Madalina Iliescu, R. L. Craciun and Angelica Nela Stavar
Introduction: Liver represents the main place of drug metabolisation. Drugs and toxic substances reach the level of liver after absorption at gastro-intestinal level. Drug hepatotoxicity represents an important chapter of iatrogenic pathology, because the hepatic lesions induced by drugs include extremely diverse clinical, biological and histological expressions that can take the aspect of any form of acute or chronic hepatobiliary disease. Hepatic lesions induced by drugs (LHIM) represent a histological and/or biochemical alteration caused and attributed to the consumption of a drug. Hepatic elastography (Fibroscan) represents a noninvasive method of quantification of hepatic fibrosis.
Material and method: We carried out a retrospective study and longitudinally prospective study that included a set of patients under treatment with Methotrexate, amounting to 76, divided into 2 subsets: a subset consisting of patients with hepatitis to Methotrexate, subset 1, of 23 patients, a subset of patients under treatment with Methotrexate but with normal hepatic samples, subset b, of 53 patients.
Results: We carried out fibroscan at all the patients treated with Methotrexate, obtaining a medium score of fibrosis of 6.23 for the subset a with hepatitis at Methotrexate and of 5.33 for the subset b with normal hepatic samples. We made a correlation between the cumulated dose of Methotrexate and the change of hepatic samples.
Conclusions: There is a significant correlation between hepatic fibrosis induced by Methotrexate and the cumulated dose of Methotrexate. The possibility of utilization of fibroscan which is a completely painless method, reproducible, for the monitoring of the treatment with Methotrexate both at patients with changed values of the hepatic tests as weir as those with normal values must be considered.
Radka T. Komitova, Vasko A Grklanov, Konstantinos K. Lindas and Petya V. Ganeva
Low-dose once weekly methotrexate (MTX) is the first-line disease-modifying antirheumatic drug (DMARD) to treat rheumatoid arthritis and psoriasis. Although methotrexate is generally considered to have a good safety profile it can occasionally induce severe side effects such as pancytopenia, mucositis, disorders of kidney and liver. Oral mucositis should alert physicians to MTX toxicity. We report a 64-year-old woman with a severe drug reaction including disseminated shingles, oral mucositis and pancytopenia only three days after starting a therapeutic low-dose of MTX. Initially, mucositis and myelosuppression couldn’t be accounted for by the underlying disease. In taking the patient’s history, MTX intake 10 days ago was missed, the patient reporting only current medications. However, there was more to the skin rash than meets the eye. Only after further inquiry did the patient reveal the intake of 2 doses of MTX and the subsequent withdrawal of medication. Arriving at the correct diagnosis in difficult cases, as in the case presented, requires further evaluation, including repeat history taking and eliciting more details if diagnosis remains elusive.
Maria G. Ganeva, Tanya T. Gancheva, Ivan D. Baldaranov, Nataliya J. Kiriyak and Evgeniya H. Hristakieva
Methotrexate (MTX) is a cytostatic agent used in oncology. Because of its immunosuppressive properties, MTX is also used in autoimmune disorders. Low-dose MTX regimens in the treatment of rheumatoid arthritis and severe psoriasis are considered to be safe. However, pharmacovigilance centers warn of serious and even fatal incidents due to errors in oral MTX administration. The aim of this case series presentation was to identify the specific factors related to the development of adverse drug reactions (ADRs) induced by MTX. A prospective pharmacovigilance study was conducted at the Clinic of Dermatology, University Hospital, Stara Zagora. We report 3 cases of patients with psoriasis vulgaris in which severe haematological abnormalities associated with previous administration of MTX were detected during hospitalization. A 73-year old female with malaise, vomiting and oral ulcers who had taken approximately 120 mg MTX was found to have pancytopenia. A 59-year old male hospitalized for psoriatic erythroderma who had erroneously taken 10 mg MTX daily instead of weekly for 8 days, was diagnosed with bicytopenia and toxic hepatitis. An 88-year old male with psoriatic arthritis presented with aphthous stomatitis, erosive crusted lesions, ecchymoses and aplastic anemia 2 weeks after treatment with 12.5 mg MTX once weekly plus i.m. Movalis®, followed by Diclophenac Duo®. The main predisposing factors for the development of these ADRs were patient-related dosage errors and concomitant administration of NSAIDs. Safe use of oral MTX requires clear dosing instructions and strict patient compliance. Potential drug interactions of MTX with other drugs should also be considered.
Barbara Faganel Kotnik, Janez Jazbec, Petra Bohanec Grabar, Cristina Rodriguez-Antona and Vita Dolzan
We investigated the clinical relevance of SLC 19A1 genetic variability for high dose methotrexate (HD-MTX) related toxicities in children and adolescents with acute lymphoblastic leukaemia (ALL) and non Hodgkin malignant lymphoma (NHML).
Patients and methods
Eighty-eight children and adolescents with ALL/NHML were investigated for the influence of SLC 19A1 single nucleotide polymorphisms (SNPs) and haplotypes on HD-MTX induced toxicities.
Patients with rs2838958 TT genotype had higher probability for mucositis development as compared to carriers of at least one rs2838958 C allele (OR 0.226 (0.071–0.725), p < 0.009). Haplotype TGTTCCG (H4) statistically significantly reduced the risk for the occurrence of adverse events during treatment with HD-MTX (OR 0.143 (0.023–0.852), p = 0.030).
SLC 19A1 SNP and haplotype analysis could provide additional information in a personalized HD-MTX therapy for children with ALL/NHML in order to achieve better treatment outcome. However further studies are needed to validate the results.
Magdalena Izdebska, Iwona Piątkowska-Chmiel and Ewa Jagiełło-Wójtowicz
In in vitro study on green monkey kidney (GMK) cell culture, the cytotoxicity of Ukrain, methotrexate (MTX), and their combination was investigated. The effect of these drugs and their combination on viability (MTT test) and apoptosis of the cells was assessed. The IC10 and IC50 values for Ukrain and MTX were also indicated. After 24 h of incubation of GMK cells with Ukrain, IC10 amounted to 84.6 μmol/L and IC50 was 256.3 μmol/L, while MTX IC10 amounted to 7.18 μmol/L and IC50 was 154.8 μmol/l. After 24 h of simultaneous incubation of GMK cells with 50 μmol/L of Ukrain and 5.5 μmol/L of MTX, 15.33 % of cytotoxicity of the drugs in LDH test was found. The most significant increase in the cytotoxicity (42.10 %) was noted after 24 h incubation of GMK cells with 150 μmol/L of Ukrain and 5.5 μmol/L of MTX. Likewise, in the MTT assay the greatest decrease in the cells viability was found after incubation with 150 μmol/L of Ukrain and 5.5 μmol/L of MTX. The evaluation of apoptosis also indicated the adverse effect of combined application of both drugs on GMK cells.
Methotrexate (MTX) is an antimetabolite which interferes with DNA synthesis. It is used for the treatment of many diseases, such as psoriasis, rheumatoid arthritis and various neoplastic diseases. It may cause, among various adverse reactions, oral ulceration and oral mucositis. 3 cases of methotrexate related oral ulcers are reported along with a brief review of the relevant literature.
Frantisek Drafi, Katarina Bauerova, Viera Kuncirova, Silvester Ponist, Danica Mihalova, Tatiana Fedorova, Juraj Harmatha and Radomir Nosal
Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis. A certain correlation was observed between oxidative stress, arthritis and the immune system. Reactive oxygen species produced in the course of cellular oxidative phosphorylation and by activated phagocytic cells during oxidative burst, exceed the physiological buffering capacity and result in oxidative stress. The excessive production of ROS can damage protein, lipids, nucleic acids, and matrix components. Patients with rheumatoid arthritis have an altered antioxidant defense capacity barrier. In the present study the effect of substances with antioxidative properties, i.e. pinosylvin and carnosine, was determined in monotherapy for the treatment of adjuvant arthritis (AA). Moreover carnosine was evaluated in combination therapy with methotrexate. Rats with AA were administered first pinosylvin (30 mg/kg body mass daily per os), second carnosine (150 mg/kg body mass daily per os) in monotherapy for a period of 28 days. Further, rats with AA were administered methotrexate (0.3 mg/kg body mass 2-times weekly per os), and a combination of methotrexate+carnosine, with the carnosine dose being the same as in the previous experiment. Parameters, i.e. changes in hind paw volume and arthritic score were determined in rats as indicators of destructive arthritis-associated clinical changes. Plasmatic levels of TBARS and lag time of Fe2+- induced lipid peroxidation (tau-FeLP) in plasma and brain were specified as markers of oxidation. Plasmatic level of CRP and activity of γ-glutamyltransferase (GGT) in spleen and joint were used as inflammation markers. In comparison to pinosylvin, administration of carnosine monotherapy led to a significant decrease in the majority of the parameters studied. In the combination treatment with methotrexate+carnosine most parameters monitored were improved more remarkably than by methotrexate alone. Carnosine can increase the disease-modifying effect of methotrexate treatment in rat AA.
Laurenţiu Lucaci, Ștefana Maria Moisă, Marin Burlea and Lucian Miron
Introduction: Methotrexate, a structural analogue to the folic acid, is one of the most frequently used antimetabolites in pediatric oncologic pathology. Its mode of action and toxic effects are now well known. Material
and method: Our study aimed to describe the quantitation of the drug in serum of 40 children with acute lymphatic leukemia receiving high doses of methotrexate and to predict serum methotrexate levels at 96 hours, based on 48 h, 72h levels and on alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine serum levels. The above mentioned parameters were analyzed by sampling serum levels at 48h, 72h and 96 hours after methotrexate administration and a logical regression model being projected upon obtained results. Results and conclusions: methotrexate serum level at 96 hours does not depend on either AST, ALT, urea, creatinine levels or on the methotrexate level determined at 48 hours, it only depends on the methotrexate serum level at 72 hours.
Lilia G. Zisova, Cvetana I. Abadjieva, Elena V. Obreshkova, Georgi K. Chernev and Nina I. Vutova
Eosinophilic fasciitis is a rare inflammatory disease of unknown etiology, described for the first time by Shulman in 1974. The disease presents with induration of the skin, connective tissue and the underlying muscle fascia, sometimes accompanied by myalgia, most commonly in the lower extremities. Unlike scleroderma, it presents with absence of visceral organ involvement and Raynaud’s phenomenon. Hypergammaglobulinemia and eosinophilia have been reported. Eosinophilic fasciitis is often associated with hematological disorders - there are reports of combinations with other autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, Hashimoto thyroiditis, Sjogren syndrome, vitiligo, etc. Occurrence of morphea, in the course of eosinophil fasciitis is considered a rarity. We have observed such a case with the simultaneous presence of both types of lesions. A 20-year-old female patient is reported, wherein the clinical picture developed for 6 months. The initial erythematous edema and subsequently the livedo-like painful plaques in both lower legs gradually swell, thicken and hyperpigment. Almost simultaneously with these complaints small brown livid body plaques emerged. The patient was diagnosed based on history, clinical picture, peripheral eosinophilia and histological findings from the affected areas. There was no systemic involvement and accompanying hematologic or other disease. Therapeutic management and significant clinical improvement were achieved using systemic corticosteroid therapy combined with methotrexate.
Nina Erculj, Barbara Faganel Kotnik, Marusa Debeljak, Janez Jazbec and Vita Dolzan
Background. We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL). Patients and methods. In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms.
Results. Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype.
Conclusions. Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTXrelated toxicity in children with NHL.