Administration Of Methotrexate Research Articles

Korisnost ponovljenih merenja nivoa leka nakon infuzije visoke doze metotreksata za planiranje lečenja kod pedijatrijske leukemije

Introduction: Although high-dose Methotrexate (MTX) is a successful chemotherapeutic agent used in the treatment of acute lymphoblastic leukemia in childhood, life-threatening toxic effects are rarely seen. Therefore, frequent follow-up of drug levels is recommended. The study researched the necessity of drug level measurement and a minimum safe number of measurements. Materials and Methods: The files of pediatric patients with Acute Lymphoblastic Leukemia receiving high-dose MTX treatment in a single center between 2018 and 2021 were retrospectively reviewed. The treatment protocol was: 3000 mL/m2 alkaline hydration fluid was continued until the 72nd hour together with 2 gr/m2 continuous MTX infusion in the low-risk group and 5 gr/m2 in moderate and high-risk groups, and 15 mg/m2 /dose folinic acid was given at the 42nd, 48th and 54th hours. Findings: 456 MTX treatments were evaluated in 114 patients. Similar results (p > 0.05) were obtained in the MTX level measurements performed at the 24th, 42nd, 48th, and 54th hours after MTX administration. In the repeated measurements, the data at the 42nd hour were similar (p = 0.021). The number of cases that were > 150 µmol/L at the 24th hour of methotrexate infusion and above 1 µmol/L at the 42nd, 48th, and 52nd hours were found to be similar in the repeated measurements. Conclusion: Although recommended, frequent follow-up of MTX levels might not always indicate toxicity. In centers with limited laboratory facilities, the MTX level measured at the 42nd hour in the first treatment might be a practical approach to guide the management of other MTX treatments.

Interventional radiology in ectopic pregnancy management

Ectopic pregnancies especially cervical, tubal and cesarean scar pregnancies, represent obstetrical emergencies that endanger the fertility and, more important, the life of women. Interventional radiology has gained popularity over the last years in the treatment of ectopic pregnancy as combined treatment with methotrexate administration in cases of tubal pregnancy, first line treatment in cases of cesarean scar pregnancies or, more recently, as single line management in cases of cervical pregnancies with astonishing results and numerous benefits. Its primary advantage is represented by fertility preservation among young fertile women simultaneously with the avoidance of an invasive surgical method with the subsequent risks and possible complications. We present a narrative review regarding success rates of uterine artery embolization in the treatment of ectopic pregnancies.

Patient-reported adverse effects when switching from oral to subcutaneous administration of methotrexate: A prospective, multicenter, paired cohort study

To the Editor: Many inflammatory skin disorders can be treated with weekly low-dose oral methotrexate (oMTX). However, nausea (25%) and asthenia (15%) are common adverse effects (AEs) that reduce drug survival. Changing from oral to subcutaneous methotrexate (scMTX) may reduce the AEs, but the results of a few prior studies are inconsistent.1,2

The features of the course of virus-associated acute lung injury in mice with induced immunosuppression

BACKGROUND: Among all groups of patients with virus-associated acute lung injury with influenza infection, the most severe course is observed in patients with immunosuppression. In this case, despite the studied mechanism of the course of combined pathology, the question of therapy in this group of patients remains unclear.
 AIM: To study the features of the course of acute lung injury in influenza infection with secondary immunosuppression in an experiment for the possibility of searching for experimental therapy for this combined pathology.
 MATERIALS AND METHODS: The study was performed on 115 outbred female mice. The mouse-adapted pandemic influenza virus A/California/7/09MA (H1N1)pdm09 was used for modeling viral acute lung injury. Experimental immunosuppression was reproduced by administration of methotrexate (1.25 mg/kg intraperitoneally, once every 3 days during 3 weeks before infection). During the experiment, mortality, blood oxygen saturation, the concentration of pro-inflammatory cytokines in the lungs, and the severity of lung injury were measured.
 RESULTS: The presence of experimental immunosuppression led to an exacerbation of acute lung injury in infected animals in terms of mortality and lung damage. Changes in the dynamics of proinflammatory cytokines (TNF-, IL-6, IL-1) in the lungs were observed during acute lung injury. Retarded recovery of the lungs functional activity was noted.
 CONCLUSIONS: The experimental immunosuppression contributed to the exacerbation of acute lung injury and to an increase in the duration of the pathology. These changes could be associated with an altered process of elimination of the pathogen. The reproduced model of combined pathology was used for searching a therapy for these complications.

Methotrexate as a Steroid-Sparing Agent in Myasthenia Gravis: A Preliminary Retrospective Study.

Treatment approach of myasthenia gravis (MG) is still debated; corticosteroids alone or in combination with immunosuppressive agents are the most used drugs. Azathioprine (AZA) has been shown to be effective for MG with a significant steroid-sparing activity, although burdened by side effects. Few studies on methotrexate (MTX) administration showed controversial results. In this cohort, we evaluated the role of MTX as a effective steroid-sparing agent. Fifteen MG patients treated with MTX, previously treated with AZA for at least 12 months, with poor benefits and uncomfortable side effects AZA related, have been selected. Each patient was evaluated through MG-Activity of Daily Living and Quantitative MG scores 5 times/yr. Patients treated with MTX had a significant improvement of MG-Activity of Daily Living and Quantitative MG scores. Furthermore, all patients reduced prednisone dosage, and none complained of side effects. We suggest MTX is effective and well tolerated and could be considered as a steroid-sparing agent in MG treatment.

Pregnancy outcomes in patients with rheumatoid arthritis who discontinue methotrexate treatment to conceive.

Rheumatoid arthritis (RA) develops at reproductive age. Methotrexate (MTX), the anchor drug for RA treatment, is contraindicated during pregnancy. We investigated pregnancy outcomes in RA patients in whom MTX was withdrawn. Pregnancy outcomes, RA treatment, and infertility factors were examined in patients with RA who discontinued MTX prior to attempting conception. The Mann-Whitney U test and Fisher's exact test were used to evaluate differences between the groups. Of the 52 patients enrolled in this study, 33 gave birth after discontinuing MTX and 19 did not. The age at MTX discontinuation was significantly different between the childbirth and non-childbirth groups (p = 0.0258). The use of non-steroidal anti-inflammatory drugs (NSAIDs) and salazosulfapyridine was significantly different between the groups (p = 0.0079 and p = 0.0438, respectively). Patients whose time from MTX discontinuation to pregnancy was longer than 12months had a longer previous MTX administration period (p = 0.0182) and were older at the time of pregnancy (p = 0.0128) than those whose was shorter. The results suggest that to ensure successful childbirth in women with RA, the decision to conceive should be made at the youngest possible age, NSAIDs should not be used, and a shorter duration of MTX treatment should be considered before pregnancy. Nevertheless, additional studies with larger sample sizes are warranted to analyse the effects of other factors on pregnancies in patients with RA. • Patients with RA who plan to conceive must discontinue MTX therapy. • To achieve successful pregnancy outcomes, female patients with RA should become pregnant when they are young, discontinue NSAIDs prior to conception, and shorten their durations of MTX therapy before attempting pregnancy.

MTHFR and SLCO1B1 Gene Polymorphism and Methotrexate Induced Toxicity in Children with Acute Lymphoblastic Leukemia in the Northwest of Mexico

Introduction.Acute lymphoblastic leukemia (ALL) represents approximately 52% of pediatric cancer diagnoses in Mexico and is the leading cause of death by disease among children of 5 to 14 years. The use of pharmacogenomics for the detection of germline genetic variations, which are associated with sensitivity or toxicity to chemotherapy, is one of the recent strategies to improve survival. Some mutations present in genes related to the metabolism or transport of methotrexate (MTX) have been associated with the occurrence of toxicities during treatment in pediatric acute lymphoblastic leukemia. The effect of the SNP´s rs1801131, rs1901133 in the MTHFR and rs4149058, rs4149081 in the SLCO1B1 gene have not been studied in Northwest Mexican children with acute lymphoblastic leukemia.Patients and methods.Eligible patients were infants less than 1 year to adolescents less than 18 years of age, diagnosed with B-ALL at the Specialties Children's Hospital of Chihuahua, Mexico. Patients were treated according to the locally protocols based on the St. Jude Children's Research Hospital Total XIIIB and Total XV protocols. We followed-up for two to four weeks after 24 hours high dose MTX (1 to 5 g/m 2) administration. Toxicity data were collected objectively from the patient's medical files and adverse effects were classified as a dichotomous variable yes/no. Genomic DNA was extracted with the Master Pure DNA purification kit (Epicentre Illumina® Company) from peripheral blood. Genotyping assays were performed by real-time polymerase chain reaction, using rhAMp® IDT® genotyping probes (Iowa, USA) and Quant Studio 3 Applied Biosystems Real-Time System Thermal Cycler (Thermo Fisher Scientific®). For statistical analysis association between MTX dose, presence of toxicity, and genetic polymorphisms was evaluated by the chi-square or Fisher's exact test. The effect sizes of the associations were estimated by the OR's from univariate logistic regressions and multivariate logistic regressions to account for the possible confounding effect of sex and age. Analyses were performed by using SAS System and IBM SPSS Statistics Base 22.0 software.Results.The study population demographics and clinical characteristics are summarized in Table 1. MTHFR and SLCO1B1 genotype in our patients and controls obtained from the 1000 Genomes Project database are shown in table 2. In general, a predominance of toxicity events is observed in patients heterozygous for both polymorphisms in the MTHFR gene, but not in the SLCO1B1 gene (Figure 1). Through a logistic regression analysis, we observed an association of 8% between the polymorphisms rs1801131, rs1901133, rs4149058, rs4149081 and the presence of anemia. The AC heterozygous of the rs1801131 has the strongest association with a positive coefficient (+1.1355) and when comparing AC heterozygotes with CC mutated homozygotes, an Odds Ratio (OR) of 4.64 (CI: 95%, 0.719) was observed, identifying it as a risk factor. In contrast, the homozygous AA of the same gene, presented a negative coefficient (-0.7354), thus decreasing the probability of presenting anemia in this population. The presence of neutropenia was associated in 25% with the polymorphisms rs1801131, rs1901133, rs4149058, rs4149081. The AA homozygous of rs1801131 decreased the probability of developing neutropenia (coefficient -0.7643, p=0.04) and the TC heterozygous of rs4149056 increased the probability when comparing with the wild TT homozygotes (OR of 2.91, CI: 95%, 0.496). Liver enzymes elevation was associated in 84% with the polymorphisms rs1801131, rs1901133, rs4149058, rs4149081. We found that the presence of TC heterozygote of rs4149056 decreased the probability of hepatotoxicity (coefficient -1.5718, p=0.03) and GA heterozygote of rs41419081 increased it (coefficient +3.2056, p=0.004) (Table 3). According to this statistical model, we could not analyze the association between the polymorphisms rs1801131, rs1901133, rs4149058, rs4149081 and thrombocytopenia, mucositis, febrile neutropenia or creatinine elevation.ConclusionToxicity related to treatment is one of the most important causes of death among pediatric ALL patients in Mexico, the development of precision medicine through the identification of SNPs associated with the variability in our patients' response is an alternative to minimize methotrexate toxicity and maximize its benefit during its use. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of Severe Toxicities Following High Dose Methotrexate Administration By Demographics and over Time in Pediatric Patients with Acute Lymphoblastic Leukemia

Background: Methotrexate (MTX) is a cornerstone of therapy for pediatric patients with acute lymphoblastic leukemia (ALL). Administration of high dose (HD) MTX requires hospitalization and concurrent intravenous fluids and leucovorin while awaiting drug excretion. HDMTX has been associated with acute adverse events (AEs), such as mucositis, neurotoxicity, and myelosuppression, that can impact quality of life and ability to administer subsequent chemotherapy. There are limited data evaluating differences in AEs after HDMTX among demographic groups.Objective: The objective of this study was to describe AEs for patients receiving HDMTX (defined as >500 mg/m2 to account for dose reductions from protocol dosing) and to compare rates by age, race, ethnicity and dose number using a multicenter cohort.Methods: A multi-center retrospective study collected data on pediatric ALL patients ages 0-21 years at diagnosis who received at least one dose of HDMTX at Children's Healthcare of Atlanta or Cincinnati Children's Hospital Medical Center from January 2010 through December 2020. Demographic (age, sex, race, ethnicity) and clinical (vital status, Down Syndrome, HDMTX doses) variables were manually abstracted from the electronic medical record. Algorithms were developed a priori based on Common Terminology Criteria for Adverse Events v5 to identify the presence and grade of targeted AEs after HDMTX administration. The following AEs were abstracted for the time period from each HDMTX dose until the next HDMTX or other chemotherapy administration: mucositis, neurotoxicity, neutropenia, and thrombocytopenia. Only grade 4 neutropenia and grades 3-4 thrombocytopenia were collected. Institutional review board approval was obtained at each site. Descriptive and inferential statistics, including chi-square, Fisher's exact test, and generalized estimating equations (GEE) as appropriate, were calculated to evaluate differences in AEs by dichotomized age (<10, 10+), race, ethnicity, and HDMTX administration number. All analyses were performed using SAS Enterprise Guide v7.1.Results: Across sites, 543 patients with ALL patients received HDMTX (2064 administrations). The median age at first HDMTX was 8.0 years (0.1-21.0); 230 (42.4%) were female, 381 (70.2%) were White, and 441 (81.2%) were Non-Hispanic or Latino (Table 1). The median number of HDMTX administrations was 4.0 (Range 1-10). In total, 469 (86.4%) patients had at least one AE. Mucositis occurred in 386 (71.1%) patients, grade 4 neutropenia occurred in 243 (50.1%) and grade 3-4 thrombocytopenia occurred in 156 (32.2%, Table 2). Mucositis, neurotoxicity, and thrombocytopenia were significantly more likely in patients 10+ years (p=0.02, p<0.01, p<0.01, respectively, Table 2). There were no significant differences in AE rates by race or ethnicity. Table 3 describes percentages of administrations with each AE grade. Half of HDMTX administrations had at least one AE. AE rates decreased significantly from first to fourth administration (67.5% of first and 33.0% of fourth administrations with at least one AE, p<0.01). Rates of mucositis and neurotoxicity individually decreased over administrations (p<0.01, Table 3).Conclusion: AEs after administration of HDMTX are common, with 86% of patients experiencing at least one AE after receipt of HDMTX and half of administrations leading to at least one AE. Greater than half of patients experienced mucositis and neutropenia. Older patients experienced significantly more mucositis, neurotoxicity, and thrombocytopenia. Unsurprisingly, we found that overall the rate of AEs was highest after the first HDMTX administration and decreased significantly across doses, which is likely due to dose reductions in HDMTX or concurrent antimetabolite therapy and to increased supportive care (hydration and leucovorin) after experience of an AE. Chart abstraction is ongoing at a third hospital that will increase the sample size of patients, particularly those of Hispanic/Latino ethnicity, to delineate potential differences by race and ethnicity. In addition, current analyses are evaluating the impact of supportive care and dosing changes between administrations on the burden of HDMTX-related AEs and differences by age. The results of this study will provide valuable data regarding who is at highest risk for AEs and can be used to tailor supportive care during this potentially toxic chemotherapy. [Display omitted] DisclosuresBernhardt: Bristol Myers Squibb: Research Funding; BTG International: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharmaceuticals: Consultancy; Mesoblast: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. O'Brien: Jazz: Honoraria; Pfizer: Honoraria, Research Funding. Ramsey: BTG Specialty Pharmaceuticals: Honoraria, Research Funding.

Galangin mitigates oxidative stress, inflammation, and apoptosis in a rat model of methotrexate hepatotoxicity.

Methotrexate (MTX) is an efficient chemotherapeutic agent for treating various malignancies and autoimmune diseases. However, the long-term use of MTX can result in hepatotoxicity and this limits its use. Galangin (Gal) is a potent flavonoid with various biological activities; however, its protective effect against MTX hepatotoxicity has not been previously investigated. This study evaluated the hepatoprotective of Gal against MTX-induced liver injury. Rats received Gal for 10days and a single dose of MTX (20mg/kg) at day 7. The administration of MTX induced liver damage reflected by increased serum biomarkers of liver function and histopathological manifestations. MTX increased hepatic reactive oxygen species (ROS), nitric oxide (NO), malondialdehyde (MDA), and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and diminished GSH and antioxidant enzymes. Gal relieved liver injury, ameliorated liver function, oxidative stress, and inflammation markers, and increased antioxidants in MTX-treated rats. In addition, Gal decreased the expression of inflammation and apoptosis markers in MTX-treated rats. In conclusion, Gal possesses a hepatoprotective effect mediated by attenuating oxidative damage, inflammation, and apoptosis in rats.

A CASE OF METHOTREXATE-INDUCED PHOTOSENTIVITY REACTION

Methotrexate is an essential drug effectively used in acute lymphoblastic leukemia. Doses above 500 mg/m2 are defined as high-dose methotrexate (HDMTX). Since HDMTX is known to cause serious morbidity, it is given with a standard rescue therapy to prevent toxicity. Besides myelosuppression and mucositis, other side effects of methotrexate are hepatotoxicity, erythema, desquamation, allergic reactions and neurotoxicity. Methotrexate is also associated with radiation recall and false photosensitivity. A 10-year-old girl with pre-B ALL underwent hematopoietic stem cell transplantation two times due to marrow and central nervous system (CNS) relapse. On the follow-up, 3 months later she had a bone marrow relapse. After remission obtained with high dose chemotherapy, maintenance treatment was given due to relapse/refractory disease. One year later she had isolated CNS relapse again and treated with intrathecal methotrexate, Ara-C and dexamethasone. The patient was started on relapse/refractory maintenance therapy, and 1 g/m2 methotrexate was given every 4 weeks. Immediately after intravenous methotrexate was given to the patient in the 13th week of her treatment, she complained of burning, pain and redness in the areas that had previously been desquamated due to sunburn. No additional treatment was given, except alkaline hydration and calcium folinate, when the findings were observed. The patient was started on antihistamine therapy. Methotrexate drug level reached 0.02 umol/L at the 54th hour, the i.v. hydration was stopped. The patient's red and itchy lesions healed within 2 days by benefiting from the antihistamine. She is being followed-up at our outpatient clinic weekly chemotherapy without any sign of relapse. This sunburn-like erythema after methotrexate administration might be associated with impaired mononuclear cell response in sun-exposed tissues. Our case stated that he went to the sea two weeks ago and that the bullae secondary to the sunburn that developed afterwards peeled off after they burst. In conclusion, patients with a history of recent generalized sunburn should have their methotrexate delayed to avoid this complication.

Intravitreal Methotrexate.

Intravitreal methotrexate (MTX) has been proven to be an effective treatment for various intraocular diseases. In this article, a comprehensive review was performed on intravitreal applications of methotrexate. Different aspects of the administration of intravitreal MTX for various clinical conditions such as intraocular tumors, proliferative vitreoretinopathy, diabetic retinopathy, age-related macular degeneration, and uveitis were reviewed and the adverse effects of intravitreal injection of MTX were discussed. The most common indications are intraocular lymphoma and uveitis. Other applications remain challenging and more studies are needed to establish the role of intravitreal MTX in the management of ocular diseases.

Molecular Changes in the Adipose Tissue Induced by Rheumatoid Arthritis: Effects of Disease-Modifying Anti-Rheumatic Drugs

Disease severity, progression and response to therapy might be worse in obese rheumatoid arthritis (RA) patients, but paradoxically, obesity also might protect from radiographic joint damage. Thus, the intricate relationship between obesity and RA needs urgent clarification. The aim of this study was to assess the influence of obesity on the onset and development of RA and to determine whether arthritis could modify the adipose tissue biology and whether conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) can modulate these alterations. Two strategies were followed: (1) clinical profiling of two cohorts of RA: non-obese and obese patients; and (2) mechanistic studies carried out in both a collagen-induced arthritis (CIA) in an obese mouse model and 3T3-L1 adipocytes treated with cDMARDs (leflunomide, methotrexate, and hydroxychloroquine). In our cohort of RA patients with low-moderate disease activity, the presence of obesity was not related to a higher activity of the disease; actually, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) was reduced in the obese RA patients. However, the induction of arthritis promoted transcriptomic changes in the adipose tissue under obesity condition in the obese CIA model. Treatment with hydroxychloroquine reduced weight and insulin resistance, accompanied by beneficial metabolic effects in the adipose tissue. These molecular changes in adipose tissue were also observed after methotrexate administration. In sum, arthritis might affect directly the inflammatory burden and metabolic alterations associated with obesity in adipose tissue. Clinicians should be cautious measuring the activity of the disease in obesity and managing the best therapeutic options for the metabolic comorbidities of these patients, where the combination of hydroxychloroquine and methotrexate should be considered to improve adipose tissue dysfunction in obese RA.

Cesarean scar pregnancy treatment: a case series

BackgroundCesarean scar pregnancy is a complicated and potentially life-threatening type of ectopic pregnancy. This study reports two women with cesarean scar pregnancy who were successfully treated with systemic methotrexate administration, and two other women who needed local re-administration of methotrexate after systemic injection.Case presentationFour Iranian pregnant women aged 29–34 years who were between 5 to 7 gestational weeks with cesarean scar pregnancy diagnosis are described. After a single dose of systemic methotrexate injection, the level of serum beta-human chorionic gonadotropin decreased in two of the women, while fetal activity was observed in the other two women. In the latter patients, methotrexate was injected under transvaginal ultrasound guidance into the gestational sac. As a result, the serum beta-human chorionic gonadotropin level first increased and then decreased in these patients. During the follow-up period, all the patients were stable and no complications were observed. Serum beta-human chorionic gonadotropin levels reached the non-pregnancy range from 4 to 9 weeks after treatment.ConclusionWhen diagnosed at early gestation, cesarean scar pregnancy can be treated successfully with methotrexate administration alone. The clinicians should be aware that the beta-human chorionic gonadotropin level may initially increase after methotrexate injection in some patients. However, the final outcome will be promising if the patients remain stable.

Assessment of the cardioprotective effect of liraglutide on methotrexate induced cardiac dysfunction through suppression of inflammation and enhancement of angiogenesis in rats.

Methotrexate (MTX) is one of the most commonly used anti-cancer drugs for various types of neoplasms. It is associated with multiple cytotoxic effects including nephrotoxicity, hepatotoxicity and cardiotoxicity. Liraglutide (LIR) is a potent anti-diabetic drug and also has antioxidant and anti-inflammatory properties. In this study, we tried to investigate the protective effect of LIR on MTX induced cardiotoxicity and to identify the molecular mechanisms for this protection. Rats were divided into 4 groups, including control group, LIR group, MTX group and LIR + MTX group. ECG was measured then blood samples were taken, and hearts were excised for biochemical and histological investigations. MTX group exhibited a mild non-significant irregular bradycardia, an increase of CK-MB besides a decrease of total antioxidant capacity. MTX administration also resulted in downregulation of vascular endothelial growth factor (VEGF), while caused upregulation of interleukin 1 beta (IL-1B) and interleukin 6 (IL-6) in comparison to the control group. Also, MTX group showed histological abnormalities besides negative VEGF and positive iNOS as detected by immunohistochemical staining compared to the control group. LIR administration could reverse these results. LIR prevented MTX induced cardiotoxicity through its antioxidant and anti-inflammatory properties.

Tre-P-19 - Autologous stem cell transplantation in atypical mycosis fungoides with central nervous system involvement: follow-up

Mycosis fungoides (MF) is a presentation of primary cutaneous T-cell lymphoma with adverse prognosis for patients with advanced stages of the disease. Refractory disease and advanced-stage disease require systemic therapy. We reported a rare case of an atypical predominantly CD8+ folliculotropic MF, a subtype of MF with poorer prognosis, in a 59-year-old woman. She was initially diagnosed with MF restricted to the skin, of T3N0M0B0/stage IIB according to the current World Health Organization–European Organisation for Research and Treatment of Cancer classification. First-line treatment with local percutaneous radiotherapy in combination with systemic interferon alfa-2a resulted in complete remission. However, 21 months later the disease progressed to T3N0M1B0/stage IVB with development of cerebral manifestation and thus very poor prognosis. Allogeneic stem cell transplantation (SCT) was not a therapeutic option due to the lack of a suitable donor. We initiated methotrexate and cytarabine chemotherapy, followed by high-dose chemotherapy with thiotepa and carmustine with autologous SCT. Despite rapid response and complete remission of the cerebral lesions, disease recurrence of the skin occurred soon after. Readministration of interferon alfa-2a as a maintenance treatment after the salvage autologous SCT resulted in a complete remission during a follow-up period of 32.5 months after autologous SCT. After that, the disease relapsed with simultaneous skin and cerebral lesions. Despite immediate intrathecal and subsequently intravenous administration of high-dose methotrexate and cytarabin, we observed further progressed and the patient deceased 3.5 months after this second fulminant recurrence and in total 36 months after autologous SCT transplantation.

Use of Methotrexate in Gynecologic and Obstetric Practice: What the Radiologist Needs to Know.

Methotrexate (MTX) is the primary pharmaceutical agent that is used for management of disorders arising from trophoblastic tissue. Its widespread international use is mostly attributable to its noninvasive, safe, and effective characteristics as a treatment option for ectopic pregnancy (EP) and gestational trophoblastic disease (GTD), with the large added benefit of fertility preservation. Although the effects of MTX usage are well documented in the gynecologic and obstetric literature, there is a scarcity of radiologic literature on the subject. Depending on the type of EP, the route of MTX administration and dosage may vary. US plays an essential role in the diagnosis and differentiation of various types of EPs, pregnancy-related complications, and complications related to MTX therapy, as well as the assessment of eligibility criteria for MTX usage. A knowledge of expected imaging findings following MTX treatment, including variability in echogenicity and shape of the EP, size fluctuations, changes in vascularity and gestational sac content, and the extent of hemoperitoneum, is essential for appropriate patient management and avoidance of unnecessary invasive procedures. A recognition of sonographic findings associated with pregnancy progression and complications such as tubal or uterine rupture, severe hemorrhage, septic abortion, and development of arteriovenous communications ensures prompt patient surgical management. The authors discuss the use of MTX in the treatment of disorders arising from trophoblastic tissue (namely EP and GTD), its mechanism of action, its route of administration, and various treatment regimens. The authors also provide a focused discussion of the role of US in the detection and diagnosis of EP and GTD, the assessment of the eligibility criteria for MTX use, and the identification of the sonographic findings seen following MTX treatment, with specific emphasis on imaging findings associated with MTX treatment success and failure. Online supplemental material is available for this article. ©RSNA, 2021.

Effect of subcutaneous high-dose methotrexate treatment on the management of rheumatoid arthritis

Purpose: Methotrexate (MTX) is still the main treatment option for rheumatoid arthritis (RA). There is no consensus on drug administration routes and dosage when administered alone or in combination with other drugs. This study aims to identify the effects of early administration of a combination therapy containing high dose subcutaneous (SC) MTX on RA management.&#x0D; Materials and Methods: Forty-five patients with RA who newly diagnosed were divided into two groups randomly. The patients who took 12.5 mg SC MTX per week in the first 4 weeks defined as a "low dose group". The patients who took 25 mg SC MTX per week in the first 4 weeks defined as a "high dose group". Then, patients of both groups continued with 12.5 mg oral MTX per week. Clinical and laboratory findings, disease activity scores and response rates of the patients were recorded at the beginning, 3rd months and 6th months. &#x0D; Results: There was no significant difference between the two groups at 3rd month’s values. There were statistically significant improvements at 6th month’s values. Values were as follows in low and high dose groups: mean DAS28-CRP (3.5 vs 2.7), VAS pain score (3.3 vs 1.6), and TJC28 (3 vs 1.5), respectively. &#x0D; Conclusion: Early administration of high-dose SC MTX effectively controls disease activity and increases the quality of life in RA patients.

Enhanced expression of mRNA for transforming growth factor β activated kinase 1 in CD34+ cells of the bone marrow in rheumatoid arthritis.

Transforming growth factor β activated kinase 1 (TAK1) has been found to mediate maladaptive tumour necrosis factor (TNF) signalling, leading to hyperactive downstream nuclear factor Kappa β (NF-κB) signalling. We explored the expression of TAK1 mRNA in bone marrow CD34+ cells in rheumatoid arthritis (RA) to delineate the mechanism for their abnormal response to TNF-α and differentiate into fibroblast-like cells. CD34+ cells were purified from bone marrow samples obtained from 47 RA patients and 27 osteoarthritis (OA) patients during joint operations via aspiration from the iliac crest. The expression of mRNAs for TAK1 and NFκB1 was examined by quantitative RT-PCR. TAK1 mRNA expression in bone marrow CD34+ cells was significantly higher in RA than in OA (TAK1/β-actin: [11.980 ± 2.380] x 10-3 and [5.593±1.307] x 10-3 [mean ± SEM], respectively; p=0.0238). TAk1 mRNA expression was not different depending on the type of operated joints or on the severity type of RA. Nor was it correlated with serum CRP or rheumatoid factor or with administration of methotrexate, other conventional synthetic disease-modifying anti-rheumatic drugs or oral glucocorticoid. TAK1 mRNA expression was significantly correlated with NFκB1 mRNA expression in RA bone marrow CD34+ cells. These results indicate that TAK1 mRNA expression is enhanced in bone marrow CD34+ cells independently of the clinimetrics or treatment in RA. It is also suggested that the upregulation of TAK1 mRNA expression might lead to the enhanced expression of NFκB1 mRNA in bone marrow CD34+ cells, but possibly not vice versa, resulting in their abnormal response to TNF-α.

Development of PBPK model for intra-articular injection in human: methotrexate solution and rheumatoid arthritis case study

A physiologically based model describing the dissolution, diffusion, and transfer of drug from the intra-articular (IA) space to the plasma, was developed for GastroPlus® v9.8. The model is subdivided into compartments representing the synovial fluid, synovium, and cartilage. The synovium is broken up into two sublayers. The intimal layer acts as a diffusion barrier between the synovial fluid and the subintimal layer. The subintimal layer of the synovium has fenestrated capillaries that allow the free drug to be transported into systemic circulation. The articular cartilage is broken up into 10 diffusion sublayers as it is much thicker than the synovium. The cartilage acts as a depot tissue for the drug to diffuse into from synovial fluid. At later times, the drug will diffuse from the cartilage back into synovial fluid once a portion of the dose enters systemic circulation. In this study, a listing of all relevant details and equations for the model is presented. Methotrexate was chosen as a case study to show the application and utility of the model, based on the availability of intravenous (IV), oral (PO) and IA administration data in patients presenting rheumatoid arthritis (RA) symptoms. Systemic disposition of methotrexate in RA patients was described by compartmental pharmacokinetic (PK) model with PK parameters extracted using the PKPlus™ module in GastroPlus®. The systemic PK parameters were validated by simulating PO administration of methotrexate before being used for simulation of IA administration. For methotrexate, the concentrations of drug in the synovial fluid and plasma were well described after adjustments of physiological parameters to account for RA disease state, and with certain assumptions about binding and diffusion. The results indicate that the model can correctly describe PK profiles resulting from administration in the IA space, however, additional cases studies will be required to evaluate ability of the model to scale between species and/or doses.

Ginkgo biloba extract (EGb 761) mitigates methotrexate-induced testicular insult in rats: Targeting oxidative stress, energy deficit and spermatogenesis

Methotrexate (MTX) is commonly used as a therapeutic agent in the treatment of malignancies and autoimmune disorders. Risk of subsequent infertility following MTX administration has been reported as a significant side effect due to testicular toxicity. The aim of the study was to evaluate the modulatory effects of Ginkgo biloba (standardized extract, EGb 761) on MTX-induced testicular oxidative stress, energy deficits and spermatogenic status in rats. All groups received intraperitoneal injection of MTX (0.5 mg/kg) twice weekly for four weeks except the control group that received the corresponding vehicles. Other groups received oral EGb761, at doses 25, 50 or 100 mg/kg/day, for four weeks, concurrently with MTX. Blood and semen sampling followed by testis dissection were performed 24 h after last EGb 761 treatment. Semen was examined for sperm progressive motility, percent of normal spermatozoa and sperm cell concentration as well as seminal plasma essential and non-essential amino acids. Serum LH, FSH and testosterone were detected as well as testicular MDA, GSH, GSSG, TNF-α, IL-1β, IL-6, NF-κB and the nuclear, cytoplasmic and mRNA expression levels of Nrf-2 besides the testicular cell energy; AMP, ADP and ATP. Histopathological studies of interstitial fibrosis and the severity of germ cell degeneration were also conducted. MTX induced significant decline in sperm quality along with decreased essential and non-essential amino acids in seminal plasma. MTX reduced serum FSH, LH and testosterone as well as testicular ATP, GSH and Nrf2, while increased levels of testicular ADP, AMP, MDA, GSSG and TNF-α. Results were confirmed by prominent interstitial fibrosis and severe germ cell degeneration in MTX group. Concurrent treatment with EGb 761 alleviated MTX-induced testicular insult evidenced by amelioration of oxidative stress biomarkers, energy functions, seminal sperms abnormalities and spermatogenesis status. The present study suggests a beneficial role of EGb 761 in MTX-induced testicular injury and subsequent distortion of spermatogenesis.