Study of Natural Products Adverse Reactions (SONAR) in Adults with Mental Health Conditions: A Cross-Sectional Study.

INTRODUCTION: Mental illness is a leading cause of non-fatal disease burden worldwide. Natural health products (NHPs) are sought by patients with mental health conditions as a safer and more 'natural' option than conventional pharmacotherapy; however, the possible adverse events (AE) and interactions between NHPs and prescription medicines are not fully known. OBJECTIVES: The aim of this study was to determine (i) the prevalence of adult patients with mental health conditions taking prescription medications only, NHPs only, NHPs and prescription medications concurrently, or neither, (ii) which prescription medications and NHPs are most commonly used, (iii) AEs (serious and non-serious) experienced in the last 30 days for each product use group. METHODS: Mental health clinics in Alberta and Ontario, Canada, were included in an active surveillance study investigating NHP-drug interactions. On their first clinic visit, adult mental health patients were provided with a form inquiring about prescription drug use, NHP use, and any undesirable health events experienced in the last month. Healthcare professionals were also asked to report AEs. RESULTS: A total of 3079 patients were screened at 11 mental health clinics in Alberta and Ontario. In total, 620 AEs were reported in 447 patients (14.9%). The majority of adverse events were seen in patients using both NHPs and prescription medicines (58.8%), followed by patients taking only prescription medicines (37.1%), NHPs only (3.4%) and neither (0.67%). Combining NHPs and prescription medications increases the likelihood of experiencing AEs (OR 2.1; p < 0.001; 95% CI 1.7-2.6). CONCLUSIONS: Adult patients with mental health conditions who are taking both prescription medications and NHPs are more likely to report an adverse event than patients taking prescription drugs or NHPs alone. Polypharmacy increases the likelihood of an adverse event. Active surveillance is feasible and could contribute to enhanced pharmacovigilance.

Transcriptional regulation of the NADPH oxidase isoform, Nox1, in colon epithelial cells: role of GATA-binding factor(s).

Nonphagocytic NADPH oxidases (Noxs) are major sources of reactive oxygen species (ROS) and exist as a family of isoenzymes with tissue-restricted expression and functions. Nox1, expressed in colon epithelium and vascular smooth muscle, is suggested to be involved in innate immune defense and cell growth or proliferation. The transcriptional regulation of Nox1 appears to be particularly important in the modulation of its activity but the underlying mechanisms are unknown. Here we have identified the functional Nox1 promoter in human colon epithelial Caco-2 cells, and show that a 520-bp genomic fragment encompassing the CAP site is sufficient to direct high levels of expression of a linked reporter gene in these cells. Deletion analyses together with electrophoretic mobility-shift assays (EMSAs) suggest that maximal promoter activity is dependent on a GATA-binding site, conserved between human and mouse, within the proximal promoter region. The ability of mouse GATA factors to transactivate the Nox1 promoter was demonstrated in Cos-7 cells and site-directed mutagenesis of the conserved GATA-binding site further demonstrates that the regulation of Nox1 transcription is mediated by the direct binding of a GATA factor to the Nox1 proximal promoter. We also identified more distal, upstream regions which act to repress significantly expression from the Nox1 promoter.

Protection against endotoxemia-induced contractile dysfunction in mice with cardiac-specific expression of slow skeletal troponin I.

Gram negative endotoxemia is associated with an intrinsic impairment of cardiomyocyte contraction, in part due to a reduction in myofilament Ca2+ responsiveness. Endotoxemic rat hearts show increased cardiac troponin I (cTnI) phosphorylation at serines 23 and 24, residues required for the protein kinase A (PKA)-dependent reduction of myofilament Ca2+ sensitivity after beta-adrenoceptor stimulation. To investigate the functional significance of increased TnI phosphorylation in endotoxemia, we studied the contractile effects of systemic bacterial lipopolysaccharide (LPS) treatment in transgenic mice (TG) with cardiac-specific replacement of cTnI by slow skeletal TnI (ssTnI, which lacks the PKA phosphorylation sites) and matched nontransgenic littermates (NTG) on a CD1 background. In wild-type CD1 mice treated with LPS (6 mg/kg ip), after 16-18 h there was a significant reduction in the maximum rates of left ventricular pressure development and pressure decline in isolated Langendorff-perfused hearts compared with saline-treated controls and a decrease in isolated myocyte unloaded sarcomere shortening from 6.1 +/- 0.2 to 3.9 +/- 0.2% (1 Hz, 32 degrees C, P<0.05). Similarly, in NTG myocytes, endotoxemia reduced myocyte shortening by 42% from 6.7 +/- 0.2 to 3.9 +/- 0.1% (P<0.05) with no change in intracellular Ca2+ transients. However, in the TG group, LPS reduced myocyte shortening by only 13% from 7.5 +/- 0.2 to 6.5 +/- 0.2% (P<0.05). LPS treatment significantly reduced the positive inotropic effect of isoproterenol in NTG myocytes but not in TG myocytes, even though isoproterenol-induced increases in Ca2+ transient amplitude were similar in both groups. Only LPS-treated NTG hearts showed a significant increase in cTnI phosphorylation. Investigation of the sarcomere shortening-Ca2+ relationship in Triton-skinned cardiomyocytes revealed a significant reduction in myofilament Ca2+ sensitivity after LPS treatment in NTG myocytes, an effect that was substantially attenuated in TG myocytes. In conclusion, the replacement of cTnI with ssTnI in the heart provides significant protection against endotoxemia-induced cardiac contractile dysfunction, most probably by preserving myofilament Ca2+ responsiveness due to prevention of phosphorylation of TnI at PKA-sensitive sites.