In most patients, the clinical effects of therapy with encainide are mediated by the generation of the active metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide (MODE). Data from in vitro and animal studies have indicated that MODE has electrophysiologic and pharmacokinetic features that make its further evaluation desirable; in earlier studies, we found that MODE suppressed chronic high-frequency nonsustained ventricular arrhythmias at plasma concentrations of 50-160 ng/ml. We now report the clinical electrophysiology, antiarrhythmic activity, and pharmacokinetics of MODE in 17 patients with inducible ventricular tachyarrhythmias (VTs) in whom programmed electrical stimulation was performed before drug administration and after one or two sequences of loading and maintenance infusions of MODE. Because the relation between plasma concentration and effect had been incompletely defined, a dose-titration approach was adopted: available pharmacokinetic data were used to construct loading and maintenance infusion regimens that were predicted to attain low plasma concentrations in initial patients while higher infusion rates were evaluated in subsequent patients. MODE prevented VT induction in three of 17 patients and VT cycle length was increased by .100 msec in a further seven of 17; most responses to MODE occurred at plasma concentrations >556 ng/ml (>1 SD above mean plasma MODE during encainide therapy). Response to MODE did not predict subsequent response to oral therapy with encainide. MODE increased intracardiac conduction times, QT intervals during atrial and ventricular pacing, and right ventricular efective refractory periods (RVERP); changes in RVERP were most prominent at rapid pacing rates, while changes in intracardiac conduction were rate-independent at cycle lengths between 400 and 600 msec. Plasma MODE concentrations measured during electrophysiology study correlated well with those predicted by the pharmacokinetic simulations (r=0.91, p<0.001). Serial plasma sampling after programmed electrical stimulation indicated a minimum MODE elimination half-life of 8.2+5.4 hours. Side effects were confined to three instances of asymptomatic conduction system depression in subjects with latent conduction system disturbances. We conclude that MODE slows intracardiac conduction, delays repolarization, and can suppress or substantially modify inducible VT. Moreover, it was only with the adoption of the dose-titration strategy that we were able to safely demonstrate that plasma MODE concentrations higher than those routinely observed during encainide therapy were required to substantially alter cardiac electrophysiology. (Circulation 1989;80:1247-1258 I n most patients, the antiarrhythmic agent encainthose of encainide.1-5 Both metabolites have pharide is rapidly cleared to the active metabolites macologic activity equal to or more than the parent O-desmethyl encainide (ODE) and 3 -methoxydrug in a variety of in vitro and in vivo settings6-13; O-desmethyl encainide (MODE) (Figure 1), which thus,...
Background The burden of non-communicable diseases (NCDs) is rising rapidly in middle-income countries (MICs), where NCDs are often undiagnosed, untreated and uncontrolled. How comorbidity impacts diagnosis, treatment, and control of NCDs is an emerging area of research inquiry and have significant clinical implications as highlighted in the recent National Institute for Care Excellence (NICE) guidelines for treating patients suffering from multiple NCDs. This is the first study to examine the association between increasing numbers of comorbidities with being undiagnosed, intreated, and uncontrolled for NCDs, in six large MICs. Methods Cross-sectional analysis of WHO SAGE Wave 1 (2007-10), which consisted of adults aged ≥18 years from six populous MICs including, China, Ghana, India, Mexico, Russia and South Africa (overall n = 41, 557). Results Higher number of comorbidities was associated with better detection of hypertension, angina and arthritis, and better odds of having treatment for hypertension and angina. However, increasing comorbidity had the opposite effect on being uncontrolled, and was associated with increased odds of uncontrolled hypertension, angina, arthritis, and asthma. Comorbidity with concordant conditions was associated with improved diagnosis and treatment of hypertension and angina. Comorbidity with concordant conditions was not associated with decreased nor increased odds of being uncontrolled for all NCDs. Conclusions Patients with more comorbidities have better diagnosis of chronic conditions, but this does not translate into better management and control of these conditions. Improving continuity of care and monitoring treatment are priorities for health systems with ageing populations. Key messages Patients with more comorbidities have better diagnosis of chronic conditions. but this does not translate into better management and control of these conditions.
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