The importance of adequate methotrexate and adequate folinic acid rescue doses in the treatment of primary brain lymphoma

Cohen, Ian J.

doi:10.1007/s11060-018-2999-x

Cited by 8 publications

(4 citation statements)

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“…Inhibition of DHFR by methotrexate leads to blockade of folate synthesis (and nucleic acid) ( 27 ). Adding folinic acid to methotrexate treated cells rescues the cells by replenishing folate reserves, a process referred to as folinic acid rescue ( 28 ). Here, we used folinic acid rescue to study the role of DHFR inhibition by methotrexate in the suppression of virus replication ( Figure S7 ).…”

Section: Resultsmentioning

confidence: 99%

Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model

et al. 2022

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BackgroundDrug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease.MethodsHere, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC50 = 0.4 μM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms.ResultsOur in vitro studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals.ConclusionsWe demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.

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Section: Resultsmentioning

confidence: 99%

Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model

et al. 2022

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“…The misleading advice that the FA rescue dose should be kept at a minimum to prevent a reduction in cure rates by “over rescue” has been accepted without any evidence, and no reports of reduced prognosis with increased FA rescue were found 55. Clinicians do not need to worry that the price of no neurotoxicity will be poorer treatment results.…”

Section: Discussionmentioning

confidence: 99%

“…54 The misleading advice that the FA rescue dose should be kept at a minimum to prevent a reduction in cure rates by "over rescue" has been accepted without any evidence, and no reports of reduced prognosis with increased FA rescue were found. 55 Clinicians do not need to worry that the price of no neurotoxicity will be poorer treatment results. A good example is the SCOS89 osteosarcoma protocol that used 300 to 600 mg/m 2 of FA after each treatment of 12 to 20 gm/m 2 MTX and also reported 1 of the best 10-year event-free and overall survival rates to date: 80% and 78%, respectively.…”

Section: Outdated Axiomsmentioning

confidence: 99%

A Comprehensive Review of Neuropsychologic Studies Supports the Concept That Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity

Sadeh

Toledano

Cohen

2022

Journal of Pediatric Hematology/Oncology

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Purpose: To review all studies providing evidence of the correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage in neuropsychological studies of children with acute lymphoblastic leukemia or osteogenic sarcoma treated under protocols using high-dose methotrexate and FA rescue. Methods: A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990–2020, for the terms: neuropsychological, neurocognitive, and cognitive, together with acute lymphoblastic (and lymphocytic) leukemia and osteogenic sarcoma. English-language peer-reviewed articles on neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. In addition, a personal database of over 500 reprints of articles from over 130 journals was reviewed on the subjects of methotrexate and FA and their side effects. Results: Three groups of studies were found and analyzed, with (1) no evidence of cognitive deterioration, (2) evidence of cognitive deterioration, and (3) more than 1 protocol grouped together, preventing separate analysis of any protocols, Protocols without cognitive deterioration reported adequate FA rescue, and those with cognitive deterioration reported inadequate FA rescue. Conclusion: Neuropsychological evaluation supported inadequate FA being the cause of neurocognitive damage after high-dose methotrexate and that adequate FA rescue prevents this complication.

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“…The misleading advice that the FA rescue dose should be kept at a minimum to prevent a reduction in cure rates by "over rescue" has been accepted without any evidence, and no reports of reduced prognosis with increased FA rescue were found [8]. Reports that claimed increasing the FA dose reduces prognosis did not stand up to close scrutiny and have since been discredited [7], and many of the articles cited to support this concept were recently shown to be problematic [10].…”

mentioning

confidence: 99%

A Systematic Review of Neuropsychological Studies Confirms that Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity

Sadeh

Toledano

Cohen

2021

Preprint

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A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990-2020, for the terms: neuropsychological, neurocognitive, cognitive, acute lymphoblastic (and lymphocytic) leukemia, and osteogenic sarcoma, to see if there was evidence of a correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage. All English language, peer-reviewed articles of neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. Four groups of studies were found and analyzed, Those with no evidence of cognitive deterioration, Those with evidence of cognitive deterioration, studies with more than one protocol grouped together, preventing separate analysis of any protocols, and those with significant serious methodical problems. In all studies, protocols without evidence of cognitive deterioration reported adequate FA rescue, and those with evidence of cognitive deterioration reported inadequate FA rescue.

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The importance of adequate methotrexate and adequate folinic acid rescue doses in the treatment of primary brain lymphoma

Cited by 8 publications

References 4 publications

Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model

Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model

A Comprehensive Review of Neuropsychologic Studies Supports the Concept That Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity

A Systematic Review of Neuropsychological Studies Confirms that Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity

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