Efficacy and safety of macitentan in Fontan-palliated patients: 52-week randomized, placebo-controlled RUBATO Phase 3 trial and open-label extension.

Objectives: The efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL).

Methods: Patients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16.

Determination of the norepinephrine level by high-performance liquid chromatography to assess the protective effect of MAO-B inhibitors against DSP-4 toxicity.

Liquid chromatography (LC) combined with electrochemical detection (EC) is suitable for measuring oxidizable biogenic amine levels in small samples of brain tissue. The norepinephrine (NE) content in mouse hippocampus after treatment with various monoamine oxidase-B enzyme (MAO-B) inhibitors ([-]-deprenyl, [+]-rasagiline, and the noradrenergic neurotoxin N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine [DSP-4]) is determined using an LC-EC method. Treatment with a single intraperitoneal dose of (-)-deprenyl (selegiline) before DSP-4 administration markedly reduces the NE depleting effect of the toxin, and (+)-rasagiline does not significantly modify the NE level decreased by the neurotoxin.

The influence of metabolism on the MAO-B inhibitory potency of selegiline.

(-)-Deprenyl (selegiline), a propargylamine derivative of methylamphetamine, is a potent, irreversible inhibitor of monoamine-oxidase type B (MAO-B). The MAO-B inhibitory effects of various doses (0.1-0.

The effect of low oral doses of (-)-deprenyl and its metabolites on DSP-4 toxicity.

Treatment with a single oral dose of (-)-deprenyl (selegiline) before DSP-4 administration could dose-dependently decrease the noradrenaline (NA) depleting effect of the toxin in mouse hippocampus. The maximum protective effect was achieved at as low oral dose as 0.25 mg/kg.

Protective effect of 7-nitroindazole against DSP-4 induced noradrenaline depletion in mouse hippocampus.

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a selective noradrenaline (NA) uptake blocker, capable of inducing a long-lasting depletion of NA in some noradrenergic axon terminals originating from the locus coeruleus in rodents. Pretreatment with 7-nitroindazole, a fairly selective inhibitor of neuronal nitric oxide synthase in vivo, partially prevented DSP-4 induced NA depletion in mouse hippocampus measured seven days after the neurotoxic insult. Administration of L-arginine, the substrate of nitric oxide synthase, altered neither the NA depletion induced by DSP-4, nor the protective effect of 7-nitroindazole.