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Application of tetrahydropalmatine in preparation of medicine for resisting cisplatin toxicity

A technology of tetrahydropalmatine and drugs, which is applied in antidote, drug delivery, drug combination, etc., can solve the problems of enhanced nephrotoxicity and low effect of cisplatin, and achieve the effect of reducing nephrotoxicity and weakening toxicity

Active Publication Date: 2017-04-05
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, cimetidine competitively inhibits MATEs more than OCT2, but enhances cisplatin nephrotoxicity
For cisplatin ototoxicity or neurotoxicity, anti-oxidation and free radical scavenging methods are commonly used in clinic to antagonize, but the effect is very little

Method used

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  • Application of tetrahydropalmatine in preparation of medicine for resisting cisplatin toxicity
  • Application of tetrahydropalmatine in preparation of medicine for resisting cisplatin toxicity
  • Application of tetrahydropalmatine in preparation of medicine for resisting cisplatin toxicity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Cisplatin in MDCK-hOCT2 ， MDCK-hOCT2 / hMATE1 and mock Concentration-dependent toxicity on cells

[0025] 1.1 Seeding cells on a 96-well plate

[0026] Select MDCK-hOCT2, MDCK-hOCT2 / hMATE1 and mock cells in the logarithmic growth phase (constructed by Zhejiang University School of Pharmacy, see a: Lei Hongmei et al. for specific construction methods, stably express hMATE1 and co-express hMATE1 and hOCT1 or hOCT2 cells Model construction. Acta Pharmaceutica Sinica, 2015, 50(7): 842-847. b: Wang K., et al., Involvement of organic cation transporter 2 inhibition in potential mechanisms of antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry , 2014,53: 90-98), digest and collect cells. Resuspend the cells with fresh medium and adjust the cell density to 4.0 × 10 4 cells / mL, inoculated in 96-well cell plate at 0.2 mL / well.

[0027] 1.2 MTT experiment

[0028] After the cells were cultured for 24 h, the medium was discarded, and the me...

Embodiment 2

[0031] Example 2 Tetrahydropalmatine, including (-)-THP ， (+)-THP and ( ± )-THP right MPP + exist MDCK-hOCT2 and MDCK-hMATE1 Inhibition of accumulation on cells

[0032] Select MDCK-hOCT2, MDCK-hOCT2 / hMATE1 and MDCK-hMATE1 cells in the logarithmic growth phase (constructed by Zhejiang University School of Pharmacy, see a: Lei Hongmei et al. for specific construction methods, stably express hMATE1 and co-express hMATE1 and hOCT1 or Construction of hOCT2 cell model. Acta Pharmaceutica Sinica, 2015,50(7):842-847.b:Wang K., et al., Involvement of organic cation transporter 2 inhibition in potential mechanisms of antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry , 2014,53: 90-98), digest and collect cells. Resuspend the cells with fresh medium and adjust the cell density to 2.0 × 10 5 Cells / mL, inoculated at 0.5 mL / well in a 24-well cell plate for culture, when the cells grow to 90% confluence, they can be used for accumulation experi...

Embodiment 3

[0034] Example 3(-)-THP, (+)-THP and ( ± )-THP For cisplatin in MDCK-hOCT2 and MDCK-hOCT2 / hMATE1 Toxic effects on cells

[0035] 3.1 MTT experiment

[0036] Select MDCK-hOCT2 and MDCK-hOCT2 / hMATE1 in the logarithmic growth phase (constructed by the School of Pharmacy, Zhejiang University, see a: Lei Hongmei et al., construction of cell models that stably express hMATE1 and co-express hMATE1 with hOCT1 or hOCT2 .Acta Pharmaceutica Sinica, 2015,50(7):842-847.b:Wang K., et al., Involvement of organic cation transporter 2 inhibition in potential mechanisms of antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry , 2014,53: 90-98), digest and collect cells. Resuspend the cells with fresh medium and adjust the cell density to 4.0 × 10 4 mL -1, inoculated in 96-well cell plate at 0.2 mL / well. After the cells were cultured for 24 h, the medium was discarded, and a cisplatin medium solution containing 1-100 μmol / L (-)-THP, (+)-THP and (±)-THP was add...

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Abstract

The invention provides an application of tetrahydropalmatine in preparation of medicine for resisting cisplatin toxicity. The toxicity comprises kidney toxicity, ototoxicity and neurotoxicity. The research shows that tetrahydropalmatine has inhibition effect for OCT2 and MATE1, can antagonize the cytotoxicity caused by cisplatin, and obtains good verification for primary culture of a renal tubular epithelial cell model. By taking (-)-THP as a representative, the research finds that tetrahydropalmatine has good protection effect for mice kidney damage caused by cisplatin, so that tetrahydropalmatine and cisplatin are combined, accumulation of cisplatin at kidney, cochlear cells and dorsal root ganglion is reduced, so that the expection result for preventing or reducing cisplatin toxicity can be achieved. The application develops the novel purpose of the tetrahydropalmatine, because that OCT2 is highly expressed by kidney, cochlear cells and dorsal root ganglion, expression of OCT2 is lacked on tumor cells, cisplatin has certain passive permeability, so that tetrahydropalmatine and cisplatin are combined, toxicity due to cisplatin is decreased, and cisplatin antineoplastic effect is not reduced.

Description

technical field [0001] The invention belongs to the use of medicine, and relates to the application of tetrahydropalmatine in reducing the toxicity caused by cisplatin, including nephrotoxicity, ototoxicity and neurotoxicity. [0002] technical background [0003] Cisplatin is one of the most clinically effective broad-spectrum antineoplastic drugs and is widely used in the treatment of various solid tumors such as ovarian cancer, prostate cancer, lung cancer, and breast cancer. However, its severe side effects include nephrotoxicity, ear Toxicity and neurotoxicity limit its clinical application, especially nephrotoxicity and ototoxicity are the most serious. Although protective measures such as hydration therapy or forced diuresis are used clinically, the incidence of nephrotoxicity of cisplatin is still as high as 25-35%, and it occurs immediately in the initial stage of treatment. Through mechanisms such as oxidative stress, DNA damage, and inflammatory response, cisplati...

Claims

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Application Information

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IPC IPC(8): A61K31/4375A61P39/02
CPCA61K9/00A61K31/4375
Inventor 李丽萍蒋惠娣周慧曾苏
Owner ZHEJIANG UNIV
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