WO2018064851A1 - 低剂量西地那非作为抗肿瘤药物的应用 - Google Patents

低剂量西地那非作为抗肿瘤药物的应用 Download PDF

Info

Publication number
WO2018064851A1
WO2018064851A1 PCT/CN2016/103957 CN2016103957W WO2018064851A1 WO 2018064851 A1 WO2018064851 A1 WO 2018064851A1 CN 2016103957 W CN2016103957 W CN 2016103957W WO 2018064851 A1 WO2018064851 A1 WO 2018064851A1
Authority
WO
WIPO (PCT)
Prior art keywords
sildenafil
dose
tumor
low
antitumor
Prior art date
Application number
PCT/CN2016/103957
Other languages
English (en)
French (fr)
Inventor
刘誉
Original Assignee
广州市东来生物科技有限公司
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 广州市东来生物科技有限公司 filed Critical 广州市东来生物科技有限公司
Priority to US15/759,575 priority Critical patent/US20190183893A1/en
Publication of WO2018064851A1 publication Critical patent/WO2018064851A1/zh

Links

Images

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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the technical field of medicine, in particular to the application of a low dose of sildenafil as an antitumor drug.
  • Malignant tumors also known as cancers
  • Their main clinical features are rapid growth, strong invasiveness to tissues, transfer to other parts of the body, and harmful substances that destroy normal organ structures.
  • the global cancer incidence will increase by 50% by 2020, that is, 15 million cancer patients will be added each year. Not only that, but the death toll of cancer is also rising rapidly around the world.
  • this number may increase to 13.2 million.
  • 20% of new cancer patients worldwide are in China, and 24% of cancer deaths are in China.
  • “Targeted drugs” are therapeutic techniques that target killing or inhibiting cancer cells with minimal damage to normal cells, and this technology has become an important direction for studying new technologies for cancer treatment.
  • “Targeted drugs” can be divided into the following categories according to their target: (1) Gene therapy and viral therapy: As early as 2004, more than 1020 programs in the world entered the clinic, and 63.4% were used in cancer. Treatment. The anti-angiogenic factor, tumor suppressor gene, prodrug activating gene and immunostimulatory gene are mainly transported by a replication-deficient vector. Among them, adenovirus carrying P53 has the fastest clinical progress, and at least five programs in the world have entered phase III clinical trials. However, there are still many obstacles in tumor gene therapy.
  • the main problem is that the vector cannot specifically target the tumor cells, and the high expression of the therapeutic gene in the tumor cells is insufficient to eliminate the tumor, and the change of the viral vector shell.
  • Antibody therapy In recent years, breakthroughs have been made in the study of antibody drugs for treating tumors. At present, there are more than 500 kinds of antibodies in the world for diagnosis and treatment. The US FDA has approved the listing of 18 antibodies, 8 of which are targeted for tumor therapy. For example, Rituxan has been treated for more than 300,000.
  • the total response rate for first-line treatment is 60% to 75%, the efficacy is the same as chemotherapy; the effective rate of combined chemotherapy is more than 80%, the complete remission rate is 40% to 63%; the antibody against vascular endothelial growth factor Avastin makes The survival of patients with advanced colon cancer is extended by an average of 5 months. Currently, 95% of colon cancer patients in the United States use this drug.
  • antibodies are difficult to penetrate cells of solid tumors, so the efficacy of treating large-volume solid tumors is still not satisfactory; production costs and prices are very expensive; For specific receptors, it is necessary to label the antibody with an isotope or toxin, but the side effects are also increased.
  • RNA interference is a kind of mRNA degradation induced by short double-stranded RNA. This phenomenon occurs at the post-transcriptional level, also known as post-transcriptional gene silencing. RNAi only degrades the mRNA of a single endogenous gene corresponding to its sequence, with high specificity and efficiency. A transplanted tumor model that received a small interfering RNA gene therapy can simultaneously increase sensitivity to chemotherapy drugs. However, the therapeutic technique of RNAi has not been widely used so far.
  • RNAi is not easily introduced into tumor tissues, and the half-life in vivo is also relatively short.
  • Small molecule targeted drugs The development of new drugs targeting protein tyrosine kinases is progressing rapidly. This kinase catalyzes the transfer of ⁇ -phosphate groups in ATP to tyrosine residues of various proteins, which plays an important role in cell growth, proliferation and differentiation.
  • HerceptinTM (Genentech and Roche) is a humanized monoclonal antibody targeting the tyrosine kinase receptor HER2/neu, which has additive or synergistic effects with various chemotherapeutic drugs.
  • GleevecTM (Novatis, Switzerland) is a specific inhibitor of tyrosine kinase BcrAbl, which has a very good effect on the treatment of chronic myeloid leukemia. It has been approved by the FDA for early marketing and is used to treat Philadelphia chromosome-positive chronic medulla. Leukemia patients. Iressa (AstraZeneca) is an orally administrable small molecule inhibitor against EGFR tyrosine kinase. In May 2003, the FDA approved advanced non-small cell lung cancer for chemotherapy failure with platinum-containing or taxane-based regimens. It is the first targeted small molecule tyrosine kinase inhibitor for solid tumor therapy.
  • Viral vector targeted therapy In recent years, it has been found that several cells can carry viral vectors for systemic administration. These cells include macrophages, T cells, NK cells, allogeneic tumor cells, and the hottest stem cells currently studied. These tumor chemotactic cells can sense the signals emitted by the tumor microenvironment, have the role of tracking tumors and transmitting genes, but still need to be studied in more depth. Compared with traditional methods, the application of stem cells to treat diseases has the advantages of low toxicity, effective single-use, and no need to fully understand the exact mechanism of disease onset.
  • Immune cell therapy is a biological therapy that inputs immune cells with anti-tumor activity to tumor patients, directly kills tumors or stimulates the body's anti-tumor immune response to achieve therapeutic effects. Its operations include passage, expansion, modification, screening, and treatment of cells or other substances that alter cell biological behavior in vitro; somatic cells after in vitro manipulation can be used for tumor therapy as well as for tumor prevention. Somatic cell immunotherapy has become an important means of adjuvant therapy for cancer patients after radiotherapy and chemotherapy.
  • immune cell therapy is currently in its infancy, mainly for adjuvant therapy, and patients have different responses, and some patients are not sensitive to this therapy.
  • sildenafil intraperitoneal injection
  • doxorubicin Doxorubicin
  • sildenafil oral feeding
  • Swiss Regorafenib significantly inhibited the growth of liver cancer xenografts in nude mice
  • sildenafil was used alone, its anti-tumor effect was not significant (normal dose range: 25-100 mg), which was not significantly different from the control group (see the above paper) because the above study did not find the use of Westland alone.
  • the effective dose window for non-treated tumors the dose of sildenafil used is not a potent anti-tumor dose, such that sildenafil alone has substantially no anti-tumor efficacy.
  • the present invention provides a low-dose sildenafil.
  • the application technology of anti-tumor drugs has a good curative effect on tumor treatment, but has no obvious toxic and side effects, and has remarkable advancement in tumor treatment technology.
  • sildenafil for use as an anti-tumor drug
  • the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl) Base-7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate, dosage of said sildenafil It is 2 to 25 mg.
  • the manner in which the sildenafil is used includes internal administration, injection, and external use.
  • the sildenafil is an oral solution, a powder, a tablet, a capsule, an injection or an ointment.
  • the oral dose of the sildenafil is 2 to 25 mg.
  • the injection dose of the sildenafil is 2 to 10 mg.
  • the topical dose of the sildenafil: sildenafil is less than 1% by mass. It should be noted that the topical dosage is based on the total amount of sildenafil being between 2 and 25 mg.
  • the external formulation of the sildenafil ointment is as follows: sildenafil having a mass percentage of 0.01 to 1% and a fat-soluble medium petrolatum having a mass percentage of 99 to 99.99%.
  • sildenafil citrate solution dissolved in 25% ethanol
  • the tumor growth inhibition rate reached 68%.
  • the mice had no significant or observable toxic side effects during the experiment.
  • sildenafil citrate had no significant inhibitory effect on the growth of mouse xenografts.
  • sildenafil has an optimal dose window between 2 and 25 mg.
  • Sildenafil has anti-tumor efficacy and safety in this low-dose range: minimal side effects for cancer patients, but The anti-tumor effect is the best. Below or above this dose range (2-25 mg) will significantly reduce its anti-tumor efficacy. Since this dose range is significantly less than the normal dosage of sildenafil for male penile erectile dysfunction, it is referred to as "low dose" sildenafil. Compared with the normal dose (25-100mg), low-dose sildenafil can greatly improve the anti-tumor efficacy of sildenafil and avoid the side effects of sildenafil on cancer patients.
  • the optimal anti-tumor dosage of the individual will vary within this range depending on the age, weight and physical condition of the patient. For example, in general adult tumor patients (about 60 kg in weight), the optimal oral dose of sildenafil is 10 mg.
  • sildenafil anti-tumor The mechanism of low-dose sildenafil anti-tumor is still unclear.
  • high concentrations of sildenafil 200 ⁇ M have a direct inhibitory effect on the growth of cultured tumor cells, which may be caused by inhibition of cyclin and cell cycle-dependent protein kinase (CDK) in tumor cells. Tumor cells are arrested in the G1 phase and stop growing.
  • high concentrations of sildenafil 300 ⁇ M
  • ROS active oxygen
  • sildenafil citrate tablets after oral administration of 100 mg of sildenafil citrate tablets, the highest concentration of sildenafil citrate in the blood is 440 ng/mL, or 0.66 ⁇ M, which is much lower than sildenafil. Because of the concentration requirements of the above anti-tumor mechanisms, therefore, the low-dose sildenafil anti-tumor efficacy does not belong to the above-mentioned therapeutic mechanism.
  • sildenafil can stimulate the expression of the nuclear factor inhibitory protein IkB nitro-tyrosine and the apoptotic gene ligand Fas-L in human hepatoma cells (HEPG2), thereby promoting tumors. Cell wither Die. If the concentration of the drug in the blood may be less than 0.1 ⁇ M after taking oral low dose (2-10 mg) of sildenafil in adults, the antitumor activity of low dose sildenafil may not directly inhibit tumor cell growth by the above. Or a mechanism that promotes apoptosis. Therefore, the low-dose sildenafil anti-tumor efficacy may not be a mechanism by which drugs directly act on tumor cells.
  • the anti-tumor efficacy of low dose sildenafil was offset by the anti-allergic drug Chlorphenamine Maleate.
  • the tumor-bearing mice were intragastrically administered with 10 mg/Kg and 20 mg/Kg doses of sildenafil citrate (1 time per day), the tumor inhibition rates were 63% and 50%, respectively, but if 2 mg was added, /Kg dose of chlorpheniramine maleate combined with gastric perfusion, the tumor inhibition rate decreased to 16% and 7%, respectively, indicating that chlorpheniramine maleate can directly resist the anti-tumor activity of low dose sildenafil.
  • the anti-tumor effect of low-dose sildenafil in vivo is not directly through the action of drugs on tumor cells, but on the regulation of the immune system in the body, by regulating the immune function of immune cells in the body to achieve anti-tumor efficacy, because the immune cells in the body
  • lymphocytes, granulocytes, and mononuclear cells all have H1 receptors, and chlorpheniramine maleate counteracts the antitumor efficacy of low-dose sildenafil by antagonizing the H1 receptor of immune cells.
  • the present invention is applied to the treatment of malignant tumors at a daily oral dose of 2 to 25 mg, or an injection dose of 2 to 10 m, or a topical dose percentage of less than 1%, which inhibits tumor growth efficiency. It can reach more than 50% without significant toxic side effects, and can effectively control tumor growth and promote tumor improvement.
  • Figure 1 is a schematic view showing the molecular structure of sildenafil according to the present invention.
  • Figure 2 is a schematic illustration of the sildenafil anti-tumor dose window of the present invention
  • Figure 3 is a schematic diagram showing the inhibitory effect of different doses of sildenafil on gastric xenografts in mice;
  • Figure 4 is a graphical representation of the antagonism of chlorpheniramine maleate against the anti-tumor activity of sildenafil.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 10 mg, and a sugar-coated tablet is prepared by a conventional process to take an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 20 mg, which is prepared into a sugar-coated tablet by a conventional process, and is administered to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 5 mg, which is prepared into a sugar-coated tablet by a conventional process, and is used for anti-tumor action.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 10 mg, which is prepared into a powder by a conventional process, and is used to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 5 mg, which is prepared into a powder by a conventional process, and is used to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 2 mg, which is prepared into a powder by a conventional process, and is used to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 10 mg, which is made into a capsule by a conventional process, and is administered to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 20 mg, which is made into a capsule by a conventional process, and is taken to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 5 mg, which is made into a capsule by a conventional process, and is used to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxyl -3-[5-(6,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methyl
  • the molecular structure of the piperazine decanoate is shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 10 mg, and the oral solution is prepared by a conventional process, and the antitumor effect is achieved by taking it.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 20 mg, and the oral solution is prepared by a conventional process, and the anti-tumor effect is achieved by taking it.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 5 mg, and the oral solution is prepared by a conventional process, and the antitumor effect is achieved by taking it.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the oral dose of the sildenafil is 2 to 25 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window in units of mg.
  • sildenafil citrate When taking the medicine, sildenafil citrate contains an effective dose of 2 mg, which is prepared into an oral liquid by a conventional process, and is administered to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the injection dose of the sildenafil is 2 to 10 mg, and Figure 2 is sildenafil.
  • a schematic representation of the anti-tumor dose window in mg.
  • sildenafil citrate When injecting the drug, sildenafil citrate contains an effective dose of 10 mg, which is prepared by injection into a conventional process and subcutaneously injected to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the injection dose of the sildenafil is 2 to 10 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window, and the unit is mg.
  • sildenafil citrate When injecting the drug, sildenafil citrate contains an effective dose of 5 mg, which is prepared by injection into a conventional process and subcutaneously injected to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the injection dose of the sildenafil is 2 to 10 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window, and the unit is mg.
  • sildenafil citrate When injecting the drug, sildenafil citrate contains an effective dose of 2 mg, which is prepared by injection into a conventional process to achieve antitumor effect by subcutaneous injection.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the injection dose of the sildenafil is 2 to 10 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window, and the unit is mg.
  • sildenafil citrate When injecting the drug, sildenafil citrate contains an effective dose of 5 mg, which is prepared by an ordinary process and is intravenously injected to achieve an anti-tumor effect.
  • a low-dose sildenafil for use as an anti-tumor drug the chemical name of sildenafil is 1-[4-ethoxy-3-[5-(6,7-dihydro-1-methyl)
  • the base 7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidine)]benzenesulfonyl]-4-methylpiperazine decanoate has a molecular structure as shown in FIG.
  • the injection dose of the sildenafil is 2 to 10 mg
  • FIG. 2 is a schematic diagram of sildenafil as an antitumor dose window, and the unit is mg.
  • sildenafil citrate When injecting, sildenafil citrate contains 2 mg of effective drug, which is prepared by intravenous injection and intravenously. Achieve anti-tumor effects.
  • sildenafil citrate When applied externally, sildenafil citrate contains 1% of the effective drug, and the fat-soluble medium, Vaseline 99%, is made into an ointment by a conventional process, and is used for external use to achieve an anti-tumor effect.
  • sildenafil citrate When applied externally, sildenafil citrate contains 0.1% of effective drug, and the fat-soluble medium is 0.99% of Vaseline. It is made into an ointment by conventional techniques and is used for external use to achieve anti-tumor effect.
  • sildenafil citrate When applied externally, sildenafil citrate contains 0.01% of the effective drug amount and 99.99% of the fat-soluble medium Vaseline.
  • the ointment is made by a conventional process and is used for external use to achieve an anti-tumor effect.
  • examples 1 to 21 the daily oral dose of 2 to 25 mg, or the injection dose of 2 to 10 mg, or the topical dose percentage of less than 1% of sildenafil citrate, for the treatment of malignant tumors, Its anti-tumor growth efficiency is more than 50%, and it does not produce significant toxic and side effects, and achieves the effect of effectively controlling tumor growth and promoting tumor improvement.
  • the above external dosage is based on the total amount of sildenafil being between 2 and 25 mg.
  • sildenafil citrate solution dissolved in 25% ethanol
  • the tumor growth inhibition rate reached 68%.
  • the dose was 50 mg/Kg/day
  • sildenafil citrate had no significant inhibitory effect on the growth of mouse xenografts, as shown in FIG.
  • sildenafil has an optimal dose window between 2 and 25 mg.
  • Sildenafil has anti-tumor efficacy and safety in this low-dose range: minimal side effects for cancer patients, but The anti-tumor effect is the best. Below or above this dose range (2-25 mg) will significantly reduce its anti-tumor efficacy. Since this dose range is significantly less than the normal dosage of sildenafil for male penile erectile dysfunction, it is referred to as "low dose" sildenafil. Compared with the normal dose (25-100mg), low-dose sildenafil can greatly improve the anti-tumor efficacy of sildenafil and avoid the side effects of sildenafil on cancer patients.
  • the optimal anti-tumor dosage of the individual will vary within this range depending on the age, weight and physical condition of the patient. For example, in general adult tumor patients (about 60 kg in weight), the optimal oral dose of sildenafil is 10 mg.
  • sildenafil anti-tumor The mechanism of low-dose sildenafil anti-tumor is still unclear.
  • high concentrations of sildenafil 200 ⁇ M have a direct inhibitory effect on the growth of cultured tumor cells, which may be caused by inhibition of cyclin and cell cycle-dependent protein kinase (CDK) in tumor cells. Tumor cells are arrested in the G1 phase and stop growing.
  • High concentrations of sildenafil (300 ⁇ M) can also cause active oxygen (ROS) to increase in cultured tumor cells, leading to tumor cell apoptosis.
  • ROS active oxygen
  • sildenafil citrate tablets after oral administration of 100 mg of sildenafil citrate tablets, the highest concentration of sildenafil citrate in the blood is 440 ng/mL, or 0.66 ⁇ M, which is much lower than sildenafil. Because of the concentration requirements of the above anti-tumor mechanisms, therefore, the low-dose sildenafil anti-tumor efficacy does not belong to the above-mentioned therapeutic mechanism.
  • sildenafil can stimulate the expression of the nuclear factor inhibitory protein IkB nitro-tyrosine and the apoptotic gene ligand Fas-L in human hepatoma cells (HEPG2), thereby promoting tumors. Apoptosis. If the concentration of the drug in the blood may be less than 0.1 ⁇ M after taking oral low dose (2-10 mg) of sildenafil in adults, the antitumor activity of low dose sildenafil may not directly inhibit tumor cell growth by the above. Or a mechanism that promotes apoptosis. Therefore, the low-dose sildenafil anti-tumor efficacy may not be a mechanism by which drugs directly act on tumor cells.
  • Figure 4 is a graphical representation of the antagonism of chlorpheniramine maleate against the anti-tumor activity of sildenafil, specifically a two-week different dose of sildenafil or chlorpheniramine maleate 2 mg/ The inhibitory effect of Kg combined therapy on mouse tumors.
  • CHM is chlorpheniramine maleate.
  • the anti-tumor efficacy of low dose sildenafil was offset by the anti-allergic drug Chlorphenamine Maleate.
  • the tumor-bearing mice were intragastrically administered with 10 mg/Kg and 20 mg/Kg doses of sildenafil citrate (1 time per day), the tumor inhibition rates were 63% and 50%, respectively, but if 2 mg was added, /Kg dose of chlorpheniramine maleate combined with gastric perfusion, the tumor inhibition rate decreased to 16% and 7%, respectively, as shown in Figure 4, indicating that chlorpheniramine maleate can directly fight low dose sildenafil Antitumor activity.
  • the anti-tumor effect of low-dose sildenafil in vivo is not directly through the action of drugs on tumor cells, but on the regulation of the immune system in the body, by regulating the immune function of immune cells in the body to achieve anti-tumor efficacy, because the immune cells in the body
  • lymphocytes, granulocytes, and mononuclear cells all have H1 receptors, and chlorpheniramine maleate counteracts the antitumor efficacy of low-dose sildenafil by antagonizing the H1 receptor of immune cells.

Abstract

本发明提供一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，所述西地那非的使用剂量为2～25mg。本发明以每天口服剂量2～25mg，或注射剂量2～10mg，或外用剂量质量百分比含量低于1％的西地那非枸橼酸盐，应用于恶性肿瘤的治疗。

Description

低剂量西地那非作为抗肿瘤药物的应用 技术领域
本发明涉及医药技术领域，具体地说是一种低剂量西地那非作为抗肿瘤药物的应用。
背景技术
恶性肿瘤又称为癌症，可发生在身体的大多数组织器官，其主要临床特征是生长迅速，对组织的浸润性强，可转移到身体其他部位，还会产生有害物质，破坏正常器官组织结构，使机体功能失调，严重地威胁患者生命。世卫组织最新数据显示，到2020年前，全球癌症发病率将增加50％，即每年将新增1500万癌症患者。不仅如此，癌症的死亡人数也在全球迅猛上升，2007年全球共有760万人死于癌症，2030年这个数字可能会增至1320万。而且，全球20％的新发癌症病人在中国，24％的癌症死亡病人在中国。目前我国每死亡5人，即有1人死于癌症，而在0～64岁人口中，每死亡4人，即有1人死于癌症。在《2012中国肿瘤登记年报》中显示，我国每分钟就有6人被确诊为癌症患者，依此计算，我国每天就有8000多人被确诊为癌症，因而每年多达三百多万新增癌症病人。
目前尚未有特别有效的抗癌药物，相对于庞大的癌症患者数量，可选的抗癌药物不多，且价格昂贵，使大量癌症患者无法得到有效治疗。传统的西医治疗癌症主要是化疗、手术和放疗外，但副作用大、转移率和复发率高仍是有待解决的难题。因此，目前各国趋向于开发靶向药物和免疫细胞治疗技术，疗效较为明显。
“靶向药物”是定向杀伤或抑制癌细胞而极少伤害正常细胞的治疗技术，该技术已经成为研究癌症治疗新技术的重要方向。“靶向药物”按其作用的标靶不同又可分为以下几种：(1)基因治疗和病毒治疗：早在2004年，全世界就有1020多个方案进入临床，63.4％用于癌症的治疗。主要是用复制缺陷型载体转运抗血管生成因子、抑癌基因、前药活化基因以及免疫刺激基因。其中以腺病毒携带P53临床进展最为迅速，全球至少有5个方案进入Ⅲ期临床试验。但是，肿瘤基因治疗仍存在很多障碍，主要问题是载体不能特异性靶向肿瘤细胞，治疗基因在肿瘤细胞中高效表达低不足以消灭肿瘤，以及病毒载体外壳的改变等。(2)抗体治疗：近年，治疗肿瘤的抗体药物研究取得了突破性进展。目前国际上已有500多种抗体用于诊断与治疗，美国FDA已批准18个抗体上市，其中8个用于肿瘤治疗的靶向抗体，例如，治疗淋巴瘤的抗体Rituxan已治疗了30多万病人，用于一线治疗总反应率为60％～75％，其疗效与化疗相同；联合化疗有效率高达80％以上，完全缓解率达40％～63％；针对血管内皮生长因子的抗体Avastin使晚期结肠癌患者的生存期平均延长了5个月， 目前美国95％结肠癌病人使用该药。但是，目前抗体治疗实体瘤仍存在着3个难题：抗体难以穿透实体肿瘤的细胞，因此治疗大体积实体肿瘤的疗效仍不理想；生产成本及价格均非常昂贵；只能针对肿瘤细胞某个特异性受体，治疗中需要为抗体标上同位素或毒素，但副作用也随之增加。(3)信号传导途径治疗：肿瘤的发生、发展与细胞增殖、凋亡等信号传导通路中某一个环节密切相关。信号传导最重要的分子之一是蛋白质酪氨酸激酶，针对后者开发靶向药物成了抗癌药物的研究热点之一。目前已被美国FDA批准的小分子STI－571(Gleevec或Glivec)可特异性杀死肿瘤细胞。在过去的15年中，人们发现了多个可以穿入活细胞的小肽，用这些小肽携带外源物质进入细胞，效率非常之高。但是，目前这些方法还处于初步实验，还有很多问题需要解决，如穿膜肽并非可以穿入所有细胞，其穿入机制也不明确，诱发免疫反应会干扰它在体内的疗效等。(4)RNA干扰技术：RNA干扰(RNAinterference，RNAi)是一种由短的双链RNA诱发的mRNA降解。这种现象发生在转录后水平，又称为转录后基因沉默。RNAi只降解与之序列相应的单个内源基因的mRNA，具有很高的特异性与效率。接受了小干扰RNA基因药物治疗的移植瘤模型，可同时提高对化疗药物的敏感性。但是，RNAi的治疗技术迄今没有获得广泛应用，主要问题是RNAi不容易导入肿瘤组织，在体内的半衰期也比较短。(5)小分子靶向药物：以蛋白酪氨酸激酶为靶点的新药研发进展迅速。此激酶可催化ATP中γ-磷酸基转移到多种蛋白质的酪氨酸残基上，这在细胞生长、增殖和分化进程中具有重要作用。HerceptinTM(Genentech与Roche公司)是以酪氨酸激酶受体HER2/neu为靶点的人源化单克隆抗体，与多种化疗药物有相加或协同效应。GleevecTM(瑞士Novatis公司)是针对酪氨酸激酶BcrAbl的一种特异性抑制剂，对治疗慢性髓样白血病具有非常好的疗效，已被FDA批准提前上市，用于治疗费城染色体呈阳性的慢性髓样白血病患者。Iressa(AstraZeneca公司)是针对EGFR酪氨酸激酶的可口服的小分子抑制剂。2003年5月FDA批准用于经含铂类或紫杉类方案化疗失败的晚期非小细胞肺癌，是第1个用于实体瘤治疗的针对特定靶点的小分子酪氨酸激酶抑制剂。但是，小分子靶向药物通常具有较大的毒副作用，而且存在明显的个体差异，因而大部分小分子靶向药物均在试验性治疗阶段。(6)病毒载体靶向治疗：近年研究发现，有几种细胞可以携带病毒载体进行系统给药治疗。这些细胞包括巨噬细胞、T细胞、NK细胞、异体肿瘤细胞以及目前研究最热的干细胞等。这些肿瘤趋化细胞可以感应肿瘤微环境发出的信号，具有追踪肿瘤、传递基因的作用，但仍需要更深入地研究。与传统方法相比，应用干细胞治疗疾病具有毒性低、一次用药有效、不需要完全了解疾病发病的确切机理等优点。但是，由于间充质干细胞主要来源于骨髓，在放化疗后的病人难以大量扩增这类细 胞。免疫细胞疗法是向肿瘤患者输入具有抗肿瘤活性的免疫细胞，直接杀伤肿瘤或激发机体抗肿瘤免疫反应，从而达到治疗效果的生物疗法。其操作包括细胞在体外的传代、扩增、修饰、筛选及经药物或其他能改变细胞生物学行为的处理；经体外操作后的体细胞可用于肿瘤治疗，也可用于肿瘤预防。体细胞免疫治疗已成为肿瘤患者放、化疗后辅助治疗的重要手段之一，其对于促进患者免疫系统的重建、消除残留病灶及骨髓净化都具有良好效果。但是，免疫细胞疗法目前处于初级阶段，主要用于辅助治疗，而患者反应不一，部分病人对此疗法不敏感。
上述抗肿瘤药物和治疗技术虽然具有一定疗效，但是存在费用昂贵、抗肿瘤谱狭窄、副作用大等问题。因此，促使各国科技人员继续寻找其它抗肿瘤药物，其中，治疗男性勃起功能障碍药物西地那非被用于联合其它抗肿瘤药物使用，具有明显疗效。
例如，西地那非(腹腔注射)联合阿霉素(Doxorubicin)可以显著抑制前列腺癌移植瘤在裸鼠的生长(PNAS杂志2010年107卷18202页)，西地那非(口饲)联合瑞戈非尼(regorafenib)能显著抑制肝癌移植瘤在裸鼠的生长(J.Cell.Physiol杂志2015年230卷2281页)。这些研究证明，西地那非主要是增加其它抗癌药物对肿瘤的治疗效果。但是，如果单独使用西地那非则其抗肿瘤疗效不明显(正常剂量范围：25-100mg)，与对照组无显著差别(见上述论文)，其原因在于，上述研究没有找到单独使用西地那非治疗肿瘤的有效剂量窗口，所使用西地那非的剂量不是有效的抗肿瘤剂量，以致单独使用西地那非基本上没有抗肿瘤功效。
因此，亟需开发一种有效剂量的西地那非作为抗肿瘤药物的应用。
发明内容
针对目前国内外抗肿瘤药物大多存在疗效较低和毒副作用较大等问题，特别是单独使用正常剂量西地那非抗肿瘤疗效不明显的问题，本发明提供一种低剂量西地那非作为抗肿瘤药物的应用技术，对肿瘤治疗具有很好的疗效，但无明显的毒副作用，在肿瘤治疗技术上具有显著的先进性。
本发明为实现上述目的，采取以下技术方案予以实现：
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，所述西地那非的使用剂量为2～25mg。
优选地，所述西地那非的使用方式包括内服、注射和外用。
优选地，所述西地那非为口服液、散剂、片剂、胶囊、针剂或软膏。
优选地，所述西地那非的内服剂量为2～25mg。
优选地，所述西地那非的注射剂量为2～10mg。
优选地，所述西地那非的外用剂量：西地那非的质量百分比含量低于1％。应当注意的是，该外用剂量是基于西地那非的总用量在2～25mg之间的基础之上的。
优选地，所述西地那非制成软膏的外用配方如下：包括质量百分比为0.01～1％的西地那非和质量百分比为99～99.99％的脂溶性介质凡士林。
以每天口服剂量2～25mg，或注射剂量2～10mg，或外用剂量质量百分比含量低于1％的西地那非枸橼酸盐，应用于恶性肿瘤的治疗，其抑制肿瘤生长的效率达到50％以上，同时不产生显著的毒副作用，达到有效控制肿瘤生长和促进肿瘤好转的功效。
在本发明的小鼠移植瘤试验中，以西地那非枸橼酸盐溶液(溶于25％乙醇中)灌胃10mg/Kg/天，连续用药36天，肿瘤的生长抑制率达到68％，而小鼠在实验期间无显著或可观察到的毒副作用反应。但是，当剂量为50mg/Kg/天时，西地那非枸橼酸盐对小鼠移植瘤的生长则无明显的抑制作用。
西地那非的抗肿瘤作用具有一个最佳剂量窗口，位于2-25mg之间，在此低剂量范围内西地那非具有抗肿瘤高效性和安全性：对肿瘤患者造成的副作用最小，但抗肿瘤效果最佳。低于或高于这个剂量范围(2-25mg)都将显著减弱其抗肿瘤功效。由于这个剂量范围显著小于西地那非治疗男性阴茎勃起功能障碍的正常用量，故称为“低剂量”西地那非。较正常剂量(25-100mg)而言，低剂量西地那非既能大大提高了西地那非抗肿瘤疗效，又可避免西地那非对肿瘤患者产生的副作用。
因患者的年龄、体重及身体状况不同，个体抗肿瘤最佳用量将在此范围内变化。例如，一般成人肿瘤患者(体重60kg左右)，西地那非的最佳口服剂量为10mg。
低剂量西地那非抗肿瘤的机制目前尚不很清楚。实验证明，高浓度西地那非(200μM)对培养的肿瘤细胞生长具有直接的抑制作用，其机制可能是通过抑制肿瘤细胞的周期蛋白(cyclin)和细胞周期依赖性蛋白激酶(CDK)，导致肿瘤细胞停滞在G1期而停止生长。此外，高浓度西地那非(300μM)也可引起活性氧(ROS)在培养的肿瘤细胞内增加，从而导致肿瘤细胞凋亡。但是，正常人口服100mg西地那非枸橼酸盐片剂后，其血液中西地那非枸橼酸盐的最高浓度为440ng/mL，或相当于0.66μM，此浓度西地那非大大低于上述抗肿瘤机制的浓度要求，因此，低剂量西地那非抗肿瘤功效不属于上述的治疗机制。
还有研究实验证明，较低浓度(2μM)西地那非可以刺激人肝癌细胞(HEPG2)内的核因子抑制蛋白IkB nitro-tyrosine和凋亡基因配体Fas-L的表达增加，从而促进肿瘤细胞凋 亡。如果考虑到成人口服低剂量(2-10mg)西地那非后其血液中的药物浓度可能低于0.1μM，则低剂量西地那非的抗肿瘤活性可能不是通过上述的直接抑制肿瘤细胞生长或促进细胞凋亡的机制。因此，低剂量西地那非抗肿瘤功效可能不是通过药物直接作用于肿瘤细胞的机制。
在小鼠移植瘤试验中证明，低剂量西地那非的抗肿瘤功效可被抗过敏药物马来酸氯苯那敏(Chlorphenamine Maleate)抵消。当荷瘤小鼠分别用10mg/Kg和20mg/Kg剂量西地那非枸橼酸盐灌胃(每天1次)2周后，肿瘤的抑制率分别是63％和50％，但如果加2mg/Kg剂量马来酸氯苯那敏联合灌胃，肿瘤抑制率分别降为16％和7％，说明马来酸氯苯那敏可以直接对抗低剂量西地那非的抗肿瘤活性。因此，低剂量西地那非在体内的抗肿瘤作用不是通过药物直接作用于肿瘤细胞，而是涉及体内免疫系统的调节，通过调节体内免疫细胞的免疫作用达到抗肿瘤功效，因为体内的免疫细胞如淋巴细胞、粒细胞、单个核细胞均有H1受体，马来酸氯苯那敏通过对免疫细胞的H1受体拮抗而抵消低剂量西地那非的抗肿瘤功效。
与现有技术相比，本发明的有益效果如下：
本发明以每天口服剂量2～25mg，或注射剂量2～10m，或外用剂量质量百分比含量低于1％的西地那非枸橼酸盐，应用于恶性肿瘤的治疗，其抑制肿瘤生长的效率达到50％以上，同时不产生显著的毒副作用，达到有效控制肿瘤生长和促进肿瘤好转的功效。
附图说明
图1是本发明西地那非的分子结构示意图；
图2是本发明西地那非抗肿瘤剂量窗口的示意图；
图3是不同剂量西地那非灌胃对小鼠移植瘤的抑制效果的示意图；
图4是马来酸氯苯那敏对西地那非抗肿瘤活性的拮抗作用的示意图。
具体实施方式
下面结合实施例对本发明作进一步的描述，但需要说明的是，实施例并不对本发明要求保护范围的构成限制。
实施例1
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量10mg，通过常规工艺制成糖衣片，服用而达到抗肿瘤的作用。
实施例2
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量20mg，常规工艺制成糖衣片，服用而达到抗肿瘤的作用。
实施例3
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量5mg，常规工艺制成糖衣片，服用而达到抗肿瘤的作用。
实施例4
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量10mg，常规工艺制成散剂，服用而达到抗肿瘤的作用。
实施例5
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量5mg，常规工艺制成散剂，服用而达到抗肿瘤的作用。
实施例6
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量2mg，常规工艺制成散剂，服用而达到抗肿瘤的作用。
实施例7
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量10mg，常规工艺制成胶囊，服用而达到抗肿瘤的作用。
实施例8
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量20mg，常规工艺制成胶囊，服用而达到抗肿瘤的作用。
实施例9
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量5mg，常规工艺制成胶囊，服用而达到抗肿瘤的作用。
实施例10
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基 -3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量10mg，常规工艺制成口服液，服用而达到抗肿瘤的作用。
实施例11
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量20mg，常规工艺制成口服液，服用而达到抗肿瘤的作用。
实施例12
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量5mg，常规工艺制成口服液，服用而达到抗肿瘤的作用。
实施例13
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的内服剂量为2～25mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
内服药时,西地那非枸橼酸盐含有效药量2mg，常规工艺制成口服液，服用而达到抗肿瘤的作用。
实施例14
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的注射剂量为2～10mg，图2是西地那非作 为抗肿瘤剂量窗口的示意图，单位为mg。
注射用药时,西地那非枸橼酸盐含有效药量10mg，常规工艺制成注射液，皮下注射而达到抗肿瘤的作用。
实施例15
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的注射剂量为2～10mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
注射用药时,西地那非枸橼酸盐含有效药量5mg，常规工艺制成注射液，皮下注射而达到抗肿瘤的作用。
实施例16
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的注射剂量为2～10mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
注射用药时,西地那非枸橼酸盐含有效药量2mg，常规工艺制成注射液，皮下注射而达到抗肿瘤的作用。
实施例17
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的注射剂量为2～10mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
注射用药时,西地那非枸橼酸盐含有效药量5mg，常规工艺制成注射液，静脉注射而达到抗肿瘤的作用。
实施例18
一种低剂量西地那非作为抗肿瘤药物的应用，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，其分子结构如图1所示。所述西地那非的注射剂量为2～10mg，图2是西地那非作为抗肿瘤剂量窗口的示意图，单位为mg。
注射用药时,西地那非枸橼酸盐含有效药量2mg，常规工艺制成注射液，静脉注射而 达到抗肿瘤的作用。
实施例19
外用药时，西地那非枸橼酸盐含有效药量1％，脂溶性介质凡士林99％，常规工艺制成软膏，外用而达到抗肿瘤的作用。
实施例20
外用药时，西地那非枸橼酸盐含有效药量0.1％，脂溶性介质凡士林99.9％，常规工艺制成软膏，外用而达到抗肿瘤的作用。
实施例21
外用药时，西地那非枸橼酸盐含有效药量0.01％，脂溶性介质凡士林99.99％，常规工艺制成软膏，外用而达到抗肿瘤的作用。
本发明实施例1-21，以每天口服剂量2～25mg，或注射剂量2～10mg，或外用剂量质量百分比含量低于1％的西地那非枸橼酸盐，应用于恶性肿瘤的治疗，其抑制肿瘤生长的效率达到50％以上，同时不产生显著的毒副作用，达到有效控制肿瘤生长和促进肿瘤好转的功效。
应当注意的是，上述外用剂量是基于西地那非的总用量在2～25mg之间的基础之上的。
在小鼠移植瘤试验中，以西地那非枸橼酸盐溶液(溶于25％乙醇中)灌胃10mg/Kg/天，连续用药36天，肿瘤的生长抑制率达到68％，而小鼠在实验期间无显著或可观察到的毒副作用反应。但是，当剂量为50mg/Kg/天时，西地那非枸橼酸盐对小鼠移植瘤的生长则无明显的抑制作用，如图3所示。
西地那非的抗肿瘤作用具有一个最佳剂量窗口，位于2-25mg之间，在此低剂量范围内西地那非具有抗肿瘤高效性和安全性：对肿瘤患者造成的副作用最小，但抗肿瘤效果最佳。低于或高于这个剂量范围(2-25mg)都将显著减弱其抗肿瘤功效。由于这个剂量范围显著小于西地那非治疗男性阴茎勃起功能障碍的正常用量，故称为“低剂量”西地那非。较正常剂量(25-100mg)而言，低剂量西地那非既能大大提高了西地那非抗肿瘤疗效，又可避免西地那非对肿瘤患者产生的副作用。
因患者的年龄、体重及身体状况不同，个体抗肿瘤最佳用量将在此范围内变化。例如，一般成人肿瘤患者(体重60kg左右)，西地那非的最佳口服剂量为10mg。
低剂量西地那非抗肿瘤的机制目前尚不很清楚。实验证明，高浓度西地那非(200μM)对培养的肿瘤细胞生长具有直接的抑制作用，其机制可能是通过抑制肿瘤细胞的周期蛋白(cyclin)和细胞周期依赖性蛋白激酶(CDK)，导致肿瘤细胞停滞在G1期而停止生长。此外， 高浓度西地那非(300μM)也可引起活性氧(ROS)在培养的肿瘤细胞内增加，从而导致肿瘤细胞凋亡。但是，正常人口服100mg西地那非枸橼酸盐片剂后，其血液中西地那非枸橼酸盐的最高浓度为440ng/mL，或相当于0.66μM，此浓度西地那非大大低于上述抗肿瘤机制的浓度要求，因此，低剂量西地那非抗肿瘤功效不属于上述的治疗机制。
还有研究实验证明，较低浓度(2μM)西地那非可以刺激人肝癌细胞(HEPG2)内的核因子抑制蛋白IkB nitro-tyrosine和凋亡基因配体Fas-L的表达增加，从而促进肿瘤细胞凋亡。如果考虑到成人口服低剂量(2-10mg)西地那非后其血液中的药物浓度可能低于0.1μM，则低剂量西地那非的抗肿瘤活性可能不是通过上述的直接抑制肿瘤细胞生长或促进细胞凋亡的机制。因此，低剂量西地那非抗肿瘤功效可能不是通过药物直接作用于肿瘤细胞的机制。
图4是马来酸氯苯那敏对西地那非抗肿瘤活性的拮抗作用的示意图，具体是小鼠移植瘤经二周不同剂量西地那非或与马来酸氯苯那敏2mg/Kg联合治疗后对小鼠肿瘤的抑制效果。其中，CHM为马来酸氯苯那敏。
在小鼠移植瘤试验中证明，低剂量西地那非的抗肿瘤功效可被抗过敏药物马来酸氯苯那敏(Chlorphenamine Maleate)抵消。当荷瘤小鼠分别用10mg/Kg和20mg/Kg剂量西地那非枸橼酸盐灌胃(每天1次)2周后，肿瘤的抑制率分别是63％和50％，但如果加2mg/Kg剂量马来酸氯苯那敏联合灌胃，肿瘤抑制率分别降为16％和7％，如图4所示，说明马来酸氯苯那敏可以直接对抗低剂量西地那非的抗肿瘤活性。因此，低剂量西地那非在体内的抗肿瘤作用不是通过药物直接作用于肿瘤细胞，而是涉及体内免疫系统的调节，通过调节体内免疫细胞的免疫作用达到抗肿瘤功效，因为体内的免疫细胞如淋巴细胞、粒细胞、单个核细胞均有H1受体，马来酸氯苯那敏通过对免疫细胞的H1受体拮抗而抵消低剂量西地那非的抗肿瘤功效。
以上对本发明实施例所提供的技术方案进行了详细介绍，本文中应用了具体个例对本发明实施例的原理以及实施方式进行了阐述，以上实施例的说明只适用于帮助理解本发明实施例的原理；同时，对于本领域的一般技术人员，依据本发明实施例，在具体实施方式以及应用范围上均会有改变之处，综上所述，本说明书内容不应理解为对本发明的限制。

Claims (7)

  1. 一种低剂量西地那非作为抗肿瘤药物的应用，其特征在于，所述西地那非的化学名称为1-[4-乙氧基-3-[5-(6，7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4，3d]嘧啶)]苯磺酰]-4-甲基哌嗪枸橼酸盐，所述西地那非的使用剂量为2～25mg。
  2. 根据权利要求1所述的一种低剂量西地那非作为抗肿瘤药物的应用，其特征在于，所述西地那非的使用方式包括内服、注射和外用。
  3. 根据权利要求1所述的一种低剂量西地那非作为抗肿瘤药物的应用，其特征在于，所述西地那非为口服液、散剂、片剂、胶囊、针剂或软膏。
  4. 根据权利要求2所述的一种低剂量西地那非作为抗肿瘤药物的应用，其特征在于，所述西地那非的内服剂量为2～25mg。
  5. 根据权利要求2所述的一种低剂量西地那非作为抗肿瘤药物的应用，其特征在于，所述西地那非的注射剂量为2～10mg。
  6. 根据权利要求2所述的一种低剂量西地那非作为抗肿瘤药物的应用，其特征在于，所述西地那非的外用剂量：西地那非的质量百分比含量低于1％。
  7. 根据权利要求6所述的一种低剂量西地那非作为抗肿瘤药物的应用，其特征在于，所述西地那非制成软膏的外用配方如下：包括质量百分比为0.01～1％的西地那非和质量百分比为99～99.99％的脂溶性介质凡士林。
PCT/CN2016/103957 2016-10-09 2016-10-31 低剂量西地那非作为抗肿瘤药物的应用 WO2018064851A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/759,575 US20190183893A1 (en) 2016-10-09 2016-10-31 Low dose of sildenafil as an antitumor drug

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610884154.0 2016-10-09
CN201610884154.0A CN106389437A (zh) 2016-10-09 2016-10-09 低剂量西地那非作为抗肿瘤药物的应用

Publications (1)

Publication Number Publication Date
WO2018064851A1 true WO2018064851A1 (zh) 2018-04-12

Family

ID=59229120

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/103957 WO2018064851A1 (zh) 2016-10-09 2016-10-31 低剂量西地那非作为抗肿瘤药物的应用

Country Status (3)

Country Link
US (1) US20190183893A1 (zh)
CN (1) CN106389437A (zh)
WO (1) WO2018064851A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107375313A (zh) * 2017-07-14 2017-11-24 广东食品药品职业学院 一种丫蕊花甾体皂苷 yb16和西地那非复方药物组合物及其用途
CN112826936A (zh) * 2021-01-21 2021-05-25 四川省肿瘤医院 一种肿瘤抑制剂、其制备方法及应用
CN113082210B (zh) * 2021-03-09 2023-04-18 广州白云山医药集团股份有限公司白云山制药总厂 一种肿瘤化疗药物组合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101342175A (zh) * 2007-07-13 2009-01-14 王钢胜 西地那非在制备抗肿瘤药物中的应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101342175A (zh) * 2007-07-13 2009-01-14 王钢胜 西地那非在制备抗肿瘤药物中的应用

Also Published As

Publication number Publication date
CN106389437A (zh) 2017-02-15
US20190183893A1 (en) 2019-06-20

Similar Documents

Publication Publication Date Title
EP2605764B1 (en) Compositions for the treatment of cancer
US20180071339A1 (en) Combination of pharmaceutical preparations for tumor chemotherapy
JP2020512977A (ja) Ｃｈｋ１阻害剤とｗｅｅ１阻害剤との組み合わせ
EP3027191A1 (en) Combinations of a btk inhibitor and fluorouracil for treating cancers
JP2023542093A (ja) 抗腫瘍治療におけるチアウラニブと免疫チェックポイント阻害剤との組み合わせの使用
WO2018064851A1 (zh) 低剂量西地那非作为抗肿瘤药物的应用
SG187828A1 (en) Novel combination therapy for the treatment of cancer
Liu et al. Transcriptional cyclin-dependent kinases: Potential drug targets in cancer therapy
Jiang et al. Arsenic trioxide cooperate cryptotanshinone exerts antitumor effect by medicating macrophage polarization through glycolysis
JP6462147B2 (ja) Ｈｓｐ９０阻害ペプチド結合体及びその腫瘍治療における応用
Zhang et al. Advances in CD73 inhibitors for immunotherapy: antibodies, synthetic small molecule compounds, and natural compounds
WO2020000704A1 (zh) AMPK抑制剂Compound C在治疗肿瘤药物中的应用
JP2023030112A (ja) 肥満細胞疾患の処置のための方法及び医薬組成物
CN106928229A (zh) 色胺酮及其衍生物在制备hIDO2抑制剂中的用途
US20220323470A1 (en) Composition and use thereof in the manufacture of medicament for treating cancer
US20220313652A1 (en) Use of compound or pharmaceutically acceptable salt, dimer or trimer thereof in manufacture of medicament for treating cancer
CN111053780A (zh) 奥西替尼的药物组合物及其应用
CN105283180A (zh) Pi3k抑制剂与微管去稳定剂的药物组合
CN111803489B (zh) 含笑内酯及其衍生物在垂体腺瘤治疗中的应用
CN105434432B (zh) N-羟基邻苯二甲酰亚胺类化合物在制备抗肿瘤药物中的应用
EP3949970A1 (en) Combined use of a-nor-5? androstane compound drug and anticancer drug
Xu et al. Selenium promotes immunogenic radiotherapy against cervical cancer metastasis through evoking P53 activation
CN105343095A (zh) 瑞格替尼和拉帕替尼在制备抗肿瘤联合用药物中的应用
Zhang et al. CAFs-Promoted LncRNA DNM3OS Conferred Radioresistance by Regulating DNA Damage Response in a TNFSF4-Dependent Manner in Esophageal Squamous Cell Carcinoma
CN106333951A (zh) 一种mTOR激酶抑制剂与MAPK激酶抑制剂的组合物的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16918184

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 19/08/2019)

122 Ep: pct application non-entry in european phase

Ref document number: 16918184

Country of ref document: EP

Kind code of ref document: A1