CN102614180A - Use of itraconazole in preparation of drug for treating multiple myeloma - Google Patents
Use of itraconazole in preparation of drug for treating multiple myeloma Download PDFInfo
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- CN102614180A CN102614180A CN2011100299861A CN201110029986A CN102614180A CN 102614180 A CN102614180 A CN 102614180A CN 2011100299861 A CN2011100299861 A CN 2011100299861A CN 201110029986 A CN201110029986 A CN 201110029986A CN 102614180 A CN102614180 A CN 102614180A
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Abstract
The invention discloses a drug for treating multiple myeloma and especially relates to a use of itraconazole or its salts in preparation of a drug composition for treating multiple myeloma. It is accidentally discovered that itraconazole has effects of treating multiple myeloma. A treatment principle of itraconazole comprises that itraconazole mainly acts on a cancer cell Hedgehog (Hh) signal path and inhibits accumulation of Smoothened (Smo) protein in the cancer cell Hedgehog (Hh) signal path thereby inhibiting growth of cancer cells. Compared with bortezomib, itraconazole has small liver and kidney toxicity. Accidental death is not produced due to drug toxicity in a mouse test. A result of a clinical experiment shows that itraconazole has effects of treating various types of multiple myeloma and especially has good treatment effects after bone marrow transplantation. Results of treatment on 30 clinical tested patients show that a total effective rate is 95.9%. In addition, through combination with bortezomib, itraconazole has better effects.
Description
Technical field
The invention belongs to the oncotherapy field, relate to the medicine of treating multiple myeloma.
Background technology
Itraconazole is former to be synthetic azole broad-spectrum antifungal medicine, is used for the caused system of deep fungal and infects, and also can be used for candidiasis and aspergillosis.
Molecular formula: C35H38C12N8O4
Molecular weight: 705.64
CAS number: 84625-61-6
Chemical name: suitable-4-[4-[4-[4-[[2-(2, the 4-Dichlorobenzene base)-2-(1H-1,2,4-triazol radical-1-methyl)
Structural formula is:
Itraconazole belongs to triazole type broad-spectrum antifungal medicine, and the biosynthesis of the essential composition ergosterol through suppressing fungal cell membrane is brought into play its antifungic action.The dosage form of itraconazole is more complete, comprises intravenous formulations, oral capsule and oral liquid.Its novel form is oral liquid and intravenous formulations, is itraconazole is attached on the HP-, and the latter forms outside hydrophilic and the column structure of inner hydrophobic, thus the dissolubility of raising itraconazole (Int J Pharm, 2001,229:193-203).Its has a broad antifungal spectrum is in fluconazol, and all effective to the yeast and the mycete that comprise various candidiasises, safety is similar with fluconazol.Wherein very long just gastrointestinal absorption has only about 30% time of using clinically of capsule, has now increased new dosage form itraconazole oral liquid again, and dosage form is more comprehensive, to satisfy the demand of different patients' personalizations.
Multiple myeloma (multiple myeloma; MM) be the paraplasm malignant tumor of plasma cell; Be a kind of progressive ND. it is characterized by the MIg (IgG of a bone marrow plasmocytoma and a strain integrity; IgA, IgD or IgE) or Bence Jones protein (free monoclonicity κ or γ light chain) hyperplasia.Multiple myeloma is often with multiple molten bone property infringement, hypercalcemia, and anemia, kidney damage, and the susceptibility of bacterial infection increased, the generation of normal immunoglobulin receives to press down.
Disease treatment comprises: 1, chemotherapy: the M2 scheme: carmustine and cyclophosphamide.MP scheme: L-Sarcolysinum and prednisone.VAD scheme: vincristine, amycin, dexamethasone.VBAP scheme: vincristine, chlormethine, amycin, prednisone.
2, interferon:
3, anemia, infection can difficulty be given suit the medicine to the illness anti-anemia, anti-infective therapy.
4, the feasible separating plasma of high serum viscous disease;
5, bone marrow transplantation.After HDC has been separated, can consider that self or allogeneic bone marrow deposits transplanting.
Yet multiple myeloma still needs further research, obtains curative effect excellence, treatment means different drug.
Summary of the invention
The present invention has disclosed itraconazole or its salt is preparing multiple myeloma with the application in the medical composition.
In the multiple myeloma treatment, Hedgehog (Hh) signal path abnormal expression.It is reported that the survival of Hh signal path and multiple myeloma stem cell is closely related.The present invention proposes, and itraconazole mainly acts on tumor cell Hedgehog (Hh) signal path, suppresses the proteic accumulation of Smoothened (Smo) in the path, thereby reaches the purpose that suppresses tumor growth.Beneficial effect of the present invention does, this drug targeting property is strong, and the mechanism of action is clear and definite.Compare with other treatment multiple myeloma medicine, like bortezomib, the itraconazole effect is remarkable, and toxic and side effects is little.Itraconazole of the present invention or its salt can be processed multiple dosage form, that is to say that treatment that itraconazole of the present invention is used for multiple myeloma does not receive the restriction of dosage form, can be selected from but are not limited to following Chinese patent:
CN00808948、CN97199659、CN98806999、CN?99817076、CN?200410016484、CN?200410016653、CN?200410021151、CN?200410035544、CN?200510117641、CN?200610065136、CN?200610151084、CN?200910305827。
Itraconazole of the present invention or its salt is oral administration preferably, and a day taking dose is the 0.1-0.4 gram.
The preferred day taking dose of itraconazole of the present invention or its salt is 0.2 gram.Day takes number of times and is preferably 1 time.
The present invention finds that unexpectedly itraconazole has the effect of treatment multiple myeloma; The treatment principle is that itraconazole mainly acts on tumor cell Hedgehog (Hh) signal path; Suppress the proteic accumulation of Smoothened (Smo) in the path, thereby reach the purpose that suppresses tumor growth.Compare with bortezomib, the Liver and kidney toxicity of itraconazole is less, and the phenomenon of not dying unexpectedly because of drug toxicity in the mouse test takes place.Clinical trial shows for various multiple myeloma patients therapeutical effect is arranged all, and is better in particular for the therapeutic effect after the bone marrow transplantation.30 routine clinical trial patient treatments are being shown that total effective rate reaches 95.9%.In addition, this medicine and bortezomib are united use, and effect is more excellent.
Further specify the present invention through specific embodiment below.
Description of drawings
Fig. 1 is the survival curve of C57BL/KaLwRijHsd mice behind the embodiment 1 injection itraconazole.
Fig. 2 is the tumor load discharge curve in the C57BL/KaLwRijHsd mice serum behind the embodiment 1 injection itraconazole.
The specific embodiment
Administrated method; Oral
Experimental condition: adopt a cleaning level C57BL/KaLwRijHsd mice, available from Dutch Harlan company.The C57BL/KaLwRijHsd mice is in cleaning level experiment indoor feeding and experiment.
Test drug: injection itraconazole (production of U.S. SIGMA company), itraconazole is dissolved in the dimethyl sulfoxide (production of U.S. SIGMA company) and processes solution.
Test method: get the C57BL/KaLwRijHsd mice in 20 6 ages in week, be divided into 2 groups immediately, male and female animal half and half in every group, the difference on the equal not statistically significant of the body weight between each treated animal.
The dosage regimen of 2 treated animals is:
Matched group: dimethyl sulfoxide, 0.1ml/kg body weight/day
Treatment group: itraconazole 20mg/kg body weight/day (drug level is 4mg/ml)
1000000 5T33 multiple myeloma cells of C57BL/KaLwRijHsd mouse tail vein injection are pressed the administration of such scheme subcutaneous injection, 3 times weekly after one week.Weigh every day during the animals administer, confirms the dosage on the same day according to body weight, and successive administration is to dead mouse.Gather mouse vein blood weekly and preserve the death time of record mice.
Experimental result shows that subcutaneous injection itraconazole solution can prolong the life span of the C57BL/KaLwRijHsd mice that suffers from multiple myeloma, and reduces the tumor load amount (Mus LGg2b concentration) in the mice serum.Through statistical test, the time-to-live of matched group C57BL/KaLwRijHsd mice has been compared significant difference P＜0.05 with the treatment group, sees table 1.Tumor load amount in the serum of matched group C57BL/KaLwRijHsd mice has been compared significant difference P＜0.05 with the treatment group, sees table 2.
Embodiment 2 Liver and kidney toxicity tests
Trial drug: itraconazole;
Control drug: bortezomib.
Animal subject: mice.
Test method: carry out with reference to " medicine toxicological study guideline "
Result of the test: compare with bortezomib, the Liver and kidney toxicity of itraconazole is less, and the phenomenon of not dying unexpectedly because of drug toxicity in the mouse test takes place.
Embodiment 3 human trials
With reference to " antitumor drug clinical trial technological guidance principle "; Select 30 routine patients; Male's 20 examples, women's 10 examples; Age 30-65 year, observation index comprises the improving of result and quality of life, sings and symptoms (alleviating of the increase of body weight, pain) of total life cycle, DFS phase, the life cycle of getting nowhere, PD time, treatment Time To Failure, subjects reported.
Cardinal symptom is renal insufficiency 19 examples, anemia 17 examples, bone damage 16 examples, weak 6 examples, hypercalcemia 2 examples, EMP 1 example.Part patient has two or more symptoms.Clinical stages: I phases 3 example, II phases 8 example, III phases 19 example.Bone damage is made a definite diagnosis through x line, CT or MRI, whole body bone scanning.Result of the test, IgG type 11 examples among the 30 routine patients, light chain type 10, IgA type 6 examples, IgD type 1 example, IgE type 1 example, IgM type 1 example, nonsecreting type 1 example.Total effective rate is 95.9%.Tolerant invariably toxic and side effects.
Model case
1, man, 48 years old, hemoglobin＞100g/L (＜0.6 * 1012 cells/m2), M albumen synthetic ratio low IgG＜50/LIgA＜30g/L; Urine κ or lambda light chain＜4g/24 hour, blood calcium is normal, and the bone X-ray film is normal or have only indivedual bones that dissolve to sexually revise, and is diagnosed as the I phase; IgG type multiple myeloma gives 0.2 gram itraconazole, and is oral; Once a day, 3 weeks of the course of treatment, prognosis bona.
2, the man is 64 years old, hemoglobin 0.6-1.2 * 10
12Individual cell/m
2, be diagnosed as IgA type multiple myeloma: give 0.2 gram itraconazole, oral, once a day, 2 months courses of treatment, prognosis is general.
3, woman, 39 years old, hemoglobin＜85g/L was diagnosed as IgD type multiple myeloma, and κ/λ ratio is 1: 9.The renal function injury of concurrent plasma cell leukemia, and merging simultaneously, 0.2 gram itraconazole, oral, once a day, and bortezomib, drug administration by injection, was survived 12 months at 2 months courses of treatment.
4, man, 37 years old, bone marrow transplantation once, hemoglobin＞1.2 * 10
12Individual cell/m
2Be diagnosed as IgE type multiple myeloma, merge plasma cell leukemia simultaneously, 0.2 gram itraconazole, oral, once a day, 3 months courses of treatment, existence is so far.
5, man, 35 years old, once bone marrow transplantation was diagnosed as the light chain type multiple myeloma; κ/λ ratio is 1.2: 1, and with Bence Jones proteinuria, hypercalcemia, renal insufficiency, amyloidosis are arranged, 0.2 restrains itraconazole, oral; Once a day, 3 months courses of treatment, prognosis bona.
The survival natural law of C57BL/KaLwRijHsd mice behind the table 1 injection itraconazole
The above embodiment only is that preferred implementation of the present invention is described; Be not that scope of the present invention is limited; Design under the prerequisite of spirit not breaking away from the present invention; Various distortion and improvement that the ability those of ordinary skill is made technical scheme of the present invention all should fall in the definite protection domain of claims of the present invention.
Claims (7)
1. itraconazole or its salt are preparing multiple myeloma with the application in the medical composition.
2. application as claimed in claim 1 is characterized in that: said medical composition mainly acts on tumor cell Hedgehog signal path, suppresses the proteic accumulation of Smoothened in the path.
3. application as claimed in claim 1 is characterized in that: said medical composition is to be used for oral medical composition.
4. medical composition as claimed in claim 3, a day taking dose are the 0.1-0.4 gram.
5. medical composition as claimed in claim 4, a day taking dose are 0.2 gram.
6. itraconazole or its salt and bortezomib are united in the preparation multiple myeloma with the application in the medical composition.
7. like the described application of claim 1-6, be the multiple myeloma that is used for after the bone marrow transplantation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044408A (en) * | 2013-01-21 | 2013-04-17 | 万礼 | Itraconazole applied to treatment of malignant tumor or salt thereof and composition thereof |
| CN115820865A (en) * | 2023-01-31 | 2023-03-21 | 南京中医药大学 | Application of PNPO gene in preparation of multiple myeloma markers |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006036892A2 (en) * | 2004-09-24 | 2006-04-06 | Sapphire Therapeutics, Inc. | Use of inhibitors of 24-hydroxylase in the treatment of cancer |
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2011
- 2011-01-28 CN CN2011100299861A patent/CN102614180A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006036892A2 (en) * | 2004-09-24 | 2006-04-06 | Sapphire Therapeutics, Inc. | Use of inhibitors of 24-hydroxylase in the treatment of cancer |
Non-Patent Citations (1)
| Title |
|---|
| 宋强: "伊曲康唑治疗多发性骨髓瘤继发肺内感染", 《中国实用内科杂志》, vol. 28, 30 June 2008 (2008-06-30), pages 3 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044408A (en) * | 2013-01-21 | 2013-04-17 | 万礼 | Itraconazole applied to treatment of malignant tumor or salt thereof and composition thereof |
| CN115820865A (en) * | 2023-01-31 | 2023-03-21 | 南京中医药大学 | Application of PNPO gene in preparation of multiple myeloma markers |
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Application publication date: 20120801 |