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Electronic medical records (EMRs) play an important role in medical data mining and sequential data learning. In this article, we propose to use a sequential neural network with dynamic content-based memories to predict future medications, given EMRs. The local-global memory neural network contains two layers of memories: the local memory and the global memory. Particularly, our method learns the hidden knowledge within EMRs by locally remembering individual patterns of a patient (via local memory) and globally remembering group evidence of disease (via global memory). In addition, we show how our model can be modified to classify the hidden states of EMRs from different patients at each time step into different phases that indicate the progressions of medications in terms of a specific disease, in an unsupervised manner. Experimental results on real EMRs data sets show that, by learning EMRs with external local and global memories, with regard to a given disease, our model improves the prediction performance compared with several alternative methods.

Most diseases disrupt multiple proteins, and drugs treat such diseases by restoring the functions of the disrupted proteins. How drugs restore these functions, however, is often unknown as a drug's therapeutic effects are not limited to the proteins that the drug directly targets. Here, we develop the multiscale interactome, a powerful approach to explain disease treatment. We integrate disease-perturbed proteins, drug targets, and biological functions into a multiscale interactome network. We then develop a random walk-based method that captures how drug effects propagate through a hierarchy of biological functions and physical protein-protein interactions. On three key pharmacological tasks, the multiscale interactome predicts drug-disease treatment, identifies proteins and biological functions related to treatment, and predicts genes that alter a treatment's efficacy and adverse reactions. Our results indicate that physical interactions between proteins alone cannot explain treatment since many drugs treat diseases by affecting the biological functions disrupted by the disease rather than directly targeting disease proteins or their regulators. We provide a general framework for explaining treatment, even when drugs seem unrelated to the diseases they are recommended for.

Nonalcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease in the world, which is characterized by liver fat accumulation unrelated to excessive drinking. Indeed, it attracts growing attention and becomes a global health problem. Due to the complexity of the NAFLD pathogenic mechanism, no related drugs were approved by Food and Drug Administration (FDA) till now. However, it is encouraging that a series of candidate drugs have entered the clinical trial stage with expectation to treat NAFLD. In this review, we summarized the main pathways and pathogenic mechanisms of NAFLD, as well as introduced the main potential therapeutic targets and the corresponding compounds involved in metabolism, inflammation and fibrosis. Furthermore, we also discuss the progress of these compounds, such as drug design and optimization, the choice of pharmacological properties and druglikeness, and the analysis of structure-activity relationship. This review offers a medium on future drug design and development, to be beneficial to relevant studies., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A pharmacogenomics-based pathway represents a series of reactions that occur between drugs and genes in the human body after drug administration. PG-path is a pharmacogenomics-based pathway that standardizes and visualizes the components (nodes) and actions (edges) involved in pharmacokinetic and pharmacodynamic processes. It provides an intuitive understanding of the drug response in the human body. A pharmacokinetic pathway visualizes the absorption, distribution, metabolism, and excretion (ADME) at the systemic level, and a pharmacodynamic pathway shows the action of the drug in the target cell at the cellular-molecular level. The genes in the pathway are displayed in locations similar to those inside the body. PG-path allows personalized pathways to be created by annotating each gene with the overall impact degree of deleterious variants in the gene. These personalized pathways play a role in assisting tailored individual prescriptions by predicting changes in the drug concentration in the plasma. PG-path also supports counseling for personalized drug therapy by providing visualization and documentation., Competing Interests: There are no competing interests associated with this study. After having accomplished this study at Seoul National University College of Medicine, the first author is serving as a researcher in Cipherome. Therefore, Cipherome is not related to this study but is currently interested in this study result. These do not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Redispensing by pharmacies of medication unused by another patient could contribute to optimal use of healthcare resources. This study aimed to assess patient willingness to use medication returned by another patient and patient characteristics associated with this willingness., Design: Cross-sectional survey., Setting: A total of 41 community and 5 outpatient pharmacies in the Netherlands., Participants: Total of 2215 pharmacy visitors., Primary and Secondary Outcome Measures: Patients completed a questionnaire regarding their willingness to use medication returned unused to the pharmacy by another patient, assuming quality was guaranteed. Secondary outcome measures included patient sociodemographic characteristics that were associated with patient willingness, analysed using logistic regression analysis and reported as ORs with 95% CIs., Results: Of the 2215 patients (mean (SD) age 50.6(18.0) years; 61.4% female), 61.2% were willing to use medication returned unused to the pharmacy by another patient. Patients who were unwilling mostly found it risky. Men were more willing to use returned medication (OR 1.3 95% CI 1.1 to 1.6), as did patients with a high educational level (OR 1.8 95% CI 1.3 to 2.5), those who regularly use 1-3 medications (OR 1.3 95% CI 1.1 to 1.7), those who returned medication to the pharmacy for disposal (OR 1.5 95% CI 1.0 to 2.3) and those who ever had unused medication themselves (OR 1.3 95% CI 1.1 to 1.6)). Patients with non-Dutch cultural background were less willing to use returned medication (OR 0.395% CI 0.3 to 0.4))., Conclusions: When quality is guaranteed, a substantial proportion of patients are willing to use medication returned unused to the pharmacy by another patient. This suggests that implementation of redispensing may be supported by patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We studied how lagged linear regression can be used to detect the physiologic effects of drugs from data in the electronic health record (EHR). We systematically examined the effect of methodological variations ((i) time series construction, (ii) temporal parameterization, (iii) intra-subject normalization, (iv) differencing (lagged rates of change achieved by taking differences between consecutive measurements), (v) explanatory variables, and (vi) regression models) on performance of lagged linear methods in this context. We generated two gold standards (one knowledge-base derived, one expert-curated) for expected pairwise relationships between 7 drugs and 4 labs, and evaluated how the 64 unique combinations of methodological perturbations reproduce the gold standards. Our 28 cohorts included patients in the Columbia University Medical Center/NewYork-Presbyterian Hospital clinical database, and ranged from 2820 to 79,514 patients with between 8 and 209 average time points per patient. The most accurate methods achieved AUROC of 0.794 for knowledge-base derived gold standard (95%CI [0.741, 0.847]) and 0.705 for expert-curated gold standard (95% CI [0.629, 0.781]). We observed a mean AUROC of 0.633 (95%CI [0.610, 0.657], expert-curated gold standard) across all methods that re-parameterize time according to sequence and use either a joint autoregressive model with time-series differencing or an independent lag model without differencing. The complement of this set of methods achieved a mean AUROC close to 0.5, indicating the importance of these choices. We conclude that time-series analysis of EHR data will likely rely on some of the beneficial pre-processing and modeling methodologies identified, and will certainly benefit from continued careful analysis of methodological perturbations. This study found that methodological variations, such as pre-processing and representations, have a large effect on results, exposing the importance of thoroughly evaluating these components when comparing machine-learning methods., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Primarily to determine how many of our adult patients receive significant assistance from another individual with medication management. Secondarily, to determine if the number of prescribed medications can be predictors of whether the patient receives significant assistance with medication management., Design: Cross-sectional survey study., Setting: A level 3 patient-centered medical home family practice clinic in an inner city university hospital in Brooklyn, New York., Participants: Patients 40 years of age and older coming for a regular clinic visit to see the primary care physician., Intervention: Administering the survey to the patients was the intervention. MAIN OUTCOME MEASURES: The number of patients who receive significant assistance with any phase of medication management was the main outcome measure., Results: Out of 143 patients surveyed, 61 patients (42.7%) received assistance with 1 or more phases of medication management; 38.5% (n = 55) of patients received help with phase 1 (ensuring that patients have medications at home). Of those 55 patients, 28 (50.9%) received help from family members, 22 (40%) received help from pharmacies, and 5 (9.1%) received help from home health aides or visiting nurses. Thirteen patients (9%) received help with phase 2 (arranging medications to help take them properly); 11 (84.6%) of them received help from family members. Twenty-three patients (16.1%) received help with phase 3 (reminding patients to take medications or handing them to the patient); 17 (73.9%) out of 23 received help from family members. There was a statistically significant trend (Mann-Whitney 2-sided test: P <0.001) showing a direct relationship between the number of medications and the need for assistance with 1 or more phases of medication management., Conclusion: Many adult patients receive help with 1 or more phases of medication management. Family members are the major source of assistance with medication management. Pharmacies also play an important role in making certain that patients have medications at home. Patients with a higher number of medications are more likely to receive assistance from others., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Drugs are key weapons that clinicians have to battle against the profound pathologies encountered in critically ill patients. Antibiotics in particular are commonly used and can improve patient outcomes dramatically. Despite this, there are strong opportunities for further reducing the persisting poor outcomes for infected critically ill patients. However, taking these next steps for improving patient care requires a new approach to antibiotic therapy. Giving the right dose is highly likely to increase the probability of clinical cure from infection and suppress the emergence of resistant pathogens. Furthermore, in some patients with higher levels of sickness severity, reduced mortality from an optimized approach to antibiotic use could also occur. To enable optimized dosing, the use of customized dosing regimens through either evidence-based dosing nomograms or preferably through the use of dosing software supplemented by therapeutic drug monitoring data should be embedded into daily practice. These customized dosing regimens should also be given as soon as practicable as reduced time to initiation of therapy has been shown to improve patient survival, particularly in the presence of septic shock. However, robust data supporting these logical approaches to therapy, which may deliver the next step change improvement for treatment of infections in critically ill patients, are lacking. Large prospective studies of patient survival and health system costs are now required to determine the value of customized antibiotic dosing, that is, giving the right dose at the right time.

The performance of a drug in a clinical trial setting often does not reflect its effect in daily clinical practice. In this third of three reviews, we examine the applications that have been used in the literature to predict real-world effectiveness from randomized controlled trial efficacy data. We searched MEDLINE, EMBASE from inception to March 2014, the Cochrane Methodology Register, and websites of key journals and organisations and reference lists. We extracted data on the type of model and predictions, data sources, validation and sensitivity analyses, disease area and software. We identified 12 articles in which four approaches were used: multi-state models, discrete event simulation models, physiology-based models and survival and generalized linear models. Studies predicted outcomes over longer time periods in different patient populations, including patients with lower levels of adherence or persistence to treatment or examined doses not tested in trials. Eight studies included individual patient data. Seven examined cardiovascular and metabolic diseases and three neurological conditions. Most studies included sensitivity analyses, but external validation was performed in only three studies. We conclude that mathematical modelling to predict real-world effectiveness of drug interventions is not widely used at present and not well validated. © 2016 The Authors Research Synthesis Methods Published by John Wiley & Sons Ltd., (© 2016 The Authors Research Synthesis Methods Published by John Wiley & Sons Ltd.)

Safe and effective paediatric pharmacotherapy requires careful evaluation of the type of drug substance, the necessary dose and the age-appropriateness of the formulation. Generally, the younger the child, the more the attention that is required. For decades, there has been a general lack of (authorised) formulations that children are able to and willing to take. Moreover, little was known on the impact of pharmaceutical aspects on the age-appropriateness of a paediatric medicine. As a result of legislative incentives, such knowledge is increasingly becoming available. It has become evident that rapidly dissolving tablets with a diameter of 2 mm (mini-tablets) can be used in preterm neonates and non-rapidly dissolving 2 mm mini-tablets in infants from 6 months of age. In addition, uncoated 4 mm mini-tablets can be used in infants from the age of 1 year. Also, there is some evidence that children prefer mini-tablets over a powder, suspension or syrup. Other novel types of age-appropriate oral formulations such as orodispersible films may further add to the treatment possibilities. This review provides an overview of the current knowledge on oral formulations for infants and preschool children, the advantages and disadvantages of the different types of dosage forms and the age groups by which these can likely be used., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Medication errors (MEs) are preventable and can result in patient harm and increased expenses in the healthcare system in terms of hospitalization, prolonged hospitalizations and even death. We aimed to develop a screening tool to detect acutely admitted patients at low or high risk of MEs comprised by items found by literature search and the use of theoretical weighting. Predictive variables used for the development of the risk score were found by the literature search. Three retrospective patient populations and one prospective pilot population were used for modelling. The final risk score was evaluated for precision by the use of sensitivity, specificity and area under the ROC (receiver operating characteristic) curves. The variables used in the final risk score were reduced renal function, the total number of drugs and the risk of individual drugs to cause harm and drug-drug interactions. We found a risk score in the prospective population with an area under the ROC curve of 0.76. The final risk score was found to be quite robust as it showed an area under the ROC curve of 0.87 in a recent patient population, 0.74 in a population of internal medicine and 0.66 in an orthopaedic population. We developed a simple and robust score, MERIS, with the ability to detect patients and divide them according to low and high risk of MEs in a general population admitted at acute admissions unit. The accuracy of the risk score was at least as good as other models reported using multiple regression analysis., (© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Some patients are exposed to complex clinical situations, which impose a careful analysis of both the indications and contraindications of ongoing pharmacological treatments as well as of the dosing or drug adjustments to be proposed. This article illustrates some problems encountered when a new drug therapy is initiated, when medications with narrow therapeutic window should be supervised and when some drugs should be stopped mainly for safety reasons. The clinical case relates the story of a patient with type 2 diabetes, arterial hypertension and coronary heart disease, who presents a congestive heart failure associated with an episode of atrial fibrillation and a severe renal insufficiency.

The pharmaceutical industry has undergone a vast expansion in the 20th and 21st centuries. This article explores the central role now played by pills in clinical practice, but also in the public imagination. First, this article analyzes four properties that, together, account for many of the promises and perils associated with pills: They are ingestible, potent, reproducible, and miniaturized. This allows them to serve as ideal consumer items for widespread distribution and sale and also as model technological "devices" capable of downloading into the body healing chemicals. As such, they seem to promise a disburdening solution to many of life's ills. In our cultural fantasy, often shared by physician and patient alike, pills can be used not only to treat and prevent disease but also raise energy, lose weight, lessen pain, lift mood, cope with stress, and enhance sexual and athletic performance. This article also explores many adverse effects not only of pills themselves but of this exaggerated cultural fantasy of the pill. It tends to distract us from other, more holistic understandings of the locus of disease and healing. It even fosters misunderstandings of the ways in which pills themselves work, which is to assist bodily processes, and the mind's "meaning response." The intent here is not to demonize all pills-many have great therapeutic potential-but to learn how to better choose and use them wisely. We propose that this process be assisted through recontextualizing the pill as a multidimensional gift. Taken in such a way, with appropriate gratitude and discernment, we may ingest fewer pills, but with greater efficacy.

The active-controlled trial with a non-inferiority design has gained popularity in recent years. However, non-inferiority trials present some methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how a non-inferiority trial should be conducted. Moreover, in a scientific advice procedure, regulators give companies the opportunity to discuss critical trial issues prior to the start of the trial. The aim of this study was to identify potential issues that may benefit from more explicit guidance by regulators. To achieve this, we collected and analyzed questions about non-inferiority trials posed by applicants for scientific advice in Europe in 2008 and 2009, as well as the responses given by the European Medicines Agency (EMA). In our analysis we included 156 final letters of advice from 2008 and 2009, addressed to 94 different applicants (manufacturers). Our analysis yielded two major findings: (1) applicants frequently asked questions 'whether' and 'how' to conduct a non-inferiority trial, 26% and 74%, respectively, and (2) the EMA regulators seem mainly concerned about the choice of the non-inferiority margin in non-inferiority trials (36% of total regulatory answers). In 40% of the answers, the EMA recommended using a stricter margin, and in 10% of the answers regarding non-inferiority margins, the EMA questioned the justification of the proposed non-inferiority margin. We conclude that there are still difficulties in selecting the appropriate methodology for non-inferiority trials. Straightforward and harmonized guidance regarding non-inferiority trials is required, for example on whether it is necessary to conduct such a trial and how the non-inferiority margin is determined. It is unlikely that regulatory guidelines can cover all therapeutic areas; therefore, in some cases regulatory scientific advice may be used as an opportunity for tailored advice.

The administration of medicines to patients with dysphagia presents substantial challenges to patient safety. Within stroke services, where up to half of patients may experience dysphagia, ensuring safe medication management is particularly challenging. This article describes how best practice within one stroke unit is being achieved by means of a knowledge-to-action service improvement project, ongoing education and training, and the input of a specialist dysphagia practitioner.

Platelets store signaling molecules (eg, serotonin and ADP) within their granules. Transporters mediate accumulation of these molecules in platelet granules and, on platelet activation, their translocation across the plasma membrane. The balance between transporter-mediated uptake and elimination of signaling molecules and drugs in platelets determines their intracellular concentrations and effects. Several members of the 2 major transporter families, ATP-binding cassette (ABC) transporters and solute carriers (SLCs), have been identified in platelets. An example of an ABC transporter is MRP4 (ABCC4), which facilitates ADP accumulation in dense granules. MRP4 is a versatile transporter, and various additional functions have been proposed, notably lipid mediator release and a role in aspirin resistance. Several other ABC proteins have been detected in platelets with functions in glutathione and lipid homeostasis. The serotonin transporter (SERT, SLC6A4) in the platelet plasma membrane represents a well-characterized example of the SLC family. Moreover, recent experiments indicate expression of OATP2B1 (SLCO2B1), a high affinity transporter for certain statins, in platelets. Changes in transporter localization and expression can affect platelet function and drug sensitivity. This review summarizes available data on the physiologic and pharmacologic role of transporters in platelets.

Although the principles of drug disposition also apply in neonates, their specific characteristics warrant focussed assessment. Children display maturation in drug disposition, but this is most prominent in the first year of life. Besides maturational aspects of drug absorption and distribution, maturation mainly relates to (renal) elimination and (hepatic) metabolic clearance. Renal elimination clearance in early life is low and almost completely depends on glomerular filtration. Despite the overall low clearance, interindividual variability is already extensive and can be predicted by covariates like postmenstrual age, postnatal age, co-administration of a non-selective cyclo-oxygenase inhibitor, growth restriction or peripartal asphyxia. These findings are illustrated by observations on amikacin and vancomycin. Variation in phenotypic metabolic clearance is based on constitutional, environmental and genetic characteristics. In early life, it mainly reflects ontogeny, but other covariates may also become relevant. Almost all phase I and phase II metabolic processes display ontogeny in a iso-enzyme specific pattern. The impact of covariates like postmenstrual age, postnatal age, disease state characteristics and polymorphisms are illustrated based or 'probe' drugs (paracetamol, tramadol, propofol) administered as part of their medical treatment in critically ill neonates. The description of a compound specific pattern is beyond compound specific relevance. The maturational patterns described and the extent of the impact of covariates can subsequently be applied to predict in vivo time-concentration profiles for compounds that undergo similar routes of elimination. Through improved predictability, such maturational models can serve to improve both the clinical care and feasibility and safety of clinical studies in neonates.

Discontinuation of drug development projects due to lack of efficacy or adverse events is one of the main cost drivers in pharmaceutical research and development (R&D). Investments have to be written-off and contribute to the total costs of a successful drug candidate receiving marketing authorization and allowing return on invest. A vital risk for pharmaceutical innovator companies is late stage clinical failure since costs for individual clinical trials may exceed the one billion Euro threshold. To guide investment decisions and to safeguard maximum medical benefit and safety for patients recruited in clinical trials, it is therefore essential to understand the clinical consequences of all information and data generated. The complexity of the physiological and pathophysiological processes and the sheer amount of information available overcharge the mental capacity of any human being and prevent a prediction of the success in clinical development. A rigorous integration of knowledge, assumption, and experimental data into computational models promises a significant improvement of the rationalization of decision making in pharmaceutical industry. We here give an overview of the current status of modeling and simulation in pharmaceutical R&D and outline the perspectives of more recent developments in mechanistic modeling. Specific modeling approaches for different biological scales ranging from intracellular processes to whole organism physiology are introduced and an example for integrative multiscale modeling of therapeutic efficiency in clinical oncology trials is showcased.

Objectives: In 1994, the US Food and Drug Administration (FDA) proposed an approach, based on extrapolation of efficacy findings from adults to the pediatric population, to maximize the use of adult data and other data when designing pediatric drug-development programs. We examined the experience of the FDA in using extrapolation to evaluate how and when it was used and any changes in scientific assumptions over time., Methods: We reviewed 370 pediatric studies submitted to the FDA between 1998 and 2008 in response to 159 written requests (166 products) issued under the Pediatric Exclusivity Provision. We identified cases in which efficacy was extrapolated from adult data or other data, we categorized the type of pediatric data required to support extrapolation, and we determined whether the data resulted in new pediatric labeling., Results: Extrapolation of efficacy from adult data occurred for 82.5% of the drug products (137 of 166). Extrapolation was defined as complete for 14.5% of the products (24 of 166) and partial for 68% of them (113 of 166). Approaches to extrapolation changed over time for 19% of the therapeutic indications studied (13 of 67). When extrapolation was used, 61% of the drug products (84 of 137) obtained a new pediatric indication or extension into a new age group; this number decreased to 34% (10 of 29) when there was no extrapolation., Conclusions: Extrapolating efficacy from adult data or other data to the pediatric population can streamline pediatric drug development and help to increase the number of approvals for pediatric use.

In the field of pharmacogenetics, we currently have a few markers to guide physicians as to the best course of therapy for patients. For the most part, these genetic variants are within a drug metabolizing enzyme that has a large effect on the degree or rate at which a drug is converted to its metabolites. For many drugs, response and toxicity are multi-genic traits and understanding relationships between a patient's genetic variation in drug metabolizing enzymes and the efficacy and/or toxicity of a medication offers the potential to optimize therapies. This review will focus on variants in drug metabolizing enzymes with predictable and relatively large impacts on drug efficacy and/or toxicity; some of these drug/gene variant pairs have impacted drug labels by the United States Food and Drug Administration. The challenges in identifying genetic markers and implementing clinical changes based on known markers will be discussed. In addition, the impact of next generation sequencing in identifying rare variants will be addressed.

The Human Genome and the Hap Map Projects as well as the extensive use of deep resequencing worldwide, have contributed to a massive catalogue of reported single nucleotide polymorphisms (SNPs) and other genetic variations in the human genome. Pharmacogenomics is an emerging field that combines genetics with pharmacokinetics and pharmacodynamics of the drug in attempt to understand inter-individual differences among patients and develop more accurate drug dosing. However, only for the minority of those variations an association with phenotype has been established. Here, we provide an overview of genes and genetic variants that influence inter-individual dosing of three of the most widely used drugs, namely warfarin, irinotecan and thiopurine drugs, to highlight a tangible benefit of translating genomic knowledge into clinical practice. Therefore, particular SNPs in vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 2C9 (CYP2C9), uridine diphosphate glucoronosyltransferase 1A1 (UGT1A1) and thiopurine S-methyltransferase (TPMT) genes has proven to be applicable for optimising the dosage in pursuit of maximum efficacy and minimum adverse effects. Thus, they set an important paradigm of implementation of pharmacogenomics in the mainstream clinical practice.

Increasing numbers of proteins, nucleic acids and other molecular entities have been explored as therapeutic targets, hundreds of which are targets of approved and clinical trial drugs. Knowledge of these targets and corresponding drugs, particularly those in clinical uses and trials, is highly useful for facilitating drug discovery. Therapeutic Target Database (TTD) has been developed to provide information about therapeutic targets and corresponding drugs. In order to accommodate increasing demand for comprehensive knowledge about the primary targets of the approved, clinical trial and experimental drugs, numerous improvements and updates have been made to TTD. These updates include information about 348 successful, 292 clinical trial and 1254 research targets, 1514 approved, 1212 clinical trial and 2302 experimental drugs linked to their primary targets (3382 small molecule and 649 antisense drugs with available structure and sequence), new ways to access data by drug mode of action, recursive search of related targets or drugs, similarity target and drug searching, customized and whole data download, standardized target ID, and significant increase of data (1894 targets, 560 diseases and 5028 drugs compared with the 433 targets, 125 diseases and 809 drugs in the original release described in previous paper). This database can be accessed at http://bidd.nus.edu.sg/group/cjttd/TTD.asp.

Guidelines for the safe administration of drugs through an enteral feeding tube are available, but research shows that often nurses don't adhere to them. This can lead to medication error and tube obstruction, reduced drug effectiveness, and an increased risk of toxicity. This article describes the factors to consider before administering a drug through a feeding tube, examines the gap between recommended and common practice, and discusses what the most recent guidelines recommend and why.

Some issues on the formulation of Standardized manipulations of acupuncture and moxibustion-part 6: acupoint injection are debated in this paper, including the definition of acupoint injection, characteristics of the standard and application of technical index etc. In the paper, the authors suggest that the issues on the selecting acupoints and drugs should be paid attention during the standard in use. Finally, the authors propose that the technical description of the acupoint injection in the reported literatures needs to be improved in order to better serve for clinical and scientific research.

In studies that use DNA arrays to assess changes in gene expression, it is preferable to measure the significance of treatment effects on a group of genes from a pathway or functional category such as gene ontology terms (GO terms, http://www.geneontology.org) because this facilitates the interpretation of effects and may markedly increase significance. A modified meta-analysis method to combine p-values was developed to measure the significance of an overall treatment effect on such functionally-defined groups of genes, taking into account the correlation structure among genes. For hypothesis testing that allows gene expression to change in both directions, p-values are calculated under the null distribution generated by a Monte Carlo method. As a test of this procedure, we attempted to distinguish altered pathways in microarray studies performed with Mitochips, oligonucleotide microarrays specific to mitochondrial DNA-encoded transcripts. We found that our analytic method improves the specificity of selection for altered pathways, due to incorporation of the inter-gene correlation structure in each pathway. It is thus a practical method to measure treatment effects on GO groups. In many actual applications, microarray experiments measure treatment effects under complicated design structures and with small sample sizes. For such applications to real data of limited statistical power, and also in computer simulations, we demonstrate that our method gives reasonable test results.

Unlabelled: Pharmaceutical industry has been striving to reduce the costs of drug development and increase productivity. Among the many different attempts, drug repositioning (retargeting existing drugs) comes into the spotlight because of its financial efficiency. We introduce IDMap which predicts novel relationships between targets and chemicals and thus is capable of repositioning the marketed drugs by using text mining and chemical structure information. Also capable of mapping commercial chemicals to possible drug targets and vice versa, IDMap creates convenient environments for identifying the potential lead and its targets, especially in the field of drug repositioning., Availability: IDMap executable and its user manual including color images are freely available to non-commercial users at http://www.equispharm.com/idmap

The current explanations for using a logarithmic scale for the dose of a chemical, administered to a biological system, have all been empirical. There is a fundamental, thermodynamic reason why a logarithmic scale must be used. The chemical potential is the effect that a chemical exerts on any system, including biological systems. The chemical potential of a chemical in any system is directly proportional to the logarithm of its activity or concentration. Lack of understanding of this concept and the consequent use of a linear scale for dose has led to misinterpretation of many biological experiments.

Several improvements on the target interval stochastic control (TISC) method are addressed for individualizing therapy. In particular, a global optimization control strategy is implemented to obtain the optimal dosage regimen, and weighting functions are introduced to balance the drug efficacy and the risk of toxicity. Since general guidance is often lacking in the determination of a weighting function, we introduce a systematic approach, i.e., the standard reference gamble method of medical decision theory, for the determination of the weighting function. The population model for the individualization of theophylline therapy reported by D'Argenio and Katz is applied in this research. The present method of the integration of weighting functions and global optimal strategy offer an effective and safe means to balance the drug efficacy and risk of toxicity. In addition, it also achieves better accuracy than the existing TISC method which uses a local optimal strategy.

Metabolic profiling (metabonomics/metabolomics) is the untargeted analysis of metabolic composition in a biological sample, and is principally aimed at biomarker discovery. The frequent use of noninvasive biofluid analysis in metabonomics is suited to the clinic and facilitates dynamic monitoring. Analytical protocols for metabolic biomarkers are potentially robust because a metabolite is the same chemical entity irrespective of its origin, facilitating 'bench-to-bedside' translational research. Metabonomics can make an impact at several points in the drug-development process: target identification; lead discovery and optimization; preclinical efficacy and safety assessment; mode-of-action and mechanistic toxicology; patient stratification; and clinical pharmacological monitoring. This review describes and exemplifies the latest developments in each of these areas, including the impact of new data and chemical analytical techniques. The future goals for metabonomics are the validation of existing biomarkers, in terms of mechanism and translation to man, together with a focus on characterizing the individual ('personalized healthcare').

Human genome sequencing results revealed an insight into the role of human genetic variation behind differential susceptibility of human diseases, differential response to pharmacological agents and presence of varied phenotypes. This leads to the concept of personalized medicine. In the present review we have discussed the objectives and approaches for carrying out pharmacogenomics and pharmacogenetics studies. The review also incorporates the major findings categorizing the common diseases on the basis of genetic profiles and ethnic information and in establishing personalized disease diagnosis, drug responses and treatment modalities based on the genetic determinants. Overall an attempt has been made to highlight the importance of studying the genetic profiles of an individual in biomedical and pharmacogenomics research.

The use of a syringe driver to administer drugs by continuous subcutaneous infusion is common practice in the UK. Over time, drug combinations used in a syringe driver are likely to change and the aim of this survey was to obtain a more recent snapshot of practice. On four separate days, at two-week intervals, a questionnaire was completed for every syringe driver in use by 15 palliative care services. Of 336 syringe drivers, the majority contained either two or three drugs, but one-fifth contained only one drug. The median (range) volume of the infusions was 15 (9.5-48) mL, and duration of infusion was generally 24 hours. Only one combination was reported as visually incompatible, and there were 13 site reactions (4% of total). Laboratory physical and chemical compatibility data are available for less than half of the most frequently used combinations.

The pulmonary administration of drugs plays a crucial role in the management of various respiratory and systemic diseases. While the cellular properties of airway epithelial cells offer a great potential to deliver drugs into the lungs or the circulation, only little is known about the exact transport pathways. Recently, the high-affinity proton-coupled drug and peptide transporter PEPT2 was identified in the human respiratory tract. The expression of transporter mRNA and protein was localized to the airway epithelium and alveolar type II pneumocytes. In addition, transport studies revealed transporter-mediated uptake of substrates into epithelial cells indicating that the transporter is the molecular basis for the transport of peptides and peptidomimetic drugs in pulmonary epithelial cells. Since genotype analysis revealed no significant differences amongst different transporter genotypes concerning expression and function, the transporter displays an interesting novel target for pulmonary delivery of drugs.

Adverse drug reaction in patients causes more than 2 million hospitalizations including 100,000 deaths per year in the United States. This adverse drug reaction could be due to multiple factors such as disease determinants, environmental and genetic factors. In order to improve the efficacy and safety and to understand the disposition and clinical consequences of drugs, two rapidly developing fields--pharmacogenetics (focus is on single genes) and pharmacogenomics (focus is on many genes)--have undertaken studies on the genetic personalization of drug response. This is because many drug responses appear to be genetically determined and the relationship between genotype and drug response may have a very valuable diagnostic value. Identification and characterization of a large number of genetic polymorphisms (biomarkers) in drug metabolizing enzymes and drug transporters in an ethnically diverse group of individuals may provide substantial knowledge about the mechanisms of inter-individual differences in drug response. However, progress in understanding complex diseases, its negative psychosocial consequences, violation of privacy or discrimination, associated cost and availability and its complexity (extensive geographic variations in genes) may become potential barriers in incorporating this pharmacogenetic data in risk assessment and treatment decisions. In addition, it requires increased enthusiasm and education in the clinical community and an understanding of pharmacogenetics itself by the lay public. Although individualized medications remain as a challenge for the future, the pharmacogenetic approach in drug development should be still continued. If it becomes a reality, it delivers benefits to improve public health and allow genetically subgroup diseases thereby avoiding adverse drug reactions (by knowing in advance who should be treated with what drug and how).

Previous data clearly showed profound differences in nursing practices and techniques within the state of Texas regarding the administration of medications through enteral feeding catheters (EFCs) between long-term care (LTC) facilities that predominantly serve a rural vs an urban population. This study aims to determine the incidence and characteristics of medication administration through EFCs in the LTC setting in the United States with particular emphasis on the delineation between practices in facilities that predominantly serve a rural vs an urban population. A 36-item validated survey was mailed to the Directors of Nursing of the 16,400 LTC facilities registered with the U.S. Medicare LTC facility database registry. In all, 1278 (7.8%) surveys were included in this analysis. The majority of nurses responding were RNs (93%), with extensive years of experience (19 years), working in facilities predominantly serving a rural area (58%). There were significant differences between rural and urban facilities with regard to the percent of patients receiving medications through EFCs (6.6% vs 9.0%, p < .0001), number of oral medications/day (8.3 vs 9.4, p = .0003), amount of flush before and after administering medications (64 mL vs 59 mL, p = .0127), those attending a seminar/in-service on medication administration through EFCs (45% vs 56%, p < .0001), and medication obstruction rate (6.4% vs 3.9%, p = .0227). Medication obstruction rate was significantly increased when nurses used 3 or more inappropriate techniques (8.1% vs 4.8%, p = .0171), particularly crushing enteric-coated (8.9% vs 4.6%, p = .0003) and sustained-release dosage forms (8.5% vs 4.7%, p < .0001). Medication obstruction through EFCs is significantly increased when 3 or more inappropriate techniques are utilized. Techniques, complications, and sources of information vary significantly from rural to urban facilities and various parts of the country. A universal set of guidelines to administer medications through EFCs should be adopted and widely disseminated particularly to LTC facilities in rural areas.

Women substantially outnumber men among older Americans. Among the noninstitutionalized U.S. population age 65-74, for every 100 men there are 120 women. Among those age 75-84, for every 100 men there are nearly 150 women, and among those age >/=85, for every 100 men there are nearly 220 women. Among the population of nursing home residents, the sex ratios are even more dramatic. For those age 65-74 who reside in U.S. nursing homes, for every 100 men there are 132 women. Among residents of nursing homes age 75-84, for every 100 men there are 246 women, and among those age >/=85, for every 100 men there are 425 women. Unless gender-based differences in mortality narrow, the age-related demographic shifts that are occurring in the United States will remain overwhelmingly female. In considering any health-related issue in the geriatric patient population, a special focus on women is absolutely required. This is especially true with regard to pharmacotherapy in the geriatric population.

Recommendations for the safe handling of hazardous drugs have been available for more than twenty years. Evidence for continued risk of occupational exposure is abundant; however, nurses' use of the recommended precautions is not universal. This may be related to a lack of information or to a lack of serious concern for the potential hazards. This article includes a discussion of current issues related to handling hazardous drugs in the workplace and a review of the history of safe handling guidelines, current recommendations, and barriers to implementing guidelines in health care settings.

Objective: To evaluate the effectiveness and financial impact of a drug dose consolidation (optimization) program using letter intervention., Methods: This pilot program in a large, mid-Atlantic health plan utilized a randomized controlled trial research design. A review of adjudicated pharmacy claims records was performed monthly for 3 consecutive months from November 2002 through February 2003 to identify inefficient (i.e., >once-daily) regimens for any one of 68 dosage strengths of 37 single-source maintenance drugs with once-daily dosing recommendations. Prescribers who had prescribed one or more inefficient regimens were identified and randomized to one of the 2 intervention arms or a control arm. Prescribers in both intervention arms were sent personalized letters with information on their patients. inefficient regimens and suggested dose consolidation options. Patients of prescribers in one intervention arm received a complementary, patient-oriented letter. Pharmacy claims for patients in all arms were examined at 180 days after the date of the letter mailing for conversion to an efficient (once-daily) regimen. Financial modeling analysis calculated net savings as changes in pharmacy expenditures minus administrative costs., Results: A total of 2,614 inefficient regimens, representing 6.7% of claims for the targeted medications, were identified. The rate of consolidation to a suggested dosing option was lower for the Physician Letter arm (7.3%) than for the Physician/Member Letter arm (10.2%) (P = 0.046). Both intervention arms had higher consolidation rates than the Control arm (3.9%) (P = 0.018 and P = 0.000, respectively.). Approximately 30% of the regimens in each study arm were never refilled after being targeted. Financial modeling indicated that a dose consolidation intervention could save 0.03 dollars to 0.07 dollars per member per month (PMPM) in 2003 dollars with full medication compliance but only 0.02 dollars to 0.03 dollars PMPM when savings were calculated with realistic, partial compliance rates. Subanalyses performed at the drug therapy class level revealed few opportunities to justify implementing a dose consolidation program., Conclusions: After taking into consideration program administrative costs, high rates of refill discontinuation, and dose consolidation that occurs naturally without intervention, the results indicated that a letter-based dose consolidation program did not appreciably decrease pharmacy expenditures.

Drug development is a risky business, and the final product can have serious, sometimes deadly flaws. But by focusing on fixing those flaws, companies are catapulting themselves to profitability.

Erythrocytes are potential biocompatible vectors for different bioactive substances, including drugs. These can be used successfully as biological carriers of drugs, enzymes and peptides. There are currently diverse methods that permit drug encapsulation in erythrocytes with an appropriate yield. The methods most commonly employed are based on a high-haematocrit dialysis procedure, mainly hypo-osmotic dialysis. Erythrocytes loaded with drugs and other substances allow for different release rates to be obtained. Encapsulation in erythrocytes significantly changes the pharmacokinetic properties of drugs in both animals and humans, enhancing liver and spleen uptake and targeting the reticulo-endothelial system (RES). Amongst other applications, erythrocytes have been used for drug-targeting the RES with aminoglycoside antibiotics; the selective transport to certain organs and tissues of certain antineoplastic drugs, such as methotrexate, doxorubicine, etoposide, carboplatin, etc.; the encapsulation of angiotensin-converting enzyme (ACE) inhibitors, systemic corticosteroids, the encapsulation of new prodrugs with increased duration of action, etc. Erythrocytes are also attractive systems in the sense of their potential ability to deliver proteins and therapeutic peptides. Thus, erythrocytes have been used for the transport of enzymes destined for the correction of metabolic alterations as l-asparaginase, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (AlDH) among others. Erythrocytes have been used successfully as carriers of anti-HIV peptides, such as AZT, nucleoside analogues, antisense oligonucleotides, antineoplastic peptides, erythropoietin, interleukin 3, etc. Amongst other applications, mention may be made of paramagnetic erythrocytes, encapsulation of MRI contrast agents or the study of the metabolism of the red cell. Although erythrocytes have been applied with different uses in human medicine, their deployment is still very limited due to difficulties involving storage, its exposure to contamination and the absence of a validated industrial procedure for its preparation.

Biosimulation software is being used in pharmaceutical drug development to mimic diseases. Virtual clinical trials of new developing pharmaceutical drugs can be conducted on computers running disease simulations. Using virtual patients instead of clinical research patients can save both time and money for pharmaceutical companies in their search to discover new drugs and bring them to market. In the future, this type of research will be commonplace.

Engineering delivery systems of therapeutic agents has grown into an independent field, transcending the scope of traditional disciplines and capturing the interest of both academic and industrial research. At the same time, the acceleration in the discovery of new therapeutic moieties (chemical, biological, genetic and radiological) has led to an increasing demand for delivery systems capable of protecting, transporting, and selectively depositing those therapeutic agents to desired sites. The vast majority of delivery systems physically reside in the colloidal domain, while their surface properties and interfacial interactions with the biological milieu critically determine the pharmacological profiles of the delivered therapeutic agents. Interestingly though, the colloidal and surface properties of delivery systems are commonly overlooked in view of the predominant attention placed on the therapeutic effectiveness achieved. Moreover, the development and evaluation of novel delivery systems towards clinical use is often progressed by serendipity rather than a systematic design process, often leading to failure. The present article will attempt to illustrate the colloid and interfacial perspective of a delivery event, as well as exemplify the vast opportunities offered by treating, analysing and manipulating delivery systems as colloidal systems. Exploring and defining the colloid and surface nature of the interactions taking place between the biological moieties in the body and an administered delivery vehicle will allow for the rational engineering of effective delivery systems. A design scheme is also proposed on the way in which the engineering of advanced delivery systems should be practiced towards their transformation from laboratory inventions to clinically viable therapeutics. Lastly, three case studies are presented, demonstrating how rational manipulation of the colloidal and surface properties of delivery systems can lead to newly engineered systems relevant to chemotherapy, gene therapy and radiotherapy.