Effects of Sustained-Release Moxonidine, an Imidazoline Agonist, on Plasma Norepinephrine in Patients With Chronic Heart Failure

Abstract

Background-In chronic heart failure, sympathetic activation is increased. Moxonidine acts on central nervous system receptors to decrease sympathetic activation. We investigated the dose-response relationship of a new sustained-release (SR) preparation of moxonidine and the plasma concentration of norepinephrine in patients with chronic heart failure. Methods and Results-A total of 268 patients with chronic heart failure in NYHA functional class II to IV on optimal standard therapy were randomized to placebo or 1 of 5 doses of moxonidine SR: 0.3, 0.6, 0.9, 1.2, or 1.5 mg BID. After a dose-titration phase (7 weeks), patients were followed up for another 12 weeks at their maximally tolerated dose. Blood samples for plasma norepinephrine were collected at baseline and weekly during the initial 7 weeks, at week 19, and at the end of the study. At baseline and 7 and 19 weeks, sampling was also done 4 hours after the dose. After the active phases of the study, plasma norepinephrine was evaluated for an additional 3 days. A marked, statistically significant dose-related decrease in plasma norepinephrine was observed for predose levels as well as 4 hours after the dose at week 19. At the highest dose (1.5 mg BID), the trough reduction in norepinephrine was 52%. These reductions were accompanied by a modest decrease in heart rate, a modest increase in left ventricular ejection fraction, and a dose-related increase in adverse events. Conclusions-Plasma norepinephrine was markedly reduced in a dose-related manner by moxonidine SR. This reduction was accompanied by evidence of reverse remodeling, but also by an increase in adverse events.

The “Unsympathetic” Nervous System of Heart Failure

“…Table 2 13 in the MOXSE article reveals that 19 weeks of 1.5 mg SR moxonidine BID (the MOXCON study dose) lowered median values for PNE to 249 pg/mL. This corresponds to the 25th percentile of PNE values reported for healthy control subjects in the SOLVD study.…”

“…In this issue of Circulation, Swedberg et al 13 report the results of their multicenter Moxonidine Safety and Efficacy (MOXSE) trial. The principal objective of this double-blind, dose-response study, involving 268 subjects, was to determine the effect of a sustained-release (SR) preparation of moxonidine on PNE concentrations in class II-IV heart failure.…”

Ethanol extract from Epimedium brevicornum attenuates left ventricular dysfunction and cardiac remodeling through down-regulating matrix metalloproteinase-2 and -9 activity and myocardial apoptosis in rats with congestive heart failure

“…LV dysfunction and cardiac remodeling play a crucial role in the process of CHF. Noteworthy, heart failure induced by isoproterenol results in the elevation of various plasma cytokines including TNF-α, NE, Ang II and BNP, which are responsible for the development of CHF (28)(29)(30)(31). TNF-α is a cytokine that may play a role in the pathogenesis of heart failure.…”

“…For these reasons, inhibition of TNF-α appears to be a valid target for the improvement of heart failure therapy (28). Inhibition of NE in plasma has been proved beneficial for patients with chronic heart failure (29). Ang II, frequently elevated in CHF patients, contributes to decreased arterial distensibility (30).…”

Central Sympathetic Inhibition Augments Sleep-Related Ultradian Rhythm of Parasympathetic Tone in Patients With Chronic Heart Failure

“…19,20 However, an -adrenergic agonist, clonidine, is known to augment barorereflexes through the central nervous system. In the MOXICON trial, there was an excess of deaths in patients treated with 1.5 mg moxonidine, 21,22 which exerts a central sympathoinhibitory action through stimulation of imidazoline receptors. Although that dose of moxonidine was accompanied by 52% reduction in plasma NE concentrations, 22 the actual central sympathoinhibitory effect could be more potent than reflected by the plasma NE concentration.…”