OCT2013, an ischaemia-activated antiarrhythmic prodrug, devoid of the systemic side effects of lidocaine

Background and Purpose Sudden cardiac death (SCD) caused by acute myocardial ischaemia and ventricular fibrillation (VF) is an unmet therapeutic need. Lidocaine suppresses ischaemia-induced VF, but its utility is limited by side effects and a narrow therapeutic index. Here, we characterise OCT2013, a putative ischaemia-activated prodrug of lidocaine. Experimental Approach The rat Langendorff-perfused isolated heart, anaesthetised rat and rat ventricular myocyte preparations were utilised in a series of blinded and randomised studies to investigate the antiarrhythmic effectiveness, adverse effects and mechanism of action of OCT2013, compared with lidocaine. Key Results In isolated hearts, OCT2013 and lidocaine prevented ischaemia-induced VF equi-effectively, but OCT2013 did not share lidocaine's adverse effects (PR widening, bradycardia and negative inotropy). In anaesthetised rats, i.v. OCT2013 and lidocaine suppressed VF and increased survival equi-effectively; OCT2013 had no effect on cardiac output even at 64 mg·kg⁻¹ i.v., whereas lidocaine reduced it even at 1 mg·kg⁻¹. In adult rat ventricular myocytes, OCT2013 had no effect on Ca²⁺ handling, whereas lidocaine impaired it. In paced isolated hearts, lidocaine caused rate-dependent conduction slowing and block, whereas OCT2013 was inactive. However, during regional ischaemia, OCT2013 and lidocaine equi-effectively hastened conduction block. Chromatography and MS analysis revealed that OCT2013, detectable in normoxic OCT2013-perfused hearts, became undetectable during global ischaemia, with lidocaine becoming detectable. Conclusions and Implications OCT2013 is inactive but is bio-reduced locally in ischaemic myocardium to lidocaine, acting as an ischaemia-activated and ischaemia-selective antiarrhythmic prodrug with a large therapeutic index, mimicking lidocaine's benefit without adversity

The contrasted phytoplankton dynamics across a frontal system in the southwestern Mediterranean Sea

Numerical simulations have shown that finescale structures such as fronts are often suitable places for the generation of vertical velocities, transporting subsurface nutrients to the euphotic zone and thus modulating phytoplankton abundance and community structure. In these structures, direct in situ estimations of the phytoplankton growth rates are rare; although difficult to obtain, they provide precious information on the ecosystem functioning. Here, we consider the case of a front separating two water masses characterized by several phytoplankton groups with different abundances in the southwestern Mediterranean Sea. In order to estimate possible differences in growth rates, we measured the phytoplankton diurnal cycle in these two water masses as identified by an adaptive and Lagrangian sampling strategy. A size-structured population model was then applied to these data to estimate the growth and loss rates for each phytoplankton group identified by flow cytometry, showing that these two population parameters are significantly different on the two sides of the front and consistent with the relative abundances. Our results introduce a general method for estimating growth rates at frontal systems, paving the way for in situ exploration of finescale biophysical interactions.</p

CLSM method for the dynamic observation of pH change within polymer matrices for oral delivery

If acid-sensitive drugs or cells are administered orally, there is often a reduction in efficacy associated with gastric passage. Formulation into a polymer matrix is a potential method to improve their stability. The visualization of pH within these materials may help better understand the action of these polymer systems and allow comparison of different formulations. We herein describe the development of a novel confocal laser-scanning microscopy (CLSM) method for visualizing pH changes within polymer matrices and demonstrate its applicability to an enteric formulation based on chitosan-coated alginate gels. The system in question is first shown to protect an acid-sensitive bacterial strain to low pH, before being studied by our technique. Prior to this study, it has been claimed that protection by these materials is a result of buffering, but this has not been demonstrated. The visualization of pH within these matrices during exposure to a pH 2.0 simulated gastric solution showed an encroachment of acid from the periphery of the capsule, and a persistence of pHs above 2.0 within the matrix. This implies that the protective effect of the alginate-chitosan matrices is most likely due to a combination of buffering of acid as it enters the polymer matrix and the slowing of acid penetration

Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated with cellular uncoupling

We describe a human and large animal Langendorff experimental apparatus for live electrophysiological studies and measure the electrophysiological changes due to gap junction uncoupling in human and porcine hearts. The resultant ex vivo intact human and porcine model can bridge the translational gap between smaller simple laboratory models and clinical research. In particular, electrophysiological models would benefit from the greater myocardial mass of a large heart due to its effects on far-field signal, electrode contact issues and motion artefacts, consequently more closely mimicking the clinical setting. Porcine (n = 9) and human (n = 4) donor hearts were perfused on a custom-designed Langendorff apparatus. Epicardial electrograms were collected at 16 sites across the left atrium and left ventricle. A total of 1 mM of carbenoxolone was administered at 5 ml/min to induce cellular uncoupling, and then recordings were repeated at the same sites. Changes in electrogram characteristics were analysed. We demonstrate the viability of a controlled ex vivo model of intact porcine and human hearts for electrophysiology with pharmacological modulation. Carbenoxolone reduces cellular coupling and changes contact electrogram features. The time from stimulus artefact to (-dV/dt)max increased between baseline and carbenoxolone (47.9 ± 4.1–67.2 ± 2.7 ms) indicating conduction slowing. The features with the largest percentage change between baseline and carbenoxolone were fractionation + 185.3%, endpoint amplitude − 106.9%, S-endpoint gradient + 54.9%, S point − 39.4%, RS ratio + 38.6% and (-dV/dt)max − 20.9%. The physiological relevance of this methodological tool is that it provides a model to further investigate pharmacologically induced pro-arrhythmic substrates

Measuring the burden of herpes zoster and post herpetic neuralgia within primary care in rural Crete, Greece

<p>Abstract</p> <p>Background</p> <p>Research has indicated that general practitioners (GPs) have good clinical judgment in regards to diagnosing and managing herpes zoster (HZ) within clinical practice in a country with limited resources for primary care and general practice. The objective of the current study was to assess the burden of HZ and post herpetic neuralgia (PHN) within rural general practices in Crete, Greece.</p> <p>Methods</p> <p>The current study took place within a rural setting in Crete, Greece during the period of November 2007 to November 2009 within the catchment area in which the Cretan Rural Practice-based Research Network is operating. In total 19 GP's from 14 health care units in rural Crete were invited to participate, covering a total turnover patient population of approximately 25, 000 subjects. For the purpose of this study an electronic record database was constructed and used as the main tool for monitoring HZ and PHN incidence. Stress related data was also collected with the use of the Short Anxiety Screening Test (SAST).</p> <p>Results</p> <p>The crude incidence rate of HZ was 1.4/1000 patients/year throughout the entire network of health centers and satellite practices, while among satellite practices alone it was calculated at 1.3/1000 patients/year. Additionally, the standardised incidence density within satellite practices was calculated at 1.6/1000 patients/year. In regards to the stress associated with HZ and PHN, the latter were found to have lower levels of anxiety, as assessed through the SAST score (17.4 ± 3.9 vs. 21.1 ± 5.7; <it>p </it>= 0.029).</p> <p>Conclusions</p> <p>The implementation of an electronic surveillance system was feasible so as to measure the burden of HZ and PHN within the rural general practice setting in Crete.</p