Methotrexate: long-term safety and efficacy in an Australian consultant rheumatology practice

Background: The aim of this study was to evaluate the rate and cause of methotrexate (MTX) termination in clinical practice, describe the types of toxicities noted, assess the incidence of achieving remission in rheumatoid arthritis (RA) patients and review the appropriateness of current clinical guidelines for monitoring MTX treatment.
Methods: A retrospective, case review of patients seen in a private rheumatology practice attached to a major Sydney Teaching Hospital was undertaken over an 18-year period. The primary outcome was time to cessation of MTX.
Results: Seven hundred and ninety patients satisfied the inclusion criteria. MTX was terminated in 272 patients (34.4%). Toxicity-related discontinuation occurred in 93 patients (11.8%) and due to non-adverse reactions in 179 patients. The median duration of therapy in these two groups was 2.0 and 2.9 years, respectively. There was no difference in the average maximum weekly dose of MTX. Of patients with RA, 47.5% were in remission at last follow up. Cox proportional hazards analyses showed that those of the female sex remained on treatment significantly longer than the male sex (hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.57–0.96; P  = 0.014); patients with RA remained on treatment significantly longer than patients with seronegative arthritis (HR 0.56, 95%CI 0.42–0.74; P  < 0.001). Being of the male sex aged more than 60 years and having a non-RA diagnosis predisposed to stopping MTX earlier.
Conclusion: MTX is a safe and effective medication. Notable remission rates are achievable in patients with RA with current conventional treatment protocols. MTX has a low toxicity profile and this study stresses the need to re-evaluate and revise the current monitoring guidelines.     

Attenuation of serum lipid abnormalities and cardiac oxidative stress by eicosapentaenoate-lipoate (EPA-LA) derivative in experimental hypercholesterolemia

BACKGROUND: Dietary cholesterol plays an important role in development of atherogenesis and cardiovascular disease. We explored the lipemic-oxidative injury in the hypercholesterolemic atherogenic animals. The effects of eicosapentaenoic acid (EPA), dl-alpha-lipoic acid (LA) and eicosapentaenoate-lipoate derivative (EPA-LA) were tested for their efficacy in controlling the atherogenic disturbances. METHODS: Four groups of male Wistar rats were fed with a high cholesterol diet (rat chow supplemented with 4% cholesterol and 1% cholic acid; HCD) for 30 days. Of these groups, 3 groups of rats were treated with either EPA (oral gavage, 35 mg/kg body weight/day), LA (oral gavage, 20 mg/kg body weight/day) or EPA-LA derivative (oral gavage, 50 mg/kg body weight/day) from 16th day to 30th day of the experimental period. RESULTS: HCD induced abnormal increase in lipid peroxidation and serum cholesterol, triglyceride, LDL and VLDL, and a decreased HDL concentration. Altered activity of cardiac and serum creatine kinase, accompanied by a depressed cardiac enzymatic and nonenzymatic antioxidants defense system were observed in HCD fed rats. These changes were partially restored in the EPA and LA treated groups, however, their combined derivative EPA-LA more effectively restored the altered parameters near to that of control (P<0.05). CONCLUSION: Lipid abnormalities and oxidative injury were induced by a hypercholesterolemic diet. Administration of the combination treatment of EPA-LA afforded protection against the lipemic-oxidative injury.     

Protective effect of lupeol and its ester on cardiac abnormalities in experimental hypercholesterolemia

Hyperlipidemia is a major risk factor for the premature development of coronary heart disease and it has been shown to increase the incidence of myocardial ischemia and cardiac events. Pentacyclic triterpenes possess antiatherosclerotic, antioxidant, anti-inflammatory and cytoprotective effects. To study the effect of plant derived triterpene, lupeol and its ester lupeol linoleate, on lipid status and biochemical changes on heart tissue, male albino Wistar rats were fed high-cholesterol diet (normal rat chow supplemented with 4% cholesterol and 1% cholic acid; HCD) for 30 days. There was a significant (p<0.001) increase in the levels of total cholesterol, triglycerides and phospholipids along with augmented activities of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase in the heart tissue. Triterpenes treatment reduced the above alterations produced in hypercholesterolemic rats. The transmembrane enzymes, namely Na(+), K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase showed a decrease in their activities. Triterpenes treatment reversed these levels, prevented the hypertrophic cardiac histology and restored the normal ultrastructural architecture. In conclusion, lupeol and lupeol linoleate intervention minimized the lipid abnormalities and abnormal biochemical changes induced by HCD fed rats. This shows that triterpenes possess cardioprotective effects which will be beneficial in hypercholesterolemic condition. Out of these two triterpenes tested, lupeol linoleate appeared to be even more effective than lupeol.