The Experts below are selected from a list of 1596 Experts worldwide ranked by ideXlab platform
Christoph Fiehn - One of the best experts on this subject based on the ideXlab platform.
-
The future of Folic Acid Antagonist therapy in rheumatoid arthritis.
Arthritis and rheumatism, 2009Co-Authors: Christoph FiehnAbstract:When, at the end of the last decade, the new and potent tumor necrosis factor (TNF ) inhibitors were approved for the treatment of rheumatoid arthritis (RA), the era of methotrexate (MTX) as the gold standard for treatment of this disease seemed to have come to an inevitable end. On the one hand, there were the new, intelligently designed and highly specific cytokine inhibitors, a result of the fast-growing knowledge about immunopathologic mechanisms of inflammation. On the other hand, there was MTX, a byproduct of oncology research from decades past. The exact mode of antiarthritic action of this antifolate drug in the complex system of inflammation could only be hypothesized. Now, several years later, MTX plays a more important role than ever as the basis of RA treatment. Due to its effectiveness and tolerability, MTX remains the drug of first choice in the treatment of RA. Moreover, in order to make the new biologic drugs as effective as possible, almost all of the new investigational drugs are tested in combination with MTX. The designs of these clinical trials mainly resemble the design of the original Anti–TNF Trial in RA with Concomitant Therapy (ATTRACT) study (1), in which MTX was given in combination with infliximab, at that time still with the purpose of inhibiting the formation of antibodies against the drug. Meanwhile, not only TNF inhibitors (2,3), but also many other new biologic drugs are given in combination with MTX because this strongly increases the magnitude and duration of the therapeutic response. Although there is now a growing number of new drugs available for the treatment of RA, it is widely accepted that the question is not whether a patient with RA should receive MTX or not, but rather, whether the patient should receive it with or without a biologic drug. Thus, the principle of folate antagonism seems to remain the foundation of immunomodulatory treatment of RA, both now and in the future. It should be emphasized that MTX is experiencing a comeback in RA clinical trials, although this drug has several pharmacologic disadvantages that one might think should be limiting its use. First, if given orally, MTX shows a wide variability of resorption, ranging in some studies from 28% to 88% (4). Second, although it is given only once a week, it has a short half-life in the circulation, consisting of only 5–8 hours (4). Therefore, it is thought that its antiarthritic effect might partly depend on the rate of polyglutamation, an intracellular transformation of MTX that results in intracellular persistence of the drug. The rate of this modification, which is possibly crucial for its therapeutic effect, has a marked interindividual variability (5) and is influenced by independent factors, such as estrogen, insulin, or dexamethasone (6). Finally, the intracellular uptake of the molecule and its pharmacologic actions on intracellular targets are characterized by a broad range of mechanisms (7). This makes differentiation between the mechanisms of the unwanted toxic effects of MTX and the wanted antiinflammatory effects difficult. Different approaches have been tried in an attempt to overcome the disadvantageous properties of MTX. Braun et al (8) recently reported the results of a clinical trial showing that MTX is more effective when given subcutaneously instead of orally. With this mode of application, the unpredictability of resorption can be avoided. My coworkers and I (9,10) have reported that MTX accumulates in inflamed joints if it is covalently Christoph Fiehn, MD: Center for Rheumatic Diseases, Baden-Baden, Germany. Dr. Fiehn has received consulting fees, speaking fees, and/or honoraria from Medac (less than $10,000). Address correspondence and reprint requests to Christoph Fiehn, MD, Center for Rheumatic Diseases, Baden-Baden, Rotenbachtalstrasse 5, D-76530 Baden-Baden, Germany. E-mail: c.fiehn@rheumazentrum-baden.de. Submitted for publication August 26, 2008; accepted in revised form October 3, 2008. Arthritis & Rheumatism
Lynn Rosenberg - One of the best experts on this subject based on the ideXlab platform.
-
The use of Folic Acid Antagonists and the risk of colorectal cancer.
Pharmacoepidemiology and drug safety, 2007Co-Authors: Patricia F. Coogan, Lynn RosenbergAbstract:Purpose Since folate is associated with a reduced risk of colorectal cancer, we hypothesized that Folic Acid Antagonists might increase the risk. We used data from a population-based case control study of medication use and colorectal cancer to evaluate the hypothesis. Methods Case patients with adenocarcinoma of the colon or rectum were ascertained from participating hospitals in Massachusetts and the Massachusetts cancer registry (MCR) from January 1, 2001, through November 30, 2004. Age-, sex-, and precinct-matched control subjects were chosen from Massachusetts town lists. Information on Folic Acid Antagonist use and other relevant data were obtained from 1809 cases and 1809 matched controls by telephone interview and by a self-administered dietary questionnaire. We used logistic regression models to estimate odds ratios among 1229 case patients and 1165 control subjects who provided satisfactory dietary information and did not have Crohn's disease or ulcerative colitis. Results The odds ratio for colorectal cancer among regular users of folate-containing supplements was 0.7 (95%CI 0.6–0.9). The odds ratio for regular use of Folic Acid Antagonists was 1.3 (95%CI 0.9–1.9). Contrary to expectation, the odds ratio was reduced in the highest category of alcohol consumption (OR = 0.5, 95%CI 0.2–1.2). The odds ratio was higher among users of drugs that inhibit dihydrofolate reductase (OR = 1.6, 95%CI 0.9–2.8) than drugs that work through other mechanisms (OR = 1.2, 95%CI 0.7–1.9). Conclusions Our data provide little support for the hypothesis that regular Folic Acid Antagonist use increases the risk of colorectal cancer. However, there is a suggestion that dihydrofolate reductase inhibitors specifically may increase the risk. Copyright © 2007 John Wiley & Sons, Ltd.
Allen A Mitchell - One of the best experts on this subject based on the ideXlab platform.
-
Folic Acid Antagonist use before and during pregnancy and risk for selected birth defects
Birth defects research, 2020Co-Authors: Stephen M Kerr, Samantha E Parker, Allen A Mitchell, Sarah C Tinker, Martha M WerlerAbstract:Background Maternal Folic Acid (FA) intake before and during early pregnancy reduces the risk for neural tube defects (NTDs); evidence suggests it may also reduce the risk for oral clefts, urinary defects, and cardiac defects. We sought to re-examine the use of drugs, which affect folate metabolism, dihydrofolate reductase inhibiting (DHFRI) medications, and anti-epileptic drugs (AEDs), in data collected in the post-FA fortification era (1998+) in the Slone Birth Defects Study. Methods We assessed maternal DHFRI and AED use and risk for NTDs, oral clefts, and urinary and cardiac defects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We assessed daily average FA intake of ≥400 mcg as a potential effect modifier. Results We analyzed data from 10,209 control and 9,625 case mothers. Among controls, the prevalence of exposure to DHFRI medications was 0.3% and to AEDs was 0.5%. Maternal use of AEDs was associated with increased risks for NTDs (OR: 3.4; 95% CI: 1.5, 7.5), oral clefts (OR: 2.3; 95% CI: 1.3, 4.0), urinary defects (OR: 1.6; 95% CI: 1.0, 2.7), and cardiac defects (OR: 1.6; 95% CI: 1.1, 2.3); similar or further increased risks were found among those with FA intake ≥400 mcg per day. DHFRI use was rare and relative risk estimates were imprecise and consistent with the null. Conclusions Similar to our previous analyses, we observed associations between AED use and these defects. For DHFRI exposure, we found no evidence for increased risk of these defects. Though statistical power to examine FA effect modification was low, we found no evidence of further protection among those with FA intake ≥400 mcg, with some associations somewhat stronger in this group.
-
case crossover and case time control designs in birth defects epidemiology
American Journal of Epidemiology, 2003Co-Authors: Sonia Hernandezdiaz, Martha M Werler, Miguel A Hernan, Katie A Meyer, Allen A MitchellAbstract:The case-crossover and the case-time-control designs can be used to evaluate the effect of intermittent exposures on the risk of acute events. To explore how birth defects epidemiology could benefit from these approaches, the authors compared them with a traditional case-control study design that evaluated the association between use of Folic Acid Antagonists during the second and third pregnancy months and the risk of cardiovascular defects. Among 3,870 cases and 8,387 control infants in the Slone Epidemiology Center Birth Defects Study (1976–1998), the odds ratio was 2.3 (95% confidence interval (CI): 1.4, 3.9). The case-crossover approach compared Folic Acid Antagonist use between the 2-month embryologically sensitive period (case window) and the 2 months preceding the last menstrual period (control window) among mothers of case infants (odds ratio = 1.0, 95% CI: 0.5, 2.0). Although it controls between-person confounding and avoids issues of control selection, this design may be biased by time trends of exposure prevalence during pregnancy. The case-timecontrol design, which adjusts for exposure time trends under certain assumptions, yielded an odds ratio of 2.9 (95% CI: 1.2, 7.2), but it requires controls. In the presence of gestational time trends of exposure, the new designs do not offer clear advantages over the case-control design. abnormalities; case-control studies; pregnancy
Patricia F. Coogan - One of the best experts on this subject based on the ideXlab platform.
-
The use of Folic Acid Antagonists and the risk of colorectal cancer.
Pharmacoepidemiology and drug safety, 2007Co-Authors: Patricia F. Coogan, Lynn RosenbergAbstract:Purpose Since folate is associated with a reduced risk of colorectal cancer, we hypothesized that Folic Acid Antagonists might increase the risk. We used data from a population-based case control study of medication use and colorectal cancer to evaluate the hypothesis. Methods Case patients with adenocarcinoma of the colon or rectum were ascertained from participating hospitals in Massachusetts and the Massachusetts cancer registry (MCR) from January 1, 2001, through November 30, 2004. Age-, sex-, and precinct-matched control subjects were chosen from Massachusetts town lists. Information on Folic Acid Antagonist use and other relevant data were obtained from 1809 cases and 1809 matched controls by telephone interview and by a self-administered dietary questionnaire. We used logistic regression models to estimate odds ratios among 1229 case patients and 1165 control subjects who provided satisfactory dietary information and did not have Crohn's disease or ulcerative colitis. Results The odds ratio for colorectal cancer among regular users of folate-containing supplements was 0.7 (95%CI 0.6–0.9). The odds ratio for regular use of Folic Acid Antagonists was 1.3 (95%CI 0.9–1.9). Contrary to expectation, the odds ratio was reduced in the highest category of alcohol consumption (OR = 0.5, 95%CI 0.2–1.2). The odds ratio was higher among users of drugs that inhibit dihydrofolate reductase (OR = 1.6, 95%CI 0.9–2.8) than drugs that work through other mechanisms (OR = 1.2, 95%CI 0.7–1.9). Conclusions Our data provide little support for the hypothesis that regular Folic Acid Antagonist use increases the risk of colorectal cancer. However, there is a suggestion that dihydrofolate reductase inhibitors specifically may increase the risk. Copyright © 2007 John Wiley & Sons, Ltd.
C Paul - One of the best experts on this subject based on the ideXlab platform.
-
effect of Folic or folinic Acid supplementation on methotrexate associated safety and efficacy in inflammatory disease a systematic review
British Journal of Dermatology, 2009Co-Authors: S Prey, C PaulAbstract:Summary Background Methotrexate is a Folic Acid Antagonist widely used for the treatment of inflammatory disorders for more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis. Folic Acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal tract and liver. However, there is still controversy regarding the usefulness of Folic Acid supplementation. Objectives We sought to assess the evidence for the efficacy of Folic Acid supplementation in patients treated with methotrexate for inflammatory diseases. We also investigated whether Folic Acid supplementation may decrease the efficacy of methotrexate. Methods Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study selection, assessment of methodological quality, data extraction and analysis were carried out by two independent researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic. Results Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were 257 patients in the placebo group, 198 patients treated with Folic Acid, and 193 patients treated with folinic Acid. The statistical analysis showed a significant reduction of 35·8% of hepatic side-effects induced by methotrexate for patients with supplementation with Folic or folinic Acid (95% confidence interval −0·467 to −0·248). There was no statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately due to a low incidence of these events in the population studied. We were unable to analyse the effect of supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not comparable. Conclusions Supplementation with Folic Acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment. There is no difference between folinic Acid and Folic Acid, but the lower cost of the latter promotes its use.