Mirvetuximab soravtansine in platinum-resistant recurrent ovarian cancer with high folate receptor-alpha expression: a cost-effectiveness analysis.

OBJECTIVE: Mirvetuximab soravtansine (MIRV), a new antibody-drug conjugate, versus the investigator's choice of chemotherapy (IC) was the first treatment to demonstrate benefits for progression-free and overall survival in platinum-resistant recurrent ovarian cancer (PROC) with high folate receptor-alpha (high-FRα) expression. Efficacy, safety, and economic effectiveness make MIRV the new standard of care for these patients. METHODS: Based on patients and clinical parameters from MIRASOL (GOG 3045/ENGOT-ov55) phase III randomized controlled trials, the Markov model with a 20-year time horizon was established to evaluate the cost and efficacy of MIRV and IC for PROC with high-FRα expression, considering the bevacizumab-pretreated situation from the American healthcare system. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and incremental net health benefits were the main outcome indicators and compared with willingness-to-pay threshold of $100,000/QALY. Sensitivity and scenario analyses were conducted. RESULTS: Compared with the IC, MIRV was associated with incremental costs of $538,251, $575,674, and $188,248 with the corresponding QALYs (LYs) increased by 0.90 (1.55), 1.09 (1.88), and 0.53 (0.79), leading to ICERs of $596,189/QALY ($347,995/LY), $530,061/QALY ($306,894/LY), and $1,011,310/QALY ($680,025/LY) in the overall, bevacizumab-naïve, and bevacizumab-pretreated patients, respectively. When MIRV is reduced by more than 75%, it may be a cost-effective treatment. CONCLUSION: At the current price, MIRV for PROC with high-FRα expression is not the cost-effective strategy in the US. However, its treatment has higher health benefits in bevacizumab-naïve patients, which is likely to be an alternative.

Clinical efficacy of pemetrexed disodium in maintenance treatment of advanced lung adenocarcinoma / 中国基层医药

Objective:To investigate the clinical efficacy and adverse reactions of pemetrexed disodium in the maintenance treatment of advanced lung adenocarcinoma after chemotherapy with pemetrexed disodium and platinum.Methods:The clinical data of 35 patients with stage Ⅳ lung adenocarcinoma who received chemotherapy with pemetrexed disodium and platinum and were well treated in Beijing Huairou Hospital from January 2013 to August 2020 were retrospectively analyzed. Maintenance therapy with pemetrexed disodium was initiated after the completion of combination chemotherapy until disease progression. The clinical characteristics, therapeutic effects, adverse reactions, progression-free survival, and overall survival of the 35 patients were evaluated.Results:Among the 35 patients, no patients had complete remission, 11 patients had partial remission, 22 patients had stable disease, and 2 patients had progressive disease. The objective remission rate was 31.4%, disease control rate was 94.3%, median progression-free survival was 9.53 months, median overall survival was 18.21 months, 1-year survival rate was 68.6%, 2-year survival rate was 31.4%, and 3-year survival rate was 11.4%. Gender, age, smoking, and the baseline characteristics of patients undergoing first-line pemetrexed disodium or second-line pemetrexed disodium treatment had no effects on progression-free survival (all P > 0.05). Positive gene mutation and receiving four or more chemotherapy cycles had a protective effect on progression-free survival (both P < 0.05). Chemotherapy-related adverse reactions mainly included myelosuppression, nausea, elevated transaminase, and nephrotoxicity, all of which were mild and were relieved after symptomatic treatment. Conclusion:Pemetrexed disodium is effective and safe in the maintenance treatment of advanced lung adenocarcinoma. The results of this study are scientific.

Short-term efficacy of pemetrexed combined with cisplatin in the treatment of malignant pleural effusion and its effect on serum carbohydrate antigen 199 level and circulating tumor cells / 中国基层医药

Objective:To investigate the short-term efficacy of pemetrexed combined with cisplatin in the treatment of malignant pleural effusion and its effect on serum carbohydrate antigen 199 level and circulating tumor cells.Methods:Sixty patients with advanced lung cancer complicated by malignant pleural effusion who received treatment in Healthcare Group of Cixi Third People's Hospital, China from January 2017 to January 2020 were included in this study. They were randomly assigned to receive intrapleural injection of cisplatin (cisplatin alone group, n = 30) or intrapleural injection of cisplatin combined with intravenous injection of pemetrexed (cisplatin + pemetrexed group, n = 30) after thoracic drainage. Before and 1 month after treatment, pleural effusion was measured to evaluate clinical efficacy and improvement in quality of life. Serum carcinoembryonic antigen level, serum carbohydrate antigen 199 level and circulating tumor cells were determined. Adverse reactions during the treatment were recorded. Results:Total effective rate and the rate of improvement in quality of life in the cisplatin + pemetrexed group were 66.67% (20/30) and 70.00% (21/30), respectively, which were significantly higher than those in the cisplatin alone group [40.00% (12/30) and 43.33% (13/30), χ2 = 4.286, 4.344, both P < 0.05]. After treatment, serum carcinoembryonic antigen and serum carbohydrate antigen 199 levels in each group were significantly decreased compared with before treatment (both P < 0.05). Serum carcinoembryonic antigen and serum carbohydrate antigen 199 level in the cisplatin + pemetrexed group were (22.26 ± 5.13) ng/mL and (20.12 ± 4.35) U/mL, respectively, which were significantly lower than those in the cisplatin alone group [(31.64 ± 6.46) ng/mL, (28.07 ± 5.61) U/mL, t = 6.228, 3.134, both P < 0.05). In the cisplatin alone group, there was no significant difference in the proportion of circulating tumor cells before and after treatment ( P > 0.05). In the cisplatin + pemetrexed group, the proportion of circulating tumor cells after treatment was significantly lower than that before treatment ( χ2 = 4.286, P < 0.05). After treatment, there was no significant difference in the proportion of circulating tumor cells between the two groups ( P > 0.05). During the treatment, there were no significant differences in the incidences of rash, nausea and vomiting, leukopenia, and anemia between the two groups (all P > 0.05). Conclusion:Pemetrexed combined with cisplatin in the treatment of malignant pleural effusion exhibits better short-term efficacy than cisplatin alone. The combined therapy is more conducive to relieving clinical symptoms and improving the quality of life with higher safety than monotherapy.

Folic acid antagonist use before and during pregnancy and risk for selected birth defects.

BACKGROUND: Maternal folic acid (FA) intake before and during early pregnancy reduces the risk for neural tube defects (NTDs); evidence suggests it may also reduce the risk for oral clefts, urinary defects, and cardiac defects. We sought to re-examine the use of drugs, which affect folate metabolism, dihydrofolate reductase inhibiting (DHFRI) medications, and anti-epileptic drugs (AEDs), in data collected in the post-FA fortification era (1998+) in the Slone Birth Defects Study. METHODS: We assessed maternal DHFRI and AED use and risk for NTDs, oral clefts, and urinary and cardiac defects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We assessed daily average FA intake of ≥400 mcg as a potential effect modifier. RESULTS: We analyzed data from 10,209 control and 9,625 case mothers. Among controls, the prevalence of exposure to DHFRI medications was 0.3% and to AEDs was 0.5%. Maternal use of AEDs was associated with increased risks for NTDs (OR: 3.4; 95% CI: 1.5, 7.5), oral clefts (OR: 2.3; 95% CI: 1.3, 4.0), urinary defects (OR: 1.6; 95% CI: 1.0, 2.7), and cardiac defects (OR: 1.6; 95% CI: 1.1, 2.3); similar or further increased risks were found among those with FA intake ≥400 mcg per day. DHFRI use was rare and relative risk estimates were imprecise and consistent with the null. CONCLUSIONS: Similar to our previous analyses, we observed associations between AED use and these defects. For DHFRI exposure, we found no evidence for increased risk of these defects. Though statistical power to examine FA effect modification was low, we found no evidence of further protection among those with FA intake ≥400 mcg, with some associations somewhat stronger in this group.

Should nitrous oxide ever be used in oncology patients receiving methotrexate therapy?

Nitrous oxide (N2 O) is frequently used for short anesthesia/analgesia in children undergoing painful or repetitive procedures. Children with acute lymphoblastic leukemia (ALL) require repeated lumbar punctures with direct instillation of intrathecal chemotherapy, usually the anti-folate agent methotrexate, during their treatment. These procedures are frequently performed under anesthesia. Concerns have been intermittently raised about a drug interaction between methotrexate and N2 O that may potentiate the undesirable side effects of methotrexate, including neurotoxicity. However, the clinical evidence consists mainly of isolated case reports leading to a lack of consensus among pediatric anesthetists about the relative risk benefits of using N2 O in children with ALL. In this article, we review the biochemical basis and scientific observations that suggest a significant interaction between N2 O and methotrexate due to their dual inhibition of the key enzyme methionine synthase. The possible role of this interaction in potentiating neurotoxicity in children with cancer is discussed, and arguments and counterarguments about the clinical significance of this largely theoretical relationship are explored. Following comprehensive review of all the available data, we make the case for the circumstantial evidence being sufficiently compelling to prompt a review of practice by pediatric anesthetists and call for a precautionary approach by avoiding the use of N2 O in children receiving concurrent methotrexate.

Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications.

: Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications.

Methotrexate preferentially affects Tc1 and Tc17 subset of CD8 T lymphocytes.

Rheumatoid arthritis is considered a T-lymphocyte-mediated disease. However, studies have focussed on CD4 T-lymphocytes, ignoring CD8 T-lymphocytes despite the latter being found abundantly in the synovium. Specifically, there is little data of the effect of methotrexate, the gold-standard DMARD, on various CD8 cytokine T-lymphocyte subsets and conflicting data on CD4 subsets. In this prospective study, patients with active rheumatoid arthritis, who were 18 to 65 years of age, were treated with methotrexate (up to 25 mg per week) for 24 weeks. At baseline and 24 weeks, frequencies of CD8+IFNγ+, CD8+IL17+, CD8+IL4+, corresponding CD4 subsets and plasma levels of IFNγ, IL-12, IL-10, IL-4 and IL-17 were determined by flow cytometry. These are summarised as median (IQR = interquartile range, 25th-75th percentile) and paired data compared using Wilcoxon signed rank test. This study included 67 patients (F/M = 4:1) with rheumatoid arthritis, 57 (85%) being RF positive and 20 receiving prednisolone at baseline. Mean (± SD) dose of methotrexate at 24 weeks was 22.9 ± 3.0 mg per week. On treatment with methotrexate, there was a significant (p = 0.04) decline in CD8+IFNγ+ cells from 37.2 (IQR 19.4-60.2) to 22.7% (IQR 8.5-49.7) and a marginal increase in CD8+IL17+ cells from 0.3 (IQR 0.1-0.6) to 0.4 (IQR 0.2-1.2), p = 0.006. There was no significant change in the other subsets. There was also a significant decline in circulating levels of IL-12, IL-10 and IL-17 and marginal increase in IL-4. On evaluating by response, non-responders but not responders had a significant increase in CD8+IL17+ (p = 0.01). There is a significant decline of CD8+IFNγ+ T cells and marginal increase in CD8+IL17+ T cells after methotrexate. Change in Tc1 subset may be mediated through reduction in IL-12 levels.

Phase I/II study of pralatrexate in Japanese patients with relapsed or refractory peripheral T-cell lymphoma.

Pralatrexate is a novel antifolate approved in the USA for the treatment of relapsed or refractory peripheral T-cell lymphoma. To assess its safety, efficacy, and pharmacokinetics in Japanese patients with this disease, we undertook a phase I/II study. Pralatrexate was given i.v. weekly for 6 weeks of a 7-week cycle. All patients received concurrent vitamin B12 and folic acid. In phase I, three patients received pralatrexate 30 mg/m2 and none experienced a dose-limiting toxicity. In phase II, we treated 22 additional patients with that dose. The median number of treatment cycles was 1 (range, 1-9). Nine of 20 evaluable patients (45%) achieved an objective response by central review, including two complete responses. All responses occurred within the first treatment cycle. At the time of data cut-off, median progression-free survival was 150 days. Median overall survival was not reached. In the total population, the most commonly reported adverse events included mucositis (88%), thrombocytopenia (68%), liver function test abnormality (64%), anemia (60%), and lymphopenia (56%). Grade 3/4 adverse events included lymphopenia (52%), thrombocytopenia (40%), leukopenia (28%), neutropenia (24%), anemia (20%), and mucositis (20%). The pharmacokinetic profile showed no drug accumulation with repeat dosing. These results indicate that pralatrexate is generally well tolerated and effective in Japanese patients with relapsed or refractory peripheral T-cell lymphoma. This trial was registered with ClinicalTrials.gov (NCT02013362).

Safety and benefits of interventions to increase folate status in malaria-endemic areas.

For decades, folic acid has routinely been given to prevent or treat anaemia in children, pregnant women and people with sickle cell disease. However, there is no conclusive evidence that folate deficiency anaemia constitutes a public health problem in any of these groups. Industrial flour fortification is recommended and implemented in many countries to combat neural tube defects. Dietary folates or folic acid can antagonise the action of antifolate drugs that play a critical role in the prevention and treatment of malaria. Randomised trials have shown that folic acid supplementation increases the rate of treatment failures with sulfadoxine-pyrimethamine. The efficacy of antifolate drugs against Plasmodium is maximized in the absence of exogenous folic acid, suggesting that there is no safe minimum dose of ingested folic acid. We here review the safety and benefits of interventions to increase folate status in malaria-endemic countries. We conclude that formal cost-benefit analyses are required.

A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors.

BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). METHODS: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m(2) on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m(2) /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. RESULTS: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. CONCLUSIONS: The recommended dose of PDX was 148 mg/m(2) . A subset of heavily pretreated patients had PFS durations of ≥6 months with this regimen.

Improved synthesis process of diethyl N-[4-[(2,4-diaminopyrido[3,2-d] pyrimidin-6-yl) methylamino] benzoyl]-L-glutamate / 北京大学学报(医学版)

Objective:To establish a new approach to synthesis of diethyl N-[4-[(2,4-diaminopyrido [3,2-d]pyrimidin-6-yl)methylamino]benzoyl]-L-glutamate.Methods:Target compound (5) was syn-thesized by the use of (2,4-dioxo-tetrahydropyridopyrimidin-6-yl) methyl acetate (1) as starting material via hydrolysis, chlorination, condensation with diethyl (p-aminobenzoyl)glutamate and aminolysis.Re-sults:A new approach to synthesis of diethyl N-[4-[(2,4-diaminopyrido[3,2-d]pyrimidin-6-yl)methyl-amino]benzoyl]-L-glutamatewas established .This synthetic route has hydrolysis reaction , chlorination, diethyl N-( p-aminobenzoyl )-L-glutamate condensation reaction and ammonolysis reaction .The total yield is 36.7%.The structures of those compounds have identified by 1 H nuclear magnetic resonance , 13 C nu-clear magnetic resonance and mass spectrometry .This synthetic route avoid the unstable brominated re-action product and improves the harsh condition of ammonolysis reaction .Conclusion:The new synthetic route has improved the reaction condition and the stability of the intermediate , and increased the extent of the derivative compounds , which has great significance to anti-folic acid of anti-tumor inhibitor synthesis .

Polimorfismos en los genes de dihidrofolato-reductasa ( dhfr ) y dihidropteroato-sintasa ( dhps ) y modelado estructural del gen dhps en aislamientos colombianos de Toxoplasma gondii / Gene polymorphisms in the dihydrofolate reductase ( dhfr ) and dihydropteroate synthase ( dhps ) genes and structural modelling of the dhps gene in Colombian isolates of Toxoplasma gondii

Introducción. No existen reportes sobre las variaciones en la secuencia de los genes blanco de los medicamentos anti- Toxoplasma en aislamientos provenientes de Suramérica. Objetivo. Clonar y secuenciar los genes de la dihidrofolato-reductasa ( dhfr ) y la dihidropteroato-sintetasa ( dhps ) de la cepa de referencia RH y de dos aislamientos colombianos de Toxoplasma gondii. Materiales y métodos. Se obtuvieron dos aislamientos de T. gondii en líquido céfalorraquídeo de pacientes colombianos positivos para HIV con toxoplasmosis cerebral. Se extrajo el ADN de los genes dhfr y dhps y se amplificaron mediante reacción en cadena de la polimerasa (PCR). Los productos fueron clonados en el vector pGEM-T y secuenciados. Resultados. Se encontró un cambio de adenina por guanina (A « G) en la posición 235 del exón 2 del gen dhps , dos cambios de guanina por citocina (G « C) en las posiciones 259 y 260 y un cambio de timina por guanina (T « G) en la posición 371 del exón 4 del gen dhps. Por análisis bioinformático, en este último exón se identificó un polimorfismo no sinónimo en la región codificante, que podría llevar al cambio de una Glu (CAA o CAG) por una His (codificada por los codones AAU o AAC). Se calculó el modelo estructural de la enzima dihidropteroato-sintetasa (DHPS) de T. gondii y se identificaron las modificaciones en la estructura secundaria ocasionadas por las mutaciones. Conclusiones. La metodología estandarizada puede servir como base para la búsqueda de polimorfismos en muestras de pacientes con diferentes manifestaciones clínicas de toxoplasmosis y para establecer su posible relación con los cambios en la sensibilidad a los antifolatos y la reacción al tratamiento.

Introduction: There are no reports describing polymorphisms in target genes of anti- Toxoplasma drugs in South American isolates. Objective: This study sought to perform cloning and sequencing of the dihydrofolate reductase ( dhfr ) and dihydropteroate-synthase ( dhps ) genes of the reference Rh strain and two Colombian isolates of Toxoplasma gondii . Materials and methods: Two isolates were obtained from the cerebrospinal fluid of HIV-infected patients with cerebral toxoplasmosis. A DNA extraction technique and PCR assay for the dhfr and dhps genes were standardized, and the products of amplification were cloned into Escherichia coli and sequenced. Results: One polymorphism (A « G) was found at position 235 of exon 2 in the dhps gene. In addition, two polymorphisms (G « C) at positions 259 and 260 and one polymorphism (T « G) at position 371 within exon 4 of the dhps gene were detected. In this last exon, a bioinformatic analysis revealed a non-synonymous polymorphism in the coding region that could lead to the substitution of Glu (CAA or CAG) for His (encoded by codons AAU or AAC). A structural model of the T. gondii DHPS protein was calculated, and the results revealed modifications in secondary structure due to mutations. Conclusions: The methods described in this study can be used as a tool to search for polymorphisms in samples from patients with different clinical manifestations of toxoplasmosis and to examine their relationship with the therapeutic response.

Biochemical characterization of the bifunctional enzyme dihydrofolate reductase-thymidylate synthase from Leishmania ( Viannia ) and its evaluation as a drug target / Caracterización bioquímica de la enzima bifuncional dihidrofolato reductasa-timidilato sintasa de Leishmania ( Viannia ) y su evaluación como blanco molecular

Introduction. Dihydrofolate reductase (DHFR) has been used successfully as a drug target in the area of anti-bacterial, anti-cancer and anti-malarial therapy. Although this bifunctional enzyme is also a potential drug target for treatment of leishmaniasis, there have been no reports on its efficacy against Leishmania ( Viannia ) species . Materials and methods. The gene encoding the bifunctional DHFR and thymidylate synthase (TS) of Le. (V.) braziliensis was isolated and expressed in E. coli. The enzyme was purified and characterized. The inhibitory effects of antifolates and four aporphine alkaloids on its activity were evaluated. Results. The full-length gene consists of a 1560-bp open reading frame encoding a 58 kDa translated peptide containing DHFR and TS domains linked together in a single polypeptide chain. The recombinant DHFR-TS enzyme revealed K m and V max values of 55.35 ± 4.02 µ M (mean ± SE) and 0.02 ± 5.34 x 10 -4 µ M/min respectively for dihydrofolic acid (H 2 F). The Le. braziliensis rDHFR-TS have Ki values for antimicrobial antifolates in the µM range. Methotrexate (MTX) was a more-potent inhibitor of enzymatic activity ( Ki = 22.0 µM) than trimethoprim ( Ki = 33 µM) and pyrimethamine ( Ki = 68 µM). These Ki values are significantly lower than those obtained for the aporphine alkaloids. Conclusion. The results of the study show the inhibitory effect of antifolate drugs on enzymatic activity, indicating that Le. braziliensis rDHFR-TS could be a model to studying antifolate compounds as potential antiprotozoal drugs.

Introducción. La dihidrofolato reductasa (DHFR) se ha utilizado como blanco molecular en tratamientos antibacterianos, anticancerígenos y antipalúdicos. También, actúa como blanco molecular en Leishmania ; sin embargo, no existen reportes de la enzima bifuncional en especies de Leishmania ( Viannia ). Materiales y métodos. Se ha aislado y expresado en Escherichia coli el gen que codifica para la enzima bifuncional DHFR y la timidilato-sintasa (TS) de Leishmania braziliensis . La enzima recombinante se purificó y caracterizó, y se evaluó el efecto inhibitorio de algunos antifolatos, así como de cuatro alcaloides aporfínicos. Resultados. El gen se compone de aproximadamente 1.560 pb y codifica un péptido de 58 kDa que contiene los dominios DHFR y TS ligados en una sola cadena polipeptídica. La enzima recombinante DHFR-TS, utilizando el dihidrofolato (H2F) como sustrato, presentó valores de K m y V max de 55,35 ± 4,02 (media ± el error estándar de la media) y de 0,02 ± 5,34 x 10 -4 , respectivamente. La enzima rDHFR-TS de L. braziliensis presentó valores de Ki para los antifolatos en el rango de micras. El metotrexato fue el inhibidor más potente de la actividad enzimática ( Ki =22,0 mM) en comparación del trimetoprim ( Ki =33 mM) y la pirimetamina ( Ki =68 mM). Estos valores de Ki son significativamente más bajos en comparación con los obtenidos para los alcaloides aporfínicos. Conclusión. Los resultados muestran el efecto inhibitorio de los antifolatos sobre la actividad enzimática, lo cual indica que la rDHFR-TS de L. braziliensis podría ser un modelo para estudiar moléculas antiprotozoarias potenciales.