Oral Administration Of Methotrexate Research Articles

A Pilot Study To Assess the Suitability of Riboflavin As a Surrogate Marker of Breast Cancer Resistance Protein in Healthy Participants.

We recently showed that riboflavin is a selected substrate of breast cancer resistance protein (BCRP) over P-glycoprotein (P-gp) and demonstrated its prediction performance in preclinical drug-drug interaction (DDI) studies. The aim of this study was to investigate the suitability of riboflavin to assess BCRP inhibition in humans. First, we assessed the substrate potential of riboflavin toward other major drug transporters using established transfected cell systems. Riboflavin is a substrate for organic anion transporter (OAT)1, OAT3, and multidrug and toxin extrusion protein (MATE)2-K, with uptake ratios ranging from 2.69 to 11.6, but riboflavin is not a substrate of organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organic cation transporter (OCT)2, and MATE1. The effects of BMS-986371, a potent in vitro inhibitor of BCRP (IC 50 0.40 μM), on the pharmacokinetics of riboflavin, isobutyryl carnitine, and arginine were then examined in healthy male adults (N = 14 or 16) after oral administration of methotrexate (MTX) (7.5 mg) and enteric-coated (EC) sulfasalazine (SSZ) (1000 mg) alone or in combination with BMS-986371 (150 mg). Oral administration of BMS-986371 increased the area under the plasma concentration-time curves (AUCs) of rosuvastatin and immediate-release (IR) SSZ to 1.38- and 1.51-fold, respectively, and significantly increased AUC(0-4h), AUC(0-24h), and C max of riboflavin by 1.25-, 1.14-, and 1.11-fold (P-values of 0.003, 0.009, and 0.025, respectively) compared with the MTX/SSZ EC alone group. In contrast, BMS-986371 did not significantly influence the AUC(0-24h) and C max values of isobutyryl carnitine and arginine (0.96- to 1.07-fold, respectively; P > 0.05). Overall, these data indicate that plasma riboflavin is a promising biomarker of BCRP that may offer a possibility to assess drug candidate as a BCRP modulator in early drug development. SIGNIFICANCE STATEMENT: Endogenous compounds that serve as biomarkers for clinical inhibition of breast cancer resistance protein (BCRP) are not currently available. This study provides the initial evidence that riboflavin is a promising BCRP biomarker in humans. For the first time, the value of leveraging the substrate of BCRP with acceptable prediction performance in clinical studies is shown. Additional clinical investigations with known BCRP inhibitors are needed to fully validate and showcase the utility of this biomarker.

Comparison of the clinical efficacy of subcutaneous vs. oral administration of methotrexate in patients with psoriasis vulgaris: arandomized controlled trial.

Evidence demonstrates that parenteral administration of methotrexate (MTX) has a higher drug bioavailability than oral administration. This difference is even more pronounced for medium to high dosages. To compare the efficacy, safety, and tolerability of oral and subcutaneous (SC) MTX for treatment of psoriasis. A randomized, comparative, single-blind, 32-week study was conducted. The clinical response was evaluated using the Psoriasis Area Severity Index (PASI) and patient global satisfaction was assessed using a visual analogue scale (VAS). In total, 77 completed the study: 38 in the SC and 39 in the oral MTX group. No significant between-group differences were found in the number attaining PASI improvement of 75% (PASI75), 90% (PASI90) and 100% (PASI100) at Weeks 16 and 32: PASI75 (P = 0.14 and P = 0.21, respectively), PASI90 (P = 0.23 and P = 0.18) and PASI100 (P = 0.62 and P = 0.22). According to the mean VAS, no significant differences between the groups were found at any time points except at Week 32 that the mean VAS was significantly higher in the SC group (P = 0.03). Adverse events were comparable in both groups. SC and oral administration of MTX had similar efficacies in improving the PASI score even at the highest tolerable dose; however, the SC MTX group had higher overall patient satisfaction than the oral MTX group. No difference in tolerability was found.

Involvement of NF-κB signal pathway in acupuncture treatment of patients with rheumatoid arthritis

To observe the effect of acupuncture on nuclear factor kappa-B(NF-κB)signaling pathway in patients with rheumatoid arthritis (RA), so as to explore the mechanism of acupuncture in the treatment of RA. A total of 120 RA patients admitted to the Xinyu Hospital of Traditional Chinese Medicine in Jiangxi Province from June 2018 to June 2019 were selected and randomly divided into a control group and a treatment group, with 60 cases in each group. The patients in the control group received oral administration of Methotrexate, (10-15) mg/time, once a week, for a total of 10 weeks. On the basis of oral administration of Methotrexate, patients in the treatment group were treated with acupuncture at Quchi(LI11), Zusanli(ST36), Taichong(LR3), Hegu(LI4), Shenshu(BL23), Geshu(BL17) and Dazhui(GV14) once daily. The treatment was conducted 6 consecutive times as a course for 10 courses. The serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), pain visual analog scale (VAS) score, number of swollen joints, and morning stiffness time before and after treatment were compared between the two groups. The expression levels of inflammatory related factors and NF-κB p65 protein in the synovial fluid were detected by enzyme-linked immunosorbent assay and Western blot separately. After treatment, both groups had significant decrease in CRP, ESR, VAS score, number of swollen joints and morning stiffness time, levels of NF-κB p65 protein, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 (P<0.05) in the joint fluid, and increase in transforming growth factor-β (TGF-β) and IL-10 (P<0.05). After treatment, compared with the control group, CRP, ESR, VAS score and morning stiffness time, and the levels of NF-κB p65, TNF-α, IL-1β and IL-6 in the treatment group were down-regulated (P<0.05), while the level of TGF-β was up-regulated (P<0.05). The treatment group had a higher total effective rate than the control group［85.0%(51/60) vs 75.0%(45/60), P<0.05］. Acupuncture can inhibit the expression of NF-κB signaling pathway in RA patients, regulate the levels of related inflammatory factors, and thus improve the symptoms of RA patients.

Modulation of methotrexate-induced intestinal mucosal injury by dietary factors.

Methotrexate (MTX)-induced intestinal mucosal injury in animals has been studied to understand how MTX can cause gastrointestinal disorders, but the pathogenesis of gastrointestinal disorders is still uncertain. We have attempted to reveal how dietary factors influence intestinal toxicity due to MTX. Mice were fed normal chow (NC) or a high-fat high-sucrose diet (HFHSD) before oral administration of MTX. While MTX significantly decreased the survival rates of mice fed HFHSD, the intestinal epithelial injury was detected. MTX excretion in the feces of mice fed HFHSD was reduced. Change of diets between NC and HFHSD influences the survival. The survival rates of the mice fed a high-sucrose diet or control diet were higher than those fed HFHSD. Higher survival rates were observed in mice fed a high-fat high-sucrose diet modified (HFHSD-M) in which casein was replaced by soybean-derived proteins. The survival rates of mice treated with vancomycin were lower than those administered neomycin. Microbiome and metabolome analyses on feces suggest a similarity of the intestinal environments of mice fed NC and HFHSD-M. HFHSD may modify MTX-induced toxicity in intestinal epithelia on account of an altered MTX distribution as a result of change in the intestinal environment.

Efficacy and adverse reactions of methotrexate in the treatment of ocular cicatricial pemphigoid: A case series study.

The application of methotrexate (MTX) in the treatment of autoimmune diseases has been gradually increasing, but reports of MTX treatment for advanced ocular cicatricial pemphigoid (OCP) are extremely rare. This study investigated the efficacy and adverse reactions of low-dose MTX in patients with OCP.This was a retrospective, noncontrolled, case series study. Eleven patients diagnosed with advanced OCP (4 cases in stage III and 7 cases in stage IV) were enrolled. Treatment by oral administration of MTX (7.5 ± 2.5 mg) alone was performed. Visual acuity of the patients, conjunctival inflammation, cicatrization, ocular surface keratinization, and toxic side effects of drugs were evaluated.All patients enrolled in this study were females aged 32 to 83 years. Patients were followed up for 4 to 33 months. Low-dose MTX improved visual acuity of 3 cases (6 eyes, 27.3%). Conjunctival inflammation of 5 patients (10 eyes) rested after treatment, and conjunctival inflammation of 3 cases (6 eyes, 27.3%) was decreased with an effective rate of 72.7%. Cicatrices of 8 cases (15 eyes) showed degeneration after treatment with an effective rate of 71.4% (15/21). Ocular surface keratinization receded in 4 cases with an effective rate of 66.7%. None of the patients discontinued the treatment due to severe toxic side effects. All patients tolerated mild drug-induced gastrointestinal reactions. Three patients terminated the treatment in advance after 4 to 6 months due to no improvement in the disease condition.Observation of clinical efficacy and safety findings demonstrated that low-dose MTX can be used to treat patients with advanced OCP.

Treatment of Rheumatoid Arthritis by Bee-venom Acupuncture

To study the clinical efficacy and safety of bee-venom acupuncture therapy for rheumatoid arthritis (RA). A total of 120 cases of RA patients were randomized into bee-sting acupuncture group (treatment) and western medicine group (control) in accordance with the random number table. The patients of the control group were treated by oral administration of Methotrexate (10 mg, once a week) and Celecoxlb (0.2 g, once a day), and those of the treatment group treated by 5 to 15 bee stings of Ashi-points or acupoints according to different conditions and corporeity, and with the bee-sting retained for about 5 min every time, once every other day. The treatment lasted for 8 weeks. The therapeutic effect was assessed by examining symptoms and signs of the affected joints as morning stiffness duration, swollen/tender joint counts (indexes), handgrip strength, 15 m-walking time, visual analogue scale (VAS), Disease Activity Score including a 28-joint count (DAS 28), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-cyclic citrullinated peptide antibody (ACCPA); and for assessing the safety of bee-venom acupuncture, the patients' responses of fever, enlargement of lymph nodes, regional red and swollen, itching, blood and urine tests for routine were examined. Findings of DAS 28 responses displayed that of the two 60 cases in the control and bee-venom acupuncture groups, 15 and 18 experienced marked improvement, 33 and 32 were effective, 12 and 10 ineffective, with the effective rates being 80% and 83. 33%, respectively. No significant difference was found between the two groups in the effective rate (P>0.05). After the treatment, both groups have witnessed a marked decrease in the levels of morning stiffness duration, arthralgia index, swollen joint count index, joint tenderness index, 15 m walking time, VAS, RF, ESR, CRP and ACCPA, and an obvious increase of handgrip strength relevant to their own levels of pre-treatment in each group (P<0.05). There were no significant differences between the two groups in the abovementioned indexes (P>0.05). The routine blood test, routine urine test, routine stool test, electrocardiogram result, the function of liver and kidney and other security index were within the normal range, without any significant adverse effects found after bee-stinging treatment. Bee-venom acupuncture therapy for RA patients is safe and effective, worthy of popularization and application in clinical practice.

Subcutaneous administration of methotrexate at high doses makes a better performance in the treatment of rheumatoid arthritis compared with oral administration of methotrexate: A systematic review and meta-analysis.

This study was conducted to determine whether subcutaneous (SC) methotrexate (MTX) makes better performance on bioavailability, clinical efficiency, side effects occurrence, and treatment failure in the treatment of RA compared with oral MTX. The databases PubMed, Web of Science, Embase, and Cochrane Library were systematically searched. Seven studies involving 1335 patients were eligible for data extraction and meta-analysis. The outcomes of meta-analysis were presented as mean difference (MD) or odd ration (OR) with 95% confidence interval (95% CI). Meta-analysis showed that SC MTX can significantly increase the AUC0-t (area under plasma concentration curve from administration to last observed concentration at time t) (MD = 506.84; 95% CI: 80.80-932.89), shorten the time to reach maximum observed concentration (Tmax) (MD = -0.13; 95% CI: -0.25 to -0.01) and the apparent terminal elimination half-life (t(1/2)) (MD = -0.39; 95% CI: -0.70 to -0.08), reduce the occurrence of nausea (OR = 0.53; 95% CI: 0.28-0.97) and diarrhea (OR = 0.43; 95% CI: 0.20-0.95), improve the American College of Rheumatology criteria for 20% improvement (ACR20) (OR = 1.68; 95% CI: 1.09-2.61) and ACR70 (OR = 1.52; 95% CI: 1.02-2.26), and relieve the pain (MD = -0.65; 95% CI: -0.93 to -0.37) compared with oral MTX. However, the differences in maximum plasma concentration (Cmax), the occurrence of headache, vomiting and dyspepsia, ACR50, treatment failure were not significant between the two groups. SC route of MTX at high doses made better performance on improving the bioavailability and clinical efficacy, reducing the GI disorders, but it cannot decrease the treatment failure when compared with oral administration of MTX.

An oral methotrexate may cause intracerebral hemorrhage

The neurotoxicity of methotrexate (MTX) is a well-documented issue but the development of an intracerebral hematoma following the administration of oral MTX is extremely rare. A 25-year-old female with a history of hydatidiform mole underwent dilatation and curettage 2 months earlier. She was put on oral MTX regimen 7.5 mg thrice weekly. Mistakenly she was taking 22.5 mg daily for the past 2 months. She presented to us with skin rashes and seizures. Later, she developed a deteriorating state of consciousness, with a clinical diagnosis of stroke. Magnetic resonance imaging (MRI) of the brain demonstrated a large left parietal hematoma. We failed to prove brain or lung metastasis due to choriocarcinoma, vasculitis syndrome, antiphospholipid syndrome, demyelination, and infective etiology.We used the Naranjo Adverse Drug Reaction (ADR) Probability Scale and stopped MTX, and treated the patient successfully with leucovorin, dexamethasone, aminophylline, and other measures. She was discharged after 25 days of hospital stay. We concluded that an high dose oral MTX may cause intracerebral hemorrhage.

Risks of Oral Methotrexate Administration in Outpatients

Abstract 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.

Bisphosphonate-associated Osteonecrosis of Jaw Reoccurrence after Methotrexate Therapy: A Case Report

IntroductionBisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-known complication caused by amino-bisphosphonate therapy. We document one case of BRONJ associated with oral administration of methotrexate, a known immunosuppressive drug used to treat rheumatoid arthritis. MethodsA 66-year-old woman was referred for evaluation and endodontic surgery of recently re-treated tooth 13. Tooth 14 was extracted 3 months prior, and the extraction site had not completely healed. Her medical history revealed rheumatoid arthritis and osteoporosis. She had been taking Fosamax (alendronate) 70 mg daily. Because of adequate root canal therapy of tooth 13, endodontic surgery was performed. Five months after apicoectomy, her symptoms had not changed. Tooth 13 was extracted, and the socket healed without complications. The socket of extracted tooth 14 was also healing. At the 3-month recall visit, bone exposure and purulent discharge at the site of extracted tooth 14 were noted. The patient had recently received methotrexate. The methotrexate was discontinued, and she was given course of amoxicillin. ResultsAt the 18-month follow-up, the healing progressed, and the wound was closed. ConclusionsA medication that suppresses the immune system such as methotrexate may complicate the management of BRONJ. Once a diagnosis of BRONJ is made, a closely monitored conservative approach is recommended.

THU0130 Assessment of transaminasitis with daily methotrexate therapy in patients with inflammatory rheumatic diseases. A long-term follow-up cohort study

BackgroundMethotrexate (MTX) is the most commonly used DMARD in the treatment of rheumatoid arthritis and other rheumatic diseases. MTX is often administered weekly (WMTX), because the drug has been considered...

AB0593 Subcutaneous methotrexate is more efficacious and better tolerated than oral methotrexate: The experience of a large group of patients in the rheumatology department of a district general hospital

BackgroundWith the emphasis in the management of inflammatory arthritis on early disease modification it is vital that prescribed treatments are tolerated and adhered to. Methotrexate can prove difficult for patients...

The role of antioxidant (vit-A and glutamine) in ameliorating methotrexate induced hepatic toxicity in rats

The aim of this study was to investigate the status of antioxidant glutathione peroxidase (GSH-Px) during oxidative stress in blood serum of rats subjected to oral methotrexate administration at a dose 10 mg/kg B.W and administrated antioxidant therapy (vit A and glutamine) to reduced or ameliorate such stress. A total of thirty six, male Sprague-Dawley rats weighing (250 – 300) g divided equally into six groups. The first group, control, were fed only standard rat chow as their diet and water ad libitum. The second group administered orally a single dose of methotrexate at a dose of 10 mg/kg B.W. The third group, given a single dose of methotrexate 10 mg/kg B.W + Vit-A (5000 IU/kg B.W) orally by stomach tube, twice daily. The fourth group, given a single dose of methotrexate 10 mg/kg B.W + Glutamine (500 mg/kg B.W), twice daily dosing. fifth group, given vit-A at dose 5000 IU/kg B.W orally, twice daily. Sixth group, given glutamate at dose 500 mg/BW orally, twice daily, all this dosing continue for 8 days. At the end from all animal, draw blood from heart by syring to obtained serum to determine its level then sacrificed and take section from liver for histopathology resulted in. It was found that methotrexate caused a signifcant increase in GSH levels (an important marker of lipid peroxidation) when compared with the control group while the level GSH were signifcantly decreased in the methotrexate + vitamin A group, methotrexate+ glutamine group, vitamin A group and glutamine group. The results indicate that methotrexate cause oxidative stress by reducing the activities and consequently the effectiveness of the antioxidant enzyme defense system. while the antioxidant therapy reducing of oxidative stress. Histopathological examination observed was normal in methotrexate treated rats and MTX with glutamine and vitmine A . but showed hydrodegenerate in treated groups of MTX+vit A while the glutamine treated group showed a necrosis and amyliod change.

Resolution of Recalcitrant Uveitic Optic Disc Edema Following Administration of Methotrexate: Two Case Reports

A 13-year-old male and a 15-year-old female presented with optic disc edema associated with chronic recurrent uveitis. While the ocular inflammation responded to high doses of oral prednisolone, the disc edema showed little improvement. After oral administration of methotrexate, the disc edema and ocular inflammation were resolved, and the dose of oral corticosteroid could be reduced.

Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

Anaemia is a significant prognostic factor in cancer patients receiving anticancer drugs such as methotrexate (MTX). This study focuses on the effects of toxicological changes on the hematopoietic systems in male and female Wistar Hannover rats when MTX is orally administered at a dose of 0, 0.05, 0.15, or 0.45 mg/(kg·day) for a period of 28 days. Both male and female rats receiving 0.45 mg/kg MTX showed a decrease in the haemoglobin concentration (Hb), haematocrit, and erythrocyte count. Female rats showed a decrease in mean corpuscular volume (MCV) and an increase in cell mean Hb (CHCM) in total erythrocytes, including the mature erythrocytes. These results indicate that MTX causes the production of small, mature erythrocytes that contain a high concentration of Hb. MTX reduced the number of peripheral reticulocytes but produced the cells with a large size and a high concentration of Hb, as demonstrated by the reticulocyte MCV and CHCM as well as the content of haemoglobin per reticulocyte (CHr). Consistent with these findings, bone marrow haematopoiesis was impaired by MTX, as there was a reduction in erythroid count in rats of both sexes. The number of cells of the myeloid lineage reduced in female rats, followed by a reduction in the total leukocyte and neutrophil counts in peripheral blood. Thrombocytopenia was detected in a small population of rats. These results indicate that MTX induces hyperchromic microcytic anaemia and pancytopenia, and the use of MCV and CHCM in mature erythrocytes and reticulocytes, along with the CHr, gives a better understanding of the development and nature of anaemia.

Alleviation of rheumatoid arthritis by cell-transducible methotrexate upon transcutaneous delivery

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is initiated and maintained by various inflammatory/immune cells and their cytokines, leading to cartilage degradation and bone erosion. Despite its potent therapeutic efficacy on RA, the oral administration of methotrexate (MTX) provokes serious adverse systemic complications, thus necessitating the local application of MTX. Here, we show that transcutaneous MTX (TC-MTX) can efficiently penetrate joint skin ex vivo and in vivo, and that TC-MTX can significantly improve the various inflammatory symptoms associated with RA. Further, TC-MTX preserved the joint-structures in mice with collagen-induced arthritis (CIA), which was also confirmed by three-dimensional micro-computed tomography scan. TC-MTX markedly decreased the secretion of inflammatory cytokines both in the serum and in inflamed joints of CIA mice. Further, its therapeutic potential is comparable to that of etanercept, a biological agent that block tumor necrosis factor (TNF)-α. Importantly, the systemic cytotoxicity of TC-MTX was not detected. Thus, TC-MTX can be a new therapeutic modality for RA patients without systemic complications.

Medical methods for first trimester abortion

Surgical abortion by vacuum aspiration or dilatation and curettage has been the method of choice for early pregnancy termination since the 1960s. Medical abortion became an alternative method of first trimester pregnancy termination with the availability of prostaglandins in the early 1970s and anti-progesterones in the 1980s. The most widely researched drugs are prostaglandins (PGs) alone, mifepristone alone, methotrexate alone, mifepristone with prostaglandins and methotrexate with prostaglandins. To compare different medical methods for first trimester abortion. The Cochrane Controlled Trials Register, MEDLINE and Popline were systematically searched. Reference lists of retrieved papers were also searched. Experts in WHO/HRP were contacted. Types of studies Randomised controlled trials comparing different medical methods for abortion during first trimester (e.g. single drug, combination) were considered. Trials were assessed and included if they had adequate concealment of allocation, randomisation procedure and follow-up. Women, pregnant during the first trimester, undergoing medical abortion were the participants. The outcomes were mortality, failure to achieve complete abortion, surgical evacuation, ongoing pregnancy at follow-up, time until passing of conceptus, blood transfusion, side effects and women's dissatisfaction with the procedure. Two reviewers independently selected trials for inclusion from the results of the search strategy described previously.The selection of trials for inclusion in the review was performed independently by two reviewers after employing the search strategy described previously. Trials under consideration were evaluated for appropriateness for inclusion and methodological quality without consideration of their results. Data were processed using Revman software. Fifty-eight trials were included in the review. The effectiveness outcomes below refer to 'failure to achieve complete abortion' with the intended method unless otherwise stated. 1) Combined regimen mifepristone/prostaglandin: Mifepristone 600 mg compared to 200 mg shows similar effectiveness in achieving complete abortion (4 trials, RR 1.07, 95% CI 0.87 to 1.32). Misoprostol administered orally is less effective (more failures) than the vaginal route (RR 3.00, 95% CI 1.44 to 6.24) and may be associated with more frequent side effects such as nausea and diarrhoea. Sublingual and buccal routes were similarly effective compared to the vaginal route, but had higher rates of side effects. 2) Mifepristone alone is less effective when compared to the combined regimen mifepristone/prostaglandin (RR 3.76 95% CI 2.30 to 6.15). 3) Five trials compared prostaglandin alone to the combined regimen (mifepristone/prostaglandin). All but one reported higher effectiveness with the combined regimen. The results of these studies could not be combined but the RR of failure with prostaglandin alone is reportedly between 1.4 to 3.75 with the 95% confidence intervals indicating statistical significance. 4) In one trial comparing gemeprost 0.5 mg with misoprostol 800 mcg, misoprostol was more effective (failure with gemeprost: RR 2.86, 95% CI 1.14 to 7.18). 5) There was no difference in effectiveness with use of a divided dose compared to a single dose of prostaglandin. 6) Combined regimen methotrexate/prostaglandin demonstrates similar rates of failure to complete abortion when comparing intramuscular to oral methotrexate administration (RR 2.04, 95% CI 0.51 to 8.07). Similarly, day 3 vs. day 5 administration of prostaglandin following methotrexate administration showed no significant differences (RR 0.72, 95% CI 0.36 to 1.43). One trial compared the effect of tamoxifen vs. methotrexate and no statistically significant differences were observed in effectiveness between the groups. Safe and effective medical abortion methods are available. Combined regimens are more effective than single agents. In the combined regimen, the dose of mifepristone can be lowered to 200 mg without significantly decreasing the method effectiveness. Vaginal misoprostol is more effective than oral administration, and has less side effects than sublingual or buccal. Some results are limited by the small numbers of participants on which they are based. Almost all trials were conducted in settings with good access to emergency services, which may limit the generalizability of these results.

Weekly vs. daily administration of oral methotrexate (MTX) for generalized plaque psoriasis: a randomized controlled clinical trial

Methotrexate (MTX) treatment for psoriasis is most often administered weekly, because the drug has been considered more hepatotoxic when taken daily. However, some patients may tolerate smaller, more frequent doses better. To study the efficacy and toxicity of daily vs. weekly MTX. In a randomized controlled trial, 101 patients with generalized plaque psoriasis received oral MTX 2.5 mg daily for weeks, 4 weeks and monthly for a total of 4 months. Changes in PASI scores were classified into three categories: >75% improvement was considered significant; 25-75% moderate; and <25% poor. Sixty Group 1 patients and 81 Group 2 patients showed a significant response (P-value 0.001); 19 patients in Group 1 and 14 in Group 2 responded moderately; 22 patients in Group 1 and six patients from Group 2 responded poorly. Forty-five patients in Group 1 and 33 in Group 2 developed transient increases in liver enzymes (P-value 0.11). Nausea, headache, fatigue, and gastrointestinal upset were noted in four Group 1 patients and 30 Group 2 patients (P-value 0.0001). Nausea, vomiting, headache, and fatigue were significantly less common side effects in our patients who received MTX daily, but liver enzyme abnormalities were less common, and clinical efficacy was greater in the patients who received MTX weekly.

Effects of methotrexate on antioxidant enzyme status in a rodent model

Methotrexate (MTX), a folic acid antagonist is widely used as a cytotoxic chemotherapeutic agent, however its associated hepatotoxicity is considered to be a major clinical side-effect. The aim of this study was to investigate the status of antioxidant enzymes during oxidative stress in liver homogenates of rats subjected to oral methotrexate administration. A total of forty two, 7-week old male Wistar rats with mean weight of 172 g, divided into two groups were used. The first group, control (n = 6), were fed only standard rat chow as their diet and water ad libitum. The second group (n = 36, subdivided into six sub-groups), fed on the same rat chow diet, received orally administered methotrexate at a dose of 13.4 mg/kg at weekly intervals for 6 consecutive weeks. Thiobarbituric acid reactive substance (TBARS) levels and the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) were subsequently determined spectrophotometrically on liver homogenates of all animals. It was found that methotrexate caused a significant increase in TBARS levels (an important marker of lipid peroxidation) in the methotrexate administered groups when compared with the control group (P < 0.05). The activities of superoxide dismutase, catalase, and glutathione reductase were significantly decreased in the methotrexate groups at weeks 2, 3, 4, 5 and 6 when compared with the control group (P < 0.05). The results therefore indicate that methotrexate causes oxidative stress by reducing the activities and consequently the effectiveness of the antioxidant enzyme defense system.

Impact of Abcc2 [Multidrug Resistance-Associated Protein (Mrp) 2], Abcc3 (Mrp3), and Abcg2 (Breast Cancer Resistance Protein) on the Oral Pharmacokinetics of Methotrexate and Its Main Metabolite 7-Hydroxymethotrexate

The ATP-binding cassette (ABC) transporters ABCC2 [multidrug resistance-associated protein (MRP) 2], ABCC3 (MRP3), and ABCG2 (breast cancer resistance protein) are involved in the efflux of potentially toxic compounds from the body. We have shown before that ABCC2, ABCC3, and ABCG2 together influence the pharmacokinetics of the anticancer and antirheumatic drug methotrexate (MTX) and its toxic metabolite 7-hydroxymethotrexate (7OH-MTX) after intravenous MTX administration. We now have used Abcc2;Abcc3;Abcg2(-/-) and corresponding single and double knockout mice to investigate the relative impact of these transporters on MTX and 7OH-MTX pharmacokinetics after oral MTX administration (50 mg/kg). The plasma areas under the curve (AUC(plasma)) in Abcg2(-/-) and Abcc2;Abcg2(-/-) mice were 1.7- and 3.0-fold higher than those in wild-type mice, respectively, suggesting additive effects of Abcc2 and Abcg2 on oral MTX pharmacokinetics. However, the AUC(plasma) in Abcc2;Abcc3;Abcg2(-/-) mice was not different from that in wild-type mice, indicating that Abcc3 protein is necessary for increased MTX plasma concentrations in the absence of Abcc2 and/or Abcg2. Furthermore, 2 h after administration, MTX liver levels were increased in Abcg2-deficient strains and MTX kidney levels were 2.2-fold increased in Abcc2;Abcg2(-/-) mice compared with those in wild-type mice. The absence of Abcc2 and/or Abcg2 also led to significantly increased liver and kidney levels of 7OH-MTX. Our results suggest that inhibition of ABCG2 and/or ABCC2, genetic polymorphisms or mutations reducing expression or activity of these proteins may increase the oral availability of MTX. Such conditions may also present risk factors for increased MTX-related toxicity in patients treated with oral MTX.