Low dose oral methotrexate in rheumatoid arthritis: an uncontrolled trial and review of the literature.

New therapeutic alternatives are needed for patients with progressive RA unresponsive to gold or D-penicillamine. Azathioprine and cyclophosphamide can be effective but have been linked with the development of lymphoreticular malignancies. In an effort to exploit a less toxic agent, we have been impressed by the results and minimal toxicity of low dose oral MTX. Extensive application of this regimen in psoriasis and psoriatic arthritis indicates that low dose MTX does not have an unusual risk for developing cancer. In addition, prior experience with other rheumatic disorders and preliminary studies on the mechanism of action suggest a potential value in RA. We present our initial retrospective results in 28 patients with refractory RA given low dose oral MTX over the past 2.5 yr. An apparent positive response was noted in 19 of these patients (67%) and is similar to the experience of other clinicians. At the same time, the toxicity has been low and, with one exception, amenable to dose modification. Methotrexate in various regimens is being increasingly employed in refractory RA. Issues concerning the pharmacology and potential toxicity are, therefore, important. These topics are reviewed with emphasis on low dose therapy and hepatotoxicity. Despite the encouraging preliminary results it is unclear whether MTX can prevent erosions or improve long-term function and quality of life in RA. There are still no controlled perspective studies comparing MTX to placebo or other immunosuppressive agents in RA. Although short-term toxicity is low, long-term toxicity, especially hepatic, is uncertain. As a result, a controlled, long-term prospective study is necessary

Hyperglycemia Mediates a Shift From Cap-Dependent to Cap-Independent Translation Via a 4E-BP1–Dependent Mechanism

Diabetes and its associated hyperglycemia induce multiple changes in liver function, yet we know little about the role played by translational control of gene expression in mediating the responses to these conditions. Here, we evaluate the hypothesis that hyperglycemia-induced O-GlcNAcylation of the translational regulatory protein 4E-BP1 alters hepatic gene expression through a process involving the selection of mRNA for translation. In both streptozotocin (STZ)-treated mice and cells in culture exposed to hyperglycemic conditions, expression of 4E-BP1 and its interaction with the mRNA cap-binding protein eIF4E were enhanced in conjunction with downregulation of cap-dependent and concomitant upregulation of cap-independent mRNA translation, as assessed by a bicistronic luciferase reporter assay. Phlorizin treatment of STZ-treated mice lowered blood glucose concentrations and reduced activity of the cap-independent reporter. Notably, the glucose-induced shift from cap-dependent to cap-independent mRNA translation did not occur in cells lacking 4E-BP1. The extensive nature of this shift in translational control of gene expression was revealed using pulsed stable isotope labeling by amino acids in cell culture to identify proteins that undergo altered rates of synthesis in response to hyperglycemia. Taken together, these data provide evidence for a novel mechanism whereby O-GlcNAcylation of 4E-BP1 mediates translational control of hepatic gene expression.</jats:p

Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Clinical Trial.

Importance: Although opioids are used to treat neonatal abstinence syndrome (NAS), the best pharmacologic treatment has not been established. Objective: To compare the safety and efficacy of methadone and morphine in NAS. Design, Setting, and Participants: In this randomized, double-blind, intention-to-treat trial, term infants from 8 US newborn units whose mothers received buprenorphine, methadone, or opioids for pain control during pregnancy were eligible. A total of 117 infants were randomized to receive methadone or morphine from February 9, 2014, to March 6, 2017. Mothers who declined randomization could consent to data collection and standard institutional treatment. Interventions: Infants were assessed with the Finnegan Neonatal Abstinence Scoring System every 4 hours and treated with methadone or placebo every 4 hours or morphine every 4 hours. Infants with persistently elevated Finnegan scores received dose increases. Infants who exceeded a predetermined opioid dose received phenobarbital. Dose reductions occurred every 12 to 48 hours when signs of NAS were controlled with therapy, stopping at 20% of the original dose. Main Outcomes and Measures: The primary end point was length of hospital stay (LOS). The secondary end points were LOS attributable to NAS and length of drug treatment (LOT). Results: A total of 183 mothers consented to have their infants in the study; 117 infants required treatment. Because 1 parent withdrew consent, data were analyzed on 116 infants (mean [SD] gestational age, 39.1 [1.1] weeks; mean [SD] birth weight, 3157 [486] g; 58 [50%] male). Demographic variables and risk factors were similar except for more prenatal cigarette exposure in infants who received methadone. Adjusting for study site and maternal opioid type, methadone was associated with decreased mean number of days for LOS by 14% (relative number of days, 0.86; 95% CI, 0.74-1.00; P = .046), corresponding to a difference of 2.9 days; 14% reduction in LOS attributable to NAS (relative number of days, 0.86; 95% CI, 0.77-0.96; P = .01), corresponding to a difference of 2.7 days; and 16% reduction in LOT (relative number of days, 0.84; 95% CI, 0.73-0.97; P = .02), corresponding to a difference of 2.3 days. Methadone was also associated with reduced median LOS (16 vs 20 days, P = .005), LOS attributable to NAS (16 vs 19 days, P = .005), and LOT (11.5 vs 15 days, P = .009). Study infants had better short-term outcomes than 170 nonrandomized infants treated with morphine per standard institutional protocols. Conclusions and Relevance: With use of weight- and sign-based treatment for NAS, short-term outcomes were better in infants receiving methadone compared with morphine. Assessment of longer-term outcomes is ongoing. Trial Registration: ClinicalTrials.gov Identifier: NCT01958476