Use of compounds for the prevention of drug-induced cell toxicity

A cytotoxicity, compound technology, applied in the directions of heterocyclic compound active ingredients, drug combinations, antitoxic agents, etc., can solve the problems of reducing cytotoxicity, not disclosed, etc.

Inactive Publication Date: 2006-06-28
RECEPTICON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This document does not disclose cytotoxicity-reducing compounds or drugs that bind to vitamin B12 receptor receptors and / or megalin receptors and / or megalin and vitamin B12 co-receptors

Method used

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  • Use of compounds for the prevention of drug-induced cell toxicity
  • Use of compounds for the prevention of drug-induced cell toxicity
  • Use of compounds for the prevention of drug-induced cell toxicity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0232] The effect of the compound of the invention 2-[4-(2-aminoethyl)piperazin-1-yl]ethylamine (Aldrich, D2, 340-8, lot 06028BO-332) was tested in vivo. The uptake of gentamicin in the kidneys of mice following intraperitoneal (i.p.) administration of the compound was determined.

[0233] For the normal administration of radioactive gentamicin, the following protocol was followed: 50 mg / kg tritiated gentamicin and 3 mg inhibitor or no 3 mg inhibitor were injected intraperitoneally per mouse. This is equivalent to the clinical dose of gentamicin used in 1% of patients.

[0234] To compete for the clinical dose of gentamicin, each mouse was injected with a total of 3 mg of 2-[4-(2-aminoethyl)piperazin-1-yl]ethylamine combined with 50 mg / kg tritiated gentamicin A mixture of gentamycin and 5 mg / kg non-radioactive gentamicin (clinical dose). The control group was given gentamicin only. Compared with the control group, the inhibition rate was 40%.

Embodiment 2

[0236] in vitro test

[0237] Interactions between gentamicin and inhibitors were assessed by proton surface resonance (SPR) analysis on a Biacore 2000 instrument. Megalin receptors were purified from rabbit kidneys and fixed at 28-40 fmol / mm as described by Bim et al. 2 concentration. Sample dissolved in 10mM Hepes, 150mM NaCl, 1.5mM CaCl 2 , 1mMEGTA, 0.005% Tween-20pH 7.4. The same buffer was used as running buffer. After each analysis, regeneration of the sensor chip was performed with 1.6M glycine-HCl buffer pH 3.0. Biacore responses are expressed in relative response units (RU), the difference in response between the protein and the control fluidic channel. Samples contained 2 mM gentamicin and 0-10 mM or 0-20 mM inhibitor. Responses were recorded at the maximum and corrected for the effect of inhibitor responses.

[0238] The test detected 3,5-diamino-1,2,4-triazole, malonamide, piperidine, 2,5-piperazinedione, piperazine, 3-methylamino-1-(4-methyl Inhibitory eff...

Embodiment 3

[0240] By the evaluation method described in Example 2, this test shows the inhibitory effect of diaminoalkanes. The results are shown in Figure 4 middle.

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PUM

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Abstract

The present invention relates to the use of a compound for the preparation of a medicament for the prevention and / or treatment of induced cytotoxicity, such as nephrotoxicity and ototoxicity, in particular said cytotoxicity is induced as a result of drug treatment. In a preferred embodiment, the compound has at least two nitrogen atoms, more preferably at least two amino groups. The compound of the present invention can block the binding of cytotoxic compounds to megalin receptors, thereby inhibiting the uptake of the cytotoxic compounds into cells. The present invention also relates to novel compounds for use in said treatment, as well as methods of reducing the cytotoxicity of cytotoxic compounds, more particularly gentamicin.

Description

field of invention [0001] The present invention relates to the technical field of cytotoxic therapy and discloses compounds and combination medicaments for the above-mentioned therapy. Background of the invention [0002] The present invention relates to compounds for the prevention of organ damage, particularly kidney and inner ear organ damage resulting from the administration of therapeutic agents. [0003] Many drugs in clinical use are toxic to organs such as the kidneys and inner ear. Among the well-known drugs are cisplatin, ifosfamide, cyclosporine, amphotericin B, valproate, polymyxin B and therapeutic antibodies. Of particular importance, however, are the aminoglycosides, which are among the most important antibiotics for the treatment of severe bacterial infections. They are preferred agents against Gram-negative bacteria. At present, the market share of aminoglycosides in the field of anti-infective agents is growing rapidly. Most notably due to the general i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/132A61K31/16A61K31/195A61K31/198A61K31/4192A61K31/4196A61K31/445A61K31/495A61K31/53A61K31/7008A61K45/06A61P39/00
CPCA61K31/132A61K31/16A61K31/195A61K31/198A61K31/4192A61K31/4196A61K31/445A61K31/53A61K31/7008A61K45/06A61P39/00A61P39/02A61P43/00Y02A50/30
Inventor 安德斯·尼克杰尔
Owner RECEPTICON
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