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WO2025241125A1 - Utilisation de duloxétine et d'un médicament chimiothérapeutique dans la préparation d'une composition pharmaceutique pour le traitement ou la prévention du cancer - Google Patents

Utilisation de duloxétine et d'un médicament chimiothérapeutique dans la préparation d'une composition pharmaceutique pour le traitement ou la prévention du cancer

Info

Publication number
WO2025241125A1
WO2025241125A1 PCT/CN2024/094805 CN2024094805W WO2025241125A1 WO 2025241125 A1 WO2025241125 A1 WO 2025241125A1 CN 2024094805 W CN2024094805 W CN 2024094805W WO 2025241125 A1 WO2025241125 A1 WO 2025241125A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
duloxetine
group
small cell
breast cancer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/094805
Other languages
English (en)
Chinese (zh)
Inventor
陈丘泓
魏宗德
杨彩秀
刘家全
翁郁琇
杨德伦
林锦华
刘良智
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Launxp Biomedical Co Ltd
Original Assignee
Launxp Biomedical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Launxp Biomedical Co Ltd filed Critical Launxp Biomedical Co Ltd
Priority to PCT/CN2024/094805 priority Critical patent/WO2025241125A1/fr
Priority to PCT/CN2025/096659 priority patent/WO2025242178A1/fr
Publication of WO2025241125A1 publication Critical patent/WO2025241125A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This disclosure relates to the use of a pharmaceutical composition for the treatment or prevention of cancer, and more particularly to the use of duloxetine and chemotherapy drugs for the preparation of a pharmaceutical composition for the treatment or prevention of cancer.
  • Cancer has long been the leading cause of death worldwide, and the number of people diagnosed with it is increasing year by year, making cancer treatment a crucial issue. Cancer treatment can be categorized into surgical treatment, radiation therapy, chemotherapy, and targeted therapy. Cancer cells are characterized by uncontrolled cell proliferation and the potential to invade or metastasize to distant tissues. Clinical manifestations of cancer include weight loss, muscle atrophy, decreased activity, fatigue, loss of appetite, easy satiety, drowsiness, pallor, anemia, emaciation, electrolyte imbalance, decreased protein and lipid synthesis, and unstable blood sugar. When a patient experiences a weight loss of more than 5% within 6 months along with the above symptoms, it is known as "cachexia,” which in severe cases is commonly referred to as "skin and bones.”
  • Duloxetine and chemotherapy drugs are used in the preparation of pharmaceutical compositions for the treatment or prevention of cancer.
  • a method of treating or preventing cancer includes administering an effective amount of duloxetine and chemotherapy drugs to an individual in need.
  • a pharmaceutical composition for the treatment or prevention of cancer comprising an effective amount of duloxetine and a chemotherapy drug.
  • Figure 1 shows the effects of duloxetine and docetaxel on triple-negative breast cancer (MDA-MB-231 cell line).
  • G1 IC50 of docetaxel (0.004 ⁇ M);
  • G2 1/2 IC50 of docetaxel (0.002 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + docetaxel (0.002 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + docetaxel (0.004 ⁇ M).
  • Figure 2 shows the effects of duloxetine and cisplatin on triple-negative breast cancer (MDA-MB-231 cell line).
  • G1 IC50 of cisplatin (3 ⁇ M);
  • G2 IC50 of cisplatin (1/2) (1.5 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + cisplatin (1/2) (3 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + cisplatin (1.5 ⁇ M).
  • Figure 3 shows the effects of duloxetine and cyclophosphamide on triple-negative breast cancer (MDA-MB-231 cell line).
  • G1 IC50 of cyclophosphamide (40 ⁇ M);
  • G2 IC50 of cyclophosphamide (1/2) (20 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + cyclophosphamide (1/2) (20 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + cyclophosphamide (40 ⁇ M).
  • Figure 4 shows the effects of duloxetine and 5-fluorouracil on triple-negative breast cancer (MDA-MB-231 cell line).
  • G1 IC50 of 5-fluorouracil (400 ⁇ M);
  • G2 IC50 of 5-fluorouracil (200 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + 5-fluorouracil (200 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + 5-fluorouracil (400 ⁇ M).
  • Figure 5 shows the effects of duloxetine and doxorubicin on triple-negative breast cancer (MDA-MB-231 cell line).
  • G1 IC50 of doxorubicin (0.5 ⁇ M);
  • G2 IC50 of doxorubicin.
  • G3 Duloxetine (5 ⁇ M);
  • G4 Duloxetine (5 ⁇ M) + Doxorubicin (1/2 IC 50 0.25 ⁇ M);
  • G5 Duloxetine (5 ⁇ M) + Doxorubicin ( 0.5 ⁇ M).
  • Figure 6 shows the effects of duloxetine and temozolomide on triple-negative breast cancer (MDA-MB-231 cell line).
  • G1 IC50 of temozolomide (400 ⁇ M);
  • G2 IC50 of temozolomide (1/2) (200 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + temozolomide ( 1/2 ) (400 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + temozolomide (200 ⁇ M).
  • Figure 7 shows the effects of duloxetine and osimertinib (AZD-9291) on triple-negative breast cancer (MDA-MB-231 cell line).
  • G1 IC50 of osimertinib (5 ⁇ M);
  • G2 IC50 of osimertinib (1/2) (2.5 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + osimertinib ( 1/2 ) (2.5 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + osimertinib (5 ⁇ M).
  • Figure 8 shows the effects of duloxetine and etoposide on triple-negative breast cancer (MDA-MB-231 cell line).
  • G1 IC50 of etoposide (100 ⁇ M);
  • G2 IC50 of etoposide (1/2) (50 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + etoposide (1/2) (50 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + etoposide (100 ⁇ M).
  • Figure 9 shows the effects of duloxetine and docetaxel on non-small cell lung cancer (A549 cell line).
  • G1 IC50 of docetaxel (0.004 ⁇ M);
  • G2 1/2 IC50 of docetaxel (0.002 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + 1/2 IC50 of docetaxel (0.002 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + docetaxel (0.004 ⁇ M).
  • Figure 10 shows the effects of duloxetine and 5-fluorouracil on non-small cell lung cancer (A549 cell line).
  • G1 IC50 of 5-fluorouracil (400 ⁇ M);
  • G2 1/2 IC50 of 5-fluorouracil (200 ⁇ M);
  • G3 Duloxetine (5 ⁇ M); G4: Duloxetine (5 ⁇ M) + 5-fluorouracil IC50 (200 ⁇ M); G5: Duloxetine (5 ⁇ M) + 5-fluorouracil IC50 (400 ⁇ M).
  • Figure 11 shows the effects of duloxetine and doxorubicin on non-small cell lung cancer (A549 cell line).
  • G1 IC50 of doxorubicin (0.5 ⁇ M);
  • G2 IC50 of doxorubicin (0.25 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + doxorubicin (0.25 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + doxorubicin (0.5 ⁇ M).
  • Figure 12 shows the effects of duloxetine and temozolomide on non-small cell lung cancer (A549 cell line).
  • G1 IC50 of temozolomide (400 ⁇ M);
  • G2 IC50 of temozolomide (1/2) (200 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + temozolomide (1/2) (400 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + temozolomide (200 ⁇ M).
  • Figure 13 shows the effects of duloxetine and osimertinib (AZD-9291) on non-small cell lung cancer (A549 cell line).
  • G1 IC50 of osimertinib (5 ⁇ M);
  • G2 IC50 of osimertinib (1/2) (2.5 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + osimertinib (1/2) (2.5 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + osimertinib (5 ⁇ M).
  • Figure 14 shows the effects of duloxetine and sorafenib on non-small cell lung cancer (A549 cell line).
  • G1 IC50 of sorafenib (20 ⁇ M);
  • G2 IC50 of sorafenib (1/2) (10 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + IC50 of sorafenib (1/2) (10 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + sorafenib (20 ⁇ M).
  • Figure 15 shows the effects of duloxetine and etoposide on non-small cell lung cancer (A549 cell line).
  • G1 IC50 of etoposide (100 ⁇ M);
  • G2 IC50 of etoposide (1/2) (50 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + etoposide (1/2) (50 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + etoposide (100 ⁇ M).
  • Figure 16 shows the effects of duloxetine and cisplatin on pancreatic cancer (Mia-PaCa2 cell line).
  • G1 IC50 of cisplatin (3 ⁇ M);
  • G2 IC50 of cisplatin (1/2) (1.5 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + cisplatin (1/2) (3 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + cisplatin (1.5 ⁇ M).
  • Figure 17 shows the effects of duloxetine and doxorubicin on pancreatic cancer (Mia-PaCa2 cell line).
  • G1 IC50 of doxorubicin (0.5 ⁇ M);
  • G2 IC50 of doxorubicin (0.25 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + doxorubicin (0.25 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + doxorubicin (0.5 ⁇ M).
  • Figure 18 shows the effects of duloxetine and osimertinib (AZD-9291) on pancreatic cancer (Mia-PaCa2 cell line).
  • G1 IC50 of osimertinib (5 ⁇ M);
  • G2 1/2 IC50 of osimertinib (2.5 ⁇ M);
  • G3 Duloxetine (5 ⁇ M); G4: Duloxetine (5 ⁇ M) + Osimertinib 1/2 IC 50 (2.5 ⁇ M); G5: Duloxetine (5 ⁇ M) + Osimertinib IC 50 (5 ⁇ M).
  • Figure 19 shows the effects of duloxetine and etoposide on pancreatic cancer (Mia-PaCa2 cell line).
  • G1 IC50 of etoposide (100 ⁇ M);
  • G2 1/2 IC50 of etoposide (50 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 1/2 IC50 of duloxetine (5 ⁇ M) + etoposide (50 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + etoposide (100 ⁇ M).
  • Figure 20 shows the effects of duloxetine and docetaxel on hepatocellular carcinoma (PLC/PRF/5 cell line).
  • G1 IC50 of docetaxel (0.004 ⁇ M);
  • G2 1/2 IC50 of docetaxel (0.002 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + 1/2 IC50 of docetaxel (0.002 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + docetaxel (0.004 ⁇ M).
  • Figure 21 shows the effects of duloxetine and cisplatin on hepatocellular carcinoma (PLC/PRF/5 cell line).
  • G1 IC50 of cisplatin (3 ⁇ M);
  • G2 IC50 of cisplatin (1/2) (1.5 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + cisplatin (1/2) (3 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + cisplatin (1.5 ⁇ M).
  • Figure 22 shows the effects of duloxetine and 5-fluorouracil on hepatocellular carcinoma (PLC/PRF/5 cell line).
  • G1 IC50 of 5-fluorouracil (400 ⁇ M);
  • G2 1/2 IC50 of 5-fluorouracil (200 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 Duloxetine (5 ⁇ M) + 1/2 IC50 of 5-fluorouracil (200 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + 5-fluorouracil (400 ⁇ M).
  • Figure 23 shows the effects of duloxetine and doxorubicin on hepatocellular carcinoma (PLC/PRF/5 cell line).
  • G1 IC50 of doxorubicin (0.5 ⁇ M);
  • G2 IC50 of doxorubicin (0.25 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + doxorubicin (0.25 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + doxorubicin (0.5 ⁇ M).
  • Figure 24 shows the effects of duloxetine and sorafenib on hepatocellular carcinoma (PLC/PRF/5 cell line).
  • G1 IC50 of sorafenib (20 ⁇ M);
  • G2 IC50 of sorafenib (1/2) (10 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + IC50 of sorafenib (1/2) (10 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + sorafenib (20 ⁇ M).
  • Figure 25 shows the effects of duloxetine and etoposide on hepatocellular carcinoma (PLC/PRF/5 cell line).
  • G1 IC50 of etoposide (100 ⁇ M);
  • G2 IC50 of etoposide (1/2) (50 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + etoposide (1/2) (50 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + etoposide (100 ⁇ M).
  • Figure 26 shows the effects of duloxetine and docetaxel on glioblastoma (LN-229 cell line).
  • G1 IC50 of docetaxel (0.004 ⁇ M);
  • G2 1/2 IC50 of docetaxel (0.002 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + 1/2 IC50 of docetaxel (0.002 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + docetaxel (0.004 ⁇ M).
  • Figure 27 shows the effects of duloxetine and cyclophosphamide on glioblastoma (LN-229 cell line).
  • G1 IC50 of cyclophosphamide (40 ⁇ M);
  • G2 IC50 of cyclophosphamide (1/2) (20 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + cyclophosphamide (1/2) (20 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + cyclophosphamide (40 ⁇ M).
  • Figure 28 shows the effects of duloxetine and 5-fluorouracil on glioblastoma (LN-229 cell line).
  • G1 IC50 of 5-fluorouracil (400 ⁇ M);
  • G2 1/2 IC50 of 5-fluorouracil (200 ⁇ M);
  • G3 duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + 1/2 IC50 of 5-fluorouracil (200 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + 5-fluorouracil (400 ⁇ M).
  • Figure 29 shows the effects of duloxetine and temozolomide on glioblastoma (LN-229 cell line).
  • G1 IC50 of temozolomide (400 ⁇ M);
  • G2 IC50 of temozolomide (1/2) (200 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + temozolomide (1/2) (400 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + temozolomide (200 ⁇ M).
  • Figure 30 shows the effects of duloxetine and osimertinib (AZD-9291) on glioblastoma (LN-229 cell line).
  • G1 IC50 of osimertinib (5 ⁇ M);
  • G2 IC50 of osimertinib (1/2) (2.5 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + osimertinib (1/2) (2.5 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + osimertinib (5 ⁇ M).
  • Figure 31 shows the effects of duloxetine and etoposide on hepatocellular carcinoma (PLC/PRF/5 cell line).
  • G1 IC50 of etoposide (100 ⁇ M);
  • G2 IC50 of etoposide (1/2) (50 ⁇ M);
  • G3 Duloxetine (5 ⁇ M);
  • G4 IC50 of duloxetine (5 ⁇ M) + etoposide (1/2) (50 ⁇ M);
  • G5 IC50 of duloxetine (5 ⁇ M) + etoposide (100 ⁇ M).
  • Figure 32 shows the tumor shrinkage rate after 24 weeks of treatment in the duloxetine + neoadjuvant chemotherapy (NACT) group.
  • R001, R002, R003, R004, R005, R006, and R008 represent the tumor shrinkage rates of the seven subjects, and 22.65% represents the mean tumor shrinkage rate.
  • R002, R004, and R008 are complete remissions (CRs), so they are collinear.
  • Figure 33 shows the tumor shrinkage rate in the NACT group and the duloxetine + NACT group. ***: P ⁇ 0.001.
  • Figure 34 shows a waterfall plot of tumor shrinkage rate between the NACT group and the duloxetine + NACT group.
  • Figure 35 shows the changes in tumor computed tomography images before treatment (left half) and after treatment (right half) in the duloxetine + NACT group for patients with complete response (CR) and patients with partial response (PR) and patients with partial response (PR) and patients with partial response (PR) and patients with partial response (PR) and patients with partial response (PR) and patients with partial response (PR) and patients with partial response (PR) and patients with partial response (PR) and patients with partial response (PR) and patients with partial response (PR) respectively.
  • Figure 36 shows the objective response rate (ORR) of patients receiving standard therapy.
  • Figure 37 shows the Foxp3 expression of peripheral blood mononuclear cells before and after treatment in the duloxetine + NACT group (top half) and the regression analysis of Foxp3-V1 with tumor shrinkage rate (bottom half).
  • V1 1st visit
  • V8 8th visit
  • V16 16th visit
  • V18 18th visit.
  • Figure 38 shows the IDO-1 expression of peripheral blood mononuclear cells before and after treatment in the duloxetine + NACT group (top half) and the regression analysis of IDO-1-V1 with tumor shrinkage rate (bottom half).
  • V1 1st visit
  • V8 8th visit
  • V16 16th visit
  • V18 18th visit.
  • Figure 39 shows the IGKC performance of peripheral blood mononuclear cells before and after treatment in the duloxetine + NACT group (top half) and the regression analysis of IGKC-V18 with tumor shrinkage rate (bottom half).
  • V1 1st visit; V8: 8th visit; V16: 16th visit; V18: 18th visit.
  • the articles “a,” “an,” and “the” refer to one or more (i.e., at least one) grammatical object of the article.
  • the term “or” is used interchangeably with the term “and/or” unless otherwise clearly stated.
  • the term “including/contains” is used herein to mean the phrase “including/contains but not limited to” and is used interchangeably with it.
  • the term “about” refers to a typical tolerance range within the relevant technical field. For example, “about” can be understood as approximately 2 standard deviations from the mean. When “about” appears before a series of numbers or ranges, it should be understood that “about” may modify each number in that series or range.
  • numerical values are intended to cover variations with ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or ⁇ 0.1% of the numerical value.
  • numerical ranges are inclusive and composable; any numerical value falling within a numerical range herein can be considered a maximum or minimum value from which subranges are derived.
  • the numerical range "20 to 30%” includes any subrange between the minimum value of 20% and the maximum value of 30%, such as a subrange from 20% to 25%, from 25% to 30%, and from 22.5% to 27.5%.
  • variations in value may be due to, for example: experimental errors, typical errors in the measurement or handling of the compound, composition, concentrate, or formulation, starting materials, or other factors described in this disclosure. This may be due to differences in the source, manufacturing, or purity of the ingredients used, or similar considerations.
  • the individual is used to refer to any vertebrate, including but not limited to humans or mammals such as deer, mules, elk, and black-tailed deer.
  • the individual is a mammal, such as a human or a non-human mammal, such as a domesticated mammal, such as a dog, cat, horse, rat, mouse, etc., or a livestock mammal, such as a cow, sheep, pig, deer, etc.
  • the terms “comprising,” “including,” “having,” “containing,” “including,” and any other variations thereof are intended to cover non-exclusionary inclusion.
  • an object when describing an object as “comprising” as a limiting element, other components, elements, elements, structures, regions, parts, devices, systems, steps, or connections may be additionally included unless otherwise stated, and other limiting elements should not be excluded.
  • the term "effective amount” refers to an amount of an active agent or pharmaceutical composition sufficient to produce a preventive or therapeutic effect in an individual of need.
  • an effective amount of the composition promotes the prevention or reduction of appearance and/or symptoms associated with an undesirable condition. This effective amount may be varied by those skilled in the art, depending on the use of the excipient, the route of administration, the possibility of co-administration with other therapeutic treatments, or the condition to be treated, but this disclosure is not limited thereto.
  • the term "application” refers to the delivery of an active ingredient into an individual by means of a method or route, such that at least a portion of the active ingredient is located at a desired site to produce the desired effect.
  • the active ingredients of this disclosure can be applied to an individual by injection or topical application, but this disclosure is not limited thereto.
  • the application of the compositions of this disclosure can be performed in the systemic or local environment of an individual.
  • the site of topical application can be any site in the body where tissue development is desired or beneficial, such as: joints, surgical sites, intersegmental bone spaces or sites of nonunion fractures, wounds, ulcers, or inflammatory rashes.
  • prevention refers to preventive or avoidance measures against a disease, symptom, or condition, such as, but not limited to, the application or administration of one or more active agents to a patient who has not been diagnosed with the disease, symptom, or condition but may be susceptible to or prone to the disease, symptom, or condition.
  • treatment refers to achieving a desired pharmacological or physiological effect, such as, but not limited to, inhibiting the growth of cancer cells or shrinking lesions or tumors.
  • This effect can be preventative, i.e., complete or partial prevention of the condition, appearance, disease, or symptoms, and/or therapeutic, i.e., partial or complete cure of the condition and/or side effects attributable to the condition or disease.
  • the term "pharmaceutically acceptable carrier or excipient” refers to pharmaceutically acceptable materials, compositions, or carriers, such as liquid or solid fillers, diluents, solvents, or encapsulation materials.
  • each component is "pharmaceutically acceptable” in the sense of compatibility with other ingredients in a cosmetic or pharmaceutical formulation and is suitable for contact with the tissues or organs of an individual (e.g., a human or animal) without causing excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit/risk ratio. See Remington: The Science and Practice of Pharmaceuticals, 22nd ed.
  • IC50 refers to the half-inhibitory concentration (or half-inhibition rate). It is a crucial data point in the standard curve of an indirect competitive ELISA, which is an S-shaped curve.
  • B0 the OD value of the control group without added drug
  • B/B0% the binding rate
  • concentration of drug corresponding to a binding rate of 50% is called the IC50 .
  • the smaller the IC50 value the stronger the inhibitory effect of the drug.
  • tumor includes all proliferative cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues.
  • cancer includes diseases of the skin, organs, blood, and blood vessels, such as, but not limited to: bladder cancer, bone cancer, leukemia, brain cancer, breast cancer, cervical cancer, chest cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, head cancer, kidney cancer, liver cancer, lymph node cancer, lung cancer, oral cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, stomach cancer, testicular cancer, throat cancer, and uterine cancer.
  • Specific cancers include, but are not limited to, advanced malignant diseases, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, brainstem glioma, malignant brain tumors with poor prognosis, malignant gliomas, recurrent malignant gliomas, multimorphic astrocytoma, multimorphic oligodendroglioma, neuroendocrine tumors, rectal adenocarcinoma, Duke's C and D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, and Kaposi's sarcoma.
  • Sarcoma karyotype acute myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis.
  • Leiomyosarcoma progressive ossifying fibrous dysplasia, hormone-resistant prostate cancer, high-risk resection soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, mild myeloma, indolent myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, urachal cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyosarcoma.
  • Ki-67 levels are closely related to breast cancer proliferation in its development, and Ki-67 performance is a known prognostic and outcome indicator. Tumors can be classified according to their Ki-67 index; tumors with high Ki-67 indices have a large number of proliferating cells and therefore may grow faster. Ki-67 can currently be detected using immunohistochemistry (IHC).
  • IHC immunohistochemistry
  • Foxp3 (forkhead box P3) is a member of the forkhead transcription factor family. Foxp3 performance is associated with poor prognosis. In in vitro and in vivo studies, Foxp3 is widely recognized as a gene associated with breast and prostate cancer.
  • IDO-1 indoleamine 2,3-dioxygenase 1
  • IDO-1 is a tryptophan-catabolizing enzyme. IDO-1 is considered not only an immunomodulator during pregnancy, but also in autoimmune diseases, chronic inflammation, and tumor immunity. Furthermore, IDO-1 has recently been identified as a novel target for cancer immunotherapy.
  • the immunoglobulin kappa constant (IGKC) is currently available as a single and powerful immunomarker for predicting metastasis-free survival and chemotherapy response.
  • administration of an effective amount of duloxetine and the chemotherapy drug to an individual in need may be included.
  • the chemotherapy drug may be administered to the individual first, followed by the duloxetine.
  • the cancer may be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma.
  • the breast cancer may be triple-negative breast cancer.
  • the chemotherapeutic agent may be selected from alkylating antineoplastic agents, antimitotic agents, DNA intercalating agents, and topoisomerase inhibitors. It is at least one of the group consisting of an inhibitor, a DNA cleaving agent, an antimetabolites agent, and a tyrosine kinase inhibitor.
  • the chemotherapeutic agent may include an antimitotic agent, and the cancer is selected from at least one group consisting of breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma.
  • the antimitotic agent may be selected from at least one group consisting of docetaxel, vinblastine, vincristine, and hupehenine.
  • the chemotherapeutic agent may be docetaxel, and the cancer is selected from at least one group consisting of breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma.
  • the chemotherapeutic agent may include an alkylated antitumor agent, and the cancer may be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma.
  • the alkylated antitumor agent may be selected from cisplatin, cyclophosphamide, temozolomide, nitrogen mustards, chlormethine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, nitrosoureas, carmustine, lomustine, streptozocin, and alkyl sulfonates.
  • the alkylating antitumor agent may be at least one of the group consisting of busulfan, platinum, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, triplatin tetranitrate, triazenes, dacarbazine, mitozolomide, procarbazine, and tretamine.
  • the alkylating antitumor agent may be cisplatin, and the cancer may be at least one selected from the group consisting of breast cancer, pancreatic cancer, and liver cancer.
  • the chemotherapeutic agent may be cyclophosphamide, and the cancer may be breast cancer and/or glioblastoma.
  • the chemotherapy drug may be temozolomide, and the cancer may be breast cancer and/or non-small cell lung cancer.
  • the chemotherapy drug may include an antimetabolite, and the cancer may...
  • the antimetabolite is selected from at least one of the group consisting of breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma.
  • the antimetabolite is selected from at least one of the group consisting of 5-fluorouracil, cytarabine, 6-mercaptopurine, and methotrexate.
  • the antimetabolite may be 5-fluorouracil
  • the cancer may be selected from at least one of the group consisting of breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma.
  • the chemotherapeutic agent may include a DNA intercalator or a DNA cleavage agent, and the cancer may be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, and liver cancer.
  • the DNA intercalator may be at least one selected from the group consisting of doxorubicin, actinomycin D, and daunorubicin
  • the DNA cleavage agent may be at least one selected from the group consisting of doxorubicin, bleomycin, and daunorubicin.
  • the DNA intercalator or DNA cleavage agent may be doxorubicin
  • the cancer may be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, and liver cancer.
  • the chemotherapy drug may include a tyrosine kinase inhibitor
  • the cancer may be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma.
  • the tyrosine kinase inhibitor may be at least one selected from the group consisting of osimertinib, sorafenib, imatinib, sunitinib, erlotinib, gefitinib, dasatinib, and lapatinib.
  • the tyrosine kinase inhibitor may be osimertinib, and the cancer may be at least one selected from the group consisting of breast cancer, non-small cell lung cancer, pancreatic cancer, and glioblastoma. In some embodiments, the tyrosine kinase inhibitor may be sorafenib, and the cancer is non-small cell lung cancer and/or liver cancer.
  • the chemotherapeutic agent may include a topoisomerase inhibitor, but not etoposide.
  • the topoisomerase inhibitor may be at least one selected from the group consisting of camptothecin, topotecan, irinotecan, and podophyllotoxin.
  • the topoisomerase inhibitor includes a type I topoisomerase inhibitor but does not include a type II topoisomerase inhibitor.
  • the topoisomerase inhibitor does not contain etoposide.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may be formulated into a dosage form selected from tablets, capsules, injections, lozenges, powders, granules, and any combination thereof.
  • the chemotherapeutic agent may be at least one selected from the group consisting of docetaxel, cisplatin, cyclophosphamide, 5-fluorouracil, doxorubicin, temozolomide, osimertinib, sorafenib, and any combination thereof.
  • the pharmaceutical composition of this disclosure can reduce Ki-67.
  • the pharmaceutical composition of this disclosure can reduce tumors by at least 40% (e.g., but not limited to: 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%).
  • the pharmaceutical composition of this disclosure shows that: 1) docetaxel combined with duloxetine has better efficacy against triple-negative breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma compared to docetaxel alone; 2) cisplatin combined with duloxetine has better efficacy against triple-negative breast cancer, pancreatic cancer, and liver cancer compared to cisplatin alone; 3) cyclophosphamide combined with duloxetine has better efficacy against triple-negative breast cancer and glioblastoma compared to cyclophosphamide alone; 4) 5-fluorouracil combined with duloxetine has better efficacy against triple-negative breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma compared to 5-fluorouracil alone.
  • doxorubicin alone Compared to doxorubicin alone, doxorubicin combined with duloxetine showed better efficacy against triple-negative breast cancer, non-small cell lung cancer, pancreatic cancer, and liver cancer; 6) Compared to temozolomide alone, temozolomide combined with duloxetine showed better efficacy against triple-negative breast cancer and non-small cell lung cancer; 7) Compared to osimertinib alone, osimertinib combined with duloxetine showed better efficacy against triple-negative breast cancer, non-small cell lung cancer, pancreatic cancer, and glioblastoma; and 8) Compared to sorafenib alone, sorafenib combined with duloxetine showed better efficacy against non-small cell lung cancer and liver cancer; and 9) Compared to doxorubicin alone...
  • etoposide and the combination of etoposide and duloxetine, has not produced good efficacy in the treatment of triple-negative breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma.
  • results showed that duloxetine + NACT combination effectively improved tumor shrinkage rate, increased the number of complete responses, and reduced Ki-67.
  • the relative tumor reduction in the duloxetine + NACT group was 22.65%
  • the tumor shrinkage rate in the duloxetine + NACT group was higher than that in the NACT group
  • the tumor shrinkage ratio in the duloxetine + NACT group was higher than that in the NACT group
  • the proportion of individuals with complete response (CR) in the duloxetine + NACT group (42.9%) was higher than that in the NACT group (0%)
  • individuals with lower pre-treatment Foxp3 concentration (Foxp3-V1) were more likely to achieve better tumor shrinkage rate
  • individuals with lower pre-treatment IDO-1 concentration (IDO-1-V1) were more likely to achieve better tumor shrinkage rate
  • individuals with lower post-treatment IGKC concentration (IGKC-V18) were more likely to achieve better tumor shrinkage rate.
  • the drug concentrations in the embodiments are listed in Table 1, and the cancer cell model information is listed in Table 2.
  • Example 1 Establishment of a method for analyzing cell lines and cancer cell survival
  • Subculture cell lines for different cancer types calculate the cell number, and re-seed 1x104 cells. After 24 hours, add the drug (as shown in Table 1). After 72 hours, add MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide). Detect at 570 nm after 90 minutes. Calculate the cell inhibition rate (100% minus cell viability). If the G5 value is higher than G1, or the G4 value is higher than G2, then the combined use is superior to using chemotherapy drugs alone. The results are shown in Figures 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, and 31.
  • Example 1 Referring to Tables 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 below, the results of Example 1 are shown in Table 13. The results showed that: 1) Compared with docetaxel alone, docetaxel combined with duloxetine showed better efficacy against triple-negative breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma; 2) Compared with cisplatin alone, cisplatin combined with duloxetine showed better efficacy against triple-negative breast cancer, pancreatic cancer, and liver cancer; 3) Compared with cyclophosphamide alone, cyclophosphamide combined with duloxetine showed better efficacy against triple-negative breast cancer and glioblastoma; 4) Compared with 5-fluorouracil alone, 5-fluorouracil combined with duloxetine showed better efficacy against triple-negative breast cancer, non-small cell lung cancer, liver cancer, and glioblastoma; 5) Compared with doxorubicin alone, doxorubicin
  • Temozolomide combined with duloxetine showed better efficacy in treating triple-negative breast cancer and non-small cell lung cancer compared to temozolomide alone;
  • Osimertinib combined with duloxetine showed better efficacy in treating triple-negative breast cancer, non-small cell lung cancer, pancreatic cancer, and glioblastoma compared to osimertinib alone;
  • Sorafenib combined with duloxetine showed better efficacy in treating non-small cell lung cancer and liver cancer compared to sorafenib alone;
  • Etoposide combined with duloxetine did not show better efficacy in treating triple-negative breast cancer, non-small cell lung cancer, pancreatic cancer, liver cancer, and glioblastoma compared to etoposide alone.
  • Table 5 shows the results of the combined use of cyclophosphamide (IC50) and duloxetine in this disclosure.
  • Table 6 shows the results of using 5-fluorouracil (1/2 IC50) and duloxetine in combination in this disclosure.
  • Inclusion criteria Women aged ⁇ 20 years with newly diagnosed stage II triple-negative breast cancer (tumor ⁇ 2cm) who have not undergone breast surgery or systemic chemotherapy.
  • NACT The regimen consists of four cycles of docetaxel, followed by four cycles of cyclophosphamide and doxorubicin, and finally surgical resection of the lesion.
  • Duloxetine + NACT After clinical enrollment, duloxetine is started one week before chemotherapy, and the dosage is reduced two weeks after chemotherapy, followed by surgical resection of the lesion.
  • the pretreatment process is detailed below.
  • four whole blood samples were collected using purple-tipped tubes containing EDTA anticoagulant and pretreated at room temperature on the same day.
  • Two tubes of whole blood from the subject were centrifuged (340g, 5min), and the supernatant (plasma) was collected and placed in a 2mL microcentrifuge tube.
  • the tube was labeled with the sample number, photographed, and tested for hemolysis.
  • the tubes were then stored at -80°C. After all four tubes of samples from the same subject were collected, an ELISA test was performed.
  • the third tube of whole blood was stored at 4°C without centrifugation for later use.
  • the fourth tube was used for flow cytometry pretreatment.
  • 1X RBC (Red blood cell) lysis buffer was diluted 10-fold with deionized and distilled water (dd water). The whole blood was gently mixed thoroughly, and 500 ⁇ l was added to 9.5mL of 1X RBC lysis buffer. After thorough mixing, the mixture was allowed to stand in the dark for 15min. After the reaction was complete, the tubes were centrifuged (340g, 5min) and the supernatant was removed. Add 200 ⁇ l of staining buffer to disperse the cells on the tube wall and transfer to a 1.75 mL microcentrifuge tube. Centrifuge (340 g, 5 min) and remove the supernatant. Add 0.5 mL of fixation buffer and incubate in the dark for 20 min. After fixation, centrifuge (340 g, 5 min) and remove the supernatant. Add 0.5 mL of staining buffer and store at 4°C.
  • the antibodies used in this disclosure are listed in Table 14. The chemicals are listed in Table 15.
  • Centrifuge the pretreated sample (340g, 5min) to remove the supernatant, add 300 ⁇ l of staining buffer to resuspend, mix well, and divide into three equal tubes, each with a volume of 100 ⁇ l.
  • Foxp3 staining was performed using the second tube (permeabilization). 100 ⁇ l of the sample was centrifuged (340 g, 5 min), and the supernatant was removed. 200 ⁇ l of intracellular staining permeabilization buffer was added, mixed thoroughly, and permeabilized. After standing for 10 min, the sample was centrifuged again (340 g, 5 min), and the supernatant was removed. 100 ⁇ l of staining buffer was added to resuspend the sample. The volume of the Foxp3 antibody corresponding to the chromosome was taken, mixed thoroughly, and incubated in the dark for 20 min. 400 ⁇ l of staining buffer was added to bring the total volume for the flow cytometer to 500 ⁇ l. The sample was analyzed using flow cytometry (Novocyte 3000, Agilent), with 10,000 white blood cells selected for analysis.
  • IDO-1 staining was performed using tube 3 (permeabilized). 100 ⁇ l of the sample was centrifuged (340 g, 5 min), and the supernatant was removed. 200 ⁇ l of intracellular staining permeabilization buffer was added, thoroughly mixed, and permeated. After standing for 10 min, the sample was centrifuged again (340 g, 5 min), and the supernatant was removed. 100 ⁇ l of staining buffer was added to resuspend the sample. The corresponding chromosome volume for antibody IDO-1 was taken, mixed thoroughly, and incubated in the dark for 20 min. 400 ⁇ l of staining buffer was added to bring the total volume for the flow cytometer to 500 ⁇ l. Analysis was performed using a flow cytometer (Novocyte 3000, Agilent), with 10,000 white blood cells analyzed.
  • monoamine oxidase inhibitors used within 14 days prior to registration; concomitant use with phenothiazines (including thioridazine), propafenone, flecainide, triptans, MAO-I, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants.
  • MAO-I monoamine oxidase inhibitors
  • phenothiazines including thioridazine
  • propafenone propafenone
  • flecainide triptans
  • MAO-I selective serotonin reuptake inhibitors
  • SNRIs serotonin-norepinephrine reuptake inhibitors
  • cardiovascular diseases or those with autoimmune diseases or those using immunosuppressants (excluding steroids) are not suitable for participation in this disclosure: symptomatic congestive heart failure, myocardial infarction, severe or unstable angina (within 6 months prior to the screening date), high risk of arrhythmia, and uncontrolled hypertension.
  • the following individuals are not suitable to participate in this disclosed embodiment: Patients with the following conditions: hepatic insufficiency, chronic liver disease, severe kidney disease; symptomatic chronic lung disease, symptomatic restrictive lung disease, interstitial pneumonia, or other pulmonary function abnormalities that may affect patient safety; uncontrolled angle-closure glaucoma or clinically significant coagulation disorders; uncontrolled bacterial or viral infections, or patients with active or recent (within 6 months) fungal infections at the time of participation; patients with active central nervous system disorders at the time of participation; patients currently suffering from primary mental illness (schizophrenia, psychosis) or with suicidal ideation, a history of bipolar disorder, or epileptic seizures.
  • hepatic insufficiency chronic liver disease, severe kidney disease
  • symptomatic chronic lung disease symptomatic restrictive lung disease, interstitial pneumonia, or other pulmonary function abnormalities that may affect patient safety
  • uncontrolled angle-closure glaucoma or clinically significant coagulation disorders uncontrolled bacterial or viral infections, or patients with
  • Serologically positive for HIV infection or HIV-positive, acute phase of HBV or HCV known hypersensitivity to any investigational treatment (including excipients of the investigational drug).
  • the relative tumor reduction in the duloxetine + NACT group was 22.65%.
  • the tumor shrinkage rate in the duloxetine + NACT group was higher than that in the NACT group.
  • the tumor shrinkage rate waterfall plot shows that the tumor shrinkage rate in the duloxetine + NACT group was higher than that in the NACT group.
  • the results show that the proportion of individuals with complete remission (CR) in the duloxetine + NACT group (42.9%) was higher than that in the NACT group. Group (0%).
  • ECOG Eastern Cooperative Oncology Group.
  • TNMIIa T0-2; N0-1; M0;
  • TNMIIb T2-3; N0-1; M0;
  • TNMIIIc Any of T, N3, and M0.
  • SD Standard deviation.
  • the medication adherence in the duloxetine + NACT group was approximately 80 to 90%.
  • the tumor size, blood pressure, and Ki-67 (%) of the duloxetine + NACT group decreased significantly after treatment.
  • the average tumor shrinkage rate of the duloxetine + NACT group was higher than that of the NACT group.
  • Table 18 Changes in body weight, blood pressure, and tumor size after treatment in the NACT group and the duloxetine + NACT group.
  • the NACT group only showed a partial response.
  • 3 individuals had a complete response and 4 individuals had a partial response. It is evident that the duloxetine + NACT group had a better effect than the NACT group.
  • This table includes only individuals for whom RECIST response is evaluable.
  • CR Complete response
  • PR Partial response
  • SD Stable disease
  • PD Progressive disease.
  • NACT Neoadjuvant chemotherapy group.
  • RBC Red blood cells. WBC: White blood cells. DC: Differential count. Neutrophils: Neutrophils. Eos: Eosinophils. Baso: Basophils. Mono: Monocytes. RDW: Red blood cell distribution width. MCV: Mean corpuscular volume. MCHC: Mean corpuscular heme concentration. ANC: Absolute neutrophil count. SD: Standard deviation.
  • BUN Blood urea nitrogen.
  • TG Triglycerides.
  • SD Standard deviation.
  • results of this embodiment show that the combination of duloxetine and NACT can effectively improve the tumor shrinkage rate, increase the number of people with complete responses, and reduce Ki-67.

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Abstract

L'invention concerne l'utilisation de duloxétine et d'un médicament chimiothérapeutique dans la préparation d'une composition pharmaceutique pour le traitement ou la prévention du cancer, comprenant l'administration d'une quantité efficace de duloxétine et d'un médicament chimiothérapeutique à un individu en ayant besoin, permettant d'obtenir un meilleur effet par rapport à l'administration de duloxétine seule ou du médicament chimiothérapeutique seul.
PCT/CN2024/094805 2024-05-22 2024-05-22 Utilisation de duloxétine et d'un médicament chimiothérapeutique dans la préparation d'une composition pharmaceutique pour le traitement ou la prévention du cancer Pending WO2025241125A1 (fr)

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PCT/CN2025/096659 WO2025242178A1 (fr) 2024-05-22 2025-05-22 Utilisation de duloxétine et d'un médicament chimiothérapeutique dans la préparation d'une composition pharmaceutique pour le traitement ou la prévention du cancer

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PCT/CN2025/096659 Pending WO2025242178A1 (fr) 2024-05-22 2025-05-22 Utilisation de duloxétine et d'un médicament chimiothérapeutique dans la préparation d'une composition pharmaceutique pour le traitement ou la prévention du cancer

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