An insight to self emulsifying drug delivery systems, their applications and importance in novel drug delivery

Abstract Since last couple of years Self-emulsifying drug delivery systems are becoming important tool in novel drug delivery. It is very useful in solving problems such as low bioavailability issues associated with poorly water soluble drugs. The bioavailability of lipophilic drugs (BCS-II and IV) can be enhanced by these systems. SEDDS is released in the lumen of the gastrointestinal tract (GIT) after administration and with the aid of GI fluid a fine emulsion (micro-/nanoemulsion) is formed. The increased surface area and amphoteric nature of SEDDS lead to increase in bioavailability. The hepatic first-pass effect can be bypassed by these systems because the drugs can subsequently be absorbed by lymphatic pathways. In this review we present a report on the formulation, characterization and dosage forms and applications of selfemulsifying formulations, with examples of currently marketed preparations

Omnipolarity applied to equi-spaced electrode array for ventricular tachycardia substrate mapping

Aims : Bipolar electrogram (BiEGM)-based substrate maps are heavily influenced by direction of a wavefront to the mapping bipole. In this study, we evaluate high-resolution, orientation-independent peak-to-peak voltage (Vpp) maps obtained with an equi-spaced electrode array and omnipolar EGMs (OTEGMs), measure its beat-to-beat consistency, and assess its ability to delineate diseased areas within the myocardium compared against traditional BiEGMs on two orientations: along (AL) and across (AC) array splines. Methods and results: The endocardium of the left ventricle of 10 pigs (three healthy and seven infarcted) were each mapped using an Advisor™ HD grid with a research EnSite Precision™ system. Cardiac magnetic resonance images with late gadolinium enhancement were registered with electroanatomical maps and were used for gross scar delineation. Over healthy areas, OTEGM Vpp values are larger than AL bipoles by 27% and AC bipoles by 26%, and over infarcted areas OTEGM Vpp values are 23% larger than AL bipoles and 27% larger than AC bipoles (P < 0.05). Omnipolar EGM voltage maps were 37% denser than BiEGM maps. In addition, OTEGM Vpp values are more consistent than bipolar Vpps showing less beat-by-beat variation than BiEGM by 39% and 47% over both infarcted and healthy areas, respectively (P < 0.01). Omnipolar EGM better delineate infarcted areas than traditional BiEGMs from both orientations. Conclusion: An equi-spaced electrode grid when combined with omnipolar methodology yielded the largest detectable bipolar-like voltage and is void of directional influences, providing reliable voltage assessment within infarcted and non-infarcted regions of the heart.This work was funded by Abbott Laboratories, St. Paul, MN, USA.S

Intracardiac Electrogram Targets for Ventricular Tachycardia Ablation

The pathogenesis of ventricular tachycardia (VT) in most patients with a prior myocardial scarring is reentry involving compartmentalized muscle fibers protected within the scar. Often the 12-lead ECG morphology of the VT itself is not available when treated with a defibrillator. Consequently, VT ablation takes on an interesting challenge of finding critical targets in sinus rhythm. High-density recordings are essential to evaluate a substrate based on whole electrogram voltage and activation delay, supplemented with substrate perturbation through alternate site pacing or introducing an extra stimulation. In this article, we discuss contemporary intracardiac electrogram targets for VT ablation, with explanation on each of their specific fundamental physiology

High density mapping of ventricular scar: insights into mechanisms of ventricular tachycardia.

Ventricular tachyarrhythmias related to structural heart disease are the most common cause of sudden cardiac death. Many of these occur in patients with ventricular scarring, related predominantly to coronary artery disease or dilated cardiomyopathies. These regions of scarring remodel over time with ongoing collagen turnover and do not stay stable, such that patients are often subject to repeated episodes of the arrhythmia. Ventricular scars are composed of variable regions of dense interstitial fibrosis that create conduction block, interspersed with viable myocyte channels with diminished coupling which produce substrate for circuitous slow conduction pathways that promote reentry. During sinus rhythm, these channels can be identified by the presence of late potentials and long stimulus to QRS intervals during pacing in the channel. A high density of sampling in the left ventricle allows recording of small amplitude electrograms that are of fundamental emphasis in ventricular substrate mapping. Several studies have characterized channels in patients with ventricular scar and ventricular tachycardia (VT). However, there has been no assessment on the functional characteristics of these channels and whether channels that are critical to the VT circuit differ from non-VT channels. Chapter 1 reviews literature on arrhythmic burden and epidemiology of scar related VT, its cellular mechanisms, substrate characterization, techniques of VT mapping and gaps in the current knowledge. Chapter 2 presents the high density characterization of substrate in ischemic cardiomyopathy (lCM) patients with W and compares the features of VT supporting channels with channels that do not support VT. This study showed that compared to non-VT channels, VT channels are more often located in the dense scar, longer in length, have long stimulus to QRS latencies and slower conduction velocity. Chapter 3 describes the electrogram properties in regions of VT channels, and development of a stepwise model from multiple electrogram properties to ensemble regions supporting VT(s) during sinus rhythm. It also discusses the application of Shannon entropy, a fundamental measure of information content in signals, to map VT channels in sinus rhythm. This system of ablation along with high density mapping will significantly advance VT mapping and help individualize substrate based ablation. Chapter 4 presents data on high density characterization of substrate in ICM patients with W and compares with those who do not have spontaneous VT. It showed that patients without spontaneous VT have fewer channels with shorter lengths and faster conduction, compared to VT patients. These observations partly explain the relative higher predilection of few selected surviving myocyte channels in the post infarct ventricles to sustain VT. Structural heterogeneity in the scar produces spatial and temporal disturbances in ventricular repolarization over multiple time scales. Chapter 5 evaluates the role of acute autonomic modulation on beat-to-beat QT variability in patients with heart failure with and without VT and contrasts it with patients without structural heart disease. It showed that acute pacing and humoral modulation including beta-blockade fail to bring down high repolarization instability in heart failure patients and VT. Catheter ablation is the mainstay for treatment of recurrent ventricular arrhythmias in patients with structural heart disease. Chapter 6 analyses published literature on ventricular arrhythmia storm ablation in a systematic review and meta-analysis. It showed that the interventions are safe and patients often need multiple procedures including non-radiofrequency ablation measures. Although patients who had successful ablation had good long-term outcomes, a failed procedure portended an early and high rate of mortality compared with medically managed historic controls. It raised a pertinent concern of possible harmful effects of catheter ablation in a high risk patient population. In summary, this thesis has developed innovative insights into the surviving myocyte channels in patients with ischemic cardiomyopathy. It describes a novel tool for ventricular substrate mapping that is readily applicable in the clinical laboratory. The repolarization instability is elevated in these patients and is resistant to modulation by acute beta-blocker treatment. Finally, catheter ablation is safe and should be advised in most patients with ventricular arrhythmia storm.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201

Prophylactic anticoagulation in sinus rhythm for stroke prevention in cardiovascular disease: contemporary meta-analysis of large randomized trials

Aims: Anticoagulation with non-vitamin K oral anticoagulants (NOACs) to prevent stroke is a mainstay of atrial fibrillation (AF) management. However, multiple cardiovascular diseases (CVDs) are associated with elevated ischaemic stroke risk even in sinus rhythm. In this meta-analysis, we assess efficacy and safety of prophylactic NOAC agents for stroke prevention in patients without AF. Methods and results: A search was conducted for randomized controlled trials (RCTs) that evaluated an NOAC and control drug (placebo or antiplatelet) in non-AF patients with mixed CVD. The primary efficacy and safety outcomes were ischaemic stroke and major bleeding, respectively. Results were stratified based on primary- and mini-NOAC doses. Thirteen RCTs were identified with a total of 89 383 patients with CVD in sinus rhythm (53 778 on NOAC, 35 605 on control drug; mean age 65.5 ± 2.7 years). Over a mean follow-up of 18.3 months, 1429 (1.6%) ischaemic strokes occurred. Use of NOAC was associated with 26% reduction in stroke [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.62-0.87; 1.1 vs. 1.8 events per 100 person-years], with numbers needed to treat of 153 patients to prevent one stroke. Major bleeding was increased with NOAC (OR 1.74, 95% CI 1.44-2.09; 2.1 vs. 1.0 events per 100 person-years). The weighted net clinical benefit (wNCB, composite of ischaemic stroke and bleeding) did not suggest a favourable effect with any NOAC dose (wNCB for primary-dose: -0.35; mini-dose: -0.06).' Conclusion: Current evidence does not support use of NOACs for stroke prevention in non-AF CVD population as risk of major bleeding still exceeds ischaemic stroke benefit

The Role of Artificial Intelligence and Machine Learning in Clinical Cardiac Electrophysiology

In recent years, numerous applications for artificial intelligence (AI) in cardiology have been found, due in part to large digitized data sets and the evolution of high-performance computing. In the discipline of cardiac electrophysiology (EP), a number of clinical, imaging, and electrical waveform data are considered in the diagnosis, prognostication, and management of arrhythmias, which lend themselves well to automation through AI. But equally relevant, AI offers a unique opportunity to discover novel EP concepts and improve clinical care through its inherent, hierarchical tenets of self-learning. In this review we focus on the application of AI in clinical EP and summarize state-of-the art, large, clinical studies in the following key domains: (1) electrocardiogram-based arrhythmia and disease classification; (2) atrial fibrillation source detection; (3) substrate and risk assessment for atrial fibrillation and ventricular tachyarrhythmias; and (4) predicting outcomes after cardiac resynchronization therapy. Many are small, single-centre, proof-of-concept investigations, but they still show ground-breaking performance of deep learning, a subdomain of AI, which surpasses traditional statistical analysis. Larger studies, for instance classifying arrhythmias from electrocardiogram recordings, have further provided external validation of their high accuracy. Ultimately, the performance of AI is dependent on the quality of the input data and the rigour of algorithm development. The field is still nascent and several barriers will need to be overcome, including prospective validation in large, well labelled data sets and more seamless information technology-based data collection/integration, before AI can be adopted into broader clinical EP practice. This review concludes with a discussion of these challenges and future work

Results of Radiofrequency Ablation of Permanent Atrial Fibrillation of >2 Years Duration and Left Atrial Size >5 cm Using 2-mm Irrigated Tip Ablation Catheter and Targeting Areas of Complex Fractionated Atrial Electrograms

Complex fractionated atrial electrograms (CFAEs) have shown promise as target sites for ablation of atrial fibrillation (AF); however, the data are limited with regard to patients with a large left atrium (LA) (>5 cm), and/or a permanent AF duration of >2 years. We tested the hypothesis that ablation of user-defined, computer-generated CFAE and pulmonary vein isolation, without additional lines would help long-term maintenance of sinus rhythm (SR). A total of 21 patients, 9 men and 12 women, aged 32 to 78 years (mean 44 ± 3.3) were selected. All had chronic AF for >2 years (range 2 to 20; mean 3.8) and a LA of 5.3 to 11.3 cm (mean 6.4 cm). The underlying structural heart disease was rheumatic mitral valve disease in 18, aortic stenosis in 1, and hypertension in 2. Mapping and ablation was done using the NAVx Ensite system and a 2-mm-tip IBI Therapy Cool Path ablation catheter. The target included circumferential pulmonary vein ablation and elimination of areas in the LA and proximal coronary sinus showing CFAEs. During ablation, 3 patients converted to SR. In 15 others, significant organization of the atrial activity occurred. They then underwent successful electrical cardioversion. Three patients showed no change in atrial activity nor had electrical cardioversion. No procedural complications occurred. Patients took oral amiodarone for 3 months after the procedure. At 3 to 12 months (mean 9.8) of follow-up, 3 patients who were in AF at the end of the ablation procedure continued to be in AF. Of the rest, all but 3 were able to maintain SR without antiarrhythmic drugs. In conclusion, ablation using a 2-mm tip irrigation catheter, targeting user-defined CFAEs and pulmonary vein isolation facilitated maintenance of SR in most patients with a LA >5 cm and an AF duration of >2 years

Signature signal strategy: electrogram-based ventricular tachycardia mapping

Multiple decades of work have recognized complexities of substrates responsible for ventricular tachycardia (VT). There is sufficient evidence that 3 critical components of a re-entrant VT circuit, namely, region of slow conduction, zone of unidirectional block, and exit site, are located in spatial vicinity to each other in the ventricular scar. Each of these components expresses characteristic electrograms in sinus rhythm, at initiation of VT, and during VT, respectively. Despite this, abnormal electrograms are widely targeted without appreciation of these signature electrograms during contemporary VT ablation. Our aim is to stimulate physiology-based VT mapping and a targeted ablation of VT. In this article, we focus on these 3 underappreciated aspects of the physiology of ischemic scar-related VT circuits that have practical applications during a VT ablation procedure. We explore the anatomic and functional elements underlying these distinctive bipolar electro-grams, specifically the contribution of tissue branching, conduction restitution, and wave curvature to the substrate, as they pertain to initiation and maintenance of VT. We propose a VT ablation approach based on these 3 electrogram features that can be a potential practical means to recognize critical elements of a VT circuit and target ablation