CN102258520B - Medicinal composition for preventing or treating cystitis caused by chemotherapy - Google Patents
Medicinal composition for preventing or treating cystitis caused by chemotherapy Download PDFInfo
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Abstract
The invention relates to a medicinal composition for preventing or treating cystitis caused by chemotherapy. The medicinal composition consists of mesna, 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid or a 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid derivative and a pharmaceutically acceptable medicinal carrier. The combined medication of the 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid as well as the derivative thereof and the mesna has an unexpected therapeutic effect on preventing or treating the cystitis caused by a chemotherapeutic medicament. The medicinal composition contributes to relieving the pain of a chemotherapy patient; and the tolerance dose of the patient to the chemotherapeutic medicament is improved. Compared with the conventional medicaments such as the mesna and the like, the medicinal composition has the advantages that: the composition of the 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid as well as the derivative thereof and the mesna has a wide therapeutic effect on the cystitis caused by the chemotherapeutic medicament and has a limited prevention effect.
Description
Technical field
The present invention relates to the pharmaceutical composition of the cystitis of a kind of prevention or treatment initiation.
Background technology
Tumor is one of common disease that threatens human health.Research about tumor has obtained bigger progress, developed the method such as various radiotherapies, chemotherapy of multiple treatment tumor, but all there is limitation in various medicine and therapy, are difficult to reach ideal effect, and is prone to drug resistance and side effect.The tumor mortality rate still occupy first of the various diseases.
Data show, China had 3,000,000 people to die from cancer in 2006, and tumor incidence still is in ascendant trend.In less than the time in 20 years, China's tumor incidence has risen 69% according to statistics, and mortality rate has risen 29.4%.Therefore, the new developing effective tumor treating medicaments of research is still the main direction of present oncotherapy.Solid tumor is generally adopted the method for excision, but excision is bigger to patient's damage, and is difficult to guarantee that excision is clean, after tumor tissues occurred soaking into adhesion, obscure boundary excision difficulty was higher, and some cerebral tissue solid tumor excision risk is very high.
Radiotherapy also is one of common method in oncotherapy; But it is comparatively serious to injury of human, often causes patient's system to descend; Prognosis mala; Be difficult to bear the side effect of chemotherapy for the part patient, and radiotherapeutic effect is also unsatisfactory, and cost issues also is one of reason of its application of restriction.Therefore the Drug therapy to tumor is still the method for the most generally using.
Along with a large amount of uses of tumor chemotherapeutic drug, the toxic and side effects of chemotherapeutics becomes one of healthy major reason of harm humans.All there is significant toxic action in known numerous chemotherapeutics with better antitumor action, has significant cardiac toxicity like anthracene ring antitumor medicinal, and toxic mechanism is very complicated; Methotrexate (MTX) often causes hypersensitivity pneumonitis; Heavy dose of prolonged application bleomycin can cause pulmonary fibrosis; Ifosfamide, cyclophosphamide, mitomycin, cantharidin, camptothecine etc. can make slow patient lower abdomen discomfort or a series of non-infectious cystitis symptoms such as distending pain, hematuria occur.
Therefore, before radiotherapy or chemotherapy arrival normal structure, take some drugs, become the supplementary means of oncotherapy with the protection normal structure.It is reported, take nephrotoxicity, hematotoxicity, neurotoxicity, ototoxicity that amifostine (ethyol) can alleviate chemotherapeutics during chemotherapy; ((dexrazozan) can alleviate the cardiac toxicity of anthracene ring antitumor medicinal to take dexrazoxane.
And the bladder toxicity of chemotherapeutics only has mesna (mesna) can prevent and reduce the incidence rate of the cystitis of cyclophosphamide and ifosfamide initiation at present, and being essential will cooperate with measures such as a large amount of transfusions, alkalized urine and diuresis, the competence exertion certain effect.And the cystitis of initiations such as mitomycin, cantharidin, camptothecine is not still had prophylactic agent preferably.Cystitis to chemotherapeutics causes except that the narrow spectrum prophylactic agent of minority, lacks effective broad spectrum prevention medicine or the efficacious therapy medicine is arranged at present, big limitations the using dosage and the long term administration of chemotherapeutics.
1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic; Be commonly called as tetrahydropyrimidine, English ectoine by name, CAS number is 96702-03-3, chemistry 2-Methyl-1 by name; 4,5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4; 5,6-tetra-hydro pyrimidine-4-carboxylic acid or 1,4,5; 6-tetrahydro-2-methyl-4-pyrimidine carbonic acid is the amino acid derivativges of finding in 1985, effect such as have the microbial cell of adjusting osmotic pressure, preserve moisture; Discovered in recent years has certain mitigation to allergic disease like allergic rhinitis etc., maybe be relevant with its moisture-keeping function.In addition 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic has been used to cosmetics, as preserving moisture or suntan lotion.
Summary of the invention
To above-mentioned prior art, the purpose of this invention is to provide the pharmaceutical composition of the cystitis of a kind of prevention or the initiation of treatment chemotherapy.
For realizing above-mentioned purpose, the present invention adopts following technical proposals:
The pharmaceutical composition of the cystitis that a kind of prevention or treatment chemotherapy cause, by mesna and 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic acid derivatives and pharmaceutically acceptable pharmaceutical carrier are formed.
Preferably, said 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic acid derivatives is 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
Preferably, said mesna and 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 1,4,5, the mass ratio of 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic acid derivatives is (3-5): 1.
Said pharmaceutical composition is a tablet; Each component and weight ratio are in the tablet: 1; 4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic: mesna: microcrystalline Cellulose: lactose: carboxymethyl starch sodium: magnesium stearate: polyvinylpyrrolidone is 20: 60: 50: 100: 37.5: 12: 30.
Said pharmaceutical composition is a tablet; Each component and weight ratio are in the tablet: 1; 4; 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic: mesna: microcrystalline Cellulose: carboxymethyl starch sodium: micropowder silica gel: polyvinylpyrrolidone: sodium lauryl sulphate is 10: 40: 10: 12: 20: 30: 5.
Said pharmaceutical composition is an injection, and each components contents is in the injection: in 1000ml, and 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic is 20g, and mesna is 70g, and polyvinylpyrrolidone is 5g, adds the injection water and makes.
The discovery that the inventor is surprised under study for action, 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and derivant thereof and mesna drug combination have unexpected curative effect to the cystitis of prevention or the initiation of treatment chemotherapeutics.Help alleviating the misery of accepting patients undergoing chemotherapy, improve the tolerance dose of patient chemotherapeutics.
Compare with medicine such as existing mesna, of the present invention 1,4,5, the compositions of 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and derivant and mesna has the wide range of therapeutic effect to the cystitis that chemotherapeutics causes, and has limited preventive effect and be not only.
Described in the technical scheme of the present invention 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic is commonly called as tetrahydropyrimidine; English ectoine by name, CAS number is 96702-03-3, chemistry 2-Methyl-1 by name, 4; 5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5; 6-tetra-hydro pyrimidine-4-carboxylic acid or 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid; 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is commonly called as the hydroxy tetrahydro pyrimidine, and this is that those skilled in the art are known.
The specific embodiment
Below in conjunction with embodiment the present invention is done further explanation.Should be understood that following examples only are used to explain the present invention, rather than restriction protection scope of the present invention.
Embodiment 11, and 4,5, the preparation of 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and mesna composition tablet
Fill a prescription as follows:
With 1,4,5 of prescription, 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and mesna are crossed 150 μ m sieve, and it is subsequent use that adjuvant is crossed 180 μ m sieve; Existing 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic mixes with microcrystalline Cellulose, successively mixes with lactose, carboxymethyl starch sodium, polyvinylpyrrolidone, magnesium stearate again with 1,4,5, and tabletting gets final product behind the mix homogeneously.
Embodiment 21, and 4,5, the preparation of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and mesna composition tablet
With 1,4,5 of prescription, it is subsequent use that 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and mesna are crossed 180 μ m sieve; With sieve 1,4,5; Press large stretch of behind 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and microcrystalline Cellulose, carboxymethyl starch sodium and the polyvinylpyrrolidone mixing; With obtaining smaller particles behind large stretch of crushing and pelletizing, add sodium lauryl sulphate and micropowder silica gel, the mixing tabletting gets final product.
Embodiment 31, and 4,5, the preparation of 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and mesna composition injection
With 1,4,5 of recipe quantity, 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic, mesna and polyvinylpyrrolidone mix; Add water for injection 800ml, add activated carbon then, filter de-carbon, add the injection water then to 1000ml; Fine straining, embedding, 115 ℃ of sterilizations got final product in 30 minutes.
Embodiment 41, and 4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and mesna compositions are to the therapeutical effect of the cystitis of chemotherapeutics initiation
Animal: new zealand rabbit, female, 3 months ages, body weight 1.49 ± 0.10kg, 7 days quanrantines.Finish the back quanrantine and select 72 of the qualified rabbit of quarantine; The auricular vein injection gives cyclophosphamide (200.0mg/kg respectively; Give 15 rabbit), mitomycin (100.0mg/kg; Give 15 rabbit), cantharidin (86.0mg/kg gives 15 rabbit) or camptothecine (100.0mg/kg gives 15 rabbit).
The observation of the frequency of urinating: rabbit places exsiccant cage tool to raise, and the ferrum cage is outstanding to be divided into two-layerly, and the upper strata is rabbit feed and playground, and lower floor is a pallet, the exsiccant crimped paper of tiling one deck, and take out the wet back of urine, wipes away dried pallet, changes crimped paper.The record urination time, the number of micturitions in the accumulative total certain hour.
The observation of blood smear: get one of blood from auricular vein, process push jack, 10% formaldehyde fixed 30rain, HE dyeing is observed under inverted microscope and the counting leukocyte.
The observation of Urine sediments analyzer: auricular vein injection air execution rabbit, dissect abdominal cavity and pelvic cavity, expose bladder, aseptic condition extracts urine down, gets urine one and drops in observation Urine sediments analyzer under the inverted microscope.
The morphological observation of wall of urinary bladder: dissect bladder fast after putting to death rabbit, get the wall of urinary bladder holostrome tissue between the two defeated dung mouths of pipe, place fixedly 2w of 10% formaldehyde, make paraffin section, HE dyeing is observed under inverted microscope.
After the modeling success, every group is stayed 14 rabbit by following dosage regimen administration:
14 animals of cyclophosphamide group are divided into two groups at random, and every group of 7 rabbit are irritated preparation that stomach gives embodiment 1 respectively by mesna, and dosage is 5mg/kg and mesna (20mg/kg);
14 animals of mitomycin group are divided into two groups at random, and every group of 7 rabbit are irritated preparation that stomach gives embodiment 1 respectively by mesna, and dosage is 5mg/kg and auricular vein injection glutathion (20mg/kg);
14 animals of cantharidin group are divided into two groups at random, and every group of 7 rabbit are irritated preparation that stomach gives embodiment 2 respectively by mesna, and dosage is that 5mg/kg and auricular vein injection give glutathion (20mg/kg);
14 animals of camptothecine group are divided into two groups at random, and every group of 7 rabbit are irritated preparation that stomach gives embodiment 2 respectively by mesna, and dosage is that 5mg/kg and auricular vein injection give amifostine (10mg/kg).
Each is organized rabbit and all adopts administration once a day, altogether 7 days dosage regimen of administration.
In the administration process every day urinate frequency and hematuria observation of symptoms, the next day carry out the blood smear inspection, carry out after administration is accomplished that Urine sediments analyzer is observed and the morphological observation of wall of urinary bladder.
The result shows, mesna and 1,4; 5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 1,4; 5, the compositions of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic has the good curing effect to inductive cystitis such as cyclophosphamide, mitomycin, cantharidin and camptothecines.Each is organized the comprehensive contrast of therapeutical effect and sees table 1.
Table 1
Visible by table 1, mesna and 1,4; 5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 1,4; 5; The compositions of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic has the good curing effect to inductive cystitis such as cyclophosphamide, mitomycin, cantharidin and camptothecines, and its therapeutical effect significantly is superior to mesna, glutathion and amifostine, and dosage is lower.
Embodiment 51,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and 1,4,5, and 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and mesna compositions are to the preventive effect of the cystitis of chemotherapeutics initiation
Animal: new zealand rabbit, female, 3 months ages, body weight 1.49 ± 0.10kg, 7 days quanrantines.Finish the back quanrantine and select the qualified rabbit of quarantine, irritate compositions (by mesna, dosage is 5mg/kg), mesna (20mg/kg) that stomach gives embodiment 1 and 2 respectively, auricular vein gives glutathion (20mg/kg), amifostine (10mg/kg).
After administration finishes; Each administration group auricular vein injection respectively gives cyclophosphamide (200.0mg/kg gives 15 rabbit), mitomycin (100.0mg/kg gives 15 rabbit), cantharidin (86.0mg/kg; Give 15 rabbit) or camptothecine (100.0mg/kg gives 15 rabbit).
Add up the cystitis sickness rate of each family on the 3rd day after the modeling, see table 2.
Table 2
By the visible mesna and 1,4 of table 2,5; 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 1; 4,5, the compositions of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic has the good preventing effect to inductive cystitis such as cyclophosphamide, mitomycin, cantharidin and camptothecines.And the preventive effect when low dosage is higher than common drugs such as mesna, glutathion and amifostine.
Claims (4)
1. the pharmaceutical composition of the cystitis that causes of prevention or treatment chemotherapy is by mesna and 1,4,5; 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and pharmaceutically acceptable pharmaceutical carrier are formed; Said mesna and 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 1; 4,5, the mass ratio of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is (3-5): 1.
2. the pharmaceutical composition of the cystitis that a kind of prevention according to claim 1 or treatment chemotherapy cause; It is characterized in that: said pharmaceutical composition is a tablet; Each component and weight ratio are in the tablet: 1; 4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic: mesna: microcrystalline Cellulose: lactose: carboxymethyl starch sodium: magnesium stearate: polyvinylpyrrolidone is 20:60:50:100:37.5:12:30.
3. the pharmaceutical composition of the cystitis that a kind of prevention according to claim 1 or treatment chemotherapy cause; It is characterized in that: said pharmaceutical composition is a tablet; Each component and weight ratio are in the tablet: 1; 4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic: mesna: microcrystalline Cellulose: carboxymethyl starch sodium: micropowder silica gel: polyvinylpyrrolidone: sodium lauryl sulphate is 10:40:10:12:20:30:5.
4. the pharmaceutical composition of the cystitis that a kind of prevention according to claim 1 or treatment chemotherapy cause, it is characterized in that: said pharmaceutical composition is an injection, each components contents is in the injection: in 1000ml; 1,4,5; 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic is 20g; Mesna is 70g, and polyvinylpyrrolidone is 5g, adds the injection water and makes.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008071245A1 (en) * | 2006-12-12 | 2008-06-19 | Farco-Pharma Gmbh | Pharmaceutical preparation for the treatment of inflammatory diseases of the urogenital tract |
| CN101491526A (en) * | 2009-03-03 | 2009-07-29 | 山东大学 | Use of tetrahydropyridines in preparing medicine for treating arthritis |
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| EP1858519B1 (en) * | 2005-03-12 | 2013-02-20 | Bitop Aktiengesellschaft Für Biotechnische Optimierung | Ectoin and/or hydroxyectoin for the prevention and treatment of inflammatory bowel diseases |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008071245A1 (en) * | 2006-12-12 | 2008-06-19 | Farco-Pharma Gmbh | Pharmaceutical preparation for the treatment of inflammatory diseases of the urogenital tract |
| CN101491526A (en) * | 2009-03-03 | 2009-07-29 | 山东大学 | Use of tetrahydropyridines in preparing medicine for treating arthritis |
Non-Patent Citations (1)
| Title |
|---|
| Sonja Kolp et.al..Compatible solutes as protectants for zymogens against proteolysis.《Biochimica et Biophysica Acta》.2006,1234–1242. * |
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