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High-dose methotrexate (HDMTX) is used in the treatment of a range of adult and childhood cancers. Although HDMTX can provide effective anti-tumor activity with an acceptable safety profile for most patients, delayed methotrexate elimination (DME) develops in a minority of patients receiving HDMTX and may be accompanied by renal dysfunction and potentially life-threatening toxicity. A panel of European physicians with experience in the use of HDMTX as well as of glucarpidase convened to develop a series of consensus statements to provide practical guidance on the prevention and treatment of DME, including the use of glucarpidase. Robust implementation of supportive measures including hyperhydration and urine alkalinization emerged as critical in order to reduce the risk of DME with HDMTX treatment, with leucovorin rescue critical in reducing the risk of DME complications. Early recognition of DME is important to promptly implement appropriate treatment including, intensified hydration, high-dose leucovorin and, when appropriate, glucarpidase. [ABSTRACT FROM AUTHOR]

Background Methotrexate (MTX) is administered for the treatment of central nervous system (CNS) hematologic cancers, prophylaxis of CNS dissemination of certain hematological cancers, and in solid tumor leptomeningeal disease. MTX treatment can be limited by CNS toxicity. Dextromethorphan is used to treat MTX neurotoxicity, with most data derived from pediatric case series. In this report, we profile 4 adult patients who developed intrathecal (IT) MTX neurotoxicity to better characterize their response to dextromethorphan treatment. Methods A case series of 4 patients who developed neurologic symptoms attributed to IT MTX neurotoxicity subsequently treated with dextromethorphan was devised. Demographic data, clinical characteristics, electroencephalography results, magnetic resonance imaging, cerebrospinal fluid (CSF) characteristics, and dextromethorphan treatment outcomes were described. Results Of the 4 patients developing MTX neurotoxicity, neurologic symptoms developed over a timeframe of 2 to 14 days from the precedent MTX exposure. Radiologic phenotypes included subcortical white matter diffusion-restricting lesions, bi-hemispheric subcortical white matter T2-FLAIR hyperintensities, as well as other findings described in the report. Time elapsed from initiation of dextromethorphan to neurologic symptom resolution ranged from 1 to 2 days. Conclusions The profiles of 4 adult patients developing suspected IT MTX neurotoxicity syndromes with subsequent response to Dextromethorphan add further data to guide the management of such patients. [ABSTRACT FROM AUTHOR]

Background. A significant advancement in the treatment of high-grade aggressive non-Hodgkin’s lymphomas and acute lymphoblastic leukemia is the inclusion of high-dose (1000–5000 mg/m2) methotrexate in the treatment protocol. This approach has significantly increased the long-term survival rate, but it has been associated with toxicity, requiring supportive care. Factors that predict toxicity were identified, including genes involved in the metabolism (MTHFR) or transport (SLCO1B1) of methotrexate. The analysis of methotrexate metabolism has identified additional genes responsible for the elimination of this drug, allowing for more effective prevention and treatment of methotrexate-associated toxicity.Aim. To study the genetic polymorphisms of enzymes involved in the methotrexate metabolism and associated toxicity in the treatment of pediatric acute lymphoblastic leukemia and non-Hodgkin’s lymphomas.Materials and methods. Data were analyzed in specialized medical databases such as Pubmed, Scopus, Web of Science, Frontiers, and Google Scholar from 2001 to 2024.Results. The main predictors of high-dose methotrexate-associated toxicity are gene polymorphisms in MTHFR, SLCO1B1, ARID5B.Conclusion. Despite the contradictory data presented in the literature, it is important to consider the detection of polymorphisms during high-dose methotrexate treatment in order to administer timely supportive care and prevent significant toxicity.

We describe the case of a 14-year-old girl with osteosarcoma who was treated with high-dose methotrexate (12 g/m2). Twenty-four hours after the infusion, her plasma methotrexate concentration was elevated at 937 μmol/L (normal

Acute methotrexate (MTX) toxicity is most commonly due to overdose of the drug, which may be due to the patient's noncompliance to doctor's orders or physician's prescription error. Other causes include acute renal failure, concomitant use of other drugs, and genetic susceptibility. MTX toxicity presents with pancytopenia, mucositis, hepatotoxicity, pulmonary toxicity, and acute renal failure. Treatment involves a polypragmatic approach which includes vigorous hydration, urinary alkalinization, administration of leucovorin, and glucarpidase. Administration of granulocyte colony-stimulating factor should be considered in cases of severe neutropenia. Here, we present two cases of acute MTX toxicity in chronic plaque psoriasis presenting with ulceration of psoriatic lesions and mucosal ulceration successfully treated with leucovorin and pegylated granulocyte colony-stimulating factor (G-CSF). This case report demonstrates that G-CSF might be lifesaving by contributing to rapid reconstitution of leukopoiesis.

Aside from rheumatoid arthritis, methotrexate is also used to treat cancer, psoriasis, and other diseases. Side effects with methotrexate are possible, as they are with any medication. This drug is extremely potent and has the potential to produce serious adverse effects. Those who use this medication need to be tracked often. We provide a case of a patient with psoriasis vulgaris who died due to methotrexate administration without proper dosage verification. A female patient in her forties had a history of psoriasis vulgaris of the lower limbs. Under treatment, she developed acute methotrexate toxicity. This drug was taken as an intramuscular injection per day in an infirmary without checking that the dose regimen prescribed was per week. She developed extensive bullous and pustular lesions associated with digestive signs related to generalized toxiderma. But at that point, she had septic shock, which led to her death a few weeks after the methotrexate injection. The medical responsibilities of the doctor, pharmacist, and nurse were discussed. To conclude, methotrexate is not a killer drug in most cases, but it can be extremely harmful if it's overused. Acute toxicity is a potentially fatal condition, and a deeper understanding of its potential toxicity is still necessary. [ABSTRACT FROM AUTHOR]

Abstract Background Methotrexate is an antifolate antimetabolite that inhibits the activity of dihydrofolate reductase by acting as a false substrate, which leads to defects of DNA synthesis, specifically the inhibition of purine and pyrimidine synthesis. Thus, methotrexate is a powerful agent for treating autoimmune diseases and cancer. In general, methotrexate is thought to be cardioprotective and reports of methotrexate-induced cardiomyopathy are rare. We present a case of methotrexate-induced severe cardiotoxicity diagnosed by exclusion of all other potential causes. Case presentation The patient was a 54-year-old Caucasian man presenting to an outside hospital with a chief complaint of abdominal pain and bloating who reported taking methotrexate up to 20 mg per week for systemic sclerosis. After a transthoracic echocardiogram found a left ventricular ejection fraction of 10% and coronary catheterization demonstrated no significant disease, he was transferred to our hospital for advanced heart failure therapies. His condition deteriorated, and he was eventually placed on veno-arterial extracorporeal membrane oxygenation. Owing to a lack of an identifiable etiology of cardiac failure, toxicology consultation recommended 24 hours of intravenous leucovorin therapy to overcome any residual and potentially cardiotoxic methotrexate still in his system. Over the next 5 days, his cardiac function improved daily, such that on day 5 of extracorporeal membrane oxygenation, he had a left ventricular ejection fraction of 40% and was able to be decannulated. Two days later, his ejection fraction improved to 60% and normal right ventricular function. Initially, his renal function improved while on extracorporeal membrane oxygenation, but over the next week deteriorated such that he required intermittent hemodialysis until hospital discharge. Conclusions After a process of elimination, the most likely cause of this patient’s acute decline and rapid recovery of bi-ventricular function was methotrexate toxicity. Leucovorin may have aided the reversal of methotrexate toxicity.

An elderly male patient, a known case of psoriasis vulgaris, presented with ulcerations in preexisting psoriatic lesions. The patient had fever with chills and severe pain and burning sensations in the lesions. There was a history of intramuscular methotrexate (Mtx) injection 15 mg followed by oral Mtx 7.5 mg once daily from next day for 5 days. Laboratory investigations revealed severe pancytopenia and abnormal renal and liver function tests. A diagnosis of acute Mtx toxicity was made and started treatment with intravenous leucovorin and subcutaneous granulocyte colony-stimulating factor (filgrastim) for 4 days. The patient responded to the treatment with improvement in skin lesions and laboratory parameters. The present case underlines the importance of patient counseling regarding the dosage schedule of the drugs and their adverse effects. The ulceration of preexisting lesions helps in early diagnosis, evaluation, and initiation of specific therapy.

Background: Methotrexate is an antifolate antimetabolite that inhibits the activity of dihydrofolate reductase by acting as a false substrate, which leads to defects of DNA synthesis, specifically the inhibition of purine and pyrimidine synthesis. Thus, methotrexate is a powerful agent for treating autoimmune diseases and cancer. In general, methotrexate is thought to be cardioprotective and reports of methotrexate-induced cardiomyopathy are rare. We present a case of methotrexate-induced severe cardiotoxicity diagnosed by exclusion of all other potential causes.Case Presentation: The patient was a 54-year-old Caucasian man presenting to an outside hospital with a chief complaint of abdominal pain and bloating who reported taking methotrexate up to 20 mg per week for systemic sclerosis. After a transthoracic echocardiogram found a left ventricular ejection fraction of 10% and coronary catheterization demonstrated no significant disease, he was transferred to our hospital for advanced heart failure therapies. His condition deteriorated, and he was eventually placed on veno-arterial extracorporeal membrane oxygenation. Owing to a lack of an identifiable etiology of cardiac failure, toxicology consultation recommended 24 hours of intravenous leucovorin therapy to overcome any residual and potentially cardiotoxic methotrexate still in his system. Over the next 5 days, his cardiac function improved daily, such that on day 5 of extracorporeal membrane oxygenation, he had a left ventricular ejection fraction of 40% and was able to be decannulated. Two days later, his ejection fraction improved to 60% and normal right ventricular function. Initially, his renal function improved while on extracorporeal membrane oxygenation, but over the next week deteriorated such that he required intermittent hemodialysis until hospital discharge.Conclusions: After a process of elimination, the most likely cause of this patient's acute decline and rapid recovery of bi-ventricular function was methotrexate toxicity. Leucovorin may have aided the reversal of methotrexate toxicity. [ABSTRACT FROM AUTHOR]

Splenunculus, or congenital accessory spleen, is a benign anatomical variation, and is rarely of clinical consideration in routine clinical practice. We describe a patient who presented with synchronous herpes simplex 1 viraemia and myelosuppression, with a splenunculus mimicking splenomegaly, and we discuss the implications on clinical practice, investigations, and management. [ABSTRACT FROM AUTHOR]

There are multiple concerns associated with methotrexate (MTX), widely recognized for anti-neoplastic and anti-inflammatory effects in life-threatening disease conditions, i.e., acute lymphoblastic leukemia, non-Hodgkin's lymphoma, psoriasis, and rheumatoid arthritis, due to long-term side effects and associated toxicity, which limits its valuable potential. MTX acts as an inhibitor of dihydrofolate reductase, leading to suppression of purine and pyrimidine synthesis in high metabolic and turnover cells, targeting cancer and dysregulated immune cells. Due to low discrimination between neoplastic cells and naturally high turnover cells, MTX is prone to inhibiting the division of all fast-dividing cells, causing toxicity in multiple organs. Nutraceutical compounds are plant-based or food-derived compounds, used for their preventive and therapeutic role, ascertained in multiple organ dysfunctions, including cardiovascular disease, ischemic stroke, cancer, and neurodegenerative diseases. Gut microbiota and microbiota-derived metabolites take part in multiple physiological processes, their dysregulation being involved in disease pathogenesis. Modulation of gut microbiota by using nutraceutical compounds represents a promising therapeutic direction to restore intestinal dysfunction associated with MTX treatment. In this review, we address the main organ dysfunctions induced by MTX treatment, and modulations of them by using nutraceutical compounds. Moreover, we revealed the protective mechanisms of nutraceuticals in MTX-induced intestinal dysfunctions by modulation of gut microbiota. [ABSTRACT FROM AUTHOR]

Cardiotoxicity is one of the most devastating complications of cancer treatment by methotrexate (MTX). The present study aimed to investigate the potential anti-cardiotoxic efficacy of taurine (Tau) and enzymatically modified isoquercitrin (EMIQ) alone or combined against MTX-induced cardiotoxicity in adult male rats. A total of 36 rats were randomly divided into six groups (six animals each): control, MTX (a single i.p. dose of 20 mg/kg), EMIQ + MTX (26 mg/kg of EMIQ, p.o. for 16 days), Tau + MTX (500 mg/kg of Tau, p.o. for 16 days), EMIQ + Tau + MTX at the same previous doses, and (EMIQ + Tau) ½  + MTX. MTX reduced the percentage of body weight change, the expression of dihydrofolate reductase (DHFR) and folypolyglutamyl synthetase (FPGS), the cleaved tumor necrosis factor alpha (TNF-α) level in the cardiac tissue, and the elevated serum TNF-α level. MTX extensively deteriorated the electrocardiography (ECG), inducing tachycardia with shortening of the time intervals between successive heartbeats (R-R interval), associated with elongation of ventricular depolarization (QRS interval), and the corrected total time for ventricular de- and repolarization (QTc) duration. Treatment with MTX resulted in a significant reduction in atrial depolarization (P amplitude) and rapid repolarization (T amplitude) and a significant elevation in plateau phase (ST height). MTX treatment resulted in swelling of cardiomyocytes with extensive vacuolization of sarcoplasm with numerous variably sized vacuoles in addition to apoptotic cells. Tau and EMIQ protected against MTX-induced deteriorations in the conductivity and rhythmicity of the heart through antioxidative, anti-inflammatory, and antiapoptotic activities. Treatment with tau and EMIQ combined at high or low doses offered superior protection to the heart than using each agent alone., (© 2024 John Wiley & Sons Ltd.)

Methotrexate (MTX), an anti-metabolite agent, is a widely used chemotherapeutic anticancer drug, but its hepatotoxicity severely limits its clinical application. Nevertheless, the precise mechanisms of MTX-caused liver damage are extremely intricate and still need to be fully clarified. In the current study, we investigated the role of the STING-ERS-ferroptosis axis in MTX-triggered hepatic toxicity in vivo and in vitro models. Male C57BL/6 J mice exposed to a single dose of MTX (0, 2, 5, and 20 mg/kg) for 3 days exhibited severe liver damage and overactivated STING signaling. Moreover, we found that ferroptosis was also involved in MTX-mediated liver damage. Interestingly, STING deficiency alleviated liver damage, inhibited liver inflammation, as well as suppressed hepatic lipid peroxidation and ferroptosis in MTX-treated mice. Consistently, STING inhibitor (C-176) pretreatment also alleviated MTX-induced STING signaling activation, ROS overproduction and ferroptosis in AML12 cells. Finally, we verified that ER stress was responsible for the MTX-induced liver injury and ferroptosis caused by STING activation. Taken together, our study uncovered a novel link between STING signaling and ferroptosis in MTX-triggered hepatic damages, and suggested that targeting the STING-ER stress-ferroptosis axis might be a promising and effective therapeutic approach against MTX-induced liver damage., Competing Interests: Declaration of Competing Interest The authors have declared that the research is conducted in the absence of any commercial or financial relationships that can be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Methotrexate (MTX) is a folic acid reductase inhibitor that manages various malignancies as well as immune-mediated inflammatory chronic diseases. Despite being frequently prescribed, MTX's severe multiple toxicities can occasionally limit its therapeutic potential. Intestinal toxicity is a severe adverse effect associated with the administration of MTX, and patients are significantly burdened by MTX-provoked intestinal mucositis. However, the mechanism of such intestinal toxicity is not entirely understood, mechanistic studies demonstrated oxidative stress and inflammatory reactions as key factors that lead to the development of MTX-induced intestinal injury. Besides, MTX causes intestinal cells to express pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which activate nuclear factor-kappa B (NF-κB). This is followed by the activation of the Janus kinase/signal transducer and activator of the transcription3 (JAK/STAT3) signaling pathway. Moreover, because of its dual anti-inflammatory and antioxidative properties, nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) has been considered a critical signaling pathway that counteracts oxidative stress in MTX-induced intestinal injury. Several agents have potential protective effects in counteracting MTX-provoked intestinal injury such as omega-3 polyunsaturated fatty acids, taurine, umbelliferone, vinpocetine, perindopril, rutin, hesperidin, lycopene, quercetin, apocynin, lactobacillus, berberine, zinc, and nifuroxazide. This review aims to summarize the potential redox molecular mechanisms of MTX-induced intestinal injury and how they can be alleviated. In conclusion, studying these molecular pathways might open the way for early alleviation of the intestinal damage and the development of various agent plans to attenuate MTX-mediated intestinal injury., (© 2024. The Author(s).)

Methotrexate (MTX) is an anti-folate chemotherapeutic commonly used to treat cancer and autoimmune diseases. Despite its widespread clinical use, MTX has been linked to serious neurotoxicity side effects. Vinpocetine (VNP) has been widely used clinically to treat many neurological conditions. This study was conducted to study the potential neuroprotective effects of VNP against MTX hippocampal intoxication in rats. Thirty-two rats were randomly allocated into 4 groups: (I) control (Vehicle); (II) VNP-treated group (20 mg/kg/day, p.o); (III) MTX-control (20 mg/kg/once, i.p.) group; and (IV) the VNP + MTX group. VNP was administered orally for 10 days, during which MTX was given intraperitoneally once at the end of day 5. Our data indicated that VNP administration significantly improved MTX-induced neuronal cell death, odema, vacuolation and degeneration. VNP attenuated oxidative injury mediated by significant upregulation of the Nrf2, HO-1, and GCLC genes, while the Keap-1 mRNA expression downregulated. Moreover, VNP suppressed cytokines release mediated by increasing IκB expression level while it caused a marked downregulation in NF-κB and AP-1 (C-FOS and C-JUN) levels. Additionally, VNP attenuated apoptosis by reducing hippocampal Bax levels while increasing Bcl2 levels in MTX-intoxicated rats. In conclusion, our results suggested that VNP significantly attenuated MTX hippocampal intoxication by regulating Keap-1/Nrf2, NF-κB/AP-1, and apoptosis signaling in these effects.

Ethnopharmacological Relevance: Morinda officinalis How. is a commonly used traditional Chinese herb with the pharmacological properties of tonifying liver and kidney, and enhancing bone and muscle. Iridoid glycosides are the predominant components of this plant, including monotropein, asperuloside, deacetylasperuloside and deacetylasperulosidic acid with their contents reaching more than 2%. Methotrexate (MTX) is the drug of choice for the treatment of rheumatoid arthritis (RA), but liver injury induced by MTX limits its wider use for RA. Morindaofficinalis iridoid glycoside (MOIG) is reported as having anti-RA and hepatoprotective effects, but the exact efficacy on MTX-induced liver injury and the underlying molecular mechanism remain unclear., Aim: To elucidate the mitigating effect of MOIG against liver injury in RA rats treated with MTX, and explore the possible mechanism., Materials and Methods: The effect and mechanism of MOIG were investigated in Wistar rats with collagen-induced arthritis (CIA) which were then treated with MTX, and MTX-induced hepatocyte injury in vitro. Network pharmacological and transcriptomic analyses were conducted to predict the possible mechanisms of MOIG in mitigating MTX-induced liver injury, and lipidomic analysis was performed to further verify the regulatory effects of MOIG on lipid metabolism. BRL-3A hepatocytes were used to evaluate the regulatory effects of MOIG against MTX-associated liver injury., Results: MOIG treatment enhanced the anti-RA effect of MTX, and mitigated oxidative damage, inflammation and apoptosis of liver tissues in CIA rats treated with MTX. Network pharmacological and transcriptomic analyses demonstrated that MOIG attenuated liver injury by regulating autophagy and lipid metabolism. The result of lipidomic analysis showed that MOIG reversed the disturbance of lipid metabolism of the liver tissue in CIA rats after MTX treatment. In addition, MOIG also inhibited the apoptosis, reduced the levels of lactate dehydrogenase (LDH), aspartate aminotransferase (ALT) and alanine aminotransferase (AST), regulated oxidative stress, and increased the formation of autophagosome and translocation of LC3 in the nucleus and expression of autophagy regulatory genes Beclin-1, ATG5, LC3Ⅱ, ATG7 and ATG12 in hepatocytes subjected to MTX damage., Conclusion: Our findings demonstrated that MOIG could ameliorate MTX-induced liver injury in the treatment of RA through increasing hepatocyte autophagy and improving lipid metabolism homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To assess the effect of pretreatment with omega-3 alone or in combination with vitamin C on hepatotoxicity raised by methotrexate., Method: The experimental study was conducted at the animal house of the Iraqi Centre of Cancer Research and Medical Genetics and the Department of Pharmacology, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq, from November 2020 to July 2021, and comprised Swiss albino mice who were divided into 5 groups. Group A was treated with normal saline, group B was injected with methotrexate 20mg/kg intraperitoneally, group C was pretreated with omega 3 100mg/kg, group D was pretreated with vitamin C 100mg/kg, and group E was pretreated with concomitant vitamin C and omega 3 100mg/kg. The intervention lasted 9 days in each group, and were injected with methotrexate on day 10. The mice were sacrificed under chloroform anaesthesia after 48 hours. Blood sample was taken for biochemical examination. One part of liver was preserved in formalin 10% for histopathological study., Results: Of the 35 mice, there were 7(20%) in each of the 5 groups. There was a significant increase in malondialdehyde and lactate dehydrogenase levels and a decrease in the superoxide dismutase and glutathione (p<0.05)., Conclusions: Pretreatment with omega-3 and vitamin C ameliorated the hepatotoxicity induced by methotrexate due to strong antioxidant, anti-inflammatory and anti-apoptotic effects.

Objective: To examine the effect of using vitamin C and niclosamide together on liver damage caused by methotrexate., Methods: The study was conducted at the Pharmacology Department and the Iraqi Center for Cancer and Medical Genetics Research, College of Medicine, Mustansiriya University, Baghdad, Iraq, from November 2020 to July 2021, and comprised albino mice who were randomly assigned to 5 groups. Group 1 comprised controls, groups 2 to 5 was received methotrexate, niclosamide 70mg/kg/day, vitamin C 100mg/kg/day, and a combination of niclosamide and vitamin C, respectively. Mice in groups 3, 4 and 5 also received an intraperitoneal injection of methotrexate 20mg/kg to induce hepatotoxicity. After 48 hours of the injection, the mice were sacrificed under chloroform anaesthesia. Cardiac blood samples were drawn for biochemical examination. The liver, after being washed, was divided into two parts; one part was taken for histological examination, and the other was preserved in formalin 10% for histopathological analyses. Data was analysed using SPSS 16., Results: Of the 35 mice, there were 7(20%) in each of the 5 groups. The overall age ranged between 9-12 weeks and weight between 18-38gm. The results show significant hepatoprotection ( p-value <0.05) produced by both niclosamide and Vitamin C separately, reflected by a decrease in ALP, ALT, and LDH, while the combination of (niclosamide and Vitamin C) showed no additive effect (p>0.05) on enhancement of liver function., Conclusions: Niclosamide alone was found to be superior than in combination with vitamin C for treating methotrexate-induced liver damage.

Objective: To assess the hepatoprotective effect of curcumin and/or vitamin C in methotrexate-induced hepatotoxicity., Methods: The experimental study was conducted at the Department of Pharmacology, College of Medicine, and the Iraqi Centre for Cancer and Medical Genetic Research, Mustansiriya University, Baghdad, Iraq, from Nov 12, 2020, to June 1, 2021, and comprised Swiss albino female mice aged 3-4 months and weighing 30-40g each. The mice were divided into 5 groups and treated for 10 days. Group 1 received distilled water, group 2 received single-dose methotrexate on the 10th day of the trial, group 3 was treated with curcumin plus methotrexate, group 4 was treated with vitamin C plus methotrexate, and group 5 was treated with curcumin and vitamin C plus methotrexate. Parameters measured were serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase, as well as hepatic tissue malondialdehyde, superoxide dismutase and glutathione. Data was analysed using SPSS 16., Results: There were 35 mice; 7(20%) in each of the 5 groups. Hepatoprotection produced by curcumin as reflected by a decrease in lactate dehydrogenase and malondialdehyde levels was significant (p<0.05). Vitamin C also produced a significant hepatoprotection, demonstrated by a decrease in alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and malondialdehyde levels. The combination of curcumin and vitamin C reflected an additive effect demonstrated by a significant decrease in malondialdehyde (p<0.05)., Conclusions: Curcumin and/or vitamin C provided hepatoprotection against methotrexate-induced hepatotoxicity through modulation of oxidative stress biomarkers.

Methotrexate (MTX) is widely prescribed to treat different malignancies as well as autoimmune diseases. However, it causes a range of side effects in different organs such as testis. This study aims to clarify the role of dipeptidyl peptidase 4 (DPP4) in MTX-induced testicular damage via pathways involved in oxidative stress and evaluates the protective effects of sitagliptin as a DPP4 inhibitor. Twenty-four animals randomly allocated into four groups including: (I) control, (II) MTX (20 mg/kg, i.p.), (III) sitagliptin (20 mg/kg, i.p., for four consecutive days), and MTX + sitagliptin in which received chemicals resembling group II and III. Histopathological examinations conducted to assess the structural changes in testes of different experimental groups. Also, ELISA method employed to investigate the levels of DPP4, AKT, p-AKT, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). In addition, the total malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) were assessed. The results indicated that MTX administration was accompanied with testicular damage, which reversed by sitagliptin treatment. The biochemical observations demonstrated that MTX markedly increased the levels of DPP4, decreased p-AKT/AKT ratio followed by a marked decrement in Nrf2 and HO-1 levels. Also, it was observed that MTX decreased the activity of SOD and increased total MDA content in testicular specimen. However, sitagliptin treatment diminished mentioned alterations effectively. Altogether, our findings supported the possible role of DPP4 in MTX-induced testicular toxicity along with the potential protective features of sitagliptin via suppressing of the histopathological and biochemical alterations induced by MTX., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Abstract Splenunculus, or congenital accessory spleen, is a benign anatomical variation, and is rarely of clinical consideration in routine clinical practice. We describe a patient who presented with synchronous herpes simplex 1 viraemia and myelosuppression, with a splenunculus mimicking splenomegaly, and we discuss the implications on clinical practice, investigations, and management.

Methotrexate (MTX) is an antifolate metabolite that is used in the treatment of various autoimmune diseases, malignancies, and inflammatory disorders. In addition to the well-characterized side effects such as hepatotoxicity and myelosuppression, it can also rarely cause a variety of cutaneous manifestations due to acute toxicity. We are presenting case series of three patients of MTX toxicity. All three cases presented with acute ulceration and pain over the psoriatic plaques in addition to mucosal involvement. They were all given injectable folinic acid. Two out of the three patients died and one of them recovered. Although low-dose MTX appears to be relatively safe, acute MTX toxicity is a life-threatening emergency that can occur for which greater awareness of this condition is needed for its prevention, early diagnosis, and management. [ABSTRACT FROM AUTHOR]

Aims and Objectives: High dose methotrexate (HDMTx) based chemotherapy forms the backbone of therapy for patients with Primary Central Nervous system Lymphoma (PCNSL). However, delivering HDMTx in resource constrained settings, especially without therapeutic drug monitoring, is difficult. We share our experience of treatment of patients with PCNSL at our center over a 10-year period with local adaptations made to deliver HDMTx. Materials and Methods: We retrospectively analysed the case records of patients diagnosed with a PCNSL over the course of 10 years from 2010 to 2020. Results: Fifty-five patients received therapy for newly diagnosed PCNSL. Thirty-six patients received Modified De-Angelis protocol ± Rituximab with curative intent. Fourteen of these patients were unable to complete the protocol with the most common cause being development of methotrexate toxicity. Patients unable to complete the designated 5 cycles of HDMTx had a poorer PS and higher probability of having a high IELSG score at baseline. Nineteen patients were given non HDMTx based therapy either due to advanced age or poor performance status. Twenty-nine patients (52.7%) were able to achieve a complete response. The most common cause of mortality was relapse/progressive disease. The Median EFS and OS of the cohort was 29 months and 40 months respectively. Conclusion: All attempts should be made to have therapeutic drug level monitoring for administration of HDMTX based therapy for the patients with PCNSL, more so in patients who have poor performance status and a high IELSG score. If it is imperative to give HDMTx without access to TDM facility then a possible risk of higher toxicity should be explained to all patients, beforehand [ABSTRACT FROM AUTHOR]

In male C57BL/6 mice (8-12 weeks) and male Wistar rats (12 weeks), the effect of dibornol (2,6-diisobornyl-4-methylphenol) on the level of spontaneous DNA damage in cells of the bone marrow, liver, kidneys, and rectum of mice (series I) and genotoxic effects in rat testicular cells after administration of cytostatic drugs with different mechanisms of action (series II) were studied using the DNA comet assay. In series I, dibornol was intragastrically administered to mice once at doses of 200, 400, and 2000 mg/kg; in series II, dibornol was intragastrically administered to rats at a dose of 10 mg/kg for 5 days before and 5 days after the cytostatic treatment (methotrexate, doxorubicin). It was found that dibornol in all studied doses did not produce the genotoxic (carcinogenic) effect and reduced the level of spontaneous DNA damage in the bone marrow. After combined administration of cytostatic drugs (doxorubicin, methotrexate) and dibornol, the level of DNA breaks was reduced to 38.5 and 49% of the control, respectively., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

The effects of alpha-pinene (AP), a monoterpenoid, known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, on methotrexate (MTX)-induced cardiac and hepatic damage were investigated in this study. Male Sprague-Dawley rats were divided into Control, Vehicle, AP, MTX, and AP+MTX groups (n=7). AP (50 mg/kg/day, 14 days) was applied subcutaneously in the AP and AP+MTX groups. MTX (20 mg/kg) was injected three days before sacrification. Serum CK-MB, troponin T, ALT, and AST levels, as well as cardiac and hepatic MDA, GSH, caspase-3, and p53 levels, were measured by ELISA. Histological changes in tissues were evaluated by scoring in terms of tissue damage and cellular degeneration parameters after hematoxylin-eosin staining. MTX caused significant increase in serum CK-MB, troponin T, ALT, and AST levels, hepatic and cardiac lipid peroxidation, GSH depletion, and caspase-3 level. However, tissue levels of p53 did not change significantly. MTX-induced histological deterioration was observed in both tissues. These MTX-induced changes were significantly reduced in the AP+MTX group. Present results show that MTX-induced cardiac and hepatic damage is prevented by AP pretreatment. This protection can be attributed to the antioxidant and anti-apoptotic properties of AP. Considering the importance of MTX in cancer treatment, AP appears to have highly promising potential as a cardioprotective and hepatoprotective agent in anti-tumoral therapy. Key words: MDA, GSH, Caspase-3, p53, Oxidative stress, Apoptosis.

Objective: Methotrexate (MTX) is widely administered for the treatment of various cancers. However, MTX induces male reproductive toxicity. In the current study, the effect of ozone therapy (OT) on reducing the toxic effects of MTX in the mouse testicles has been investigated., Methods: Twenty-four mice were divided into four groups: control, OT (4 mg/kg ozone), MTX (20 mg/kg), and MTX + OT. Testosterone levels, histological changes, and oxidative stress biomarkers were assessed to evaluate the protective effects of OT., Results: The results demonstrated that MTX disrupted germinal epithelium, reduced serum testosterone levels, and enhanced oxidative stress in testicular tissue. However, treatment with OT attenuated these adverse effects. OT effectively restored the levels of antioxidant enzymes, such as catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD). OT reduced lipid peroxidation, as indicated by decreased malondialdehyde (MDA) levels. OT preserved normal spermatogenesis, improved morphometric parameters, and reduced histological changes by MTX. Moreover, OT effectively restored testosterone levels., Conclusions: OT protects against MTX-induced testicular damage by suppressing oxidative stress.

Introduction: Methotrexate (MTX) is a common medication used to treat rheumatoid arthritis (RA). MTX inhibits rapid cell turnover throughout the body which can lead to significant side effects. Patients who present with oral lesions may have suffered severe acute toxicity from MTX. Supportive pain treatment includes magic mouthwash solution and/or oral viscous lidocaine to manage pain and allow for healing. We report a case of MTX induced oral mucositis that did not respond to magic mouthwash but did improve with a morphine mouthwash solution. Case: A 67-year-old female with RA presented with worsening oral lesions over 2 weeks. She reported non-compliance with folic acid for 2 weeks while on MTX. Physical exam revealed ulcerating oral lesions on the mucous membranes consistent with mucositis. Pain treatment was initiated with magic mouthwash, but her pain was not well controlled after 24 hours, and still unable to swallow. An oral morphine mouthwash solution was initiated, and patient reported improved pain control over the next 48 hours. She was on the morphine mouthwash for 6 days during which improvement in the lesions was noted. Discussion: Pain management is imperative for oral mucositis. When traditional therapies do not provide adequate control, morphine mouthwash can be considered. It is a safer alternative to systemic opioids and topical opioids may influence cell proliferation and migration, which can positively impact healing of oral lesions. Conclusion: A morphine mouthwash solution can provide effective pain management for oral mucositis lesions in patients who do not respond adequately to magic mouthwash., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We describe the case of a 14-year-old girl with osteosarcoma who was treated with high-dose methotrexate (12 g/m 2 ). Twenty-four hours after the infusion, her plasma methotrexate concentration was elevated at 937 μmol/L (normal < 10 µmol/L). She exhibited severe signs of methotrexate toxicity, including encephalopathy, acute liver failure (ALF), and acute kidney injury. In this case report, we highlight the severe and rare adverse effects secondary to methotrexate administration and the efficacity of molecular adsorbent recirculating system and continuous venovenous hemodiafiltration to recover from multiple organ failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Corbisier, Von Bueren, Breunis and Grazioli.)

Methotrexate (MTX) is a commonly used immunosuppressant and chemotherapeutic agent, widely prescribed for autoimmune diseases such as psoriasis, rheumatoid arthritis, and certain malignancies. It functions by inhibiting dihydrofolate reductase, leading to impaired DNA synthesis and cell proliferation. While generally well-tolerated, MTX has a narrow therapeutic index, and its adverse effects can be severe, including hepatotoxicity, pulmonary toxicity, and hematological complications such as pancytopenia. Pancytopenia involves the reduction of all three blood cell lines and can result in significant morbidity and mortality. The risk of MTX toxicity is notably higher in patients with renal impairment, as the kidneys are the primary route of drug excretion. Renal dysfunction can lead to the accumulation of MTX, enhancing its toxicity. Numerous studies and case reports have highlighted the risks of MTX toxicity, especially in patients with renal impairment. Pancytopenia can present insidiously, with symptoms such as mucosal ulcers, fever, and generalized weakness, making early detection crucial. We report a case of a male patient in his late 40s with a complex medical history, including psoriasis, insulin-dependent type 2 diabetes mellitus, chronic kidney disease (CKD) stage 3b, and coronary artery disease (CAD). The patient presented to the emergency department with a one-week history of fever, generalized weakness, mouth sores, and a five-day history of bilateral lower limb swelling and pain. Vital signs were stable, but physical examination revealed pallor, large ulcerative lesions in the buccal mucosa, and erythematous, scaly lesions on the lower limbs. The patient's medication history included methotrexate, which he had stopped two months prior but was inadvertently resumed at an increased dose two weeks prior to presentation. Laboratory findings revealed pancytopenia with worsening trends, prompting a bone marrow biopsy that showed hypocellular marrow. The patient's CKD likely exacerbated the MTX toxicity due to impaired drug clearance, leading to pancytopenia. Treatment included intravenous leucovorin, blood and platelet transfusions, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite initial critical presentation, the patient showed significant improvement, with recovery of blood counts and resolution of symptoms. He was discharged with stable hemoglobin, platelet, and white blood cell counts., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Surapaneni et al.)

Background: Hepatotoxicity associated with methotrexate (MTX) is mainly due to disruption of redox balance and development of oxidative injury to hepatocytes. Melatonin (MLT) is a potent antioxidant and regulates wide range of biological functions, processes and utilized as adjuvant for number of medical applications. The current study investigated the mitigating effect of MLT on the MTX-induced hepatotoxicity., Methods and Results: Adult male rats received MLT (25 mg/kg, orally) for seven days flowed by single injection of MTX (20 mg/kg, ip) then treat with MLT continued for additional 7 days. The present result showed MLT treatment mitigated histopathological changes in the liver that associated with normalization of ALT and AST activity as well as bilirubin, albumin and alfa-fetoprotein levels in serum of MLT + MTX-treated rat to comparable control level. MLT treatment significantly reduced MDA content and myeloperoxidase activity while enhanced the activity of superoxide dismutase, catalase and glutathione content in the liver indicating the empowerment of the antioxidant status. Amelioration of MLT-induced oxidative stress resulted in a reduction in the inflammatory response due to antioxidant restoration and inhibited apoptosis indicated by downregulation of caspase-3 expression. The replenishment of antioxidant content powers the defense system of the hepatocytes. As a result, apoptosis is reduced which might be due to the ability of MLT protect DNA integrity thus maintaining hepatocyte functions and structure. Consequently, liver histology was protected., Conclusions: In summary, MLT modulates liver function and structure by orchestrating linked processes, including redox balance, inflammatory response, suppression of caspase-3, and DNA damage., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Methotrexate (MTX)-induced gastrointestinal mucositis is a common adverse effect characterized by redox imbalance and overproduction of inflammatory mediators that perturb intestinal integrity. Currently, there is no definitive treatment for this condition and its prevention is still far beyond comprehension. Because of its pleiotropic pharmacological actions, we aimed to explore the potential mechanisms through which cilostazol (CILO) can protect against MTX-induced intestinal mucositis. Wistar rats were allocated into 4 groups, control, CILO (100 mg/kg, p.o for 14 days), MTX (7.5 mg/kg for 4 successive days), and CILO + MTX. The improving effect of CILO on the morphological structure was confirmed by an upturn in the histopathological and transition electron microscope examinations evidenced by the increased jejunal villus height/width and the crypt depth besides the maintenance of tight junctions. These findings were verified biochemically; on the molecular level, CILO reduced the MTX-induced lipid peroxidation, cleaved caspase-3, p53, and the inflammatory parameters (TLR-2, NF-κB, IL-23, TNF-α, IL-1β), while increasing the anti-inflammatory marker IL-10 and the antioxidant enzyme SOD. Moreover, CILO decreased the injurious axis AKT/GSK-3β/cyclin-D1, and CD44 + , but increased the immunoexpression of the cell proliferating marker PCNA. CILO also upheld the intestinal barrier by enhancing the tight junction molecules (ZO-1, claudin-4) and the E-cadherin/β-catenin complex while abating the mesenchymal marker vimentin. In conclusion, CILO protected gut integrity by reducing the epithelial-mesenchymal transition process, the MTX-induced oxidative, apoptotic, and inflammatory mediators, and turning off the CD44/AKT/GSK-3β/cyclin D1 trajectory and intensifying the expression of PCNA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatotoxicity is the main off-target effect of methotrexate (MTX) limiting its effective clinical use. Besides, MDA-MB231 breast cancer cells show chemoresistance, partly via PI3K/AKT pathway. Therefore, we investigated the ameliorative potentials of the PI3K inhibitor, alpelisib (ALP) on MTX-induced hepatotoxicity (in vivo) and the restraining potentials of ALP on MDA-MB231 chemoresistance to MTX (in vitro). Twenty-eight male BALB/c mice were divided into 4 groups. In treatment groups, mice were administered ALP (2.5 and 5 mg/kg) for 5 days and MTX (20 mg/kg) from day 2 till day 5. The results showed that ALP restored hepatic architecture, reduced immune cell infiltration (F4/80, Ly6G and MPO) and repressed the rise in liver enzymes (AST and ALT) induced by MTX. Additionally, ALP rectified the MTX-induced disruption of cellular oxidant status by boosting antioxidant defense systems (HO-1 and GSH) and repressing lipid peroxidation (MDA and 4-HNE). Finally, ALP curbed MTX-induced hepatocyte apoptosis (NF-κB and BAX) and shifted the cytokine milieu away from inflammation (IL-17, IL-22, IL-6 and IL- 10). The results of the in vitro experiments revealed that ALP alone and in combination with MTX, synergistically, reduced cancer cell viability (MTT assay), migration (wound healing assay) and their capacity to establish colonies (colony formation assay) as compared to MTX alone. RT-PCR revealed the antiproliferative (Bcl-2) and proapoptotic (BAX) potentials of ALP and ALP/MTX combination especially after 24 h. In conclusion, targeting PI3K/AKT pathway is a promising strategy in triple negative breast cancer patients by ameliorating hepatotoxicity and restraining chemoresistance to chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

There are multiple concerns associated with methotrexate (MTX), widely recognized for anti-neoplastic and anti-inflammatory effects in life-threatening disease conditions, i.e., acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, psoriasis, and rheumatoid arthritis, due to long-term side effects and associated toxicity, which limits its valuable potential. MTX acts as an inhibitor of dihydrofolate reductase, leading to suppression of purine and pyrimidine synthesis in high metabolic and turnover cells, targeting cancer and dysregulated immune cells. Due to low discrimination between neoplastic cells and naturally high turnover cells, MTX is prone to inhibiting the division of all fast-dividing cells, causing toxicity in multiple organs. Nutraceutical compounds are plant-based or food-derived compounds, used for their preventive and therapeutic role, ascertained in multiple organ dysfunctions, including cardiovascular disease, ischemic stroke, cancer, and neurodegenerative diseases. Gut microbiota and microbiota-derived metabolites take part in multiple physiological processes, their dysregulation being involved in disease pathogenesis. Modulation of gut microbiota by using nutraceutical compounds represents a promising therapeutic direction to restore intestinal dysfunction associated with MTX treatment. In this review, we address the main organ dysfunctions induced by MTX treatment, and modulations of them by using nutraceutical compounds. Moreover, we revealed the protective mechanisms of nutraceuticals in MTX-induced intestinal dysfunctions by modulation of gut microbiota.

Background: High dose methotrexate (HDMTX) is used for the treatment of pediatric hemato-oncological diseases. HDMTX can induce acute kidney injury in cases of delayed elimination. The use of leucovorin remains the most effective rescue action. Further treatment options are of difficult access in the rare cases where leucovorin fails to prevent renal failure from occurring. Glucarpidase is an effective treatment in cases of methotrexate (MTX) delayed elimination, but cost is high and availability is limited. Charcoal hemoperfusion (CHP) is a very efficient procedure to remove protein-bound drugs, promoting fast MTX elimination, but is rarely considered as a treatment option.Methods: We present three pediatric cases with prolonged exposure to MTX after HDMTX and delayed elimination in which hemoperfusion was performed as rescue treatment for methotrexate intoxication.Results: Charcoal hemoperfusion was performed with positive results and no complications as bridging until glucarpidase was available in two cases and in one case where two doses of glucarpidase led to insufficient reduction of MTX levels.Conclusions: CHP can be considered as a rescue treatment option in MTX intoxication, since it is an effective and safe extracorporeal method for removing MTX, in cases where rescue with leucovorin is insufficient and glucarpidase is not available or while waiting for delivery.

Overdosing is the major cause of acute methotrexate toxicity in psoriasis patients. There are no published data regarding the acute cumulative dose causing acute toxicity, duration to achieve acute cumulative toxic dose and various reasons for wrong dosing of methotrexate in Indian patients. We are presenting a series of seven cases of toxicity due to overdosing of methotrexate in psoriasis. The acute cumulative dose of methotrexate ranging from 35 mg to 150 mg, taken over 3–7 days was responsible for acute toxicity in the psoriasis cases. Lack of counselling regarding the disease course, drug dosing, schedule and awareness about possible outcome of high and daily dose were found to be the causes of overdosing and toxicity in our patients. All cases presented with ulceration, bleeding and pain in skin lesions and five cases had oral mucosal ulceration and genital mucosa was involved in two cases. All cases were given injectable folinic acid. Five cases recovered and two cases expired. Authors postulate counselling about the course of disease, regarding dosing schedule of methotrexate and consequences of methotrexate overdosing is mandatory for all patients of psoriasis in country like India where drug regulation is not strict to prevent methotrexate toxicity and its dreaded consequences.

Introduction: Methotrexate intoxication following high-dose methotrexate-induced acute kidney injury is a life-threatening complication. Glucarpidase can quickly reduce extracellular methotrexate to safe levels, but the effectiveness and safety of its use in different episodes of nephrotoxicity remain an unknown area. Case Report: A 30-year-old male diagnosed with acute lymphoblastic T-cell lymphoma received methotrexate 5 g/m2 intravenous (IV) as part of the first consolidation cycle. On Consolidation 3, he restarted methotrexate at a dose of 3 g/m2 IV showing slow methotrexate elimination, associated myelosuppression, and hepatic toxicity. Glucarpidase was administered (total dose of 2000 International Units (IU)). No adverse events were observed, and his renal function returned to normal. One hundred and six days later, he was diagnosed with leptomeningeal and cerebellar relapse and treatment with methotrexate 3,5 g/m2 IV day 1 and cytosine arabinoside (Ara-C) 2 g/m2 IV twice per day days 1, 3, and 5 was started. At 36 h from methotrexate infusion, serum creatinine increased up to 1.89 mg/dL and methotrexate concentration was 100 µmol/L. Management and Outcome: Ara-C was suspended, and a second administration of glucarpidase (2000 IU) was dispensed. No adverse events were noticed, methotrexate levels decreased and renal function progressively improved, recovering completely three weeks later. Discussion: The effectiveness and safety of the use of glucarpidase in different episodes of nephrotoxicity remain an unknown area, and the rate and consequences of antiglucarpidase antibody formation remain poorly understood. This case report is, to our knowledge, the first case of a second administration of glucarpidase in a different cycle of high-dose methotrexate in an adult patient. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is an inhibitor of folic acid reductase used in managing a variety of malignancies. Testicular injury by MTX is one of its serious adverse effects. The current investigation aims to assess the protective effects of diacerein (DIA) on testicular injury by MTX and clarify the possible underlying mechanisms. Testicular injury in rats was induced by a single injection of 20 mg/kg body weight of MTX. DIA was given in 25 mg/kg body weight/day and 50 mg/kg body weight/day doses for 10 days. Compared to the MTX group, DIA attenuated testicular intoxication as evidenced by improvement of testicular histopathological abnormalities and increased serum testosterone and luteinizing hormone. DIA attenuated testicular oxidative stress changes by lowering testicular MDA and boosting GSH content and SOD activity. Moreover, administration of DIA attenuated MTX-induced testicular inflammation, as proved by decreased TNF-α and IL-6. At the molecular level, DIA induced significant upregulation in Nrf2, HO-1, PPAR-γ, and cytoglobin protein expression. The present results proved that DIA, in a dose-dependent manner, exhibited notable amelioration of testicular toxicity induced by MTX through augmentation of anti-inflammatory and antioxidant effects combined by upregulating Nrf2/HO-1, PPAR-γ, and cytoglobin signaling., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Methotrexate-induced nephrotoxicity is a medical emergency which is associated with a variety of side effects. Vanillic acid (VA), as an antioxidant, removes free radical oxygen to protect cell defense. Therefore, this study investigated VA's beneficial effects on nephrotoxicity induced by methotrexate through its anti-apoptosis, antioxidant, and anti-inflammatory properties. Our study included five groups of male Wistar rats (n = 8): sham, MTX (Methotrexate) group: rats receiving methotrexate (20 mg/kg, intraperitoneally) on Day 2. Moreover, the remaining groups consisted of animals that received vanillic acid (25, 50, and 100 mg/kg, orally for seven days) plus MTX on the 2 nd day. The rats were deeply anesthetized on the eighth day to obtain blood and renal tissue samples. The results showed that MTX can increase blood urea nitrogen and creatinine. However, VA (50 and 100 mg/kg) improved renal function as approved by histological findings. Compared with MTX-treated rats, VA enhanced the contents of total antioxidant capacity (TAC) and reduced renal malondialdehyde (MDA). Moreover, VA reduced mRNA expressions of caspase-3 and Bcl-2-associated x protein (Bax) and caused mRNA overexpression of the renal B-cell lymphoma-2 (Bcl-2), and Nrf-2 (Nuclear factor erythroid 2-related factor 2) compared to the MTX group. Also, VA administration significantly reduced inflammatory agents. Overall, VA protects the kidneys against methotrexate-induced nephrotoxicity via anti-apoptosis, antioxidant, and anti-inflammatory properties. Our results revealed that the most effective dose of VA was 100 mg/kg., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Methotrexate (MTX) is a widely used medication for various cancers, yet its use is associated with adverse effects on organs, notably the lungs. Cannabidiol (CBD), known for its antioxidant and anti-inflammatory properties, was investigated for its potential protective effects against MTX-induced lung injury. Thirty-two female Wistar Albino rats were divided into four groups: control, MTX (single 20 mg/kg intraperitoneal dose), MTX + CBD (single 20 mg/kg MTX with 0.1 ml of 5 mg/kg CBD for 7 days intraperitoneally) and CBD only (for 7 days). Lung tissues were analysed using histopathological, immunohistochemical and PCR methods after the study. Histopathological assessment of the MTX group revealed lung lesions like hyperemia, edema, inflammatory cell infiltration and epithelial cell loss. Immunohistochemical examination showed significant increases in Cas-3, tumour necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB) expressions. PCR analysis indicated elevated expressions of apoptotic peptidase activating factor 1 (Apaf 1), glucose-regulated protein 78 (GRP 78), CCAAT-enhancer-binding protein homologous protein (CHOP) and cytochrome C (Cyt C), along with reduced B-cell lymphoma-2 (BCL 2) expressions in the MTX group, though not statistically significant. Remarkably, CBD treatment reversed these findings. This study highlights CBD's potential in mitigating MTX-induced lung damage, suggesting its therapeutic promise., (© 2024 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

We investigated the possible ameliorative effects of nobiletin (NBL) against methotrexate (MTX)-induced hepatorenal toxicity in rats. Twenty-eight Wistar albino rats were randomly divided into four groups, namely: Control; MTX (administered 20 mg/kg MTX); MTX+NBL (administered 20 mg/kg MTX and 10 mg/kg NBL per day); and NBL (administered 10 mg/kg/day NBL). Histopathological, immunohistochemical and biochemical analyses were performed on the kidney and liver tissues of rats at the end of the study. MTX caused renal toxicity, as indicated by increases in malondialdehyde (MDA) and caspase-3, as well as decreases in reduced glutathione (GSH), glucose-6-phosphate dehydrogenase (G6PD), glutathione peroxidase (GPx), catalase (CAT) and B-cell lymphoma-2 (Bcl-2). MTX also caused hepatotoxicity, as indicated by increases in 8-hydroxy-2'-deoxyguanosine (8-OHdG), tumor necrosis factor alpha (TNF-α), MDA and caspase-3 and decrease in interleukin 10 (IL-10), GSH, total antioxidant capacity, GPx, G6PD, CAT and Bcl-2. MTX caused histopathological changes in kidney and liver tissues indicating tissue and cellular damage. Administration of NBL concurrently with methotrexate reduced oxidative stress, inflammatory and apoptotic signs, and prevented kidney and liver damage caused by methotrexate. We consider NBL has attenuating and ameliorating effects on methotrexate-induced hepatorenal toxicity.

Methotrexate is the most common disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis. The side effects which are known to occur include pancytopenia, hepatic dysfunction, pulmonary toxicity, and acute renal failure. This is a case report of a patient who presented with florid manifestations of methotrexate toxicity which happened due to mistaken overdosing of methotrexate which had been prescribed to her for rheumatoid arthritis.

Methotrexate (MTX), one of the important disease‐modifying anti‐rheumatic drugs, is the first‐line drug for rheumatoid arthritis (RA) treatment. However, its adverse drug effects (ADEs) often lead to the abortion of MTX therapy. Human organic anion‐transporting polypeptide 1A2 (OATP1A2, also referred as OATP‐A or OATP1) encoded by SLCO1A2 gene is an important isoform of the solute carrier transporter (SLC) family. It is known to participate in the cellular uptake of MTX. In our previous study, we identified four OATP1A2 natural variants (E184K, D185N, T259P, and D288N) with impaired MTX uptake activity. This study aimed to evaluate the association of the SLCO1A2 genetic variations encoding these OATP1A2 variants and MTX‐related toxicity in RA patients. A total of 60 RA patients were genotyped for these four polymorphisms (G550A, G553A, A775C, and G862A). The association between SLCO1A2 genetic variations and MTX toxicity was analyzed by binary logistic regression analysis. Single nucleotide polymorphisms (SNPs) analysis revealed that A775C and G862A SNPs were not detected in RA patients enrolled in this study, and the presence of 550AA genotype was associated with a high risk of MTX ADEs. Haplotype analysis revealed that H3 (H3 = AG) showed a high risk of MTX ADEs. Furthermore, there was a significant association of 550AA genotype and impaired MTX disposition, which might be the cause of the increased incidence of MTX ADEs in RA patients. Therefore, genetic variations in SLCO1A2 gene are risk factors for MTX toxicity and its information contributes to the prediction of MTX‐related toxicity in RA treatment. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) forms the backbone of maintenance cycles in childhood acute lymphoblastic leukemia (ALL) chemotherapy, including interim maintenance. There is sufficient published data describing toxicities of high dose MTX (HD-MTX), but toxicities with escalating doses of MTX (Capizzi regimen) is not well documented. Capizzi regimen is thought to be relatively safe; we contend that even low escalating doses of MTX have significant toxicities. Our study intends to characterise such events with Capizzi MTX in comparison to that seen with HD-MTX. The retrospective study was conducted at a tertiary care centre of North India. We looked for the presence of six main toxicities: febrile neutropenia, thrombocytopenia, mucositis, hepatic toxicity, renal toxicity and skin toxicity from the clinical records of children with newly diagnosed acute lymphoblastic leukemia and lymphoma (intermediate and high risk disease), treated at our centre from November 2013 to July 2018. Intermediate risk ALL (IR-ALL) received Capizzi MTX, whereas high risk ALL (HR-ALL/T-NHL), received HD-MTX. Both these regimens do not use L-asparaginase. A total of 237 cycles of Capizzi escalating MTX and 151 cycles of HD-MTX (B cell: 3 gm/m2 and T cell ALL/T-NHL: 5 gm/m2) during interim maintenance were studied in 93 children. Fifty-four (54) children were of IR (all B cell ALL) and 39 of HR-ALL (21 B-ALL, 18 T-ALL/T-NHL). The combined incidence of toxicities, were similar between the two groups: 68/237 cycles (28.7%) of Capizzi MTX and 45/151 cycles (29.8%) of HD-MTX (P = 0.815). However, mucositis was more commonly witnessed in the later group at 22/151 cycle (14.6%) versus 13/237 cycles (5.5%) in Capizzi MTX (P = 0.002). Nephrotoxicity and skin toxicity was seen only in the HD-MTX group. There was no difference in the severity of toxicity, graded using NCI CTCAE v 5.0, between the two groups. There was no mortality directly attributable to methotrexate toxicity (Grade V toxicity). Serum MTX levels were available in 69/151 (45.7%) cycles of HD-MTX and showed no association with toxicity in this group. Also, there was no difference in the incidence of combined toxicities between groups with (19/69 cycles) or without (26/82 cycles) available serum MTX levels in the HR group (P = 0.577). Male gender, lower baseline ANC and lower BMI had significant association with toxicity. Methotrexate related toxicity is common with both Capizzi and HD-MTX schedule in childhood ALL with a correlation of lower BMI, baseline ANC and male gender. However, it is possible to administer Capizzi as well as HD-MTX in lower middle income countries, with manageable toxicity. Further studies will be required to substantiate our findings and determine the predictors of such events. [ABSTRACT FROM AUTHOR]

Background: Globally, 0.5-1% general population are suffering from rheumatoid arthritis (RA). RA is a chronic systemic self-immune medicated inflammatory disorders, affects synovial fluids and the lining of synovial joints. To treat RA required multiple drug therapy such as glucocorticoids, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs (DMARDs), and biologics. DMARDs such as methotrexate (MTX), hydroxychloroquine, and leflunomide are routinely used in RA either as a monotherapy or combination therapy. MTX is a well-established DMARD used as first-line therapy in RA due to cost-effectiveness and efficacious. Even though MTX acts as gold standard drug therapy in the management of RA, it possesses various toxicity that may be related to the organ. Organ related toxicity includes gastrointestinal (GI) toxicity, hematological toxicity, hepatic toxicity, renal toxicity, cutaneous toxicity, and infections. This leads to the withdrawal of MTX therapy in 5-57% of patients within 1-2 years. Hence, we aimed to conduct a review of case studies to identify the types and nature of MTX -induced organ toxicity and management of that toxicity. Search strategies: We conducted a medical database search to identify case studies and found a total of 27 case studies, having 40 RA patients presentation, who experienced MTX -induced organ toxicity. The mean age of RA patients experienced with MTX -induced organ toxicity was 66.2 years and the age of affected patients was ranging from 30 to 82 years. Maximum number (n = 30) of MTX toxicity was seen in 61-80 years group of RA patients. The MTX -induced organ toxicity was GI toxicity, hematological toxicity, pulmonary toxicity, hepatic toxicity, renal toxicity, cutaneous toxicity, and various types of infections. Conclusion: MTX -induced organ toxicity can occur at any stage of MTX therapy even after taking care of precautions. This toxicity may be acute or chronic. The severity lies mild to severe in nature and rarely even cause death. This toxicity enhances economic burden and suffering to the patients. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX), a chemotherapeutic antimetabolite, has been linked to cognitive impairment in cancer patients. MTX-induced metabolic pathway disruption may result in decreased antioxidant activity and increased oxidative stress, influencing hippocampal neurogenesis and microglial activation. Nuclear factor-kappa B (NF-κB), an oxidative stress byproduct, has been linked to MTX toxicity via the activation of NLRP3 inflammasome signaling. Macrophage activation and polarization plays an important role in tissue injury. This differentiation may be mediated via either the Toll-like receptor 4 (TLR4) or NLRP3 inflammasome. Interestingly, Canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor has been recently reported to exert anti-inflammatory effects by modulating macrophage polarization balance. This study aimed to investigate CANA's protective effect against MTX-induced cognitive impairment, highlighting the possible involvement of TLR4/ NF-κB crosstalk with NLRP3 inflammasome activation and macrophage polarization. Forty-eight Male Wistar rats were divided into 4 groups; (1) received saline orally for 30 days and intravenously on days 8 and 15. (2) received Canagliflozin (CANA; 20 mg/kg/day; p.o.) for 30 days. (3) received MTX (75 mg/kg, i.v.) on day 8 and 15, then they were injected with four i.p. injections of leucovorin (LCV): the first dose was 6 mg/ kg after 18 h, and the remaining doses were 3 mg/kg after 26, 42, and 50 h of MTX administration. (4) received MTX and LCV as in group 3 in addition to CANA as in group 2. MTX-treated rats showed cognitive deficits in spatial and learning memory as evidenced in the novel object recognition and Morris water maze tests. MTX exerted an oxidative effect which was evident by the increase in MDA and decline in SOD, GSH and GPx. Moreover, it exerted an inflammatory effect via elevated caspase-1, IL-1β and IL-8. CANA treatment restored cognitive ability, reduced MTX-induced oxidative stress and neuroinflammation via attenuation of TLR4/NF-κB/NLRP3 signaling, and rebalanced macrophage polarization by promoting the M2 phenotype. Hence, targeting molecular mechanisms manipulating macrophage polarization may offer novel neuroprotective strategies for preventing or treating MTX-induced immune modulation and its detrimental sequel., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)