Trimetrexate (CI-898)
(Synonyms: 三甲曲沙; CI-898) 目录号 : GC33915
Trimetrexate (CI-898) (CI-898) 是一种抗生素，也是一种有效且具有口服活性的二氢叶酸还原酶 (DHFR) 抑制剂，可减少 DNA 和 RNA 前体的产生并导致细胞死亡，IC50 值为 4.74 nM 和 1.35 nM 用于人类 DHFR 和弓形虫 DHFR。
Cas No.:52128-35-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Trimetrexate(CI-898) is a potent competitive inhibitor of bacterial, protozoan, and mammalian dihydrofolate reductase.IC50 value:Target: Antibiotic Trimetrexate therapy had minimal toxicity; transient neutropenia or thrombocytopenia occurred in 12 patients and mild elevation of serum aminotransferases in 4. We conclude that the combination of trimetrexate and leucovorin is safe and effective for the initial treatment of pneumocystis pneumonia in patients with AIDS and for the treatment of patients with intolerance or lack of response to standard therapies [1]. In noncomparative trials trimetrexate was effective in the treatment of P. carinii pneumonia (PCP) in patients with AIDS who were intolerant of or refractory to cotrimoxazole (trimethoprim/sulfamethoxazole) and pentamidine treatment. In these patients, 2- to 4-week survival rates of 48 to 69% were reported. In a comparative trial in the initial therapy of PCP, trimetrexate was less effective than cotrimoxazole in moderate to severe disease as evidenced by a significantly higher failure rate [2]. trimetrexate plus leucovorin was effective, albeit inferior to TMP-SMZ, for moderately severe P. carinii pneumonia but was better tolerated than TMP-SMZ [3].
[1]. Allegra CJ, et al. Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1987 Oct 15;317(16):978-85. [2]. Fulton B, et al. Trimetrexate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of Pneumocystis carinii pneumonia. Drugs. 1995 Apr;49(4):563-76. [3]. Sattler FR, et al. Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031. J Infect Dis. 1994 Jul;170(1):165-72.
| Cas No. | 52128-35-5 | SDF | |
| 别名 | 三甲曲沙; CI-898 | ||
| Canonical SMILES | NC1=C(C(C)=C2CNC3=CC(OC)=C(OC)C(OC)=C3)C(C=C2)=NC(N)=N1 | ||
| 分子式 | C19H23N5O3 | 分子量 | 369.42 |
| 溶解度 | DMSO : ≥ 61.5 mg/mL (166.48 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.7069 mL | 13.5347 mL | 27.0695 mL |
| 5 mM | 0.5414 mL | 2.7069 mL | 5.4139 mL |
| 10 mM | 0.2707 mL | 1.3535 mL | 2.7069 mL |
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Treatment of Pneumocystis jirovecii pneumonia in HIV-infected patients: a review
Expert Rev Anti Infect Ther 2017 Sep;15(9):873-892.PMID:28782390DOI:10.1080/14787210.2017.1364991.
Pneumocystis pneumonia is a potentially life-threatening pulmonary infection that occurs in immunocompromised individuals and HIV-infected patients with a low CD4 cell count. Trimethoprim-sulfamethoxazole has been used as the first-line agent for treatment, but mutations within dihydropteroate synthase gene render potential resistance to sulfamide. Despite advances of combination antiretroviral therapy (cART), Pneumocystis pneumonia continues to occur in HIV-infected patients with late presentation for cART or virological and immunological failure after receiving cART. Areas covered: This review summarizes the diagnosis and first-line and alternative treatment and prophylaxis for Pneumocystis pneumonia in HIV-infected patients. Articles for this review were identified through searching PubMed. Search terms included: 'Pneumocystis pneumonia', 'Pneumocystis jirovecii pneumonia', 'Pneumocystis carinii pneumonia', 'trimethoprim-sulfamethoxazole', 'primaquine', 'Trimetrexate', 'dapsone', 'pentamidine', 'atovaquone', 'echinocandins', 'human immunodeficiency virus infection', 'acquired immunodeficiency syndrome', 'resistance to sulfamide' and combinations of these terms. We limited the search to English language papers that were published between 1981 and March 2017. We screened all identified articles and cross-referenced studies from retrieved articles. Expert commentary: Trimethoprim-sulfamethoxazole will continue to be the first-line agent for Pneumocystis pneumonia given its cost, availability of both oral and parenteral formulations, and effectiveness or efficacy in both treatment and prophylaxis. Whether resistance due to mutations within dihydropteroate synthase gene compromises treatment effectiveness remains controversial. Continued search for effective alternatives with better safety profiles for Pneumocystis pneumonia is warranted.
Cell cycle effects of Trimetrexate (CI-898)
Cancer Chemother Pharmacol 1986;16(2):116-20.PMID:2936525DOI:10.1007/BF00256159.
The cell cycle phase specificity of Trimetrexate (CI-898) was examined. CHO cells synchronized by mitotic selection were exposed to 50 microM trimetrexate for 2 h at various time points after release from Colcemid block. Only S phase cells were sensitive to trimetrexate when survival was measured by a cloning assay. Comparison of plateau phase and log phase cultures indicated that plateau phase CHO cells were relatively insensitive to 5 microM trimetrexate. Exponentially growing L1210 cells were continuously exposed to either 30 nM or 3 nM trimetrexate and analyzed by DNA flow cytometry. Incubation with 30 nM trimetrexate produced cell cycle arrest in late G1 or early S phase, while exposure to 3 nM trimetrexate caused only a delay in progression through S phase. In an in vivo schedule dependence study with mice bearing approximately 3 X 10(6) P388 leukemia cells, trimetrexate was most effective with frequent administration. Mice treated on the optimal schedule, every 3 h X 8 on days 1, 5, and 9 after tumor implant, had life-span increases in excess of 100%.
Therapeutic synergy of Trimetrexate (CI-898) in combination with doxorubicin, vincristine, cytoxan, 6-thioguanine, cisplatin, or 5-fluorouracil against intraperitoneally implanted P388 leukemia
NCI Monogr 1987;(5):99-104.PMID:2963231doi
In order to support planning of clinical trials of Trimetrexate (CI-898) in combination chemotherapy regimens, several studies were carried out to determine the potential for therapeutic synergy between CI-898 and several clinically proven agents including doxorubicin, cytoxan, FUra, 6-thioguanine (6-TG), vincristine, methotrexate, and cisplatin. F1 hybrid mice bearing either early or advanced stage P388 leukemia were treated with either the single agents or with various combination regimens and observed for lifespan. These studies demonstrated a high degree of therapeutic synergism between CI-898 and doxorubicin, cytoxan, and 6-TG. Combinations of CI-898 with FUra, vincristine, and cisplatin also produced enhanced tumor cell kill, although the results were less dramatic than those mentioned above. The host toxicities of CI-898 and methotrexate were synergistic and appeared to negate any potential therapeutic benefit of the combination. The synergistic effect of the doxorubicin, vincristine, and cytoxan combinations may have been due to a lack of overlapping host toxicities, but the synergy observed with 6-TG was obtained in spite of synergistic host toxicity.
[Phase I study of CI-898. CI-898 Study Group]
Gan To Kagaku Ryoho 1991 Aug;18(10):1599-612.PMID:1831340doi
We conducted a phase I study of CI-898 (Trimetrexate), a new diaminoquinazoline antifolate in 22 patients with solid cancer in a multicenter collaborative study. The dosage schedule was single-dose intravenous administration (single treatment), followed by one or two courses of 5-day intravenous administration (5-day treatment) at 3-week intervals. Starting at 2 mg/m2 (1 n), the dose was increased up to 15 mg/m2 (7.5 n) for single treatment and 12 mg/m2 (6 n) for 5-day treatment. Evaluable cases numbered 18 for single treatment and 17 for 5-day treatment. In single treatment, the highest dose of 15 mg/m2 caused no serious side effect and did not reach the maximum tolerated dose (MTD). In 5-day treatment, leukocytopenia and thrombocytopenia were found dose dependently, the dose-limiting factor was bone marrow depression, and MTD was 10 mg/m2/day. The leukocyte and platelet counts reached the nadir in 1-3 weeks after initiation of 5-day treatment. The recovery from the nadir required about one week. Subjective side effects included mucitis (mouth, anus), malaise and gastro-intestinal symptoms (nausea, anorexia, diarrhea). None of alopecia, cardiotoxicity and nephrotoxicity were found. In the present phase I study, a tendency of tumor reduction was found in one case each of breast cancer (adenoma) and lung cancer (squamous cell carcinoma). The plasma concentration of the unchanged compound after single treatment showed a biphasic elimination pattern (t1/2 alpha 0.8-1.4 hr, t1/2 beta 9.4-13.0hr). The urinary excretion of the unchanged compound was 14.7-23.5% of the administered dose. In 5-day treatment, no accumulation was found. From the results of the present study, the recommended dosage of CI-898 in the early phase II study was considered to be 8 mg/m2/day intravenously for 5 days (every 3-4 weeks).
Clinical pharmacokinetics and pharmacology of Trimetrexate
Clin Pharmacokinet 1994 Mar;26(3):190-200.PMID:8194282DOI:10.2165/00003088-199426030-00003.
Trimetrexate represents one of a number of new antimetabolites that have been studied in malignant, rheumatological and infectious disease. Methotrexate, the classical antifolate agent, is active in a broad spectrum of clinical settings, but its use is limited ny pre-existing or acquired cellular resistance. Trimetrexate is an agent that does not require uptake by the folate carrier transport system, a major mechanism of cellular resistance both in vitro and in vivo. Both dihydrofolate reductase inhibition and high performance liquid chromatography (HPLC) assays can be used to determine drug concentrations. Clearance of Trimetrexate has been reported to follow biphasic or triphasic patterns. Elimination is primarily by biotransformation with less than 5% of the drug excreted renally in an unchanged form. Both active and inactive metabolites have been found, but the precise metabolic pathways have yet to be defined. The role of Trimetrexate in the treatment of Pneumocystis carinii pneumonia is limited to compassionate use, as clinical studies have shown cotrimoxazole (trimethoprim-sulfamethoxazole) to be superior to Trimetrexate. However, in a wide spectrum of malignant processes, Trimetrexate appears to have a role either as a high-dose single agent, with calcium folinate (leucovorin calcium) rescue, or in combination with other antineoplastic agents. However, further trials are needed to fully establish the efficacy of Trimetrexate in these settings. Increased knowledge of the pattern of resistance for individual tumours and tumour types may result in Trimetrexate becoming more widely used clinically.