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The molecular cross-sectional area (σ) has proved to be an interesting molecular measure not only in the field of adsorption phenomena on solids but also in biochemistry, physiology, or surfactant chemistry. The existing methods to estimate the cross-sectional areas are either not readily applicable or can only be applied to a limited number of compounds. The aim of this work was to describe a method, as general as possible, quick and easy to perform. To that end, the molecular cross-sectional areas were correlated with topological indices. The Emmett-Brunauer formula was used to calculate the reference cross-sectional areas (σEB) of 431 compounds. The correlations of the Wiener (W), hyper-Wiener (WW), Balaban (J), and Randic (χ) indices with σEB were compared for n-alkanes as well as branched and cyclic alkanes. Only the Wiener and hyper-Wiener indices correlated well with σEB, with the data being best fitted by power law regression curves. The lower degeneracy of the hyper-Wiener index did not translate into any significant gain of performance when correlated with σEB. Following the parsimony principle, the less complex Wiener index was thus selected to correlate with the σEB of compounds representing 31 other monofunctional and structural families. The integration of all the compound families into a single curve allowed a quick rough estimation of the cross-sectional areas. The specific reference equations σEB = qWp were determined for the 34 selected families, allowing the fast and reliable calculation of the cross-sectional area of any monofunctional compound.
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Compostos Orgânicos , Compostos Orgânicos/química , Alcanos/químicaRESUMO
INTRODUCTION: The purpose of this study was to describe and evaluate the outcomes of an optometrist-led virtual glaucoma clinic (VGC). METHODS: New patients referred to the glaucoma service who were consultant triaged as 'low risk' were assessed virtually by specialist-trained optometrists in the VGC and either discharged or monitored for a period of 3 years. Ten percent of virtual case notes were audited by a glaucoma consultant to verify quality and generate learning objectives. Retrospective case-note review and analysis of all patients seen in the virtual clinic between 2014 and 2016 was undertaken to determine 3-year outcomes. RESULTS: A total of 1710 new patients were seen in the clinic between 1 January 2014 and 31 December 2016. Of these, 1033 (60.4%) patients required no outpatient input in 3 years of follow-up. Additionally, 320 (18.7%) were discharged at the first visit, and the proportion of glaucoma suspect and ocular hypertension patients who converted to glaucoma was 12.1% and 5.8%, respectively. At 3 years, 95 patients had died, 159 were lost to follow-up, 576 were discharged and 371 were diagnosed with glaucoma at baseline or during the 3-year follow-up. The cumulative discharge proportion from the service at the end of 3 years was 82.6%. No patients required emergency eye treatment or sight-impairment registration, and of the 12 referred back to the clinic on discharge, only five required ongoing monitoring. CONCLUSION: This optometrist-led VGC combined two aspects of novel service delivery to reduce the burden of glaucoma monitoring in outpatient departments and consolidate consultant contact to patients requiring more intervention. This model will be of value in units establishing virtual services and looking to expand the role of allied health professionals.
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Glaucoma , Hipertensão Ocular , Optometristas , Optometria , Humanos , Pressão Intraocular , Estudos Retrospectivos , Campos Visuais , Glaucoma/diagnóstico , Glaucoma/terapia , Hipertensão Ocular/diagnóstico , Encaminhamento e ConsultaRESUMO
Background Blockade of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess the safety, tolerability, and target engagement of MEDI6570, a high-affinity monoclonal blocking antibody to LOX-1. Methods and Results This phase 1, first-in-human, placebo-controlled study (NCT03654313) randomized 88 patients with type 2 diabetes to receive single ascending doses (10, 30, 90, 250, or 500 mg) or multiple ascending doses (90, 150, or 250 mg once monthly for 3 months) of MEDI6570 or placebo. Primary end point was safety; secondary and exploratory end points included pharmacokinetics, immunogenicity, free soluble LOX-1 levels, and change in coronary plaque volume. Mean age was 57.6/58.1 years in the single ascending doses/multiple ascending doses groups, 31.3%/62.5% were female, and mean type 2 diabetes duration was 9.7/8.7 years. Incidence of adverse events was similar among cohorts. MEDI6570 exhibited nonlinear pharmacokinetics, with terminal half-life increasing from 4.6 days (30 mg) to 11.2 days (500 mg), consistent with target-mediated drug disposition. Dose-dependent reductions in mean soluble LOX-1 levels from baseline were observed (>66% at 4 weeks and 71.61-82.96% at 10 weeks in the single ascending doses and multiple ascending doses groups, respectively). After 3 doses, MEDI6570 was associated with nonsignificant regression of noncalcified plaque volume versus placebo (-13.45 mm3 versus -8.25 mm3). Conclusions MEDI6570 was well tolerated and demonstrated dose-dependent soluble LOX-1 suppression and a pharmacokinetic profile consistent with once-monthly dosing. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT03654313.
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Diabetes Mellitus Tipo 2 , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Lectinas/uso terapêutico , Método Duplo-Cego , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND: For psychiatric service users suffering from severe mental disorders, the social support provided by personal social networks is essential for living a meaningful life within the community. However, the importance of the support received depend on the relations between the providers of social support. Yet this hasn't been addressed in the literature so far for people with severe mental disorders. This article seeks to investigate how characteristics of service users with severe mental disorders, their social contacts, and the pattern of relationships between those contacts influence the distribution and provision of social support to people with severe mental disorders. METHODS: We collected personal network data relating to 380 psychiatric service users from a random sample of health care providers in Belgium. We computed various measures of the structure of those networks and of the position of support persons within those networks. We conducted a multilevel analysis of the importance of the support provided by each support persons. RESULTS: The results show that the more central a support person was in the network of a service user, the more important his or her support was considered to be by the service user. Also, the denser the network in which a support person was embedded, the less important was the support he or she offers, but only for hospitalised service users. CONCLUSION: These finding highlight the collective dimension of social support. We discuss the implications for the organisation of mental health care.
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Transtornos Mentais , Masculino , Feminino , Humanos , Análise Multinível , Transtornos Mentais/terapia , Transtornos Mentais/psicologia , Apoio Social , Rede Social , Pessoal de Saúde/psicologiaRESUMO
Objective: We aimed to evaluate the feasibility of an online High-Intensity Interval Training (HIIT) program on clinical psychological symptoms in higher education students in the context of the COVID-19 pandemic lockdown. Materials and Methods: During the lockdown, 30 students aged 18-25 years, who had been screened previously with a cut-off score ≥5 in the Generalized Anxiety Disorder-7 (GAD-7) questionnaire, were randomly assigned to either the 4-week HIIT program with three sessions per week conducted through online videos, or a no-intervention control group. The primary outcome was the feasibility assessment. The secondary outcome was a psychological self-report with the 21-items Depression, Anxiety, and Stress Scale (DASS-21). Assessment and intervention were performed in compliance with social distancing rules. Results: Two participants in the HIIT were lost to follow-up, leaving 13 participants vs. 15 in the control group. We observed high adherence (87%) and complete safety for mental and physical status with the HIIT intervention delivered by online videos. The Mann-Whitney test demonstrated a significant (group × time, P-Value = 0.046) reduction of clinical stress symptoms and a trend (group × time, P-Value = 0.08) toward reduction of clinical depression symptoms, both favoring the HIIT group. No significant (group × time, P-Value = 0.118) interaction was found for anxiety symptoms. Conclusion: The online HIIT program was found to be feasible and safe in a clinical sample of young adults, who were experiencing social and physical restrictions due to COVID-19. HIIT reduced stress and depressive symptoms and thus these preliminary results show promise for broader application among higher education students during the present lockdown necessitated by the global COVID-19 health crisis.
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The present data article provides a dataset of psychological scores, additional description of used measures, and descriptive data of participants related to the research article entitled "Impact of physical exercise on depression and anxiety in adolescent inpatients: a randomized controlled trial" (Philippot et al., 2022). This randomized controlled trial aimed at assessing the effect of add-on treatment with structured physical exercise compared to social relaxation activities in a clinical population of adolescents hospitalized for depression and anxiety in a psychiatric hospital. A group of 40 adolescents was randomly assigned to either a physical exercise or a control program three to four times per week over six weeks. The primary outcome was the Hospital Anxiety Depression Scale (HADS) for evaluation of depression and anxiety symptoms. Secondary outcomes were psychological self-assessments (The Zung Self-Assessment Depression Scale (SDS), Beck's abbreviated Depression Inventory (BDI-13), The Child Depression Inventory (CDI), The State-Trait Anxiety Inventory (STAI)), diagnostic interview (Hamilton Depression Rating Scale), and physical examinations (an adapted version of the Astrand-Rhyming Sub-Maximal Effort Test and BMI measures). These questionnaires and tests were filled at baseline and after intervention.
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BACKGROUND: Physical exercise therapy is of proven efficacy in the treatment of adults with depression, but corresponding evidence is lacking in depressed adolescent inpatients. The aim of this study was to document the effect of add-on treatment with structured physical exercise in a clinical population of adolescents hospitalized for depression and anxiety in a psychiatric hospital. METHODS: A group of 52 adolescent inpatients was randomly assigned to a physical exercise or control program three to four times per week over a six-week period (20 hours in total). The primary outcome was the Hospital Anxiety Depression Scale (HADS) for evaluation of depression and anxiety symptoms. Secondary outcomes were psychological self-assessments, diagnostic interviews, and physical examinations. RESULTS: Six participants were lost in each group, leaving 20 inpatients each in the intervention and control groups. A linear mixed model with F-test revealed a significant interaction in favor of physical exercise in reducing the mean depression score (HADS-D) by 3.8 points [95% (CI), range 1.8 to 5.7], compared to a mean reduction score of 0.7 [95% (CI), range -0,7 to 2.0] in the control group. No significant interaction was found for anxiety symptoms (HADS-A). LIMITATIONS: The investigation was limited to the six-week hospital window and the small sample size prevented exploring differences in social characteristics. CONCLUSION: Structured physical exercise add-on therapy integrated into the psychiatric hospitalization of adolescents has led to a reduction in their depressive symptoms, demonstrating its effectiveness in the care of adolescent inpatients with depression.
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Depressão , Pacientes Internados , Adolescente , Adulto , Ansiedade/psicologia , Transtornos de Ansiedade/terapia , Depressão/psicologia , Exercício Físico , HumanosRESUMO
Mathematical models in oncology aid in the design of drugs and understanding of their mechanisms of action by simulation of drug biodistribution, drug effects, and interaction between tumor and healthy cells. The traditional approach in pharmacometrics is to develop and validate ordinary differential equation models to quantify trends at the population level. In this approach, time-course of biological measurements is modeled continuously, assuming a homogenous population. Another approach, agent-based models, focuses on the behavior and fate of biological entities at the individual level, which subsequently could be summarized to reflect the population level. Heterogeneous cell populations and discrete events are simulated, and spatial distribution can be incorporated. In this tutorial, an agent-based model is presented and compared to an ordinary differential equation model for a tumor efficacy model inhibiting the pERK pathway. We highlight strengths, weaknesses, and opportunities of each approach.
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Modelos Teóricos , Neoplasias , Simulação por Computador , Humanos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Distribuição TecidualRESUMO
AIMS: Concentration-QT modelling (C-QTc) of first-in-human data has been rapidly adopted as the primary evaluation of QTc interval prolongation risk. Here, we evaluate the performance of C-QTc in early oncology settings (i.e., patients, no placebo or supratherapeutic dose, 3 + 3 designs). METHODS: C-QTc performance was evaluated across three oncology scenarios using a simulation-estimation approach: (scen1) typical dose-escalation testing six dose levels (n = 21); (scen2) small dose-escalation testing two dose levels (n = 9); (scen3) expansion cohorts at one dose level (n = 6-140). True ΔΔQTc effects ranged from 3 ms ("no effect") to 20 ms ("large effect"). Performance was assessed based on the upper limit of the ΔQTc two-sided 90% CI against a threshold of 10 or 20 ms. RESULTS: The performance against the 10 ms threshold was limited based on C-QTc data from typical dose escalation (scen1) and acceptable performance was observed only for relatively large expansions (n ≥ 45; scen3). Performance against the 20 ms threshold was acceptable based on C-QTc data from a typical dose escalation (scen1) or dose expansion cohort n > 10 (scen3). In general, pooling C-QTc data from dose escalation and expansion cohorts substantially improved the performance and reduced the ΔQTc 90% CI width. CONCLUSION: C-QTc performance appeared limited using a 10 ms threshold, but acceptable against a 20 ms threshold. Selection of threshold may be informed by the benefit-risk balance in a specific disease area. Acceptable precision (i.e., confidence intervals) of the estimated ΔQTc, regardless of its magnitude, can be facilitated by pooling data from dose escalation and expansion cohorts.
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Eletrocardiografia , Síndrome do QT Longo , Simulação por Computador , Relação Dose-Resposta a Droga , Frequência Cardíaca , Humanos , Síndrome do QT Longo/induzido quimicamente , OncologiaRESUMO
Molecular dynamics is often considered as a numerical experiment. The error bars on the results are therefore mandatory, but sometimes difficult to determine and computationally demanding. As a low-cost approach, we describe the application of the bootstrap (BS) method to the quantification of uncertainties pertaining to the time correlation functions. We chose the autocorrelation functions of velocity and interdiffusion current for a binary ionic mixture as a test bed, and we assessed the merit of the Darken approximation relating both of them. The intrinsic errors related to phase space sampling is investigated comparing the BS method with the reference method of replica. We also study how the BS method can assist in addressing the finite-size effects.
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INTRODUCTION: This article aims to take stock of the ways in which the concept of participation is used in mental health, particularly in the literature relating to patient support. Based on the debates and issues identified, we propose a framework for analyzing participatory practices. METHOD: The methodology is based on a literature review to which a meta-synthesis has been applied. This method of secondary analysis of qualitative research initially made it possible to synthesise and structure knowledge on the subject studied. Secondly, an interpretative analysis has been carried out to identify a proposal for a framework for analyzing practices. RESULTS: The search process, conducted from two databases, returned 28 articles after exclusion for full data extraction and analysis. Through the meta-synthesis of the data, three ideal models of participation in mental health emerged: the linear approach, the conditional approach and the unconditional approach. CONCLUSION: Our results show that the advantage of mobilizing conceptual variations of participation from the point of view of caregivers in health support does not lie in the opposition of concepts. Rather, it rests on the possibility of shedding light on the different forms that this participation takes in the representation of professionals and their evolution in field practice.
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Saúde Mental , Participação do Paciente , Humanos , Pesquisa QualitativaRESUMO
A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and functionally neutralizes interleukin-13. Thirty-two healthy male adults were enrolled into a dose-escalation clinical trial. Four active doses were tested (30, 105, 300, and 600 mg) with 6 volunteers enrolled per cohort. Eight volunteers received placebo as control. Following single subcutaneous administration (SC), individual time courses of serum MEDI7836 concentrations, and the resulting serum IL13 modulation in vivo, were quantified. A binding pharmacokinetic-pharmacodynamic (PK-PD) indirect response model was built to characterize the exposure-driven modulation of the target over time by MEDI7836. While the validated bioanalytical assay specification quantified the level of free target (i.e., a free IL13 assay), emerging clinical data suggested dose-dependent increase in systemic IL13 concentration over time, indicative of a total IL13 assay. The target time course was modelled as a linear combination of free target and a percentage of the drug-target complex to fit the clinical data. This novel PK-PD modelling approach integrates independent knowledge about the assay characteristics to successfully elucidate apparently complex observations.
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We developed and evaluated a method for making early predictions of best overall response (BOR) and overall survival at 6 months (OS6) in patients with cancer treated with immunotherapy. This method combines machine learning with modeling of longitudinal tumor size data. We applied our method to data from durvalumab-exposed patients with recurrent/metastatic head and neck cancer. A fivefold cross-validation was used for model selection. Independent trial data, with various degrees of data truncation, were used for model validation. Mean classification error rates (90% confidence intervals [CIs]) from cross-validation were 5.99% (90% CI 2.98%-7.50%) for BOR and 19.8% (90% CI 15.8%-39.3%) for OS6. During model validation, the area under the receiver operating characteristic curves was preserved for BOR (0.97, 0.97, and 0.94) and OS6 (0.85, 0.84, and 0.82) at 24, 18, and 12 weeks, respectively. These results suggest our method predicts trial outcomes accurately from early data and could be used to aid drug development.
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Anticorpos Monoclonais/farmacocinética , Antineoplásicos Imunológicos/farmacocinética , Imunoterapia/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Desenvolvimento de Medicamentos , Quimioterapia Combinada , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Valor Preditivo dos Testes , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Análise de SobrevidaRESUMO
BACKGROUND: For psychiatric service users, the personal social network offers resources such as behavioural guidance, social support, and coherence of care delivery. So far, most research on the subject has assessed the availability of these resources using size and composition measures. However, the availability of network resources also depends on the cohesion of the relationships between network members, a topic that is rarely addressed in the literature. AIMS: In this article, we aim to describe the cohesion of psychiatric service users' networks. METHOD: We carried out a personal network survey and collected data on the social networks of 380 service users recruited in outpatient and inpatient services in Belgium. We used an ego-network mapping technique. The data were analysed using several structural metrics describing size, composition, and cohesion. We carried out analysis of variance (ANOVA) in relation to residential status, level of education, psychiatric history, and psychosocial functioning and analysed three cohesion indicators (density, fragmentation, and centralisation) with regression analyses. RESULTS: Personal social networks were small and not very cohesive. Most were composed of a dense subgroup as well as several isolated network members. The analyses revealed that highly educated psychiatric service users had more fragmented networks, while users living in independent accommodation had less dense networks. Density and fragmentation were not associated with the severity of psychosocial functioning, whereas centralisation was. CONCLUSIONS: The low level of cohesion may indicate that service users aim to access multiple and diverse social resources and that better-off service users are more successful at doing so. On the whole, however, these personal social networks were fragile, because they contained a high number of isolated network members. Finally, it could be beneficial for professionals to pay special attention to the central persons within the networks of psychiatric service users.
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Serviços de Saúde Mental , Apoio Social , Atenção à Saúde , Humanos , Rede Social , Inquéritos e QuestionáriosRESUMO
The real-time improvement of the intraoperative discrimination between different tissue types (particularly between tumor and adjacent normal tissue) using intraoperative imaging represents a considerable advance for oncology surgeons. However, the development of imaging agents is much slower than that of drug therapies, although surgery represents one of the few curative treatments for many solid tumors. SGM-101 is a recently described, innovative antibody conjugate in which the near-infrared fluorochrome BM-104 is covalently linked to a chimeric monoclonal antibody against carcinoembryonic antigen (CEA). SGM-101 was developed with the goal of providing oncology surgeons with an intraoperative imaging tool that allows the visualization of CEA-overexpressing tumors. This antigen is overexpressed in a wide range of human carcinomas, such as colorectal, gastric, pancreatic, non-small cell lung and breast carcinomas. Here we characterized SGM-101 safety prior to its clinical testing for real-time cancer mapping by oncology surgeons. Safety pharmacology and toxicology studies were performed after intravenous injection of SGM-101 in Wistar rats and in Beagle dogs. SGM-101 metabolism and pharmacokinetics were analyzed in rats and mice. Finally, the potential toxicity of the BM-104 dye and SGM-101 cross-reactivity were assessed in a panel of 42 human tissues. Our pre-clinical toxicology, pharmacology and pharmacokinetic results demonstrated the absence of significant adverse effects of both SGM-101 and BM-104 at doses well above the anticipated maximal human exposure. Taken together, the results of the pharmacology, pharmacokinetic and toxicology studies support the development of SGM-101 as a potentially useful and safe tumor-specific imaging tool that might improve the complete tumor resection rate.
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PURPOSE: For severely mentally ill (SMI) users, continuity of care requires consistency between the supports provided by the members of their social support network. However, we know little about their network cohesion and its association with continuity of care. We set out to investigate this association and hypothesised that it would depend on the severity of the user's situation and on his/her living arrangements. METHODS: We conducted face-to-face interviews with 380 SMI users recruited in outpatient and inpatient mental health services in three areas in Belgium. Data regarding users' social networks were collected using an ego-network mapping technique and analysed with social network analysis. The cohesion indicators were density (frequency of connections between network members), centralisation (having a small number of central people), and egobetweenness (the user's centrality in his/her own network). Participants' perception of continuity of care was measured by the Alberta Continuity of Services Scale. RESULTS: Results show that cohesion indicators were associated with continuity of care only for users with high-severity problems, regardless of their living arrangements. The numbers of network members, professionals, and services in the network were all negatively associated with continuity of care for all the users. CONCLUSIONS: Satisfactory continuity of care requires fewer professionals or services in a user's network and a dense network for users with the most severe problems. This implies that those providing care must not only be able to increase cohesion within a network, but also to adapt their interventions to support the transition to a different, individualised network structure when severity decreases.
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Continuidade da Assistência ao Paciente/estatística & dados numéricos , Transtornos Mentais/psicologia , Transtornos Mentais/terapia , Serviços de Saúde Mental/estatística & dados numéricos , Rede Social , Adulto , Bélgica , Feminino , Humanos , Masculino , Satisfação do Paciente/estatística & dados numéricos , Apoio SocialRESUMO
The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, an anti-PD-L1 antibody, and quantify the impact of baseline and time-varying patient/disease characteristics on PK. Pooled data from two studies (1,409 patients providing 7,407 PK samples) were analyzed with nonlinear mixed effects modeling. Durvalumab PK was best described by a two-compartment model with both linear and nonlinear clearances. Three candidate models were evaluated: a time-invariant clearance (CL) model, an empirical time-varying CL model, and a semimechanistic time-varying CL model incorporating longitudinal covariates related to disease status (tumor shrinkage and albumin). The data supported a slight decrease in durvalumab clearance with time and suggested that it may be associated with a decrease in nonspecific protein catabolic rate among cancer patients who benefit from therapy. No covariates were clinically relevant, indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following weight-based and flat-dosing regimens.
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Anticorpos Monoclonais/farmacocinética , Cálculos da Dosagem de Medicamento , Taxa de Depuração Metabólica , Neoplasias/tratamento farmacológico , Antineoplásicos Imunológicos/farmacocinética , Antígeno B7-H1/imunologia , Simulação por Computador , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Estadiamento de Neoplasias , Neoplasias/classificação , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to assess the probability of QT interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate nonclinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of dromotropic drug effects in humans. ECG and drug concentration data from a safety pharmacology study in dogs were analyzed using nonlinear mixed effects modeling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration versus time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QT interval of ≥5 and ≥10 ms. Point estimates for the slope in dogs suggested low probability of ≥10 ms prolongation in humans, whereas an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals of the drug-specific parameter in dogs. Interspecies differences in drug disposition appear to explain the discrepancies between predicted and observed QT prolonging effects in humans. Extrapolation of the effects of racemic compound may not be sufficient to describe the increase in QT interval observed after administration of methadone to patients. Assessment of the contribution of enantioselective metabolism and active metabolites is critical.
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BACKGROUND: Cataract is the leading cause of world blindness. The only available treatment for cataract is surgery. Surgery requires highly-trained individuals with expensive operating facilities. Where these are not available, patients go untreated. A form of treatment that did not involve surgery would be a useful alternative for people with symptomatic cataract who are unable or unwilling to undergo surgery. If an eye drop existed that could reverse or even prevent progression of cataract, then this would be a useful additional treatment option.Cataract tends to result from oxidative stress. The protein, L-carnosine, is known to have an antioxidant effect on the cataractous lens, so biochemically there is sound logic for exploring L-carnosine as an agent to reverse or even prevent progression of cataract. When applied as an eye drop, L-carnosine cannot penetrate the eye. However, when applied to the surface of the eye, N-acetylcarnosine (NAC) penetrates the cornea into the front chamber of the eye (near to where the cataract is), where it is metabolised into L-carnosine. Hence, it is possible that use of NAC eye drops may reverse or even prevent progression of cataract, thereby improving vision and quality of life. OBJECTIVES: To assess the effectiveness of NAC drops to prevent or reverse the progression of cataract. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), Allied and Complementary Medicine Database (AMED) (January 1985 to June 2016), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 June 2016. We handsearched the American Society of Cataract and Refractive Surgery (ASCRS) and the European Society of Cataract and Refractive Surgeons (ESCRS) meetings from 2005 until September 2015. SELECTION CRITERIA: We planned to include randomized or quasi-randomised controlled trials where NAC was compared to control in people with age-related cataract. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified two potentially eligible studies from Russia and the United States. One study was split into two arms: the first arm ran for six months, with two-monthly follow-up; the second arm ran for two years with six-monthly follow-up. The other study ran for four months with a data collection point at the start and end of the study only. A total of 114 people were enrolled in these studies. The ages ranged from 55 to 80 years.We were unable to obtain sufficient information to reliably determine how both these studies were designed and conducted. We have contacted the author of these studies, but have not yet received a reply. Therefore, these studies are assigned as 'awaiting classification' in the review until sufficient information can be obtained from the authors. AUTHORS' CONCLUSIONS: There is currently no convincing evidence that NAC reverses cataract, nor prevents progression of cataract (defined as a change in cataract appearance either for the better or for the worse). Future studies should be randomized, double-masked, placebo-controlled trials with standardised quality of life outcomes and validated outcome measures in terms of visual acuity, contrast sensitivity and glare, and large enough to detect adverse effects.