Quality of hypertension pharmacotherapy in Quebec: a population-based study.

BACKGROUND: Choosing the initial pharmacotherapy for new antihypertensive users and ensuring adherence to therapy can be problematic. OBJECTIVES: We sought to assess the quality of pharmacotherapy among new users of antihypertensives in Quebec, and to measure persistence with treatment in the short and longer term. METHODS: Using provincial administrative databases, a historical population-based study was conducted with a cohort of Quebec adults who filled their first antihypertensive prescription between January 1, 2007, and December 31, 2009. We described antihypertensive treatment for those with a diagnosis of hypertension (HTN) in the 5 years preceding initiation of drug therapy. Conformity with criteria for optimal use based on the 2006 Canadian Hypertension Education Program (CHEP) was evaluated. Persistence with treatment was estimated at 3 months, 1 year and 2 years after pharmacotherapy initiation. RESULTS: Among the 79,181 new antihypertensive users with HTN who started treatment between 2007 and 2009, 82.5% were first prescribed only one drug, usually an angiotensin II receptor blocker or an angiotensin-converting enzyme inhibitor and rarely a diuretic. 24.2% of newly treated hypertensive persons aged 60 or older in our sample received a beta-blocker, which is not recommended practice. The initial treatment conformed to CHEP recommendations for 72.8% of those with uncomplicated HTN. After 3 months, 69.8% of new users still persisted with their treatment. This proportion remained stable after 1 year (69.1%) and 2 years (69.2%). CONCLUSION: Conformity of antihypertensive treatment with CHEP criteria, and patient persistence with therapy, was fairly high for new users in the province of Quebec. Research is needed, however, on how to further improve pÉÉharmacotherapy quality and persistence in new users.

Comparative safety of antipsychotics: another look at the risk of diabetes.

OBJECTIVE: The association between the use of antipsychotics and diabetes mellitus (DM) is still unclear, as depicted by several conflicting reports. Our study aims to assess the risk of DM in new users of antipsychotics. METHODS: Our nested case-control study used the Quebec Health Insurance Board databases. People in the source cohort were DM-free and had initiated an antipsychotic treatment. Subjects were cohort members who initiated an antidiabetic or had a diagnosis of DM during their follow-up period. Three variables were used to assess antipsychotic exposure: the antipsychotic used (any typical, clozapine, olanzapine, quetiapine, risperidone, or more than 1 drug); the number of 30-day periods of use; and antipsychotic use at index date (current or past). A paired multivariate logistic regression model was used to calculate adjusted odds ratios. RESULTS: Among the 88 467 people included in the cohort, 6109 subjects with DM were identified and were matched to 61 090 control subjects. New users of quetiapine were less likely to develop DM than new users of typical antipsychotics (OR, 0.89; 95% CI 0.81 to 0.99). The risk of DM was not statistically different across the atypical antipsychotics. A longer exposure to any antipsychotic (for each 30-day period, OR 1.009; 95% CI 1.006 to 1.011) and current use of antipsychotics (OR 1.26; 95% CI 1.17 to 1.36) were associated with DM. CONCLUSION: These results suggest that metabolic parameters of people exposed to antipsychotics should be monitored, irrespective of the drug taken, among the drugs available at the time of analysis.

Specific and overlapping sphingosine-1-phosphate receptor functions in human synoviocytes: impact of TNF-alpha.

Sphingosine-1-phosphate (S1P), via interaction with its G protein-coupled receptors, regulates various physiological and pathological responses. The present study investigated the role of S1P/S1P receptor signaling in several functional responses of human fibroblast-like synoviocytes (FLSs) that may contribute to the pathogenesis of rheumatoid arthritis (RA). We report that FLSs express the S1P(1), S1P(2), and S1P(3) receptors. Moreover, exogenously applied S1P induces FLS 1) migration, 2) secretion of inflammatory cytokines/chemokines, and 3) protection from apoptosis. Using specific S1P receptor agonists/antagonists, we determined that S1P stimulates FLS migration through S1P(1) and S1P(3), induces cytokine/chemokine secretion through S1P(2) and S1P(3), and protects from cell apoptosis via S1P(1). The S1P-mediated cell motility and cytokine/chemokine secretion seem to be regulated by the p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK, and Rho kinase signal transduction pathways. Interestingly, treatment of FLSs with tumor necrosis factor-alpha increases S1P(3) expression and correlates with the enhancement of S1P-induced cytokine/chemokine production. Our data suggest that S1P(1), S1P(2), and S1P(3) play essential roles in the pathogenesis of RA by modulating FLS migration, cytokine/chemokine production, and cell survival. Moreover, the cytokine-rich environment of the inflamed synovium may synergize with S1P signaling to exacerbate the clinical manifestations of this autoimmune disease.

Regulation of lysophosphatidic acid receptor expression and function in human synoviocytes: implications for rheumatoid arthritis?

Lysophosphatidic acid (LPA), via interaction with its G-protein coupled receptors, is involved in various pathological conditions. Extracellular LPA is mainly produced by the enzyme autotaxin (ATX). Using fibroblast-like synoviocytes (FLS) isolated from synovial tissues of patients with rheumatoid arthritis (RA), we studied the expression profile of LPA receptors, LPA-induced cell migration, and interleukin (IL)-8 and IL-6 production. We report that FLS express LPA receptors LPA(1-3). Moreover, exogenously applied LPA induces FLS migration and secretion of IL-8/IL-6, whereas the LPA(3) agonist l-sn-1-O-oleoyl-2-methyl-glyceryl-3-phosphothionate (2S-OMPT) stimulates cytokine synthesis but not cell motility. The LPA-induced FLS motility and cytokine production are suppressed by LPA(1/3) receptor antagonists diacylglycerol pyrophosphate and (S)-phosphoric acid mono-(2-octadec-9-enoylamino-3-[4-(pyridine-2-ylmethoxy)-phenyl]-propyl) ester (VPC32183). Signal transduction through p42/44 mitogen-activated protein kinase (MAPK), p38 MAPK, and Rho kinase is involved in LPA-mediated cytokine secretion, whereas LPA-induced cell motility requires p38 MAPK and Rho kinase but not p42/44 MAPK. Treatment of FLS with tumor necrosis factor-alpha (TNF-alpha) increases LPA(3) mRNA expression and correlates with enhanced LPA- or OMPT-induced cytokine production. LPA-mediated superproduction of cytokines by TNF-alpha-primed FLS is abolished by LPA(1/3) receptor antagonists. We also report the presence of ATX in synovial fluid of patients with RA. LPA(1/3) receptor antagonists and ATX inhibitors reduce the synovial fluid-induced cell motility. Together the data suggest that LPA(1) and LPA(3) may contribute to the pathogenesis of RA through the modulation of FLS migration and cytokine production. The above results provide novel insights into the relevance of LPA receptors in FLS biology and as potential therapeutic targets for the treatment of RA.