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Membrane-protein NMR occupies a unique niche for determining structures, assessing dynamics, examining folding, and studying the binding of lipids, ligands and drugs to membrane proteins. However, NMR analyses of membrane proteins also face special challenges that are not encountered with soluble proteins, including sample preparation, size limitation, spectral crowding and sparse data accumulation. This Perspective provides a snapshot of current achievements, future opportunities and possible limitations in this rapidly developing field.

Abuse-deterrent formulations are one strategy for mitigating the epidemic of prescription opioid abuse. Regulatory guidance documents describe the requirements for developing abuse-deterrent formulations of novel drugs and formulations; however, they do not address "abuse-deterrence equivalence" for generic formulations. As generics may be produced with different excipients and formulations compared to reference drugs, differences in their properties may impact their abuse-deterrent features. Currently, it is unclear what specific studies are needed to support generic abuse-deterrence claims. This commentary outlines several recommendations on the in vitro and in vivo testing required, including the conditions for conducting a human abuse potential study.

Rationale: Parenteral nutrition (PN) may be provided through compounded or premixed solutions., Objective: To determine the proportion of stable custom-compounded PN prescriptions that would fit within a 20% deviance of an existing premixed PN solution., Methods: A retrospective study design was used. Inpatients who received PN in non-critical care units in the preceding year were screened for eligibility. Results are reported descriptively as means (95% confidence intervals) and proportions., Results: We reviewed 97 PN prescriptions that met inclusion criteria. Stable hospital PN prescriptions compared with the reference premixed prescription provided 1838 (1777-1898) vs 1843 (1781-1905) kcal/d, P = .43; dextrose, 266 (254-277) vs 225 (216-234) g/d, P < .001; amino acids, 100 (95.9-104) vs 95.2 (91.7-98.7) g/d, P < .001; and lipids, 53.2 (51.3-55.1) vs 76.5 (73.8-79.2) g/d, P < .001. Fifty-eight of 97 (59.8%) matched for 2 of 3 macronutrients. Hospital compared with premixed lipid was lower 53.6 (43-64.2) g/d vs 75.5 (60.5-90.5) g/d, P < .001. Electrolytes differed between hospital and premixed solutions: sodium, 98.6 (95.0-102) vs 66.9 (64.6-69.9) mmol/L, P < .001; potassium, 93.7 (89.0-98.3) vs 57.4 (55.4-59.4) mmol/L, P < .001; and magnesium, 5.4 (4.8-5.4) vs 7.6 (7.4-7.9) mmol/L., Conclusions: Calories and protein were remarkably similar, but dextrose, lipid, and electrolytes differed between hospital PN and the reference premixed prescription. We believe that there may be a role for premixed solutions in quaternary centers in stable non-critically ill patients., (© 2016 American Society for Parenteral and Enteral Nutrition.)

Background and Aims: Hyperphosphatemia increases the risk of cardiovascular morbidity but the use of medicines as a source of phosphate has not been investigated yet. This study aims to explore the use of absorbable phosphate-containing drugs in CKD patients., Methods and Results: Incident CKD patients were identified within the Arianna database (containing data from 158,510 persons in Caserta (Southern Italy) registered with 123 general practitioners) from 2005 to 2011. Drugs prescribed to these patients were classified as phosphate-containing based on the summary of product characteristics (SPC), PubChem and Micromedex. The number and duration of prescriptions for these drugs as well as the overall intake of phosphate were estimated. Out of 1989 CKD patients, 1381 (70%) were prescribed 266 medicinal products containing absorbable phosphate over a median follow-up of 6 years (interquartile range (IQR) = 5.2-6.0). Most patients were prescribed ATC A (650; 47.1%) and C (660; 47.8%) phosphate-containing drug products targeting the gastrointestinal and cardiovascular system for a median of 232 (IQR: 56-656) and 224 (IQR: 56-784) days respectively., Conclusions: Several medications, especially chronically prescribed ones, contain absorbable phosphate. This study's findings confirm the relevance of medicines as a phosphate source for the first time., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Many drugs are carbon-based, and carbon-hydrogen bonding is particularly relevant for understanding important properties of drug molecules. Deuteration refers to the selective replacement of protium hydrogen isotope atoms in small-molecule drugs with deuterium hydrogen isotope atoms. Deuteration of a drug is most likely to affect pharmacokinetic properties, such as metabolism, rather than its pharmacodynamic effects. For this reason, the metabolism of certain drugs may be favorably influenced when deuterium is substituted for protium, resulting in improved safety, tolerability, or efficacy. Examples of deuterated drugs that have been evaluated in clinical studies include paroxetine, tetrabenazine, and dextromethorphan., (Copyright 2015, SLACK Incorporated.)

A high dietary intake of phosphorus is considered by most to be a significant health threat for dialysis patients. Efforts to include the phosphorus content of foods on the nutrition label in the US have, to date, been fruitless. Another source of phosphorus, largely unrecognized, is prescription medications. These may contain phosphorus as indicated on their package label; the amount is not quantified. We examined the labels of the branded forms of 200 of the most widely prescribed medications in Dialysis Clinic centers in the United States and found that 23 (11.5%) contained phosphorus. A sampling of different doses and manufacturers (generic and branded) of these drugs was analyzed for phosphorus content and found levels as high as 111.5 mg/dose (40 mg paroxetine). Notable were the phosphorus content of a generic 10 mg lisinopril (32.6 mg) and a generic 10 mg amlodipine (40.1 mg). The significant potential for iatrogenic injury accruing from the use of these drugs warrants efforts at remediation. Specific information on the phosphorus content of medications used by dialysis population needs to be made available to the dialysis community.

Importance: In an effort to reduce wide-scale abuse of the proprietary oxycodone hydrochloride formulation OxyContin, an abuse-deterrent formulation (ADF) was introduced in 2010. Although the reformulation produced an immediate drop in abuse rates, a definite ceiling effect appeared over time, beyond which no further decrease was seen., Objective: To examine the factors that led to the initial steep decline in OxyContin abuse and the substantial levels of residual abuse that have remained relatively stable since 2012., Design, Setting, and Participants: We used data from the ongoing Survey of Key Informants' Patients program, part of the Researched Abuse, Diversion and Addiction-Related Surveillance system that collects and analyzes postmarketing data on misuse and diversion of prescription opioid analgesics and heroin. For our survey study, patients with a DSM-V diagnosis of opioid use disorder and primary drug of abuse consisting of a prescription opioid or heroin (N = 10,784) at entry to 1 of 150 drug treatment programs in 48 states completed an anonymous structured survey of opioid abuse patterns (surveys completed from January 1, 2009, through June 30, 2014). A subset of these patients (n = 244) was interviewed to add context and expand on the structured survey., Main Outcomes and Measures: In addition to key demographic measures, past-month abuse of opioids was the primary measure in the structured surveys. In the interviews, the effect of the introduction of the ADF on drug-seeking behavior was examined., Results: Reformulated OxyContin was associated with a significant reduction of past-month abuse after its introduction (45.1% [95% CI, 41.2%-49.1%] in January to June 2009 to 26.0% [95% CI, 23.6%-28.4%] in July to December 2012; P < .001; χ(2) = 230.83), apparently owing to a migration to other opioids, particularly heroin. However, this reduction leveled off, such that 25% to 30% of the sample persisted in endorsing past-month abuse from 2012 to 2014 (at study end [January to June 2014], 26.7% [95% CI, 23.7%-29.6%]). Among the 88 participants who indicated experience using pre-ADF and ADF OxyContin, this residual level of abuse reflects the following 3 phenomena: (1) a transition from nonoral routes of administration to oral use (38 participants [43%]); (2) successful efforts to defeat the ADF mechanism leading to a continuation of inhaled or injected use (30 participants [34%]); and (3) exclusive use of the oral route independent of formulation type (20 participants [23%])., Conclusions and Relevance: Abuse-deterrent formulations can have the intended purpose of curtailing abuse, but the extent of their effectiveness has clear limits, resulting in a significant level of residual abuse. Consequently, although drug abuse policy should focus on limiting supplies of prescription analgesics for abuse, including ADF technology, efforts to reduce supply alone will not mitigate the opioid abuse problem in this country.

Objective: To quantify the potential impact of reductions in positive subjective measures from human abuse liability studies on real-world rates of nonmedical use of prescription drugs and associated healthcare resource utilization and costs., Design: Positive subjective endpoints "overall drug liking," in-the-moment "drug liking," and "drug high" Emaxs (peak effects) were recorded from published studies. Nonmedical use data were obtained from the 2010 National Survey on Drug Use and Health (NSDUH) and Drug Abuse Warning Network surveys. Multivariate regressions evaluated the association between the positive subjective endpoints and nonmedical use rates, controlling for prescription volume, whether the drug is an opioid, and controlled substance schedule. A published budget-impact model was used to assess healthcare resource utilization and cost impacts of abuse-deterrent opioid formulations., Results: A five-point reduction in overall drug liking/drug liking/drug high Emax was associated with a 0.25/0.10/0.05 (standard errors: 0.11/0.12/0.07) percentage point decrease in the NSDUH lifetime nonmedical use rates. Those decreases yielded a 11.3/4.2/2.1 percent reduction compared to the samples' lifetime nonmedical use rates of 2.21/2.38/2.36 percent. On the basis of a number of assumptions, these reductions were associated with private payer cost reductions for a morphine and oxycodone abuse-deterrent formulation in the ranges of $147.9-324.1 million and $230.7-958.7 million, respectively., Conclusions: Reductions in overall drug liking were significantly associated with reduced real-world nonmedical use, healthcare utilization, and costs. Associations using drug high and drug liking were directionally consistent with this finding though not statistically significant. A reduction in positive subjective measures associated with an abuse-deterrent formulation has potential to reduce abuse and associated healthcare utilization and costs.

Introduction: Gastric access devices such as nasogastric tubes and gastrostomy tubes are increasingly being used in clinical practice to provide both short- and long-term nutrition support therapy. Increasingly these devices are being utilized to help deliver oral medications, where swallowing is impaired. This concomitant administration of medications and enteral formulas could derive potential benefits in regard to time and cost; however, uncertainty exists regarding potential drug and nutrient interactions and the influence this may have on both safety and efficacy., Areas Covered: This article provides an overview of the differing gastric access devices used in clinical practice and evaluates the evidence base for using oral medications via these routes. Alternative methods of drug administration are discussed, alongside common drug nutrient interactions and potential complications., Expert Opinion: Delivering medications via gastric access devices can be performed safely; however, careful consideration needs to be made regarding tube and patient influences, alongside drug-nutrient interactions. Improving practice in this area in the future necessitates enhancement of an evidence base to substantiate the safety of drug delivery via gastric access devices and improvement in education among healthcare professionals about the potential problems.

Background and Overview: Oral adverse events such as cariogenicity are often overlooked as drug-associated effects because the sugar content of many medications may be negligible compared with the patients' overall dietary intake of sugar. There are, however, several liquid formulations of medications with significantly high sugar content that are commonly used in patients with swallowing difficulties. These medications may be associated with negative oral health sequelae and should be considered part of the oral health care providers' differential diagnosis of oral pathologies., Methods: We reviewed the literature regarding the sugar content of oral liquid medications commonly prescribed by oral health care providers, with consideration to their caries potential. Where not available via public sources, pharmaceutical companies were contacted directly for additional information on the sugar (carbohydrate) content of these oral liquid medication formulations., Results: Over 50 commonly used oral liquid medications prescribed for patients with swallowing difficulties were reviewed and found to contain sugar in varying amounts up to 4 grams per dose (usually 1 teaspoon or 5 milliliters). Patients who are required to take multiple doses per day of these sugar-containing oral liquid medications may be at increased risk for caries and associated oral health consequences., Conclusions and Practical Implications: Recognition and avoidance of sugar-containing oral liquid medications can help clinicians optimize patient treatment, decreasing the risk for potential drug-induced caries while emphasizing patient safety and improved oral health., (Copyright © 2015 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Purpose: The establishment of a database for the identification of the presence of gluten in excipients of prescription medications is described., Summary: While resources are available to ascertain the gluten content of a given medication, these resources are incomplete and often do not contain a source and date of contact. The drug information service (DIS) at Robert Wood Johnson University Hospital (RWJUH) determined that directly contacting the manufacturer of a product is the best method to determine the gluten content of medications. The DIS sought to establish a resource for use within the institution and create directions for obtaining this information from manufacturers to ensure uniformity of the data collected. To determine the gluten content of a medication, the DIS analyzed the manufacturer's package insert to identify any statement indicating that the product contained gluten or inactive ingredients from known sources of gluten. If there was any question about the source of an inactive ingredient or if no information about gluten content appeared in the package insert, the manufacturer of the particular formulation of the queried medication was contacted to provide clarification. Manufacturers' responses were collected, and medications were categorized as "gluten free," "contains gluten," or "possibly contains gluten." To date, the DIS at RWJUH has received queries about 84 medications and has cataloged their gluten content., Conclusion: The DIS at RWJUH developed a database that categorizes the gluten status of medications, allowing clinicians to easily identify drugs that are safe for patients with celiac disease., (Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

With the demand to enhance the speed of the drug discovery process there has been an increased usage of computational approaches in drug discovery studies. However because of their probabilistic outcomes, the challenge is to exactly mimic the natural environment which can provide the exact charge polarization effect while estimating the binding energy between protein and ligand. There has been a large number of scoring functions from simple one to the complex one available for estimating binding energy. The quantum mechanics/molecular mechanics (QM/MM) hybrid approach has been the preferred choice of interest since last decade for modeling reactions in biomolecular systems. The application of QM/MM approach has been expanded right from rescoring the already known complexes and depicting the correct position of some novel molecule to ranking a large number of molecules. It is expected that the application of QM/MM-based scoring will grow in all areas of drug discovery. However, the most promising area will be its application in repositioning, that is, assigning novel functions or targets to the already existing drugs, as this would stop the rising attrition rates as well as reduce the overall time and cost of drug discovery procedure., (© 2015 Elsevier Inc. All rights reserved.)

This study presents a showcase for the novel Quantum Chemistry Electron Ionization Mass Spectrometry (QCEIMS) method on five FDA-approved drugs. The method allows a first-principles electronic structure-based prediction of EI mass spectra in principle for any molecule. The systems in this case study are organic substances of nominal masses between 404 and 853 atomic mass units and cover a wide range of functional groups and organic molecular structure motifs. The results demonstrate the widespread applicability of the QCEIMS method for the unbiased computation of EI mass spectra even for larger molecules. Its strengths compared to standard (static) or database driven approaches in such cases are highlighted. Weak points regarding the required computation times or the approximate character of the employed QC methods are also discussed. We propose QCEIMS as a viable and robust way of predicting EI mass spectra for sizeable organic molecules relevant to medicinal and pharmaceutical chemistry.

Objective: This study was intended to assess the knowledge, attitude and practice of pediatricians and pharmacists about sugar free medications (SFMs) and their impact on oral health., Materials and Methods: Self-administered close ended questionnaire was handed out to all pediatricians and pharmacists in five tertiary hospitals in Riyadh (King Khalid University Hospital, King Saud Medical City, King Fahad Medical City, Prince Sultan Medical Military City, Security Forces Hospital) to investigate the knowledge, attitude and practice concerning SFMs., Results: Eighty-five pediatricians and 77 pharmacists participated in this study. The results showed that pediatricians and pharmacists have a good knowledge, but negative attitude toward SFMs. Only (5.9%) of pediatricians had formal undergraduate training which is significantly lower than pharmacists (15.6%) (p = 0.04). One-third of pediatricans and pharmacists prescribe or dispense SFMs. The most influencing factors toward prescription (pediatrician) of SFMs was the medical status of the patient (70.6%), while the most influencing factor of dispensing (pharmacists) SFMs was the availability in the pharmacy (64.9%). Two-third of pediatricians (67%) guide the parents about the risk associated with sugar-containing medications (SCMs) which is significantly higher than pharmacists (p < 0.0001). Also, 53% of pediatricians recommend oral hygiene instructions when prescribing SCMs which is also significantly higher than pharmacists (p = 0.0 02)., Conclusion: There is a considerable knowledge about SFMs and its impact on dental caries, among pediatricians and pharmacists participated in this study. However, their attitude toward prescribing or dispensing SFMs was not positive and may be linked to the gap in knowledge. Further training and education of healthcare providers regarding the use of SFMs and its negative impact on dental caries has to be reiterated.

Two factors contribute to the inefficiency associated with screening pharmaceutical library collections as a means of identifying new drugs: [1] the limited success of virtual screening (VS) methods in identifying new scaffolds; [2] the limited accuracy of computational methods in predicting off-target effects. We recently introduced a 3D shape-based similarity algorithm of the SABRE program, which encodes a consensus molecular shape pattern of a set of active ligands into a 4D fingerprint descriptor. Here, we report a mathematical model for shape similarity comparisons and ligand database filtering using this 4D fingerprint method and benchmarked the scoring function HWK (Hamza-Wei-Korotkov), using the 81 targets of the DEKOIS database. Subsequently, we applied our combined 4D fingerprint and HWK scoring function VS approach in scaffold-hopping and drug repurposing using the National Cancer Institute (NCI) and Food and Drug Administration (FDA) databases, and we identified new inhibitors with different scaffolds of MycP1 protease from the mycobacterial ESX-1 secretion system. Experimental evaluation of nine compounds from the NCI database and three from the FDA database displayed IC50 values ranging from 70 to 100 μM against MycP1 and possessed high structural diversity, which provides departure points for further structure-activity relationship (SAR) optimization. In addition, this study demonstrates that the combination of our 4D fingerprint algorithm and the HWK scoring function may provide a means for identifying repurposed drugs for the treatment of infectious diseases and may be used in the drug-target profile strategy.

Desorption electrospray ionization (DESI) was coupled to an ambient pressure drift tube ion mobility time-of-flight mass spectrometer (IM-TOFMS) for the direct analysis of active ingredients in pharmaceutical samples. The DESI source was also coupled with a standalone IMS demonstrating potential of portable and inexpensive drug-quality testing platforms. The DESI-IMS required no sample pretreatment as ions were generated directly from tablets and cream formulations. The analysis of a range of over-the-counter and prescription tablet formations was demonstrated for amphetamine (methylphenidate), antidepressant (venlafaxine), barbiturate (Barbituric acid), depressant (alprazolam), narcotic (3-methylmorphine) and sympatholytic (propranolol) drugs. Active ingredients from soft and liquid formulations, such as Icy Hot cream (methyl salicylate) and Nyquil cold medicine (acetaminophen, dextromethorphan, doxylamine) were also detected. Increased sensitivity for selective drug responses was demonstrated through the formation of sodiated adduct ions by introducing small quantities of NaCl into the DESI solvent. Of the drugs and pharmaceuticals tested in this study, 68% (22 total samples) provided a clear ion mobility response at characteristic mobilities either as (M + H)(+), (M - H)(-), or (M + Na)(+) ions.

A reversed-phase high-performance liquid chromatography method was developed for the simultaneous determination of the diuretic, hydrochlorothiazide, along with six drugs representing the most commonly prescribed antihypertensive pharmacological classes such as atenolol, a selective β1 blocker, amlodipine besylate, a calcium channel blocker, moexipril hydrochloride, an angiotensin-converting-enzyme inhibitor, valsartan and candesartan cilexetil, which are angiotensin II receptor blockers, and aliskiren hemifumarate, a renin inhibitor, using irbesartan as an internal standard. The chromatographic separation was achieved using acetonitrile/sodium phosphate dibasic buffer (0.02 M, pH 5.5) at a flow rate of 1 mL/min in gradient elution mode at ambient temperature on a stationary phase composed of an Eclipse XDB-C18 (4.6 × 150 mm, 5 μm) column. UV detection was carried out at 220 nm. The method was validated according to ICH guidelines. Linearity, accuracy, and precision were satisfactory over the concentration ranges of 2-40 μg/mL for hydrochlorothiazide and candesartan cilexetil, 20-120, 10-160, 5-40, 20-250, and 5-50 μg/mL for atenolol, valsartan, moexipril hydrochloride, aliskiren hemifumarate, and amlodipine besylate, respectively. The method was successfully applied for the determination of each of the studied drugs in their combined formulations with hydrochlorothiazide. The developed method is suitable for the quality control and routine analysis of the cited drugs in their pharmaceutical dosage forms., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Excipients in various formulations of active drugs occasionally include known contact allergens. Their ingestion may trigger dermatitis or cause it to become widespread or refractory to therapy., Objective: The aim of this study was to investigate the prevalence of common contact allergens among the excipients of oral antihistamines available in this country., Methods: We gathered the complete ingredient lists of 2119 different preparations of 12 oral antihistamines from the National Library of Medicine data bank and entered them into an electronic database for analysis., Results: More than half the formulations (55.0%) contained at least 1 member of the 10 allergen families assessed. Most brompheniramine and doxepin preparations included potentially allergenic excipients, whereas fexofenadine was most often free of them. Sorbitan group members, azo dyes, and propylene glycol were the allergens found most frequently in the antihistamines, each present in over 25% of the products. Elixirs, liquids, solutions, suspensions, and syrups were more likely than nonchewable caplets, capsules, and tablets to contain the allergens tabulated (100% vs 39.3%, respectively). Chewable pills frequently contained azo dyes., Conclusions: Ingestion of antihistamines could precipitate a systemic contact dermatitis in a patient sensitized to an allergen present as an excipient in the medicine.

Quantitative analysis of known drug-target interactions emerged in recent years as a useful approach for drug repurposing and assessing side effects. In the present study, we present a method that uses probabilistic matrix factorization (PMF) for this purpose, which is particularly useful for analyzing large interaction networks. DrugBank drugs clustered based on PMF latent variables show phenotypic similarity even in the absence of 3D shape similarity. Benchmarking computations show that the method outperforms those recently introduced provided that the input data set of known interactions is sufficiently large--which is the case for enzymes and ion channels, but not for G-protein coupled receptors (GPCRs) and nuclear receptors. Runs performed on DrugBank after hiding 70% of known interactions show that, on average, 88 of the top 100 predictions hit the hidden interactions. De novo predictions permit us to identify new potential interactions. Drug-target pairs implicated in neurobiological disorders are overrepresented among de novo predictions.

Earlier (Kireeva et al. Mol. Inf. 2012, 31, 301-312), we demonstrated that generative topographic mapping (GTM) can be efficiently used both for data visualization and building of classification models in the initial D-dimensional space of molecular descriptors. Here, we describe the modeling in two-dimensional latent space for the four classes of the BioPharmaceutics Drug Disposition Classification System (BDDCS) involving VolSurf descriptors. Three new definitions of the applicability domain (AD) of models have been suggested: one class-independent AD which considers the GTM likelihood and two class-dependent ADs considering respectively, either the predominant class in a given node of the map or informational entropy. The class entropy AD was found to be the most efficient for the BDDCS modeling. The predominant class AD can be directly visualized on GTM maps, which helps the interpretation of the model.

Mutations in drug targets can alter the therapeutic effects of drugs. Therefore, evaluating the effects of single-nucleotide polymorphisms (SNPs) on drug-target binding is of significant interest. This study focuses on the analysis of the structural and energy properties of SNPs in successful drug targets by using the data derived from HapMap and the Therapeutic Target Database. The results show the following: (i) Drug targets undergo strong purifying selection, and the majority (92.4%) of the SNPs are located far from the drug-binding sites (>12 Å). (ii) For SNPs near the drug-binding pocket (≤12 Å), nearly half of the drugs are weakly affected by the SNPs, and only a few drugs are significantly affected by the target mutations. These results have direct implications for population-based drug therapy and for chemical treatment of genetic diseases as well.

The rapidly increasing amount of publicly available data in biology and chemistry enables researchers to revisit interaction problems by systematic integration and analysis of heterogeneous data. Herein, we developed a comprehensive python package to emphasize the integration of chemoinformatics and bioinformatics into a molecular informatics platform for drug discovery. PyDPI (drug-protein interaction with Python) is a powerful python toolkit for computing commonly used structural and physicochemical features of proteins and peptides from amino acid sequences, molecular descriptors of drug molecules from their topology, and protein-protein interaction and protein-ligand interaction descriptors. It computes 6 protein feature groups composed of 14 features that include 52 descriptor types and 9890 descriptors, 9 drug feature groups composed of 13 descriptor types that include 615 descriptors. In addition, it provides seven types of molecular fingerprint systems for drug molecules, including topological fingerprints, electro-topological state (E-state) fingerprints, MACCS keys, FP4 keys, atom pair fingerprints, topological torsion fingerprints, and Morgan/circular fingerprints. By combining different types of descriptors from drugs and proteins in different ways, interaction descriptors representing protein-protein or drug-protein interactions could be conveniently generated. These computed descriptors can be widely used in various fields relevant to chemoinformatics, bioinformatics, and chemogenomics. PyDPI is freely available via https://sourceforge.net/projects/pydpicao/.

Due to the increasing rate in the demand of extemporaneous formulations, it became necessary to assess the pattern of prescription and preparation in a developing institution. The purpose of this study was to assess the pattern of extemporaneous prescription and preparation in the University of Benin Teaching Hospital, Benin City, Nigeria. Records of prescription and preparation of extemporaneous formulations were assessed retrospectively between 2007 and 2011. Fifty-nine different types of drugs were prescribed with a frequency of 6,882 times during the period. These were indicated for eight classes of systemic disease. Eighteen drugs were indicated for central nervous diseases, followed by 16 drugs for cardiovascular diseases. Of the 18 drugs indicated for central nervous diseases, pyridoxine was the most common. Rifampicin for tuberculosis was the most frequently formulated, followed by spironolactone for cardiovascular disorders. Most preparations were labeled to be used for a maximum of two weeks. They were all liquid preparations packaged in amber-colored bottles. Distilled water was the most common vehicle utilized for trituration; while ascorbic acid syrup was commonly used to bulk the solution and as a sweetening agent. None of the patients reported with any form of pharmaceutical degradation or toxicity within two weeks of expected use. There were reports of spillages due to poor handling. Maximum volume prepared was 75 mL. The study suggests an adequate setup of a quality-control unit in the institution to meet the increasing demand for specific agents. This will enhance an effective healthcare delivery among patients.

The quality of essential medicines for pediatric populations in developing countries is largely unknown. This review examines quality studies (2000-2011) of medicines on the WHO Essential Medicine List for Children, the quality of a subset of pediatric formulations, and the association of these poor quality medicines with adverse clinical outcomes. We searched Embase, Medline, BIOSIS, and IPA using MeSH subject terms for quality measures, medicine formulations, and substandard medicines and combined these with 267 medicines, and 91 low-income and lower-middle-income countries. Seventy articles met our inclusion criteria examining the quality of 75 medicines from 28 countries. Content and dissolution tests were utilized most often. Results indicate that antibacterials, antifungals, and antiretrovirals were consistently of good quality. Quality tests on pediatric formulations were performed on 55 of 75 of the medicines studied and followed the general trend of quality results. Three studies were included that examined clinical consequences of substandard medicines-two cases of diethylene glycol poisoning and one case of substandard malaria drugs. We conclude that there is a need for more quality studies of pediatric formulations of essential medicines in developing countries and their clinical consequences., (Copyright © 2013 Wiley Periodicals, Inc.)

Plasma protein binding has a profound impact on the pharmacokinetic and pharmacodynamic properties of many drug candidates and is thus an integral component of drug discovery. Nevertheless, extant methods to examine small-molecule interactions with plasma protein have various limitations, thus creating a need for alternative methods. Herein we present a comprehensive and cross-validated in silico workflow for the prediction of small-molecule binding to Human Serum Albumin (HSA), the most ubiquitous plasma protein. This protocol reliably predicts small-molecule interactions with HSA, including a binding affinity calculation using multiple linear regression methods, binding site prediction using a naive-Bayes classifier, and a three-dimensional binding pose using induced fit docking. Furthermore, this workflow is implemented in a portable and automated format that can be downloaded and used by other end users, either as is or with customization.

Prediction of polypharmacological profiles of drugs enables us to investigate drug side effects and further find their new indications, i.e. drug repositioning, which could reduce the costs while increase the productivity of drug discovery. Here we describe a new computational framework to predict polypharmacological profiles of drugs by the integration of chemical, side effect, and therapeutic space. On the basis of our previous developed drug side effects database, named MetaADEDB, a drug side effect similarity inference (DSESI) method was developed for drug-target interaction (DTI) prediction on a known DTI network connecting 621 approved drugs and 893 target proteins. The area under the receiver operating characteristic curve was 0.882 ± 0.011 averaged from 100 simulated tests of 10-fold cross-validation for the DSESI method, which is comparative with drug structural similarity inference and drug therapeutic similarity inference methods. Seven new predicted candidate target proteins for seven approved drugs were confirmed by published experiments, with the successful hit rate more than 15.9%. Moreover, network visualization of drug-target interactions and off-target side effect associations provide new mechanism-of-action of three approved antipsychotic drugs in a case study. The results indicated that the proposed methods could be helpful for prediction of polypharmacological profiles of drugs.

Low levels of pharmaceutical compounds have been detected in aquatic environments worldwide, but their human and ecological health risks associated with low dose environmental exposure is largely unknown due to the large number of these compounds and a lack of information. Therefore prioritization and ranking methods are needed for screening target compounds for research and risk assessment. Previous efforts to rank pharmaceutical compounds have often focused on occurrence data and have paid less attention to removal mechanisms such as human metabolism. This study proposes a simple prioritization approach based on number of prescriptions and toxicity information, accounting for metabolism and wastewater treatment removal, and can be applied to unmeasured compounds. The approach was performed on the 200 most-prescribed drugs in the US in 2009. Our results showed that under-studied compounds such as levothyroxine and montelukast sodium received the highest scores, suggesting the importance of removal mechanisms in influencing the ranking, and the need for future environmental research to include other less-studied but potentially harmful pharmaceutical compounds., (Copyright © 2012. Published by Elsevier Inc.)

Guanine-rich sequences found in telomeres and oncogene promoters have the ability to form G-quadruplex structures. In this paper we describe the use of a virtual screening assay to search a database of FDA-approved compounds for compounds with the potential to bind G-quadruplex DNA. More than 750 telomerase inhibitors were identified in a literature search as acting through G-quadruplex stabilization, and from evaluation of these compounds, theoretical models capable of discriminating new compounds that bind G-quadruplex DNA were developed. Six compounds predicted to bind to the G-quadruplex structure were tested for their ability to bind to the human telomeric DNA sequence. Prochloroperazine, promazine, and chlorpromazine stabilized the G-quadruplex structure as determined by fluorescence resonance energy transfer techniques. These compounds also bound to promoter sequences of oncogenes such as c-myc and K-ras. Amitriptyline, imipramine, and loxapine were less stabilizing but did bind to the G-quadruplex. The ability of prochloroperazine, promazine, and chlorpromazine to recognize G-quadruplex structures was confirmed using a fluorescent intercalator displacement assay, in which displacement of thiazole orange from G-quadruplex structures was demonstrated. Interestingly, these compounds exhibited selectivity for the G-quadruplex structure as all had poor affinity for the duplex sequence.

Molecular properties such as the molecular weight, hydrophobicity parameter logP, and the total polar surface area (TPSA) have been used extensively in modern drug discovery. We investigated these properties and ADMET scores of the top 200 therapeutic drugs by the U.S. retail sales (2010) and classified them according to the clinical indications and/or routes of administration. This list of drugs provides ample information of these molecular descriptors for successfully approved drugs. The mean logP for oral drugs is 2.5 while the logP for injectable drugs seems to be smaller. Among different types of clinical indications, drugs used for anti-HIV, and antibiotics tend to have lower logP. The molecular weights of anti-HIV drugs, antihypertensives and antibiotics appear to be larger. The ADMET scores, derived from a combination of molecular weights and logP, are consistent for oral drugs, with a mean score of 1.5 and a standard deviation of 1.0. Many clinical drugs that violate Lipinski's rule of five criteria can still exhibit ADMET scores that are very close to the mean value for oral drugs (1.5) and lie within the acceptable standard deviation. The molecular properties of MW, logP, and TPSA appear to vary according to their clinical indications. Many drugs form salts or cocrystals with acids or solvents that increase their solubility. Our data show that addition of hydrochloride is the most common method to increase solubility of drug ingredients. Cytochrome P450 isozymes 3A4, 2D6, 2C9, 2C8 and 3C5 are the top five proteins that metabolize the 200 most prescribed drugs. Drugs metabolized by 3A4 appear to have larger molecular weights and those metabolized by 2D6 have lower molecular weights. CYP2C8-metabolized drugs appear to be most hydrophilic, with the smallest logP and the largest polar surface areas.

Glucuronidation has been recognized as an important clearance mechanism in humans. Therefore, knowledge about the contribution of glucuronidation to clearance of drug candidates is of great value in early drug development. In this article, we discuss the recent progress made to predict in vivo glucuronidation parameters (e.g., hepatic clearance, and intestinal availability) using in vitro data, which are readily obtained using microsomes and hepatocytes, so called "in vitro- in vivo extrapolation" (IVIVE). Of note the intrinsic clearances obtained from microsomal incubations in the presence of bovine serum albumin (BSA) provide accurate predictions of the in vivo clearances in addition to those from hepatocytes. Further, we describe the lack of correlation between cellular and microsomal production of glucuronide and provide possible reasons. Due to the high prediction accuracy, those who study in vitro glucuronidation are encouraged to map their data to in vivo using IVIVE strategy for more informative data interpretation.

Unlabelled: The U.S. Food and Drug Administration has formally requested that pharmaceutical manufacturers limit the amount of acetaminophen (APAP) in prescription products. The goal of this study was to describe a state-wide poison control system's experience with prescription APAP ingestions that resulted in hepatic injury or death. Retrospective analysis of statewide California Poison Control System electronic database for cases from the years 2000 through 2009., Inclusion Criteria: adults ≥18 years of age following therapeutic use of an acetaminophen-containing prescription with laboratory evidence of liver injury. Forty cases met the inclusion criteria. All cases involved at least two concurrent acetaminophen-containing products. Prescription APAP strengths of 500 mg per tablet or greater were involved in 32 of 40 cases (80 %). Thirty patients survived, three died, one underwent liver transplantation and seven cases were lost to follow up. The ingestion of concentrated prescription APAP-containing medications in combination with other sources of APAP can result in severe liver injury and death. Limiting the amount of APAP from prescription medications in conjunction with enhanced prescriber and patient education regarding the hazards of ingesting multiple APAP-containing products may assist in decreasing the overall incidence of unintentional APAP poisonings in the United States. Future prospective studies are required to determine if these measures will have a significant impact on both the morbidity and mortality associated with APAP administration.

Drug molecules consist of a few tens of atoms connected by covalent bonds. How many such molecules are possible in total and what is their structure? This question is of pressing interest in medicinal chemistry to help solve the problems of drug potency, selectivity, and toxicity and reduce attrition rates by pointing to new molecular series. To better define the unknown chemical space, we have enumerated 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens forming the chemical universe database GDB-17, covering a size range containing many drugs and typical for lead compounds. GDB-17 contains millions of isomers of known drugs, including analogs with high shape similarity to the parent drug. Compared to known molecules in PubChem, GDB-17 molecules are much richer in nonaromatic heterocycles, quaternary centers, and stereoisomers, densely populate the third dimension in shape space, and represent many more scaffold types.

Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties play key roles in the discovery/development of drugs, pesticides, food additives, consumer products, and industrial chemicals. This information is especially useful when to conduct environmental and human hazard assessment. The most critical rate limiting step in the chemical safety assessment workflow is the availability of high quality data. This paper describes an ADMET structure-activity relationship database, abbreviated as admetSAR. It is an open source, text and structure searchable, and continually updated database that collects, curates, and manages available ADMET-associated properties data from the published literature. In admetSAR, over 210,000 ADMET annotated data points for more than 96,000 unique compounds with 45 kinds of ADMET-associated properties, proteins, species, or organisms have been carefully curated from a large number of diverse literatures. The database provides a user-friendly interface to query a specific chemical profile, using either CAS registry number, common name, or structure similarity. In addition, the database includes 22 qualitative classification and 5 quantitative regression models with highly predictive accuracy, allowing to estimate ecological/mammalian ADMET properties for novel chemicals. AdmetSAR is accessible free of charge at http://www.admetexp.org.

A new method for determination of L-tryptophan (L-try) using the flow injection chemiluminescence (FI-CL) system of KMnO(4)-SnCl(2)-CHOH based on a graphene oxide-magnetite-molecularly imprinted polymer (GM-MIP) is described. The L-try GM-MIP was synthesized using graphene oxide (G) which improved the adsorption capacity as carrier, and magnetite nanoparticles which made the polymers easier to use in the sensor. The adsorption performance and properties were characterized. The GM-MIP was used in CL analysis to increase the selectivity and the possible mechanism was also discussed. The CL sensor responded linearly to the concentration of L-try over the range from 2.10×10(-7) to 7.09×10(-4) M with a detection limit of 2.11×10(-8) M (3σ). The relative standard deviation (RSD) for the determination of 3.0×10(-5) M L-try was 2.40% (n=11). On the basis of speediness and sensitivity, the sensor is reusable and shows a great improvement in selectivity and adsorption capacity over other sensors. The sensor has been used for the determination of L-try in drug samples., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: Dysphagia is a swallowing disorder with a high incidence in the geriatric patient related with an increased risk for undernutrition and pneumonia due to bronchial aspiration. In this condition, it is usual to add commercial thickeners in liquids, as well as the addition of drugs in this mixture to improve their administration. However, there are no studies regarding the possible change in viscosity produced by their addition., Objectives: To assess the change in viscosity of water thickened with commercial products by adding the drugs frequently used in elderly patients., Methods: Samples of water mixed with the commercial thickener Resource (modified corn starch) or Nutilis (modified corn starch, maltodextrin, and gums: tara, xhantan, and guar) to achieve an intermediate consistence as "honey". The viscosity of these samples was measured as well as for similar samples to which one of the following drugs was added: galantamine, rivastigmin, ciprofloxacin, cholecalciferol, memantine, fosfomycin, calcium, and amoxicillin/clavulanic acid., Results: In the samples with Resource thickener we observed decreased viscosity by adding galantamine, memantine, fosfomycin or calcium, and increased viscosity with amoxicillin/clavulanic acid. The viscosity of the samples with Nutilis® decreased with galantamine, rivastigmine, amoxicillin/clavulanic acid, fosfomycin and calcium., Conclusion: The viscosity of water with commercial thickeners may be affected by some drugs or their preservatives, which may influence the swallowing capability. It is recommended to perform further in vitro and in vivo studies in order to adjust these formulations if necessary.

Background: Patients use several types of devices to measure liquid medication. Using a criterion ranging from a 10% to 40% variation from a target 5 mL for a teaspoon dose, previous studies have found that a considerable proportion of patients or caregivers make errors when dosing liquid medication with measuring devices., Objective: To determine the rate and magnitude of liquid medication dose errors that occur with patient/caregiver use of various measuring devices in a community pharmacy., Methods: Liquid medication measurements by patients or caregivers were observed in a convenience sample of community pharmacy patrons in Korea during a 2-week period in March 2011. Participants included all patients or caregivers (N = 300) who came to the pharmacy to buy over-the-counter liquid medication or to have a liquid medication prescription filled during the study period. The participants were instructed by an investigator who was also a pharmacist to select their preferred measuring devices from 6 alternatives (etched-calibration dosing cup, printed-calibration dosing cup, dosing spoon, syringe, dispensing bottle, or spoon with a bottle adapter) and measure a 5 mL dose of Coben (chlorpheniramine maleate/phenylephrine HCl, Daewoo Pharm. Co., Ltd) syrup using the device of their choice. The investigator used an ISOLAB graduated cylinder (Germany, blue grad, 10 mL) to measure the amount of syrup dispensed by the study participants. Participant characteristics were recorded including gender, age, education level, and relationship to the person for whom the medication was intended., Results: Of the 300 participants, 257 (85.7%) were female; 286 (95.3%) had at least a high school education; and 282 (94.0%) were caregivers (parent or grandparent) for the patient. The mean (SD) measured dose was 4.949 (0.378) mL for the 300 participants. In analysis of variance of the 6 measuring devices, the greatest difference from the 5 mL target was a mean 5.552 mL for 17 subjects who used the regular (etched) dosing cup and 4.660 mL for the dosing spoon (n = 10; P < 0.001). Doses were within 10% of the 5 mL target volume for 88.7% (n = 266) of the participant samples. Only 34 cases (11.3%) had dose errors greater than 10%, and only 6 cases (2.0%) had a variance of more than 20% from the 5 mL target volume. Dose errors greater than 10% of the target volume were more common for the etched dosing cup (47.1%, n = 8), the dosing spoon (50.0%, n = 5), and the printed dosing cup (30.8%, n = 4), but these 3 devices were used by only 13.3% of the study participants., Conclusions: Approximately 1 in 10 participants measured doses of liquid medication with a volume error greater than 10%, and these dose errors were more common with the etched dosing cup, the dosing spoon, and the printed dosing cup. Pharmacists have an opportunity to counsel patients or caregivers regarding the appropriate use of measuring devices for liquid medication.

Cylindrical copolypeptide brushes PLLF-g-(PLF-b-PLG) with poly(L-lysine-co-L-phenylalanine) (PLLF) as the backbone and poly(L-phenylalanine)-b-poly(L-glutamic acid) (PLF-b-PLG) as the side chains have been synthesized and evaluated as drug delivery carriers. The synthesized copolypeptide brushes were characterized by (1)H NMR, gel permeation chromatography (GPC), and transmission electron microscopy (TEM). In aqueous solution, the copolypeptide brushes adopt cylindrical morphologies and resemble unimolecular polymeric micelles with a hydrophobic poly(L-phenylalanine) core and a hydrophilic poly(L-glutamate) shell. An encapsulation study demonstrated that these water soluble, biodegradable copolypeptide brushes encapsulate hydrophobic compounds and cationic hydrophilic guest molecules simultaneously. Furthermore, the encapsulated cationic model compounds exhibit a pH-responsive releasing property., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This paper explores possibilities of applying enantiomeric profiling to solving problems related to estimation of drugs usage in communities via the sewage epidemiology approach: for the identification of whether drug residue results from consumption of illicit drug or metabolism of other drugs, verification of potency of used drugs and monitoring of changing patterns of drugs abuse. Due to the very complex nature of wastewater used in sewage epidemiology, which comes from the whole community rather than one individual, verification of the above is challenging but vital in accurate estimations of drugs abuse as well as providing comprehensive information regarding drug abuse trends. The results of this study indicated that amphetamine in raw wastewater was enriched with R(-)-enantiomer due to its abuse as racemate. Methamphetamine was found to be racemic or to be enriched with S(+)-enantiomer. MDMA was enriched with R(-)-MDMA, which was to be expected as MDMA is abused as racemate. MDA was enriched with S(+)-enantiomer, which suggests that its presence might be associated with MDMA abuse and not intentional MDA use. Out of the four possible isomers of ephedrine only natural 1R,2S(-)-ephedrine and 1S,2S(+)-pseudoephedrine were detected in raw wastewater and their diastereomeric fractions were found to be season dependent with higher contribution from 1S,2S(+)-pseudoephedrine over winter months and an enrichment with 1R,2S(-)-ephedrine during the spring and summer months. These findings were accompanied by a decrease of cumulative concentration of ephedrines throughout the sampling campaign between February and August. This is a very important finding indicating that non-enantioselective measurement of ephedrine concentrations cannot be a reliable indicator of actual potency of ephedrines used., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Therapeutic drugs and environmental pollutants may exhibit high reactivity toward DNA bases and backbone. Understanding the mechanisms of drug-DNA binding is crucial for predicting their potential genotoxicity. We developed a fluorescence analytical method for the determination of the preferential binding mode for drug-DNA interactions. Two nucleic acid dyes were employed in the method: TO-PRO-3 iodide (TP3) and 4',6-diamidino-2-phenylindole (DAPI). TP3 binds DNA by intercalation, whereas DAPI exhibits minor groove binding. Both dyes exhibit significant fluorescence magnification on binding to DNA. We evaluated the DNA binding constant, K(b), for each dye. We also performed fluorescence quenching experiments with 11 molecules of various structures and measured a C(50) value for each compound. We determined preferential binding modes for the aforementioned molecules and found that they bound to DNA consistently, as indicated by other studies. The values of the likelihood of DNA intercalation were correlated with the partition coefficients of the molecules. In addition, we performed nuclear magnetic resonance (NMR) studies of the interactions with calf thymus DNA for the three molecules. The results were consistent with the fluorescence method described above. Thus, we conclude that the fluorescence method we developed provides a reliable determination of the likelihoods of the two different DNA binding modes., (Published by Elsevier Inc.)

Background: This work compares the concentration of active ingredients and preservatives in commonly used brand name versus generic glaucoma medications., Materials and Methods: Active ingredient and benzalkonium chloride (BAK) concentrations in brand name latanoprost and dorzolamide-timolol were each compared to two generic counterparts using liquid chromatography-mass spectrometry at baseline and after exposure to 25°C and 50°C for 30 days. Micro flow imaging was used to quantify particulate material greater than one micron in diameter., Results: Brand name formulations contained active ingredients and BAK in concentrations that were generally in agreement with their package inserts at baseline. The two generic formulations of latanoprost contained baseline levels of active ingredients that were 10% greater than their labeled value. Generic latanoprost formulations had significant loss of active ingredient concentration after exposure to 25°C and 50°C for 30 days. Both generic and brand name dorzolamide-timolol appeared relatively resistant to degradation. BAK concentrations remained stable at 25°C but decreased in some bottles at 50°C. Bottles of both generic medications had higher levels of particulate matter compared to brand name versions., Conclusions: Exposure to temperatures at the high end of the labeled value may lead to a significant decrease in concentration of active ingredients in generic formulations that could influence clinical efficacy. Re-evaluation of intraocular pressure lowering efficacy may be indicated in glaucoma patients switching from brand name to generic formulations.

Objective: To determine whether brand-name glaucoma drops differ from generic equivalents in bottle design, viscosity, surface tension, and volume in North America., Design: Experimental study., Participants: We studied 5 bottles each of 11 kinds of glaucoma drops., Methods: Density-based calculations of drop volume were assessed using 0.1 mg analytic balance. Viscosity was measured using rotational rheometery. Bottle tip diameter was measured using 0.05 mm Vernier calipers. Surface tension was measured using a Fisher Scientific (Ottawa, ON) tensiometer., Results: For the American brand-name Timoptic XE, the average drop volume was 38 ± 3.1 μL versus 24 ± 1.5 μL of Timolol GFS (p < 0.0001). For the Canadian brand-name Timoptic XE, the average drop volume was 42 ± 4.0 μL versus 25 ± 2 μL of timolol maleate EX (p < 0.0001). The Canadian brand-name Timoptic drop volume was 28 ± 1.4 μL versus 35 ± 1.9 μL Apo-Timop (p < 0.01). At a 0.1 per second shear rate, the viscosity of Canadian Timoptic XE was 20 times higher than that of its generic equivalent, whereas the viscosity of American Timoptic XE differed from the generic by a factor of 100. The surface tension of Canadian Timoptic XE was 31% higher than that of the generic (p < 0.001), whereas the surface tension of American Timoptic XE was 21% higher than that of the generic (p < 0.001). The bottle tips of the Canadian and American Timoptic XE measured about 3.5 times larger than those of their generics., Conclusion: American and Canadian Timoptic XE eye drops vary significantly from the generics in drop volume, viscosity, surface tension, and bottle tip. Canadian brand-name Timoptic delivered significantly smaller drop volumes than generic Apo-Timop. Careful consideration should be given to drop viscosity and bottle design when generic ophthalmic products are evaluated for interchangeability and market entry., (Copyright © 2012 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Most drugs exert their effects via multitarget interactions, as hypothesized by polypharmacology. While these multitarget interactions are responsible for the clinical effect profiles of drugs, current methods have failed to uncover the complex relationships between them. Here, we introduce an approach which is able to relate complex drug-protein interaction profiles with effect profiles. Structural data and registered effect profiles of all small-molecule drugs were collected, and interactions to a series of nontarget protein binding sites of each drug were calculated. Statistical analyses confirmed a close relationship between the studied 177 major effect categories and interaction profiles of ca. 1200 FDA-approved small-molecule drugs. On the basis of this relationship, the effect profiles of drugs were revealed in their entirety, and hitherto uncovered effects could be predicted in a systematic manner. Our results show that the prediction power is independent of the composition of the protein set used for interaction profile generation.