140 research outputs found
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 64âmg¡kgâťÂš i.v., whereas lidocaine reduced it even at 1âmg¡kgâťÂš. In adult rat ventricular myocytes, OCT2013 had no effect on Ca²⺠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
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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
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 Âą 3.9 vs. 21.1 Âą 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
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An in vitro approach to study effects of prebiotics and probiotics on the faecal microbiota and selected immune parameters relevant to the elderly
The aging process leads to alterations of gut microbiota and modifications to the immune response, such changes may be associated with increased disease risk. Prebiotics and probiotics can modulate microbiome changes induced by aging; however, their effects have not been directly compared. The aim of this study was to use anaerobic batch culture fermenters to assess the impact of various fermentable carbohydrates and microorganisms on the gut microbiota and selected immune markers. Elderly volunteers were used as donors for these experiments to enable relevance to an aging population. The impact of fermentation supernatants on immune markers relevant to the elderly were assessed in vitro. Levels of IL-1β, IL-6, IL-8, IL-10 and TNF-ι in peripheral blood mononuclear cell culture supernatants were measured using flow cytometry. Trans-galactooligosaccharides (B-GOS) and inulin both stimulated bifidobacteria compared to other treatments (p<0.05). Fermentation supernatants taken from faecal batch cultures supplemented with B-GOS, inulin, B. bifidum, L. acidophilus and Ba. coagulans inhibited LPS induced TNF-ι (p<0.05). IL-10 production, induced by LPS, was enhanced by fermentation supernatants from faecal batch cultures supplemented with B-GOS, inulin, B. bifidum, L. acidophilus, Ba. coagulans and Bac. thetaiotaomicron (p<0.05). To conclude, prebiotics and probiotics could lead to potentially beneficial effects to host health by targeting specific bacterial groups, increasing saccharolytic fermentation and decreasing inflammation associated with aging. Compared to probiotics, prebiotics led to greater microbiota modulation at the genus level within the fermenters
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 (nâ=â9) and human (nâ=â4) 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 (47.9âÂąâ4.1â67.2âÂąâ2.7 ms) indicating conduction slowing. The features with the largest percentage change between baseline and carbenoxolone were fractionation +â185.3%, endpoint amplitude ââ106.9%, S-endpoint gradient +â54.9%, S point ââ39.4%, RS ratio +â38.6% and (-dV/dt)max ââ20.9%. The physiological relevance of this methodological tool is that it provides a model to further investigate pharmacologically induced pro-arrhythmic substrates
Intrauterine device migration to the urinary bladder causing sexual dysfunction: A case report
Background: Intravesical migration represents an uncommon complication of intrauterine device (IUD) insertion. We present the case of an IUD that migrated to the urinary bladder, causing significant sexual complaints. Case report: A 38-year-old woman presented with complaints of gradually evolving dyspareunia and recurrent urinary tract infections during the past 12 months. She reported an IUD insertion 18 months before. Further detailed evaluation revealed disorders in all sexual domains. Imaging and cystoscopy detected the presence of IUD in the urinary bladder. Under anesthesia, the IUD was removed out of the bladder without any complications. In her follow-up evaluation after six months, her sexual function was significantly improved and she had no urinary symptoms. Conclusion: Sexual difficulties in a woman with an IUD should raise the suspicion of device dislodgement or dislocation. Š 2016, Lithografia Antoniadis I - Psarras Th G.P. All rights reserved
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