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methotrexate

Methotrexate

Methotrexate (INN, AAN, BAN and USAN; Listeni/mɛθɵˈtrɛkseɪt/), abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug.

It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions.

It acts by inhibiting the metabolism of folic acid.

Methotrexate began to replace the more toxic antifolate aminopterin starting in the 1950s. The drug was originally synthesised by the Indian biochemist Yellapragada Subbarow and clinically developed by the American paediatrician Sidney Farber.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.

Indications

In modern neurooncology and onco-hematology, intraventricular injection of chemotherapeutic agents (most typically, methotrexate) is an inevitable part of many protocols for treating patients with malignant tumors of the CNS, neuroleukemia, CNS lymphomas and some other disorders.

Primary central nervous system lymphoma

Patients with leptomeningeal carcinomatosis face a particularly grim prognosis. Current treatment consists of intrathecal delivery of methotrexate (MTX) or cytosine arabinoside (Ara-C) via Ommaya reservoir or lumbar puncture. Yet despite these interventions, the median survival after diagnosis is only 4-7 months 1).


A study provides Class III evidence that in immunocompetent patients with primary CNS lymphomas (PCNSLs), high-dose methotrexate (HD-MTX) plus rituximab compared with HD-MTX alone improves complete response (CR) and overall survival rates 2).


A catheter was surgically placed into the fourth ventricle and attached to a ventricular access device. Cerebrospinal fluid (CSF) flow was confirmed by CINE MRI postoperatively. Each cycle consisted of 4 consecutive daily methotrexate infusions (2 milligrams). Disease response was monitored with serial MRI scans and CSF cytologic analysis. Trough CSF methotrexate levels were sampled. Five patients (3 with medulloblastoma and 2 with ependymoma) received 18, 18, 12, 9, and 3 cycles, respectively. There were no serious adverse events or new neurological deficits attributed to methotrexate. Two additional enrolled patients were withdrawn prior to planned infusions due to rapid disease progression. Median serum methotrexate level 4 h after infusion was 0.04 µmol/L. Range was 0.02-0.13 µmol/L. Median trough CSF methotrexate level 24 h after infusion was 3.18 µmol/L (range 0.53-212.36 µmol/L). All three patients with medulloblastoma had partial response or stable disease until one patient had progressive disease after cycle 18. Both patients with ependymoma had progressive disease after 9 and 3 cycles, respectively. Low-dose methotrexate can be infused into the fourth ventricle without causing neurological toxicity. Some patients with recurrent medulloblastoma experience a beneficial anti-tumor effect both within the fourth ventricle and at distant sites 3).


Arthrorheumatism with methotrexate-associated lymphoproliferative disorder in the brain 4).

1)
Chen TC, Napolitano GR, Adell F, Schönthal AH, Shachar Y. Development of the Metronomic Biofeedback Pump for leptomeningeal carcinomatosis: technical note. J Neurosurg. 2015 Aug;123(2):362-72. doi: 10.3171/2014.10.JNS14343. Epub 2015 May 8. PubMed PMID: 25955873.
2)
Holdhoff M, Ambady P, Abdelaziz A, Sarai G, Bonekamp D, Blakeley J, Grossman SA, Ye X. High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Neurology. 2014 Jul 15;83(3):235-9. doi: 10.1212/WNL.0000000000000593. Epub 2014 Jun 13. PubMed PMID: 24928128; PubMed Central PMCID: PMC4117362.
3)
Sandberg DI, Rytting M, Zaky W, Kerr M, Ketonen L, Kundu U, Moore BD, Yang G, Hou P, Sitton C, Cooper LJ, Gopalakrishnan V, Lee DA, Thall PF, Khatua S. Methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial. J Neurooncol. 2015 Aug 9. [Epub ahead of print] PubMed PMID: 26255071.
4)
Tamura R, Nakamura Y, Kuroshima Y. Arthrorheumatism with methotrexate-associated lymphoproliferative disorder in the brain. J Neurosurg Sci. 2016 Sep;60(3):400-401. PubMed PMID: 28097831.
methotrexate.txt · Last modified: 2017/01/18 22:14 (external edit)