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CN111603470A - Application of itraconazole isomer in preparation of drugs for treating squamous non-small cell lung cancer - Google Patents

Application of itraconazole isomer in preparation of drugs for treating squamous non-small cell lung cancer Download PDF

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CN111603470A
CN111603470A CN202010627777.6A CN202010627777A CN111603470A CN 111603470 A CN111603470 A CN 111603470A CN 202010627777 A CN202010627777 A CN 202010627777A CN 111603470 A CN111603470 A CN 111603470A
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itraconazole
isomer
lung cancer
small cell
cell lung
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傅和亮
王薇
吴蓉蓉
沈小宁
张海峰
李颖聪
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Jiangsu Aidi Pharmaceutical Co ltd
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Abstract

The invention discloses application of a 2S,4R,2 'S-itraconazole isomer in preparation of a medicament for treating squamous non-small cell lung cancer, wherein the 2S,4R, 2' S-itraconazole isomer has a good tumor inhibition effect in preparation of the medicament for treating squamous non-small cell lung cancer, the 2S,4R,2 'S-itraconazole has a positive treatment effect on squamous non-small cell lung cancer in a human body, and the 2S,4R, 2' S-itraconazole combines gemcitabine with carboplatin or combines paclitaxel with carboplatin for treating squamous non-small cell lung cancer to generate a remarkable synergistic effect.

Description

Application of itraconazole isomer in preparation of drugs for treating squamous non-small cell lung cancer
The technical field is as follows:
the invention relates to the technical field of medicines, and particularly relates to an application of an itraconazole isomer in preparation of a medicine for treating squamous non-small cell lung cancer.
Background art:
itraconazole, the english name Itraconazole, the name of Chinese academy: (±) -cis-4- [4- [4- [4- [ [2- (2, 4-dichlorophenyl) -2- (1H-1, 2, 4-triazol-1 yl-1-methyl) -1, 3-dioxan-4-yl ] methoxy ] phenyl ] -1-piperazinyl ] phenyl ] -2, 4-dihydro-2- (1-methylpropyl) -3H-1, 2, 4-triazol-3-one. Itraconazole is a racemic mixture having three chiral centers with four enantiomers mixed in a ratio of 1:1:1: 1. Itraconazole is a synthetic azole broad-spectrum antifungal agent, is used for systemic infection caused by deep fungi, and can also be used for candidiasis and aspergillosis. The antifungal clinical application is a mixture of 4 cis isomers on dioxolane in the structure of 2S,4R,2 'S-itraconazole, 2S,4R, 2' R-itraconazole, 2R,4S,2 'S-itraconazole and 2R,4S, 2' R-itraconazole. To avoid adverse effects of clinical use of the mixture, U.S. patent No. US5,474,997 discloses methods and compositions for treating local and systemic fungal, yeast and dermal mold infections using itraconazole, 2R4S, a chiral pure isomer, and international patent No. 9416701 also discloses methods and compositions for treating fungal, yeast and mold infections using itraconazole, 2S 4R. Chinese patent publication No.: CN101711156 discloses a method for preventing and treating angiogenesis related diseases by itraconazole chiral pure isomer (4S-cis-itraconazole), which can inhibit tumor neovascularization. Chinese patent publication No. CN105061411A discloses an optical isomer 2S,4R, 2' S-itraconazole crystal form, and a preparation method and application thereof, which can be used not only for resisting fungal infection, but also as an effective mTOR inhibitor, and thus can be used for the treatment of various tumors (such as non-small cell lung cancer, prostate cancer, etc.). Chinese patent publication No. CN102319260A discloses an application of cisplatin combined with itraconazole isomer in preparing a medicament for treating lung cancer, and when 2S4R itraconazole is combined with cisplatin for use, the lung cancer treatment effect is remarkably improved without increasing the dosage of cisplatin, and the side effect is not remarkably increased.
The invention content is as follows:
the invention aims to provide application of a 2S,4R, 2' S-itraconazole isomer in preparing a medicament for treating squamous non-small cell lung cancer.
The invention is realized by the following technical scheme:
application of 2S,4R, 2' S-itraconazole isomer in preparing medicament for treating squamous non-small cell lung cancer.
The medicine comprises 2S,4R, 2' S-itraconazole isomer or free base form or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers, and is prepared into required dosage forms.
Pharmaceutically acceptable carriers include diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorptive carriers, or lubricants.
The preparation comprises tablets, capsules, oral liquid, buccal agents, granules, medicinal granules, pills, powder, paste, pellets, suspensions, powder, solutions, injections, suppositories, sprays, drops or patches.
The invention also protects the application of the 2S,4R, 2' S-itraconazole in combination with gemcitabine/platinum drugs such as carboplatin, cisplatin and the like in preparing drugs for treating squamous non-small cell lung cancer. The dosage of the 2S,4R, 2' S-itraconazole is 400 mg-600 mg per day.
The invention also protects the application of the 2S,4R, 2' S-itraconazole combined with medicaments/platinum medicaments containing paclitaxel active ingredients, such as carboplatin, cisplatin and the like, in preparing medicaments for treating squamous non-small cell lung cancer. The dosage of the 2S,4R, 2' S-itraconazole is 400 mg-600 mg per day. The medicine containing paclitaxel active ingredient comprises paclitaxel and albumin paclitaxel.
The invention also provides an anti-squamous non-small cell lung cancer medicament, which comprises 2S,4R, 2' S-itraconazole or a free base form or a pharmaceutically acceptable salt thereof.
In particular, gemcitabine or a drug containing a paclitaxel active ingredient and platinum drugs such as carboplatin, cisplatin, and the like are also included.
Also comprises respective pharmaceutically acceptable carriers, and is prepared into the required dosage form.
The invention has the following beneficial effects:
1) the 2S,4R, 2' S-itraconazole isomer has better tumor inhibition effect in the application of preparing the medicine for treating squamous non-small cell lung cancer, and the tumor inhibition effect is better than that of a clinical positive medicine Cisplatin Cisplatin.
2)2S,4R, 2' S-itraconazole shows a positive therapeutic effect on squamous non-small cell lung cancer in a human body.
3) The 2S,4R, 2' S-itraconazole combined with gemcitabine and carboplatin or combined with paclitaxel and carboplatin produces obvious synergistic effect in treating squamous non-small cell lung cancer.
Description of the drawings:
FIG. 1: the inhibition curves of isomer C and cisplatin in the PDX model of human lung cancer LUPF020 in example 1.
FIG. 2: the inhibition curves of isomer C and cisplatin in the PDX model of human lung cancer LUPF023 in example 1.
FIG. 3: the inhibition curves of isomer C and cisplatin in the PDX model of human lung cancer in example 1, LUPF 045.
FIG. 4: the inhibition curves of isomer C and cisplatin in the PDX model of human lung cancer in example 1, LUPF 048.
FIG. 5: the inhibition curves of isomer C and cisplatin in the PDX model of human lung cancer in example 1.
FIG. 6: inhibition curves for itraconazole, isomer C, isomer a, isomer B and isomer D in the PDX model for human lung cancer of example 1 LUPF 020.
FIG. 7: inhibition curves for itraconazole, isomer C, isomer a, isomer B and isomer D in the PDX model for human lung cancer in example 1 LUPF 045.
FIG. 8: inhibition curves for itraconazole, isomer C, isomer a, isomer B and isomer D in the PDX model of human lung cancer in example 1 LUPF 054.
FIG. 9: mean tumor volume curves for groups of mice during experiments with cisplatin in human lung cancer nude mouse model LUPF020 and high, medium and low doses of isoform C in example 2.
FIG. 10: mean tumor volume curves for groups of mice during the experiment with cisplatin and high, medium and low doses of isoform C in the nude mouse model human lung cancer LUPF045 in example 2.
FIG. 11: mean tumor volume curves for groups of mice during cisplatin and high, medium and low dose isoform C experiments in the human lung cancer nude mouse model LUPF054 in example 2.
The specific implementation mode is as follows:
the following is a further description of the invention and is not intended to be limiting.
In the following examples, isomer C is 2S,4R, 2' S-itraconazole. Isomer a is 2S,4R,2 ' R-itraconazole, isomer B is 2R,4S,2 ' R-itraconazole, and isomer D is 2R,4S,2 ' S-itraconazole. Cisplatin is Cisplatin.
Isomer a:
Figure BDA0002565408750000041
isomer C:
Figure BDA0002565408750000042
isomer B:
Figure BDA0002565408750000043
isomer D:
Figure BDA0002565408750000051
example 1: in vitro test, inhibition of 2S,4R, 2' S-itraconazole (isomer C) on cell proliferation of PDX model of human lung cancer
Test compounds: 2S,4R, 2' S-itraconazole (isomer C for short)
Reference compound: cisplatin, itraconazole, 2S,4R,2 ' R-itraconazole (isomer A for short), 2R,4S,2 ' R-itraconazole (isomer B for short), 2R,4S,2 ' S-itraconazole (isomer D for short)
The test system comprises: LUPF020, LUPF023, LUPF045, LUPF048 and LUPF054 cells (humanized non-small cell lung carcinoma PDX model)
The purpose is as follows: comparing the inhibition effect of isomer C and cisplatin on the proliferation of human lung cancer PDX model tumor cells under the in vitro culture condition. Cisplatin is a cytotoxic compound used clinically for lung cancer. Comparing the inhibition effect of itraconazole and 4 isomers (isomer A, isomer B, isomer C and isomer D) of itraconazole on the proliferation of human lung cancer PDX model tumor cells under in-vitro culture conditions.
The method comprises the following steps: non-small cell lung cancer tumor mass of patient is cut into small pieces in HBSS (Hank's BalancedSaltsolution) and inoculated into subcutaneous of female NU/NU nude mouse until tumor grows to 500mm3Then, passage is carried out on a nude mouse, and a human non-small cell lung cancer animal transplantation model (PDX model) is established. In the experiment, 5 personal lung cancer PDX models (LUPF020, LUPF023, LUPF045, LUPF048 and LUPF054) are established, and the model information is shown in Table 1.
TABLE 1
Figure BDA0002565408750000052
Figure BDA0002565408750000061
Taking fresh tumor tissues of tumor-bearing mice, separating single tumor cells by using a mechanical method and an enzyme digestion method, respectively mixing isomers C (0.0064-20 mu M), cisplatin (0.0064-20 mu M), itraconazole (0.0064-20 mu M), isomer A (0.0064-20 mu M), isomer B (0.0064-20 mu M) and isomer D (0.0064-20 mu M) with increasing concentrations, inoculating the mixture into a 96-well plate, continuously culturing for 6 days at 37 ℃, respectively measuring the cell activity in each plate hole, calculating the anti-tumor proliferation effect of different drug concentrations and drawing an inhibition curve.
As a result: the anti-cell proliferation effect of isomer C and cisplatin was tested in 5 human lung cancer PDX models (LUPF020, LUPF023, LUPF045, LUPF048, LUPF054), both of which showed cytotoxicity, and the inhibitory effect of isomer C was stronger than that of cisplatin. In the LUPF020 model, the isomer C shows an inhibition rate at 0.2-0.3 mu M, and the highest inhibition rate (90%) is reached at 1 uM; isomers C and IC of cisplatin500.3. mu.M and 12.23. mu.M, respectively, see Table 2 and FIG. 1. In the LUPF023 model, isomer C showed inhibition at 0.7. mu.M, and reached the highest inhibition (57%) at 1. mu.M; isomers C and IC of cisplatin500.8. mu.M and 8.92. mu.M, respectively, see Table 2 and FIG. 2. In the LUPF045 model, the isomer C shows an inhibition rate at 0.6 mu M, and the highest inhibition rate (73%) is reached at 1 mu M; isomers C and IC of cisplatin500.67. mu.M and 3.48. mu.M, respectively, see Table 2 and FIG. 3. In the LUPF048 model, the isomer C shows an inhibition rate at 0.6 mu M, and the highest inhibition rate (73%) is reached at 1 mu M; isomers C and IC of cisplatin500.78 μ M and 6.58 μ M, respectively, see Table 2 and FIG. 4. In the LUPF054 model, the inhibition of isomer C rapidly increased from 0 to the highest inhibition (72%) from around 0.6 μ M; isomers C and IC of cisplatin500.40. mu.M and 7.62. mu.M, respectively, see Table 2 and FIG. 5.
TABLE 2
Figure BDA0002565408750000071
Thereafter, itraconazole and 4 isomers (isomer a, isomer B, isomer C, isomer D) of itraconazole were tested for anti-cell proliferation in 3 PDX models of human lung cancer (LUPF020, LUPF045, LUPF 054). In the LUPF020 and LUPF045 models, isomer C was close to itraconazole, isomer a, with an antiproliferative effect, significantly stronger than isomer B and isomer D, see table 3 and figures 6 and 7. In the LUPF054 model, isomer C is significantly stronger than itraconazole, isomer a, isomer B and isomer D, see table 3 and figure 8.
TABLE 3
Figure BDA0002565408750000072
And (4) conclusion: in a human lung cancer PDX model with a pathological type of squamous cell carcinoma, the isomer C has the function of inhibiting the proliferation of tumor cells, and the activity is obviously superior to that of the preferred medicament cisplatin in lung cancer clinic; compared with 4 optical isomers of itraconazole, the activity of the isomer C is slightly higher than that of the isomer A, and is obviously higher than that of the isomer B and the isomer D.
Example 2: in vivo experiment, anti-tumor effect of ACC006 in lung cancer nude mouse tumor model
Test compounds: 2S,4R, 2' S-itraconazole (isomer C for short)
Reference compound: cis-platinum
The test system comprises: female NU/NU nude mice
The purpose is as follows: comparing the antitumor effects of isomer C and cisplatin on a human lung cancer animal model. Cisplatin is a cytotoxic compound used clinically for lung cancer.
The method comprises the following steps: non-small cell lung cancer tumor mass of patient is cut into small pieces in HBSS (Hank's BalancedSaltsolution) and inoculated into subcutaneous of female NU/NU nude mouse until tumor grows to 500mm3Then, passage is carried out on a nude mouse, and a human non-small cell lung cancer animal transplantation model (PDX model) is established. In the experiment, 3 personal lung cancer PDX models (LUPF020, LUPF045 and LUPF054) are established, and the model information is shown in Table 4.
TABLE 4
Model numbering Sex Age (age) Primary/receiving treatment Clinical diagnosis
LUPF020 For male 50 Is/is Central squamous cell carcinoma of right lung
LUPF045 For male 51 Is/is Differentiated squamous cell carcinoma of the lower left lung
LUPF054 For male 57 Is/is Squamous cell carcinoma of right upper lung
The size of the to-be-treated tumor of the mouse to be treated with the tumor is 500-1000mm3When the test is carried out, the tumor-bearing mice are euthanized, the tumors are dissected out, the tumor-bearing mice are placed in a 10cm culture dish filled with HBSS for repeated washing for 2 to 3 times, and then the tumor-bearing mice are cut into tissue blocks with the size of 10 to 15mg and inoculated to the subcutaneous back of the test NU/NU nude mice. The tumor volume of the nude mice to be tested is up to about 150mm on average3At that time, different treatments were given in random groups (n-9 per group) according to tumor size and nude mouse body weight. Different treatment conditions were vehicle, cisplatin injection (1 time per week at 4mg/kg), oral isomer C (2 times per day at 25mg/kg), oral isomer C (2 times per day at 50mg/kg), oral isomer C (2 times per day at 75 mg/kg). Tumor volume was monitored 2 times per week. At day 28 or 33 after dosing, the experiment was terminated and each mouse in each group was sampled, bled, dissected to remove the tumor, photographed and weighedAnd then, quick-freezing with dry ice, recording data, and calculating the tumor inhibition rate TGI (%).
See table 5 for results: isomer C and cisplatin were tested for anti-tumor activity on 3 nude mouse models of human lung cancer (LUPF020, LUPF045, LUPF 054). In the LUPF020 model, after 43 days of continuous dosing, the final tumor volumes were: 1670.63mm3、1258.92mm3、1349.33mm3、1191.74mm3And 909.50mm3The TGI of each experimental group is: 27.71%, 21.47%, 31.99% and 50.61%, see table 5 and fig. 9; the size of the terminal tumor volume is tested by one-way anova, and the isomer C high-dose group has significant difference (P) compared with the control group<0.05). In the LUPF045 model, after 33 consecutive days of administration, the final tumor volumes were: 1020.59mm3、576.07mm3、568.10mm3、494.86mm3And 474.45mm3The TGI of each experimental group is: 52.23%, 53.57%, 61.81% and 64.41%, see table 5 and fig. 10; the volume size of the terminal tumor is detected by one-way anova, and each experimental group has significant difference (P) compared with the control group<0.05). In the LUPF054 model, after 33 consecutive days of administration, the final tumor volumes were respectively for the blank control group (no drug injected or administered), for the cisplatin group (cisplatin injected, 1 time per week, 4mg/kg each), for the isoform C low dose group (oral isoform C, 2 times per day, 25mg/kg each), for the intermediate dose group (oral isoform C, 2 times per day, 50mg/kg each) and for the high dose group (oral isoform C, 2 times per day, 75mg/kg each): 1607.00mm3、1235.26mm3、1308.93mm3、1206.63mm3And 748.66mm3The TGI of each experimental group is: 25.44%, 20.38%, 27.39% and 58.56%, see table 5 and fig. 11; the final tumor volume was examined by one-way anova, and the isomer C high dose group was significantly different from the control group (P)<0.05)。
TABLE 5
Figure BDA0002565408750000101
And (4) conclusion: the isomer C high-dose group (75mg/kg) shows better tumor inhibition effect in a human lung cancer nude mouse model, and the tumor inhibition effect is better than that of a clinical positive medicament cisplatin.
Example 3: human data for isomer C alone or in combination with chemotherapy
A phase I clinical trial in patients with advanced solid tumors, the trial being a single-center, open, non-randomized, dose escalation trial wherein isomer C is administered orally at a starting dose of 100mg 1 or 2 times daily. The research design comprises two parts, wherein the first part is a single-drug climbing test stage of the isomer C, and the maximum tolerated dose of the isomer C is determined; the second part is an extended trial phase, using either isomer C alone or in combination with chemotherapy, for one or several tumor expansion trial populations (including squamous non-small cell lung cancer patients), to further assess safety, tolerability and primary efficacy. In the two-stage trial, 21 patients with squamous non-small cell lung cancer were enrolled. All patients signed informed consent, and the trial process was in compliance with local ethical committee on clinical trials.
Methods of treatment of isomer C single agents: isomer C was administered orally at an initial dose of 100 mg/day, at a maximum dose of 800 mg/day, 1 or 2 times daily, for a treatment period of 28 days, until the patient developed disease progression/intolerant toxicity/compliance with other withdrawal requirements.
Method of isomer C combined therapy with paclitaxel/carboplatin: daily administration of isomer COral solution, 1/day, 600mg each, 21 days is a treatment cycle until the patient develops disease progression/intolerance toxicity/compliance with other withdrawal requirements. Intravenous injection of paclitaxel at a dose of 175mg/m on day 1 of the cycle2(ii) a Intravenous drip of carboplatin at day 1 of the cycle at a dose of AUC5 mg/ml.min; paclitaxel and carboplatin were administered for up to 6 treatment cycles.
Method of isomer C combined treatment with gemcitabine/carboplatin: isomer C oral solution was taken daily for 1 time/day, 600mg each time, 21 days as a treatment cycle until the patient developed disease progression/intolerant toxicity reactions/met other withdrawal requirements. Gemcitabine was administered by intravenous drip at day 1 and day 8 of the cycle at a dose of 1000mg/m2(ii) a Intravenous drip of carboplatin at day 1 of the cycle at a dose of AUC5 mg/ml.min; gemcitabine and carboplatin were administered for up to 6 treatment cycles.
And (3) evaluating the curative effect: the curative effect evaluation is carried out according to the curative effect evaluation standard RECIST1.1 of the solid tumor.
And (3) test results:
the following is a summary of the efficacy of monotherapy 15 patients with squamous non-small cell lung carcinoma of squamous cell lung carcinoma of the invention with isomer C by 31/1/2019, as shown in table 6. The clinical data and therapeutic effects of 3 of these patients are shown in Table 7.
TABLE 6
Figure BDA0002565408750000111
TABLE 7
Figure BDA0002565408750000121
The following is a summary of the efficacy of isomer C of the present invention in combination with chemotherapy for squamous non-small cell lung cancer by day 30/6 of 2020, as shown in table 8. The clinical data and therapeutic effects of all 6 patients are shown in Table 9.
TABLE 8
Figure BDA0002565408750000122
Figure BDA0002565408750000131
TABLE 9
Figure BDA0002565408750000132
These results indicate that isomer C shows a positive therapeutic effect on squamous non-small cell lung cancer in humans, while the use of isomer C in combination with paclitaxel/carboplatin or gemcitabine/carboplatin also shows a synergistic effect in squamous non-small cell lung cancer patients, in the sense that the results of human clinical trials have been obtained to be positive, and that isomer C is clinically significant for squamous non-small cell lung cancer.

Claims (10)

  1. Use of 2S,4R, 2' S-itraconazole isomer in preparing medicament for treating squamous non-small cell lung cancer.
  2. 2. The use of the 2S,4R,2 'S-itraconazole isomer according to claim 1 for preparing a medicament for treating squamous non-small cell lung cancer, wherein said medicament comprises the 2S,4R, 2' S-itraconazole isomer or its free base form or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, and is prepared into a desired dosage form.
  3. 3. The use of the 2S,4R, 2' S-itraconazole isomer according to claim 2, wherein the pharmaceutically acceptable carrier comprises diluent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, adsorption carrier or lubricant.
  4. 4. The use of the 2S,4R, 2' S-itraconazole isomer in the preparation of a medicament for treating squamous non-small cell lung cancer according to claim 3, wherein said dosage form comprises tablet, capsule, oral liquid, buccal agent, granule, pill, powder, paste, pellet, suspension, powder, solution, injection, suppository, spray, drop or patch.
  5. The application of 2S,4R, 2' S-itraconazole combined with gemcitabine and platinum drugs in preparing drugs for treating squamous non-small cell lung cancer.
  6. The application of 2S,4R, 2' S-itraconazole combined with a medicament containing a paclitaxel active ingredient and a platinum medicament in preparing a medicament for treating squamous non-small cell lung cancer.
  7. 7. An anti-squamous non-small cell lung cancer drug, which is characterized by comprising 2S,4R, 2' S-itraconazole or a free base form or a pharmaceutically acceptable salt thereof, gemcitabine and a platinum drug.
  8. 8. An anti-squamous non-small cell lung cancer drug is characterized by comprising 2S,4R, 2' S-itraconazole, a drug containing a paclitaxel active ingredient and a platinum drug.
  9. 9. The anti-squamous non-small cell lung cancer drug according to claim 7 or 8, further comprising respective pharmaceutically acceptable carriers, and being prepared into a desired dosage form.
  10. 10. The anti-non-small cell lung squamous carcinoma drug according to claim 7 or 8, wherein the dose of 2S,4R, 2' S-itraconazole is 400mg to 600mg per day.
CN202010627777.6A 2020-07-01 2020-07-01 Application of itraconazole isomer in preparation of drugs for treating squamous non-small cell lung cancer Pending CN111603470A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102319260A (en) * 2011-09-21 2012-01-18 广州维美投资有限公司 The application of cisplatin combined itraconazole isomer in preparation treatment lung-cancer medicament
CN105061411A (en) * 2015-06-23 2015-11-18 扬州艾迪生物科技有限公司 Optical isomer 2S,4R,2'S-itraconazole crystal form, preparation method and applications thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102319260A (en) * 2011-09-21 2012-01-18 广州维美投资有限公司 The application of cisplatin combined itraconazole isomer in preparation treatment lung-cancer medicament
CN105061411A (en) * 2015-06-23 2015-11-18 扬州艾迪生物科技有限公司 Optical isomer 2S,4R,2'S-itraconazole crystal form, preparation method and applications thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOONG SUP SHIM等: "Divergence of Antiangiogenic Activity and Hepatotoxicity of Different Stereoisomers of Itraconazole", 《CLINICAL CANCER RESEARCH》 *
江涛等: "吉西他滨加卡铂与紫杉醇加卡铂治疗晚期非小细胞肺癌临床对比研究", 《中国肺癌杂志》 *

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