Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P = 0.02), time to first event (hazard ratio [HR] = 0.56; P < 0.05), as well as total events (35 versus 57; P = 0.04), and was associated with fewer HE hospitalizations (13 versus 25; P = 0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P < 0.01), time to first event (HR = 0.29; P < 0.01), and total events (7 versus 31; P < 0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events. Conclusion: GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167). (Hepatology 2014;59:1073-1083)
Acute tests on cats with altered sympathetic innervation of the heart show that the protective action exerted by dalargin against the development of ischemic ventricular fibrillation is due to a modulating influence of this leu-enkephalin analog on both the sympathetic and parasympathetic regulation of cardiac activity. Key Words: dalargin; ischemic arrhythmias; stellate gangliaThe sympathetic nervous system is known to play an important role in the development of ischemic arrhythmias [3,13]. Therefore, the search for agents capable of modulating this system's activity is important. Of interest in this respect are opioid peptides, because they alter excitation transmission in sympathetic ganglia by inducing slow inhibitory postsynaptic potentials and restrict norepinephrine release from sympathetic nerve endings by acting on presynaptic opiate receptors [9,12]. We found previously that dalargin (DG), a synthetic leu-enkephalin analog, can protect against the development of ventricular fibrillation in myocardial ischemia (MI) [4]. DG has also been shown to modulate the activity of the sympathoadrenal system [1,2,8]. In view of this, and also considering the important contribution of the sympathetic nervous system to ischemic arrhythmias, in the present study we tested DG for its effect on the development of ischemic arrhythmias in animals with altered sympathetic innervation of the heart. MATERIALS AND METHODSThe tests were performed on 26 Nembutal-anesthetized (40 mg/kg intraperitoneally) and artificially ventilated cats of both sexes weighing 2-4 kg. MI was produced by occluding, using a controllable loop, the circumflex branch of the left coronary artery near its Russian State Medical University, Moscow orifice. The development of ischemia in the myocardium was recorded over 15 rain of coronary artery occlusion and 15 min of the reperfusion period. ECG and pressure in the femoral artery were recorded with a BIOKOMB-8 recorder (ORION/EMG). The events considered in the analysis were solitary and grouped extrasystoles, ventricular tachycardia, and ventricular fibrillation. Sympathetic nerve supply to the heart was altered by cutting, 5 min prior to coronary artery occlusion, the inferior cardiac nerve and caudal subclavicular loop at the site of their exit from the stellate ganglion. The synthetic leu-enkephalin analog DG (produced by the Laboratory of Peptide Synthesis at the Cardiology Research Center, Moscow) was infused dropwise intravenously in a dose of 10 gg/kg (which does cross the bloodbrain barrier) throughout the period of coronary artery occlusion [10]. The statistical significance of differences was estimated by Student's t test and the sign test. RESULTSIn the first series, DG in a dose of 10 gg/kg known not to penetrate the blood-brain barrier was tested for its effect on the incidence of ischemic arrhythmias under conditions of disrupted sympathetic nerve supply to the MI zone. Since myocardial excitability in the ischemic zone resulting from compression of the circumflex branch of the left coronar...
Preliminary administration of dynorphin AH3 tO narcotized cats with myocardial ischemia attenuated cardiac fibrillation, but increased the incidence of ventricular tachycardia. Protective effect of dynorphin A1_13 was observed only under conditions of intact sympathetic cardiac innervation. Key Words: dynorphin A~.13; to-opiate receptors; myocardial ischemia; cardiac arrhythmia; stellate ganglionRecent studies demonstrated the presence of la-,~5-, and K:-opiate receptors in the heart. Dynorphin AH3 (DYN) is a selective agonist of n-opiate receptors [6]. Agonists of ~t-and ~-opiate receptors posses considerable antiarrhythmic properties in myocardial ischemia [7,12], but the role of~:-opiate receptors and the effects of DYN on heart rhythm received little attention. Experiments on the isolated heart showed that DYN increased the incidence of cardiac arrhythmia and cAMP concentration in the heart, while naloxone completely abolished these effects [11]. Neurogenie mechanisms play an important role in the pathogenesis of ischemic cardiac arrhythmias [3]. Moreover, n-opiate receptors were found in brain regions involved in the regulation of the cardiovascular system and in sympathetic postganglionic fibers innervating coronary vessels and cardiomyocytes [14]. Here we studied the effects of DYN on the development of cardiac arrhythmias and possible sympathetic mechanisms of this action. MATERIALS AND METHODSExperiments were performed on 49 male and female cats weighing 2-4 kg and narcotized with Nembutal Russian State Medical University, Moscow (40 mg/kg intraperitoneally). Myocardial ischemia was induced by occlusion of circumflex branch of the left coronary artery. The development of arrhythmia was monitored over 15-min myocardial ischemia and 15-min reperfusion. Our previous studies showed that under these conditions, idioventricular rhythm, ventricular tachycardia, and ventricular fibrillation were observed in 72, 28, and 56% observations, respectively [8].Electrocardiogram and blood pressure in the femoral artery and left ventricle were recorded on a Biokomb-8 polyphysiograph (Orion/EMG).The selective ~:-opiate receptor agonist DYN (Laboratory of Peptide Synthesis, Russian Cardiology Research Center) in a dose of 40 pg/kg was intravenously infused for 15 min from the moment of coronary occlusion.In series I (n=12), coronary occlusion (CO) was performed against the background of DYN administration and intact cardiac innervation. In series II (n=10), CO and infusion of DYN was preceded by bilateral vagotomy and transection of cardiac branches of the stellate ganglia (5 min before CO). In series III, cardiac branches of stellate ganglia were transected 5 min before CO in animals with (n=10) or without (n= 10) DYN infusion. In series 4 (n=7), DYN effects on adrenergic properties of the heart were studied by 0007-4888/00/0001-27525.00 9Kluwer Academic/Plenum Publishers
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