Methods of treating tyrosine kinase inhibitor-induced diarrhea
Patent Information
- Application Number
- TW109101579
- Authority / Receiving Office
- TW · TW
- Patent Type
- Patents
- Current Assignee / Owner
- Priority Date
- 2019-01-16
- Filing Date
- 2020-01-16
- Publication Date
- 2026-09-01
- Estimated Expiration
- 2040-01-15
AI Technical Summary
Current management of tyrosine kinase inhibitor (TKI)-associated diarrhea, a common side effect of cancer chemotherapy, is inadequate, with existing treatments like rehydration and antimotility agents providing limited relief and a significant unmet need for targeted and safe antidiarrheal therapies.
Administering potassium channel inhibitors or CFTR chloride channel inhibitors, or a combination thereof, to reduce intestinal fluid secretion and diarrhea caused by TKIs, by targeting the underlying mechanisms of potassium and chloride channel activation in the intestinal epithelium.
Effectively reduces diarrhea and intestinal fluid secretion by blocking potassium and chloride channels, providing a targeted and safer alternative to existing treatments.
Smart Images
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Abstract
Description
[Technical Field] This invention relates to a method for treating diarrhea caused by tyrosine kinase inhibitors by administering potassium channel inhibitors, CFTR chloride channel inhibitors, or combinations thereof. [Previous Technology] Diarrhea is a common, and sometimes insidious, side effect of chemotherapy, a limiting therapy for cancer. Small molecule ErbB tyrosine kinase inhibitors (TKIs) are used to treat a variety of cancers that overexpress the ErbB receptor, including breast cancer, non-small cell lung cancer (NSCLC), and head and neck cancer. Approximately 40-60% of patients experience diarrhea associated with ErbB TKIs, with 10-20% experiencing severe (grade 3-4) diarrhea. In some cases with ErbB TKIs, >90% of patients experience diarrhea. Current management of TKI-related diarrhea includes fluid replacement, anti-motor drugs such as loperamide, and, in some cases, reducing or discontinuing the TKI dose. Given the reduced morbidity and clinical outcomes associated with severe diarrhea following TKI therapy, the need for effective, targeted, and safe antidiarrheal therapies remains unmet. [Summary of the Invention] The present invention relates to a method for treating an individual suffering from diarrhea caused by a tyrosine kinase inhibitor, comprising administering to the individual a certain amount of potassium channel inhibitor or a certain amount of CFTR chloride channel inhibitor or a combination of potassium channel inhibitor and CFTR channel inhibitor that are effective in treating diarrhea caused by a tyrosine kinase inhibitor. In addition, the present invention also relates to a method for reducing intestinal fluid secretion in an individual in need, which is caused by activation of potassium channels induced by tyrosine kinase inhibitors or activation of CFTR chloride channels induced by tyrosine kinase inhibitors in the intestinal epithelium. The method comprises administering to the individual a certain amount of potassium channel inhibitor or a certain amount of CFTR chloride channel inhibitor or a combination of a certain amount of potassium channel inhibitor and CFTR channel inhibitor to effectively reduce the intestinal fluid secretion. Other aspects of the present invention relate to a method for reducing potassium channel currents or CFTR chloride channel currents induced by tyrosine kinase inhibitors in the intestinal epithelium of an individual in need, comprising administering to the individual a certain amount of potassium channel inhibitor or a certain amount of CFTR chloride channel inhibitor that effectively reduces the potassium channel currents or CFTR chloride channel currents induced by the tyrosine kinase inhibitor. Other aspects of the invention relate to improving the treatment of cancer in an individual by administering a specific amount of a tyrosine kinase inhibitor that is effective in treating the individual's cancer. This improvement includes administering an amount of a potassium channel inhibitor or a CFTR chloride channel inhibitor, or a combination of a potassium channel inhibitor and a CFTR channel inhibitor, in an amount that effectively treats diarrhea induced by the tyrosine kinase inhibitor in the individual. Some aspects of the present invention relate to a method of treating cancer in an individual, comprising administering to the individual a certain amount of tyrosine kinase inhibitor that is effective in treating the individual's cancer; and a potassium channel inhibitor or CFTR chloride channel inhibitor or a combination of potassium channel inhibitor and CFTR chloride channel inhibitor in an amount that is effective in treating diarrhea caused by the tyrosine kinase inhibitor in the individual. Finally, the present invention relates to a method for treating diarrhea in an individual who is being treated with a tyrosine kinase inhibitor, comprising determining whether the diarrhea is caused by the tyrosine kinase inhibitor; and if the determination is that the diarrhea is caused by the tyrosine kinase inhibitor, administering to the individual a certain amount of potassium channel inhibitor or a certain amount of CFTR chloride channel inhibitor or a combination of a certain amount of potassium channel inhibitor and CFTR chloride channel inhibitor to effectively treat the diarrhea.
Implementation Method
Claims
1. The use of a combination of a Ca2+-activated potassium channel inhibitor and BPO-27 for the preparation of a pharmaceutical agent for treating individuals suffering from diarrhea caused by a tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is afatinib, axitinib, bosutinib, canertinib, cetuximab, crizotinib, cabozantinib, dasatinib, EKB-569, entrectinib, erlotinib, fostamatinib, gefitinib, etc. Fitinib, ibrutinib, imatinib, lapatinib, leflunomide, lenvatinib, neratinib, nilotinib, pazopanib, ruxolitinib, semaxinib, sorafenib, sunitinib, SU6656, sutent, vandetanib, or vtalanib; or a pharmaceutically acceptable salt thereof, or a combination thereof.
2. As claimed in claim 1, wherein the tyrosine kinase inhibitor is afatinib, canenatinib, cetuximab, erlotinib, gefitinib, or lapatinib; or a pharmaceutically acceptable salt thereof, or a combination thereof.
3. As claimed in claim 2, wherein the tyrosine kinase inhibitor is afatinib or a pharmaceutically acceptable salt thereof.
4. As claimed in any of claims 1 to 3, wherein the Ca2+-activated potassium channel inhibitor is clotrimazole, senicapoc, nitrendipine, 4-[[3-(trifluoromethyl)phenyl]methyl]-2h-1,4-benzothiazin-3(4h)-one, paxilline, penicillin A, 1-[(2-chlorophenyl)diphenylmethyl]-1h-pyrazole, 2-chloro-α,α-diphenylacetonitrile, UCL 1684, triphenylmethyl-3-pyridinemethylamine, or methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-sideoxy-4,7-dihydro-1h-2-benzofuran-5-carboxylate, or a combination thereof.
5. For any of the uses of requests 1 to 3, wherein the BPO-27 is (R)-BPO-27.
6. As requested in item 4, wherein the BPO-27 is (R)-BPO-27.