A deep learning-based electrocardiogram risk score for long term cardiovascular death and disease.

The electrocardiogram (ECG) is the most frequently performed cardiovascular diagnostic test, but it is unclear how much information resting ECGs contain about long term cardiovascular risk. Here we report that a deep convolutional neural network can accurately predict the long-term risk of cardiovascular mortality and disease based on a resting ECG alone. Using a large dataset of resting 12-lead ECGs collected at Stanford University Medical Center, we developed SEER, the Stanford Estimator of Electrocardiogram Risk. SEER predicts 5-year cardiovascular mortality with an area under the receiver operator characteristic curve (AUC) of 0.83 in a held-out test set at Stanford, and with AUCs of 0.78 and 0.83 respectively when independently evaluated at Cedars-Sinai Medical Center and Columbia University Irving Medical Center. SEER predicts 5-year atherosclerotic disease (ASCVD) with an AUC of 0.67, similar to the Pooled Cohort Equations for ASCVD Risk, while being only modestly correlated. When used in conjunction with the Pooled Cohort Equations, SEER accurately reclassified 16% of patients from low to moderate risk, uncovering a group with an actual average 9.9% 10-year ASCVD risk who would not have otherwise been indicated for statin therapy. SEER can also predict several other cardiovascular conditions such as heart failure and atrial fibrillation. Using only lead I of the ECG it predicts 5-year cardiovascular mortality with an AUC of 0.80. SEER, used alongside the Pooled Cohort Equations and other risk tools, can substantially improve cardiovascular risk stratification and aid in medical decision making.

Early Outpatient Treatment With Remdesivir in Patients at High Risk for Severe COVID-19: A Prospective Cohort Study.

Background: Early treatment of coronavirus disease 2019 (COVID-19) with remdesivir in high-risk patients, including those with immunosuppression of different causes, has not been evaluated. The objective of this study was to assess the clinical effectiveness of early remdesivir treatment among patients with mild to moderate COVID-19 at high risk of progression. Methods: This prospective cohort comparative study was conducted in a tertiary referral center in Mexico City. Patients with mild to moderate COVID-19 at high risk for progression were treated with an ambulatory 3-day course of remdesivir. The primary efficacy composite outcome was hospitalization or death at 28 days after symptom onset. A Cox proportional hazards regression model was used to identify associations with the primary outcome. Results: From December 1, 2021, to April 30, 2022, a total of 196 high-risk patients were diagnosed with COVID-19, of whom 126 were included in this study (43%, 54/126, received remdesivir; 57%, 72/126, did not receive remdesivir). Baseline clinical characteristics were similar between groups; autoimmune diseases (39/126), solid organ transplant (31/126), and malignant neoplasms (24/126) were the most common immunocompromising conditions. Diabetes mellitus was strongly associated with the primary outcome in both groups. Prior severe acute respiratory syndrome coronavirus 2 infection or vaccination was not independently associated with COVID-19 progression. Treatment with remdesivir significantly reduced the odds of hospitalization or death (adjusted hazard ratio, 0.16; 95% CI, 0.06-0.44; P < .01). Conclusions: Early outpatient treatment with remdesivir significantly reduces hospitalization or death by 84% in high-risk, majority immunosuppressed patients with Omicron variant COVID-19.

Proposed Tool to Compare and Assess the Applicability of Taste Assessment Techniques for Pharmaceuticals.

Palatability is amongst the most important determinants of whether or not a child will take a medicine. In order to increase concordance with treatment regimens it is often necessary to utilise a range of formulation techniques to improve the palatability of medicines. These can include selecting a different molecule or version of a molecule (such as a different polymorph or salt form), various taste masking techniques and/or the inclusion of flavours and sweeteners. In order to be able to understand the taste of the Active Pharmaceutical Ingredient (API) and to validate the formulation approach used, it is necessary to be able to use the most reliable taste evaluation method possible. Multiple in vivo and in vitro methods exist nowadays or are proposed in the literature but are often little understood by the pharmaceutical product development community. In particular, different methods may be more relevant at different stages of product development. The aim of this article is to propose a tool to guide the selection of the most appropriate method for the desired evaluation. A spreadsheet-based tool is proposed that is designed to allow the systematic assessment of the applicability of any taste assessment technique existing or new to the users proposed application. A series of criteria are defined that will allow the user to assess the analytical, usability and availability factors for the technique that is being considered. Such a systematic review will help the user to understand the benefits and risks of using each methodology for that application. The use of the tool is illustrated based on currently available data and literature. As new/existing methods are developed/improved, the outcomes of the tool may change.

Multimodal deep learning enhances diagnostic precision in left ventricular hypertrophy.

Aims: Determining the aetiology of left ventricular hypertrophy (LVH) can be challenging due to the similarity in clinical presentation and cardiac morphological features of diverse causes of disease. In particular, distinguishing individuals with hypertrophic cardiomyopathy (HCM) from the much larger set of individuals with manifest or occult hypertension (HTN) is of major importance for family screening and the prevention of sudden death. We hypothesized that an artificial intelligence method based joint interpretation of 12-lead electrocardiograms and echocardiogram videos could augment physician interpretation. Methods and results: We chose not to train on proximate data labels such as physician over-reads of ECGs or echocardiograms but instead took advantage of electronic health record derived clinical blood pressure measurements and diagnostic consensus (often including molecular testing) among physicians in an HCM centre of excellence. Using more than 18 000 combined instances of electrocardiograms and echocardiograms from 2728 patients, we developed LVH-fusion. On held-out test data, LVH-fusion achieved an F1-score of 0.71 in predicting HCM, and 0.96 in predicting HTN. In head-to-head comparison with human readers LVH-fusion had higher sensitivity and specificity rates than its human counterparts. Finally, we use explainability techniques to investigate local and global features that positively and negatively impact LVH-fusion prediction estimates providing confirmation from unsupervised analysis the diagnostic power of lateral T-wave inversion on the ECG and proximal septal hypertrophy on the echocardiogram for HCM. Conclusion: These results show that deep learning can provide effective physician augmentation in the face of a common diagnostic dilemma with far reaching implications for the prevention of sudden cardiac death.

[Workplace violence against emergency service nurses: an integrative reviewViolência no trabalho contra os profissionais de enfermagem em serviços de emergência: revisão integrativa]. / Violencia en el trabajo hacia los profesionales de enfermería en los servicios de emergencias: revisión integrativa.

OBJECTIVE: Learn the worldwide frequency of physical and verbal violence against emergency service nurses, and its health and occupational impact. METHODS: An integrative review study was conducted in February 2020 of the MEDLINE, LILACS, CINAHL, and SciELO bibliographic databases, using the descriptors "Nurses," "Workplace Violence," "Physical Aggression," "Psychological Aggression," "Stress, Psychological," "Psychological Trauma," "Aggression," "Health Impact Assessment," "Health Impact," "Impacts on Health," "Impact Assessment, Health," and "Occupational Health." RESULTS: Of the articles located, 18 were included in the analysis. The studies confirmed that the health workers most affected by violence were nurses, and the most common types of violence were verbal aggression, followed by physical violence. In the hospital, these assaults most often occurred in the emergency service. The correlated impact on nurses' health included stress, emotional exhaustion, anxiety, and fear, among other symptoms. With regard to occupational impact, significant indirect accounts related to the reduction in productivity were evident. All these aspects led nurses to consider leaving their jobs in emergency services. CONCLUSIONS: The results enabled identifying a risk profile for violence against nurses in emergency services, seen in the high incidence of physical and verbal violence that led to reduced productivity on the job and the onset of symptoms of burnout syndrome.

OBJETIVO: Conhecer a frequência mundial da violência física e verbal contra os profissionais de enfermagem nos serviços de emergência e seu impacto na saúde e no trabalho. MÉTODOS: A pesquisa foi realizada em fevereiro de 2020 por meio de uma revisão integrativa nas bases de dados MEDLINE, LILACS, CINAHL e SciELO utilizando os seguintes descritores: "Nurses", "Workplace Violence", "Physical Aggression", "Psychological Aggression", "Stress, Psychological", "Psychological Trauma", "Aggression", "Health Impact Assessment", "Health Impact", "Impacts on Health", "Impact Assessment, Health" e "Occupational Health". RESULTADOS: Dentre os artigos identificados, 18 foram incluídos na análise. Os estudos confirmaram que os profissionais da saúde mais afetados pela violência são os profissionais de enfermagem. Agressões verbais e violência física são as formas mais comuns de violência. O local dentro do hospital onde mais ocorrem as agressões é o serviço de emergência. O impacto na saúde dos profissionais de enfermagem está associado ao estresse, esgotamento emocional, ansiedade e medo, entre outros sintomas. Da perspectiva do trabalho, evidencia-se uma relação indireta significativa com queda de produtividade. Todos estes aspectos fazem com que os profissionais de enfermagem considerem desistir de trabalhar nos serviços de emergência. CONCLUSÕES: Os resultados do estudo permitem identificar um perfil de risco de violência contra os profissionais de enfermagem nos serviços de emergência, evidenciado pela alta incidência de violência física e verbal que repercute com queda de produtividade no trabalho e surgimento de sintomas relacionados à síndrome de burnout.

Violencia en el trabajo hacia los profesionales de enfermería en los servicios de emergencias: revisión integrativa

[RESUMEN]. Objetivo. Conocer la frecuencia de la violencia, tanto física como verbal, hacia los profesionales de enfermería, a nivel mundial en los servicios de emergencias y su impacto en la salud y en el contexto laboral. Métodos. La investigación fue realizada mediante una revisión integrativa, en febrero de 2020, de las bases bibliográfícas MEDLINE, LILACS, CINAHL y SciELO, utilizando los descriptores “Nurses”, “Workplace Violence”, “Physical Aggression”, “Psychological Aggression”, “Stress, Psychological”, “Psychological Trauma”, “Aggression”, “Health Impact Assessment”, “Health Impact”, “Impacts on Health”, “Impact Assessment, Health” y “Occupational Health”. Resultados. De los artículos localizados, 18 fueron incluidos en el análisis. Los estudios confirmaron que los profesionales de la salud más afectados por la violencia eran los profesionales de enfermería y el tipo más común fueron las agresiones verbales, seguidas por la violencia física. El área intrahospitalaria más común donde ocurrían dichas agresiones era el servicio de emergencias. El impacto en la salud de los profesionales de enfermería se correlacionó con el estrés, el agotamiento emocional, la ansiedad y el miedo, entre otros síntomas. Con respecto al impacto laboral, se evidenciaron relaciones indirectas significativas vinculadas con la reducción de la productividad. Todos estos aspectos llevaban a los profesionales de enfermería a considerar el abandono de sus trabajos en los servicios de emergencias. Conclusiones. Los resultados permitieron identificar un perfil de riesgo de violencia contra los profesionales de enfermería en los servicios de emergencias evidenciado por la alta incidencia de violencia física y verbal que repercutió en la disminución de la productividad en su trabajo y la aparición de síntomas relacionados al síndrome de burnout.

[ABSTRACT]. Objective. Learn the worldwide frequency of physical and verbal violence against emergency service nurses, and its health and occupational impact. Methods. An integrative review study was conducted in February 2020 of the MEDLINE, LILACS, CINAHL, and SciELO bibliographic databases, using the descriptors “Nurses,” “Workplace Violence,” “Physical Aggression,” “Psychological Aggression,” “Stress, Psychological,” “Psychological Trauma,” “Aggression,” “Health Impact Assessment,” “Health Impact,” “Impacts on Health,” “Impact Assessment, Health,” and “Occupational Health.” Results. Of the articles located, 18 were included in the analysis. The studies confirmed that the health workers most affected by violence were nurses, and the most common types of violence were verbal aggression, followed by physical violence. In the hospital, these assaults most often occurred in the emergency service. The correlated impact on nurses’ health included stress, emotional exhaustion, anxiety, and fear, among other symptoms. With regard to occupational impact, significant indirect accounts related to the reduction in productivity were evident. All these aspects led nurses to consider leaving their jobs in emergency services. Conclusions. The results enabled identifying a risk profile for violence against nurses in emergency services, seen in the high incidence of physical and verbal violence that led to reduced productivity on the job and the onset of symptoms of burnout syndrome.

[RESUMO]. Objetivo. Conhecer a frequência mundial da violência física e verbal contra os profissionais de enfermagem nos serviços de emergência e seu impacto na saúde e no trabalho. Métodos. A pesquisa foi realizada em fevereiro de 2020 por meio de uma revisão integrativa nas bases de dados MEDLINE, LILACS, CINAHL e SciELO utilizando os seguintes descritores: “Nurses”, “Workplace Violence”, “Physical Aggression”, “Psychological Aggression”, “Stress, Psychological”, “Psychological Trauma”, “Aggression”, “Health Impact Assessment”, “Health Impact”, “Impacts on Health”, “Impact Assessment, Health” e “Occupational Health”. Resultados. Dentre os artigos identificados, 18 foram incluídos na análise. Os estudos confirmaram que os profissionais da saúde mais afetados pela violência são os profissionais de enfermagem. Agressões verbais e violência física são as formas mais comuns de violência. O local dentro do hospital onde mais ocorrem as agressões é o serviço de emergência. O impacto na saúde dos profissionais de enfermagem está associado ao estresse, esgotamento emocional, ansiedade e medo, entre outros sintomas. Da perspectiva do trabalho, evidencia-se uma relação indireta significativa com queda de produtividade. Todos estes aspectos fazem com que os profissionais de enfermagem considerem desistir de trabalhar nos serviços de emergência. Conclusões. Os resultados do estudo permitem identificar um perfil de risco de violência contra os profissionais de enfermagem nos serviços de emergência, evidenciado pela alta incidência de violência física e verbal que repercute com queda de produtividade no trabalho e surgimento de sintomas relacionados à síndrome de burnout.

Analysis of RNA yield in extracellular vesicles isolated by membrane affinity column and differential ultracentrifugation.

Extracellular vesicles (EV) have attracted much attention as potential biomarkers due to their protein, RNA and other nucleic acid content. The most common method used for EV isolation is differential ultracentrifugation (DU), however given the DU technical difficulties, other more practical methods have surged, such as membrane-affinity column commercial kits. Here, we assessed one commercial kit in terms of EV recovery and EV-derived RNA yield and compared it with a DU protocol. Our data shows that the commercial kit preparation results in a lower count of EV-like structures and a reduced expression of EV markers when compared to DU samples. Thus, apparently suggesting that the commercial kit had a lower EV yield. However, these findings did not reflect on RNA yield, which was greater with the commercial kit, even after an enzymatic treatment with proteinase K and RNAse A. We conclude that the kit has a higher EV-derived RNA yield in comparison to our DU protocol, suggesting that it may be the method of choice for RNA sequencing purposes.

Multi-task deep learning for cardiac rhythm detection in wearable devices.

Wearable devices enable theoretically continuous, longitudinal monitoring of physiological measurements such as step count, energy expenditure, and heart rate. Although the classification of abnormal cardiac rhythms such as atrial fibrillation from wearable devices has great potential, commercial algorithms remain proprietary and tend to focus on heart rate variability derived from green spectrum LED sensors placed on the wrist, where noise remains an unsolved problem. Here we develop DeepBeat, a multitask deep learning method to jointly assess signal quality and arrhythmia event detection in wearable photoplethysmography devices for real-time detection of atrial fibrillation. The model is trained on approximately one million simulated unlabeled physiological signals and fine-tuned on a curated dataset of over 500 K labeled signals from over 100 individuals from 3 different wearable devices. We demonstrate that, in comparison with a single-task model, our architecture using unsupervised transfer learning through convolutional denoising autoencoders dramatically improves the performance of atrial fibrillation detection from a F1 score of 0.54 to 0.96. We also include in our evaluation a prospectively derived replication cohort of ambulatory participants where the algorithm performed with high sensitivity (0.98), specificity (0.99), and F1 score (0.93). We show that two-stage training can help address the unbalanced data problem common to biomedical applications, where large-scale well-annotated datasets are hard to generate due to the expense of manual annotation, data acquisition, and participant privacy.

Multi-Methodological Quantitative Taste Assessment of Anti-Tuberculosis Drugs to Support the Development of Palatable Paediatric Dosage Forms.

The unpalatability of antituberculosis drugs is often cited as a major cause of non-adherence in children, yet limited quantitative taste assessment data are available. The aim of this research was to quantify the bitterness of isoniazid, rifampicin, pyrazinamide, and ethambutol dihydrochloride using two in vivo (a human taste panel and a rat brief-access taste aversion (BATA) model) and one in vitro (sensor) method. The response of the Insent TS-5000Z electronic tongue was compared to the in vivo drug concentration found to elicit and suppress half the maximum taste response (EC50 in human and IC50 in rats). Using dose-relevant concentrations, an overarching rank order of bitterness was derived (rifampicin > ethambutol > pyrazinamid~isoniazid). In vitro, only ethambutol exhibited a linear response for all sensors/concentrations. Based on the EC50/IC50 generated, a 'taste index' was proposed to allow for anticipation of the likelihood of taste issues in practice, taking in account the saturability in the saliva and therapeutic doses; ethambutol and isoniazid were found to be the worst tasting using this measure. The study presents the first quantitative taste analysis of these life-saving drugs and has allowed for a comparison of three methods of obtaining such data. Such information allows the operator to identify and prioritise the drugs requiring taste masking to produce palatable formulations.

Lesiones premalignas y malignas del estómago en pacientes sin tamización para cáncer gástrico / Premalignant and malignant findings of the stomach in patients without gastric cancer screening

Introducción. Para establecer una frecuencia de seguimiento como método de tamización en cáncer gástrico, se propone la endoscopia en pacientes mayores de 35 años con síntomas de dispepsia, y en pacientes mayores de 40 años con alto riesgo. La demora en la realización de la primera endoscopia en la vida de un paciente incrementa el riesgo de no detectar lesiones premalignas ni cáncer potencialmente prevenible. Los objetivos de nuestro estudio fueron describir el número de pacientes mayores de 40 años con endoscopia de primera vez y evaluar la presencia de lesiones premalignas y malignas del estómago en pacientes sin tamización. Métodos. Revisión retrospectiva de base de datos. Se describieron hallazgos de informes de histopatología en pacientes mayores de 40 años (lesiones premalignas y malignas). Adicionalmente se describieron las variables sociodemográficas de los pacientes con endoscopia de primera vez y la presencia de infección por Helicobacter pylori en la población mencionada. Resultados. Setenta y ocho pacientes (23,6 %) tuvieron una endoscopia de primera vez siendo mayores de 40 años. En el 44 % de los pacientes se encontró la presencia de Helicobacter pylori, 25,4 % de los pacientes presentaron atrofia gástrica, 23,1 % metaplasia, ningún paciente presentó displasia y un paciente (1,3 %) presentó un adenocarcinoma gástrico. Discusión. Los resultados de nuestro estudio muestran un número elevado de pacientes sin endoscopia de tamización. Nuestro estudio resalta la importancia del uso de la endoscopia de tamización en la prevención, así como en el diagnóstico temprano de cáncer gástrico y sugiere mayor adherencia a las guías de práctica clínica

Introduction. To establish a frequency of follow-up as a screening method for gastric cancer, endoscopy is pro-posed in patients older than 35 years with symptoms of dyspepsia, and in patients older than 40 years at high risk. The delay in performing the first endoscopy in a patient's life increases the risk of not detecting premalignant lesions or potentially preventable cancer. The aims of our study were to describe the number of patients older than 40 years with first-time endoscopy and to assess the presence of premalignant and malignant stomach lesions in patients without screening.Methods. Retrospective database review. Histopathology report findings in patients older than 40 years (prema-lignant and malignant lesions) were described. Additionally, the sociodemographic variables of patients with first-time endoscopy and the presence of Helicobacter pylori infection in the mentioned population were described.Results. Seventy-eight patients (23.6%) had a first-time endoscopy being older than 40 years. Helicobacter pylori was found in 44% of the patients, 25.4% of the patients had gastric atrophy, 23.1% had metaplasia, no patient had dysplasia and one patient (1.3%) had gastric adenocarcinoma. Discusions. The results of our study show a high number of patients without screening endoscopy. Our study highlights the importance of the use of screening endoscopy in prevention, as well as in the early diagnosis of gastric cancer, and suggests greater adherence to clinical practice guidelines

Rats can predict aversiveness of Active Pharmaceutical Ingredients.

Taste is crucial for patient acceptability and compliance with prescribed medicines, in particular with pediatric patients. Evaluating the taste of new active pharmaceutical ingredients (APIs) is therefore essential to put in place adequate taste-masking techniques, if needed, which will lead to acceptable palatable formulations. Thus, there is an urgent need to develop and optimize taste assessment methods that could be used at different stages of the drug development process. The aim of this study was to investigate the suitability of the rat brief-access taste aversion (BATA) model as a screening tool for assessment of APIs aversiveness that could predict human taste responses. Presently, the taste intensity of nine marketed APIs known to have different levels of bitter intensity (quinine hydrochloride dihydrate, 6-n-propylthiouracil, sildenafil citrate, diclofenac sodium, ranitidine hydrochloride, caffeine citrate, isoniazid, telbivudine and paracetamol) was investigated at different overlapping concentrations with two in vivo taste assessment methods: the rat BATA model and human taste panels with the intention of determining the drugs' concentrations to produce half of the maximal rating. Overall there was a strong correlation (R2 = 0.896) between rats IC50 and humans EC50 values. This correlation verifies the BATA model as a rapid and reliable tool for quantitative assessment of API aversiveness. A comparable ranking order was obtained mainly for high and medium aversive compounds, whereas it was less aligned for weakly aversive compounds. It was nonetheless possible to propose a classification of poor taste intensity determined in rats that would predict human taste tolerability.

Artificial Intelligence in Cardiology.

Artificial intelligence and machine learning are poised to influence nearly every aspect of the human condition, and cardiology is not an exception to this trend. This paper provides a guide for clinicians on relevant aspects of artificial intelligence and machine learning, reviews selected applications of these methods in cardiology to date, and identifies how cardiovascular medicine could incorporate artificial intelligence in the future. In particular, the paper first reviews predictive modeling concepts relevant to cardiology such as feature selection and frequent pitfalls such as improper dichotomization. Second, it discusses common algorithms used in supervised learning and reviews selected applications in cardiology and related disciplines. Third, it describes the advent of deep learning and related methods collectively called unsupervised learning, provides contextual examples both in general medicine and in cardiovascular medicine, and then explains how these methods could be applied to enable precision cardiology and improve patient outcomes.

Solid state characterisation and taste masking efficiency evaluation of polymer based extrudates of isoniazid for paediatric administration.

Hot melt extrusion has gained considerable attention as a novel technique for taste masking of bitter APIs. The aim of this study was to investigate whether hot melt extrusion could be used to develop taste masked formulations of isoniazid and also to evaluate and correlate different taste assessment methods Two polymers with different physico-chemical properties, Soluplus and Eudragit E-PO were chosen as carriers for the drug. Eudragit E-PO has already been widely used for taste masking due to its selective release properties, while Soluplus has not been studied in this regard but provides a useful comparator of a polymer that should release the drug reasonably efficiently. Polymeric formulations of isoniazid were produced with drug loadings of 20% and 30% w/w. The solid state characteristics of the formulations were assessed by differential scanning calorimetry and powder X-ray diffraction. The taste of isoniazid was assessed using the rodent Brief Access Taste Aversion (BATA) model, while formulations were assessed using the electronic tongue and dissolution under simulated oral conditions. Investigation into the drug loading effect with these two polymers showed that all Soluplus based extrudates with drug loading up to 30% w/w were fully amorphous while Eudragit E-PO based extrudates contained crystalline drug as demonstrated by both DSC and PXRD, dependent on loading. BATA testing of isoniazid gave an IC50 value, i.e. the dose of drug which inhibits 50% of licks, of 11.1mg/mL. Taste assessment of the formulations using both simulated oral drug release and the electronic tongue demonstrated that Eudragit E-PO based formulations had a better taste masking efficiency than Soluplus. This is due to the fact that significantly less isoniazid is released from the Eudragit E-PO based formulations under oral conditions.

Taste evaluation of a novel midazolam tablet for pediatric patients: In vitro drug dissolution, in vivo animal taste aversion and clinical taste perception profiles.

Harmonized methodologies are urgently required for the taste evaluation of novel pediatric medicines. This study utilized in vitro, in vivo and clinical data to evaluate the palatability of a novel midazolam chocolate tablet. In vitro dissolution experiments showed the crushed tablet to release within 5 min 1.68 mg of midazolam into simulated saliva. This translated to a drug level of 0.84 mg/ml in the oral cavity, which would be higher than the midazolam bitterness detection threshold concentration of 0.03 mg/ml determined in a rat 'brief access taste aversion' (BATA) model. The visual analogue scale scores of patients aged 4-16 years prescribed with midazolam pre-surgery showed a clear preference for the midazolam chocolate tablets (3.35 ± 1.04, n = 20) compared to the control midazolam solution (1.47 ± 0.62, n = 17). The clinical data was in agreement with the in vivo rodent data in showing the novel chocolate tablet matrix to be effective at taste-masking the bitter midazolam.

Toxicity and Apoptosis Related Effects of Benzimidazo [3,2-α] Quinolinium Salts Upon Human Lymphoma Cells.

OBJECTIVES: The present study evaluates novel cationic quinoline derivatives known as benzimidazo[3,2-a]quinolinium salts (BQS) named NBQ-48 and ABQ-48 that have structural similarities to known anti-cancer substances such as ellipticine and berberine. METHODS: Toledo human lymphoma (ATCC CRL2631) cells were treated for 24 to 48 hours. Apoptosis related endpoints such as cell cycle arrest, mitochondrial damage, RNS and ROS generation and the activity of several apoptosis related proteins such as caspases and apoptosis inducing factor (AIF) were studied using fluorescence staining and western blot respectively. RESULTS: Results indicated a higher toxicity from the amino substituted ABQ-48 versus the NBQ-48 (GI50's of 50uM versus 100uM respectively). Both compounds induced cell death through various apoptosis related endpoints including a decrease in mitochondrial membrane potential with an increase in ROS and activation of the effector caspase 3. Interestingly, AIF release was observed on cells treated with the amino substituted ABQ-48 but not on the nitro substituted NBQ-48 samples suggesting a caspase independent mechanism for ABQ-48. CONCLUSIONS: The results obtained presents the toxic effects of two novel benzimidazo[3,2-a]quinolinium salts in human lymphoma tumor cells. The identified mechanism of action includes multiple apoptosis related effects. Furthermore the data presents a clear variation in caspase dependent or independent mechanism for each compound.

Non-human tools for the evaluation of bitter taste in the design and development of medicines: a systematic review.

Taste evaluation is a crucial factor for determining acceptance of medicines by patients. The human taste panel test is the main method used to establish the overall palatability and acceptability of a drug product to a patient towards the end of development. Non-human in vitro and in vivo taste-evaluation tools are very useful for pre-formulation, quality control and screening of formulations. These non-human taste assessment tools can be used to evaluate all aspects of taste quality. The focus of this review is bitterness because it is a key aspect of taste in association with the development of medicines. In this review, recent in vitro (analytical) and in vivo (non-human) tools are described for the assessment of the bitter taste of medicines. Their correlations with human taste data are critically discussed. The potential for their use in early screening of the taste of active pharmaceutical ingredients (APIs) to expedite paediatric formulation development is also considered.

Development of a model for robust and exploratory analysis of the rodent brief-access taste aversion data.

The rodent brief-access taste aversion (BATA) model is an efficient in vivo screening tool for taste assessment. A new E(max) (maximum effect attributable to the drug) model was developed and further investigated in comparison with three previously published models for analysing the rodent BATA data; the robustness of all the models was discussed. The rodent BATA data were obtained from a series of experiments conducted with a bitter reference compound, quinine hydrochloride dihydrate (QHD). A new E(max) model that could be applied to both "lick numbers" and "lick ratios" was built and three published models that used lick ratios were employed for analysing the BATA data. IC50, the concentration that inhibits 50% of the maximum lick numbers, quantified the oral aversiveness of QHD. One thousand bootstrap datasets were generated from the original data. All models were applied to estimate the confidence intervals of the IC50s without symmetric assumption. The IC50 value obtained from the new E(max) model was 0.0496 mM (95% CI 0.0297-0.0857) using the lick numbers for analysis, while an IC50 of 0.0502 mM (95% CI 0.0267-0.0859) was acquired with the lick ratios. Except one published model, the IC50 values have a similar range for the 95% CI. The new E(max) model enabled the analysis of both "lick numbers" and "lick ratios" whereas other models could only handle data presented as "lick ratios". IC50s obtained with these two types of datasets showed similarity among all models thereby justified the robustness of the new E(max) model.