Pharmaceutical composition for the treatment of alpers-huttenlocher syndrome

A technology of syndrome and composition, applied in the direction of drug combination, pharmaceutical formula, active ingredients of anhydride/acid/halide, etc., can solve the problems of high mortality and high mortality

Active Publication Date: 2019-06-21
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Sodium valproate (Sodium Valproate, VPA) is a broad-spectrum anti-epileptic drug, it has a good effect on the treatment of epilepsy, but it induces high mortality when using VPA to treat AHS patients, the study found that patients taking VPA Death rate up to 1 / 3

Method used

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  • Pharmaceutical composition for the treatment of alpers-huttenlocher syndrome
  • Pharmaceutical composition for the treatment of alpers-huttenlocher syndrome
  • Pharmaceutical composition for the treatment of alpers-huttenlocher syndrome

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Experimental program
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Embodiment 1

[0037] In this embodiment, fibroblasts are used to induce pluripotent stem cells, and then differentiate into hepatocytes. The four strains of hepatocytes used are: 2 strains of hepatocytes differentiated from pluripotent stem cells from AHS patients (AHS iPSCs-derived hepatocytes), referred to as AHS hepatocytes, respectively derived from patient 1 and patient 2 (the fibroblasts of patient 1 were derived from Kindly provided by Prof. André Schaller, Department of Human Genetics, University of Bern, Switzerland, and fibroblasts from patient 2 were kindly provided by Prof. Bénédicte Mousson de Camaret, Center for Biosciences, Chulyon, France). The other two strains are control hepatocytes, which are control iPSCs-derived hepatocytes (Control iPSCs-derived hepatocytes) from healthy people, which are derived from fibroblasts of healthy people, (Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences) obtained and stored by the Key Laboratory of Regenerative Bio...

Embodiment 2

[0055]The Ctrl iPSCs-Hep, H1 iPSCs-Hep obtained in Example 1, Patient 1AHSiPSCs-Hep and Patient 2AHS iPSCs-Hep were treated with VPA, and the apoptosis of the cells was detected.

[0056] In this experiment, the differentiated AHS iPSCs-Hep and normal control differentiated hepatoid cells were treated with VPA, and the apoptosis was detected by Annexin V apoptosis kit after treatment for 0 hour, 12 hours and 24 hours respectively. The kit for detecting apoptosis used in this experiment was purchased from Roche Company, the product number is 11858777001. The operation steps are as follows:

[0057] 1. Treat the differentiated hepatocytes with VPA for 0 hour, 12 hours and 24 hours respectively.

[0058] 2. Collect the VPA-treated cells, treat each well with 300 μl of 0.25% trypsin for 20 minutes, stop with 500 μl of serum-containing medium, blow down the cells and transfer them to a 1.5 ml EP tube. Cells were collected by centrifugation at 300 g in a centrifuge for 5 minutes. ...

Embodiment 3

[0063] Calcein release assay (Calcein release assay) method was used to detect the open frequencies of Ctrl, H1 and patient 1 AHS iPSCs-Hep mitochondrial mPTP obtained in Example 1. The principle of this method is to transfect the above-mentioned iPSCs-Hep cells with Calcein, the cells will emit green fluorescence, add CoCl 2 , the intracellular CoCl 2 Will bind to bleached Calcein to make cells lose fluorescence (in extracellular CoCl 2 Does not react with Calcein, Calcein can enter mitochondria without barriers, but CoCl 2 It can only enter the mitochondria through mPTP, so the fluorescence intensity of Calcein in the mitochondria represents the frequency of mPTP opening, the higher the opening frequency of CoCl 2 The more it enters the mitochondria, the more Calcein is combined and bleached, the weaker the fluorescence of the cell, so after CoCl 2 The weaker the fluorescence of the cells after bleaching, the higher the frequency of mPTP opening. Here we treat the cells ...

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Abstract

The invention discloses a pharmaceutical composition for treating Alpers-Huttenlocher syndrome, particularly drugs of the pharmaceutical composition and application of the drugs and pharmaceutical composition. The pharmaceutical composition for treating Alpers-Huttenlocher syndrome comprises sodium valproate and an anti-hepatic injury drug, wherein the anti-hepatic injury drug is selected from at least one of cyclosporin A, L-carnitine and N-acetylcysteine. The pharmaceutical composition can be used for treating Alpers-Huttenlocher syndrome, has favorable treatment effect, and is capable of obviously inhibit hepatocyte apoptosis, obviously relieving acute hepatic failure when the sodium valproate is used for treating patients with Alpers-Huttenlocher syndrome, and lowering the mortality of the patients.

Description

technical field [0001] The present invention relates to the field of biopharmaceuticals, specifically to medicines, pharmaceutical compositions and uses thereof, and more specifically to pharmaceutical compositions for treating Alpers-Huttenlocher syndrome. Background technique [0002] Alpers-Huttenlocher syndrome (Alpers-Huttenlocher syndrome, AHS) often clinically has refractory epilepsy, progressive liver failure and episodic psychomotor hypoxia and other neurological symptoms. The disease occurs in infants, young children, or as late as adolescents, and even at the age of 25 (Simonati A et al., 2003; Hunter MFea al., 2011). Sodium valproate (Sodium Valproate, VPA) is a broad-spectrum antiepileptic drug, which has a good effect on the treatment of epilepsy, but it induces high mortality when using VPA to treat AHS patients. The study found that patients taking VPA The mortality rate is as high as 1 / 3. [0003] Therefore, drugs for the treatment of Alpers-Huttenlocher s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/13A61K31/205A61K31/198A61P25/08A61P1/16A61P25/14A61P25/06A61P9/06A61P25/18A61K31/19
Inventor 刘兴国应仲富李生彪郭璟祎
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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