Combinations of QT-prolonging drugs: towards disentangling pharmacokinetic and pharmaco-dynamic effects in their potentially additive nature.

Background: Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions. Methods: In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses. Results: Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and coadministration of a ‘known’ risk drug as a further risk factor. Conclusions: These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs

Comparing Long-Acting Antipsychotic Discontinuation Rates Under Ordinary Clinical Circumstances: A Survival Analysis from an Observational, Pragmatic Study

Background: Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective: Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods: The STAR Network ‘Depot Study’ was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results: The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4–44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3–43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4–84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6–40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6–27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742–0.981; p = 0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003–4.634; p = 0.049). Conclusions: Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, taking into account individual characteristics and possible obstacles related to the practicalities of each formulation

Off–label long acting injectable antipsychotics in real–world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction: Information on the off–label use of Long–Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on– vs off–label LAIs and predictors of off–label First– or Second–Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off– or on–label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off–label group. Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on– and off–label use. Approximately 1 in 4 patients received an off–label prescription. In the off–label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off–label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co–morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

Electrochemical Detection of Single Microbeads Manipulated by Optical Tweezers in the Vicinity of Ultramicroelectrodes

Latex micrometric beads are manipulated by optical tweezers in the vicinity of an ultramicroelectrode (UME). They are optically trapped in solution and approached the electrode surface. After the electrochemical measurement, they are optically removed from the surface. The residence time of the particle on the electrode is thus controlled by the optical tweezers. The detection is based on diffusional hindrance by the insulating objects which alters the fluxes of the redox Ru(NH3)6 3+ species toward the UME and thus its mass-transfer limited current. We have optically deposited successively 1, 2, and 3 beads of 3-μm radius on the UME surface, and we have recorded the variations of the current depending on their landing locations that were optically controlled. Finally we decreased the current by partially blocking the electroactive surface with a six-bead assembly. The variation of the steady-state current and the approach curves allow for the indirect electrochemical localization of the bead in the vicinity of the UME, not only when the bead is in contact but also when it is levitated at distances lower than the UME radius. ...

Clinical epidemiology: health information

Clinical epidemiology is the application of epidemiological methods and tools with a clinical purpose: to design health information. From the beginning, it has played a central role in the generation of evidence, its critical appraisal, the efficient storage and retrieval of data, in evidence-based medicine and evidence synthesis. The increase in the use of electronic medical records in veterinary medicine offers the opportunity to use a large volume of data and new technologies allow the data set management and processing. The objective of this work was to carry out a synthesis on the evolution of clinical epidemiology and its application in Veterinary Sciences. The application of Clinical Epidemiology is presented at the veterinary teaching hospital of the Facultad de Ciencias Veterinarias ? Universidad de Buenos Aires, where it began to transform the daily medical practice data into valid information. From the collection, classification and coding of the data present in the electronic medical records, several research lines emerged: to observe changes in the epidemiological patterns of companion animals? diseases, another line is about canine monocytic ehrlichiosis with the aim of advancing in the knowledge of clinical and diagnostic aspects. Among the prevalent diseases, Toxoplasma gondii and Neospora caninum through a case-control study. Another research line seeks to know which non-traditional animal species require medical attention and the most frequent diseases. Also, as an emergent situation, the antimicrobial use at the clinic. Knowledge advances and it must be incorporated into the profession efficiently. Clinical Epidemiology and informatics offer new possibilities within veterinary medicine and between veterinary medicine and human medicine and contributing to ?One Health? initiatives.Fil: López, C. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: López, C. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Loiza, Y. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Loiza, Y. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Sierra, M.F. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Sierra, M.F. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Cornero, F. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Cornero, F. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE). Buenos Aires, ArgentinaFil: Safar, S. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Salud Pública. Buenos Aires, ArgentinaFil: Safar, S. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Estudios Transdisciplinarios de Epidemiología (CETE).Buenos Aires, ArgentinaFil: Sanz, R. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Medicina Veterinaria. Buenos Aires, ArgentinaFil: Gallardo, M.D. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Medicina Veterinaria. Buenos Aires, ArgentinaFil: Suppo, J. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Medicina Veterinaria. Buenos Aires, ArgentinaFil: Suraniti, A. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Medicina Veterinaria. Buenos Aires, ArgentinaLa epidemiologia clínica es la aplicación de métodos y herramientas epidemiológicas con una finalidad clínica: diseñar información en salud. Desde sus inicios ha jugado un papel central en la generación de evidencia, su valoración crítica, el eficiente almacenamiento y recuperación de datos, en la medicina basada en evidencia y la síntesis de evidencia. El incremento en el uso de historias clínicas electrónicas en medicina veterinaria ofrece la oportunidad de utilizar un gran volumen de datos de pacientes y las nuevas tecnologías permiten la gestión y procesamiento del conjunto de datos. El objetivo del presente trabajo fue realizar una síntesis sobre la evolución de la epidemiología clínica y su aplicación en las Ciencias Veterinarias. Se presenta la aplicación de la epidemiología clínica en el Hospital Escuela de la Facultad de Ciencias Veterinarias de la Universidad de Buenos Aires donde se comenzó a transformar los datos que surgen de la práctica médica diaria en información válida. A partir de la recolección, clasificación y codificación de los datos presentes en las Historias Clínicas Electrónicas (HCE), surgieron diversas líneas de investigación: observar los cambios en los patrones epidemiológicos de las enfermedades de los animales de compañía, otra línea está dirigida a la ehrlichiosis monocítica canina con el objetivo de avanzar en el conocimiento de aspectos clínicos y de diagnóstico. Dentro de las enfermedades prevalentes, Toxoplasma gondii y Neospora caninum a través de un estudio de casos y controles. Otra línea de investigación busca conocer qué especies de animales no tradicionales requieren atención y las patologías más frecuentes. Como situación emergente, el uso de antimicrobianos en la clínica. El conocimiento avanza y debe ser incorporado a la profesión de manera eficiente. La epidemiologia clínica y la informática brindan nuevas posibilidades dentro de la medicina veterinaria y entre la medicina veterinaria y la medicina humana, aportando a las iniciativas de ?Una Salud?

Spectroscopic and Crystallographic Characterization of "Alternative Resting" and "Resting Oxidized" Enzyme Forms of Bilirubin Oxidase: Implications for Activity and Electrochemical Behavior of Multicopper Oxidases

4 pagesInternational audienceWhile there is broad agreement on the catalytic mechanism of multicopper oxidases (MCOs), the geometric and electronic structures of the resting trinuclear Cu cluster have been variable, and their relevance to catalysis has been debated. Here, we present a spectroscopic characterization, complemented by crystallographic data, of two resting forms occurring in the same enzyme and define their interconversion. The resting oxidized form shows similar features to the resting form in Rhus vernicifera and Trametes versicolor laccase, characterized by "normal" type 2 Cu electron paramagnetic resonance (EPR) features, 330 nm absorption shoulder, and a short type 3 (T3) Cu−Cu distance, while the alternative resting form shows unusually small A∥ and high g∥ EPR features, lack of 330 nm absorption intensity, and a long T3 Cu−Cu distance. These different forms are evaluated with respect to activation for catalysis, and it is shown that the alternative resting form can only be activated by low-potential reduction, in contrast to the resting oxidized form which is activated via type 1 Cu at high potential. This difference in activity is correlated to differences in redox states of the two forms and highlights the requirement for efficient sequential reduction of resting MCOs for their involvement in catalysis

Spectroscopic and Crystallographic Characterization of “Alternative Resting” and “Resting Oxidized” Enzyme Forms of Bilirubin Oxidase: Implications for Activity and Electrochemical Behavior of Multicopper Oxidases

While there is broad agreement on the catalytic mechanism of multicopper oxidases (MCOs), the geometric and electronic structures of the resting trinuclear Cu cluster have been variable, and their relevance to catalysis has been debated. Here, we present a spectroscopic characterization, complemented by crystallographic data, of two resting forms occurring in the same enzyme and define their interconversion. The resting oxidized form shows similar features to the resting form in <i>Rhus vernicifera</i> and <i>Trametes versicolor</i> laccase, characterized by “normal” type 2 Cu electron paramagnetic resonance (EPR) features, 330 nm absorption shoulder, and a short type 3 (T3) Cu–Cu distance, while the alternative resting form shows unusually small <i>A</i>_∥ and high <i>g</i>_∥ EPR features, lack of 330 nm absorption intensity, and a long T3 Cu–Cu distance. These different forms are evaluated with respect to activation for catalysis, and it is shown that the alternative resting form can only be activated by low-potential reduction, in contrast to the resting oxidized form which is activated via type 1 Cu at high potential. This difference in activity is correlated to differences in redox states of the two forms and highlights the requirement for efficient sequential reduction of resting MCOs for their involvement in catalysis

Spectroscopic and Crystallographic Characterization of “Alternative Resting” and “Resting Oxidized” Enzyme Forms of Bilirubin Oxidase: Implications for Activity and Electrochemical Behavior of Multicopper Oxidases

While there is broad agreement on the catalytic mechanism of multicopper oxidases (MCOs), the geometric and electronic structures of the resting trinuclear Cu cluster have been variable, and their relevance to catalysis has been debated. Here, we present a spectroscopic characterization, complemented by crystallographic data, of two resting forms occurring in the same enzyme and define their interconversion. The resting oxidized form shows similar features to the resting form in <i>Rhus vernicifera</i> and <i>Trametes versicolor</i> laccase, characterized by “normal” type 2 Cu electron paramagnetic resonance (EPR) features, 330 nm absorption shoulder, and a short type 3 (T3) Cu–Cu distance, while the alternative resting form shows unusually small <i>A</i>_∥ and high <i>g</i>_∥ EPR features, lack of 330 nm absorption intensity, and a long T3 Cu–Cu distance. These different forms are evaluated with respect to activation for catalysis, and it is shown that the alternative resting form can only be activated by low-potential reduction, in contrast to the resting oxidized form which is activated via type 1 Cu at high potential. This difference in activity is correlated to differences in redox states of the two forms and highlights the requirement for efficient sequential reduction of resting MCOs for their involvement in catalysis