compound a therapeutically effective amount of at least one compound having selective β-glucuronidase inhibitor activity, the compound selected from the group consisting of