CN103285003A - Use of isoprenaline hydrochloride in reduction of liver toxicity caused by sprycel - Google Patents

Abstract

The invention provides an application of an isoprenaline hydrochloride and sprycel composition in preparation of a sprycel liver toxicity treatment drug, wherein an amount ratio of the isoprenaline hydrochloride to the sprycel in the composition is 1:6.25*10<6>, and the application is that 8 ng/kg of the isoprenaline hydrochloride and 50 mg/kg of the sprycel are applied per day. According to the present invention, a p38 specific agonist isoprenaline is adopted to up-regulate a p38 expression level and induce liver cell autophagy generation so as to achieve a purpose of liver protection. With the present invention, theoretical basis is provided for prevention and treatment of tinib drug liver toxicity, and high clinical practicality is provided.

Description

The purposes of hepatotoxicity due to the isoprenaline reduction Dasatinib

Technical field

The invention belongs to medicinal usage, relate to the application of a kind of isoprenaline in preparation treatment Dasatinib hepatotoxicity medicine.

Background technology

Dasatinib (trade name Sprycel) is a kind of novel many target spots of the micromolecule tyrosine kinase inhibitor (TKI) by the research and development of U.S. Bristol-Myers Squibb company, and is inhibited to the tyrosine kinase (RTK) of multiple receptor.Dasatinib is mainly used in chronic myelogenous leukemia (CML) patient that the Imatinib treatment is failed or do not tolerated clinically at present, the acute lymphoblastic leukemia adult patient of the Philadelphia chromosome positive that also is used for other therapy drug resistances simultaneously or does not tolerate, its curative effect surpasses the effect of using high dose Imatinib treatment, and do not find its drug resistance, so has important clinical application value.General meaning, tyrosine kinase inhibitor for patient's toxic and side effects less than conventional cell poison class medicine, yet Dasatinib its hepatotoxicity after listing is reported successively.

Dasatinib can significantly be induced liver cell generation autophagy when causing hepatotoxicity, and this autophagy is the protectiveness autophagy, and p38 has brought into play the important regulating and controlling effect in autophagy simultaneously.If can optionally adopt the p38 agonist clinically, improve the autophagy of liver cell, can weaken the hepatotoxicity that Dasatinib causes to a certain extent.

Summary of the invention

The invention provides the purposes that isoprenaline reduces hepatotoxicity due to the Dasatinib, be the application of a kind of isoprenaline in preparation treatment Dasatinib hepatotoxicity medicine, isoprenaline chemical name 4-[(2-isopropylamino-1-hydroxyl) ethyl]-1,2-Benzodiazepines hydrochlorate, molecular weight 247.72, molecular formula C11H17NO3HCl, Dasatinib chemical name N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-ethoxy)-1-piperazinyl]-2-methyl-4-pyrimidine radicals] amino]-5-thiazole carboxamides (a water thing), molecular weight 506.02, molecular formula C22H26ClN7O2S.H2O, isoprenaline on the external hepatocyte model in the described medicine: Dasatinib dosage ratio is 1: 1250, be isoprenaline 10 nM: Dasatinib 12.5 mM, combined effect 24 hours.Isoprenaline on the interior ICR mouse model of body in the described medicine: Dasatinib dosage is than being 1:6.25 * 10 ⁶, namely give isoprenaline 8 ng/kg/ days and Dasatinib 50 mg/kg/ days every day, combined effect 30 days.

The mechanism of action that the invention provides the hepatotoxicity that isoprenaline protection Dasatinib causes is: the exciting p38 of isoprenaline; increase the p38 activity; increase the generation of cytoprotective autophagy; can alleviate the hepatotoxicity that Dasatinib causes, thereby reach the hepatotoxic effect that protection dasatininb causes.

Isoprenaline or the pharmaceutical composition that contains isoprenaline can pass through the different way of administration administration, comprise intestinal or non-intestinal, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.

Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloid solution), Emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, injectable powder and transfusion), eye drop, nasal drop, lotion and liniment etc.; Solid dosage forms can make tablet (comprising ordinary tablet, enteric coatel tablets, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, oral cavity disintegration tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, drop pill, suppository, membrane, paster, the agent of gas (powder) mist, spray etc.; Semisolid dosage form can be ointment, gel, paste etc.

Isoprenaline can be made ordinary preparation, also can be made into slow releasing preparation, controlled release preparation, targeting preparation and various particulate delivery system.

For isoprenaline is made tablet, can be extensive use of art-recognized various excipient, comprise diluent, adhesive, wetting agent, disintegrating agent, lubricant, fluidizer.Diluent can make starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline Cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, isopropyl alcohol etc.; Adhesive can make starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, Polyethylene Glycol etc.; Disintegrating agent can be dried starch, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate etc.; Lubricant and fluidizer can be Pulvis Talci, silicon dioxide, stearate, tartaric acid, liquid paraffin, Polyethylene Glycol etc.

Tablet further can also be made coated tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or two in flakes and multilayer tablet.

For isoprenaline is made capsule, can say that effective ingredient mixes with diluent, fluidizer, directly places hard capsule or soft capsule with mixture.Also isoprenaline granule or micropill be can be made with diluent, adhesive, disintegrating agent earlier, hard capsule or soft capsule placed again.The capsule that also can be used for preparing isoprenaline for the preparation of various diluent, adhesive, wetting agent, disintegrating agent, the fluidizer kind of isoprenaline tablet.

For isoprenaline is made injection, can water, ethanol, isopropyl alcohol, propylene glycol or their mixture as solvent and add the solubilizing agent commonly used of an amount of this area, cosolvent, PH and adjust agent, osmotic pressure regulator.Solubilizing agent or cosolvent can be poloxamer, lecithin, HP-etc.; PH adjustment agent can make phosphate, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can make sodium chloride, mannitol, glucose, phosphate, acetate etc.As prepare lyophilized injectable powder, also can add mannitol, glucose etc. as proppant.

In addition if needed, also can in pharmaceutical preparation, add coloring agent, antiseptic, spice, correctives or other additives.

The present invention selects the specific agonist isoproterenol of p38 for use, raises the expression of p38, induces the generation of liver cell autophagy, thereby realizes liver-protective purpose.The present invention reaches the purpose of the protection Dasatinib hepatotoxicity of inducing by isoprenaline and Dasatinib use in conjunction.On cellular level, isoprenaline can significantly reverse the liver cell death of being induced by Dasatinib.On the animal level, isoprenaline can significantly reverse the mouse liver necrosis of being induced by Dasatinib.The mechanism of action of the hepatotoxicity that isoprenaline protection Dasatinib causes is: the exciting p38 of isoprenaline, increase the p38 activity, and increase the generation of cytoprotective autophagy, thereby reach the hepatotoxic effect that the protection Dasatinib causes.

Do not report the medicine with the caused hepatotoxicity of protection Dasatinib at present as yet.Seeking hepatoprotective at the mechanism of Dasatinib hepatotoxicity is to prevent and treat one of approach for Buddhist nun's class medicine hepatotoxicity.Therefore isoprenaline is protected the effect of the hepatotoxicity of Dasatinib by rise p38; not only illustrate isoprenaline and can be used as the protectant function of Dasatinib hepatotoxicity; and the convenient drug administration of isoprenaline own; moderate cost has very high Clinical feasibility.

Description of drawings

Fig. 1 is the hepatotoxicity of the external protection Dasatinib of isoprenaline.

Fig. 2 is that the hepatotoxicity blood parameters of isoprenaline endogenous protective Dasatinib changes.

Fig. 3 is the hepatotoxicity ICR mice body weight change of isoprenaline endogenous protective Dasatinib.

Fig. 4 is that the hepatotoxicity hepatic tissue section dyeing of isoprenaline endogenous protective Dasatinib changes.

Fig. 5 is that isoprenaline associating Dasatinib is to the influence of inside and outside liver cell apoptosis and autophagy associated protein.

The specific embodiment

The present invention is further described in conjunction with the accompanying drawings and embodiments.

Embodiment 1:

In extracorporeal experiment system, liver cell (L02 and chang liver) is inoculated in 96 orifice plates, every hole cumulative volume 200 ml, the blank group is set, Dasatinib 12.5 mM group (namely in the volume of 200 ml, adding Dasatinib 2.5 nmol), isoprenaline 10 nM group (namely in the volume of 200 ml, adding isoprenaline 2 pmol) and Dasatinib 12.5 mM+ isoprenalines 10 nM group.Dasatinib 12.5 mM effect liver cells are after 24 hours; obvious apoptosis all appears in L02 and Chang liver; apoptosis rate surpasses 50%; and work as and 10 nM isoprenaline synergy 24 hours; the LO2 that Dasatinib causes and Chang liver apoptosis rate significantly reduce, and isoprenaline shows the effect (referring to Fig. 1) of obvious in-vitro the liver protecting cell.

Embodiment 2:

The ICR mice is divided into four groups at random, matched group, and isoproterenol 8 ng/kg group, Dasatinib 50 mg/kg group, isoprenaline and Dasatinib are united group.The ICR mice is given Dasatinib and passes through lumbar injection isoprenaline, successive administration 10 days by irritating stomach respectively.Weigh in every day, measures first day and administration serum liver last day enzyme ALT, AST, and the LDH activity, after the last administration 24 hours, put to death animal, separate liver 10% formaldehyde fixed, carry out histopathological examination (referring to Fig. 2,3,4).Result of study shows, compares with the isoprenaline group with matched group, and isoprenaline can raise the weight of animals reduction that Dasatinib causes.Tangible liver both central necrotic appears in the mice that Dasatinib is handled, and the mice that diffusivity ballooning degeneration and inflammatory cell, isoprenaline were handled then has significant improvement.In addition, isoprenaline can significantly reduce the Serum ALT that Dasatinib causes, AST, and LDH raises.These results show, the hepar damnification that isoprenaline can protect Dasatinib to induce in animal body.

Embodiment 3:

In vivo with in vitro tests in, use the western-blot method to detect apoptosis, autophagy associated protein, find the crack fragment expression that all can raise caspase3 and PARP in vivo and in vitro of Dasatinib list, cause apoptotic generation (referring to Fig. 5, A and B: apoptosis and autophagy associated protein on the external hepatocyte model; Apoptosis and autophagy associated protein on the C:ICR mouse liver).Isoprenaline unite the activity that use then can activate p38, stimulate the generation of inducing autophagy, thereby reduce the expression of the crack fragment of caspase3 and PARP, reach the purpose that reduces the liver cell apoptosis.The mechanism that can draw the hepatotoxicity that isoprenaline protection Dasatinib induces from the result of the test of inside and outside is: the exciting p38 of isoprenaline; increase the p38 activity; increase the generation of cytoprotective autophagy; reduce the level of apoptosis of liver cell, thereby reach the hepatotoxic effect that protection dasatininb causes.

Claims (3)

1. an isoprenaline and the Dasatinib compositions application in preparation treatment Dasatinib hepatotoxicity medicine, isoprenaline chemical name 4-[(2-isopropylamino-1-hydroxyl) ethyl]-1,2-Benzodiazepines hydrochlorate, Dasatinib chemical name N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-ethoxy)-1-piperazinyl]-2-methyl-4-pyrimidine radicals] amino]-the 5-thiazole carboxamides, it is characterized in that described compositions is by isoprenaline: Dasatinib is according to dosage than being 1:6.25 * 10 ⁶Combination, described application is to give isoprenaline 8 ng/kg/ days and Dasatinib 50 mg/kg/ days every day.

2. a kind of isoprenaline according to claim 1 and the Dasatinib compositions application in preparation treatment Dasatinib hepatotoxicity medicine, it is characterized in that, described compositions is by isoprenaline: Dasatinib is according to dosage than being 1: 1250 combination, i.e. isoprenaline 10 nM: Dasatinib 12.5 mM.

3. a kind of isoprenaline according to claim 1 and the Dasatinib compositions application in preparation treatment Dasatinib hepatotoxicity medicine is characterized in that route of administration is intestinal or non-intestinal.

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