Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) - A subgroup analysis of the ARIES-E clinical trial.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, demonstrated efficacy and safety in treating patients with PAH due to WHO Group I etiologies. These analyses describe the 3-year efficacy and safety of ambrisentan in patients specifically with CTD associated PAH (CTD-PAH). METHODS: Patients with CTD-PAH participating in the ARIES-1 and -2 clinical trials and their long-term extension were evaluated. Efficacy evaluations including 6-min walk distance (6MWD), clinical worsening, and survival were collected at routine study visits. Additional analyses of 6MWD categorical (30 m) breakpoints were conducted to determine any relationship between 6MWD and a prognostic threshold for survival. RESULTS: 124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening and 76% of patients were still alive (Kaplan-Meier estimates). Identified factors holding prognostic relevance for survival include: baseline functional class, CTD-PAH subgroup, patient sex, improvement in 6MWD ≥30 m over the first 12 weeks of treatment, the most recent 6MWD, and a 6MWD absolute threshold of 222 m. CONCLUSION: These first analyses of the 3-year treatment of CTD-PAH patients with ambrisentan revealed fewer clinical worsening events and improved survival compared to historical controls. Key exercise parameters were also identified which appear important in guiding treatment

EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) ; Scientific Opinion on Flavouring Group Evaluation 06, Revision 4 (FGE.06Rev4 ): Straight - and branched - chain aliphatic unsaturated primary alcohols, aldehydes, carboxylic acids and esters from chemical groups 1, 3 and 4

The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 56 flavouring substances in the Flavouring Group Evaluation 6, Revision 4, using the Procedure in Commission Regulation (EC) No 1565/2000. This revision is made due to the inclusion of six additional flavouring substances, (-)-3,7-dimethyl-6-octen-1-ol [FL-no: 02.229], dec-4(cis)-enal [FL-no: 05.137], neral [FL-no: 05.170], trans-3,7-dimethylocta-2,6-dienal (geranial) [FL-no: 05.188], trans-3-hexenyl formate [FL-no: 09.562] and cis-3-hexenyl 2-methylbutanoate [FL-no: 09.854]. None of the substances were considered to have genotoxic potential. The substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern and available data on metabolism and toxicity. The Panel concluded that the 56 substances [FL-no: 02.125, 02.138, 02.152, 02.170, 02.175, 02.176, 02.195, 02.201, 02.222, 02.229, 02.234, 05.061, 05.082, 05.137, 05.143, 05.170, 05.174, 05.188, 05.203, 05.217, 05.218, 05.220, 05.226, 08.074, 08.100, 08.102, 09.341, 09.368, 09.377, 09.562, 09.567, 09.569, 09.572, 09.575, 09.612, 09.638, 09.640, 09.643, 09.672, 09.673, 09.674, 09.831, 09.838, 09.854, 09.855, 09.871, 09.872, 09.884, 09.885, 09.897, 09.898, 09.928, 09.937, 09.938, 09.939 and 09.950] do not give rise to safety concern at their levels of dietary intake, estimated on the basis of the MSDI approach. Besides the safety assessment of these flavouring substances, the specifications for the materials of commerce have also been considered. Adequate specifications including complete purity criteria and identity for the materials of commerce have been provided for all 56 candidate substances

Cholinergic mechanisms in depression

Evidence supporting a cholinergic hypothesis of depression is presented. First, cholinergic overdrive produces behavioral, neuroendocrine, and polysomnographic features of melancholia, and melancholics exhibit state-independent supersensitivity to cholinergic overdrive. Drugs inducing up-regulation and supersensitivity of cholinergic systems produce behavioral, polysomnographic, and neuroendocrine effects of melancholia when withdrawn. These observations also implicate cholinergic system supersensitivity as a factor in the pathophysiology of certain affective disorders. Cholinergic and monoaminergic mechanisms reciprocally regulate drive-reduction, and substances of abuse either activate monoaminergic networks or antagonize cholinergic systems. These points are consistent with the hypothesis that dynamic interaction between cholinergic and monoaminergic systems is involved in the regulation of mood and affect. Finally, antimuscarinic agents have antidepressant effects. Thus, the hypothesis that supersensitivity of cholinergic systems is involved in the pathophysiology of affective disorders is supported by several lines of evidence. This evidence is reviewed; directions for future research and promising methods of investigation are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26059/1/0000133.pd