Uso de metotrexato en dermatología: una antigua droga aún vigente / Use of methotrexate in dermatology

El Metotrexato es una droga ampliamente utilizada en dermatología con propiedades antiinflamatorias, antiproliferativas e inmunosupresoras. La dosis usada es variable, se administra de preferencia por vía oral, y sus efectos se ven desde la sexta semana de tratamiento. Su metabolismo es hepático y se excreta por la orina. Se debe comprobar que el paciente no tenga contraindicaciones para su uso previo al inicio de la terapia, y evaluar al paciente con exámenes de laboratorio antes y durante la terapia. Durante el tratamiento se recomienda suplementar con ácido fólico. Presenta toxicidad de órganos, principalmente mielosupresión, hepatotoxicidad y toxicidad pulmonar; es importante también considerar su potencial teratogenicidad, su capacidad de reactivar infecciones oportunistas, su potencial oncogénico y el síndrome “Recall”. Esta revisión tiene como objetivo ser una guía práctica actualizada para el uso de MTX enpatologías dermatológicas.

Methotrexate is a drug widely used in dermatology with anti-inflammatory, antiproliferative and immunosuppressive properties. The dose used is variable and is preferably administered orally; its effects are seen from the sixth week of treatment. It has hepatic metabolism and is excreted in the urine. Patients shouldn’t have any contraindications to receive MTX and should be evaluated with laboratory tests before and during therapy. Supplementation with folic acid is recommended. It has organ toxicity, mainly myelosuppression, hepatotoxicity and pulmonary toxicity; is also important to consider their potential teratogenicity, its ability to reactivate opportunistic infections, their oncogenic potential and “Recall” syndrome. This review is an updated practical guide for the use of MTX in dermatologic skin diseases.

Intravitreal injection of methotrexate in an experimental rabbit model: Determination of pharmacokinetics.

Purpose: To investigate the pharmacokinetics of intravitreally administered methotrexate. Materials and Methods: Twenty-one New Zealand white rabbits were used in the study. The pharmacokinetics of intravitreally injected 800 μg/0.1 ml of methotrexate was investigated. Intravitreal concentration of the drug was measured at seven different times, in six eyes at each occasion, on a total of 42 eyes of 21 rabbits from a period of 30 minutes to 72 hours. Results: The volume of distribution was calculated as 1.33 ml following intravitreal injection of 800 μg methotrexate. Vitreous concentrations of the drug were found to be decreasing related to the specific mathematical equation; drug concentration= 1426.73 e-0.1182(time) and remained over effective dose by 81 hours with a half life of 5.9 hours. Conclusions: These findings evidenced those vitreous levels of methotrexate at various time intervals after 800 μg intravitreal injections which formulated a mathematical equation for calculation of vitreous level of the drug at each hour.

Collateral methotrexate resistance in cisplatin-selected murine leukemia cells

Resistance to anticancer drugs is a major cause of failure of many therapeutic protocols. A variety of mechanisms have been proposed to explain this phenomenon. The exact mechanism depends upon the drug of interest as well as the tumor type treated. While studying a cell line selected for its resistance to cisplatin we noted that the cells expressed a >25,000-fold collateral resistance to methotrexate. Given the magnitude of this resistance we elected to investigate this intriguing collateral resistance. From a series of investigations we have identified an alteration in a membrane protein of the resistant cell as compared to the sensitive cells that could be the primary mechanism of resistance. Our studies reviewed here indicate decreased tyrosine phosphorylation of a protein (molecular mass = 66) in the resistant cells, which results in little or no transfer of methotrexate from the medium into the cell. Since this is a relatively novel function for tyrosine phosphorylation, this information may provide insight into possible pharmacological approaches to modify therapeutic regimens by analyzing the status of this protein in tumor samples for a better survival of the cancer patients

Comparative studies of quality and bioavailability of methotrexate in Thai patients with rheumatoid arthritis.

The bioavailability of the two generic methotrexate oral preparations (Emtrexate, Pharmachemie Company, Holland and Methotrexate Remedica, Remedica, Cyprus as the test preparations), were compared to the innovator (Methotrexate Lederle, Lederle, U.S.A. as the reference) in 10 patients with rheumatoid arthritis. A single 7.5 mg oral dose of each preparation was given to the subjects in a randomized, double-blind, three-period crossover design with a 1 week washout period. Serum methotrexate concentrations were determined by using Fluorescence Polarization Immunoassay (Abbott TDx). No significant differences in pharmacokinetic parameters (AUC, Cmax, and Tmax) were observed between the test and reference preparations. The mean and 90 per cent CI of the ratio Emtrexate/Methotrexate Lederle and Methotrexate Remedica/Methotrexate Lederle of the Cmax, AUC0-8, and AUC0-alpha were 0.93 (0.87-1.00), 0.9 (0.82-0.98), 0.88 (0.79-0.99) and 0.97 (0.93-1.02), 0.95 (0.90-0.99), 0.94 (0.86-1.02), respectively. These values were well within the acceptable bioequivalence range of 0.8-1.25. The mean and 90 per cent CI of Tmax difference between Emtrexate-Methotrexate Lederle and Methotrexate Remedica-Methotrexate Lederle also overlapped the stipulated bioequivalence range of the Tmax differences of +/- 0.25 hour. Thus, Emtrexate and Methotrexate Remedica were considered bioequivalent to the reference Methotrexate Lederle regarding the rate of absorption and the extent of absorption.

Metotrexate en artritis reumatoidea: efectos colaterales y adherencia al tratamiento / Methotrexate in rheumatoid arthritis: side effects and adherence at treatment

Del presente trabajo basado en la revisión de 134 casos de artritis reumatoídea tratados con dosis bajas de metotrexate (7,5 a 15 mg semanales) se desprende que: el metotrexate aparece como un recurso terapéutico que ha reemplazado o desplazado otras drogas modificadoras de la evolución del tratamiento de la artritis reumatoídea (sales de oro, penicilina, cloroquina); su instauración ha sido variable en cuanto a edad y tiempo de evolución de la enfermedad pero, en general, es actualmente más precoz que antes cuando se recurría al metotrexate ante el fracaso de otros tratamientos; sus efectos adversos son preferentemente gastrointestinales y hepáticos pero de baja intensidad y frecuencia; la adherencia al tratamiento con metotrexato es alta. No hubo suspensión por fracaso terapéutico

pilot study on disposition and clinical efficacy of methotrexate in patients with rheumatoid arthritis following weekly low intramuscular dosing

In sixteen patients with rheumatoid arthritis [RA], plasma concentrations of methotrexate [MTX] were monitored for 24 hours following the intramuscular [im] dosing with 10 mg per week for at least six weeks. Peak concentrations [0.7 +/- 0.5 mumol/l] were achieved 15 minutes following im injection of the drug, while immeasurable drug levels were observed after 24 hours following its injection. Total body clearance [CL/F] and apparent volume of distribution [V/F] averaged 157 ml/min and 0.64 L/kg, respectively. The elimination half-life was 3.0 +/- 1.1 hours. Clinical assessment of the patients showed less pronounced morning stiffness, improved functional capacity and significant reduction in both articular index score and joint swelling. Nausea was the most common side effect of MTX in this dosage regimen. It was concluded that MTX [10 mg im/week] possess a favorable benefit/risk ratio for the treatment of RA and in such patients the pharmacokinetic parameters are variable but comparable to literature data. There is no relation between the serum level of the drug and its efficacy in RA when administered once weekly