A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly

PubMed Central

Wongrakpanich, Supakanya; Wongrakpanich, Amaraporn; Melhado, Katie; Rangaswami, Janani

2018-01-01

NSAIDs, non-steroidal anti-inflammatory drugs, are one of the most commonly prescribed pain medications. It is a highly effective drug class for pain and inflammation; however, NSAIDs are known for multiple adverse effects, including gastrointestinal bleeding, cardiovascular side effects, and NSAID induced nephrotoxicity. As our society ages, it is crucial to have comprehensive knowledge of this class of medication in the elderly population. Therefore, we reviewed the pharmacodynamics and pharmacokinetics, current guidelines for NSAIDs use, adverse effect profile, and drug interaction of NSAIDs and commonly used medications in the elderly. PMID:29392089

Cardiovascular drugs inducing QT prolongation: facts and evidence.

PubMed

Taira, Carlos A; Opezzo, Javier A W; Mayer, Marcos A; Höcht, Christian

2010-01-01

Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking I(Kr). Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.

The effectiveness and cost-effectiveness of diversion and aftercare programmes for offenders using class A drugs: a systematic review and economic evaluation.

PubMed

Hayhurst, Karen P; Leitner, Maria; Davies, Linda; Flentje, Rachel; Millar, Tim; Jones, Andrew; King, Carlene; Donmall, Michael; Farrell, Michael; Fazel, Seena; Harris, Rochelle; Hickman, Matthew; Lennox, Charlotte; Mayet, Soraya; Senior, Jane; Shaw, Jennifer

2015-01-01

The societal costs of problematic class A drug use in England and Wales exceed £15B; drug-related crime accounts for almost 90% of costs. Diversion plus treatment and/or aftercare programmes may reduce drug-related crime and costs. To assess the effectiveness and cost-effectiveness of diversion and aftercare for class A drug-using offenders, compared with no diversion. Adult class A drug-using offenders diverted to treatment or an aftercare programme for their drug use. Programmes to identify and divert problematic drug users to treatment (voluntary, court mandated or monitored services) at any point within the criminal justice system (CJS). Aftercare follows diversion and treatment, excluding care following prison or non-diversionary drug treatment. Thirty-three electronic databases and government online resources were searched for studies published between January 1985 and January 2012, including MEDLINE, PsycINFO and ISI Web of Science. Bibliographies of identified studies were screened. The UK Drug Data Warehouse, the UK Drug Treatment Outcomes Research Study and published statistics and reports provided data for the economic evaluation. Included studies evaluated diversion in adult class A drug-using offenders, in contact with the CJS. The main outcomes were drug use and offending behaviour, and these were pooled using meta-analysis. The economic review included full economic evaluations for adult opiate and/or crack, or powder, cocaine users. An economic decision analytic model, estimated incremental costs per unit of outcome gained by diversion and aftercare, over a 12-month time horizon. The perspectives included the CJS, NHS, social care providers and offenders. Probabilistic sensitivity analysis and one-way sensitivity analysis explored variance in parameter estimates, longer time horizons and structural uncertainty. Sixteen studies met the effectiveness review inclusion criteria, characterised by poor methodological quality, with modest sample sizes, high attrition rates, retrospective data collection, limited follow-up, no random allocation and publication bias. Most study samples comprised US methamphetamine users. Limited meta-analysis was possible, indicating a potential small impact of diversion interventions on reducing drug use [odds ratio (OR) 1.68, 95% confidence interval (CI) 1.12 to 2.53 for reduced primary drug use, and OR 2.60, 95% CI 1.70 to 3.98 for reduced use of other drugs]. The cost-effectiveness review did not identify any relevant studies. The economic evaluation indicated high uncertainty because of variance in data estimates and limitations in the model design. The primary analysis was unclear whether or not diversion was cost-effective. The sensitivity analyses indicated some scenarios where diversion may be cost-effective. Nearly all participants (99.6%) in the effectiveness review were American (Californian) methamphetamine users, limiting transfer of conclusions to the UK. Data and methodological limitations mean it is unclear whether or not diversion is effective or cost-effective. High-quality evidence for the effectiveness and cost-effectiveness of diversion schemes is sparse and does not relate to the UK. Importantly this research identified a range of methodological limitations in existing evidence. These highlight the need for research to conceptualise, define and develop models of diversion programmes and identify a core outcome set. A programme of feasibility, pilot and definitive trials, combined with process evaluation and qualitative research is recommended to assess the effectiveness and cost-effectiveness of diversionary interventions in class A drug-using offenders. The National Institute for Health Research Health Technology Assessment programme.

Antidysrhythmic agents at the turn of the twenty-first century: a current review.

PubMed

Haugh, Kathy Henley

2002-03-01

The use of class IA agents is gradually on the decline, primarily as a result of its unfavorable risk-to-benefit ratio. Lidocaine, a class IB agent, has been widely used in the acute treatment of VT. However, alternate drugs are being considered increasingly as first-line agents in the acute treatment of VT. Class IC drugs are contraindicated in patients with structural cardiac abnormalities and have a limited usefulness in the management of dysrhythmias. Beta-blockers continue to increase their role in cardiology, and subsequently their use in managing dysrhythmias. Class III agents, including amiodarone, sotalol, ibutilide, and dofetilide, are among the most widely used antidysrhythmics. Class IV calcium channel blockers have a limited usefulness in tachydysrhythmias. Digoxin and adenosine have unique antidysrhythmic properties and will likely retain their roles as antidysrhythmic agents. In the wake of the effectiveness of amiodarone, the drug that crosses all classes, some now question the benefit of pure agents that block a single, specific ion channel in the heart. After CAST8 demonstrated that antidysrhythmics can increase mortality while seemingly suppressing dysrhythmias, new drugs will continue to undergo intense scrutiny with regard to their efficacy, safety, and usefulness in treating dysrhythmias.

Multiple factors govern the association between pharmacology and toxicity in a class of drugs: toward a unification of class effect terminology.

PubMed

Smith, Dennis A; Harrison, Anthony; Morgan, Paul

2011-04-18

The term class effect has gained in use to describe a side effect including toxicity common to a series of drugs. There is no definition of what constitutes a class effect, and it is not applied against a rigid set of criteria.Thus, the finding of toxicity in one of a series of drugs can raise the concern of a class effect, especially if one or more of the others shows findings even slightly related or at very much lower incidence. This is particularly problematic when the term is used loosely or speculatively on initial events that are themselves of low incidence and serious. This speculation exaggerates and distorts the scientific process in establishing the true benefit risk of the individual drugs and can lead to lengthy development times, or highly restrictive labeling, to the detriment of patient welfare. To provide better definition and application of the term, we suggest that the term class effect toxicity is only used when a clear mechanistic link has been established between a safety concern and drug class based on (I) where the primary pharmacology delivers a clear rationale for the observed findings and toxicities; and (II) where the secondary pharmacology is obligate to the class of the molecule and not subject to variation of structure, and the selectivity cannot be impacted significantly by variations in potency introduced by structural manipulation. With these categorizations, we believe class effect toxicity will be mainly confined to I with examples such as the tetracycline class of antibacterials which inhibit protein synthesis both as a mechanism of antibacterial activity and to produce hepatic injury by mitochondrial injury in the liver.

Factors associated with prescribing restriction on oncology formulary drugs in Malaysia.

PubMed

Fatokun, Omotayo; Olawepo, Michael N

2016-10-01

Background Drugs listed on formularies are often subjected to a variety of utilization restriction measures. However, the degree of restriction is influenced by multiple factors, including the characteristics and attributes of the listed drugs. Objective To identify the factors that are associated with the levels of prescribing restriction on oncology formulary drugs in Malaysia. Setting Oncology formulary in Malaysia. Method The Malaysia Drug Code assigned to each of the drug products on the Malaysia Ministry of Health (MOH) drug formulary was used to identify oncology drugs belonging to WHO ATC class L (antineoplastic and immunomodulating agents). Main outcome measures Categories of prescribing restrictions, therapeutic class, drug type, administration mode, number of sources and the post-approval use period. Results Oncology drugs having a shorter post-approval use period (p < 0.001), biologic oncology drugs (p = 0.01) and oncology drugs belonging to immunosuppressant therapeutic class (p = 0.03) were all significantly associated with a greater likelihood of being subjected to a higher level of prescribing restriction. Conclusion This study suggests that safety concerns, costs and potentials for inappropriate use were the important considerations influencing a higher level of prescribing restriction placement on oncology drugs in the Malaysia MOH drug formulary.

A Guide for the Management of Speical Education Programs. 4.0 Drug Information for Educators, Parents, and Students. Newday Operations Guide for Drug Dependent Minor Programs.

ERIC Educational Resources Information Center

Santa Cruz County Superintendent of Schools, CA.

Presented is the fourth component of a special day class program for drug dependent minors, Drug Information for Educators, Parents, and Students. The first section, intended for educators, includes a drug abuse chart, information on the drug subculture, information on patterns of drug abuse and misconceptions about drugs, and suggested activities…

Pain: Systematic Review of Pharmacy Compounding of Pain Medication.

PubMed

Shawaqfeh, Mohammad S; Harrington, Catherine

2018-01-01

There are limited resources available for pharmacists and doctors to reference proper compounded formulas for pain medications. The systematic review discussed within this article provides the foundation for a searchable database, allowing users to find various compounded formulations. It also provides data about the safety and efficacy of the preparations. Compounding information about several drug classes was reviewed. Those drug classes included, but were not limited to, opioids, non-steroidal anti-inflammatory drugs, central nervous system agents, and anesthetics, with evidence that of the various drugs that could be compounded for pain, anesthetics, non-steroidal anti-inflammatory drugs, and opioids ranked highest within the articles researched. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Safety considerations in the pharmacological management of atrial fibrillation.

PubMed

Camm, A John

2008-07-21

The pharmacological management of atrial fibrillation (AF) requires careful consideration from a safety perspective. This article focuses primarily on maintenance therapy using antiarrhythmic drugs (AADs). The foremost safety issue for AADs is the propensity of class IA and III agents to cause torsade de pointes arrhythmias. Class IA drugs, particularly quinidine, can induce torsade de pointes at low or subtherapeutic doses, but higher doses are not necessarily associated with an increased incidence. 'Pure' class III drugs such as dofetilide induce torsade de pointes in a dose-related manner, but some class III agents with more complex actions such as amiodarone have a markedly lower potential to cause this arrhythmia. The risk of torsade de pointes precludes the use of class IA and 'pure' class III agents in patients with left ventricular hypertrophy and bradycardia. Class IC agents may cause sustained monomorphic ventricular tachycardias and are generally precluded in ischaemic and structural heart disease. Advanced heart failure patients may be treated with amiodarone or dofetilide, but most other AADs are unsuitable. The most important extracardiac toxicities occurring with AADs are those of amiodarone. Drug interactions are a significant safety issue in the management of AF, including pharmacokinetic interactions in which plasma levels of the AAD are raised - increasing the risk of proarrhythmia - and concomitant use of drugs that prolong the QT interval. Notwithstanding these considerations, most patients with AF can be considered for rhythm control, provided there is adequate pre-treatment assessment and protocols for initiation, dosing and monitoring are followed with care.

Highlights from Drug Use Among American High School Students 1975-1977.

ERIC Educational Resources Information Center

Johnston, Lloyd D.; And Others

The current prevalence of drug use among American high school seniors and the trends in use since 1975 are the two major topics treated. Also reported are prevailing attitudes and beliefs among seniors concerning various types of drug use. Eleven separate classes of drugs are distinguished: marihuana (including hashish), inhalants, hallucinogens,…

Inferring anatomical therapeutic chemical (ATC) class of drugs using shortest path and random walk with restart algorithms.

PubMed

Chen, Lei; Liu, Tao; Zhao, Xian

2018-06-01

The anatomical therapeutic chemical (ATC) classification system is a widely accepted drug classification scheme. This system comprises five levels and includes several classes in each level. Drugs are classified into classes according to their therapeutic effects and characteristics. The first level includes 14 main classes. In this study, we proposed two network-based models to infer novel potential chemicals deemed to belong in the first level of ATC classification. To build these models, two large chemical networks were constructed using the chemical-chemical interaction information retrieved from the Search Tool for Interactions of Chemicals (STITCH). Two classic network algorithms, shortest path (SP) and random walk with restart (RWR) algorithms, were executed on the corresponding network to mine novel chemicals for each ATC class using the validated drugs in a class as seed nodes. Then, the obtained chemicals yielded by these two algorithms were further evaluated by a permutation test and an association test. The former can exclude chemicals produced by the structure of the network, i.e., false positive discoveries. By contrast, the latter identifies the most important chemicals that have strong associations with the ATC class. Comparisons indicated that the two models can provide quite dissimilar results, suggesting that the results yielded by one model can be essential supplements for those obtained by the other model. In addition, several representative inferred chemicals were analyzed to confirm the reliability of the results generated by the two models. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. Copyright © 2017 Elsevier B.V. All rights reserved.

An overview of the regulatory aspects of medical devices from the viewpoint of research and device manufacturing.

PubMed

Patrick, J

1993-01-01

To review the Food and Drug Administration's regulatory requirements for bringing a new or substantially changed medical device to market in the United States, noting the history and current requirements for the continuous spinal catheter. The relevant laws and guidelines for classifying, testing, and submitting a device to Food and Drug Administration approval are reviewed. The Food and Drug Administration categorizes medical devices into three classes, based on potential risk for illness or injury presented by a malfunction or failure. Class III devices are the most critical ones, and require a Premarket Approval that includes clinical trials before market introduction. Classes I and II usually require a 510(k), or premarket notification, which usually does not need any clinical data. Testing requirements include biocompatibility testing; physical, functional, and packaging testing; and sterility testing. The continuous spinal catheter (25-32 gauge) was marketed under a 510(k) claiming substantial equivalence to the Bizzarri-Giuffrida 24-gauge catheter, which was a pre-Amendment device. After incidences of cauda equina syndrome were reported with use of the continuous spinal technique, the Food and Drug Administration reclassified the small-gauge catheters as Class III devices, which require a Premarket Approval before being marketed.

Classification of natural products as sources of drugs according to the biopharmaceutics drug disposition classification system (BDDCS).

PubMed

Li, Ji; Larregieu, Caroline A; Benet, Leslie Z

2016-12-01

Natural products (NPs) are compounds that are derived from natural sources such as plants, animals, and micro-organisms. Therapeutics has benefited from numerous drug classes derived from natural product sources. The Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed to serve as a basis for predicting the importance of transporters and enzymes in determining drug bioavailability and disposition. It categorizes drugs into one of four biopharmaceutical classes according to their water solubility and extent of metabolism. The present paper reviews 109 drugs from natural product sources: 29% belong to class 1 (high solubility, extensive metabolism), 22% to class 2 (low solubility, extensive metabolism), 40% to class 3 (high solubility, poor metabolism), and 9% to class 4 (low solubility, poor metabolism). Herein we evaluated the characteristics of NPs in terms of BDDCS class for all 109 drugs as wells as for subsets of NPs drugs derived from plant sources as antibiotics. In the 109 NPs drugs, we compiled 32 drugs from plants, 50% (16) of total in class 1, 22% (7) in class 2 and 28% (9) in class 3, none found in class 4; Meantime, the antibiotics were found 5 (16%) in class 2, 22 (71%) in class 3, and 4 (13%) in class 4; no drug was found in class 1. Based on this classification, we anticipate BDDCS to serve as a useful adjunct in evaluating the potential characteristics of new natural products. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

[Effects of Drugs Given During Pregnancy and Lactation on the Unborn Child and Neonate.

ERIC Educational Resources Information Center

Kelsey, Frances O.

This symposium presentation outlines the activity of the Food and Drug Administration (FDA) in regulating the use during pregnancy and lactation of drugs which affect the fetus and neonate. When presented with an unexpected adverse effect of a drug or of a class of drugs, the FDA can take several steps. These steps include ordering total removal…

78 FR 72901 - Draft Guidance; Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-04

... the Drug Quality and Security Act to remove the unconstitutional advertising, promotion, and... 503A are met. The conditions of section 503A of the FD&C Act included restrictions on the advertising or promotion of the compounding of any particular drug, class of drug, or type of drug, and the...

Establishing the pharmaceutical quality of Chinese herbal medicine: a provisional BCS classification.

PubMed

Fong, Sophia Y K; Liu, Mary; Wei, Hai; Löbenberg, Raimar; Kanfer, Isadore; Lee, Vincent H L; Amidon, Gordon L; Zuo, Zhong

2013-05-06

The Biopharmaceutical Classification System (BCS), which is a scientific approach to categorize active drug ingredient based on its solubility and intestinal permeability into one of the four classes, has been used to set the pharmaceutical quality standards for drug products in western society. However, it has received little attention in the area of Chinese herbal medicine (CHM). This is likely, in part, due to the presence of multiple active components as well as lack of standardization of CHM. In this report, we apply BCS classification to CHMs provisionally as a basis for establishing improved in vitro quality standards. Based on a top-200 drugs selling list in China, a total of 31 CHM products comprising 50 official active marker compounds (AMCs) were provisionally classified according to BCS. Information on AMC content and doses of these CHM products were retrieved from the Chinese Pharmacopoeia. BCS parameters including solubility and permeability of the AMCs were predicted in silico (ACD/Laboratories). A BCS classification of CHMs according to biopharmaceutical properties of their AMCs is demonstrated to be feasible in the current study and can be used to provide a minimum set of quality standards. Our provisional results showed that 44% of the included AMCs were classified as Class III (high solubility, low permeability), followed by Class II (26%), Class I (18%), and Class IV (12%). A similar trend was observed when CHMs were classified in accordance with the BCS class of AMCs. Most (45%) of the included CHMs were classified as Class III, followed by Class II (16%), Class I (10%), and Class IV (6%); whereas 23% of the CHMs were of mixed class due to the presence of multiple individual AMCs with different BCS classifications. Moreover, about 60% of the AMCs were classified as high-solubility compounds (Class I and Class III), suggesting an important role for an in vitro dissolution test in setting quality control standards ensuring consistent biopharmaceutical quality for the commercially available CHM products. That is, provisionally, more than half of the AMCs of the top-selling CHMs included in this study would be candidates for a bioequivalence (BE) biowaiver, based on WHO recommendations and EMEA guidelines. Thus a dissolution requirement on these AMCs would represent a significant advance in the pharmaceutical quality of CHM today.

Structural insights into ligand recognition and selectivity for class A, B, and C GPCRs

PubMed Central

Lee, Sang-Min; Booe, Jason M.; Pioszak, Augen A.

2015-01-01

The G protein-coupled receptor (GPCR) superfamily constitutes the largest collection of cell surface signaling proteins with approximately 800 members in the human genome. GPCRs regulate virtually all aspects of physiology and they are an important class of drug targets with ~30% of drugs on the market targeting a GPCR. Breakthroughs in GPCR structural biology in recent years have significantly expanded our understanding of GPCR structure and function and ushered in a new era of structure-based drug design for GPCRs. Crystal structures for nearly thirty distinct GPCRs are now available including receptors from each of the major classes, A, B, C, and F. These structures provide a foundation for understanding the molecular basis of GPCR pharmacology. Here, we review structural mechanisms of ligand recognition and selectivity of GPCRs with a focus on selected examples from classes A, B, and C, and we highlight major unresolved questions for future structural studies. PMID:25981303

Agreement between PRE2DUP register data modeling method and comprehensive drug use interview among older persons

PubMed Central

Taipale, Heidi; Tanskanen, Antti; Koponen, Marjaana; Tolppanen, Anna-Maija; Tiihonen, Jari; Hartikainen, Sirpa

2016-01-01

Background PRE2DUP is a modeling method that generates drug use periods (ie, when drug use started and ended) from drug purchases recorded in dispensing-based register data. It is based on the evaluation of personal drug purchasing patterns and considers hospital stays, possible stockpiling of drugs, and package information. Objective The objective of this study was to investigate person-level agreement between self-reported drug use in the interview and drug use modeled from dispensing data with PRE2DUP method for various drug classes used by older persons. Methods Self-reported drug use was assessed from the GeMS Study including a random sample of persons aged ≥75 years from the city of Kuopio, Finland, in 2006. Drug purchases recorded in the Prescription register data of these persons were modeled to determine drug use periods with PRE2DUP modeling method. Agreement between self-reported drug use on the interview date and drug use calculated from register-based data was compared in order to find the frequently used drugs and drug classes, which was evaluated by Cohen’s kappa. Kappa values 0.61–0.80 were considered to represent good and 0.81–1.00 as very good agreement. Results Among 569 participants with mean age of 82 years, the agreement between interview and register data was very good for 75% and very good or good for 93% of the studied drugs or drug classes. Good or very good agreement was observed for drugs that are typically used on regular bases, whereas “as needed” drugs represented poorer results. Conclusion PRE2DUP modeling method validly describes regular drug use among older persons. For most of drug classes investigated, PRE2DUP-modeled register data described drug use as well as interview-based data which are more time-consuming to collect. Further studies should be conducted by comparing it with other methods and in different drug user populations. PMID:27785101

Multiscale Modelling of Relationships between Protein Classes and Drug Behavior Across all Diseases Using the CANDO Platform

PubMed Central

Samudrala, Ram

2015-01-01

We have examined the effect of eight different protein classes (channels, GPCRs, kinases, ligases, nuclear receptors, proteases, phosphatases, transporters) on the benchmarking performance of the CANDO drug discovery and repurposing platform (http://protinfo.org/cando). The first version of the CANDO platform utilizes a matrix of predicted interactions between 48278 proteins and 3733 human ingestible compounds (including FDA approved drugs and supplements) that map to 2030 indications/diseases using a hierarchical chem and bio-informatic fragment based docking with dynamics protocol (> one billion predicted interactions considered). The platform uses similarity of compound-proteome interaction signatures as indicative of similar functional behavior and benchmarking accuracy is calculated across 1439 indications/diseases with more than one approved drug. The CANDO platform yields a significant correlation (0.99, p-value < 0.0001) between the number of proteins considered and benchmarking accuracy obtained indicating the importance of multitargeting for drug discovery. Average benchmarking accuracies range from 6.2 % to 7.6 % for the eight classes when the top 10 ranked compounds are considered, in contrast to a range of 5.5 % to 11.7 % obtained for the comparison/control sets consisting of 10, 100, 1000, and 10000 single best performing proteins. These results are generally two orders of magnitude better than the average accuracy of 0.2% obtained when randomly generated (fully scrambled) matrices are used. Different indications perform well when different classes are used but the best accuracies (up to 11.7% for the top 10 ranked compounds) are achieved when a combination of classes are used containing the broadest distribution of protein folds. Our results illustrate the utility of the CANDO approach and the consideration of different protein classes for devising indication specific protocols for drug repurposing as well as drug discovery. PMID:25694071

Purely in silico BCS classification: science based quality standards for the world's drugs.

PubMed

Dahan, Arik; Wolk, Omri; Kim, Young Hoon; Ramachandran, Chandrasekharan; Crippen, Gordon M; Takagi, Toshihide; Bermejo, Marival; Amidon, Gordon L

2013-11-04

BCS classification is a vital tool in the development of both generic and innovative drug products. The purpose of this work was to provisionally classify the world's top selling oral drugs according to the BCS, using in silico methods. Three different in silico methods were examined: the well-established group contribution (CLogP) and atom contribution (ALogP) methods, and a new method based solely on the molecular formula and element contribution (KLogP). Metoprolol was used as the benchmark for the low/high permeability class boundary. Solubility was estimated in silico using a thermodynamic equation that relies on the partition coefficient and melting point. The validity of each method was affirmed by comparison to reference data and literature. We then used each method to provisionally classify the orally administered, IR drug products found in the WHO Model list of Essential Medicines, and the top-selling oral drug products in the United States (US), Great Britain (GB), Spain (ES), Israel (IL), Japan (JP), and South Korea (KR). A combined list of 363 drugs was compiled from the various lists, and 257 drugs were classified using the different in silico permeability methods and literature solubility data, as well as BDDCS classification. Lastly, we calculated the solubility values for 185 drugs from the combined set using in silico approach. Permeability classification with the different in silico methods was correct for 69-72.4% of the 29 reference drugs with known human jejunal permeability, and for 84.6-92.9% of the 14 FDA reference drugs in the set. The correlations (r(2)) between experimental log P values of 154 drugs and their CLogP, ALogP and KLogP were 0.97, 0.82 and 0.71, respectively. The different in silico permeability methods produced comparable results: 30-34% of the US, GB, ES and IL top selling drugs were class 1, 27-36.4% were class 2, 22-25.5% were class 3, and 5.46-14% were class 4 drugs, while ∼8% could not be classified. The WHO list included significantly less class 1 and more class 3 drugs in comparison to the countries' lists, probably due to differences in commonly used drugs in developing vs industrial countries. BDDCS classified more drugs as class 1 compared to in silico BCS, likely due to the more lax benchmark for metabolism (70%), in comparison to the strict permeability benchmark (metoprolol). For 185 out of the 363 drugs, in silico solubility values were calculated, and successfully matched the literature solubility data. In conclusion, relatively simple in silico methods can be used to estimate both permeability and solubility. While CLogP produced the best correlation to experimental values, even KLogP, the most simplified in silico method that is based on molecular formula with no knowledge of molecular structure, produced comparable BCS classification to the sophisticated methods. This KLogP, when combined with a mean melting point and estimated dose, can be used to provisionally classify potential drugs from just molecular formula, even before synthesis. 49-59% of the world's top-selling drugs are highly soluble (class 1 and class 3), and are therefore candidates for waivers of in vivo bioequivalence studies. For these drugs, the replacement of expensive human studies with affordable in vitro dissolution tests would ensure their bioequivalence, and encourage the development and availability of generic drug products in both industrial and developing countries.

21 CFR 868.1575 - Gas collection vessel.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Gas collection vessel. 868.1575 Section 868.1575 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... for subsequent analysis. It does not include a sampling pump. (b) Classification. Class I (general...

21 CFR 868.1575 - Gas collection vessel.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Gas collection vessel. 868.1575 Section 868.1575 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... for subsequent analysis. It does not include a sampling pump. (b) Classification. Class I (general...

21 CFR 868.1575 - Gas collection vessel.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Gas collection vessel. 868.1575 Section 868.1575 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... for subsequent analysis. It does not include a sampling pump. (b) Classification. Class I (general...

[Hepatox: database on hepatotoxic drugs].

PubMed

Quinton, A; Latry, P; Biour, M

1993-01-01

Hepatox is a data base on the hepatotoxic drugs file published every year in Gastroentérologie Clinique et Biologique. The program was developed under Omnis 7 for Apple computers, and under Visual Basic Professional Toolkit and Code Base for IBM PC and compatibles computers. The data base includes forms of 866 drugs identified by their approved name and those of their 1,300 corresponding proprietary names in France; drugs are distributed among 104 pharmacological classes. It is possible to have instantaneously access to the card of a drug identified by its approved name. Acceding to a drug identified by its proprietary name gives a list of the approved name of its components; going from a name of this list to the correspondent card of hepatoxicity is immediate. It is easy to extract lists of drugs responsible of a type of hepatic injury, and a table of types of hepatic injuries induced by the drugs of a pharmacological class.

Antiretroviral treatment sequencing strategies to overcome HIV type 1 drug resistance in adolescents and adults in low-middle-income countries.

PubMed

De Luca, Andrea; Hamers, Raphael L; Schapiro, Jonathan M

2013-06-15

Antiretroviral treatment (ART) is expanding to human immunodeficiency virus type 1 (HIV-1)-infected persons in low-middle income countries, thanks to a public health approach. With 3 available drug classes, 2 ART sequencing lines are programmatically foreseen. The emergence and transmission of viral drug resistance represents a challenge to the efficacy of ART. Knowledge of HIV-1 drug resistance selection associated with specific drugs and regimens and the consequent activity of residual drug options are essential in programming ART sequencing options aimed at preserving ART efficacy for as long as possible. This article determines optimal ART sequencing options for overcoming HIV-1 drug resistance in resource-limited settings, using currently available drugs and treatment monitoring opportunities. From the perspective of drug resistance and on the basis of limited virologic monitoring data, optimal sequencing seems to involve use of a tenofovir-containing nonnucleoside reverse-transcriptase inhibitor-based first-line regimen, followed by a zidovudine-containing, protease inhibitor (PI)-based second-line regimen. Other options and their consequences are explored by considering within-class and between-class sequencing opportunities, including boosted PI monotherapies and future options with integrase inhibitors. Nucleoside reverse-transcriptase inhibitor resistance pathways in HIV-1 subtype C suggest an additional reason for accelerating stavudine phase out. Viral load monitoring avoids the accumulation of resistance mutations that significantly reduce the activity of next-line options. Rational use of resources, including broader access to viral load monitoring, will help ensure 3 lines of fully active treatment options, thereby increasing the duration of ART success.

Proteomic Analyses of the Effects of Drugs of Abuse on Monocyte-Derived Mature Dendritic Cells

PubMed Central

Reynolds, Jessica L.; Mahajan, Supriya D.; Aalinkeel, Ravikunar; Nair, B.; Sykes, Donald E.; Schwartz, Stanley A.

2010-01-01

Drug abuse has become a global health concern. Understanding how drug abuse modulates the immune system and how the immune system responds to pathogens associated with drug abuse, such hepatitis C virus (HCV) and human immunodeficiency virus (HIV-1), can be assessed by an integrated approach comparing proteomic analyses and quantitation of gene expression. Two-dimensional (2D) difference gel electrophoresis was used to determine the molecular mechanisms underlying the proteomic changes that alter normal biological processes when monocyte-derived mature dendritic cells were treated with cocaine or methamphetamine. Both drugs differentially regulated the expression of several functional classes of proteins including those that modulate apoptosis, protein folding, protein kinase activity, and metabolism and proteins that function as intracellular signal transduction molecules. Proteomic data were validated using a combination of quantitative, real-time PCR and Western blot analyses. These studies will help to identify the molecular mechanisms, including the expression of several functionally important classes of proteins that have emerged as potential mediators of pathogenesis. These proteins may predispose immunocompetent cells, including dendritic cells, to infection with viruses such as HCV and HIV-1, which are associated with drug abuse. PMID:19811410

Pretest Differences in Drug-Related Variables among Intact College Classes: Implications for Outcome Evaluation in Drug Education.

ERIC Educational Resources Information Center

Gonzalez, Gerardo M.; Haney, Michael L.

1992-01-01

Identified significant pretest differences in drug-related variables in college students from alcohol and drug education class (n=99), stress management class (n=44), and social problems class (n=80). Higher levels of alcohol and drug abuse among students in drug abuse course suggests student users are possibly being attracted to course as means…

Antimicrobial peptides: a new class of antimalarial drugs?

PubMed Central

Vale, Nuno; Aguiar, Luísa; Gomes, Paula

2014-01-01

A range of antimicrobial peptides (AMP) exhibit activity on malaria parasites, Plasmodium spp., in their blood or mosquito stages, or both. These peptides include a diverse array of both natural and synthetic molecules varying greatly in size, charge, hydrophobicity, and secondary structure features. Along with an overview of relevant literature reports regarding AMP that display antiplasmodial activity, this review makes a few considerations about those molecules as a potential new class of antimalarial drugs. PMID:25566072

A Guide for the Management of Special Education Programs. 1.0 Program Organization. Newday Operations Guide for Drug Dependent Minor Programs.

ERIC Educational Resources Information Center

Santa Cruz County Superintendent of Schools, CA.

Presented is the first component, Program Organization, of a special day class educational program emphasizing rehabilitation, remedial instruction, and return to regular school programs for drug dependent minors. Included are statistics on drug use in California and the administrative code under which drug dependent minors are eligible for…

Creating a new class of pharmaceutical services provider for underserved areas: the Tanzania accredited drug dispensing outlet experience.

PubMed

Rutta, Edmund; Senauer, Katie; Johnson, Keith; Adeya, Grace; Mbwasi, Romuald; Liana, Jafary; Kimatta, Suleiman; Sigonda, Margareth; Alphonce, Emmanuel

2009-01-01

In developing countries, the most accessible source of treatment for common conditions is often an informal drug shop, where drug sellers are untrained and operations are unmonitored. We sought to describe a public-private initiative in Tanzania that created a new class of provider in government-accredited drug outlets, which improved the quality of medicines and pharmaceutical services in previously underserved areas. The accredited drug-dispensing outlet program combines changing behavior and expectations of community members who use, own, regulate, and work in drug shops. Success resulted from including community stakeholders from the beginning of the process. Addressing shortages in qualified health care providers by training and accrediting private sector drug dispensers to recognize common conditions and provide quality pharmaceutical products and services is feasible in a developing country, when supported by an appropriate policy and regulatory environment. Scaling up and sustaining the program will be a challenge.

Beyond 'Doing Gender': Incorporating Race, Class, Place, and Life Transitions into Feminist Drug Research.

PubMed

Miller, Jody; Carbone-Lopez, Kristin

2015-05-01

This essay draws from our research with US rural women methamphetamine users in 2009 to offer strategies for "revisioning" the drug use(r) field to better understand the impact of gender on drug use and drug market participation. We highlight the insights and limitations of a popular strategy in feminist research that conceptualizes gender as performance- commonly referred to as "doing gender"-using illustrations from our research. We encourage scholars to move beyond a primarily normative orientation in studying gender, and investigate gendered organizational features of social life including their intersections with other aspects of social inequality such as those of race, class, and place. In addition, we suggest that feminist scholars can integrate gender in a rigorous way into theoretical perspectives that are typically inattentive to its import, as a means of challenging, enriching, and refining research on drug use, drug users, and drug market participation.

How Safe and Innovative Are First-in-Class Drugs Approved by Health Canada: A Cohort Study

PubMed Central

2016-01-01

Introduction: First-in-class drugs use a unique mechanism of action. This study assessed the therapeutic innovativeness and safety of these drugs approved by Health Canada from 1997–2012. Methods: A list of new drugs was compiled and a database from the Food and Drug Administration was used to determine first-in-class status. Post-market safety warnings and drugs withdrawn for safety reasons were identified from the MedEffect Canada website. Therapeutic innovation evaluations came from the Patented Medicine Prices Review Board (PMPRB) and Prescrire International. The proportion of first-in-class drugs that were innovative was compared to the proportion of non-first-in-class drugs that were innovative. Kaplan–Meier survival curves assessed safety. Results: In all, 462 drugs were approved by Health Canada during the period under study. Among these, 345 were evaluated by PMPRB and/or Prescrire, and first-in-class data were available for 292. Ninety-eight of the 292 were first-in-class and 16 were innovative compared to 9 of 194 drugs that were not-first-in-class. There was no difference in safety between the two groups. Discussion: Overall, the benefit-to-harm ratio of first-in-class drugs, as measured by post-market safety warnings/withdrawals, is better than those that were not-first-in-class. PMID:28032825

Tricyclic GyrB/ParE (TriBE) Inhibitors: A New Class of Broad-Spectrum Dual-Targeting Antibacterial Agents

PubMed Central

Tari, Leslie W.; Li, Xiaoming; Trzoss, Michael; Bensen, Daniel C.; Chen, Zhiyong; Lam, Thanh; Zhang, Junhu; Lee, Suk Joong; Hough, Grayson; Phillipson, Doug; Akers-Rodriguez, Suzanne; Cunningham, Mark L.; Kwan, Bryan P.; Nelson, Kirk J.; Castellano, Amanda; Locke, Jeff B.; Brown-Driver, Vickie; Murphy, Timothy M.; Ong, Voon S.; Pillar, Chris M.; Shinabarger, Dean L.; Nix, Jay; Lightstone, Felice C.; Wong, Sergio E.; Nguyen, Toan B.; Shaw, Karen J.; Finn, John

2013-01-01

Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models. PMID:24386374

Determinants of orphan drugs prices in France: a regression analysis.

PubMed

Korchagina, Daria; Millier, Aurelie; Vataire, Anne-Lise; Aballea, Samuel; Falissard, Bruno; Toumi, Mondher

2017-04-21

The introduction of the orphan drug legislation led to the increase in the number of available orphan drugs, but the access to them is often limited due to the high price. Social preferences regarding funding orphan drugs as well as the criteria taken into consideration while setting the price remain unclear. The study aimed at identifying the determinant of orphan drug prices in France using a regression analysis. All drugs with a valid orphan designation at the moment of launch for which the price was available in France were included in the analysis. The selection of covariates was based on a literature review and included drug characteristics (Anatomical Therapeutic Chemical (ATC) class, treatment line, age of target population), diseases characteristics (severity, prevalence, availability of alternative therapeutic options), health technology assessment (HTA) details (actual benefit (AB) and improvement in actual benefit (IAB) scores, delay between the HTA and commercialisation), and study characteristics (type of study, comparator, type of endpoint). The main data sources were European public assessment reports, HTA reports, summaries of opinion on orphan designation of the European Medicines Agency, and the French insurance database of drugs and tariffs. A generalized regression model was developed to test the association between the annual treatment cost and selected covariates. A total of 68 drugs were included. The mean annual treatment cost was €96,518. In the univariate analysis, the ATC class (p = 0.01), availability of alternative treatment options (p = 0.02) and the prevalence (p = 0.02) showed a significant correlation with the annual cost. The multivariate analysis demonstrated significant association between the annual cost and availability of alternative treatment options, ATC class, IAB score, type of comparator in the pivotal clinical trial, as well as commercialisation date and delay between the HTA and commercialisation. The orphan drug pricing is a multivariate phenomenon. The complex association between drug prices and the studied attributes and shows that payers integrate multiple variables in decision making when setting orphan drug prices. The interpretation of the study results is limited by the small sample size and the complex data structure.

Overcoming Multidrug Resistance in Human Cancer Cells by Natural Compounds

PubMed Central

Nabekura, Tomohiro

2010-01-01

Multidrug resistance is a phenomenon whereby tumors become resistant to structurally unrelated anticancer drugs. P-glycoprotein belongs to the large ATP-binding cassette (ABC) transporter superfamily of membrane transport proteins. P-glycoprotein mediates resistance to various classes of anticancer drugs including vinblastine, daunorubicin, and paclitaxel, by actively extruding the drugs from the cells. The quest for inhibitors of anticancer drug efflux transporters has uncovered natural compounds, including (-)-epigallocatechin gallate, curcumin, capsaicin, and guggulsterone, as promising candidates. In this review, studies on the effects of natural compounds on P-glycoprotein and anticancer drug efflux transporters are summarized. PMID:22069634

Identifying high-risk medication: a systematic literature review.

PubMed

Saedder, Eva A; Brock, Birgitte; Nielsen, Lars Peter; Bonnerup, Dorthe K; Lisby, Marianne

2014-06-01

A medication error (ME) is an error that causes damage or poses a threat of harm to a patient. Several studies have shown that only a minority of MEs actually causes harm, and this might explain why medication reviews at hospital admission reduce the number of MEs without showing an effect on length of hospital stay, readmissions, or death. The purpose of this study was to define drugs that actually cause serious MEs. We conducted a literature search of medication reviews and other preventive efforts. A systematic search in PubMed, Embase, Cochrane Reviews, Psycinfo, and SweMed+ was performed. Danish databases containing published patient complaints, patient compensation, and reported medication errors were also searched. Articles and case reports were included if they contained information of an ME causing a serious adverse reaction (AR) in a patient. Information concerning AR seriousness, causality, and preventability was required for inclusion. This systematic literature review revealed that 47 % of all serious MEs were caused by seven drugs or drug classes: methotrexate, warfarin, nonsteroidal anti-inflammatory drugs (NSAIDS), digoxin, opioids, acetylic salicylic acid, and beta-blockers; 30 drugs or drug classes caused 82 % of all serious MEs. The top ten drugs involved in fatal events accounted for 73 % of all drugs identified. Increasing focus on seven drugs/drug classes can potentially reduce hospitalizations, extended hospitalizations, disability, life-threatening conditions, and death by almost 50 %.

Current Development and Future Prospects in Chemotherapy of Tuberculosis

PubMed Central

Nuermberger, Eric L.; Spigelman, Melvin K.; Yew, Wing Wai

2015-01-01

Although treatment of drug-susceptible tuberculosis (TB) under ideal conditions may be successful in ≥95% of cases, cure rates in the field are often significantly lower due to the logistical challenges of administering and properly supervising the intake of combination chemotherapy for 6–9 months. Success rates are far worse for multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases. There is general agreement that new anti-TB drugs are needed to shorten or otherwise simplify treatment for drug-susceptible and MDR/XDR-TB, including TB associated with HIV infection. For the first time in over 40 years, a nascent pipeline of new anti-TB drug candidates has been assembled. Eleven candidates from 7 classes are currently being evaluated in clinical trials. They include novel chemical entities belonging to entirely new classes of antibacterials, agents approved for use against infections other than TB, and an agent already approved for limited use against TB. In this article, we review the current state of TB treatment and its limitations and provide updates on the status of new drugs in clinical trials. In the conclusion, we briefly highlight ongoing efforts to discover new compounds and recent advances in alternative drug delivery systems. PMID:20546189

Anthelmintic Resistance in Haemonchus contortus: History, Mechanisms and Diagnosis.

PubMed

Kotze, A C; Prichard, R K

2016-01-01

Haemonchus contortus has shown a great ability to develop resistance to anthelmintic drugs. In many instances, resistance has appeared less than 10years after the introduction of a new drug class. Field populations of this species now show resistance to all major anthelmintic drug classes, including benzimidazoles (BZs), imidazothiazoles and macrocyclic lactones. In addition, resistance to the recently introduced amino-acetonitrile derivative class (monepantel) has already been reported. The existence of field populations showing resistance to all three major drug classes, and the early appearance of resistance to monepantel, threatens the sustainability of sheep and goat production systems worldwide. This chapter reviews the history of the development of resistance to the various anthelmintics in H. contortus and examines the mechanisms utilized by this species to resist the effects of these drugs. Some of these mechanisms are well understood, particularly for BZ drugs, while our knowledge and understanding of others are increasing. Finally, we summarize methods available for the diagnosis of resistance. While such diagnosis currently relies largely on the faecal egg count reduction test, which suffers from issues of expense and sensitivity, we describe past and current efforts to utilize cheaper and less laborious phenotypic assays with free-living life stages, and then describe progress on the development of molecular assays to provide sensitive resistance-detection tests. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Drug innovation and reverse thinking].

PubMed

Guo, Zong-ru

2016-03-01

Drug innovation involves an individual molecular operation, and every new molecular entity features a hard-duplicated track of R&D. The transformation from an active compound to a new medicine carries out almost in a chaotic system devoid of regularity and periodic alteration. Since new millennium the dominant position in drug innovation has been occupied by the first-in-class drugs, yet the number of launched follow-on drugs has been distinctly decreased. The innovation of first-in-class drugs is characterized by a high risk throughout the whole process. To achieve initiative and uniqueness of drug discovery, the strategy and method of the inverse thinking might be a feasible way, because the inertial and conformity thinkings in drug discovery normally lead to ensemble with similar drug category. However, the study from the flipside or opposite of things(e.g. targets or effects) brand new routes might be opened. This article is to describe the strategy of reverse thinking in drug discovery by some examples including opioid receptor antagonist eluxadoline, HSP90 activator, h ERG channel agonist, covalent drugs, and ultra-small drugs.

Correlates and subgroups of injecting drug use in UK gay and bisexual men: Findings from the 2014 Gay Men's Sex Survey.

PubMed

Melendez-Torres, G J; Bourne, Adam; Hickson, Ford; Reid, David; Weatherburn, Peter

2018-04-16

Evidence to understand which gay and bisexual men (GBM) inject drugs remains scant, especially in the UK. We describe correlates of last-year injecting in UK GBM, and characterise subgroups of GBM who inject drugs by types of drugs used. Using data from the 2014 Gay Men's Sex Survey, an opportunistic internet-based survey conducted of GBM living in the UK, we examined via logistic regression correlates with any injecting of six drugs (amphetamine/speed, crystal methamphetamine, heroin, mephedrone, GHB/GBL, and ketamine) in the last year. We estimated latent class models to understand underlying subgroups of injecting drug use among GBM reporting injecting drug use in the last year. Injecting was most common in GBM who were of middle age, who were HIV seropositive, and who lived in London, and was significantly associated with sexual risk with multiple partners in the last year, whether steady or non-steady. Most GBM who engaged in injecting either injected crystal methamphetamine, mephedrone or both (class 1, chemsex, 88.6% of injectors), whereas a smaller group had a focus on opiates (class 2, opiate, 7.9%). A small but identifiable subgroup (class 3, eclectic, 3.5%) engaged in injecting across the range of drugs examined. This is the first epidemiological analysis to describe subgroups of injecting, and to describe correlates of injecting drug use, in UK GBM. Implications for design of harm reduction services include a need to focus on injecting drug use beyond opiates, currently the focus of most harm reduction services. Copyright © 2018 Elsevier B.V. All rights reserved.

Neuro-psychopharmacological perspective of Orphan receptors of Rhodopsin (class A) family of G protein-coupled receptors.

PubMed

Khan, Muhammad Zahid; He, Ling

2017-04-01

In the central nervous system (CNS), G protein-coupled receptors (GPCRs) are the most fruitful targets for neuropsychopharmacological drug development. Rhodopsin (class A) is the most studied class of GPCR and includes orphan receptors for which the endogenous ligand is not known or is unclear. Characterization of orphan GPCRs has proven to be challenging, and the production pace of GPCR-based drugs has been incredibly slow. Determination of the functions of these receptors may provide unexpected insight into physiological and neuropathological processes. Advances in various methods and techniques to investigate orphan receptors including in situ hybridization and knockdown/knockout (KD/KO) showed extensive expression of these receptors in the mammalian brain and unmasked their physiological and neuropathological roles. Due to these rapid progress and development, orphan GPCRs are rising as a new and promising class of drug targets for neurodegenerative diseases and psychiatric disorders. This review presents a neuropsychopharmacological perspective of 26 orphan receptors of rhodopsin (class A) family, namely GPR3, GPR6, GPR12, GPR17, GPR26, GPR35, GPR39, GPR48, GPR49, GPR50, GPR52, GPR55, GPR61, GPR62, GPR63, GPR68, GPR75, GPR78, GPR83, GPR84, GPR85, GPR88, GPR153, GPR162, GPR171, and TAAR6. We discussed the expression of these receptors in mammalian brain and their physiological roles. Furthermore, we have briefly highlighted their roles in neurodegenerative diseases and psychiatric disorders including Alzheimer's disease, Parkinson's disease, neuroinflammation, inflammatory pain, bipolar and schizophrenic disorders, epilepsy, anxiety, and depression.

The role of training dose in drug discrimination: a review

PubMed Central

Stolerman, Ian P; Childs, Emma; Ford, Matthew M; Grant, Kathleen A

2011-01-01

Drug discrimination has been an important technique in behavioural pharmacology for at least 40 years. The characteristics of drug-produced discriminative stimuli are influenced by behavioural and pharmacological variables, including the doses used to establish discriminations. This review covers studies on the effects of varying the training dose of a drug in a search for general principles that are applicable across different drug classes and methodological approaches. With respect to quantitative changes, relationships between training dose and rate of acquisition or magnitude of stimulus control were found for most drug classes. Acquisition accelerated with dose up to a point beyond which drug-induced impairments of performance had a deleterious impact. Sensitivity to the training drug as measured by ED50 values typically increased when the training dose was reduced. Qualitative changes were more complex and appeared to fall into three categories: (i) changes in profiles of generalisation between partial and full agonists; (ii) reduced specificity of some discriminations at small training doses and (iii) changes in the relative salience of actions mediated through different neurotransmitter systems or from central and peripheral sites. Three-lever discrimination procedures incorporating ‘drug versus drug’ or “dose versus dose” contingencies enabled detection of more subtle differences than the simple ‘drug versus no drug’ approach when applied to the opioid, hallucinogen and barbiturate classes of drugs. These conclusions have implications for the interpretation of data from studies that utilise either within- or between-subject designs for studying the discriminative stimulus effects of drugs. PMID:21808191

The prevalence of antiretroviral multidrug resistance in highly active antiretroviral therapy-treated patients with HIV/AIDS between 2004 and 2009 in South Korea.

PubMed

Choi, Ju-yeon; Kwon, Oh-Kyung; Choi, Byeong-Sun; Kee, Mee-Kyung; Park, Mina; Kim, Sung Soon

2014-06-01

Highly active antiretroviral therapy (HAART) including protease inhibitors (PIs) has been used in South Korea since 1997. Currently, more than 20 types of antiretroviral drugs are used in the treatment of human immunodeficiency virus-infected/acquired immune deficiency syndrome patients in South Korea. Despite the rapid development of various antiretroviral drugs, many drug-resistant variants have been reported after initiating HAART, and the efficiency of HAART is limited by these variants. To investigate and estimate the annual antiretroviral drug resistance and prevalence of antiretroviral multi-class drug resistance in Korean patients with experience of treatment. The amplified HIV-1 pol gene in 535 patients requested for genotypic drug resistance testing from 2004 to 2009 by the Korea Centers for Disease Control and Prevention was sequenced and analyzed annually and totally. The prevalence of antiretroviral drug resistance was estimated based on "SIR" interpretation of the Stanford sequence database. Of viruses derived from 787 specimens, 380 samples (48.3%) showed at least one drug class-related resistance. Predicted NRTI drug resistance was highest at 41.9%. NNRTI showed 27.2% resistance with 23.3% for PI. The percent of annual drug resistance showed similar pattern and slightly declined except 2004 and 2005. The prevalence of multi-class drug resistance against each drug class was: NRTI/NNRTI/PI, 9.8%; NRTI/PI, 21.9%; NNRTI/PI, 10.4%; and NRTI/NNRTI, 21.5%. About 50% and less than 10% of patients infected with HIV-1 have multidrug and multiclass resistance linked to 16 antiretroviral drugs, respectively. The significance of this study lies in its larger-scale examination of the prevalence of drug-resistant variants and multidrug resistance in HAART-experienced patients in South Korea. Copyright © 2014 Elsevier B.V. All rights reserved.

Drug adherence in treatment resistant and in controlled hypertension-Results from the Swedish Primary Care Cardiovascular Database (SPCCD).

PubMed

Holmqvist, Lina; Boström, Kristina Bengtsson; Kahan, Thomas; Schiöler, Linus; Qvarnström, Miriam; Wettermark, Björn; Hjerpe, Per; Hasselström, Jan; Manhem, Karin

2018-03-01

To assess drug adherence in patients treated with ≥3 antihypertensive drug classes, with both controlled and uncontrolled blood pressure and describe associated factors for nonadherence. Patients with hypertension, without cardiovascular comorbidity, aged >30 years treated with ≥3 antihypertensive drug classes were followed for 2 years. Both patients with treatment resistant hypertension (TRH) and patients with controlled hypertension were included. Clinical data were derived from a primary care database. Pharmacy refill data from the Swedish Prescribed drug registry was used to calculate proportion of days covered (PDC). Patients with a PDC level ≥ 80% were included. We found 5846 patients treated ≥3 antihypertensive drug classes, 3508 with TRH (blood pressure ≥ 140/90), and 2338 with controlled blood pressure (<140/90 mm Hg). TRH patients were older (69.1 vs 65.8 years, P < .0001) but had less diabetes (28.5 vs 31.7%, P < .009) compared with patients with controlled blood pressure. The proportion of patients with PDC ≥ 80% declined with 11% during the first year in both groups. Having diabetes was associated with staying adherent at 1 year (RR 0.82; 95% CI, 0.68-0.98) whilst being born outside Europe was associated with nonadherence at one and (RR 2.05; 95% CI, 1.49-2.82). Patients with multiple antihypertensive drug therapy had similar decline in adherence over time regardless of initial blood pressure control. Diabetes was associated with better adherence, which may imply that the structured caregiving of these patients enhances antihypertensive drug treatment. Copyright © 2018 John Wiley & Sons, Ltd.

Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays

PubMed Central

Oliver, Sarah; Willard, Francis S.; Heidler, Steven; Peery, Robert B.; Oler, Jennifer; Chu, Shaoyou; Southall, Noel; Dexheimer, Thomas S.; Smallwood, Jeffrey; Huang, Ruili; Guha, Rajarshi; Jadhav, Ajit; Cox, Karen; Austin, Christopher P.; Simeonov, Anton; Sittampalam, G. Sitta; Husain, Saba; Franklin, Natalie; Wild, David J.; Yang, Jeremy J.; Sutherland, Jeffrey J.; Thomas, Craig J.

2015-01-01

Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS) pharmaceutical collection (NPC) is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD) phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/) (AID 1117321). Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben. PMID:26177200

Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays.

PubMed

Lee, Jonathan A; Shinn, Paul; Jaken, Susan; Oliver, Sarah; Willard, Francis S; Heidler, Steven; Peery, Robert B; Oler, Jennifer; Chu, Shaoyou; Southall, Noel; Dexheimer, Thomas S; Smallwood, Jeffrey; Huang, Ruili; Guha, Rajarshi; Jadhav, Ajit; Cox, Karen; Austin, Christopher P; Simeonov, Anton; Sittampalam, G Sitta; Husain, Saba; Franklin, Natalie; Wild, David J; Yang, Jeremy J; Sutherland, Jeffrey J; Thomas, Craig J

2015-01-01

Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS) pharmaceutical collection (NPC) is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD) phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/) (AID 1117321). Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben.

Alcohol and Other Drug Use Among Undergraduates at Indiana University, Bloomington, Including a Comparison Between I.U. Students and the State's High School Population. Indiana Studies in Higher Education, No. 49.

ERIC Educational Resources Information Center

Wakefield, Linda Morton

The use of alcohol and six classes of illicit drugs among 485 undergraduates at Indiana University, Bloomington, was studied in 1981-1982 and compared to a state study of alcohol/drug use by high school students. Attention was focused on the following questions: When does drug experimentation begin, and which drugs are currently most popular? How…

Tricyclic GyrB/ParE (TriBE) Inhibitors. A new class of broad-spectrum dual-targeting antibacterial agents

DOE PAGES

Tari, Leslie W.; Li, Xiaoming; Trzoss, Michael; ...

2013-12-26

Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. Growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highlymore » conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Moreover, lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.« less

Tricyclic GyrB/ParE (TriBE) Inhibitors. A new class of broad-spectrum dual-targeting antibacterial agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tari, Leslie W.; Li, Xiaoming; Trzoss, Michael

Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. Growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highlymore » conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Moreover, lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.« less

Using Clinical Data, Hypothesis Generation Tools and PubMed Trends to Discover the Association between Diabetic Retinopathy and Antihypertensive Drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Senter, Katherine G; Sukumar, Sreenivas R; Patton, Robert M

Diabetic retinopathy (DR) is a leading cause of blindness and common complication of diabetes. Many diabetic patients take antihypertensive drugs to prevent cardiovascular problems, but these drugs may have unintended consequences on eyesight. Six common classes of antihypertensive drug are angiotensin converting enzyme (ACE) inhibitors, alpha blockers, angiotensin receptor blockers (ARBs), -blockers, calcium channel blockers, and diuretics. Analysis of medical history data might indicate which of these drugs provide safe blood pressure control, and a literature review is often used to guide such analyses. Beyond manual reading of relevant publications, we sought to identify quantitative trends in literature from themore » biomedical database PubMed to compare with quantitative trends in the clinical data. By recording and analyzing PubMed search results, we found wide variation in the prevalence of each antihypertensive drug in DR literature. Drug classes developed more recently such as ACE inhibitors and ARBs were most prevalent. We also identified instances of change-over-time in publication patterns. We then compared these literature trends to a dataset of 500 diabetic patients from the UT Hamilton Eye Institute. Data for each patient included class of antihypertensive drug, presence and severity of DR. Graphical comparison revealed that older drug classes such as diuretics, calcium channel blockers, and -blockers were much more prevalent in the clinical data than in the DR and antihypertensive literature. Finally, quantitative analysis of the dataset revealed that patients taking -blockers were statistically more likely to have DR than patients taking other medications, controlling for presence of hypertension and year of diabetes onset. This finding was concerning given the prevalence of -blockers in the clinical data. We determined that clinical use of -blockers should be minimized in diabetic patients to prevent retinal damage.« less

Physician prescribing behavior and its impact on patient-level outcomes.

PubMed

Joyce, Geoffrey F; Carrera, Mariana P; Goldman, Dana P; Sood, Neeraj

2011-12-01

Concerns over rising drug costs, pharmaceutical advertising, and potential conflicts of interest have focused attention on physician prescribing behavior. We examine how broadly physicians prescribe within the 10 most prevalent therapeutic classes, the factors affecting their choices, and the impact of their prescribing behavior on patient-level outcomes. Retrospective study from 2005 to 2007 examining prescribers with at least 5 initial prescriptions within a class from 2005 to 2007. Medical and pharmacy claims are linked to prescriber information from 146 different health plans, reflecting 1975 to 8923 unique providers per drug class. Primary outcomes are the number of distinct drugs in a class initially prescribed by a physician over 1- and 3-year periods, medication possession ratio, and out-of-pocket costs. In 8 of 10 therapeutic classes, the median physician prescribes at least 3 different drugs and fewer than 1 in 6 physicians prescribe only brand drugs. Physicians prescribing only 1 or 2 drugs in a class are more likely to prescribe the most advertised drug. Physicians who prescribe fewer drugs are less likely to see patients with other comorbid conditions and varied formulary designs. Prescribing fewer drugs is associated with lower rates of medication adherence and higher out-ofpocket costs for drugs, but the effects are small and inconsistent across classes. Physicians prescribe more broadly than commonly perceived. Though narrow prescribers are more likely to prescribe highly advertised drugs, few physicians prescribe these drugs exclusively. Narrow prescribing has modest effects on medication adherence and out-of-pocket costs in some classes.

Effect of adolescent substance use and antisocial behavior on the development of early adulthood depression.

PubMed

Choi, Tai Kiu; Worley, Matthew J; Trim, Ryan S; Howard, David; Brown, Sandra A; Hopfer, Christian J; Hewitt, John K; Wall, Tamara L

2016-04-30

Major depressive disorder (MDD) is a prevalent and frequently comorbid psychiatric disorder. This study evaluates the development of depressive symptoms, MDD diagnosis, and suicidal ideation in a high-risk sample (N=524) diagnosed with conduct disorder (CD) and substance use disorder (SUD) symptoms as youth and re-assessed approximately 6.5 years later. Dual trajectory classes of both alcohol and other drug use (AOD) and antisocial behavior (ASB), previously identified using latent class growth analyses (LCGA), were used to predict depression outcomes. The Dual Chronic, Increasing AOD/Persistent ASB, and Decreasing Drugs/Persistent ASB classes had higher past-week depression scores, more past-year MDD symptoms, and were more likely to have past-year MDD than the Resolved class. The Dual Chronic and Decreasing Drugs/Persistent ASB classes also had more past-year MDD symptoms than the Persistent AOD/Adolescent ASB class. Youth at highest risk for developing or maintaining depression in adulthood had the common characteristic of persistent antisocial behavior. This suggests young adulthood depression is associated more with persistent antisocial behavior than with persistent substance use in comorbid youth. As such, interventions targeting high-risk youth, particularly those with persistent antisocial behavior, are needed to help reduce the risk of severe psychosocial consequences (including risk for suicide) in adulthood. Published by Elsevier Ireland Ltd.

Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine.

PubMed

Halpin, Laura E; Collins, Stuart A; Yamamoto, Bryan K

2014-02-27

Amphetamines are a class of psychostimulant drugs that are widely abused for their stimulant, euphoric, empathogenic and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, methamphetamine and 3,4 methylenedioxymethamphetamine (MDMA) produce persistent damage to dopamine and serotonin nerve terminals. This review summarizes the numerous interdependent mechanisms including excitotoxicity, mitochondrial damage and oxidative stress that have been demonstrated to contribute to this damage. Emerging non-neuronal mechanisms by which the drugs may contribute to monoaminergic terminal damage, as well as the neuropsychiatric consequences of this terminal damage are also presented. Methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) have similar chemical structures and pharmacologic properties compared to other abused substances including cathinone (khat), as well as a relatively new class of novel synthetic amphetamines known as 'bath salts' that have gained popularity among drug abusers. © 2013.

Neurotoxicity of Methamphetamine and 3,4-methylenedioxymethamphetamine

PubMed Central

Halpin, Laura E.; Collins, Stuart A.; Yamamoto, Bryan K.

2013-01-01

Amphetamines are a class of psychostimulant drugs that are widely abused for their stimulant, euphoric, empathogenic and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, methamphetamine and 3,4 methylenedioxymethamphetamine (MDMA) produce persistent damage to dopamine and serotonin nerve terminals. This review summarizes the numerous interdependent mechanisms including excitotoxicity, mitochondrial damage and oxidative stress that have been demonstrated to contribute to this damage. Emerging non-neuronal mechanisms by which the drugs may contribute to monoaminergic terminal damage, as well as the neuropsychiatric consequences of this terminal damage are also presented. Methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) have similar chemical structures and pharmacologic properties compared to other abused substances including cathinone (khat), as well as a relatively new class of novel synthetic amphetamines known as ‘bath salts’ that have gained popularity amongst drug abusers. PMID:23892199

Risks versus benefits of medication use during pregnancy: what do women perceive?

PubMed

Mulder, Bianca; Bijlsma, Maarten J; Schuiling-Veninga, Catharina Cm; Morssink, Leonard P; van Puijenbroek, Eugene; Aarnoudse, Jan G; Hak, Eelko; de Vries, Tjalling W

2018-01-01

Understanding perception of risks and benefits is essential for informed patient choices regarding medical care. The primary aim of this study was to evaluate the perception of risks and benefits of 9 drug classes during pregnancy and associations with women's characteristics. Questionnaires were distributed to pregnant women who attended a Dutch Obstetric Care facility (first- and second-line care). Mean perceived risk and benefit scores were computed for 9 different drug classes (paracetamol, antacids, antibiotics, antifungal medication, drugs against nausea and vomiting, histamine-2 receptor antagonists/proton pump inhibitors, antidepressants, nonsteroidal anti-inflammatory drugs, and sedatives/anxiolytics). For each participant, we computed weighted risk and benefit sum scores with principal component analysis. In addition, major concerns regarding medication use were evaluated. The questionnaire was completed by 136 women (response rate 77%). Pregnant women were most concerned about having a child with a birth defect (35%), a miscarriage (35%), or their child developing an allergic disease (23%), respectively, as a result of drug use. The majority of studied drug classes were perceived relatively low in risk and high in benefit. Higher risk scores were reported if women were in their first trimesters of pregnancy ( p =0.007). Lower benefit scores were reported if women were single ( p =0.014), smoking ( p =0.028), nulliparous ( p =0.006), or did not have a family history of birth defects ( p =0.005). Pregnant women's concerns regarding potential drug adverse effects were not only focused on congenital birth defects but also included a wider range of adverse outcomes. This study showed that most of the studied drug classes were perceived relatively low in risk and high in benefit.

Drug-target interaction prediction via class imbalance-aware ensemble learning.

PubMed

Ezzat, Ali; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

2016-12-22

Multiple computational methods for predicting drug-target interactions have been developed to facilitate the drug discovery process. These methods use available data on known drug-target interactions to train classifiers with the purpose of predicting new undiscovered interactions. However, a key challenge regarding this data that has not yet been addressed by these methods, namely class imbalance, is potentially degrading the prediction performance. Class imbalance can be divided into two sub-problems. Firstly, the number of known interacting drug-target pairs is much smaller than that of non-interacting drug-target pairs. This imbalance ratio between interacting and non-interacting drug-target pairs is referred to as the between-class imbalance. Between-class imbalance degrades prediction performance due to the bias in prediction results towards the majority class (i.e. the non-interacting pairs), leading to more prediction errors in the minority class (i.e. the interacting pairs). Secondly, there are multiple types of drug-target interactions in the data with some types having relatively fewer members (or are less represented) than others. This variation in representation of the different interaction types leads to another kind of imbalance referred to as the within-class imbalance. In within-class imbalance, prediction results are biased towards the better represented interaction types, leading to more prediction errors in the less represented interaction types. We propose an ensemble learning method that incorporates techniques to address the issues of between-class imbalance and within-class imbalance. Experiments show that the proposed method improves results over 4 state-of-the-art methods. In addition, we simulated cases for new drugs and targets to see how our method would perform in predicting their interactions. New drugs and targets are those for which no prior interactions are known. Our method displayed satisfactory prediction performance and was able to predict many of the interactions successfully. Our proposed method has improved the prediction performance over the existing work, thus proving the importance of addressing problems pertaining to class imbalance in the data.

PHYSICIAN PRESCRIBING BEHAVIOR AND ITS IMPACT ON PATIENT-LEVEL OUTCOMES

PubMed Central

Joyce, Geoffrey F.; Carrera, Mariana; Goldman, Dana P.; Sood, Neeraj

2013-01-01

OBJECTIVE Concerns over rising drug costs, pharmaceutical advertising and potential conflicts of interest have focused attention on physician prescribing behavior. We examine how broadly physicians prescribe within the ten most prevalent therapeutic classes, the factors affecting their choices, and its impact on patient-level outcomes. STUDY DESIGN Retrospective study from 2005 to 2007 examining prescribers with at least five initial prescriptions within a class from 2005–2007. Medical and pharmacy claims are linked to prescriber information from 146 different health plans, reflecting 1,975 to 8,923 unique providers per drug class. METHODS Primary outcomes are the number of distinct drugs in a class initially prescribed by a physician over 1- and 3-year periods, medication possession ratio, and out of pocket costs. RESULTS In 8 of 10 therapeutic classes, the median physician prescribes at least 3 different drugs and less than one in six physicians prescribes only brand drugs. Physicians prescribing only one or two drugs in a class are more likely to prescribe the most advertised drug. Physicians who prescribe fewer drugs are less likely to see patients with other comorbid conditions and varied formulary designs. Prescribing fewer drugs is associated with lower rates of medication adherence and higher out-of-pocket costs for drugs, but the effects are small and inconsistent across classes. CONCLUSIONS Physicians prescribe more broadly than commonly perceived. Though narrow prescribers are more likely to prescribe highly advertised drugs, few physicians prescribe these drugs exclusively. Narrow prescribing has modest effects on medication adherence and out of pocket costs in some classes. PMID:22216870

Skin cancer associated with commonly prescribed drugs: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and statins -weighing the evidence.

PubMed

Nardone, Beatrice; Orrell, Kelsey A; Vakharia, Paras P; West, Dennis P

2018-02-01

Skin cancers, including both malignant melanoma (MM) and nonmelanoma skin cancer (NMSC), are the most commonly diagnosed cancers in the US. The incidence of both MM and NMSC continues to rise. Areas covered: Current evidence for an association between four of the most commonly prescribed classes of drugs in the U.S. and risk for MM and NMSC is reported. Medline was searched (January 2000 to May 2017) for each drug in the classes and for 'basal cell carcinoma', 'squamous cell carcinoma', 'non-melanoma skin cancer', 'skin cancer' and 'melanoma'. Skin cancer risk information was reported for: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins). Expert opinion: Since skin cancer risk is associated with all four classes of these commonly prescribed drugs that represent nearly 20% of the Top 100 drugs in the U.S., these important findings warrant enhanced education, especially for prescribers and those patients at high risk for skin cancer.

Simultaneous screening and confirmation of multiple classes of drug residues in fish by liquid chromatography-ion trap mass spectrometry.

PubMed

Smith, Shani; Gieseker, Charles; Reimschuessel, Renate; Decker, Christie-Sue; Carson, Mary C

2009-11-13

LC-ion trap mass spectrometry was used to screen and confirm 38 compounds from a variety of drug classes in four species of fish: trout, salmon, catfish, and tilapia. Samples were extracted with acetonitrile and hexane. The acetonitrile phase was evaporated, redissolved in water and acetonitrile, and analyzed by gradient chromatography on a phenyl column. MS(2) or MS(3) spectra were monitored for each compound. Qualitative method performance was evaluated by the analysis over several days of replicate samples of control fish, fish fortified with a drug mixture at 1 ppm, 0.1 ppm and 0.01 ppm, and fish dosed with a representative from each drug class. Half of the 38 drugs were confirmed at 0.01 ppm, the lowest fortification level. This included all of the quinolones and fluoroquinolones, the macrolides, malachite green, and most of the imidazoles. Florfenicol amine, metronidazole, sulfonamides, tetracyclines, and most of the betalactams were confirmed at 0.1 ppm. Ivermectin and penicillin G were only detectable in the 1 ppm fortified samples. With the exception of amoxicillin, emamectin, metronidazole, and tylosin, residue presence was confirmed in all the dosed fish.

A Safer and Convenient Synthesis of Sulfathiazole for Undergraduate Organic and Medicinal Chemistry Classes

ERIC Educational Resources Information Center

Boyle, Jeff; Otty, Sandra; Sarojini, Vijayalekshmi

2012-01-01

A safer method for the synthesis of the sulfonamide drug sulfathiazole, for undergraduate classes, is described. This method improves upon procedures currently followed in several undergraduate teaching laboratories for the synthesis of sulfathiazole. Key features of this procedure include the total exclusion of pyridine, which has potential…

Gradient of association between parenting styles and patterns of drug use in adolescence: A latent class analysis.

PubMed

Valente, Juliana Y; Cogo-Moreira, Hugo; Sanchez, Zila M

2017-11-01

To identify different patterns of drug use in adolescence and determine if these are associated with parenting styles and other sociodemographic factors. A latent class analysis was conducted using baseline data collected in a sample (n=6381) from a randomized controlled trial conducted to evaluate the effectiveness of the #Tamojunto drug-use prevention program, carried out with 7th- and 8th-grade public school students in six Brazilian cities. Three latent classes were identified among the students: 1) abstainers/low users (81.54%), 2) alcohol users/binge drinkers (16.65%), and 3) polydrug users (1.80%). A gradient of inverse association was found between parenting styles (authoritative, authoritarian, and indulgent, with the neglectful style as a reference point) and the classes "alcohol users/binge drinkers" (aOR=0.36, 95%CI=0.27-0.47; aOR=0.56, 95%CI=0.43-0.72; and aOR=0.64, 95%CI=0.51-0.80, respectively) and "polydrug users" (aOR=0.09, 95%CI=0.03-0.24; aOR=0.23, 95%CI=0.11-0.52; and aOR=0.24, 95%CI=0.08-0.74, respectively). Associations were also revealed between the latent classes and the adolescent's age and socioeconomic status. The results suggest that activities to develop parenting skills should be included in school programs aimed at the prevention of drug use among adolescents in order to reduce neglectful practices and thereby possibly reduce drug use among the children. Copyright © 2017. Published by Elsevier B.V.

The effect of new and continuing prescription drug use on cost: a longitudinal analysis of chronic and seasonal utilization.

PubMed

Fairman, K A

2000-05-01

To provide basic information about 2 factors contributing to rising prescription drug costs--utilization trends and product selection. Prescription drug costs have risen sharply in recent years, and continued growth is expected. There is little consensus about appropriate cost-management strategies, in part because quantitative data on the causes and implications of increased drug costs are lacking. This study followed 463,820 continuously enrolled adult (> or = 18 years of age on January 1, 1996) utilizers of 15 chronic or seasonal therapeutic classes for 2.5 years (January 1996 through June 1998) using a pharmacy benefit manager's multiple-payer claims database. Outcome measures included (1) change in utilization rate, (2) relationship between new use and utilization growth, (3) stability of the treated population (ie, mostly long-term use vs high rates of turnover), and (4) product mix changes (ie, cost per dispensed day for 1996 vs 1997 and for new vs continuing users, controlling for inflation). Of the 463,820 utilizers, 97% were commercially insured and 3% enrolled in Medicare risk plans; 40% were enrolled in managed care and the remainder covered by indemnity insurance. Rates of growth and turnover varied substantially by class. The highest 2-year utilization rate change was 66.7% for antihyperlipidemic agents; change was < 10% in only 3 classes. Across classes, an average of 38.7% of 1997 users were new (ie, no use in 1996) and an average of 34.0% of 1996 users were dropouts (ie, no use in 1997). Utilization growth depended heavily on treatment continuation; classes with high dropout rates (eg, antirheumatic, antiasthmatic) did not have high growth rates, even with high rates of new use. In most classes, costs were not higher for new than for continuing users. In some classes, however (eg, antipsychotic, antidiabetic), both new and continuing users increased their use of newer, more expensive products. Because factors underlying rising prescription drug costs vary by therapeutic class, cost-containment strategies should address these differences. Further research is needed to assess the clinical and economic costs and benefits of rapid growth in the utilization of certain therapeutic classes.

Computational health economics for identification of unprofitable health care enrollees

PubMed Central

Rose, Sherri; Bergquist, Savannah L.; Layton, Timothy J.

2017-01-01

SUMMARY Health insurers may attempt to design their health plans to attract profitable enrollees while deterring unprofitable ones. Such insurers would not be delivering socially efficient levels of care by providing health plans that maximize societal benefit, but rather intentionally distorting plan benefits to avoid high-cost enrollees, potentially to the detriment of health and efficiency. In this work, we focus on a specific component of health plan design at risk for health insurer distortion in the Health Insurance Marketplaces: the prescription drug formulary. We introduce an ensembled machine learning function to determine whether drug utilization variables are predictive of a new measure of enrollee unprofitability we derive, and thus vulnerable to distortions by insurers. Our implementation also contains a unique application-specific variable selection tool. This study demonstrates that super learning is effective in extracting the relevant signal for this prediction problem, and that a small number of drug variables can be used to identify unprofitable enrollees. The results are both encouraging and concerning. While risk adjustment appears to have been reasonably successful at weakening the relationship between therapeutic-class-specific drug utilization and unprofitability, some classes remain predictive of insurer losses. The vulnerable enrollees whose prescription drug regimens include drugs in these classes may need special protection from regulators in health insurance market design. PMID:28369273

Fixed-dose combination and single active ingredient drugs: a comparative cost analysis.

PubMed

Hao, Jing; Rodriguez-Monguio, Rosa; Seoane-Vazquez, Enrique

2016-01-01

Fixed-dose combination (FDC) drugs are formulations of two or more active ingredients. To assess the pricing structure and price difference of all US FDA-approved FDCs and single drugs included in the combination. Data were collected from the FDA Orange Book and Drugs@FDA. Average Wholesale Price (AWP) unit price data were derived from The Red Book. The FDA approved 117 FDC. The average AWP difference percentage between the FDC and the sum of the single drugs in the FDC is 84.9 ± 26.2%, and varied by therapeutic class (p < 0.001). The FDC AWP averaged 83.3 ± 23.4% of the single drug AWP sum when there are no generics, and 95.1 ± 42.3% (p < 0.01) when there are two generic single active ingredients in the FDC. The price difference between FDC and single active ingredients in the combination is correlated with the therapeutic class, the year of FDC approval, and the number of single ingredients in the combination that have generics.

Management of unstable arrhythmias in cardiogenic shock.

PubMed

Saidi, Abdulfattah; Akoum, Nazem; Bader, Feras

2011-08-01

Atrial and ventricular arrhythmias commonly arise in the setting of cardiogenic shock and often result in hemodynamic deterioration. Causative factors include myocardial ischemia, volume overload, and metabolic disturbances. Correcting these factors plays an important role in managing arrhythmias in this setting. Ventricular arrhythmias are more ominous compared to atrial arrhythmias but both require prompt intervention with electrical shock and anti-arrhythmic drug suppression. Coronary reperfusion is key to improving survival, including reducing the risk of sudden cardiac arrest, in acute myocardial infarction. Case series have also demonstrated the value of intra-aortic balloon pump counter-pulsation in suppressing ventricular arrhythmias in cardiogenic shock. The mechanism of arrhythmia suppression may be due to improved coronary perfusion and afterload reduction. Percutaneous ventricular assist device placement may be effective in this setting; however, data addressing this specific endpoint are lacking. Anti-arrhythmic drug options for ventricular and atrial arrhythmia suppression, in the setting of cardiogenic shock, are relatively limited. Common class I agents are excluded due to the inherent abnormal cardiac structure and function in the setting of cardiogenic shock. Class III drug options include dofetilide and amiodarone. The other Class III agents, sotalol and dronedarone, are excluded due to associated mortality observed in the SWORD and ANDROMEDA trials, respectively. Dofetilide is renally excreted and causes QT interval prolongation. Care should be taken to avoid excessive drug accumulation due to poor kidney perfusion and function. Dofetilide is approved for use for atrial arrhythmias and has not been studied for ventricular arrhythmia suppression. The DIAMOND-CHF trial established its safety in the setting of heart failure. Amiodarone is very effective in suppressing both atrial and ventricular arrhythmias. It is often the drug of choice in heart failure. Its off-label use for atrial arrhythmias is very common. Care should be taken with intravenous amiodarone to avoid hypotension.

Prices, profits, and innovation: examining criticisms of new psychotropic drugs' value.

PubMed

Huskamp, Haiden A

2006-01-01

High profits and high drug costs have brought increased scrutiny of the pharmaceutical industry over the issue of whether the drugs they produce are worth the costs. I examine several related complaints, including the proliferation of me-too drugs and product reformulations, which some argue have little value relative to their cost; the baseless promotion of newer drug classes as more effective than existing, less expensive drugs; legal strategies to extend market exclusivity that result in high brand-name drug prices for an extended period of time; and large promotional expenditures that result in higher prices.

Medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and invention of boron tracedrugs as innovative future-architectural drugs.

PubMed

Hori, Hitoshi; Uto, Yoshihiro; Nakata, Eiji

2010-09-01

We describe herein for the first time our medicinal electronomics bricolage design of hypoxia-targeting antineoplastic drugs and boron tracedrugs as newly emerging drug classes. A new area of antineoplastic drugs and treatments has recently focused on neoplastic cells of the tumor environment/microenvironment involving accessory cells. This tumor hypoxic environment is now considered as a major factor that influences not only the response to antineoplastic therapies but also the potential for malignant progression and metastasis. We review our medicinal electronomics bricolage design of hypoxia-targeting drugs, antiangiogenic hypoxic cell radiosensitizers, sugar-hybrid hypoxic cell radiosensitizers, and hypoxia-targeting 10B delivery agents, in which we design drug candidates based on their electronic structures obtained by molecular orbital calculations, not based solely on pharmacophore development. These drugs include an antiangiogenic hypoxic cell radiosensitizer TX-2036, a sugar-hybrid hypoxic cell radiosensitizer TX-2244, new hypoxia-targeting indoleamine 2,3-dioxygenase (IDO) inhibitors, and a hypoxia-targeting BNCT agent, BSH (sodium borocaptate-10B)-hypoxic cytotoxin tirapazamine (TPZ) hybrid drug TX-2100. We then discuss the concept of boron tracedrugs as a new drug class having broad potential in many areas.

Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation.

PubMed

Lafuente-Lafuente, Carmelo; Valembois, Lucie; Bergmann, Jean-François; Belmin, Joël

2015-03-28

Atrial fibrillation is the most frequent sustained arrhythmia. Atrial fibrillation frequently recurs after restoration of normal sinus rhythm. Antiarrhythmic drugs have been widely used to prevent recurrence, but the effect of these drugs on mortality and other clinical outcomes is unclear. This is an update of a review previously published in 2008 and 2012. To determine in patients who have recovered sinus rhythm after having atrial fibrillation, the effects of long-term treatment with antiarrhythmic drugs on death, stroke, embolism, drug adverse effects and recurrence of atrial fibrillation. We updated the searches of CENTRAL in The Cochrane Library (2013, Issue 12 of 12), MEDLINE (to January 2014) and EMBASE (to January 2014). The reference lists of retrieved articles, recent reviews and meta-analyses were checked. Two independent authors selected randomised controlled trials comparing any antiarrhythmic drug with a control (no treatment, placebo, drugs for rate control) or with another antiarrhythmic drug in adults who had atrial fibrillation and in whom sinus rhythm was restored. Post-operative atrial fibrillation was excluded. Two authors independently assessed quality and extracted data. Studies were pooled, if appropriate, using Peto odds ratio (OR). All results were calculated at one year of follow-up. In this update three new studies, with 534 patients, were included making a total of 59 included studies comprising 21,305 patients. All included studies were randomised controlled trials. Allocation concealment was adequate in 17 trials, it was unclear in the remaining 42 trials. Risk of bias was assessed in all domains only in the trials included in this update.Compared with controls, class IA drugs quinidine and disopyramide (OR 2.39, 95% confidence interval (95% CI) 1.03 to 5.59, number needed to treat to harm (NNTH) 109, 95% CI 34 to 4985) and sotalol (OR 2.23, 95% CI 1.1 to 4.50, NNTH 169, 95% CI 60 to 2068) were associated with increased all-cause mortality. Other antiarrhythmics did not seem to modify mortality, but our data could be underpowered to detect mild increases in mortality for several of the drugs studied.Several class IA (disopyramide, quinidine), IC (flecainide, propafenone) and III (amiodarone, dofetilide, dronedarone, sotalol) drugs significantly reduced recurrence of atrial fibrillation (OR 0.19 to 0.70, number needed to treat to beneft (NNTB) 3 to 16). Beta-blockers (metoprolol) also significantly reduced atrial fibrillation recurrences (OR 0.62, 95% CI 0.44 to 0.88, NNTB 9).All analysed drugs increased withdrawals due to adverse affects and all but amiodarone, dronedarone and propafenone increased pro-arrhythmia. Only 11 trials reported data on stroke. None of them found any significant difference with the exception of a single trial than found less strokes in the group treated with dronedarone compared to placebo. This finding was not confirmed in others studies on dronedarone.We could not analyse heart failure and use of anticoagulation because few original studies reported on these measures. Several class IA, IC and III drugs, as well as class II drugs (beta-blockers), are moderately effective in maintaining sinus rhythm after conversion of atrial fibrillation. However, they increase adverse events, including pro-arrhythmia, and some of them (disopyramide, quinidine and sotalol) may increase mortality. Possible benefits on clinically relevant outcomes (stroke, embolism, heart failure) remain to be established.

An Assessment of Drug Education-Prevention Programs in the U. S. Army. Army Research Institute Technical Paper 261.

ERIC Educational Resources Information Center

Cook, Royer F.; Morton, Anton S.

In recent years the Army has been concerned about the widespread use of psychoactive drugs by all classes of young people and the effects of this use on the Army. In order to curb this use among soldiers the Army initiated a comprehensive program to prevent and control the abuse of alcohol and drugs. Prevention was considered to include education,…

Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites.

PubMed

Kevin Ii, Dion A; Meujo, Damaris Af; Hamann, Mark T

2009-02-01

As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections. Despite the long history of use of this class of drugs, very limited medicinal chemistry and drug optimization studies have been reported, thus leaving the door open to these opportunities in the future. Scifinder and PubMed were the main search engines used to locate articles relevant to the topic presented in the present review. Keywords used in our search were specific names of each of the 88 compounds presented in the review as well as more general terms such as polyethers, ionophores, carboxylic polyethers and polyether antibiotics.

Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites

PubMed Central

Kevin, Dion A; Meujo, Damaris AF; Hamann, Mark T

2016-01-01

Background As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Objective Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Conclusion Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections. Despite the long history of use of this class of drugs, very limited medicinal chemistry and drug optimization studies have been reported, thus leaving the door open to these opportunities in the future. Scifinder and PubMed were the main search engines used to locate articles relevant to the topic presented in the present review. Keywords used in our search were specific names of each of the 88 compounds presented in the review as well as more general terms such as polyethers, ionophores, carboxylic polyethers and polyether antibiotics. PMID:23480512

Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage.

PubMed

Chan, Rosa; Wei, Chun-Yu; Chen, Yuan-Tsong; Benet, Leslie Z

2016-05-01

Cutaneous adverse reactions (CARs) from antiepileptic drugs (AEDs) are common, ranging from mild to life-threatening, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The identification of subjects carrying the HLA-B*15:02, an inherited allelic variant of the HLA-B gene, and the avoidance of carbamazepine (CBZ) therapy in these subjects are strongly associated with a decrease in the incidence of carbamazepine-induced SJS/TEN. In spite of the strong genetic associations, the initiation of hypersensitivity for AEDs is still not very well characterized. Predicting the potential for other AEDs to cause adverse reactions will be undoubtedly beneficial to avoid CARs, which is the focus of this report. Here, we explore the use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to distinguish AEDs associated with and without CARs by examining the binding relationship of AEDs to HLA-B*15:02 and data from extensive reviews of medical records. We also evaluate the lack of benefit from a Hong Kong population policy on the effects of screening for HLA-B*15:02 and previous incorrect structure-activity hypotheses. Our analysis concludes that BDDCS class 2 AEDs are more prone to cause adverse cutaneous reactions than certain BDDCS class 1 AEDs and that BDDCS Class 3 drugs have the lowest levels of cutaneous adverse reactions. We propose that BDDCS Class 3 AEDs should be preferentially used for patients with Asian backgrounds (i.e., Han Chinese, Thai, and Malaysian populations) if possible and in patients predisposed to skin rashes.

Synthesis and in vitro activity of dicationic bis-benzimidazoles as a new class of anti-MRSA and anti-VRE agents.

PubMed

Hu, Laixing; Kully, Maureen L; Boykin, David W; Abood, Norman

2009-03-01

A new class of novel bis-benzimidazole diamidine compounds have been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Anti-MRSA and anti-VRE activities of the most potent compound 1 were more active than Vancomycin. The mechanism of action for this class of compounds appears to be different from existing antibiotics. Bis-benzimidazole diamidine compounds have potential for further investigation as a new class of potent anti-MRSA and anti-VRE agents.

Lipid-Based Nanoparticles as Pharmaceutical Drug Carriers: From Concepts to Clinic

PubMed Central

Puri, Anu; Loomis, Kristin; Smith, Brandon; Lee, Jae-Ho; Yavlovich, Amichai; Heldman, Eli; Blumenthal, Robert

2010-01-01

In recent years, various nanotechnology platforms in the area of medical biology, including both diagnostics and therapy, have gained remarkable attention. Moreover, research and development of engineered multifunctional nanoparticles as pharmaceutical drug carriers have spurred exponential growth in applications to medicine in the last decade. Design principles of these nanoparticles, including nano-emulsions, dendrimers, nano-gold, liposomes, drug-carrier conjugates, antibody-drug complexes, and magnetic nanoparticles, are primarily based on unique assemblies of synthetic, natural, or biological components, including but not limited to synthetic polymers, metal ions, oils, and lipids as their building blocks. However, the potential success of these particles in the clinic relies on consideration of important parameters such as nanoparticle fabrication strategies, their physical properties, drug loading efficiencies, drug release potential, and, most importantly, minimum toxicity of the carrier itself. Among these, lipid-based nanoparticles bear the advantage of being the least toxic for in vivo applications, and significant progress has been made in the area of DNA/RNA and drug delivery using lipid-based nanoassemblies. In this review, we will primarily focus on the recent advances and updates on lipid-based nanoparticles for their projected applications in drug delivery. We begin with a review of current activities in the field of liposomes (the so-called honorary nanoparticles), and challenging issues of targeting and triggering will be discussed in detail. We will further describe nanoparticles derived from a novel class of amphipathic lipids called bolaamphiphiles with unique lipid assembly features that have been recently examined as drug/DNA delivery vehicles. Finally, an overview of an emerging novel class of particles (based on lipid components other than phospholipids), solid lipid nanoparticles and nanostructured lipid carriers will be presented. We conclude with a few examples of clinically successful formulations of currently available lipid-based nanoparticles. PMID:20402623

Current and evolving approaches for improving the oral permeability of BCS Class III or analogous molecules.

PubMed

Dave, Vivek S; Gupta, Deepak; Yu, Monica; Nguyen, Phuong; Varghese Gupta, Sheeba

2017-02-01

The Biopharmaceutics Classification System (BCS) classifies pharmaceutical compounds based on their aqueous solubility and intestinal permeability. The BCS Class III compounds are hydrophilic molecules (high aqueous solubility) with low permeability across the biological membranes. While these compounds are pharmacologically effective, poor absorption due to low permeability becomes the rate-limiting step in achieving adequate bioavailability. Several approaches have been explored and utilized for improving the permeability profiles of these compounds. The approaches include traditional methods such as prodrugs, permeation enhancers, ion-pairing, etc., as well as relatively modern approaches such as nanoencapsulation and nanosizing. The most recent approaches include a combination/hybridization of one or more traditional approaches to improve drug permeability. While some of these approaches have been extremely successful, i.e. drug products utilizing the approach have progressed through the USFDA approval for marketing; others require further investigation to be applicable. This article discusses the commonly studied approaches for improving the permeability of BCS Class III compounds.

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

PubMed Central

Heinsbroek, J. A.; Gipson, C. D.; Kupchik, Y. M.; Spencer, S.; Smith, A. C. W.; Roberts-Wolfe, D.; Kalivas, P. W.

2016-01-01

The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances. PMID:27363441

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis.

PubMed

Scofield, M D; Heinsbroek, J A; Gipson, C D; Kupchik, Y M; Spencer, S; Smith, A C W; Roberts-Wolfe, D; Kalivas, P W

2016-07-01

The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Psychotropic Polypharmacy in Patients with Dementia: Prevalence and Predictors.

PubMed

Nørgaard, Ane; Jensen-Dahm, Christina; Gasse, Christiane; Hansen, Elsebet Steno; Waldemar, Gunhild

2017-01-01

Antipsychotics and other psychotropics are frequently used to treat neuropsychiatric symptoms in patients with dementia, even though the evidence for effect is limited. Concerns have been raised about the safety of antipsychotics, but concomitant use of multiple psychotropic drug classes (psychotropic polypharmacy) may also pose a risk for patients. To investigate the prevalence and predictors associated with use of psychotropic polypharmacy in patients with dementia. A population-based study using nationwide registers. Patients with dementia were identified among all Danish residents ≥65 years on January 1, 2012. Data on prescriptions and comorbidity was included in the analysis. Overlapping prescriptions for different psychotropic drug classes were used to determine psychotropic polypharmacy. A multivariable logistic regression analysis was conducted to evaluate factors independently associated with the prescription of other psychotropic drug classes among patients already using antipsychotics. Among all patients registered with dementia (34,553), 25.3% (8,728) used ≥2 psychotropic drugs. Among patients treated with antipsychotics 75.8% (5,403) used at least one other psychotropic drug during the antipsychotic treatment period. Nursing home residency, number of non-psychotropic medications used in 2011, and prior psychiatric diagnosis were associated with psychotropic polypharmacy among antipsychotic drug users. The most frequent combination of psychotropic drugs was antipsychotics and antidepressants. Concomitant use of psychotropic drugs was frequent in dementia patients. Patients living in nursing homes had the highest risk of receiving a combination of antipsychotics and other psychotropic drugs. Concomitant use of psychotropics may cause adverse events, and potential consequences for patients' safety call for further investigation.

A benefit-risk assessment of class III antiarrhythmic agents.

PubMed

Brendorp, Bente; Pedersen, Oledyg; Torp-Pedersen, Christian; Sahebzadah, Naji; Køber, Lars

2002-01-01

With beta-blockers as the exception, increasing doubt is emerging on the value of antiarrhythmic drug therapy following a series of trials that have either shown no mortality benefit or even an excess mortality. Vaughan Williams class I drugs are generally avoided in patients with structural heart disease, and class IV drugs are avoided in heart failure. Unfortunately, arrhythmias are a growing problem due to an increase in the incidence of atrial fibrillation and sudden death. The population is becoming older and more patients survive for a longer time period with congestive heart failure, which again increases the frequency of both supraventricular as well as ventricular arrhythmias. Class III antiarrhythmic drugs act by blocking repolarising currents and thereby prolong the effective refractory period of the myocardium. This is believed to facilitate termination of re-entry tachyarrhythmias. This class of drugs is developed for treatment of both supraventricular and ventricular arrhythmias. Amiodarone, sotalol, dofetilide, and ibutilide are examples of class III drugs that are currently available. Amiodarone and sotalol have other antiarrhythmic properties in addition to pure class III action, which differentiates them from the others. However, all have potential serious adverse events. Proarrhythmia, especially torsade de pointes, is a common problem making the benefit-risk ratio of these drugs a key question. Class III drugs have been evaluated in different settings: primary and secondary prevention of ventricular arrhythmias and in treatment of atrial fibrillation or flutter. Based on existing evidence there is no routine indication for antiarrhythmic drug therapy other than beta-blockers in patients at high risk of sudden death. Subgroup analyses of trials with amiodarone and dofetilide suggest that patients with atrial fibrillation may have a mortality reduction with these drugs. However, this needs to be tested in a prospective trial. Similarly, subgroups that will benefit from prophylactic treatment with class III antiarrhythmic drugs may be found based on QT-intervals or - in the future - from genetic testing. Class III drugs are effective in converting atrial fibrillation to sinus rhythm and for the maintenance of sinus rhythm after conversion. This is currently by far the most important indication for this class of drugs. As defined by recent guidelines, amiodarone and dofetilide have their place as second-line therapy except for patients with heart failure where they are first line therapy being the only drugs where the safety has been documented for this group of high risk patients.

Using cooperative learning for a drug information assignment.

PubMed

Earl, Grace L

2009-11-12

To implement a cooperative learning activity to engage students in analyzing tertiary drug information resources in a literature evaluation course. The class was divided into 4 sections to form expert groups and each group researched a different set of references using the jigsaw technique. Each member of each expert group was reassigned to a jigsaw group so that each new group was composed of 4 students from 4 different expert groups. The jigsaw groups met to discuss search strategies and rate the usefulness of the references. In addition to group-based learning, teaching methods included students' writing an independent research paper to enhance their abilities to search and analyze drug information resources. The assignment and final course grades improved after implementation of the activity. Students agreed that class discussions were a useful learning experience and 75% (77/102) said they would use the drug information references for other courses. The jigsaw technique was successful in engaging students in cooperative learning to improve critical thinking skills regarding drug information.

Computational health economics for identification of unprofitable health care enrollees.

PubMed

Rose, Sherri; Bergquist, Savannah L; Layton, Timothy J

2017-10-01

Health insurers may attempt to design their health plans to attract profitable enrollees while deterring unprofitable ones. Such insurers would not be delivering socially efficient levels of care by providing health plans that maximize societal benefit, but rather intentionally distorting plan benefits to avoid high-cost enrollees, potentially to the detriment of health and efficiency. In this work, we focus on a specific component of health plan design at risk for health insurer distortion in the Health Insurance Marketplaces: the prescription drug formulary. We introduce an ensembled machine learning function to determine whether drug utilization variables are predictive of a new measure of enrollee unprofitability we derive, and thus vulnerable to distortions by insurers. Our implementation also contains a unique application-specific variable selection tool. This study demonstrates that super learning is effective in extracting the relevant signal for this prediction problem, and that a small number of drug variables can be used to identify unprofitable enrollees. The results are both encouraging and concerning. While risk adjustment appears to have been reasonably successful at weakening the relationship between therapeutic-class-specific drug utilization and unprofitability, some classes remain predictive of insurer losses. The vulnerable enrollees whose prescription drug regimens include drugs in these classes may need special protection from regulators in health insurance market design. © The Author 2017. Published by Oxford University Press.

Few Drugs Display Flip-Flop Pharmacokinetics and These Are Primarily Associated with Classes 3 and 4 of the BDDCS.

PubMed

Garrison, Kimberly L; Sahin, Selma; Benet, Leslie Z

2015-09-01

This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Patterns of HIV Risks and Related Factors among People Who Inject Drugs in Kermanshah, Iran: A Latent Class Analysis.

PubMed

Sharifi, Hamid; Mirzazadeh, Ali; Noroozi, Alireza; Marshall, Brandon D L; Farhoudian, Ali; Higgs, Peter; Vameghi, Meroe; Mohhamadi Shahboulaghi, Farahnaz; Qorbani, Mostafa; Massah, Omid; Armoon, Bahram; Noroozi, Mehdi

2017-01-01

The objective of this study was to explore patterns of drug use and sexual risk behaviors among people who inject drugs (PWID) in Iran. We surveyed 500 PWID in Kermanshah concerning demographic characteristics, sexual risk behaviors, and drug-related risk behaviors in the month prior to study. We used latent class analysis (LCA) to establish a baseline model of risk profiles and to identify the optimal number of latent classes, and we used ordinal regression to identify factors associated with class membership. Three classes of multiple HIV risk were identified. The probability of membership in the high-risk class was 0.33, compared to 0.26 and 0.40 for the low- and moderate-risk classes, respectively. Compared to members in the lowest-risk class (reference group), the highest-risk class members had higher odds of being homeless (OR = 4.5, CI: 1.44-8.22; p = 0.001) in the past 12 months. Members of the high-risk class had lower odds of regularly visiting a needle and syringe exchange program as compared to the lowest-risk class members (AOR = 0.42, CI: 0.2-0.81; p = 0.01). Findings show the sexual and drug-related HIV risk clusters among PWID in Iran, and emphasize the importance of developing targeted prevention and harm reduction programs for all domains of risk behaviors, both sexual and drug use related.

A hybrid method for prediction and repositioning of drug Anatomical Therapeutic Chemical classes.

PubMed

Chen, Lei; Lu, Jing; Zhang, Ning; Huang, Tao; Cai, Yu-Dong

2014-04-01

In the Anatomical Therapeutic Chemical (ATC) classification system, therapeutic drugs are divided into 14 main classes according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties. This system, recommended by the World Health Organization (WHO), provides a global standard for classifying medical substances and serves as a tool for international drug utilization research to improve quality of drug use. In view of this, it is necessary to develop effective computational prediction methods to identify the ATC-class of a given drug, which thereby could facilitate further analysis of this system. In this study, we initiated an attempt to develop a prediction method and to gain insights from it by utilizing ontology information of drug compounds. Since only about one-fourth of drugs in the ATC classification system have ontology information, a hybrid prediction method combining the ontology information, chemical interaction information and chemical structure information of drug compounds was proposed for the prediction of drug ATC-classes. As a result, by using the Jackknife test, the 1st prediction accuracies for identifying the 14 main ATC-classes in the training dataset, the internal validation dataset and the external validation dataset were 75.90%, 75.70% and 66.36%, respectively. Analysis of some samples with false-positive predictions in the internal and external validation datasets indicated that some of them may even have a relationship with the false-positive predicted ATC-class, suggesting novel uses of these drugs. It was conceivable that the proposed method could be used as an efficient tool to identify ATC-classes of novel drugs or to discover novel uses of known drugs.

Novel targets for HIV therapy.

PubMed

Greene, Warner C; Debyser, Zeger; Ikeda, Yasuhiro; Freed, Eric O; Stephens, Edward; Yonemoto, Wes; Buckheit, Robert W; Esté, José A; Cihlar, Tomas

2008-12-01

There are currently 25 drugs belonging to 6 different inhibitor classes approved for the treatment of human immunodeficiency virus (HIV) infection. However, new anti-HIV agents are still needed to confront the emergence of drug resistance and various adverse effects associated with long-term use of antiretroviral therapy. The 21st International Conference on Antiviral Research, held in April 2008 in Montreal, Canada, therefore featured a special session focused on novel targets for HIV therapy. The session included presentations by world-renowned experts in HIV virology and covered a diverse array of potential targets for the development of new classes of HIV therapies. This review contains concise summaries of discussed topics that included Vif-APOBEC3G, LEDGF/p75, TRIM 5alpha, virus assembly and maturation, and Vpu. The described viral and host factors represent some of the most noted examples of recent scientific breakthroughs that are opening unexplored avenues to novel anti-HIV target discovery and validation, and should feed the antiretroviral drug development pipeline in the near future.

Advancements in Non-steroidal Antiandrogens as Potential Therapeutic Agents for the Treatment of Prostate Cancer.

PubMed

Kaur, Paranjeet; Khatik, Gopal L

2016-01-01

Prostate cancer (PCa) is a leading cause of death in men worldwide. The main reason for the progression of prostate cancer is identified as over activation of androgen receptor (AR) through androgens. Its development can be diagnosed by monitoring the prostate specific antigen (PSA). Treatment of PCa includes prostatectomy, radiotherapy, and chemotherapy, among them chemotherapy is normally employed in early and advanced prostate cancer. Chemotherapy mainly includes two classes of drugs which are steroidal and non-steroidal antiandrogens. The non-steroidal classes of compounds are preferred over steroidal because they are relatively safe, cost effective and diverse. Non-steroidal drugs are commonly used for the treatment of PCa, however these drugs are associated with serious side effects and acquired resistance. So researchers are working in the direction to develop better analogue which can address the issue related to resistant type of prostate cancer. This review discusses the advancement in the non-steroidal antiandrogens which offers a better potential in the treatment of prostate cancer.

Prices, Profits and Innovation: Examining Criticisms of the Value of New Psychotropic Drugs

PubMed Central

Huskamp, Haiden A.

2008-01-01

High profits and high drug costs have brought increased scrutiny of the pharmaceutical industry over the issue of whether the drugs they produce are worth the costs. I examine several related complaints, including the proliferation of me-too drugs and product reformulations, which some argue have little value relative to their cost; promotion of newer drug classes as more effective than existing, less expensive drugs in the absence of evidence of superior effectiveness; legal strategies to extend market exclusivity that result in high brand drug prices for an extended period of time; and large promotional expenditures that result in higher prices. PMID:16684726

Patterns of Drug Use and Serum Sodium Concentrations in Older Hospitalized Patients: A Latent Class Analysis Approach.

PubMed

Woodman, Richard J; Wood, Karen M; Kunnel, Aline; Dedigama, Maneesha; Pegoli, Matthew A; Soiza, Roy L; Mangoni, Arduino A

2016-12-01

Several drugs may lower serum sodium concentrations (NaC) in older patients. However, distinguishing their individual effects is particularly difficult in this population because of the high prevalence of polypharmacy and disease states that are per se associated with hyponatremia. Our objective was to identify specific patterns of medication use in older hospitalized patients and determine whether these patterns were associated with serum NaC. We collected clinical and demographic data, pre-admission drugs, Drug Burden Index (DBI) score, and average NaC during hospitalization in a consecutive series of older medical patients (n = 101, mean ± standard deviation [SD] age 87 ± 6 years). We used latent class analysis (LCA) to identify specific patterns of drug use and multivariate regression to determine the associations between 14 separate drug classes, identified patterns of drug use, and NaC. LCA revealed three patterns: lower overall drug use (class 1), anticoagulant use and higher drug use (class 2), and antiplatelet use (class 3). Mean (±SD) DBI score in each class was 2.7 ± 1.3, 3.3 ± 1.6, and 2.4 ± 1.5, respectively (p = 0.04). Mean (± SD) NaC in classes 1, 2, and 3 were 140.6 ± 6.8, 138.7 ± 5.3, and 136.5 ± 4.7 mmol/l, respectively (p = 0.006). After adjustment for age, sex, Charlson Comorbidity Index score, estimated glomerular filtration rate (eGFR), DBI score, and digoxin use, mean NaC in class 2 and class 3 was significantly lower than in class 1 (-3.9 mmol/l; 95% confidence interval [CI] -7.1 to -0.8, p = 0.01 and -5.2 mmol/l; 95% CI -7.9 to -2.5, p < 0.001, respectively). Mean serum NaC was not significantly associated with any of the 14 individually assessed drug classes. In addition to latent class, increasing age and higher eGFR were also independently associated with lower serum NaC (p = 0.002 and p = 0.03, respectively). LCA enabled us to identify patterns of drug use associated with lower serum NaC in older inpatients. Our results suggest that older patients using antiplatelets or anticoagulants are especially at risk of lower serum NaC.

Ofloxacin Ophthalmic

MedlinePlus

... including conjunctivitis (pink eye) and ulcers of the cornea. Ofloxacin is in a class of medications called ... send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http:// ...

Considerations for a Pediatric Biopharmaceutics Classification System (BCS): application to five drugs.

PubMed

Gandhi, Shivani V; Rodriguez, William; Khan, Mansoor; Polli, James E

2014-06-01

It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m(2) adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.

Biowaiver extension potential and IVIVC for BCS Class II drugs by formulation design: Case study for cyclosporine self-microemulsifying formulation.

PubMed

Yang, Su-Geun

2010-11-01

The objective of this work was to suggest the biowaiver potential of biopharmaceutical classification system (BCS) Class II drugs in self-microemulsifying drug delivery systems (SMEDDS) which are known to increase the solubility, dissolution and oral absorption of water-insoluble drugs. Cyclosporine was selected as a representative BCS Class II drug. New generic candidate of cyclosporine SMEDDS (test) was applied for the study with brand SMEDDS (reference I) and cyclosporine self-emulsifying drug delivery systems (SEDDS, reference II). Solubility and dissolution of cyclosporine from SMEDDS were critically enhanced, which were the similar behaviors with BCS class I drug. The test showed the identical dissolution rate and the equivalent bioavailability (0.34, 0.42 and 0.68 of p values for AUC₀(→)₂₄(h), C(max) and T(max), respectively) with the reference I. Based on the results, level A in vitro-in vivo correlation (IVIVC) was established from these two SMEDDS formulations. This study serves as a good example for speculating the biowaiver extension potential of BCS Class II drugs specifically in solubilizing formulation such as SMEDDS.

BDDCS Class Prediction for New Molecular Entities

PubMed Central

Broccatelli, Fabio; Cruciani, Gabriele; Benet, Leslie Z.; Oprea, Tudor I.

2012-01-01

The Biopharmaceutics Drug Disposition Classification System (BDDCS) was successfully employed for predicting drug-drug interactions (DDIs) with respect to drug metabolizing enzymes (DMEs), drug transporters and their interplay. The major assumption of BDDCS is that the extent of metabolism (EoM) predicts high versus low intestinal permeability rate, and vice versa, at least when uptake transporters or paracellular transport are not involved. We recently published a collection of over 900 marketed drugs classified for BDDCS. We suggest that a reliable model for predicting BDDCS class, integrated with in vitro assays, could anticipate disposition and potential DDIs of new molecular entities (NMEs). Here we describe a computational procedure for predicting BDDCS class from molecular structures. The model was trained on a set of 300 oral drugs, and validated on an external set of 379 oral drugs, using 17 descriptors calculated or derived from the VolSurf+ software. For each molecule, a probability of BDDCS class membership was given, based on predicted EoM, FDA solubility (FDAS) and their confidence scores. The accuracy in predicting FDAS was 78% in training and 77% in validation, while for EoM prediction the accuracy was 82% in training and 79% in external validation. The actual BDDCS class corresponded to the highest ranked calculated class for 55% of the validation molecules, and it was within the top two ranked more than 92% of the times. The unbalanced stratification of the dataset didn’t affect the prediction, which showed highest accuracy in predicting classes 2 and 3 with respect to the most populated class 1. For class 4 drugs a general lack of predictability was observed. A linear discriminant analysis (LDA) confirmed the degree of accuracy for the prediction of the different BDDCS classes is tied to the structure of the dataset. This model could routinely be used in early drug discovery to prioritize in vitro tests for NMEs (e.g., affinity to transporters, intestinal metabolism, intestinal absorption and plasma protein binding). We further applied the BDDCS prediction model on a large set of medicinal chemistry compounds (over 30,000 chemicals). Based on this application, we suggest that solubility, and not permeability, is the major difference between NMEs and drugs. We anticipate that the forecast of BDDCS categories in early drug discovery may lead to a significant R&D cost reduction. PMID:22224483

Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases

PubMed Central

Gul, Waseem; Hamann, Mark T.

2016-01-01

The marine environment produces natural products from a variety of structural classes exhibiting activity against numerous disease targets. Historically marine natural products have largely been explored as anticancer agents. The indole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. This report reviews the literature on indole alkaloids of marine origin and also highlights our own research. Specific biological activities of indole alkaloids presented here include: cytotoxicity, antiviral, antiparasitic, anti-inflammatory, serotonin antagonism, Ca-releasing, calmodulin antagonism, and other pharmacological activities. PMID:16236327

Buprenorphine Injection

MedlinePlus

Buprenorphine extended-release injection is used to treat opioid dependence (addiction to opioid drugs, including heroin and narcotic painkillers) ... sublingual buprenorphine for at least 7 days. Buprenorphine extended-release injection is in a class of medications ...

The Next Wave of Influenza Drugs.

PubMed

Shaw, Megan L

2017-10-13

Options for influenza therapy are currently limited to one class of drug, the neuraminidase inhibitors. Amidst concerns about drug resistance, much effort has been placed on the discovery of new drugs with distinct targets and mechanisms of action, with great success. There are now several candidates in late stage development which include small molecules targeting the three subunits of the viral polymerase complex and monoclonal antibodies targeting the hemagglutinin, as well as host-directed therapies. The availability of drugs with diverse mechanisms now opens the door to exploring combination therapies for influenza, and the range of administration routes presents more opportunities for treating hospitalized patients.

Classification of drugs with different risk profiles.

PubMed

Saedder, Eva Aggerholm; Brock, Birgitte; Nielsen, Lars Peter; Bonnerup, Dorthe Krogsgaard; Lisby, Marianne

2015-08-01

A risk stratification approach is needed to identify patients at high risk of medication errors and a resulting high need of medication review. The aim of this study was to perform risk stratification (distinguishing between low-risk, medium-risk and high-risk drugs) for drugs found to cause serious adverse reactions due to medication errors. The study employed a modified Delphi technique. Drugs from a systematic literature search were included into two rounds of a Delphi process. A panel of experts was asked to evaluate each identified drug's potential for harm and for clinically relevant drug-drug interactions on a scale from 1 (low risk) to 9 (high risk). A total of 36 experts were appointed to serve on the panel. Consensus was reached for 29/57 (51%) drugs or drug classes that cause harm, and for 32/57 (56%) of the drugs or drug classes that cause interactions. For the remaining drugs, a decision was made based on the median score. Two lists, one stating the drugs' potential for causing harm and the other stating clinically relevant drug-drug interactions, were stratified into low-risk, medium-risk and high-risk drugs. Based on a modified Delphi technique, we created two lists of drugs stratified into a low-risk, a medium-risk and a high-risk group of clinically relevant interactions or risk of harm to patients. The lists could be incorporated into a risk-scoring tool that stratifies the performance of medication reviews according to patients' risk of experiencing adverse reactions. none. not relevant.

Fragment Based Strategies for Discovery of Novel HIV-1 Reverse Transcriptase and Integrase Inhibitors.

PubMed

Latham, Catherine F; La, Jennifer; Tinetti, Ricky N; Chalmers, David K; Tachedjian, Gilda

2016-01-01

Human immunodeficiency virus (HIV) remains a global health problem. While combined antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance to drugs used for treatment, rendering available drugs less effective and limiting treatment options. Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight molecules (<300 Da) screened using primarily biophysical assays. FBDD is aimed at not only finding novel drug scaffolds, but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search for novel classes of HIV-1 drugs.

Potential drug delivery approaches for XFS-associated and XFS-associated glaucoma.

PubMed

Kulkarni, Shreya S; Kompella, Uday B

2014-01-01

Key tissue targets in treating exfoliation syndrome (XFS) and the associated glaucoma include lens, iris, and ciliary body, which produce the exfoliative material, and the trabecular meshwork, which may be impaired by the exfoliative material. In addition to antiglaucoma drug therapy, strategies for treating the disease include approaches for preventing formation of exfoliative material as well as those aimed at digesting exfoliative material. A variety of drug molecules including small molecules, protein drugs, and nucleic acids are potential candidates for treating XFS. Potential drug classes include antioxidants, lysyl oxidase-like 1 enhancers, antifibrotics, anti-inflammatory agents, proteases, and chaperones. However, the delivery of these agents to the target tissues in the anterior segment is hindered by protective static and dynamic barriers of the eye. Thus, unique drug delivery approaches are needed for each drug type (small molecules, proteins, and nucleic acids). In addition, there is a need for sustaining drug therapy for treating XFS, which can potentially be addressed by using nanoparticles, microparticles, implants, and contact lens delivery systems. This article provides an overview of drug delivery challenges and opportunities in treating XFS with the focus being on nanomedicines.

Complex Drug Use Patterns and Associated HIV Transmission Risk Behaviors in an Internet Sample of U.S. Men Who Have Sex with Men

PubMed Central

Yu, Gary; Wall, Melanie M.; Chiasson, Mary Ann; Hirshfield, Sabina

2015-01-01

Although the relationship between drug use and HIV risk among men who have sex with men (MSM) is well described, relatively few studies have employed empirical methods to assess underlying classes of drug use that may better predict the risk of HIV or sexually transmitted infections (STIs) among MSM. The aim of this study was to determinewhether latent class analysis (LCA) would identify underlying drug classes reported prior to sex, as well as predict unprotected anal intercourse (UAI) in the last sexual encounter among MSM. From 2004 to 2005, an anonymous online survey was conducted among 8,717 sexually active MSM recruited from gay-affiliated U.S. websites. LCA clustered participants into six distinct drug use classes based on the specific types and number of drugs used: (1) low/no drug use, (2) recreational drug use, (3) poppers with prescription erectile dysfunction (ED) drug use, (4) poppers with both prescription and non-prescription ED drug use, (5) recreational, club, and ED drug use, and (6) high polydrug use. Compared with men in Class 1, men in the highest drug use class were 4.84 times more likely to report UAI in their last sexual encounter and 3.78 times more likely to report an STI in the past year (both ps<.001). Younger MSM aged 18–29 were significantly more likely to report an STI than men aged 50 and above (p<.001). There is a need to better understand the complex relationship between a diverse set of drugs used among MSM and how polydrug use impacts sexual negotiation over time. PMID:25104104

A peek into the drug development scenario of endometriosis - A systematic review.

PubMed

Goenka, Luxitaa; George, Melvin; Sen, Maitrayee

2017-06-01

Endometriosis is a gynaecological disease that is characterised by the presence of endometrium like tissue-epithelium and stroma that develops outside the uterine cavity, which is responsible for pelvic pain and infertility. Even though several medical therapies exist for the treatment of endometriosis, each of the drug class has its own limitations such as cost of treatment, side-effects and its short-term effect on the symptoms of endometriosis. In this review, we have attempted to summarize the current status and challenges of drug development for endometriosis. A systematic review was done and all the RCTs were selected from the identified hits. We included studies that explored the usage of therapeutic drugs on endometriosis patients from inception till November 2016. The search term used was 'Endometriosis' using PubMed and Clinicaltrials.gov. For the final analysis, 60 articles were analyzed and we identified the newly emerging drug therapies for endometriosis treatment and have briefed their current status and challenges in drug development for endometriosis. The quality of the selected studies was assessed based on the degree of bias. The current classes of drugs that have shown promising therapeutic results include Gonadotropin- releasing hormone (GnRH) antagonists, aromatase inhibitors (AI), and selective progesterone and estrogen receptor modulators, dopamine receptor-2-agonists and statins. The drugs that failed midway during development include tanezumab, rosiglitazone, infliximab, pentoxifylline, telapristone acetate, asoprisnil and raloxifene. From the literature review, it appears that the most promising molecules for the treatment of endometriosis in the near future include elagolix, mifepristone, TAK-385, KLH-2109 and ASP1707 and cabergoline. It remains to be seen if these molecules would succeed large phase 3 clinical trials and overcome the regulatory hurdles to become an essential tool in the gynaecologist's armamentarium against endometriosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Intraoperative floppy-iris syndrome associated with use of antipsychotic drugs.

PubMed

Matsuo, Masato; Sano, Ichiya; Ikeda, Yoshifumi; Fujihara, Etsuko; Tanito, Masaki

2016-08-01

We report 3 cases of intraoperative floppy-iris syndrome (IFIS) during cataract surgery in patients without a history of selective α1-blocker use but with a long-term history of antipsychotic drug use. We reviewed previously reported cases of antipsychotic drug-associated IFIS cases. Observational case series. In case 1, bilateral IFIS developed in a 39-year-old man with chronic angle-closure glaucoma. He had used several classes of antipsychotic drugs to treat schizophrenia, including the first-generation antipsychotic drugs haloperidol and chlorpromazine, the dopamine system stabilizer aripiprazole, the dopamine serotonin antagonists olanzapine and quetiapine, and the serotonin dopamine antagonists risperidone and blonanserin for 7 years. In case 2, a 63-year-old woman with schizophrenia had used aripiprazole, quetiapine, and risperidone for more than 10 years. In case 3, a 65-year-old woman with an organic mental disorder had used haloperidol for more than 10 years. At least 5 cases of antipsychotic drug-induced IFIS have been reported in the literature. Any class of antipsychotic drugs can cause IFIS. Although antipsychotic drug-induced IFIS can be mild, surgeons should be alert to the possibility of IFIS when they treat patients with current and past use of antipsychotic drugs. Copyright © 2016 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

Occurrence of Multiple Sclerosis After Drug Exposure: Insights From Evidence Mapping.

PubMed

Antonazzo, Ippazio Cosimo; Raschi, Emanuel; Vignatelli, Luca; Baldin, Elisa; Riise, Trond; D'Alessandro, Roberto; De Ponti, Fabrizio; Poluzzi, Elisabetta

2017-09-01

The role of drugs in the occurrence of multiple sclerosis (MS) is perceived to be insufficiently investigated. The aim of this study was to map and assess the evidence on MS occurrence after drug exposure, in order to identify possible signals of causal association. A search strategy was performed in MEDLINE and Embase as of July 2016; references consistent with the aim of the study were analysed to extract relevant measures of causal association between drugs and MS. The Newcastle-Ottawa Scale and appropriate guidelines from the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) were used to assess the quality of included studies. After screening 832 articles, 58 were selected (of which 14 were found by checking the reference lists of reviews): 30 case reports and case series, 24 longitudinal studies and four randomized controlled trials. Seven longitudinal studies had good (at least 7 out of 9) quality scores, whereas case reports/case series presented several limitations. Half of included articles focused on immunomodulatory drugs (etanercept, infliximab and adalimumab), especially in case reports/series, suggesting an association with MS occurrence. Contraceptives and antibacterials were investigated in some population-based studies, without definite results. A heterogeneous pharmacological profile of identified classes emerged. Low strength of evidence and conflicting results highlighted the difficulties in addressing the possible contribution of drugs in MS occurrence. Methodological advances are needed, especially to control the confounding role of underlying disease for specific drug classes.

Differences between Drug-Induced and Contrast Media-Induced Adverse Reactions Based on Spontaneously Reported Adverse Drug Reactions.

PubMed

Ryu, JiHyeon; Lee, HeeYoung; Suh, JinUk; Yang, MyungSuk; Kang, WonKu; Kim, EunYoung

2015-01-01

We analyzed differences between spontaneously reported drug-induced (not including contrast media) and contrast media-induced adverse reactions. Adverse drug reactions reported by an in-hospital pharmacovigilance center (St. Mary's teaching hospital, Daejeon, Korea) from 2010-2012 were classified as drug-induced or contrast media-induced. Clinical patterns, frequency, causality, severity, Schumock and Thornton's preventability, and type A/B reactions were recorded. The trends among causality tools measuring drug and contrast-induced adverse reactions were analyzed. Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021%) and 3.9/100,000 (outpatients, 0.004%). The most common adverse drug reaction-associated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast media-induced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p < 0.001), and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001). Females were over-represented among drug-induced adverse reactions (68.1%, p < 0.001) but not among contrast media-induced adverse reactions (56.6%, p = 0.066). Causality patterns differed between the two adverse reaction classes. The World Health Organization-Uppsala Monitoring Centre causality evaluation and Naranjo algorithm results significantly differed from those of the Korean algorithm version II (p < 0.001). We found differences in sex, preventability, severity, and type A/B reactions between spontaneously reported drug and contrast media-induced adverse reactions. The World Health Organization-Uppsala Monitoring Centre and Naranjo algorithm causality evaluation afforded similar results.

Differences between Drug-Induced and Contrast Media-Induced Adverse Reactions Based on Spontaneously Reported Adverse Drug Reactions

PubMed Central

Suh, JinUk; Yang, MyungSuk; Kang, WonKu; Kim, EunYoung

2015-01-01

Objective We analyzed differences between spontaneously reported drug-induced (not including contrast media) and contrast media-induced adverse reactions. Methods Adverse drug reactions reported by an in-hospital pharmacovigilance center (St. Mary’s teaching hospital, Daejeon, Korea) from 2010–2012 were classified as drug-induced or contrast media-induced. Clinical patterns, frequency, causality, severity, Schumock and Thornton’s preventability, and type A/B reactions were recorded. The trends among causality tools measuring drug and contrast-induced adverse reactions were analyzed. Results Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021%) and 3.9/100,000 (outpatients, 0.004%). The most common adverse drug reaction-associated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast media-induced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p < 0.001), and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001). Females were over-represented among drug-induced adverse reactions (68.1%, p < 0.001) but not among contrast media-induced adverse reactions (56.6%, p = 0.066). Causality patterns differed between the two adverse reaction classes. The World Health Organization–Uppsala Monitoring Centre causality evaluation and Naranjo algorithm results significantly differed from those of the Korean algorithm version II (p < 0.001). Conclusions We found differences in sex, preventability, severity, and type A/B reactions between spontaneously reported drug and contrast media-induced adverse reactions. The World Health Organization–Uppsala Monitoring Centre and Naranjo algorithm causality evaluation afforded similar results. PMID:26544039

Co-morbidity and clinically significant interactions between antiepileptic drugs and other drugs in elderly patients with newly diagnosed epilepsy.

PubMed

Bruun, Emmi; Virta, Lauri J; Kälviäinen, Reetta; Keränen, Tapani

2017-08-01

A study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy. From the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000-2013 (n=529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011-2012 as monotherapy (n=1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX-PHARAO database, were analysed. Hypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co-morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class-C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class-D interactions. Patients with 3-5 (OR 4.22; p=0.05) or over six (OR 8.86; p=0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs. Elderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic interactions with other drugs, especially if exposed to carbamazepine, but these interactions can be controlled via rational drug choices and with prediction of the possible drug-to-drug interactions. Patients on dihydropyridine calcium-channel blockers, statins, warfarin, and risperidone face the highest risk of interactions. Copyright © 2017 Elsevier Inc. All rights reserved.

AIDSinfo Drug Database

MedlinePlus

... HIV/AIDS-related drugs for that condition. OK Filters Approval: What's this? FDA-Approved Investigational Class: What's ... Encephalitis Tuberculosis Varicella-Zoster Virus Diseases Update Loading... Filter by approval status, drug class, and condition Browse ...

Comparative cost evaluation of brand name and generic ophthalmology medications in Ontario.

PubMed

Popovic, Marko; Chan, Clara; Lattanzio, Nisha; El-Defrawy, Sherif; Schlenker, Matthew B

2018-04-01

Medication cost for the same indication can vary considerably and can affect patient compliance. In this comparative cost analysis of commonly prescribed ophthalmology medications, the differences in cost between generic and brand name medications as well as different medications within an individual drug class were evaluated. Eye preparations from the Ontario Drug Benefit Formulary were identified, and further agents commonly prescribed by ophthalmologists were included. The standardized prescription drug cost, which includes the cost of the medication, mark-up, and dispensing cost, was provided by Ontario Shoppers Drug Mart stores in July 2016 for 103 common medications using typical dosages and durations. Based on medication class, the highest and lowest cost medications were antiallergy agents (Zaditor [ketotifen], Vasocon [naphazoline]), antibiotic ophthalmic solutions (Vigamox [moxifloxacin], generic ciprofloxacin), oral antibiotics (Cipro [ciprofloxacin], generic cephalexin), antibiotic ophthalmic ointments (generic erythromycin, Tobrex [tobramycin]), antiviral treatment (Valtrex [oral valacyclovir], Viroptic [topical trifluridine]), blepharitis treatment (Zithromax [oral azithromycin], generic oral tetracycline), beta-adrenergic inhibitors (Timoptic [topical timolol], generic topical timolol), topical prostaglandin analogues (Xalatan [latanoprost], generic travoprost), oral carbonic anhydrase inhibitors (methazolamide, acetazolamide), topical carbonic anhydrase solutions (Trusopt preservative-free [dorzolamide], Azopt [brinzolamide]), topical alpha-adrenergic agonists (Alphagan [brimonidine], generic brimonidine), topical muscarinic agonists (Isopto carpine [pilocarpine], Diocarpine [pilocarpine]), topical combination glaucoma agents (Cosopt [dorzolamide-timolol], generic dorzolamide-timolol), topical lubricants (Lacri-lube, Isopto tears), topical nonsteroidal anti-inflammatory drugs (Acuvail [ketorolac], Ilevro [nepafenac]), and steroids (Durezol [difluprednate], Pred mild [prednisolone]). Substantial cost differences exist between ophthalmology medications of the same class. We encourage ophthalmologists to be aware of the associated costs of the medications they prescribe and to use this information in their decision making. Copyright © 2018 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

Body Image Disturbance in 1000 Male Appearance and Performance Enhancing Drug Users

PubMed Central

Hildebrandt, Tom; Alfano, Lauren; Langenbucher, James W.

2010-01-01

Body image disturbance (BID) among men has only recently become a phenomenon of clinical significance with noted heterogeneity in the behavioral consequences of these disturbances. The degree of heterogeneity among appearance and performance enhancing drug (APED) users is unknown and an empirically derived framework for studying BID is necessary. 1000 APED users were recruited via the Internet and they completed a comprehensive online assessment APED use patterns, motivations, consequences, and BID. Data were evaluated using latent trait, latent class, and factor mixture models. Model results were validated using a range of covariates including cycle characteristics, age, APED history, and APED risk. A 1-Factor, 4-Class model provided the best fit to the data with Class 1 scoring the highest on all measures of BID and Class 4 the lowest on all measures. Class 2 differed in their preference for being lean over muscular and Class 3 preferred adding mass and size. Each class was associated with unique risks, APED history, and training identity. Not all APED users suffer from significant BID and there are unique profiles for those with elevated BID. Future research on male BID should account for this structure in order to better define relevant diagnostic categories and evaluate the clinical significance of BID. PMID:20110092

[Comparisons outpatient drug prescriptions: France, Denmark, Norway, Sweden].

PubMed

Dezileaux, Barbara; Martinez, Florie

2016-06-01

Comparisons outpatient drug prescriptions: France, Denmark, Norway, Sweden. Project compares quantitatively outpatient drug prescriptions in France, Denmark, Norway and Sweden. Data were obtained from national databases; the unit of measurement was defined daily dose per 1000 inhabitants. The five most prescribed drug classes were compared in each country in 2009, then benzodiazepines and antibiotics from 2006 to 2012. A literature review was focused on the context of prescriptions for each country. In 2009, the five most prescribed drug classes in the four countries represented seven classes in total. France was not the biggest prescriber of drugs, but from 2006 to 2012 benzodiazepines and antibiotics were prescribed much more in France than in the other countries. The evolution of prescriptions was different for each country, and very stable in France. In 2009, France was not the biggest drugs consumer of all classes, but was characterized by high prescriptions in some classes. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Investigation into the Emerging Role of the Basic Amino Acid L-Lysine in Enhancing Solubility and Permeability of BCS Class II and BCS Class IV Drugs.

PubMed

Abdelkader, Hamdy; Fathalla, Zeinab

2018-06-18

The search for a simple and scalable approach that can improve the two key biopharmaceutical processes (solubility and permeability) for BCS Class II and BCS Class IV has still been unmet need. In this study, L-lysine was investigated as a potential excipient to tackle problems with solubility and permeability. Bendazac (Class II); quercetin and rutin (Class IV) were employed. Drugs-lysine complexes in 1:1 M ratios were prepared by co-precipitation and co-grinding; characterized for solubility, partition coefficient, DSC, FTIR, SEM, dissolution rate and permeability. Chemical stability of quercetin-lysine and rutin-lysine was studied by assessing antioxidant capacity using Trolox and CUPRAC assays. Drugs-lysine salt/complexes were confirmed. Solubility enhancement factors ranged from 68- to 433-fold increases and dissolution rates were also significantly enhanced by up to 6-times, compared with drugs alone. With the exception of rutin-lysine, P app for bendazac-lysine and quercetin-lysine enhanced by 2.3- to 4-fold. P app for quercetin (Class IV) benefited more than bendazac (Class II) when complexed with lysine. This study warrants the use of L-lysine as a promising excipient for enhanced solubility and permeability of Class II and Class IV, providing that the solubility of the drug is ensured at 'the door step' of absorption sites.

Controlling prescription drug expenditures: a report of success.

PubMed

Miller, David P; Furberg, Curt D; Small, Ronald H; Millman, Franklyn M; Ambrosius, Walter T; Harshbarger, Julia S; Ohl, Christopher A

2007-08-01

To determine whether a multi-interventional program can limit increases in prescription drug expenditures while maintaining utilization of needed medications. Quasi-experimental, pre-post design. The program included formulary changes, quantity limits, and mandatory pill splitting for select drugs implemented in phases. We assessed the short-term effects of each intervention by comparing class-specific drug spending and generic medication use before and after benefit changes. Long-term effects were determined by comparing overall spending with projected spending estimates, and by examining changes in the planwide use of generic medications over time. Effects on medication utilization were assessed by examining members' use of selected classes of chronic medications before and after the policy changes. Over 3 years, the plan and members saved $6.6 million attributed to the interventions. Most of the savings were due to the reclassification of select brand-name drugs to nonpreferred status (estimated annual savings, $941,000), followed by the removal of nonsedating antihistamines from the formulary (annual savings, $565,000), and the introduction of pill splitting (annual savings, $342,000). Limiting quantities of select medications had the smallest impact (annual savings, $135,000). Members' use of generic medications steadily increased from 40% to 57%. Although 17.5% of members stopped using at least 1 class of selected medications, members' total use of chronic medications remained constant. A combination of interventions can successfully manage prescription drug spending while preserving utilization of chronic medications. Additional studies are needed to determine the effect of these cost-control interventions on other health outcomes.

Effect of contraindicated drugs for heart failure on hospitalization among seniors with heart failure

PubMed Central

Girouard, Catherine; Grégoire, Jean-Pierre; Poirier, Paul; Moisan, Jocelyne

2017-01-01

Abstract Little is known about the effect of nonsteroidal anti-inflammatory drugs (NSAIDs), thiazolidinediones (TZDs), nifedipine and nondihydropyridine calcium channel blockers (CCBs) usage on the risk of all-cause hospitalization among seniors with heart failure (HF). We assessed the risk of all-cause hospitalization associated with exposure to each of these drug classes, in a population of seniors with HF. Using the Quebec provincial databases, we conducted a nested case-control study in a population of individuals aged ≥65 with a first HF diagnosis between 2000 and 2009. Patients were considered users of a potentially inappropriate drug class if their date of hospital admission occurred in the interval between the date of the last drug claim and the end date of its days’ supply. The risks of hospitalization were estimated using multivariate conditional logistic regression. Of the 128,853 individuals included in the study population, 101,273 (78.6%) were hospitalized. When compared to nonusers, users of NSAIDs (adjusted odds ratio: 1.16; 95% confidence interval: 1.13–1.20), TZD (1.09; 1.04–1.14), and CCBs (1.03; 1.01–1.05) had an increased risk of all-cause hospitalization, but not the users of nifedipine (1.00; 0.97–1.03). Seniors with HF exposed to a potentially inappropriate drug class are at increased risk of worse health outcomes. Treatment alternatives should be considered, as they are available. PMID:28248890

A decade of safety-related regulatory action in the Netherlands: a retrospective analysis of direct healthcare professional communications from 1999 to 2009.

PubMed

Mol, Peter G M; Straus, Sabine M J M; Piening, Sigrid; de Vries, Jonie T N; de Graeff, Pieter A; Haaijer-Ruskamp, Flora M

2010-06-01

As pre-approval trials are inherently limited in assessing the complete benefit-risk profile of a new drug, serious safety issues may emerge once a drug gains widespread use after approval. Regulators face the dilemma of balancing timely market access with the need for complete data on risks. This challenge has led to a life-cycle approach but, so far, few data are available on post-approval safety issues requiring regulatory action. The aim of this study is to determine the frequency, timing and nature of safety issues that necessitated safety-related regulatory action in the form of a Direct Healthcare Professional Communication (DHPC) issued by pharmaceutical companies in collaboration with the Dutch Medicines Evaluation Board during the past decade. All DHPCs issued in the Netherlands from 1 January 1999 to 1 January 2009 were retrospectively collected from the national regulatory authorities. Elapsed time between the approval date and the issue of the DHPC was determined. Characteristics of the action including the nature of the safety issue (according to Medical Dictionary for Regulatory Activities [MedDRA] terminology), type of drug and procedural aspects of the regulatory action taken were reviewed. DHPC characteristics were tabulated and explorative non-parametric tests were performed to study the effect of safety issue, drug class, drug type, orphan drug and first-in-class status on elapsed time from approval to the DHPC. 157 DHPCs were issued concerning 112 different active substances, approximately 9% (112/1200) of active substances available in the Netherlands in 2007. The number of DHPCs issued increased by 2.1 (95% CI 1.2, 3.1; p < 0.001) DHPCs per year over the past decade, reaching a total of 25 in 2008. The median time between approval and DHPC was 5.3 years (range 0.13-48 years). No significant trend in elapsed time to DHPC was observed in relation to the studied years (p = 0.06). One-third of all DHPCs were issued in the first 3 years after approval, but 27% (n = 43/157) of the DHPCs were issued 10 or more years after approval. Timing of DHPCs differed depending on safety issue, drug class, drug type and orphan drug status. DHPCs mostly concerned adverse events in the system organ class of 'cardiac disorders' (15%), 'injury, poisoning and procedural complications' (13%) and 'general disorders and administration site conditions' (10%). In ten cases the drug was eventually withdrawn. Withdrawal occurred a median duration of 2.4 years after registration (range of 1.5-48 years) and was most frequently due to cardiac disorders (including QT interval prolongation; four occasions) and hepatobiliary disorders (two occasions). In the past decade, the number of DHPCs has increased over time. This is likely caused by a multitude of factors: increased risk awareness by the public, media, regulators and other stakeholders; the type of drugs approved, such as orphan drugs and biologicals; and the regulatory process, including conditional approvals. The number of DHPCs may in the future increase further with the possibility of screening large epidemiological databases proactively for adverse drug events. Nine percent of all marketed drugs required a safety-related action. Regulatory action is taken shortly (<3 years) after market approval nearly as often as after intermediate (3-10 years) and long-term (>10 years) market exposure. These findings underline the need for risk management during the whole life cycle of a drug.

Investigation of the Anti-Prostate Cancer Properties of Marine-Derived Compounds

PubMed Central

Fan, Meiqi; Nath, Amit Kumar; Tang, Yujiao; Choi, Young-Jin; Debnath, Trishna; Choi, Eun-Ju

2018-01-01

This review focuses on marine compounds with anti-prostate cancer properties. Marine species are unique and have great potential for the discovery of anticancer drugs. Marine sources are taxonomically diverse and include bacteria, cyanobacteria, fungi, algae, and mangroves. Marine-derived compounds, including nucleotides, amides, quinones, polyethers, and peptides are biologically active compounds isolated from marine organisms such as sponges, ascidians, gorgonians, soft corals, and bryozoans, including those mentioned above. Several compound classes such as macrolides and alkaloids include drugs with anti-cancer mechanisms, such as antioxidants, anti-angiogenics, antiproliferatives, and apoptosis-inducing drugs. Despite the diversity of marine species, most marine-derived bioactive compounds have not yet been evaluated. Our objective is to explore marine compounds to identify new treatment strategies for prostate cancer. This review discusses chemically and pharmacologically diverse marine natural compounds and their sources in the context of prostate cancer drug treatment. PMID:29757237

Opioids in the Frame of New Psychoactive Substances Network: A Complex Pharmacological and Toxicological Issue.

PubMed

Ventura, Ludovic; Carvalho, Felix; Dinis-Oliveira, Ricardo Jorge

2018-01-01

New psychoactive substances (NPS), often referred to as "legal highs" or "designer drugs", are derivatives and analogues of existing psychoactive drugs that are introduced in the recreational market to circumvent existing legislation on drugs of abuse. This systematic review aims to gather the state of the art regarding chemical, molecular pharmacology and toxicological information of opioid class of NPS. Chemical, pharmacological, toxicological and clinical effects of opioid class of NPS were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Within this class, fentanyl analogues are among the most frequently abused and pose several clinical concerns and therefore will be thoroughly discussed. Other opioid sub-categories of NPS frequently misused include AH-7921, MT-45, U-47700, U-50488, desomorphine, mitragynine, tramadol, tapentadol, salvinorin A and its analogue herkinorin. Due to inefficient monitoring techniques, as well as limited knowledge regarding the acute and long-term effects of opioids NPS, further clinical and forensic toxicological studies are required. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Application of liposomal technologies for delivery of platinum analogs in oncology

PubMed Central

Liu, Demin; He, Chunbai; Wang, Andrew Z; Lin, Wenbin

2013-01-01

Platinum-based chemotherapy, such as cisplatin, oxaliplatin, and carboplatin, is one of the most widely utilized classes of cancer therapeutics. While highly effective, the clinical applications of platinum-based drugs are limited by their toxicity profiles as well as suboptimal pharmacokinetic properties. Therefore, one of the key research areas in oncology has been to develop novel platinum analog drugs and engineer new platinum drug formulations to improve the therapeutic ratio further. Such efforts have led to the development of platinum analogs including nedaplatin, heptaplatin, and lobaplatin. Moreover, reformulating platinum drugs using liposomes has resulted in the development of L-NDPP (Aroplatin™), SPI-77, Lipoplatin™, Lipoxal™, and LiPlaCis®. Liposomes possess several attractive biological activities, including biocompatibility, high drug loading, and improved pharmacokinetics, that are well suited for platinum drug delivery. In this review, we discuss the various platinum drugs and their delivery using liposome-based drug delivery vehicles. We compare and contrast the different liposome platforms as well as speculate on the future of platinum drug delivery research. PMID:24023517

Analysis of A Drug Target-based Classification System using Molecular Descriptors.

PubMed

Lu, Jing; Zhang, Pin; Bi, Yi; Luo, Xiaomin

2016-01-01

Drug-target interaction is an important topic in drug discovery and drug repositioning. KEGG database offers a drug annotation and classification using a target-based classification system. In this study, we gave an investigation on five target-based classes: (I) G protein-coupled receptors; (II) Nuclear receptors; (III) Ion channels; (IV) Enzymes; (V) Pathogens, using molecular descriptors to represent each drug compound. Two popular feature selection methods, maximum relevance minimum redundancy and incremental feature selection, were adopted to extract the important descriptors. Meanwhile, an optimal prediction model based on nearest neighbor algorithm was constructed, which got the best result in identifying drug target-based classes. Finally, some key descriptors were discussed to uncover their important roles in the identification of drug-target classes.

Risk-taking related to drug use: an application of the shift-to-risk design.

PubMed

Deren, S; Des Jarlais, D C

1977-01-01

The utility of the shift-to-risk design for studying the influence of peer groups on drug taking was investigated. Two studies using this design with drug content were conducted, varying the level of information provided about a drug. Subjects were from two college classes consisting of 26 and 28 students. Results indicated that the specification of possible harmful drug effects which are somewhat minimal lead to a significantly greater willingness to recommend trying the drug. In addition, a tendency for a shift-to-caution was found. It was concluded that the shift-to-risk designwas useful for studying decision-making regarding drug use, and that both users and nonusers of drugs should be included in future research.

Suicide behavior and associated psychosocial factors among adolescents in Campeche, Mexico.

PubMed

González-Forteza, Catalina; Juárez-López, Carlos E; Jiménez, Alberto; Montejo-León, Liliana; Rodríguez-Santisbón, Ulises R; Wagner, Fernando A

2017-12-01

Suicide is an important public health problem that requires a preventive approach. The present study aimed at assessing suicidal behaviors and their relations with other psychosocial factors in Campeche, Mexico, in order to inform the design of potential preventive interventions. A multistage probability sample of 2386 students representative of all middle schools of the state of Campeche, Mexico, took a standardized, paper-and-pencil survey covering selected psychosocial constructs including suicide behavior, depression, drug use, familial relationships, locus of control, impulsivity, and self-esteem, among others. Latent classes were identified and multinomial logistic regression was used to analyze associations between class membership and psychosocial covariates. An estimated 8% of the middle school population in Campeche had three or more psychosocial problems in the past month including drug use, major depression episode symptoms, as well as suicidal problems like attempts and self-inflicted injuries. Four latent classes were identified, one with lowest risk and three with varying characteristics in terms of binge alcohol and other drug use, depression, and suicide behaviors. Associations between psychosocial covariates and latent class were observed, as predicted based on a multi-dimensional theoretical framework. Heterogeneity across "High-Risk" groups and their potential determinants highlight the need for differentiated, specialized efforts ranging from universal to indicated interventions. Given the high level of risk factors in this population, universal preventive interventions should aim at building resiliency among youth by helping them develop an array of coping resources, as well as by creating a more nurturing psychosocial environment. Copyright © 2017 Elsevier Inc. All rights reserved.

Metabolism of designer drugs of abuse.

PubMed

Staack, Roland F; Maurer, Hans H

2005-06-01

Abuse of designer drugs is widespread among young people, especially in the so-called "dance club scene" or "rave scene", worldwide. Severe and even fatal poisonings have been attributed to the consumption of such drugs of abuse. However, in contrast to new medicaments, which are extensively studied in controlled clinical studies concerning metabolism, including cytochrome P450 isoenzyme differentiation, and further pharmacokinetics, designer drugs are consumed without any safety testing. This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years. Para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA) and 4-methylthioamphetamine (4-MTA), were taken into consideration as new "classical" amphetamine-derived designer drugs. Furthermore, N-benzylpiperazine (BZP), 1-(3, 4-methylenedioxybenzyl)piperazine (MDBP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (mCPP) and 1-(4-methoxyphenyl)piperazine (MeOPP) were taken into consideration as derivatives of the class of piperazine-derived designer drugs, as well as alpha-pyr-rolidinopropiophenone (PPP), 4'-methoxy-alpha-pyrrolidinopropiophenone (MOPPP), 3', 4'-methylenedioxy-alpha-pyrrolidino-propiophenone (MDPPP), 4'-methyl-alpha-pyrrolidinopropiophenone (MPPP), and 4'-methyl-alpha-pyrrolidinoexanophenone (MPHP) as derivatives of the class of alpha-pyrrolidinophenone-derived designer drugs. Papers describing identification of in vivo or in vitro human or animal metabolites and cytochrome P450 isoenzyme dependent metabolism have been considered and summarized.

Vertigo/dizziness as a Drugs' adverse reaction.

PubMed

Chimirri, Serafina; Aiello, Rossana; Mazzitello, Carmela; Mumoli, Laura; Palleria, Caterina; Altomonte, Mariolina; Citraro, Rita; De Sarro, Giovambattista

2013-12-01

Vertigo, dizziness, and nausea encompass a spectrum of balance-related symptoms caused by a variety of etiologies. Balance is affected by many systems: Proprioceptive pathways and visual, cerebellar, vestibulocochlear, and vascular / vasovagal systems. Vertigo is a subtype of dizziness, in which a subject, as a result to a dysfunction of the vestibular system, improperly experiments the perception of motion. The most useful clinical subdivision is to categorize vertigo into true vertigo and pseudovertigo, whereas from a pathophysiological point of view, vertigo can be classified into central, peripheral, and psychogenic. It is not easy to identify the cause of vertigo since the patients often are not able to precisely describe their symptoms. An impressive list of drugs may cause vertigo or dizziness. The aim of the present study was to analyze the data extracted from the reporting cards of the ADRs (adverse drug reactions), received at our Pharmacovigilance Regional Center (Calabria, Italy) in 2012. In particular, the data concerning the occurrence of vertigo and dizziness, after taking certain classes of drugs, have been considered. Our results show that, among the side-effects of different classes of drugs such as anti-convulsants, anti-hypertensives, antibiotics, anti-depressants, anti-psychotics, and anti-inflammatory, also vertigo or dizziness are included. Spontaneous reports of vertigo or dizziness, as side-effect of certain drugs, received at our Pharmacovigilance Center, represented the 5% of all reports in 2012. Considering the high incidence of such an ADR for several drugs' classes, it can be speculated that under-reporting also affect vertigo and dizziness. Despite the fact that these ADRs might not represent a direct threaten for life, indirectly they can cause secondary damage to patients such as falls, fractures etc. Balance should be accurately monitored during drug use and particularly in fragile patients.

Dentist-prescribed drugs and the patients receiving them.

PubMed

Wall, Thomas P; Brown, L Jackson; Zentz, Ronald R; Manski, Richard J

2007-01-01

Outpatient prescription drugs continue to play an ever-increasing role in health care delivery in the United States. This paper focuses on the drugs prescribed by dentists and the patients who receive those drugs. The authors analyzed data from the 2001 Medical Expenditure Panel Survey (MEPS) for the U.S. community-based population. They developed estimates of the total market for prescription drugs related to a dental visit in terms of total number of prescriptions, total expenditures, and sources of payment. Also included are breakdowns by the type of dentist and the therapeutic class of drug prescribed. They also present a model that identifies the patient characteristics that best predict the likelihood of receiving a dental visit related prescription drug. Dental patients who were 18 years and older, African American patients, patients whose education level was less than a college degree, patients whose dental visit frequency was less than twice a year, and patients without medical insurance were most likely to report a prescription drug. Respondents' socioeconomic background and other demographic factors were related to the likelihood of receiving a prescription drug related to a dental visit. Patient age was related to the therapeutic class of the drug prescribed. Patients with fewer than two dental visits per year were more likely to report a dental prescription than patients with at least two visits per year.

Drug Use among Seniors on Public Drug Programs in Canada, 2012.

PubMed

Proulx, Jeff; Hunt, Jordan

2015-01-01

Seniors take more drugs than younger Canadians because, on average, they have a higher number of chronic conditions. Although taking multiple medications may be necessary to manage these conditions, it is important to consider the benefits and risks of each medication and the therapeutic goals of the patient. This article provides an in-depth look at the number and types of drugs used by seniors using drug claims data from the CIHI's National Prescription Drug Utilization Information System Database, representing approximately 70% of seniors in Canada. In 2012, almost two-thirds (65.9%) of seniors on public drug programs had claims for five or more drug classes, while 27.2% had claims for 10 or more, and 8.6% had claims for 15 or more. The most commonly used drug class was statins, used by nearly half (46.6%) of seniors. Nearly two-thirds (60.9%) of seniors living in long-term care (LTC) facilities had claims for 10 or more drug classes. Proton pump inhibitors were the most commonly used drug class among seniors living in LTC facilities (used by 37.0% of seniors in LTC facilities), while statins ranked seventh (29.8%).

The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research

PubMed Central

Bossert, Jennifer M.; Marchant, Nathan J.; Calu, Donna J.; Shaham, Yavin

2013-01-01

Background and Rationale Results from many clinical studies suggest that drug relapse and craving are often provoked by acute exposure to the self-administered drug or related drugs, drug-associated cues or contexts, or certain stressors. During the last two decades, this clinical scenario has been studied in laboratory animals by using the reinstatement model. In this model, reinstatement of drug seeking by drug priming, drug cues or contexts, or certain stressors is assessed following drug self-administration training and subsequent extinction of the drug-reinforced responding. Objective In this review, we first summarize recent (2009-present) neurobiological findings from studies using the reinstatement model. We then discuss emerging research topics, including the impact of interfering with putative reconsolidation processes on cue- and context-induced reinstatement of drug seeking, and similarities and differences in mechanisms of reinstatement across drug classes. We conclude by discussing results from recent human studies that were inspired by results from rat studies using the reinstatement model. Conclusions Main conclusions from the studies reviewed highlight: (1) the ventral subiculum and lateral hypothalamus as emerging brain areas important for reinstatement of drug seeking, (2) the existence of differences in brain mechanisms controlling reinstatement of drug seeking across drug classes, (3) the utility of the reinstatement model for assessing the effect of reconsolidation-related manipulations on cue-induced drug seeking, and (4) the encouraging pharmacological concordance between results from rat studies using the reinstatement model and human laboratory studies on cue- and stress-induced drug craving. PMID:23685858

77 FR 37058 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-20

...] Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance... availability of the draft guidance entitled ``Class II Special Controls Guidance Document: Implanted Blood... blood access devices may comply with the requirement of special controls for class II devices. This...

HIV Infection and Risk Characteristics Among Female Sex Workers in Hanoi, Vietnam

PubMed Central

Tran, Trung Nam; Detels, Roger; Long, Hoang Thuy; Van Phung, Le; Lan, Hoang Phuong

2010-01-01

Summary The prevalence of HIV/sexually transmitted diseases (STDs) was determined, the risk characteristics examined, and factors associated with HIV infection identified among noninstitutionalized female sex workers (FSWs), using a cross-sectional survey with 2-stage cluster sampling. Four hundred FSWs were interviewed face to face using a structured questionnaire and tested for HIV, syphilis, Chlamydia infection, and gonorrhea. HIV seroprevalence was 12%, syphilis 17% (using the treponemal pallidum hemagglutination assay), Chlamydia infection 3.8% (using polymerase chain reaction [PCR]), and gonorrhea 6.3% (PCR). Lower-class FSWs averaged 2 clients per day, and middle-class FSWs about 1.2. Median duration in sex work was 2.3 years. Consistent condom use was 63% with irregular clients, 41% with regular clients, and only 4.8% with “love mates.” Fifty-five percent had had sex with a drug user(s). Thirty-eight percent used drugs, of whom 83% injected. Factors associated with HIV included being young, having a low level of education, longer residence in Hanoi, being a lower-class FSW, having higher income compared with peers, perception of self being at low risk for HIV, poor knowledge of HIV, and sharing injecting equipment. Intervention strategies should include reduction of both stigmatization and sharing of drug paraphernalia, promotion of nonstigmatizing voluntary testing and counseling, and aggressive marketing and promotion of condoms. PMID:16044011

An evaluation of prescribing trends and patterns of claims within the Preferred Drugs Initiative in Ireland (2011-2016): an interrupted time-series study.

PubMed

McDowell, Ronald; Bennett, Kathleen; Moriarty, Frank; Clarke, Sarah; Barry, Michael; Fahey, Tom

2018-04-20

To examine the impact of the Preferred Drugs Initiative (PDI), an Irish health policy aimed at enhancing evidence-based cost-effective prescribing, on prescribing trends and the cost of prescription medicines across seven medication classes. Retrospective repeated cross-sectional study spanning the years 2011 - 2016. Health Service Executive Primary Care Reimbursement Service pharmacy claims data for General Medical Services (GMS) patients, approximately 40% of the Irish population. Adults aged ≥18 years between 2011 and 2016 are eligible for the GMS scheme. The percentage of PDI medications within each drug class per calendar quarter. Linear regression was used to model prescribing of the preferred drug within each medication group and to assess the impact of PDI guidelines and other relevant changes in prescribing practice. Savings in drug expenditure were estimated. Between 2011 and 2016, around a quarter (23.59%) of all medications were for single-agent drugs licensed in the seven drug classes. There was a small increase in the percentage of PDI drugs, increasing from 4.64% of all medications in 2011 to 4.76% in 2016 (P<0.001). The percentage of preferred drugs within each drug class was significantly higher immediately following publication of the guidelines for all classes except urology, with the largest increases noted for lansoprazole (1.21%, 95% CI: 0.84% to 1.57%, P<0.001) and venlafaxine (0.71%, 95% CI: 0.15% to 1.27%, P=0.02). Trends in prescribing of the preferred drugs between PDI guidelines and the end of 2016 varied between drug classes. Total cost savings between 2013 and 2016 were estimated to be €2.7 million. There has been a small increase in prescribing of PDI drugs in response to prescribing guidelines, with inconsistent changes observed across therapeutic classes. These findings are relevant where health services are seeking to develop more active prescribing interventions aimed at changing prescribing practice. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

76 FR 43690 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-21

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2007-D-0149] (Formerly 2007D-0309) Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document: Electrocardiograph Electrodes; Availability AGENCY: Food and Drug...

Drug substitution associated with a hospital stay in Belgium: a retrospective analysis of a claims database.

PubMed

Simoens, Steven; Dubois, Cécile; Spinewine, Anne; Foulon, Veerle; Paulus, Dominique

2014-04-01

This study measures the extent of drug substitution associated with a hospital stay in Belgium. Data were extracted from the 2006-2007 dataset of the Belgian Agency of Health Insurance Funds on drug use of patients hospitalized in acute hospitals. Reimbursed drugs received in ambulatory care during the 3 months prior to hospitalization were compared with drugs received during the 3 months following hospital discharge. Both a narrow definition and a broad definition were used for drug substitution. Narrow substitution (switches between generic and originator drugs) was computed for 14 drug classes for chronic conditions with the highest public expenditure. Broad substitution (changes between chemical substances within the drug class at ATC level 4, changes in brand name) was calculated for statins and proton-pump inhibitors only. The database included 17 764 patients (mean age 66 ± 17 years; 60% female). In 71% of cases an originator drug was received prior to and following hospitalization. A generic drug was received prior to and following hospitalization in 25% of cases. Some form of narrow substitution occurred in 4% of cases: a generic drug was replaced by an originator drug in 2% of cases and an originator drug was replaced by a generic drug in 2% of cases. Some form of broad substitution occurred in 25% of cases for proton-pump inhibitors and 13% of cases for statins. Hospitalization was not a trigger for changes between originator and generic versions of a drug. Broad substitution associated with a hospital stay was relatively limited for statins and proton-pump inhibitors. © 2013 Royal Pharmaceutical Society.

The Biopharmaceutics Classification System: subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC.

PubMed

Tsume, Yasuhiro; Mudie, Deanna M; Langguth, Peter; Amidon, Greg E; Amidon, Gordon L

2014-06-16

The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include sub-specification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification. This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology. Such a dissolution methodology can be used by development scientists to assess the likelihood of a formulation and dosage form functioning as desired in humans, can be optimized along with parallel human pharmacokinetic studies to set a dissolution methodology for Quality by Design (QbD) and in vitro-in vivo correlations (IVIVC) and ultimately can be used as a basis for a dissolution standard that will ensure continued in vivo product performance. Copyright © 2014 Elsevier B.V. All rights reserved.

The Biopharmaceutics Classification System: Subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC

PubMed Central

Tsume, Yasuhiro; Mudie, Deanna M.; Langguth, Peter; Amidon, Greg E.; Amidon, Gordon L.

2014-01-01

The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include subspecification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification. This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology. Such a dissolution methodology can be used by development scientists to assess the likelihood of a formulation and dosage form functioning as desired in humans, can be optimized along with parallel human pharmacokinetic studies to set a dissolution methodology for Quality by Design (QbD) and in vitro–in vivo correlations (IVIVC) and ultimately can be used as a basis for a dissolution standard that will ensure continued in vivo product performance. PMID:24486482

Drug carrier systems for solubility enhancement of BCS class II drugs: a critical review.

PubMed

Kumar, Sumit; Bhargava, Deepak; Thakkar, Arti; Arora, Saahil

2013-01-01

Poor aqueous solubility impedes a drug's bioavailability and challenges its pharmaceutical development. Pharmaceutical development of drugs with poor water solubility requires the establishment of a suitable formulation layout among various techniques. Various approaches have been investigated extensively to improve the aqueous solubility and poor dissolution rate of BCS class II and IV drugs. In this literature review, novel formulation options, particularly for class II drugs designed for applications such as micronization, self-emulsification, cyclodextrin complexation, co-crystallisation, super critical fluid technology, solubilisation by change in pH, salt formation, co-solvents, melt granulation, and solid dispersion, liposomal/niosomal formulations, are discussed in detail to introduce biopharmaceutical challenges and recent approaches to facilitate more efficient drug formulation and development.

Screen of FDA-approved drug library reveals compounds that protect hair cells from aminoglycosides and cisplatin

PubMed Central

Vlasits, Anna L.; Simon, Julian A.; Raible, David W.; Rubel, Edwin W; Owens, Kelly N.

2012-01-01

Loss of mechanosensory hair cells in the inner ear accounts for many hearing loss and balance disorders. Several beneficial pharmaceutical drugs cause hair cell death as a side effect. These include aminoglycoside antibiotics, such as neomycin, kanamycin and gentamicin, and several cancer chemotherapy drugs, such as cisplatin. Discovering new compounds that protect mammalian hair cells from toxic insults is experimentally difficult because of the inaccessibility of the inner ear. We used the zebrafish lateral line sensory system as an in vivo screening platform to survey a library of FDA-approved pharmaceuticals for compounds that protect hair cells from neomycin, gentamicin, kanamycin and cisplatin. Ten compounds were identified that provide protection from at least two of the four toxins. The resulting compounds fall into several drug classes, including serotonin and dopamine-modulating drugs, adrenergic receptor ligands, and estrogen receptor modulators. The protective compounds show different effects against the different toxins, supporting the idea that each toxin causes hair cell death by distinct, but partially overlapping, mechanisms. Furthermore, some compounds from the same drug classes had different protective properties, suggesting that they might not prevent hair cell death by their known target mechanisms. Some protective compounds blocked gentamicin uptake into hair cells, suggesting that they may block mechanotransduction or other routes of entry. The protective compounds identified in our screen will provide a starting point for studies in mammals as well as further research discovering the cellular signaling pathways that trigger hair cell death. PMID:22967486

Therapeutic options and emerging alternatives for multidrug resistant staphylococcal infections.

PubMed

Magana, Maria; Ioannidis, Anastasios; Magiorkinis, Emmanouil; Ursu, Oleg; Bologa, Cristian G; Chatzipanagiotou, Stylianos; Hamblin, Michael R; Tegos, George P

2015-01-01

Methicillin-resistant Staphylococcus aureus (MRSA) remains the single biggest challenge in infectious disease in the civilized world. Moreover, vancomycin resistance is also spreading, leading to fears of untreatable infections as were common in ancient times. Molecular microbiology and bioinformatics have revealed many of the mechanisms involved in resistance development. Mobile genetic elements, up-regulated virulence factors and multi-drug efflux pumps have been implicated. A range of approved antibiotics from the glycopeptide, lipopeptide, pleuromutilin, macrolide, oxazolidinone, lincosamide, aminoglycoside, tetracycline, steptogramin, and cephalosporin classes has been employed to treat MRSA infections. The upcoming pipeline of drugs for MRSA includes some new compounds from the above classes, together with fluoroquinolones, antibacterial peptide mimetics, aminomethylciclines, porphyrins, peptide deformylase inhibitors, oxadiazoles, and diaminopyrimidines. A range of non-drug alternative approaches has emerged for MRSA treatment. Bacteriophage-therapy including purified lysins has made a comeback after being discovered in the 1930s. Quorum-sensing inhibitors are under investigation. Small molecule inhibitors of multi-drug efflux pumps may potentiate existing antibiotics. The relative failure of staphylococcal vaccines is being revisited by efforts with multi-valent vaccines and improved adjuvants. Photodynamic therapy uses non-toxic photosensitizers and harmless visible light to produce reactive oxygen species that can nonspecifically destroy bacteria while preserving host cells. Preparation of nanoparticles can kill bacteria themselves, as well as improve the delivery of anti-bacterial drugs. Anti-MRSA drug discovery remains an exciting field with great promise for the future.

Macrocyclic drugs and synthetic methodologies toward macrocycles

PubMed Central

Yu, Xufen; Sun, Dianqing

2015-01-01

Macrocyclic scaffolds are commonly found in bioactive natural products and pharmaceutical molecules. So far, a large number of macrocyclic natural products have been isolated and synthesized. The construction of macrocycles is generally considered as a crucial and challenging step in the synthesis of macrocyclic natural products. Over the last several decades, numerous efforts have been undertaken toward the synthesis of complex naturally occurring macrocycles and great progresses have been made to advance the field of total synthesis. The commonly used synthetic methodologies toward macrocyclization include macrolactonization, macrolactamization, transition metal-catalyzed cross coupling, ring-closing metathesis, and click reaction, among others. Selected recent examples of macrocyclic synthesis of natural products and druglike macrocycles with significant biological relevance are highlighted in each class. The primary goal of this review is to summarize currently used macrocyclic drugs, highlight the therapeutic potential of this underexplored drug class and outline the general synthetic methodologies for the synthesis of macrocycles. PMID:23708234

Everyday Discrimination and Mood and Substance Use Disorders: A Latent Profile Analysis with African Americans and Caribbean Blacks

PubMed Central

Clark, Trenette T.; Salas-Wright, Christopher P.; Vaughn, Michael G.; Whitfield, Keith E.

2016-01-01

Perceived discrimination is a major source of health-related stress. The purpose of this study was to model the heterogeneity of everyday-discrimination experiences among African American and Caribbean Blacks and to identify differences in the prevalence of mood and substance use outcomes, including generalized anxiety disorder, major depressive disorder, alcohol-use disorder, and illicit drug-use disorder among the identified subgroups. The study uses data from the National Survey of American Life obtained from a sample of African American and Caribbean Black respondents (N = 4,462) between 18 and 65 years. We used latent profile analysis and multinomial regression analyses to identify and validate latent subgroups and test hypotheses, yielding 4 classes of perceived everyday discrimination: Low Discrimination, Disrespect and Condescension, General Discrimination, and Chronic Discrimination. Findings show significant differences exist between the Low Discrimination and General Discrimination classes for major depressive disorder, alcohol-use disorder, and illicit drug-use disorder. Moreover, we find significant differences exist between the Low Discrimination and Chronic Discrimination classes for the four disorders examined. Compared with the Chronic Discrimination class, members of the other classes were significantly less likely to meet criteria for generalized anxiety disorder, major depressive disorder, alcohol-use disorder, and illicit drug-use disorder. Findings suggest elevated levels of discrimination increase risk for mood and substance-use disorders. Importantly, results suggest the prevalence of mood and substance-use disorders is a function of the type and frequency of discrimination that individuals experience. PMID:25254321

Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei

PubMed Central

Kalidas, Savitha; Cestari, Igor; Monnerat, Severine; Li, Qiong; Regmi, Sandesh; Hasle, Nicholas; Labaied, Mehdi; Parsons, Marilyn; Stuart, Kenneth

2014-01-01

Human African trypanosomiasis (HAT) is an important public health threat in sub-Saharan Africa. Current drugs are unsatisfactory, and new drugs are being sought. Few validated enzyme targets are available to support drug discovery efforts, so our goal was to obtain essentiality data on genes with proven utility as drug targets. Aminoacyl-tRNA synthetases (aaRSs) are known drug targets for bacterial and fungal pathogens and are required for protein synthesis. Here we survey the essentiality of eight Trypanosoma brucei aaRSs by RNA interference (RNAi) gene expression knockdown, covering an enzyme from each major aaRS class: valyl-tRNA synthetase (ValRS) (class Ia), tryptophanyl-tRNA synthetase (TrpRS-1) (class Ib), arginyl-tRNA synthetase (ArgRS) (class Ic), glutamyl-tRNA synthetase (GluRS) (class 1c), threonyl-tRNA synthetase (ThrRS) (class IIa), asparaginyl-tRNA synthetase (AsnRS) (class IIb), and phenylalanyl-tRNA synthetase (α and β) (PheRS) (class IIc). Knockdown of mRNA encoding these enzymes in T. brucei mammalian stage parasites showed that all were essential for parasite growth and survival in vitro. The reduced expression resulted in growth, morphological, cell cycle, and DNA content abnormalities. ThrRS was characterized in greater detail, showing that the purified recombinant enzyme displayed ThrRS activity and that the protein localized to both the cytosol and mitochondrion. Borrelidin, a known inhibitor of ThrRS, was an inhibitor of T. brucei ThrRS and showed antitrypanosomal activity. The data show that aaRSs are essential for T. brucei survival and are likely to be excellent targets for drug discovery efforts. PMID:24562907

Association Between Academic Medical Center Pharmaceutical Detailing Policies and Physician Prescribing.

PubMed

Larkin, Ian; Ang, Desmond; Steinhart, Jonathan; Chao, Matthew; Patterson, Mark; Sah, Sunita; Wu, Tina; Schoenbaum, Michael; Hutchins, David; Brennan, Troyen; Loewenstein, George

2017-05-02

In an effort to regulate physician conflicts of interest, some US academic medical centers (AMCs) enacted policies restricting pharmaceutical representative sales visits to physicians (known as detailing) between 2006 and 2012. Little is known about the effect of these policies on physician prescribing. To analyze the association between detailing policies enacted at AMCs and physician prescribing of actively detailed and not detailed drugs. The study used a difference-in-differences multivariable regression analysis to compare changes in prescribing by physicians before and after implementation of detailing policies at AMCs in 5 states (California, Illinois, Massachusetts, Pennsylvania, and New York) that made up the intervention group with changes in prescribing by a matched control group of similar physicians not subject to a detailing policy. Academic medical center implementation of policies regulating pharmaceutical salesperson visits to attending physicians. The monthly within-drug class market share of prescriptions written by an individual physician for detailed and nondetailed drugs in 8 drug classes (lipid-lowering drugs, gastroesophageal reflux disease drugs, diabetes drugs, antihypertensive drugs, hypnotic drugs approved for the treatment of insomnia [sleep aids], attention-deficit/hyperactivity disorder drugs, antidepressant drugs, and antipsychotic drugs) comparing the 10- to 36-month period before implementation of the detailing policies with the 12- to 36-month period after implementation, depending on data availability. The analysis included 16 121 483 prescriptions written between January 2006 and June 2012 by 2126 attending physicians at the 19 intervention group AMCs and by 24 593 matched control group physicians. The sample mean market share at the physician-drug-month level for detailed and nondetailed drugs prior to enactment of policies was 19.3% and 14.2%, respectively. Exposure to an AMC detailing policy was associated with a decrease in the market share of detailed drugs of 1.67 percentage points (95% CI, -2.18 to -1.18 percentage points; P < .001) and an increase in the market share of nondetailed drugs of 0.84 percentage points (95% CI, 0.54 to 1.14 percentage points; P < .001). Associations were statistically significant for 6 of 8 study drug classes for detailed drugs (lipid-lowering drugs, gastroesophageal reflux disease drugs, antihypertensive drugs, sleep aids, attention-deficit/hyperactivity disorder drugs, and antidepressant drugs) and for 9 of the 19 AMCs that implemented policies. Eleven of the 19 AMCs regulated salesperson gifts to physicians, restricted salesperson access to facilities, and incorporated explicit enforcement mechanisms. For 8 of these 11 AMCs, there was a significant change in prescribing. In contrast, there was a significant change at only 1 of 8 AMCs that did not enact policies in all 3 areas. Implementation of policies at AMCs that restricted pharmaceutical detailing between 2006 and 2012 was associated with modest but significant reductions in prescribing of detailed drugs across 6 of 8 major drug classes; however, changes were not seen in all of the AMCs that enacted policies.

Trends in prescription drug expenditures by Medicaid enrollees.

PubMed

Banthin, Jessica S; Miller, G Edward

2006-05-01

As prescription drug expenditures consume an increasingly larger portion of Medicaid budgets, states are anxious to control drug costs without endangering enrollees' health. In this report, we analyzed recent trends in Medicaid prescription drug expenditures by therapeutic classes and subclasses. Identifying the fastest growing categories of drugs, where drugs are grouped into clinically relevant classes and subclasses, can help policymakers decide where to focus their cost containment efforts. We used data from the Medical Expenditure Panel Survey linked to a prescription drug therapeutic classification system, to examine trends between 1996/1997 and 2001/2002 in utilization and expenditures for the noninstitutionalized Medicaid population. We separated aggregate trends into changes in population with use and changes in expenditures per user, and percent generic. We also highlighted differences within the Medicaid population, including children, adults, disabled, and elderly. We found rapid growth in expenditures for antidepressants, antipsychotics, antihyperlipidemics, antidiabetic agents, antihistamines, COX-2 inhibitors, and proton pump inhibitors and found evidence supporting the rapid take-up of new drugs. In some cases these increases are the result of increased expenditures per user and in other cases the overall growth also comes from an increase in the population with use. Medicaid programs may want to reassess their cost-containment policies in light of the rapid take-up of new drugs. Our analysis also identifies areas in which more information is needed on the comparative effectiveness of new versus existing treatments.

The value of irbesartan in the management of hypertension.

PubMed

Bramlage, Peter; Durand-Zaleski, Isabelle; Desai, Nisha; Pirk, Olaf; Hacker, Caroline

2009-08-01

Elevated blood pressure levels are highly prevalent and are a major reason for cardiovascular events and thus place a significant financial burden on healthcare systems worldwide. Guidelines recommend five first-line anti-hypertensive drug classes, but compelling indications may indicate favoring one drug class over another. Angiotensin receptor blockers (ARBs) have demonstrated a blood pressure lowering efficacy which is at least comparable with other drug classes, including ACE inhibitors (ACE-I), beta-blockers, calcium channel blockers and diuretics. They have, in addition, a lower side effect profile than other drug classes and patients on ARBs are more persistent with therapy. Compelling indications for the use of ARBs are heart failure, post-myocardial infarction, diabetic nephropathy, proteinuria/microalbuminuria, left ventricular hypertrophy, atrial fibrillation, metabolic syndrome and ACE-I induced cough. The ARB irbesartan has demonstrated a high efficacy in lowering blood pressure, which has been shown to be at least comparable with ACE-Is and superior to other ARBs such as losartan and valsartan. This translated into a better cost-effectiveness for irbesartan than for valsartan and losartan in the treatment of hypertension. In addition, irbesartan has been shown to be effective in both early and late stage diabetic nephropathy. It has further demonstrated considerable cost savings over standard therapy including beta-blockers, diuretics and non-dihydropyridine calcium channel blockers at all stages of kidney disease. Based on efficacy data from the Irbesartan Diabetic Nephropathy Trial and Reduction of Endpoints in NIDDM (non insulin dependant diabetes melitis) with the Angiotensin II Antagonist Losartan Study, it has also demonstrated cost savings over losartan in late stage renal disease. While both losartan and irbesartan are registered for the treatment of late stage diabetic nephropathy, irbesartan is also registered for early stage diabetic nephropathy in the EU. In summary, the data from randomized clinical trials on the efficacy of antihypertensive drugs provides an indication of their real value to patients. In addition observational data from clinical practice and proven end-organ protection in diabetic nephropathy provides further evidence of the true value of irbesartan compared to other ARBs in the treatment of hypertension.

Latent Classes of Polydrug Users as a Predictor of Crash Involvement and Alcohol Consumption.

PubMed

Scherer, Michael; Romano, Eduardo; Voas, Robert; Taylor, Eileen

2018-05-01

Polydrug users have been shown to be at higher risk for alcohol consumption and crash involvement. However, research has shown that polydrug groups differ in some important ways. It is currently unknown how polydrug-using groups differ in terms of crash involvement and alcohol consumption. The current study used latent class analysis to examine subgroups of polydrug users (n = 384) among a sample of drivers in Virginia Beach, Virginia (N = 10,512). A series of logistic regression analyses were conducted to determine the relationship between polydrug use categories and crash involvement and alcohol consumption. Four distinct subclasses of users were identified among polydrug-using drivers: Class 1 is the "marijuana-amphetamines class" and accounts for 21.6% of polydrug users. Class 2 is the "benzo-antidepressant class" and accounts for 39.0% of polydrug users. Class 3 is the "opioid-benzo class" and accounts for 32.7% of polydrug users. Finally, Class 4 is the "marijuana-cocaine class" and accounts for 6.7% of the study sample. Drivers in the opioid-benzo class were significantly more likely than those in any other class as well as non-drug users and single-drug users to be involved in a crash and were more likely than those in most other conditions to consume alcohol. No significant difference was found between marijuana-amphetamine users or benzo-antidepressant users and non-drug users on crash risk. Some polydrug users are indeed at greater risk for crash involvement and alcohol consumption; however, not all polydrug users are significantly worse than single-drug users and/or non-drug users, and the practice of lumping polydrug users together when predicting crash risk runs the risk of inaccurately attributing crash involvement to certain drivers.

Drug resistance in B and non-B subtypes amongst subjects recently diagnosed as primary/recent or chronic HIV-infected over the period 2013-2016: Impact on susceptibility to first-line strategies including integrase strand-transfer inhibitors.

PubMed

Andreis, Samantha; Basso, Monica; Scaggiante, Renzo; Cruciani, Mario; Ferretto, Roberto; Manfrin, Vinicio; Panese, Sandro; Rossi, Maria Cristina; Francavilla, Ermenegildo; Boldrin, Caterina; Alvarez, Mario; Dal Bello, Federico; Mengoli, Carlo; Turriziani, Ombretta; Sarmati, Loredana; Antonelli, Guido; Andreoni, Massimo; Palù, Giorgio; Parisi, Saverio Giuseppe

2017-09-01

To characterize the prevalence of transmitted drug resistance mutations (TDRMs) by plasma analysis of 750 patients at the time of HIV diagnosis from January 1, 2013 to November 16, 2016 in the Veneto region (Italy), where all drugs included in the recommended first line therapies were prescribed, included integrase strand transfer inhibitors (InNSTI). TDRMs were defined according to the Stanford HIV database algorithm. Subtype B was the most prevalent HIV clade (67.3%). A total of 92 patients (12.3%) were expected to be resistant to one drug at least, most with a single class mutation (60/68-88.2% in subtype B infected subjectsand 23/24-95.8% in non-B subjects) and affecting mainly NNRTIs. No significant differences were observed between the prevalence rates of TDRMs involving one or more drugs, except for the presence of E138A quite only in patients with B subtype and other NNRTI in subjects with non-B infection. The diagnosis of primary/recent infection was made in 73 patients (9.7%): they had almost only TDRMs involving a single class. Resistance to InSTI was studied in 484 subjects (53 with primary-recent infection), one patient had 143C in 2016, a total of thirteen 157Q mutations were detected (only one in primary/recent infection). Only one major InSTI-TDRM was identified but monitoring of TDRMs should continue in the light of continuing presence of NNRTI-related mutation amongst newly diagnosed subjects, sometime impacting also to modern NNRTI drugs recommended in first-line therapy. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

Do advertisements for antihypertensive drugs in Australia promote quality prescribing? A cross-sectional study.

PubMed

Montgomery, Brett D; Mansfield, Peter R; Spurling, Geoffrey K; Ward, Alison M

2008-05-20

Antihypertensive medications are widely prescribed by doctors and heavily promoted by the pharmaceutical industry. Despite strong evidence of the effectiveness and cost-effectiveness of thiazide diuretics, trends in both promotion and prescription of antihypertensive drugs favour newer, less cost-effective agents. Observational evidence shows correlations between exposure to pharmaceutical promotion and less ideal prescribing. Our study therefore aimed to determine whether print advertisements for antihypertensive medications promote quality prescribing in hypertension. We performed a cross-sectional study of 113 advertisements for antihypertensive drugs from 4 general practice-oriented Australian medical publications in 2004. Advertisements were evaluated using a quality checklist based on a review of hypertension management guidelines. Main outcome measures included: frequency with which antihypertensive classes were advertised, promotion of thiazide class drugs as first line agents, use of statistical claims in advertisements, mention of harms and prices in the advertisements, promotion of assessment and treatment of cardiovascular risk, promotion of lifestyle modification, and targeting of particular patient subgroups. Thiazides were the most frequently advertised drug class (48.7% of advertisements), but were largely promoted in combination preparations. The only thiazide advertised as a single agent was the most expensive, indapamide. No advertisement specifically promoted any thiazide as a better first-line drug. Statistics in the advertisements tended to be expressed in relative rather than absolute terms. Drug costs were often reported, but without cost comparisons between drugs. Adverse effects were usually reported but largely confined to the advertisements' small print. Other than mentioning drug interactions with alcohol and salt, no advertisements promoted lifestyle modification. Few advertisements (2.7%) promoted the assessment of cardiovascular risk. Print advertisements for antihypertensive medications in Australia provide some, but not all, of the key messages required for guideline-concordant care. These results have implications for the regulation of drug advertising and the continuing education of doctors.

Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson s disease patients with motor complications.

PubMed

Stowe, Rebecca; Ives, Natalie; Clarke, Carl E; Deane, Katherine; Wheatley, Keith; Gray, Richard; Handley, Kelly; Furmston, Alex

2010-07-07

One of the complications of long-term treatment of Parkinson's disease (PD) with levodopa is the development of motor complications. Generally, when motor complications develop, clinicians add in an additional drug (to the levodopa regimen) from one of three other classes of anti-Parkinsonian treatments (dopamine agonists, catechol-O-methyl transferase inhibitors (COMTIs) or monoamine oxidase type B inhibitors (MAOBIs)). However, despite trials having shown that these drugs are beneficial compared to placebo, it remains unclear as to the best way to treat patients experiencing motor complications and whether one class of drug is more effective than another. This meta-analysis aims to assess more reliably the benefits and risks of the three classes of drugs (dopamine agonists, COMTIs and MAOBIs) currently used as adjuvant treatment to levodopa in PD patients suffering from motor complications. The three drug classes were compared with the aim of determining whether one class of drug provides better symptomatic control than another. We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications. Randomised trials comparing an orally administered dopamine agonist, COMTI or MAOBI versus placebo, both on a background of levodopa therapy, in PD patients experiencing motor complications. Two authors independently extracted data on off-time, levodopa dose, motor complications, side-effects, treatment concordance, clinician-rated disability, mortality, quality of life and health economic data. Forty-four eligible trials, involving 8436 participants were identified. Compared to placebo, adjuvant therapy significantly reduced off-time (-1.05 hours/day, 95% confidence interval (CI) -1.19 to -0.90; P<0.00001), the required levodopa dose (-55.65 mg/day, CI -62.67 to -48.62; P<0.00001) and improved UPDRS scores (UPDRS ADL score: -1.31 points, CI -1.62 to -0.99; P<0.00001; UPDRS motor score: -2.84 points, CI -3.36 to -2.32; P<0.00001; UPDRS total score: -3.26 points, CI -4.52 to -2.00; P<0.00001). However, dyskinesia (odds ratio (OR) 2.50, CI 2.21 to 2.84; P<0.00001) and side-effects including constipation (OR 3.19, CI 2.17 to 4.68; P<0.00001), dizziness (OR 1.57, CI 1.30 to 1.90; P<0.00001), dry mouth (OR 2.33, CI 1.22 to 4.47; P=0.01), hallucinations (OR 2.16, CI 1.70 to 2.74; P<0.00001), hypotension (OR 1.47, CI 1.18 to 1.83; P=0.0007), insomnia (OR 1.38, CI 1.09 to 1.74; P=0.007), nausea (OR 1.78, CI 1.53 to 2.07; P<0.00001), somnolence (OR 1.87, CI 1.40 to 2.51; P<0.0001) and vomiting (OR 2.56, CI 1.67 to 3.93; P<0.0001) were all increased with adjuvant therapy.Indirect comparisons of the three drug classes suggested that dopamine agonists were more efficacious in reducing off-time (dopamine agonist: -1.54 hours/day; COMTI: -0.83 hours/day; MAOBI: -0.93 hours/day; test for heterogeneity between drug classes P=0.0003) and levodopa dose (dopamine agonist: -116 mg/day; COMTI: -52 mg/day; MAOBI: -29 mg/day; test for heterogeneity between drug classes P<0.00001). UPDRS scores also improved more with dopamine agonists than with COMTI or MAOBI (UPDRS total scores - dopamine agonist: -10.01 points versus COMTI: -1.46 points versus MAOBI: -2.20 points; test for heterogeneity between drug classes P<0.00001), although more dyskinesia were seen with dopamine agonists (OR 2.70) and COMTI (OR 2.50) than with MAOBI (OR 0.94) (test for heterogeneity between drug classes P=0.009). Although the increase in the overall incidence of side-effects was generally more marked with dopamine agonists (OR 1.52) and COMTI (OR 2.0) than with MAOBI (OR 1.32), heterogeneity between drug classes was only of borderline significance (P=0.07). Compared to placebo, adjuvant therapy reduces off-time, levodopa dose, and improves UPDRS scores in PD patients who develop motor complications on levodopa therapy. However, this is at the expense of increased dyskinesia and numerous other side-effects. Indirect comparisons suggest that dopamine agonist therapy may be more effective than COMTI and MAOBI therapy, which have comparable efficacy. However, as indirect comparisons should be interpreted with caution, direct head-to-head randomised trials assessing the impact of these different drug classes on overall patient-rated quality of life are needed.

77 FR 14403 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-D-0167] Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document: Norovirus Serological Reagents; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice...

Surveillance of HIV antiretroviral drug resistance in treated individuals in England: 1998-2000.

PubMed

Scott, Paul; Arnold, Eve; Evans, Barry; Pozniak, Anton; Moyle, Graeme; Shahmenesh, Mohsen; White, David; Shirley, Jane; Cane, Patricia; Pillay, Deenan

2004-03-01

To establish a surveillance programme for HIV drug resistance within the UK covering the years from 1998 to 2000, following the introduction of triple combination antiretroviral therapy. Sentinel sites included large, medium sized and small clinical centres. Data were analysed until December 2000. Of nearly 300 samples tested, results from 91, 92 and 92 patients, respectively in 1998, 1999 and 2000, who were receiving HIV therapy with a viral load >2000 copies/mL, the majority had viruses with some degree of drug resistance. Overall, the presence of any resistance increased between 1998 and 1999, and fell again in 2000 (69% versus 88% versus 55%). However, major differences were observed between drug classes, such that non-nucleoside analogue reverse transcriptase inhibitor (NNRTI) resistance rose dramatically over the period studied. We show that this correlated with increased NNRTI prescribing. Furthermore, an overall increase in prevalence of viruses with resistance to one or more drugs within all three available classes was observed. A higher prevalence of drug resistance was observed in patients from smaller clinical centres. This is the first such sentinel surveillance dataset from the UK, and is unique in correlating these data with national antiretroviral prescribing patterns. Our findings are relevant to the increased transmission of HIV drug resistance observed over this period.

Drug delivery strategies for poorly water-soluble drugs.

PubMed

Fahr, Alfred; Liu, Xiangli

2007-07-01

The drug candidates coming from combinatorial chemistry research and/or the drugs selected from biologically based high-throughput screening are quite often very lipophilic, as these drug candidates exert their pharmacological action at or in biological membranes or membrane-associated proteins. This challenges drug delivery institutions in industry or academia to develop carrier systems for the optimal oral and parenteral administration of these drugs. To mention only a few of the challenges for this class of drugs: their oral bioavailability is poor and highly variable, and carrier development for parenteral administration is faced with problems, including the massive use of surface-active excipients for solubilisation. Formulation specialists are confronted with an even higher level of difficulties when these drugs have to be delivered site specifically. This article addresses the emerging formulation designs for delivering of poorly water-soluble drugs.

The FDA alert on suicidality and antiepileptic drugs: Fire or false alarm?

PubMed

Hesdorffer, Dale C; Kanner, Andres M

2009-05-01

In January 2008, the U.S. Food and Drug Administration (FDA) issued an alert about an increased risk for suicidality in 199 clinical trials of 11 antiepileptic drugs (AEDs) for three different indications, including epilepsy. An advisory panel voted against a black-box warning on AED labels, and the FDA has accepted this recommendation. We discuss three potential problems with the alert. First, adverse event data were used rather than systematically collected data. Second, the 11 drugs grouped together as a single class of AEDs have different mechanisms of action and very different relative risks, many of which were not statistically significant and some of which were smaller than one. These facts suggest that they should not be grouped as a class. Third, the risk of adverse effects from uncontrolled seizures almost certainly outweighs the small risk of suicidality. We place our comments in the context of a review of the literature on suicidality and depression in epilepsy and the sparse literature on AEDs and suicidality. We recommend that all patients with epilepsy be routinely evaluated for depression, anxiety, and suicidality, and that future clinical trials include validated instruments to systematically assess these conditions to determine whether the possible signal observed by the FDA is real.

LC-MS-sMRM Method Development and Validation of Different Classes of Pain Panel Drugs and Analysis of Clinical Urine Samples.

PubMed

Athar Masood, M; Veenstra, Timothy D

2017-08-26

Urine Drug Testing (UDT) is an important analytical/bio-analytical technique that has inevitably become an integral and vital part of a testing program for diagnostic purposes. This manuscript presents a tailor-made LC-MS/MS quantitative assay method development and validation for a custom group of 33 pain panel drugs and their metabolites belonging to different classes (opiates, opioids, benzodiazepines, illicit, amphetamines, etc.) that are prescribed in pain management and depressant therapies. The LC-MS/MS method incorporates two experiments to enhance the sensitivity of the assay and has a run time of about 7 min. with no prior purification of the samples required and a flow rate of 0.7 mL/min. The method also includes the second stage metabolites for some drugs that belong to different classes but have first stage similar metabolic pathways that will enable to correctly identify the right drug or to flag the drug that might be due to specimen tampering. Some real case examples and difficulties in peak picking were provided with some of the analytes in subject samples. Finally, the method was deliberated with some randomly selected de-identified clinical subject samples, and the data evaluated from "direct dilute and shoot analysis" and after "glucuronide hydrolysis" were compared. This method is now used to run routinely more than 100 clinical subjects samples on a daily basis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Pills, Thrills and Bellyaches: Case Studies of Prescription Pill Use and Misuse among Marijuana/Blunt Smoking Middle Class Young Women.

PubMed

Bardhi, Flutura; Sifaneck, Stephen J; Johnson, Bruce D; Dunlap, Eloise

2007-01-01

Recent survey research has documented important increases during the 2000s in the misuse and abuse of several prescription drugs (Vicodin, Percocet, Codeine, Dilaudid, Xanax, Klonopin, Valium, Ativan, Adderall, Ritalin, among others). This article focuses upon the patterns of pill use and misuse among young women who are middle-class white and college-educated, and they are also experienced marijuana users who report recreational consumption of other illegal drugs. The ethnographic data provides insights about various ways and reasons that such prescription pill misuse occurs among 12 college-educated, (upper) middle-class, white/Asian women in their 20s who were involved in a major ethnographic study of marijuana and blunts. Three patterns of pill use were observed: recreational; quasi-medical; and legal medical; shifts among these patterns of pill use was common. Few reported that their pill use interfered with their conventional jobs and lifestyles; they concealed such use from their employers and coworkers, and from non-using friends and family members. None reported contacts with police nor seeking treatment specifically for their pill misuse. Many reported misusing prescription pills in conjunction with illegal drugs (marijuana, cocaine, ecstasy) and alcohol. Pills were used as a way to enhance the euphoric effects of other drugs, as well as a way to avoid the negative side effects of illegal drugs. Some reported pill use as a means for reducing expenditures (and use of) alcohol and cocaine. The implications suggest a hidden subpopulation of prescription pill misusers among regular users of marijuana and other illegal drugs. Future research should include users and misusers of various pills to better understand how prescriptions pills interact with illegal drug use patterns.

Pills, Thrills and Bellyaches: Case Studies of Prescription Pill Use and Misuse among Marijuana/Blunt Smoking Middle Class Young Women

PubMed Central

Bardhi, Flutura; Sifaneck, Stephen J.; Johnson, Bruce D.; Dunlap, Eloise

2008-01-01

Recent survey research has documented important increases during the 2000s in the misuse and abuse of several prescription drugs (Vicodin, Percocet, Codeine, Dilaudid, Xanax, Klonopin, Valium, Ativan, Adderall, Ritalin, among others). This article focuses upon the patterns of pill use and misuse among young women who are middle-class white and college-educated, and they are also experienced marijuana users who report recreational consumption of other illegal drugs. The ethnographic data provides insights about various ways and reasons that such prescription pill misuse occurs among 12 college-educated, (upper) middle-class, white/Asian women in their 20s who were involved in a major ethnographic study of marijuana and blunts. Three patterns of pill use were observed: recreational; quasi-medical; and legal medical; shifts among these patterns of pill use was common. Few reported that their pill use interfered with their conventional jobs and lifestyles; they concealed such use from their employers and coworkers, and from non-using friends and family members. None reported contacts with police nor seeking treatment specifically for their pill misuse. Many reported misusing prescription pills in conjunction with illegal drugs (marijuana, cocaine, ecstasy) and alcohol. Pills were used as a way to enhance the euphoric effects of other drugs, as well as a way to avoid the negative side effects of illegal drugs. Some reported pill use as a means for reducing expenditures (and use of) alcohol and cocaine. The implications suggest a hidden subpopulation of prescription pill misusers among regular users of marijuana and other illegal drugs. Future research should include users and misusers of various pills to better understand how prescriptions pills interact with illegal drug use patterns. PMID:19081798

Simultaneous analysis of aminoglycosides with many other classes of drug residues in bovine tissues by ultrahigh-performance liquid chromatography-tandem mass spectrometry using an ion-pairing reagent added to final extracts.

PubMed

Lehotay, Steven J; Lightfield, Alan R

2018-01-01

The way to maximize scope of analysis, sample throughput, and laboratory efficiency in the monitoring of veterinary drug residues in food animals is to determine as many analytes as possible as fast as possible in as few methods as possible. Capital and overhead expenses are also reduced by using fewer instruments in the overall monitoring scheme. Traditionally, the highly polar aminoglycoside antibiotics require different chromatographic conditions from other classes of drugs, but in this work, we demonstrate that an ion-pairing reagent (sodium 1-heptanesulfonate) added to the combined final extracts from two sample preparation methods attains good separation of 174 targeted drugs, including 9 aminoglycosides, in the same 10.5-min ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. The full method was validated in bovine kidney, liver, and muscle tissues according to US regulatory protocols, and 137-146 (79-84%) of the drugs gave between 70 and 120% average recoveries with ≤ 25% RSDs in the different types of tissues spiked at 0.5, 1, and 2 times the regulatory levels of interest (10-1000 ng/g depending on the drug). This method increases sample throughput and the possible number of drugs monitored in the US National Residue Program, and requires only one UHPLC-MS/MS method and instrument for analysis rather than two by the previous scheme. Graphical abstract Outline of the streamlined approach to monitor 174 veterinary drugs, including aminoglycosides, in bovine tissues by combining two extracts of the same sample with an ion-pairing reagent for analysis by UHPLC-MS/MS.

Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study.

PubMed

Kesselheim, Aaron S; Wang, Bo; Franklin, Jessica M; Darrow, Jonathan J

2015-09-23

To evaluate the use of special expedited development and review pathways at the US Food and Drug Administration over the past two decades. Cohort study. FDA approved novel therapeutics between 1987 and 2014. Publicly available sources provided each drug's year of approval, their innovativeness (first in class versus not first in class), World Health Organization Anatomic Therapeutic Classification, and which (if any) of the FDA's four primary expedited development and review programs or designations were associated with each drug: orphan drug, fast track, accelerated approval, and priority review. Logistic regression models evaluated trends in the proportion of drugs associated with each of the four expedited development and review programs. To evaluate the number of programs associated with each approved drug over time, Poisson models were employed, with the number of programs as the dependent variable and a linear term for year of approval. The difference in trends was compared between drugs that were first in class and those that were not. The FDA approved 774 drugs during the study period, with one third representing first in class agents. Priority review (43%) was the most prevalent of the four programs, with accelerated approval (9%) the least common. There was a significant increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved agent (incidence rate ratio 1.026, 95% confidence interval 1.017 to 1.035, P<0.001), and a 2.4% increase in the proportion of drugs associated with at least one such program (odds ratio 1.024, 95% confidence interval 1.006 to 1.043, P=0.009). Driving this trend was an increase in the proportion of approved, non-first in class drugs associated with at least one program for drugs (P=0.03 for interaction). In the past two decades, drugs newly approved by the FDA have been associated with an increasing number of expedited development or review programs. Though expedited programs should be strictly limited to drugs providing noticeable clinical advances, this trend is being driven by drugs that are not first in class and thus potentially less innovative. © Kesselheim et al 2015.

Consumption Patterns of Nightlife Attendees in Munich: A Latent-Class Analysis.

PubMed

Hannemann, Tessa-Virginia; Kraus, Ludwig; Piontek, Daniela

2017-09-19

The affinity for substance use among patrons of nightclubs has been well established. With novel psychoactive substances (NPS) quickly emerging on the European drug market, trends, and patterns of use are potentially changing. (1) The detection of subgroups of consumers in the electronic dance music scene of a major German metropolitan city, (2) describing the consumption patterns of these subgroups, (3) exploring the prevalence and type of NPS consumption in this population at nightlife events in Munich. A total of 1571 patrons answered questions regarding their own substance use and the emergence of NPS as well as their experience with these substances. A latent class analysis was employed to detect consumption patterns within the sample. A four class model was determined reflecting different consumption patterns: the conservative class (34.9%) whose substance was limited to cannabis; the traditional class (36.6%) which especially consumed traditional club drugs; the psychedelic class (17.5%) which, in addition to traditional club drugs also consumed psychedelic drugs; and an unselective class (10.9%) which displayed the greatest likelihood of consumption of all assessed drugs. "Smoking mixtures" and methylone were the new substances mentioned most often, the number of substances mentioned differed between latent classes. Specific strategies are needed to reduce harm in those displaying the riskiest substance use. Although NPS use is still a fringe phenomenon its prevalence is greater in this subpopulation than in the general population, especially among users in the high-risk unselective class.

Recent advances in targeting protein arginine methyltransferase enzymes in cancer therapy.

PubMed

Smith, Emily; Zhou, Wei; Shindiapina, Polina; Sif, Said; Li, Chenglong; Baiocchi, Robert A

2018-05-21

Exploration in the field of epigenetics has revealed the diverse roles of the protein arginine methyltransferase (PRMT) family of proteins in multiple disease states. These findings have led to the development of specific inhibitors and discovery of several new classes of drugs with potential to treat both benign and malignant conditions. Areas covered: We provide an overview on the role of PRMT enzymes in healthy and malignant cells, highlighting the role of arginine methylation in specific pathways relevant to cancer pathogenesis. Additionally, we describe structure and catalytic activity of PRMT and discuss the mechanisms of action of novel small molecule inhibitors of specific members of the arginine methyltransferase family. Expert opinion: As the field of PRMT biology advances, it's becoming clear that this class of enzymes is highly relevant to maintaining normal physiologic processes as well and disease pathogenesis. We discuss the potential impact of PRMT inhibitors as a broad class of drugs, including the pleiotropic effects, off target effects the need for more detailed PRMT-centric interactomes, and finally, the potential for targeting this class of enzymes in clinical development of experimental therapeutics for cancer.

The effect of transmitted HIV-1 drug resistance on pre-therapy viral load.

PubMed

Harrison, Linda; Castro, Hannah; Cane, Patricia; Pillay, Deenan; Booth, Clare; Phillips, Andrew; Geretti, Anna Maria; Dunn, David

2010-07-31

Reduced replication capacity of viruses expressing drug resistant mutations implies that patients with transmitted drug resistance (TDR) could have lower HIV RNA viral load than those infected with wild-type virus. We performed analysis using data from the UK HIV Drug Resistance Database and the UK CHIC study. Eligible patients had a resistance test performed between 1997 and 2007 while naive to antiretroviral therapy, were 16 years or older, and had a viral load and CD4 cell count measurement within 6 months of this test. Models were adjusted for CD4 cell count, viral subtype, ethnicity, risk group, sex, age, calendar year, clinical centre, and viral load assay. Of a total of 7994 patients included, 709 (9%) had TDR: 604 (85%) had resistance to one drug class only [350 nucleos(t)ide reverse transcriptase inhibitors (NRTIs), 164 non-nucleos(t)ide reverse transcriptase inhibitors (NNRTIs), 90 protease inhibitors (PIs)], 77 (11%) to two classes (42 NRTIs/NNRTIs, 31 NRTIs/PIs, 4 NNRTIs/PIs), and 28 (4%) had resistance to all three classes. The overall mean (SD) viral load at the time of resistance testing was 4.60 (0.82) log(10) copies/ml, and did not differ by class of TDR. However, patients harbouring M184V/I (n = 61) had a significantly lower viral load [adjusted mean difference -0.33 log10 copies/ml (95% CI -0.54 to -0.11), 53% lower (95% CI 22 to 71%), P = 0.002] compared to wild-type virus. Our study provides clear evidence of an in-vivo fitness cost associated with the M184V/I mutation independent of drug effects which select for this mutation. This was not observed for any other mutation, but true effects may have been obscured by reversion of initially resistant viruses to wild-type.

Internalization, Trafficking, Intracellular Processing and Actions of Antibody-Drug Conjugates.

PubMed

Xu, Shi

2015-11-01

This review discusses the molecular mechanism involved in the targeting and delivery of antibody-drug conjugates (ADCs), the new class of biopharmaceuticals mainly designed for targeted cancer therapy. this review goes over major progress in preclinical and clinical studies of ADCs, in the past 5 years. The pharmacokinetics and pharmacodynamics of ADCs involve multiple mechanisms, including internalization of ADCs by target cells, intracellular trafficking, release of conjugated drugs, and payload. These mechanisms actually jointly determine the efficacy of ADCs. Therefore, the optimization of ADCs should take them as necessary rationales.

Eliciting the Intension of Drug Value Sets – Principles and Quality Assurance Applications

PubMed Central

Bahr, Nathan J.; Nelson, Scott D.; Winnenburg, Rainer; Bodenreider, Olivier

2018-01-01

Value sets (VSs) used in electronic clinical quality measures are lists of codes from standard terminologies (“extensional” VSs), whose purpose (“intension”) is not always explicitly stated. We elicited the intension for the 09/01/2014 release of extensional medication value sets by comparison to drug classes from the October 2014 release of RxClass. Value sets matched drug classes if they shared common ingredients, as evidenced by Jaccard similarity score. We elicited the intension of 80 extensional value sets. The average Jaccard similarity was 0.65 for single classes and 0.80 for combination classes, with 34% (27/80) of the value sets having high similarity scores. Manual review by a pharmacist indicated 51% (41/80) of the drug classes selected as the best mapping for a value set matched the intension reflected in that value set name. This approach has the potential for facilitating the development and maintenance of medication value sets. PMID:29295218

Latent classes of polydrug and polyroute use and associations with human immunodeficiency virus risk behaviours and overdose among people who inject drugs in Tijuana, Baja California, Mexico.

PubMed

Meacham, Meredith C; Roesch, Scott C; Strathdee, Steffanie A; Lindsay, Suzanne; Gonzalez-Zuniga, Patricia; Gaines, Tommi L

2018-01-01

Patterns of polydrug use among people who inject drugs (PWID) may be differentially associated with overdose and unique human immunodeficiency virus (HIV) risk factors. Subgroups of PWID in Tijuana, Mexico, were identified based on substances used, route of administration, frequency of use and co-injection indicators. Participants were PWID residing in Tijuana age ≥18 years sampled from 2011 to 2012 who reported injecting an illicit substance in the past month (n = 735). Latent class analysis identified discrete classes of polydrug use characterised by 11 indicators of past 6 months substance use. Multinomial logistic regression examined class membership association with HIV risk behaviours, overdose and other covariates using an automated three-step procedure in mplus to account for classification error. Participants were classified into five subgroups. Two polydrug and polyroute classes were defined by use of multiple substances through several routes of administration and were primarily distinguished from each other by cocaine use (class 1: 5%) or no cocaine use (class 2: 29%). The other classes consisted primarily of injectors: cocaine, methamphetamine and heroin injection (class 3: 4%); methamphetamine and heroin injection (class 4: 10%); and heroin injection (class 5: 52%). Compared with the heroin-only injection class, memberships in the two polydrug and polyroute use classes were independently associated with both HIV injection and sexual risk behaviours. Substance use patterns among PWID in Tijuana are highly heterogeneous, and polydrug and polyroute users are a high-risk subgroup who may require more tailored prevention and treatment interventions. [Meacham MC, Roesch SC, Strathdee SA, Lindsay S, Gonzalez-Zuniga P, Gaines TL. Latent classes of polydrug and polyroute use and associations with human immunodeficiency virus risk behaviours and overdose among people who inject drugs in Tijuana, Baja California, Mexico. Drug Alcohol Rev 2018;37:128-136]. © 2017 Australasian Professional Society on Alcohol and other Drugs.

NIH study uncovers new mechanism of action for class of chemotherapy drugs

Cancer.gov

NIH researchers have discovered a significant new mechanism of action for a class of chemotherapy drugs known as poly (ADP-ribose) polymerase inhibitors, or PARP inhibitors. They have also identified differences in the toxic capabilities of three drugs in

[Psychotropic drugs in the Family Health Strategy: profile of use, access and strategies to promote rational use].

PubMed

da Rocha, Bruno Simas; Werlang, Maria Cristina

2013-11-01

The use of psychotropic drugs is on the increase, and there are few studies in Brazil investigating their use in the population and in Primary Health Care (PHC). This study aimed to determine the prevalence and patterns of psychotropic drug use by patients of a Family Health Unit in Porto Alegre, through an observational, descriptive, retrospective and cross-sectional study. The sample consisted of patients who received prescriptions for controlled psychotropic drugs and the data collected from medical records. The study included 329 patients, with prevalence of the use of psychotropic drugs of 7.30%, mean age of 53.14 (SD = 18.58) years and 72% female. The average number of prescribed drugs and psychotropic drugs per user was 3.56 (SD = 2.36) and 1.66 (SD = 0.90), respectively. The most widely used class was antidepressants, followed by antiepileptics, anxiolytics and antipsychotics. It is necessary to develop strategies to improve access, treatment of patients and rational use of psychotropic drugs, including the revision of lists of essential drugs and training of professionals in PHC.

Scientific perspectives on extending the provision for waivers of in vivo bioavailability and bioequivalence studies for drug products containing high solubility-low permeability drugs (BCS-Class 3).

PubMed

Stavchansky, Salomon

2008-06-01

Recently, there has been increased interest in extending the provision for waivers of in vivo bioavailability and bioequivalence (BA-BE) studies that appeared in the guidance published by the Food and Drug Administration (FDA) (1) to pharmaceutical products containing Class 3 drugs (High solubility-Low Permeability). The extension of the Biopharmaceutics Classification System (BCS) to Class 3 drugs is meritorious because of its impact on public health policy considerations. The rate limiting step in the absorption of Class 3 drugs is the permeability through the intestinal membrane. This commentary will focus its attention on the scientific considerations which need to be examined to assess the risk and the benefit prior to granting a waiver of in vivo bioavailability and/or bioequivalence studies for Class 3 drugs. It will examine the forces affecting the interconnectivity of the neuronal, immunological and hormonal systems in the gastrointestinal tract that may affect its permeability and functionality. It will also challenge the assumption that in vitro dissolution and in vitro permeability studies in tissue cultures in the presence and absence of excipients are good predictors for in vivo dissolution and in vivo permeability which are at the heart of the BCS.

High Levels of Dual-Class Drug Resistance in HIV-Infected Children Failing First-Line Antiretroviral Therapy in Southern Ethiopia

PubMed Central

Kinloch, Natalie N.; Lapointe, Hope R.; Cobarrubias, Kyle D.; Foster, Byron A.; Jerene, Degu; Makonnen, Eyasu; Brumme, Zabrina L.

2018-01-01

Clinical monitoring of pediatric HIV treatment remains a major challenge in settings where drug resistance genotyping is not routinely available. As a result, our understanding of drug resistance, and its impact on subsequent therapeutic regimens available in these settings, remains limited. We investigate the prevalence and correlates of HIV-1 drug resistance among 94 participants of the Ethiopia Pediatric HIV Cohort failing first-line combination antiretroviral therapy (cART) using dried blood spot-based genotyping. Overall, 81% (73/90) of successfully genotyped participants harbored resistance mutations, including 69% (62/90) who harbored resistance to both Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs). Strikingly, 42% of resistant participants harbored resistance to all four NRTIs recommended for second-line use in this setting, meaning that there are effectively no remaining cART options for these children. Longer cART duration and prior regimen changes were significantly associated with detection of drug resistance mutations. Replicate genotyping increased the breadth of drug resistance detected in 34% of cases, and thus is recommended for consideration when typing from blood spots. Implementation of timely drug resistance testing and access to newer antiretrovirals and drug classes are urgently needed to guide clinical decision-making and improve outcomes for HIV-infected children on first-line cART in Ethiopia. PMID:29389912

pH-Dependent solubility and permeability criteria for provisional biopharmaceutics classification (BCS and BDDCS) in early drug discovery.

PubMed

Varma, Manthena V; Gardner, Iain; Steyn, Stefanus J; Nkansah, Paul; Rotter, Charles J; Whitney-Pickett, Carrie; Zhang, Hui; Di, Li; Cram, Michael; Fenner, Katherine S; El-Kattan, Ayman F

2012-05-07

The Biopharmaceutics Classification System (BCS) is a scientific framework that provides a basis for predicting the oral absorption of drugs. These concepts have been extended in the Biopharmaceutics Drug Disposition Classification System (BDDCS) to explain the potential mechanism of drug clearance and understand the effects of uptake and efflux transporters on absorption, distribution, metabolism, and elimination. The objective of present work is to establish criteria for provisional biopharmaceutics classification using pH-dependent passive permeability and aqueous solubility data generated from high throughput screening methodologies in drug discovery settings. The apparent permeability across monolayers of clonal cell line of Madin-Darby canine kidney cells, selected for low endogenous efflux transporter expression, was measured for a set of 105 drugs, with known BCS and BDDCS class. The permeability at apical pH 6.5 for acidic drugs and at pH 7.4 for nonacidic drugs showed a good correlation with the fraction absorbed in human (Fa). Receiver operating characteristic (ROC) curve analysis was utilized to define the permeability class boundary. At permeability ≥ 5 × 10(-6) cm/s, the accuracy of predicting Fa of ≥ 0.90 was 87%. Also, this cutoff showed more than 80% sensitivity and specificity in predicting the literature permeability classes (BCS), and the metabolism classes (BDDCS). The equilibrium solubility of a subset of 49 drugs was measured in pH 1.2 medium, pH 6.5 phosphate buffer, and in FaSSIF medium (pH 6.5). Although dose was not considered, good concordance of the measured solubility with BCS and BDDCS solubility class was achieved, when solubility at pH 1.2 was used for acidic compounds and FaSSIF solubility was used for basic, neutral, and zwitterionic compounds. Using a cutoff of 200 μg/mL, the data set suggested a 93% sensitivity and 86% specificity in predicting both the BCS and BDDCS solubility classes. In conclusion, this study identified pH-dependent permeability and solubility criteria that can be used to assign provisional biopharmaceutics class at early stage of the drug discovery process. Additionally, such a classification system will enable discovery scientists to assess the potential limiting factors to oral absorption, as well as help predict the drug disposition mechanisms and potential drug-drug interactions.

The utility of rat jejunal permeability for biopharmaceutics classification system.

PubMed

Zakeri-Milani, Parvin; Valizadeh, Hadi; Tajerzadeh, Hosnieh; Islambulchilar, Ziba

2009-12-01

The biopharmaceutical classification system has been developed to provide a scientific approach for classifying drug compounds based on their dose/solubility ratio and human intestinal permeability. Therefore in this study a new classification is presented, which is based on a correlation between rat and human intestinal permeability values. In situ technique in rat jejunum was used to determine the effective intestinal permeability of tested drugs. Then three dimensionless parameters--dose number, absorption number, and dissolution number (D(o), A(n), and D(n))--were calculated for each drug. Four classes of drugs were defined, that is, class I, D(0) < 0.5, P(eff(rat)) > 5.09 x 10(-5) cm/s; class II, D(o) > 1, P(eff(rat)) > 5.09 x 10( -5) cm/s; class III, D(0) < 0.5, P(eff(rat)) < 4.2 x 10(-5) cm/s; and class IV, D(o) > 1, P(eff(rat)) < 4.2 x 10(-5) cm/s. A region of borderline drugs (0.5 < D(o) < 1, 4.2 x 10(-5) < P(eff(rat)) < 5.09 x 10(-5) cm/s) was also defined. According to obtained results and proposed classification for drugs, it is concluded that drugs could be categorized correctly based on dose number and their intestinal permeability values in rat model using single-pass intestinal perfusion technique. This classification enables us to remark defined characteristics for intestinal absorption of all four classes using suitable cutoff points for both dose number and rat effective intestinal permeability values.

Drug selection in French university hospitals: analysis of formularies for nine competitive pharmacological classes.

PubMed

Gallini, Adeline; Juillard-Condat, Blandine; Saux, Marie-Claude; Taboulet, Florence

2011-11-01

To give a panorama of the selectivity and agreement of French university hospitals' drug formularies (HDF) for nine competitive classes. All university hospitals were asked to send their HDF and selection criteria as of January 2009 for nine competitive pharmacological classes (proton pump inhibitors, serotonin antagonists, low molecular weight heparins, erythropoietins, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, statins, α-adrenoreceptor antagonists and selective serotonin re-uptake inhibitors). Selectivity of HDF was estimated by the percentage of drug entities selected by the hospital within the pharmacological class. Agreement between hospitals was assessed with modified kappa coefficients for multi-raters. Twenty-one out of the 29 hospitals agreed to participate. These hospitals selected between 34% and 63% of the drug entities available for the nine classes, which represented 18 to 35 agents. Regarding the nature of chosen drug entities, the overall level of agreement was 'fair' and varied with pharmacological classes. Selection criteria were sent by only 12 hospitals. The technical component was the most important element in all hospitals. The weight of the economic component varied between 20% and 40% in the tender's grade. Large variations were seen in the number and nature of drugs selected by university hospitals which can be attributable to two successive decision-making processes (evaluation by the Drug and Therapeutics Committee followed by the purchasing process). © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Sexual Initiation and Complex Recent Polydrug Use Patterns Among Male Sex Workers in Vietnam: A Preliminary Epidemiological Trajectory.

PubMed

Yu, Gary; Goldsamt, Lloyd A; Clatts, Michael C; Giang, Lê Minh

2016-05-01

Little is known about the age of onset of sexual and drug risk and their association with complex patterns of recent drug use among male sex workers (MSW) in a developing country, such as Vietnam. The aim of this study was to determine whether latent class analysis (LCA) would aid in the detection of current individual and polydrug use combinations to predict how different trajectories of sexual and drug initiation contribute to different patterns of current illicit drug use. Data were collected from a cross-sectional survey administered to young MSWs between 2010 and 2011 in Vietnam (N = 710). LCA clustered participants into recent drug use groups, incorporating both the specific types and overall count of different drugs used. Men reported drug use within a 1 month period from an 11-item drug use list. LCA identified three distinct drug use classes: (1) alcohol use, (2) alcohol and tobacco use, and (3) high polydrug use. The current drug use classes are associated with sex worker status, housing stability, income level, educational attainment, marital status, sexual identity, and sexual preferences. High levels of drug use are strongly associated with being a recent sex worker, not having recent stable housing, higher than median income, more than a high school education, less likely to be currently in school and more likely to have non-homosexual preferences and heterosexual partners. An event history analysis approach (time-event displays) examined the timing of the age of onset of drug and sexual risks. Early ages of drug and sexual initiation are seen for all three classes. High current drug users show earlier onset of these risks, which are significantly delayed for moderate and low current drug users. LCA incorporating an overall count of different drugs detected three distinct current drug use classes. The data illustrates that the complexity of drug factors that must be accounted for, both in advancing our epidemiological understanding of the complexity of drug use and the use of drug and sexual risk initiation data to predict current drug use subtypes among high-risk populations.

Antihypertensive drugs.

PubMed

Laurent, Stéphane

2017-10-01

Successful treatment of hypertension is possible with limited side effects given the availability of multiple antihypertensive drug classes. This review describes the various pharmacological classes of antihypertensive drugs, under two major aspects: their mechanisms of action and side effects. The mechanism of action is analysed through a pharmacological approach, i.e. the molecular receptor targets, the various sites along the arterial system, and the extra-arterial sites of action, in order to better understand in which type of hypertension a given pharmacological class of antihypertensive drug is most indicated. In addition, side effects are described and explained through their pharmacological mechanisms, in order to better understand their mechanism of occurrence and in which patients drugs are contra-indicated. This review does not address the effectiveness of monotherapies in large randomized clinical trials and combination therapies, since these are the matters of other articles of the present issue. Five major pharmacological classes of antihypertensive drugs are detailed here: beta-blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium channel blockers. Four additional pharmacological classes are described in a shorter manner: renin inhibitors, alpha-adrenergic receptor blockers, centrally acting agents, and direct acting vasodilators. Copyright © 2017. Published by Elsevier Ltd.

An improved approach to measuring drug innovation finds steady rates of first-in-class pharmaceuticals, 1987-2011.

PubMed

Lanthier, Michael; Miller, Kathleen L; Nardinelli, Clark; Woodcock, Janet

2013-08-01

For more than a decade, industry analysts and policy makers have raised concerns about declining pharmaceutical innovation, citing declining numbers of new molecular entities (NMEs) approved in the United States each year. Yet there is little consensus on whether this is the best measure of "innovation." We examined NME approvals during 1987-2011 and propose the three distinct subcategories of NMEs--first-in-class, advance-in-class, and addition-to-class--to provide more nuanced and informative insights into underlying trends. We found that trends in NME approvals were largely driven by addition-to-class, or "me too," drug approvals, while first-in-class approvals remained fairly steady over the study period. Moreover, the higher proportion of first-in-class drug approvals over the most recent decade is an encouraging sign of the health of the industry as a whole.

Combination Approaches to Combat Multi-Drug Resistant Bacteria

PubMed Central

Worthington, Roberta J.; Melander, Christian

2013-01-01

The increasing prevalence of infections caused by multi-drug resistant bacteria is a global health problem that is exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein we describe recent developments toward combination therapies for the treatment of multi-drug resistant bacterial infections. These efforts include antibiotic-antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of β-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems. We also discuss screening of libraries of previously approved drugs to identify non-obvious antimicrobial adjuvants. PMID:23333434

Competitiveness in follow-on drug R&D: a race or imitation?

PubMed

DiMasi, Joseph A; Faden, Laura B

2011-01-01

The development of 'follow on' or 'me too' drugs - generally defined as a drug with a similar chemical structure or the same mechanism of action as a drug that is already marketed - has attracted contrasting views. Some have argued that follow-on drugs often provide useful alternative or enhanced therapeutic options for particular patients or patient subpopulations, as well as introducing price competition. Others, however, consider that the development of such drugs is duplicative and that the resources needed would be better directed elsewhere. Implicit in some of this criticism is the notion that the development of me-too drugs is undertaken after a first-in-class drug has made it to market and proved commercially successful. In this Perspective, using analysis of development and patent filing histories of entrants to new drug classes in the past five decades, we provide new evidence that the development of multiple new drugs in a given class is better characterized as a race, rather than the imitation of successful products.

Prevalence and treatment of persistent pulmonary hypertension in the newborn in a Mexican pediatric hospital.

PubMed

Ortiz, Mario I; Estévez-Castillo, Ramón; Bautista-Rivas, Martha M; Romo-Hernández, Georgina; López-Cadena, Juan M; Copca-García, José A

2010-01-01

Persistent pulmonary hypertension of the newborn is defined as the failure of the normal circulatory transition that occurs after birth. It is a syndrome characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left extra-pulmonary shunting of blood. In the treatment of persistent pulmonary hypertension of the newborn, the goal is to increase oxygen flow to the baby's organs to prevent serious health problems. Treatment may include medication, mechanical ventilation and respiratory therapy. We performed a retrospective, descriptive and transversal study to investigate the prevalence and treatment of neonatal patients with persistent pulmonary hypertension who were admitted at the Hospital del Niño DIF from 2004 to 2008. Data, collected from hospital charts, included demographic, clinical course and use of medication. A total of 38 patients were included (prevalence of 5.7%). The average age of patients was 8.4 +/- 1.4 days. The mortality rate was 42.1%. Data were collected and 45 different drugs were given to the pediatric patients. The median number of drugs/inpatient was 8.3 (1-18). The therapeutic class most prescribed was anti-infective (29.9% of all the prescriptions), followed by cardiovascular and renal drugs (26.4% of all the prescriptions) and gastrointestinal agents (14.6% of all the prescriptions). Ranitidine was the drug most commonly used, followed by ampicillin and midazolam. We found a high mortality rate and as in many studies, the therapeutic class most used were anti-infectives.

Possible immunosuppressive effects of drug exposure and environmental and nutritional effects on infection and vaccination.

PubMed

Huemer, H P

2015-01-01

A variety of drugs which are not primarily considered to be immunosuppressive agents have been described to modulate the humoral and cellular immune response in humans or animals. Thereby they may have an influence on the effectiveness and possible side effects of vaccines. This mini review lists some of the different substance classes and also some of endogeneous, infectious, nutritional, and environmental influences with suspected capability to interfere with immunizations. Studies in most cases focused on substances with known immunosuppressive functions, but there is growing evidence for immunomodulatory effects also of commonly used drugs with wide distribution. In particular combinations of those antiproliferative and antiphlogistic side effects of different substance classes have not been studied in detail but may substantially interfere with the development of a functional humoral and cellular immune response. The drugs of importance include antipyretics, anticoagulants, tranquilizers, and substances influencing lipid metabolism but also commonly used drugs of abuse like alcohol or cannabinoids. Additional substances of environmental, nutritional, or microbiological origin may also play a role but their combinatory/synergistic effects have been disregarded so far due to the lack of systematic data and the complex study designs necessary to elucidate those complex epidemiologic questions.

Patent extension policy for paediatric indications: an evaluation of the impact within three drug classes in a state Medicaid programme.

PubMed

Nelson, Richard E; McAdam-Marx, Carrie; Evans, Megan L; Ward, Robert; Campbell, Benjamin; Brixner, Diana; Lafleur, Joanne

2011-05-01

The Food and Drug Administration Modernization Act (FDAMA) of 1997, Best Pharmaceuticals for Children Act (BPCA) of 2002 and Pediatric Research Equity Act of 2007 provide an extended period of 6 months of marketing exclusivity (i.e. patent extension) to prescription drug manufacturers that conduct paediatric studies. Branded drugs in the statin, ACE inhibitor and selective serotonin reuptake inhibitor (SSRI) classes were three of many classes with drugs granted patent extensions. We estimated the cost impact of the 6-month exclusivity extension policy on the Utah Medicaid drug programme by comparing actual costs to projected costs had the 6-month exclusivity extension not been granted for these drugs and thus less expensive generic alternatives been available sooner. Using these results, we then projected the cost impact of this policy on Medicaid programmes in the US during the 18 months following patent expiration. The Utah Medicaid prescription claims obtained for statins, ACE inhibitors and SSRIs included reimbursement amount, number of units dispensed, days supplied, date of service and drug strength. Actual expenditures for each drug were calculated for the 6 months before and 12 months after generic availability. The percentage difference between the brand name prescription reimbursement amount to Medicaid in the last 2 months of the 6-month extension and the generic prescription reimbursement amount to Medicaid in the first 2 months following exclusivity expiration was then calculated for each drug. This was done using data from the 5 months surrounding the exclusivity expiration by regressing the log-transformed Utah Medicaid reimbursement amount on an indicator for patent expiration, controlling for number of units, volume of sales, month filled and strength. This was used to estimate what the initial generic prescription price would have been without the 6-month patent extension and what costs would have been in the 18 months following the original expiration date if the patent extension had not been granted. Medicaid rebates were assumed to be 15.1% for branded products and 11% for generics. The 6-month extension policy was estimated to cost Utah's Medicaid $US2.2 (95% CI 1.9, 2.4) million for these three drug classes over the 18 months following the original patent expiration date (year 2007 values). Projected to the US Medicaid population, this cost was $US430 (95% CI 371, 475) million. For the individual drugs that we examined, the percentage cost decrease in reimbursement amount resulting from exclusivity expiration and generic entry ranged from 24.4% (p < 0.001) for enalapril to 3.8% (p = 0.0951) for pravastatin sodium. Makers of the branded drugs evaluated were given market exclusivity extensions for conducting studies of their medications in children. The costs found in this study are just a small portion of the total paid, which include those born by other payers. Whether the benefits of this policy outweigh these costs is an open question, but these results suggest that the costs to Medicaid and thus taxpayers are substantial.

Investigating heterogeneity in violent offending liability among injection drug users from a developmental perspective.

PubMed

Torok, Michelle; Darke, Shane; Shand, Fiona; Kaye, Sharlene

2016-09-01

Violence is a major burden of harm among injecting drug users (IDU), however, the liability to violent offending is not well understood. The current study aimed to better understand differences in the liability to violence by determining whether IDU could be disaggregated into distinct violent offending classes, and determining the correlates of class membership. A total of 300 IDU from Sydney, Australia were administered a structured interview examining the prevalence and severity of drug use and violent offending histories, as well as early life risk factors (maltreatment, childhood mental disorder, trait personality). IDU were disaggregated into four distinct latent classes, comprising a non-violent class (24%), an adolescent-onset persistent class (33%), an adult-onset transient class (24%) and an early-onset, chronic class (19%). Pairwise and group comparisons of classes on predispositional and substance use risks showed that the EARLY class had the poorest psychosocial risk profile, while the NON class had the most favourable. Multinomial logistic regression revealed that higher trait impulsivity and aggression scores, having a history of conduct disorder, frequent childhood abuse, and more problematic alcohol use, were independently associated with more temporally stable and severe violent offending. The model explained 67% of variance in class membership (χ(2)=207.7, df=51, p<0.001). IDU can be meaningfully disaggregated into distinct violent offending classes using developmental criteria. The age of onset of violence was indicative of class membership insomuch as that the extent of early life risk exposure was differentially associated with greater long-term liability to violence and drug use. Copyright © 2016 Elsevier Ltd. All rights reserved.

High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations

PubMed Central

Mott, Bryan T.; Eastman, Richard T.; Guha, Rajarshi; Sherlach, Katy S.; Siriwardana, Amila; Shinn, Paul; McKnight, Crystal; Michael, Sam; Lacerda-Queiroz, Norinne; Patel, Paresma R.; Khine, Pwint; Sun, Hongmao; Kasbekar, Monica; Aghdam, Nima; Fontaine, Shaun D.; Liu, Dongbo; Mierzwa, Tim; Mathews-Griner, Lesley A.; Ferrer, Marc; Renslo, Adam R.; Inglese, James; Yuan, Jing; Roepe, Paul D.; Su, Xin-zhuan; Thomas, Craig J.

2015-01-01

Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. PMID:26403635

The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis

PubMed Central

Cadwallader, Amy B; de la Torre, Xavier; Tieri, Alessandra; Botrè, Francesco

2010-01-01

Diuretics are drugs that increase the rate of urine flow and sodium excretion to adjust the volume and composition of body fluids. There are several major categories of this drug class and the compounds vary greatly in structure, physicochemical properties, effects on urinary composition and renal haemodynamics, and site and mechanism of action. Diuretics are often abused by athletes to excrete water for rapid weight loss and to mask the presence of other banned substances. Because of their abuse by athletes, diuretics have been included on The World Anti-Doping Agency's (WADA) list of prohibited substances; the use of diuretics is banned both in competition and out of competition and diuretics are routinely screened for by anti-doping laboratories. This review provides an overview of the pharmacology and toxicology of diuretics and discusses their application in sports. The most common analytical strategies currently followed by the anti-doping laboratories accredited by the WADA are discussed along with the challenges laboratories face for the analysis of this diverse class of drugs. PMID:20718736

Psychotropic drugs and bruxism.

PubMed

Falisi, Giovanni; Rastelli, Claudio; Panti, Fabrizio; Maglione, Horacio; Quezada Arcega, Raul

2014-10-01

Sleep and awake bruxism is defined as 'a parafunctional activity including clenching, bracing, gnashing, and grinding of the teeth'. Some evidence suggests that bruxism may be caused by, or associated with, alterations in the CNS neurotransmission. Several classes of psychotropic drugs interfering with CNS activity may potentially contribute to bruxism. Thus, the purpose of this study was to examine relevant peer-reviewed papers to identify and describe the various classes of psychotropic substances that may cause, exacerbate or reduce bruxism as the result of their pharmacological action in CNS neurons. A literature search from 1980 to the present was performed using PubMed database. The term 'bruxism' was used in association with 'psychotropic', 'dopamine (DA)', 'serotonin', 'histamine', 'antipsychotics', 'antidepressants', 'antihistaminergics' and 'stimulants'. Studies on the effects of DA agonists (Levo-DOPA, psychostimulants) and antagonists (antipsychotics) identified a central role of DA in the pathogenesis of pharmacologically induced bruxism. Important information from studies on drugs acting on serotonin neurotransmission (antidepressants) was recognized. Other mechanisms involving different neurotransmitters are emerging. This is the case of antihistaminergic drugs which may induce bruxism as a consequence of their disinhibitory effect on the serotonergic system.

Noble metal nanostructures in optical biosensors: Basics, and their introduction to anti-doping detection.

PubMed

Malekzad, Hedieh; Zangabad, Parham Sahandi; Mohammadi, Hadi; Sadroddini, Mohsen; Jafari, Zahra; Mahlooji, Niloofar; Abbaspour, Somaye; Gholami, Somaye; Ghanbarpoor, Mana; Pashazadeh, Rahim; Beyzavi, Ali; Karimi, Mahdi; Hamblin, Michael R

2018-03-01

Nanotechnology has illustrated significant potentials in biomolecular-sensing applications; particularly its introduction to anti-doping detection is of great importance. Illicit recreational drugs, substances that can be potentially abused, and drugs with dosage limitations according to the prohibited lists announced by the World Antidoping Agency (WADA) are becoming of increasing interest to forensic chemists. In this review, the theoretical principles of optical biosensors based on noble metal nanoparticles, and the transduction mechanism of commonly-applied plasmonic biosensors are covered. We review different classes of recently-developed plasmonic biosensors for analytic determination and quantification of illicit drugs in anti-doping applications. The important classes of illicit drugs include anabolic steroids, opioids, stimulants, and peptide hormones. The main emphasis is on the advantages that noble metal nano-particles bring to optical biosensors for signal enhancement and the development of highly sensitive (label-free) biosensors. In the near future, such optical biosensors may be an invaluable substitute for conventional anti-doping detection methods such as chromatography-based approaches, and may even be commercialized for routine anti-doping tests.

Assessing the longitudinal stability of latent classes of substance use among gay, bisexual, and other men who have sex with men.

PubMed

Card, Kiffer G; Armstrong, Heather L; Carter, Allison; Cui, Zishan; Wang, Lu; Zhu, Julia; Lachowsky, Nathan J; Moore, David M; Hogg, Robert S; Roth, Eric A

2018-05-22

Association between substance use and HIV-risk among gay and bisexual men (GBM) is well documented. However, their substance use patterns are diverse, and it is unknown whether self-reported use patterns are stable over time. Sexually-active GBM, aged >16 years, were recruited in Metro Vancouver using respondent-driven sampling and followed across 5 study visits at six-month intervals (n = 449). To identify distinct patterns of substance use and their longitudinal stability, Latent Transition Analysis (LTA) was conducted for drugs reported by at least 30 participants. Intraclass correlation coefficients (ICC) quantified the stability of class assignments. Six classes characterizing 'limited drug use' (i.e., low use of all drugs, except alcohol), 'conventional drug use' (i.e., use of alcohol, marijuana, and tobacco), 'club drug use' (i.e., use of alcohol, cocaine, and psychedelics), 'sex drug use' (i.e., use of alcohol, crystal meth, GHB, poppers, and erectile dysfunction drugs), 'street drug use' (i.e., use of alcohol and street opioids) and 'assorted drug use' (i.e., use of most drugs) were identified. Across five visits (2.5 years), 26.3% (n = 118/449) of GBM transitioned between classes. The prevalence of limited use trended upwards (Baseline:24.5%, Visit 5:28.3%, p < 0.0001) and assorted use trended downwards (13.4%-9.6%, p = 0.001). All classes had strong longitudinal stability (ICC > 0.97). The stability of latent substance use patterns highlight the utility of these measures in identifying patterns of substance use among people who use drugs - potentially allowing for better assessment of these groups and interventions related to their health. Copyright © 2018 Elsevier B.V. All rights reserved.

SELF-BLM: Prediction of drug-target interactions via self-training SVM.

PubMed

Keum, Jongsoo; Nam, Hojung

2017-01-01

Predicting drug-target interactions is important for the development of novel drugs and the repositioning of drugs. To predict such interactions, there are a number of methods based on drug and target protein similarity. Although these methods, such as the bipartite local model (BLM), show promise, they often categorize unknown interactions as negative interaction. Therefore, these methods are not ideal for finding potential drug-target interactions that have not yet been validated as positive interactions. Thus, here we propose a method that integrates machine learning techniques, such as self-training support vector machine (SVM) and BLM, to develop a self-training bipartite local model (SELF-BLM) that facilitates the identification of potential interactions. The method first categorizes unlabeled interactions and negative interactions among unknown interactions using a clustering method. Then, using the BLM method and self-training SVM, the unlabeled interactions are self-trained and final local classification models are constructed. When applied to four classes of proteins that include enzymes, G-protein coupled receptors (GPCRs), ion channels, and nuclear receptors, SELF-BLM showed the best performance for predicting not only known interactions but also potential interactions in three protein classes compare to other related studies. The implemented software and supporting data are available at https://github.com/GIST-CSBL/SELF-BLM.

Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

PubMed

Bercu, J P; Galloway, S M; Parris, P; Teasdale, A; Masuda-Herrera, M; Dobo, K; Heard, P; Kenyon, M; Nicolette, J; Vock, E; Ku, W; Harvey, J; White, A; Glowienke, S; Martin, E A; Custer, L; Jolly, R A; Thybaud, V

2018-04-01

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication. Copyright © 2018. Published by Elsevier Inc.

Everyday discrimination and mood and substance use disorders: a latent profile analysis with African Americans and Caribbean Blacks.

PubMed

Clark, Trenette T; Salas-Wright, Christopher P; Vaughn, Michael G; Whitfield, Keith E

2015-01-01

Perceived discrimination is a major source of health-related stress. The purpose of this study was to model the heterogeneity of everyday-discrimination experiences among African American and Caribbean Blacks and to identify differences in the prevalence of mood and substance use outcomes, including generalized anxiety disorder, major depressive disorder, alcohol-use disorder, and illicit drug-use disorder among the identified subgroups. The study uses data from the National Survey of American Life obtained from a sample of African American and Caribbean Black respondents (N=4,462) between 18 and 65 years. We used latent profile analysis and multinomial regression analyses to identify and validate latent subgroups and test hypotheses, yielding 4 classes of perceived everyday discrimination: Low Discrimination, Disrespect and Condescension, General Discrimination, and Chronic Discrimination. Findings show significant differences exist between the Low Discrimination and General Discrimination classes for major depressive disorder, alcohol-use disorder, and illicit drug-use disorder. Moreover, we find significant differences exist between the Low Discrimination and Chronic Discrimination classes for the four disorders examined. Compared with the Chronic Discrimination class, members of the other classes were significantly less likely to meet criteria for generalized anxiety disorder, major depressive disorder, alcohol-use disorder, and illicit drug-use disorder. Findings suggest elevated levels of discrimination increase risk for mood and substance-use disorders. Importantly, results suggest the prevalence of mood and substance-use disorders is a function of the type and frequency of discrimination that individuals experience. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Drug Safety Rating System Based on Postmarketing Costs Associated with Adverse Events and Patient Outcomes.

PubMed

Hoffman, Keith B; Dimbil, Mo; Kyle, Robert F; Tatonetti, Nicholas P; Erdman, Colin B; Demakas, Andrea; Chen, Dingguo; Overstreet, Brian M

2015-12-01

Given the multiple limitations associated with relatively homogeneous preapproval clinical trials, inadequate data disclosures, slow reaction times from regulatory bodies, and deep-rooted bias against disclosing and publishing negative results, there is an acute need for the development of analytics that reflect drug safety in heterogeneous, real-world populations. To develop a drug safety statistic that estimates downstream medical costs associated with serious adverse events (AEs) and unfavorable patient outcomes associated with the use of 706 FDA-approved drugs. All primary suspect case reports for each drug were collected from the FDA's Adverse Event Reporting System database (FAERS) from 2010-2014. The Medical Dictionary for Regulatory Activities (MedDRA) was used to code serious AEs and outcomes, which were tallied for each case report. Medical costs associated with AEs and poor patient outcomes were derived from Agency for Healthcare Research and Quality (AHRQ) survey data, and their corresponding ICD-9-CM codes were mapped to MedDRA terms. Nonserious AEs and outcomes were not included. For each case report, either the highest AE cost or, if no eligible AE was listed, the highest outcome cost was used. All costed cases were aggregated for each drug and divided by the number of patients exposed to obtain a downstream estimated direct medical cost burden per exposure. Each drug was assigned a corresponding 1-100 point total. The 706 drugs showed an exponential distribution of downstream costs, and the data were transformed using the natural log to approximate a normal distribution. The minimum score was 8.29, and the maximum score was 99.25, with a mean of 44.32. Drugs with the highest individual scores tended to be kinase inhibitors, thalidomide analogs, and endothelin receptor antagonists. When scores were analyzed across Established Pharmacologic Class (EPC), the kinase inhibitor and endothelin receptor antagonist classes had the highest total. However, other EPCs with median scores of 75 and above included hepatitis C virus NS3/4A protease inhibitor, recombinant human interferon beta, vascular endothelial growth factor-directed antibody, and tumor necrosis factor blocker. When Anatomical Therapeutic Chemical classifications were analyzed, antineoplastic drugs were outliers with approximately 80% of their individual scores 60 and above, while approximately 20%-30% of blood and anti-infective drugs had scores of 60 and above. Within-drug class results served to differentiate similar drugs. For example, 6 serotonin reuptake inhibitors had a score range of 35 to 53. This scoring system is based on estimated direct medical costs associated with postmarketing AEs and poor patient outcomes and thereby helps fill a large information gap regarding drug safety in real-world patient populations.

Association Between Academic Medical Center Pharmaceutical Detailing Policies and Physician Prescribing

PubMed Central

Ang, Desmond; Steinhart, Jonathan; Chao, Matthew; Patterson, Mark; Sah, Sunita; Wu, Tina; Schoenbaum, Michael; Hutchins, David; Brennan, Troyen; Loewenstein, George

2017-01-01

Importance In an effort to regulate physician conflicts of interest, some US academic medical centers (AMCs) enacted policies restricting pharmaceutical representative sales visits to physicians (known as detailing) between 2006 and 2012. Little is known about the effect of these policies on physician prescribing. Objective To analyze the association between detailing policies enacted at AMCs and physician prescribing of actively detailed and not detailed drugs. Design, Setting, and Participants The study used a difference-in-differences multivariable regression analysis to compare changes in prescribing by physicians before and after implementation of detailing policies at AMCs in 5 states (California, Illinois, Massachusetts, Pennsylvania, and New York) that made up the intervention group with changes in prescribing by a matched control group of similar physicians not subject to a detailing policy. Exposures Academic medical center implementation of policies regulating pharmaceutical salesperson visits to attending physicians. Main Outcomes and Measures The monthly within-drug class market share of prescriptions written by an individual physician for detailed and nondetailed drugs in 8 drug classes (lipid-lowering drugs, gastroesophageal reflux disease drugs, diabetes drugs, antihypertensive drugs, hypnotic drugs approved for the treatment of insomnia [sleep aids], attention-deficit/hyperactivity disorder drugs, antidepressant drugs, and antipsychotic drugs) comparing the 10- to 36-month period before implementation of the detailing policies with the 12- to 36-month period after implementation, depending on data availability. Results The analysis included 16 121 483 prescriptions written between January 2006 and June 2012 by 2126 attending physicians at the 19 intervention group AMCs and by 24 593 matched control group physicians. The sample mean market share at the physician-drug-month level for detailed and nondetailed drugs prior to enactment of policies was 19.3% and 14.2%, respectively. Exposure to an AMC detailing policy was associated with a decrease in the market share of detailed drugs of 1.67 percentage points (95% CI, −2.18 to −1.18 percentage points; P < .001) and an increase in the market share of nondetailed drugs of 0.84 percentage points (95% CI, 0.54 to 1.14 percentage points; P < .001). Associations were statistically significant for 6 of 8 study drug classes for detailed drugs (lipid-lowering drugs, gastroesophageal reflux disease drugs, antihypertensive drugs, sleep aids, attention-deficit/hyperactivity disorder drugs, and antidepressant drugs) and for 9 of the 19 AMCs that implemented policies. Eleven of the 19 AMCs regulated salesperson gifts to physicians, restricted salesperson access to facilities, and incorporated explicit enforcement mechanisms. For 8 of these 11 AMCs, there was a significant change in prescribing. In contrast, there was a significant change at only 1 of 8 AMCs that did not enact policies in all 3 areas. Conclusions and Relevance Implementation of policies at AMCs that restricted pharmaceutical detailing between 2006 and 2012 was associated with modest but significant reductions in prescribing of detailed drugs across 6 of 8 major drug classes; however, changes were not seen in all of the AMCs that enacted policies. PMID:28464141

Oral amiodarone: historical overview and development.

PubMed

Pollak, P T

1998-01-01

To review the historical development of amiodarone and the changing perceptions of the drug, and discuss its electrophysiologic, pharmacologic, and pharmacokinetic properties. Review of relevant literature. In the 1970s and 1980s a plethora of new antiarrhythmic agents, including amiodarone, was introduced. Amiodarone is predominately a class III antiarrhythmic, but also possesses class I, II, and IV effects. By 1977 it was described as the ideal antiarrhythmic agent. However, clinicians underestimated potential difficulties caused by misunderstanding its variable absorption, slow initial response at nonloading dosages, and extended half-life. Elevated dosages also produced frequent adverse effects. Thus, early enthusiasm for the drug's efficacy was gradually replaced by a focus on its toxicity. The 1990s witnessed reacceptance of the agent as more logical initial regimens and lower maintenance dosages decreased adverse effects, and amiodarone emerged as one of the few drugs effective in suppressing and preventing arrhythmias that does not increase mortality. Remaining challenges include delineation of an optimal oral regimen, identification of markers useful in clinical monitoring, and elucidation of the relationship between dose-tissue concentration and response and dose-toxicity associations. Amiodarone is an increasingly valuable component of today's antiarrhythmic therapy.

Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs.

PubMed

Galia, E; Nicolaides, E; Hörter, D; Löbenberg, R; Reppas, C; Dressman, J B

1998-05-01

In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. Dissolution behavior of two class I drugs, i.e. acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.

Imbalance in chemical space: How to facilitate the identification of protein-protein interaction inhibitors.

PubMed

Kuenemann, Mélaine A; Labbé, Céline M; Cerdan, Adrien H; Sperandio, Olivier

2016-04-01

Protein-protein interactions (PPIs) play vital roles in life and provide new opportunities for therapeutic interventions. In this large data analysis, 3,300 inhibitors of PPIs (iPPIs) were compared to 17 reference datasets of collectively ~566,000 compounds (including natural compounds, existing drugs, active compounds on conventional targets, etc.) using a chemoinformatics approach. Using this procedure, we showed that comparable classes of PPI targets can be formed using either the similarity of their ligands or the shared properties of their binding cavities, constituting a proof-of-concept that not only can binding pockets be used to group PPI targets, but that these pockets certainly condition the properties of their corresponding ligands. These results demonstrate that matching regions in both chemical space and target space can be found. Such identified classes of targets could lead to the design of PPI-class-specific chemical libraries and therefore facilitate the development of iPPIs to the stage of drug candidates.

SOCIAL STABILITY AND HIV RISK BEHAVIOR: EVALUATING THE ROLE OF ACCUMULATED VULNERABILITY

PubMed Central

German, Danielle; Latkin, Carl A.

2011-01-01

This study evaluated a cumulative and syndromic relationship among commonly co-occurring vulnerabilites (homelessness, incarceration, low-income, residential transition) in association with HIV-related risk behaviors among 635 low-income women in Baltimore. Analysis included descriptive statistics, logistic regression, latent class analysis and latent class regression. Both methods of assessing multidimensional instability showed significant associations with risk indicators. Risk of multiple partners, sex exchange, and drug use decreased significantly with each additional domain. Higher stability class membership (77%) was associated with decreased likelihood of multiple partners, exchange partners, recent drug use, and recent STI. Multidimensional social vulnerabilities were cumulatively and synergistically linked to HIV risk behavior. Independent instability measures may miss important contextual determinants of risk. Social stability offers a useful framework to understand the synergy of social vulnerabilities that shape sexual risk behavior. Social policies and programs aiming to enhance housing and overall social stability are likely to be beneficial for HIV prevention. PMID:21259043

Biologically active quinoline and quinazoline alkaloids part I.

PubMed

Shang, Xiao-Fei; Morris-Natschke, Susan L; Liu, Ying-Qian; Guo, Xiao; Xu, Xiao-Shan; Goto, Masuo; Li, Jun-Cai; Yang, Guan-Zhou; Lee, Kuo-Hsiung

2018-05-01

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids. © 2017 Wiley Periodicals, Inc.

Revitalizing the drug pipeline: AntibioticDB, an open access database to aid antibacterial research and development.

PubMed

Farrell, L J; Lo, R; Wanford, J J; Jenkins, A; Maxwell, A; Piddock, L J V

2018-06-11

The current state of antibiotic discovery, research and development is insufficient to respond to the need for new treatments for drug-resistant bacterial infections. The process has changed over the last decade, with most new agents that are in Phases 1-3, or recently approved, having been discovered in small- and medium-sized enterprises or academia. These agents have then been licensed or sold to large companies for further development with the goal of taking them to market. However, early drug discovery and development, including the possibility of developing previously discontinued agents, would benefit from a database of antibacterial compounds for scrutiny by the developers. This article describes the first free, open-access searchable database of antibacterial compounds, including discontinued agents, drugs under pre-clinical development and those in clinical trials: AntibioticDB (AntibioticDB.com). Data were obtained from publicly available sources. This article summarizes the compounds and drugs in AntibioticDB, including their drug class, mode of action, development status and propensity to select drug-resistant bacteria. AntibioticDB includes compounds currently in pre-clinical development and 834 that have been discontinued and that reached varying stages of development. These may serve as starting points for future research and development.

Monitoring risk: post marketing surveillance and signal detection.

PubMed

Dart, Richard C

2009-12-01

The primary goal of postmarketing surveillance is to provide information for risk assessment of a drug. Drugs affecting the central nervous system form a unique group of products for surveillance because they are often misused, abused, and diverted. These medications include opioid analgesics, stimulants, sedative-hypnotics, muscle relaxants, anticonvulsants and other drug classes. Their adverse events are difficult to monitor because the perpetrator often attempts to conceal the misuse, abuse and diversion of the product. A postmarketing surveillance system for prescription drugs of abuse in the U.S. should include product specific information that is accurate, immediately available, geographically specific and includes all areas of the country. Most producers of branded opioid analgesic products have created systems that measure abuse from multiple vantage points: criminal justice, treatment professionals, susceptible patient populations and acute health events. In the past, the U.S. government has not established similar requirements for the same products produced by generic manufacturers. However, the Food and Drug Administration Amendments Act of 2007 includes generic opioid analgesic products by requiring that all products containing potent opioid drugs perform rigorous surveillance and risk management. While general risk management guidance has been developed by FDA, more specific analyses and guidance are needed to improve surveillance methodology for drugs which are misused, abused, diverted.

Cachexia.

PubMed

Graul, A I; Stringer, M; Sorbera, L

2016-09-01

Cachexia is a multiorgan, multifactorial and often irreversible wasting syndrome associated with cancer and other serious, chronic illnesses including AIDS, chronic heart failure, chronic kidney disease and chronic obstructive pulmonary disease. Treatment of the patient with cachexia is currently targeted to correcting the two underlying features of the condition: anorexia and metabolic disturbances. Greater understanding of the mechanisms behind cachexia and muscle wasting have led to new therapeutic possibilities, however. Several classes of drugs are under active development for cachexia including drugs acting on hormone receptors or cytokine receptors, myostatin/activin pathway antagonists, beta-adrenoceptor agonists and cannabinoids. This review will cover the pathophysiology, epidemiology, diagnosis, treatment, drug candidates under active development and targets for therapeutic intervention of cachexia. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

High-priority and low-priority drug-drug interactions in different international electronic health record systems: A comparative study.

PubMed

Cornu, Pieter; Phansalkar, Shobha; Seger, Diane L; Cho, Insook; Pontefract, Sarah; Robertson, Alexandra; Bates, David W; Slight, Sarah P

2018-03-01

To investigate whether alert warnings for high-priority and low-priority drug-drug interactions (DDIs) were present in five international electronic health record (EHR) systems, to compare and contrast the severity level assigned to them, and to establish the proportion of alerts that were overridden. We conducted a comparative, retrospective, multinational study using a convenience sample of 5 EHRs from the U.S., U.K., Republic of Korea and Belgium. Of the 15 previously defined, high-priority, class-based DDIs, alert warnings were found to exist for 11 in both the Korean and UK systems, 9 in the Belgian system, and all 15 in the two US systems. The specific combinations that were included in these class-based DDIs varied considerably in number, type and level of severity amongst systems. Alerts were only active for 8.4% (52/619) and 52.4% (111/212) of the specific drug-drug combinations contained in the Belgian and UK systems, respectively. Hard stops (not possible to override) existed in the US and UK systems only. The override rates for high-priority alerts requiring provider action ranged from 56.7% to 83.3%. Of the 33 previously defined low-priority DDIs, active alerts existed only in the US systems, for three class-based DDIs. The majority were non-interruptive. Alert warnings existed for most of the high-priority DDIs in the different EHRs but overriding them was easy in most of the systems. In addition to validating the high- and low-priority DDIs, this study reported a lack of standardization in DDI levels across different international knowledge bases. Copyright © 2017. Published by Elsevier B.V.

Vertigo/dizziness as a Drugs’ adverse reaction

PubMed Central

Chimirri, Serafina; Aiello, Rossana; Mazzitello, Carmela; Mumoli, Laura; Palleria, Caterina; Altomonte, Mariolina; Citraro, Rita; De Sarro, Giovambattista

2013-01-01

Introduction: Vertigo, dizziness, and nausea encompass a spectrum of balance-related symptoms caused by a variety of etiologies. Balance is affected by many systems: Proprioceptive pathways and visual, cerebellar, vestibulocochlear, and vascular / vasovagal systems. Vertigo is a subtype of dizziness, in which a subject, as a result to a dysfunction of the vestibular system, improperly experiments the perception of motion. The most useful clinical subdivision is to categorize vertigo into true vertigo and pseudovertigo, whereas from a pathophysiological point of view, vertigo can be classified into central, peripheral, and psychogenic. It is not easy to identify the cause of vertigo since the patients often are not able to precisely describe their symptoms. An impressive list of drugs may cause vertigo or dizziness. Materials and Methods: The aim of the present study was to analyze the data extracted from the reporting cards of the ADRs (adverse drug reactions), received at our Pharmacovigilance Regional Center (Calabria, Italy) in 2012. In particular, the data concerning the occurrence of vertigo and dizziness, after taking certain classes of drugs, have been considered. Results: Our results show that, among the side-effects of different classes of drugs such as anti-convulsants, anti-hypertensives, antibiotics, anti-depressants, anti-psychotics, and anti-inflammatory, also vertigo or dizziness are included. Conclusions: Spontaneous reports of vertigo or dizziness, as side-effect of certain drugs, received at our Pharmacovigilance Center, represented the 5% of all reports in 2012. Considering the high incidence of such an ADR for several drugs’ classes, it can be speculated that under-reporting also affect vertigo and dizziness. Despite the fact that these ADRs might not represent a direct threaten for life, indirectly they can cause secondary damage to patients such as falls, fractures etc. Balance should be accurately monitored during drug use and particularly in fragile patients. PMID:24347974

77 FR 16123 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-19

...; Class II Special Controls Guidance Document: Nucleic Acid-Based In Vitro Diagnostic Devices for the... Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document... II Special Controls Guidance Document: Nucleic Acid-Based In Vitro Diagnostic Devices for the...

Design and Implementation of an Elective on the Ethnopharmacology of Appalachia for the PharmD Curriculum

PubMed Central

2017-01-01

Objective. To create and implement a class in ethnopharmacology that would educate student pharmacists on folk medicine, including home remedies and native plants that are used as alternative medicinal sources; active components of medicinal plants including toxicity issues and the mechanism of action of beneficial compounds, such as catechins and other flavonoids; and nutraceuticals and poisonous plants. Methods. In this three-credit hour class, herbal remedies are investigated from the standpoints of medical efficacy, potential toxicities and drug interactions with prescribed medications. Class discussions are conducted on the usefulness of remedies, the attitudes of practitioners toward traditional remedy use and the risks of relying on herbal preparations. Each student prepares a 15-minute presentation on a disease state, which covers modern pharmaceuticals and herbal or folk remedy alternatives used in that disease. Special emphasis is given to drug-herb interactions. Results. The class has gained popularity among students and consistently fills within the first hour of computerized registration. Students agree that being educated in the benefits and potential toxicities of herbal products will better prepare them to counsel their patients who use these remedies. The elective has been offered 10 times since 2007. Anecdotal comments from our alumni indicate that they have found the information to be very useful in their practice environments. Conclusion. Providing our students with a greater understanding of herbal remedies is essential to prepare them for practice. By including both the uses and potential toxicities, the student pharmacist is able to counsel her patients from a standpoint of expertise on these self-administered remedies. PMID:29367772

The evolving landscape of drug products containing nanomaterials in the United States

NASA Astrophysics Data System (ADS)

D'Mello, Sheetal R.; Cruz, Celia N.; Chen, Mei-Ling; Kapoor, Mamta; Lee, Sau L.; Tyner, Katherine M.

2017-07-01

The Center for Drug Evaluation and Research (CDER) within the US Food and Drug Administration (FDA) is tracking the use of nanotechnology in drug products by building and interrogating a technical profile of products containing nanomaterials submitted to CDER. In this Analysis, data from more than 350 products show an increase in the submissions of drug products containing nanomaterials over the last two decades. Of these, 65% are investigational new drugs, 17% are new drug applications and 18% are abbreviated new drug applications, with the largest class of products being liposomal formulations intended for cancer treatments. Approximately 80% of products have average particle sizes of 300 nm or lower. This analysis identifies several trends in the development of drug products containing nanomaterials, including the relative rate of approvals of these products, and provides a comprehensive overview on the landscape of nanotechnology application in medicine.

Azilsartan, aliskiren, and combination antihypertensives utilizing renin-angiotensin-aldosterone system antagonists.

PubMed

Lanier, Gregg; Sankholkar, Kedar; Aronow, Wilbert S

2014-01-01

Health care providers managing hypertension (HTN) have a large selection of pharmacologic agents to choose from, including several different classes of drugs and many similar drugs within each class. Antagonism of the renin-angiotensin-aldosterone system has been shown to be very effective for HTN, especially in patients with cardiovascular disease, diabetes, and heart failure. Within this group, there have been 2 new agents recently introduced to the US market and approved by the Food and Drug Administration. It is important for the HTN specialist to be familiar with the merits of these 2 drugs: the angiotensin receptor blocker Edarbi (azilsartan) and the renin inhibitor Tekturna (aliskiren). Additionally, there have been several new, fixed-dose combination antihypertensives introduced to the market since 2006 that use a renin-angiotensin-aldosterone antagonist. Seven of these combine 2 drugs together in a single pill: Edarbyclor (azilsartan/chlorthalidone), Exforge (amlodipine/valsartan), Azor (olmesartan/amlodipine), Twynsta (amlodipine/telmisartan), Tekturna HCT [aliskiren/hydrochlorothiazide (HCTZ)], Valturna (aliskiren/valsartan), Tekamlo (aliskiren/amlodipine). Three triple-drug combination medications have also been introduced recently: Exforge HCT (amlodipine/valsartan/HCTZ), Tribenzor (olmesartan/amlodipine/HCTZ), and Amturnide (aliskiren/amlodipine/hydrocholorothiazide). This review will summarize the trial data and important pharmacologic merits of these 2 new renin-angiotensin-aldosterone antagonists and the advantages of initiating treatment with one of the new fixed-dose, combination drugs approved over the last 5 years.

Markov Networks of Collateral Resistance: National Antimicrobial Resistance Monitoring System Surveillance Results from Escherichia coli Isolates, 2004-2012

PubMed Central

Love, William J.; Zawack, Kelson A.; Booth, James G.; Grӧhn, Yrjo T.

2016-01-01

Surveillance of antimicrobial resistance (AMR) is an important component of public health. Antimicrobial drug use generates selective pressure that may lead to resistance against to the administered drug, and may also select for collateral resistances to other drugs. Analysis of AMR surveillance data has focused on resistance to individual drugs but joint distributions of resistance in bacterial populations are infrequently analyzed and reported. New methods are needed to characterize and communicate joint resistance distributions. Markov networks are a class of graphical models that define connections, or edges, between pairs of variables with non-zero partial correlations and are used here to describe AMR resistance relationships. The graphical least absolute shrinkage and selection operator is used to estimate sparse Markov networks from AMR surveillance data. The method is demonstrated using a subset of Escherichia coli isolates collected by the National Antimicrobial Resistance Monitoring System between 2004 and 2012 which included AMR results for 16 drugs from 14418 isolates. Of the 119 possible unique edges, 33 unique edges were identified at least once during the study period and graphical density ranged from 16.2% to 24.8%. Two frequent dense subgraphs were noted, one containing the five β-lactam drugs and the other containing both sulfonamides, three aminoglycosides, and tetracycline. Density did not appear to change over time (p = 0.71). Unweighted modularity did not appear to change over time (p = 0.18), but a significant decreasing trend was noted in the modularity of the weighted networks (p < 0.005) indicating relationships between drugs of different classes tended to increase in strength and frequency over time compared to relationships between drugs of the same class. The current method provides a novel method to study the joint resistance distribution, but additional work is required to unite the underlying biological and genetic characteristics of the isolates with the current results derived from phenotypic data. PMID:27851767

Markov Networks of Collateral Resistance: National Antimicrobial Resistance Monitoring System Surveillance Results from Escherichia coli Isolates, 2004-2012.

PubMed

Love, William J; Zawack, Kelson A; Booth, James G; Grӧhn, Yrjo T; Lanzas, Cristina

2016-11-01

Surveillance of antimicrobial resistance (AMR) is an important component of public health. Antimicrobial drug use generates selective pressure that may lead to resistance against to the administered drug, and may also select for collateral resistances to other drugs. Analysis of AMR surveillance data has focused on resistance to individual drugs but joint distributions of resistance in bacterial populations are infrequently analyzed and reported. New methods are needed to characterize and communicate joint resistance distributions. Markov networks are a class of graphical models that define connections, or edges, between pairs of variables with non-zero partial correlations and are used here to describe AMR resistance relationships. The graphical least absolute shrinkage and selection operator is used to estimate sparse Markov networks from AMR surveillance data. The method is demonstrated using a subset of Escherichia coli isolates collected by the National Antimicrobial Resistance Monitoring System between 2004 and 2012 which included AMR results for 16 drugs from 14418 isolates. Of the 119 possible unique edges, 33 unique edges were identified at least once during the study period and graphical density ranged from 16.2% to 24.8%. Two frequent dense subgraphs were noted, one containing the five β-lactam drugs and the other containing both sulfonamides, three aminoglycosides, and tetracycline. Density did not appear to change over time (p = 0.71). Unweighted modularity did not appear to change over time (p = 0.18), but a significant decreasing trend was noted in the modularity of the weighted networks (p < 0.005) indicating relationships between drugs of different classes tended to increase in strength and frequency over time compared to relationships between drugs of the same class. The current method provides a novel method to study the joint resistance distribution, but additional work is required to unite the underlying biological and genetic characteristics of the isolates with the current results derived from phenotypic data.

The evaluation of the abuse liability of drugs.

PubMed

Johanson, C E

1990-01-01

In order to place appropriate restrictions upon the availability of certain therapeutic agents to limit their abuse, it is important to assess abuse liability, an important aspect of drug safety evaluation. However, the negative consequences of restriction must also be considered. Drugs most likely to be tested are psychoactive compounds with therapeutic indications similar to known drugs of abuse. Methods include assays of pharmacological profile, drug discrimination procedures, self-administration procedures, and measures of drug-induced toxicity including evaluations of tolerance and physical dependence. Furthermore, the evaluation of toxicity using behavioural end-points is an important component of the assessment, and it is generally believed that the most valid procedure in this evaluation is the measurement of drug self-administration. However, even this method rarely predicts the extent of abuse of a specific drug. Although methods are available which appear to measure relative abuse liability, these procedures are not validated for all drug classes. Thus, additional strategies, including abuse liability studies in humans, modelled after those used with animals, must be used in order to make a more informed prediction. Although there is pressure to place restrictions on new drugs at the time of marketing, in light of the difficulty of predicting relative abuse potential, a better strategy might be to market a drug without restrictions, but require postmarketing surveillance in order to obtain more accurate information on which to base a final decision.

Nanomedicine of synergistic drug combinations for cancer therapy – strategies and perspectives

PubMed Central

Xue, Hui Yi; Eoh, June Young; Wu, Xiao Yu

2016-01-01

Nanomedicine of synergistic drug combinations has shown increasing significance in cancer therapy due to its promise in providing superior therapeutic benefits to the current drug combination therapy used in clinical practice. In this article, we will examine the rationale, principles, and advantages of applying nanocarriers to improve anticancer drug combination therapy, review the use of nanocarriers for delivery of a variety of combinations of different classes of anticancer agents including small molecule drugs and biologics, and discuss the challenges and future perspectives of the nanocarrier-based combination therapy. The goal of this review is to provide better understanding of this increasingly important new paradigm of cancer treatment and key considerations for rational design of nanomedicine of synergistic drug combinations for cancer therapy. PMID:27287891

Extending the DIDEO ontology to include entities from the natural product drug interaction domain of discourse.

PubMed

Judkins, John; Tay-Sontheimer, Jessica; Boyce, Richard D; Brochhausen, Mathias

2018-05-09

Prompted by the frequency of concomitant use of prescription drugs with natural products, and the lack of knowledge regarding the impact of pharmacokinetic-based natural product-drug interactions (PK-NPDIs), the United States National Center for Complementary and Integrative Health has established a center of excellence for PK-NPDI. The Center is creating a public database to help researchers (primarly pharmacologists and medicinal chemists) to share and access data, results, and methods from PK-NPDI studies. In order to represent the semantics of the data and foster interoperability, we are extending the Drug-Drug Interaction and Evidence Ontology (DIDEO) to include definitions for terms used by the data repository. This is feasible due to a number of similarities between pharmacokinetic drug-drug interactions and PK-NPDIs. To achieve this, we set up an iterative domain analysis in the following steps. In Step 1 PK-NPDI domain experts produce a list of terms and definitions based on data from PK-NPDI studies, in Step 2 an ontology expert creates ontologically appropriate classes and definitions from the list along with class axioms, in Step 3 there is an iterative editing process during which the domain experts and the ontology experts review, assess, and amend class labels and definitions and in Step 4 the ontology expert implements the new classes in the DIDEO development branch. This workflow often results in different labels and definitions for the new classes in DIDEO than the domain experts initially provided; the latter are preserved in DIDEO as separate annotations. Step 1 resulted in a list of 344 terms. During Step 2 we found that 9 of these terms already existed in DIDEO, and 6 existed in other OBO Foundry ontologies. These 6 were imported into DIDEO; additional terms from multiple OBO Foundry ontologies were also imported, either to serve as superclasses for new terms in the initial list or to build axioms for these terms. At the time of writing, 7 terms have definitions ready for review (Step 2), 64 are ready for implementation (Step 3) and 112 have been pushed to DIDEO (Step 4). Step 2 also suggested that 26 terms of the original list were redundant and did not need implementation; the domain experts agreed to remove them. Step 4 resulted in many terms being added to DIDEO that help to provide an additional layer of granularity in describing experimental conditions and results, e.g. transfected cultured cells used in metabolism studies and chemical reactions used in measuring enzyme activity. These terms also were integrated into the NaPDI repository. We found DIDEO to provide a sound foundation for semantic representation of PK-NPDI terms, and we have shown the novelty of the project in that DIDEO is the only ontology in which NPDI terms are formally defined.

Drug formulations intended for the global market should be tested for stability under tropical climatic conditions.

PubMed

Risha, P G; Vervaet, C; Vergote, G; Bortel, L Van; Remon, J P

2003-06-01

The quality of drugs imported into developing countries having a tropical climate may be adversely affected if their formulations have not been optimized for stability under these conditions. The present study investigated the influence of tropical climate conditions (class IV: 40 degrees C, 75% relative humidity) on the drug content, in vitro dissolution and oral bioavailability of different formulations of two essential drugs marketed in Tanzania: diclofenac sodium and ciprofloxacin tablets. Before and after 3 and 6 months storage under class IV conditions the drug content and in vitro dissolution were evaluated using United States Pharmacopoeia (USP) 24 methods. Following a randomized four-period cross-over study, the pharmacokinetic parameters of drug formulations stored for 3 months under class IV conditions were compared with those stored at ambient conditions. Drug content and drug release from all tested ciprofloxacin formulations were within USP-24 requirements and remained stable during storage at simulated tropical conditions. Oral bioavailability was also not influenced by tropical conditions. The dissolution rate of two diclofenac formulations (Diclo 50 manufactured by Camden and Dicloflame 50 manufactured by Intas) reduced significantly during storage under class IV conditions. After oral administration Camden tablets stored for 3 months under class IV conditions showed a reduction in C(max) (90% CI of C(max) ratio: 0.59 - 0.76). This reduction was smaller than expected based on the in vitro tests. Some drug formulations imported into Tanzania are not optimized for stability in a tropical climate. Manufacturers and regulatory authorities should pay more attention to the WHO recommendations for testing the stability of drugs under tropical climate conditions. Efforts should be made to improve the in vitro tests to better predict the bioavailability.

Antihypertensive drug use in resistant and nonresistant hypertension and in controlled and uncontrolled resistant hypertension.

PubMed

de la Sierra, Alejandro; Armario, Pedro; Oliveras, Anna; Banegas, José R; Gorostidi, Manuel; Vinyoles, Ernest; de la Cruz, Juan J; Segura, Julián; Ruilope, Luis M

2018-07-01

Treatment-resistant hypertension (TRH) is associated with particular clinical features, nonadherence, and suboptimal treatment. We assessed possible associations of antihypertensive drug classes, specific agents inside each class, and types of combinations, with the presence of non-TRH vs. TRH, and with controlled vs. uncontrolled TRH. Comparisons were done in 14 264 patients treated with three drugs (non-TRH: 2988; TRH: 11 276) and in 6974 treated with at least four drugs (controlled TRH: 1383; uncontrolled TRH: 5591). Associations were adjusted for age, sex, and previous cardiovascular event. In both groups of patients treated with three or with at least four drugs, aldosterone antagonists among drug classes [adjusted odds ratio (OR): 1.82 and 1.41, respectively], and ramipril (OR: 1.28 and 1.30), olmesartan (OR: 1.31 and 1.37), and amlodipine (OR: 1.11 and 1.41) inside each class were significantly associated with blood pressure control (non-TRH or controlled TRH). In patients treated with three drugs, non-TRH was also associated with the use of chlorthalidone (OR: 1.50) and bisoprolol (OR: 1.19), whereas in patients treated with at least four drugs, controlled TRH was significantly associated with the triple combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic (OR: 1.17). The use of aldosterone antagonists is associated with blood pressure control in patients treated with three or more drugs. Similar results are observed with specific agents inside each class, being ramipril, olmesartan, chlorthalidone, amlodipine, and bisoprolol those exhibiting significant results. An increased use of these drugs might probably reduce the burden of TRH.

Pain Management: Part 1: Managing Acute and Postoperative Dental Pain

PubMed Central

Becker, Daniel E.

2010-01-01

Abstract Safe and effective management of acute dental pain can be accomplished with nonopioid and opioid analgesics. To formulate regimens properly, it is essential to appreciate basic pharmacological principles and appropriate dosage strategies for each of the available analgesic classes. This article will review the basic pharmacology of analgesic drug classes, including their relative efficacy for dental pain, and will suggest appropriate regimens based on pain intensity. Management of chronic pain will be addressed in the second part of this series. PMID:20553137

Newer Antibacterials in Therapy and Clinical Trials

PubMed Central

Paknikar, Simi S; Narayana, Sarala

2012-01-01

In order to deal with the rising problem of antibiotic resistance, newer antibacterials are being discovered and added to existing pool. Since the year 2000, however, only four new classes of antibacterials have been discovered. These include the oxazolidinones, glycolipopeptides, glycolipodepepsipeptide and pleuromutilins. Newer drugs were added to existing classes of antibiotics, such as streptogramins, quinolones, beta-lactam antibiotics, and macrolide-, tetracycline- and trimethoprim-related drugs. Most of the antibacterials are directed against resistant S. aureus infections, with very few against resistant gram-negative infections. The following article reviews the antibacterials approved by the FDA after the year 2000 as well as some of those in clinical trials. Data was obtained through a literature search via Pubmed and google as well as a detailed search of our library database. PMID:23181224

High throughput screening technologies for ion channels

PubMed Central

Yu, Hai-bo; Li, Min; Wang, Wei-ping; Wang, Xiao-liang

2016-01-01

Ion channels are involved in a variety of fundamental physiological processes, and their malfunction causes numerous human diseases. Therefore, ion channels represent a class of attractive drug targets and a class of important off-targets for in vitro pharmacological profiling. In the past decades, the rapid progress in developing functional assays and instrumentation has enabled high throughput screening (HTS) campaigns on an expanding list of channel types. Chronologically, HTS methods for ion channels include the ligand binding assay, flux-based assay, fluorescence-based assay, and automated electrophysiological assay. In this review we summarize the current HTS technologies for different ion channel classes and their applications. PMID:26657056

Market entry, power, pharmacokinetics: what makes a successful drug innovation?

PubMed

Alt, Susanne; Helmstädter, Axel

2018-02-01

Depending on the timing of market entry, radical innovations can be distinguished from incremental innovations. Whereas a radical innovation typically is the first available derivative of a drug class, incremental innovations are launched later and show a certain benefit compared with the radical innovation. Here, we use historical market data relating to pharmacokinetic (PK), pharmacodynamic (PD), and other drug-related properties to investigate which derivatives within certain drug classes have been most successful on the market. Based on our investigations, we suggest naming the most successful drugs 'overtaking innovation', because they often exceed the market share of all the other derivatives. Seven drug classes showed that the overtaking innovation is never a radical innovation, but rather an early incremental innovation, with advantages in manageability and/or tolerance. Copyright © 2017 Elsevier Ltd. All rights reserved.

75 FR 59726 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-28

... method comparison section and the sample selection inclusion and exclusion criteria section. The... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-D-0428] Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

76 FR 48870 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-09

... selection inclusion and exclusion criteria section. The revisions define and differentiate the required... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-D-0428] Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document...

US Emergency Department Visits for Outpatient Adverse Drug Events, 2013-2014.

PubMed

Shehab, Nadine; Lovegrove, Maribeth C; Geller, Andrew I; Rose, Kathleen O; Weidle, Nina J; Budnitz, Daniel S

2016-11-22

The Patient Protection and Affordable Care Act of 2010 brought attention to adverse drug events in national patient safety efforts. Updated, detailed, nationally representative data describing adverse drug events can help focus these efforts. To describe the characteristics of emergency department (ED) visits for adverse drug events in the United States in 2013-2014 and describe changes in ED visits for adverse drug events since 2005-2006. Active, nationally representative, public health surveillance in 58 EDs located in the United States and participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project. Drugs implicated in ED visits. National weighted estimates of ED visits and subsequent hospitalizations for adverse drug events. Based on data from 42 585 cases, an estimated 4.0 (95% CI, 3.1-5.0) ED visits for adverse drug events occurred per 1000 individuals annually in 2013 and 2014 and 27.3% (95% CI, 22.2%-32.4%) of ED visits for adverse drug events resulted in hospitalization. An estimated 34.5% (95% CI, 30.3%-38.8%) of ED visits for adverse drug events occurred among adults aged 65 years or older in 2013-2014 compared with an estimated 25.6% (95% CI, 21.1%-30.0%) in 2005-2006; older adults experienced the highest hospitalization rates (43.6%; 95% CI, 36.6%-50.5%). Anticoagulants, antibiotics, and diabetes agents were implicated in an estimated 46.9% (95% CI, 44.2%-49.7%) of ED visits for adverse drug events, which included clinically significant adverse events, such as hemorrhage (anticoagulants), moderate to severe allergic reactions (antibiotics), and hypoglycemia with moderate to severe neurological effects (diabetes agents). Since 2005-2006, the proportions of ED visits for adverse drug events from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased. Among children aged 5 years or younger, antibiotics were the most common drug class implicated (56.4%; 95% CI, 51.8%-61.0%). Among children and adolescents aged 6 to 19 years, antibiotics also were the most common drug class implicated (31.8%; 95% CI, 28.7%-34.9%) in ED visits for adverse drug events, followed by antipsychotics (4.5%; 95% CI, 3.3%-5.6%). Among older adults (aged ≥65 years), 3 drug classes (anticoagulants, diabetes agents, and opioid analgesics) were implicated in an estimated 59.9% (95% CI, 56.8%-62.9%) of ED visits for adverse drug events; 4 anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated. Medications to always avoid in older adults according to Beers criteria were implicated in 1.8% (95% CI, 1.5%-2.1%) of ED visits for adverse drug events. The prevalence of emergency department visits for adverse drug events in the United States was estimated to be 4 per 1000 individuals in 2013 and 2014. The most common drug classes implicated were anticoagulants, antibiotics, diabetes agents, and opioid analgesics.

21 CFR 864.9400 - Stabilized enzyme solution.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Stabilized enzyme solution. 864.9400 Section 864... and Blood Products § 864.9400 Stabilized enzyme solution. (a) Identification. A stabilized enzyme... enzyme solutions include papain, bromelin, ficin, and trypsin. (b) Classification. Class II (performance...

21 CFR 864.9400 - Stabilized enzyme solution.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Stabilized enzyme solution. 864.9400 Section 864... and Blood Products § 864.9400 Stabilized enzyme solution. (a) Identification. A stabilized enzyme... enzyme solutions include papain, bromelin, ficin, and trypsin. (b) Classification. Class II (performance...

Sotalol: An important new antiarrhythmic.

PubMed

Anderson, J L; Prystowsky, E N

1999-03-01

Sotalol, the most recently approved oral antiarrhythmic drug, has a unique pharmacologic profile. Its electrophysiology is explained by nonselective beta-blocking action as well as class III antiarrhythmic activity (including fast-activating cardiac membrane-delayed rectifier current blockade), which leads to increases in action potential duration and refractory period throughout the heart and in QT interval on the surface electrocardiogram. Its better hemodynamic tolerance than other beta-blockers may be a result of enhanced inotropy associated with class III activity. Sotalol's ability to suppress ventricular ectopy is similar to that of class I agents and better than that of standard beta-blockers. Unlike class I agents, its use in a postinfarction trial was not associated with increased mortality rate. Therapeutically, it has shown superior efficacy for prevention of recurrent ventricular tachycardia and ventricular fibrillation, which was the basis for its approval. In a randomized study, the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial, sotalol was associated with an increased in-hospital efficacy prediction rate (by Holter monitor or electrophysiologic study), reduced long-term arrhythmic recurrence rate with superior tolerance, and lower mortality rate than class I ("standard") antiarrhythmic drugs. Sotalol was 1 of 2 drugs selected for comparison with implantable defibrillators in the recent National Institutes of Health Antiarrhythmics versus Implantable Defibrillator (AVID) study. Sotalol appears to be a preferred drug for use with implantable defibrillators; unlike some other agents (eg, amiodarone) it does not elevate and, indeed, may lower defibrillation threshold. Although unapproved for this use, sotalol is active against atrial arrhythmias. It has shown efficacy equivalent to propafenone and quinidine in preventing atrial fibrillation recurrence, but it is better tolerated than quinidine and provides excellent rate control during recurrence. Sotalol's major side effects are related to beta-blockade and the risk of torsades de pointes (acceptably small if appropriate precautions are taken). Unlike several other antiarrhythmics (eg, amiodarone), it has no pharmacokinetic drug-drug interactions, is not metabolized, and is entirely renally excreted. Initial dose is 80 mg twice daily, with gradual titration to 240 to 360 mg/day as needed. The daily dose must be reduced in renal failure. On the basis of favorable clinical trials and practice experience, sotalol has shown a steadily growing impact on the treatment of arrhythmias during its 5 years of market availability, a trend that is likely to continue.

An evaluation of the completeness of drug-drug interaction-related information in package inserts.

PubMed

Ng, Giok Qin; Sklar, Grant Edward; Chng, Hui Ting

2017-02-01

The project aimed to evaluate the completeness of drug-drug interaction (DDI)-related information in package inserts (PIs) and develop a systematic approach to conduct the evaluation. DDI-related information in the branded PIs of statins, macrolides, protease inhibitors and selected drugs of narrow therapeutic index (DNTI) were evaluated against the criteria distilled from the Food and Drug Administration (FDA) labelling recommendation guidance document. Decision trees were crafted and employed in the evaluation process. Scores were computed to give each PI an overall completeness score and individual criterion completeness score. The Kruskal-Wallis test and Dunn's multiple comparison test were used to assess the differences in the completeness scores. The mean overall completeness score of the 21 PIs was 35.7 ± 13.4 % (range 12.2-62 %). Eight out of the 11 individual evaluation criterion had a mean completeness score below 50 %. A subclass analysis conducted revealed that PIs from the different drug classes differed in the type of DDI-related information, such that they are more complete or less complete. The completeness score of DDI-related information in the PIs varied extensively amongst and within drug classes. A consensus between the authorities and drug companies on the type and quality of DDI-related information to be included could improve their completeness in PIs and make PIs a valuable source of DDI reference. Decision trees, albeit not validated yet, lay the groundwork for a valuable tool to evaluate DDI-related or other drug information.

Adverse drug reactions amongst adult patients admitted in Lagos State University Teaching Hospital Lagos, Nigeria.

PubMed

Aderemi-Williams, R I; Awodele, O; Boyle, C A

2015-01-01

Adverse drug reaction (ADR) is a global drug therapy problem. It has been rated as one of the top leading causes of morbidity and mortality. In Nigeria, not much is known about ADRs especially with the existing weak post marketing surveillance for monitoring drug use, and its effect on the population. The study is aimed at determining the incidence of ADRs, presentations of ADRs, classes of drugs that frequently cause ADRs and predictors of ADRs in adult medical in-patients in LASUTH. A retrospective study of six hundred and twenty four (624) case notes of all patients admitted to the medical wards in LASUTH between January 1, 2009 and December 31, 2009 was carried out. Information obtained included age, gender, and adverse drug reaction and drug details. The results obtained were analyzed using SPSS version 16 statistical software. Level of significance was set at p ≤ 0.05. A total of 624 case notes consisting of 358 males and 266 females were assessed. The number of patients who experienced adverse drug reactions was 67 (n = 624, 10.7%). The incidence rate of ADRs in LASUTH from the study was 10.7 per 100 patients' population. Most of the ADRs observed were type A reactions (97.8%). Mostly implicated classes of drugs were antidiabetics (26.7%) and NSAIDs (29.3%). The incidence rate of ADRs was 10.7%. ADRs which are predictable and preventable occur in hospitalized patients, such may be prevented or minimized by implementing measures to target specific drugs that are commonly suspected.

Genotyping for Severe Drug Hypersensitivity

PubMed Central

Karlin, Eric; Phillips, Elizabeth

2014-01-01

Over the past decade, there have been significant advances in our understanding of the immunopathogenesis and pharmacogenomics of severe immunologically-mediated adverse drug reactions. Such T-cell-mediated adverse drug reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug-induced liver disease (DILI) and other drug hypersensitivity syndromes have more recently been shown to be mediated through interactions with various class I and II HLA alleles. Key examples have included the associations of HLA-B*15:02 and carbamazepine induced SJS/TEN in Southeast Asian populations and HLA-B*57:01 and abacavir hypersensitivity. HLA-B*57:01 screening to prevent abacavir hypersensitivity exemplifies a successful translational roadmap from pharmacogenomic discovery through to widespread clinical implementation. Ultimately, our increased understanding of the interaction between drugs and the MHC could be used to inform drug design and drive pre-clinical toxicity programs to improve drug safety. PMID:24429903

Substance use predictors of victimization profiles among homeless youth: a latent class analysis.

PubMed

Bender, Kimberly; Thompson, Sanna; Ferguson, Kristin; Langenderfer, Lisa

2014-02-01

Although a substantial body of literature demonstrates high prevalence of street victimization among homeless youth, few studies have investigated the existence of victimization classes that differ on the type and frequency of victimization experienced. Nor do we know how substance use patterns relate to victimization classes. Using latent class analysis (LCA), we examined the existence of victimization classes of homeless youth and investigated substance use predictors of class membership utilizing a large purposive sample (N=601) recruited from homeless youth-serving host agencies in three disparate regions of the U.S. Results of the LCA suggest the presence of three distinct victimization profiles - youth fit into a low-victimization class, a witness class, or a high-victimization class. These three victimization classes demonstrated differences in their substance use, including rates of substance abuse/dependence on alcohol and/or drugs. The presence of distinct victimization profiles suggests the need for screening and referral for differential services. Copyright © 2013 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Medication adherence, healthcare costs and utilization associated with acne drugs in Medicaid enrollees with acne vulgaris.

PubMed

Tan, Xi; Al-Dabagh, Amir; Davis, Scott A; Lin, Hsien-Chang; Balkrishnan, Rajesh; Chang, Jongwha; Feldman, Steven R

2013-06-01

Acne vulgaris is a common chronic disease that may require long-term treatment. Medication adherence is critical to acne management; non-adherence is a common reason for treatment failure and can lead to poor quality of life. The aim of the study was to examine medication adherence, healthcare costs, and utilization associated with acne drugs among acne patients in the USA. This was a retrospective cohort study from January 2004 to December 2007 using the Marketscan Medicaid Database, a national healthcare claims database. The study followed acne patients aged 0-64 years for 90 days after the first acne drug prescription to measure acne medication adherence, acne-related outpatient visits, and total acne-related healthcare costs. Adherence was measured among different acne drug classes using medication possession ratio (MPR). Multivariate regression analyses were conducted to assess the outcomes. The study included 24,438 eligible patients, of whom 89.39 % were under 18 years old. The average adherence rate to acne drugs (MPR) was 0.34, and only 11.74 % of the patients were adherent (MPR ≥0.80). Patients with drug refills had a higher adherence rate (MPR = 0.74) than who those without refills (MPR = 0.27). Factors significantly associated with adherence were age, comorbidity, gender, number of drug refills and number of drug classes used. Patients were more adherent to oral retinoids than any other acne drug classes (MPR = 0.78, 57 % adherent). Patients were less adherent to oral antibiotics (MPR = 0.21) and topical retinoids (MPR = 0.31). After controlling for medication use behavior, the use of oral antibiotics decreased the number of acne-related outpatient visits by 50.9 % (p < 0.001) and lowered acne-related total costs by 51.7 % (p < 0.001). Medication non-adherence is generally prevalent among young acne patients enrolled in Medicaid. The combination of a topical retinoid and an antibiotic agent may be a good choice given their associated healthcare outcomes and costs. However, adherence to these agents is not satisfactory. Therefore, developing specific strategies to improve adherence to these drugs among teenage acne patients is warranted.

[Pharmacist's interventions on outpatient prescriptions in a university hospital drugs sales service].

PubMed

Chappuy, M; Garcia, S; Uhres, A-C; Janoly-Dumenil, A; Dessault, J; Chamouard, V; Bréant, V; Leboucher, G; Pivot, C; Carpentier, I

2015-07-01

For public health reasons, some drugs are only available in hospital drugs sales service. This activity takes place in a specific risk context of organization, patients and/or drugs. A systematic prescription analysis by pharmacist contributes to securise treatment dispensed. The aim of this paper is to present the main drugs problems in the analysis of outpatient prescriptions and pharmaceutical interventions in three units of hospital drugs sales service belong to university hospital. Throughout the year 2013, drug problems detected were recorded prospectively and systematically. Of the 22,279 prescriptions analyzed, 247 pharmaceutical interventions (1.1%) were detected including 27.6% of problems concerning the dosages, 15.4% the unconformity, 6.9% contraindications. Regarding ATC drugs classes, we found 43.7% for anti-infectives and 17.4% for antineoplatics. The overall acceptance rate is 81.8%. These results show the importance of the analysis of outpatient prescriptions before dispensing and the need to have all prescriptions, clinical and biological elements and to develop interprofessionality. The implementation of a platform for dematerialized data exchanges between professionals, including data from the pharmaceutical patient record should contribute to improving drug management of the patient. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Relation between body mass index, physical inactivity and use of prescription drugs: the Doetinchem Cohort Study.

PubMed

Milder, I E J; Klungel, O H; Mantel-Teeuwisse, A K; Verschuren, W M M; Bemelmans, W J E

2010-06-01

Obesity and physical inactivity are associated with several diseases such as diabetes, cardiovascular diseases, musculoskeletal complaints, osteoporosis, certain types of cancer and depression. However, few data are available on the specific types of medication associated with obesity and physical inactivity. The aim of this study was to determine the independent association of body mass index (BMI) and physical inactivity with use of specific classes of prescription drugs, and the interaction between BMI and physical inactivity. The Doetinchem Cohort Study is a population-based longitudinal study. We analyzed cross-sectional data of 1703 men and 1841 women, examined between 1998 and 2002, for whom drug-dispending data were available from the PHARMO database. Drugs were coded according to the WHO Anatomical Therapeutic Chemical (ATC) classification system. Body weight was measured during the physical examination. Physical activity was assessed using an extensive questionnaire. Persons were defined as a user of a certain drug class if they filed at least one prescription in the year around (+/-6 months) the examination. Compared with normal weight persons (BMI 18.5-25 kg m(-2)), obese persons (BMI>30 kg m(-2)) had a higher use of prescription drugs of several drug classes, especially cardiovascular drugs (OR (95% CI): 3.83 (2.61-5.64) in men and 2.80 (2.03-3.86) in women) and diabetes drugs (OR (95% CI): 5.72 (2.32-14.14) in men and 3.92 (1.80-8.54) in women). In women, physical inactivity was also associated with higher use of certain drug classes, such as drugs for blood and blood-forming organs (OR (95% CI): 2.11 (1.22-3.65)) and musculoskeletal drugs (OR (95% CI): 2.07 (1.45-2.97)), whereas in men this was not the case. We found no interaction between BMI and physical inactivity with respect to use of prescription drugs. In both men and women, obesity was associated with a higher use of several types of prescription drugs, whereas physical inactivity was only associated with a higher use of certain drug classes in women.

Chloride channels as drug targets

PubMed Central

Verkman, Alan S.; Galietta, Luis J. V.

2013-01-01

Chloride channels represent a relatively under-explored target class for drug discovery as elucidation of their identity and physiological roles has lagged behind that of many other drug targets. Chloride channels are involved in a wide range of biological functions, including epithelial fluid secretion, cell-volume regulation, neuroexcitation, smooth-muscle contraction and acidification of intracellular organelles. Mutations in several chloride channels cause human diseases, including cystic fibrosis, macular degeneration, myotonia, kidney stones, renal salt wasting and hyperekplexia. Chloride-channel modulators have potential applications in the treatment of some of these disorders, as well as in secretory diarrhoeas, polycystic kidney disease, osteoporosis and hypertension. Modulators of GABAA (γ-aminobutyric acid A) receptor chloride channels are in clinical use and several small-molecule chloride-channel modulators are in preclinical development and clinical trials. Here, we discuss the broad opportunities that remain in chloride-channel-based drug discovery. PMID:19153558

Zein-based Nanocarriers as Potential Natural Alternatives for Drug and Gene Delivery: Focus on Cancer Therapy.

PubMed

Elzoghby, Ahmed; Freag, May; Mamdouh, Hadeer; Elkhodairy, Kadria

2017-01-01

Protein nanocarriers possess unique merits including minimal cytotoxicity, numerous renewable sources, and high drug-binding capability. In opposition to delivery carriers utilizing hydrophilic animal proteins, hydrophobic plant proteins (e.g, zein) have great tendency in fabricating controlled-release particulate carriers without additional chemical modification to stiffen them, which in turn evades the use of toxic chemical crosslinkers. Moreover, zein is related to a class of alcohol-soluble prolamins and generally recognized as safe (GRAS) carrier for drug delivery. Various techniques have been adopted to fabricate zein-based nanoparticulate systems including phase separation coacervation, spray-drying, supercritical anti-solvent approach, electrospinning and self-assembly. This manuscript reviews the recent advances in the zein-based colloidal nano-carrier systems such as nanospheres, nanocapsules, micelles and nanofibers with a special focus on their physicochemical characteristics and drug delivery applications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Methodological background and descriptive features of the ESPAD 2011 Study (European School Survey Project on Alcohol and other Drugs) in Hungary].

PubMed

Gyepesi, Aron; Elekes, Zsuzsanna; Domokos, Tamás; Demetrovics, Zsolt

2013-01-01

The aim of the ESPAD (European School Survey Project on Alcohol and other Drugs) study - launched in 1995 and repeated in every four years - is to collect representative data on alcohol and drug consumption patterns of the 16 year old population, in as many European countries as possible. The survey followed standardized methodology to gain comparable data in every participating country. Students fill in the self-report questionnaire during a school lesson. Beside the compulsory core-question blocks, the Hungarian survey in 2011 contained questions on behavioral addictions (online gaming, internet, eating disorders and gambling) as well. All classes were included into the sample pool, where at least 10% of the students were born in 1995. Data collection took place between 1-20 March 2011. The sample was representative in terms of type of school; class and geographic location. Data was gathered from 370 classes and resulted in 8570 questionnaires. Only 0,96 percent of the total collected data was unreliable. Obtained data is valid and reliable; and can be compared to data from previous years, as well as to data from other ESPAD countries. Representative data on behavioral addictions is highly valuable, because our current knowledge is limited on this domain.

Are poker players all the same? Latent class analysis.

PubMed

Dufour, Magali; Brunelle, Natacha; Roy, Élise

2015-06-01

Poker is the gambling game that is currently gaining the most in popularity. However, there is little information on poker players' characteristics and risk factors. Furthermore, the first studies described poker players, often recruited in universities, as an homogeneous group who played in only one of the modes (land based or on the Internet). This study aims to identify, through latent class analyses, poker player subgroups. A convenience sample of 258 adult poker players was recruited across Quebec during special events or through advertising in various media. Participants filled out a series of questionnaires (Canadian Problem Gambling Index, Beck Depression, Beck Anxiety, erroneous belief and alcohol/drug consumption). The latent class analysis suggests that there are three classes of poker players. Class I (recreational poker players) includes those who have the lowest probability of engaging intensively in different game modes. Participants in class II (Internet poker players) all play poker on the Internet. This class includes the highest proportion of players who consider themselves experts or professionals. They make a living in part or in whole from poker. Class III (multiform players) includes participants with the broadest variety of poker patterns. This group is complex: these players are positioned halfway between professional and recreational players. Results indicate that poker players are not an homogeneous group identified simply on the basis of the form of poker played. The specific characteristics associated with each subgroup points to vulnerabilities that could potentially be targeted for preventive interventions.

76 FR 16425 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-23

...: Ovarian Adnexal Mass Assessment Score Test System; Availability AGENCY: Food and Drug Administration, HHS... assessment score test system into class II (special controls) under section 513(f)(2) of the Federal Food... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0028...

Fitness levels and physical activity among class A drug users entering prison.

PubMed

Fischer, Jan; Butt, Christine; Dawes, Helen; Foster, Charlie; Neale, Joanne; Plugge, Emma; Wheeler, Carly; Wright, Nat

2012-12-01

Physical activity could benefit drug users' physiological and mental health. Previous research has suggested that physical activity levels change when drug users enter prison. Twenty-five class A drug users who were new to prison answered physical activity and drug use cross-sectional questionnaires, took a submaximal fitness test and wore a pedometer for 1 week. Participants' mean aerobic capacity was estimated as 49 mls O2/kg/min (±12 SD). Their mean self-reported walking distance outside of prison was 4.67 miles on an average day (±4.14 SD). Pedometer data suggest they walked a mean of 1.8 miles/day in prison. Many class A drug users entering prison had high levels of fitness and physical activity before admission, often gained from walking. Walking activity reduced when they entered prison, posing a challenge to maintaining healthy activity levels.

Impact of the Food and Drug Administration approval of flecainide and encainide on coronary artery disease mortality: putting "Deadly Medicine" to the test.

PubMed

Anderson, J L; Pratt, C M; Waldo, A L; Karagounis, L A

1997-01-01

In his book Deadly Medicine and on television, Thomas Moore impugns the process of antiarrhythmic drug approval in the 1980s, alleging that the new generation of drugs had flooded the marketplace and had caused deaths in numbers comparable to lives lost during war. To assess these important public health allegations, we evaluated annual coronary artery disease death rates in relation to antiarrhythmic drug sales (2 independent marketing surveys). Predicted mortality rates were modeled using linear regression analysis for 1982 through 1991. Deviations from predicted linearity were sought in relation to rising and falling class IC and overall class I antiarrhythmic drug use. Flecainide came to market in 1986 and encainide in 1987. Combined class IC sales peaked in 1987 and 1988 (maximum market penetration, 20%, first quarter 1989). Results of the Cardiac Arrhythmia Suppression Trial (CAST) were disclosed in April 1989. Overall annual class I antiarrhythmic prescription sales actually fell slightly (-3% to -4%/yr) in the 2 years before CAST and then more abruptly (- 12%) in the year after CAST (1990). Sales of class IC drugs fell dramatically after CAST (by 75%). Coronary death rates (age adjusted) fell in a linear fashion during the decade of 1982 through 1991. No deviation from predicted rates was observed during the introduction, rise, and fall in class IC (and other class I) sales: rates were 126/100,000 in 1985 (before flecainide), 114 and 110 in 1987 and 1988 (maximum sales), and 103 in 1990 (after CAST). Deviations in death rates in the postulated range of 6,000 to 25,000 per year were shown to be excluded easily by the 95% confidence intervals about the predicted rates. Entry of new antiarrhythmic drugs in the 1980s did not lead to overall market expansion and had no adverse impact on coronary artery disease death rates, which fell progressively. Thus, the allegations in Deadly Medicine could not be confirmed.

Challenges of Obtaining Evidence-Based Information Regarding Medications and Male Fertility.

PubMed

Drobnis, Erma Z; Nangia, Ajay K

2017-01-01

In the clinic, the existing literature is insufficient to counsel our infertile men on medication use. Most studies have flaws that limit their application to evidence-based practice. In this chapter, we discuss the limitations of the current literature and the challenges to designing more useful studies. Among the most important weaknesses of existing studies is lack of power; that is, too few men are included to draw conclusions about the existence and size of medication effects. Adequate power is particularly important when confirming an absence of medication effect. Bias is also a problem in most studies. Early studies were rarely randomized, placebo-controlled, or blinded; a common example is patients receiving different medication regimes based on the severity of their symptoms-making it impossible to attribute differences between treated and untreated men to the medications. Additional bias is introduced by failing to include other factors that influence the outcome in the experimental design. A uniform population amenable to randomization and placebo-control are experimental species, and useful information has been gained from these models. However, application to humans is limited by differences from other species in route of drug administration, absorption of the drug, concentration in the male genital tract tissues, and genital tract physiology. To a lesser degree, there is variation among individual men in their response to drugs. In addition, drugs in the same class may have different effects, limiting the applicability of data across drugs of a single class. Complicating matters further, a toxic medication may seem to improve fertility endpoints by improving a disease condition that diminishes fertility. Finally, drug interactions have not been studied, and actual fertility data (pregnancy/fecundity) in humans are rare. A healthy dose of skepticism is warranted when evaluating studies of medications and male reproductive health.

The influences of Taiwan's generic grouping price policy on drug prices and expenditures: evidence from analysing the consumption of the three most-used classes of cardiovascular drugs.

PubMed

Chen, Chi-Liang; Chen, Likwang; Yang, Wei-Chih

2008-04-12

Controlling the growth of pharmaceutical expenditures is a major global challenge. Promotion of generic drug prescriptions or use is gaining increased support. There are substantial contextual differences in international experiences of implementing pharmaceutical policies related to generic drugs. Reporting these experiences from varied perspectives can inform future policy making. This study describes an experience of Taiwan, where patients with chronic (long-term) conditions are usually managed in hospitals and drugs are provided in this setting with costs reimbursed through the National Health Insurance (NHI). It investigates the effects of Taiwan's reimbursement rate adjustment based on chemical generic grouping in 2001. This research also demonstrates the use of micro-level longitudinal data to generate policy-relevant information. The research can be used to improve efficiency of health care resource use. We chose the three most-used classes of cardiovascular drugs for this investigation: beta blocking agents, calcium channel blockers mainly with vascular effects, and plain ACE inhibitors. For each drug class, we investigated changes in daily expense, consumption volume, and total expenditures from a pre-action period to a corresponding post-action period. We compared an exposure or "intervention" group of patients targeted by the action with a comparisonor "control" group of patients not targeted by the action. The data sources are a longitudinal database for 200,000 NHI enrolees, corresponding NHI registration data of health care facilities, and an archive recording all historical data on the reimbursement rates of drugs covered by the NHI. We adopted a fixed effects linear regression model to control for unobserved heterogeneity among patient-hospital groups. Additional descriptive statistics were applied to examine whether any inappropriate consumption of drugs in the three classes existed. The daily drug expense significantly decreased from the pre-action period to the post-action period for the exposure group. The average magnitudes of the decreases for the three classes of drugs mentioned above were 14.8%, 5.8% and 5.8%, respectively. In contrast, there was no reduction for the comparison group. The number of days of the prescription increased significantly from the pre- to the post-action period for both exposure and comparison groups. The total expense also significantly increased for both patient groups. For the exposure group, the average magnitudes of the growth in the total expenditure for the three classes of drugs were 47.7%, 60.0% and 55.3%, respectively. For the comparison group, they were 91.6%, 91.6% and 63.2%, respectively. After the action, approximately 50% of patients obtained more than 180 days of prescription drugs for a six-month period. The 2001 price adjustment action, based on generic grouping, significantly reduced the daily expense of each of the three classes of cardiovascular drugs. However, in response to this policy change, hospitals in Taiwan tended to greatly expand the volume of drugs prescribed for their regular patients. Consequently, the total expenditures for the three classes of drugs grew substantially after the action. These knock-on effects weakened the capability of the price adjustment action to control total pharmaceutical expenditures. This means that no saved resources were available for other health care uses. Such expansion of pharmaceutical consumption might also lead to inefficient use of the three drug classes: a large proportion of patients obtained more than one day of drugs per day in the post-action period, suggesting manipulation to increase reimbursement and offset price controls. We recommend that Taiwan's government use the NHI data to establish a monitoring system to detect inappropriate prescription patterns before implementing future policy changes. Such a monitoring system could then be used to deter hospitals from abusing their prescription volumes, making it possible to more effectively save health care resources by reducing drug reimbursement rates.

[Project to improve abdominal obesity in day care ward psychiatric patients].

PubMed

Liu, Yu-Chieh; Wang, Hui-Yu; Huang, Hui-Ling; Chen, Min-Li

2011-06-01

Over half (57.14%) of patients in our ward suffer from abdominal obesity. This rate is on a continuing upward trend. Reasons for such obesity include lack of physical activity classes, inadequate physical activity, high calorie diets and unhealthy eating habits, chronic diseases and drug side effects, poor motivation to reduce weight, and lack of crisis awareness of abdominal obesity. This project was designed to lessen the problem of abdominal obesity among psychiatric day care inpatients. Resolution measures implemented included: (1) arranging aerobic exercise classes; (2) scheduling classes to teach patients healthy diet habits and knowledge regarding diseases and drugs; (3) holding a waistline reduction competition; (4) displaying health education bulletin boards; (5) holding a quiz contest with prizes for correct answers. The eight abdominally obese patients in the ward achieved an average waist circumference reduction of 2.9 cm and the overall abdominal obesity rate in the ward fell to 35.7%. BMI, eating habits, and awareness of weight loss importance and motivation all improved. The outcome achieved targeted project objectives. We recommend the integration of obesity prevention into routine ward activities and quality control indicators. Nurses should provide patients with weight loss concepts, regularly monitor risk factors, and encourage patient family cooperation to maintain medical care quality.

Enhancing the Jamaica Defence Force Military Intelligence Unit’s Effectiveness to Conduct Counterdrug Missions

DTIC Science & Technology

2006-06-16

ecstasy and heroin but in quantities that constitute personal use or for local sampling. The apparent sporadic availability of drugs other than...is not just simply to say “fix the problem” and hope that by some stroke of magic all the intervening factors fall into place and the issue is 34...include those that are widely abused, such as Heroin, Cocaine. Ecstasy , LSD (Lysergic Acid Diethylamide), and Magic Mushrooms 2. Class B drugs

A systematic review of adverse drug events associated with administration of common asthma medications in children

PubMed Central

Johnson, David W.; Sperou, Arissa J.; Crotts, Jennifer; Saude, Erik; Hartling, Lisa; Stang, Antonia

2017-01-01

Objective To systematically review the literature and determine frequencies of adverse drug events (ADE) associated with pediatric asthma medications. Methods Following PRISMA guidelines, we systematically searched six bibliographic databases between January 1991 and January 2017. Study eligibility, data extraction and quality assessment were independently completed and verified by two reviewers. We included randomized control trials (RCT), case-control, cohort, or quasi-experimental studies where the primary objective was identifying ADE in children 1 month– 18 years old exposed to commercial asthma medications. The primary outcome was ADE frequency. Findings Our search identified 14,540 citations. 46 studies were included: 24 RCT, 15 cohort, 4 RCT pooled analyses, 1 case-control, 1 open-label trial and 1 quasi-experimental study. Studies examined the following drug classes: inhaled corticosteroids (ICS) (n = 24), short-acting beta-agonists (n = 10), long-acting beta-agonists (LABA) (n = 3), ICS + LABA (n = 3), Leukotriene Receptor Antagonists (n = 3) and others (n = 3). 29 studies occurred in North America, and 29 were industry funded. We report a detailed index of 406 ADE descriptions and frequencies organized by drug class. The majority of data focuses on ICS, with 174 ADE affecting 13 organ systems including adrenal and growth suppression. We observed serious ADE, although they were rare, with frequency ranging between 0.9–6% per drug. There were no confirmed deaths, except for 13 potential deaths in a LABA study including combined adult and pediatric participants. We identified substantial methodological concerns, particularly with identifying ADE and determining severity. No studies utilized available standardized causality, severity or preventability assessments. Conclusion The majority of studies focus on ICS, with adrenal and growth suppression described. Serious ADE are relatively uncommon, with no confirmed pediatric deaths. We identify substantial methodological concerns, highlighting need for standardization with future research examining pediatric asthma medication safety. PMID:28793336

Latent Class Analysis of HIV Risk Behaviors Among Russian Women at Risk for Alcohol-Exposed Pregnancies.

PubMed

Bohora, Som; Chaffin, Mark; Shaboltas, Alla; Bonner, Barbara; Isurina, Galina; Batluk, Julia; Bard, David; Tsvetkova, Larissa; Skitnevskaya, Larissa; Volkova, Elena; Balachova, Tatiana

2017-11-01

The number of HIV cases attributed to heterosexual contact and the proportion of women among HIV positive individuals has increased worldwide. Russia is a country with the highest rates of newly diagnosed HIV infections in the region, and the infection spreads beyond traditional risk groups. While young women are affected disproportionately, knowledge of HIV risk behaviors in women in the general population remains limited. The objectives of this study were to identify patterns of behaviors that place women of childbearing age at high risk for HIV transmission and determine whether socio-demographic characteristics and alcohol use are predictive of the risk pattern. A total of 708 non-pregnant women, aged between 18 and 44 years, who were at risk for an alcohol-exposed pregnancy were enrolled in two regions in Russia. Participants completed a structured interview focused on HIV risk behaviors, including risky sexual behavior and alcohol and drug use. Latent class analysis was utilized to examine associations between HIV risk and other demographic and alcohol use characteristics and to identify patterns of risk among women. Three classes were identified. 34.93% of participants were at high risk, combining their risk behaviors, e.g., having multiple sexual partners, with high partner's risk associated with partner's drug use (class I). Despite reporting self-perceived risk for HIV/STI, this class of participants was unlikely to utilize adequate protection (i.e., condom use). The second high risk class included 13.19% of participants who combined their risky sexual behaviors, i.e., multiple sexual partners and having STDs, with partner's risk that included partner's imprisonment and partner's sex with other women (class II). Participants in this class were likely to utilize protection/condoms. Finally, 51.88% of participants were at lower risk, which was associated primarily with their partners' risk, and these participants utilized protection (class III). The odds of being in class I compared with class III were 3.3 (95% CI [1.06, 10.38]) times higher for those women who had Alcohol Use Disorders Identification Test scores ≥ 8 than those who had lower scores, and were 3.9 (95% CI [1.69, 8.97]) times higher for those who used alcohol before sex than those who did not. In addition, women who drank more days per week were 1.36 times more likely to be in class II than in class III. The study informs prevention by identifying specific population groups and targets for interventions. Alcohol use is a significant predictor and an overarching factor of HIV risk in women. Since at-risk drinking is common among young Russian women, alcohol risk reduction should be an essential component of HIV prevention efforts.

A New Venue of TNF Targeting

PubMed Central

Libert, Claude

2018-01-01

The first Food and Drug Administration-(FDA)-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects, followed by protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-tumor necrosis factor (TNF) drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class, whereas others are linked with their mechanism of action, being pan-TNF inhibition. The effects of TNF can diverge at the level of TNF format or receptor, and we discuss the consequences of this in sepsis, autoimmunity and neurodegeneration. Recently, researchers tried to design drugs with reduced side effects. These include molecules with more specificity targeting one specific TNF format or receptor, or that neutralize TNF in specific cells. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the benefits of selective approaches in different diseases. PMID:29751683

Antibody Therapeutics in Oncology.

PubMed

Wold, Erik D; Smider, Vaughn V; Felding, Brunhilde H

2016-03-01

One of the newer classes of targeted cancer therapeutics is monoclonal antibodies. Monoclonal antibody therapeutics are a successful and rapidly expanding drug class due to their high specificity, activity, favourable pharmacokinetics, and standardized manufacturing processes. Antibodies are capable of recruiting the immune system to attack cancer cells through complement-dependent cytotoxicity or antibody dependent cellular cytotoxicity. In an ideal scenario the initial tumor cell destruction induced by administration of a therapeutic antibody can result in uptake of tumor associated antigens by antigen-presenting cells, establishing a prolonged memory effect. Mechanisms of direct tumor cell killing by antibodies include antibody recognition of cell surface bound enzymes to neutralize enzyme activity and signaling, or induction of receptor agonist or antagonist activity. Both approaches result in cellular apoptosis. In another and very direct approach, antibodies are used to deliver drugs to target cells and cause cell death. Such antibody drug conjugates (ADCs) direct cytotoxic compounds to tumor cells, after selective binding to cell surface antigens, internalization, and intracellular drug release. Efficacy and safety of ADCs for cancer therapy has recently been greatly advanced based on innovative approaches for site-specific drug conjugation to the antibody structure. This technology enabled rational optimization of function and pharmacokinetics of the resulting conjugates, and is now beginning to yield therapeutics with defined, uniform molecular characteristics, and unprecedented promise to advance cancer treatment.

Discriminative stimulus properties of intragastrically administered d-amphetamine and pentobarbital in rhesus monkeys.

PubMed

de la Garza, R; Johanson, C E

1987-12-01

Rhesus monkeys were trained to discriminate intragastrically administered d-amphetamine (AMPH) or pentobarbital (PENTO) from saline using a signaled shock-avoidance trail procedure. All monkeys maintained criterion levels (greater than 90% drug-appropriate responding) throughout the duration of the study during training sessions. In the AMPH experiment, the anorectics diethylpropion, mazindol, phendimetrazine, phenmetrazine and phentermine completely substituted for the training dose of AMPH. The atypical antidepressant bupropion and the psychomotor stimulant methylphenidate also completely substituted for AMPH. Other anorectics including benzphetamine, clortermine, fenetylline, mefenorex and the psychomotor stimulant pemoline that share some pharmacological properties with AMPH substituted for AMPH in some, but not all, of the monkeys tested. The anorectics fenfluramine and chlorphentermine failed to substitute for AMPH. Drugs from other pharmacological classes such as morphine, diazepam, nortripyline and PENTO also failed to substitute for AMPH, indicating pharmacological specificity. In the PENTO experiment, the benzodiazepines alprazolam, bromazepam, diazepam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, temazepam and triazolam and the sedatives methaqualone and phenobarbital completely substituted for the training dose of PENTO. The nonbenzodiazepine anxiolytic CL 218,872 only partially substituted for PENTO. In addition, morphine and AMPH failed to substitute for PENTO, indicating pharmacological specificity. In summary, drugs delivered intragastrically functioned as discriminative stimuli in a drug-class specific manner. The ability to use drugs delivered by this route as discriminative stimuli provides a way to compare anorectic drugs to AMPH or sedative drugs to PENTO under conditions that resemble the mode of human consumption to determine whether these drugs are likely to be associated with AMPH-like or PENTO-like drug dependence.

Twenty-first century mast cell stabilizers

PubMed Central

Finn, D F; Walsh, J J

2013-01-01

Mast cell stabilizing drugs inhibit the release of allergic mediators from mast cells and are used clinically to prevent allergic reactions to common allergens. Despite the relative success of the most commonly prescribed mast cell stabilizer, disodium cromoglycate, in use for the preventative treatment of bronchial asthma, allergic conjunctivitis and vernal keratoconjunctivitis, there still remains an urgent need to design new substances that are less expensive and require less frequent dosing schedules. In this regard, recent developments towards the discovery of the next generation of mast cell stabilizing drugs has included studies on substances isolated from natural sources, biological, newly synthesized compounds and drugs licensed for other indications. The diversity of natural products evaluated range from simple phenols, alkaloids, terpenes to simple amino acids. While in some cases their precise mode of action remains unknown it has nevertheless sparked interest in the development of synthetic derivatives with improved pharmacological properties. Within the purely synthetic class of inhibitors, particular attention has been devoted to the inhibition of important signalling molecules including spleen TK and JAK3. The statin class of cholesterol-lowering drugs as well as nilotinib, a TK inhibitor, are just some examples of clinically used drugs that have been evaluated for their anti-allergic properties. Here, we examine each approach under investigation, summarize the test data generated and offer suggestions for further preclinical evaluation before their therapeutic potential can be realized. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 PMID:23441583

Oral health impacts of medications used to treat mental illness.

PubMed

Cockburn, N; Pradhan, A; Taing, M W; Kisely, S; Ford, P J

2017-12-01

Many psychotropic medications affect oral health. This review identified oral side effects for antidepressant, antipsychotic, anticonvulsant, antianxiety and sedative drugs that are recommended in Australia for the management of common mental illnesses and provides recommendations to manage these side-effects. The Australian Therapeutic Guidelines and the Australian Medicines Handbook were searched for medications used to treat common mental health conditions. For each medication, the generic name, class, and drug company reported side-effects were extracted from the online Monthly Index of Medical Specialties (eMIMs) and UpToDate databases. Meyler's Side Effect of Drugs Encyclopaedia was used to identify additional oral adverse reactions to these medications. Fifty-seven drugs were identified: 23 antidepressants, 22 antipsychotics or mood stabilisers, and 12 anxiolytic or sedative medications. Xerostomia (91%) the most commonly reported side effect among all classes of medications of the 28 identified symptoms. Other commonly reported adverse effects included dysguesia (65%) for antidepressants, and tardive dyskinesia (94%) or increased salivation (78%) for antipsychotic medications. While xerostomia has often been reported as a common adverse effect of psychotropic drugs, this review has identified additional side effects including dysguesia from antidepressants and tardive dyskinesia and increased salivation from antipsychotics. Clinicians should consider oral consequences of psychotropic medication in addition to other side-effects when prescribing. For antidepressants, this would mean choosing duloxetine, agomelatine and any of the serotonin re-uptake inhibitors except sertraline. In the case of antipsychotics and mood stabilisers, atypical agents have less oral side effects than older alternatives. Copyright © 2017 Elsevier B.V. All rights reserved.

[Baseline characteristics and changes in treatment after a period of optimization of the patients included in the study EFICAR].

PubMed

Gómez-Marcos, Manuel A; Agudo-Conde, Cristina; Torcal, Jesús; Echevarria, Pilar; Domingo, Mar; Arietaleanizbeascoa, María; Sanz-Guinea, Aitor; de la Torre, Maria M; Ramírez, Jose I; García-Ortiz, Luis

2016-03-01

To describe the baseline date and drugs therapy changes during treatment optimization in patients with heart failure with depressed systolic function included in the EFICAR study. Multicenter randomized clinical trial. Seven Health Centers. 150 patients (ICFSD) age 68±10 years, 77% male. Sociodemographic variables, comorbidities (Charlson index), functional capacity and quality of life. Drug therapy optimization was performed. The main etiology was ischemic heart disease (45%), with 89% in functional class II. The Charlson index was 2.03±1.05. The ejection fraction mean was 37%±8, 19% with ejection fraction <30%. With the stress test 6.3±1.6 mean was reached, with the 6 minutes test 446±78 meters and the chair test 13.7±4.4 seconds. The overall quality of life with ejection fraction was 22.8±18.7 and with the Short Form-36 Health Survey, physical health 43.3±8.4 and mental health 50.1±10.6. After optimizing the treatment, the percentage of patients on drugs therapy and the dose of angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists and beta-blockers were not changed. The majority of the subjects are in functional class II, with functional capacity and quality of life decreased and comorbidity index high. A protocolized drug therapy adjustment did not increase the dose or number of patients with effective drugs for heart failure with depressed systolic function. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Factors affecting the uptake of new medicines: a systematic literature review.

PubMed

Lublóy, Ágnes

2014-10-20

The successful diffusion of new drugs is crucial for both pharmaceutical companies and patients-and of wider stakeholder concern, including for the funding of healthcare provision. Micro-level characteristics (the socio-demographic and professional characteristics of medical professionals), meso-level characteristics (the prescribing characteristics of doctors, the marketing efforts of pharmaceutical companies, interpersonal communication among doctors, drug attributes, and the characteristics of patients), and macro-level characteristics (government policies) all influence the diffusion of new drugs. This systematic literature review examines the micro- and meso-level characteristics of early prescribers of newly introduced drugs. Understanding the characteristics of early adopters may help to speed up the diffusion process, promote cost-efficient prescribing habits, forecast utilisation, and develop targeted intervention strategies. The PubMed and Scopus electronic databases were chosen for their extensive coverage of the pertinent literature and used to identify 205 potentially relevant studies by means of a four-layered search string. The 35 studies deemed eligible were then synthetized carefully and critically, to extract variables relevant to this review. Early adoption of new drugs is not a personal trait, independent of drug type, but early adopters share both micro- and meso-level characteristics. At prescriber level, doctors' interest in particular therapeutic areas, participation in clinical trials, and volume of prescribing-either in total or within the therapeutic class of the new drug-increase the likelihood of early adoption. The marketing efforts of pharmaceutical companies and doctors' professional and social interactions leading to prescribing contagion are very powerful predictors of new drug uptake. At patient level, doctors with younger patients, patients with higher socioeconomic statuses and/or patients with poorer health statuses are more inclined to prescribe new drugs early. In contrast, the socio-demographic characteristics of prescribers and many practice-related factors play little role in the adoption process. The most powerful predictors of new drug uptake include the doctors' strong scientific commitment, high prescribing volume in total or in within the therapeutic class of the new drug, high exposure to marketing, and intense communication with colleagues.

Biowaiver extension potential to BCS Class III high solubility-low permeability drugs: bridging evidence for metformin immediate-release tablet.

PubMed

Cheng, Ching-Ling; Yu, Lawrence X; Lee, Hwei-Ling; Yang, Chyun-Yu; Lue, Chang-Sha; Chou, Chen-Hsi

2004-07-01

The biopharmaceutics classification system (BCS) allows biowaiver for rapid dissolving immediate-release (IR) products of Class I drugs (high solubility and high permeability). The possibility of extending biowaivers to Class III high solubility and low permeability drugs is currently under scrutiny. In vivo bioequivalence data of different formulations of Class III drugs would support such an extension. The objective of this work was to demonstrate the bioequivalence of two marketed IR tablet products of a Class III drug, metformin hydrochloride, that are rapidly dissolving and have similar in vitro dissolution profiles. The effect of race on the systemic exposure of metformin was also explored. A randomized, open-label, two-period crossover study was conducted in 12 healthy Chinese male volunteers. Each subject received a single-dose of 500 mg of each product after an overnight fasting. The plasma concentrations of metformin were followed for 24 h. No significant formulation effect was found for the bioequivalence metrics: areas under concentration-time curve (AUC0-t, AUC0-infinity) and maximal concentration (Cmax). The 90% confidence intervals for the ratio of means were found within the acceptance range of 80-125% for the log-transformed data. Based on these results, it was concluded that the two IR products are bioequivalent. The pharmacokinetic parameters of metformin in Chinese for both products were similar and were in good agreement with those reported for metformin IR tablets in other ethnic populations. This study serves as an example for supporting biowaiver for BCS Class III drugs.

Recent advances in (therapeutic protein) drug development

PubMed Central

Lagassé, H.A. Daniel; Alexaki, Aikaterini; Simhadri, Vijaya L.; Katagiri, Nobuko H.; Jankowski, Wojciech; Sauna, Zuben E.; Kimchi-Sarfaty, Chava

2017-01-01

Therapeutic protein drugs are an important class of medicines serving patients most in need of novel therapies. Recently approved recombinant protein therapeutics have been developed to treat a wide variety of clinical indications, including cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The latest advances in protein-engineering technologies have allowed drug developers and manufacturers to fine-tune and exploit desirable functional characteristics of proteins of interest while maintaining (and in some cases enhancing) product safety or efficacy or both. In this review, we highlight the emerging trends and approaches in protein drug development by using examples of therapeutic proteins approved by the U.S. Food and Drug Administration over the previous five years (2011–2016, namely January 1, 2011, through August 31, 2016). PMID:28232867

Pharmacogenetics in cardiovascular diseases: State of the art and implementation-recommendations of the French National Network of Pharmacogenetics (RNPGx).

PubMed

Lamoureux, Fabien; Duflot, Thomas

2017-04-01

The use of genomic markers to predict drug response and effectiveness has the potential to improve healthcare by increasing drug efficacy and minimizing adverse effects. Polymorphisms associated with inter-individual variability in drug metabolism, transport, or pharmacodynamics of major cardiovascular drugs have been identified. These include single nucleotide polymorphisms (SNP) affecting clinical outcomes in patients receiving antiplatelet agents, oral anticoagulants and statins. Based on clinical evidence supporting genetic testing in the management of cardiovascular diseases using these drug classes, this short review presents clinical guidance regarding current pharmacogenetics implementation in routine medical practice. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Typology of club drug use among young adults recruited using time-space sampling

PubMed Central

Ramo, Danielle E.; Grov, Christian; Delucchi, Kevin; Kelly, Brian C.; Parsons, Jeffrey T.

2009-01-01

The present study examined patterns of recent club drug use among 400 young adults (18–29) recruited using time-space sampling in NYC. Subjects had used at least one of six club drugs (MDMA, Ketamine, GHB, Cocaine, Methamphetamine, and LSD) within the prior 3 months. We used latent class analysis (LCA) to estimate latent groups based on patterns of recent club drug use and examined differences in demographic and psychological variables by class. A 3-class model fit the data best. Patterns were: Primary cocaine users (42% of sample), Mainstream users (44% of sample), and Wide-range users (14% of sample). Those most likely to be Primary cocaine users were significantly less likely to be heterosexual males and had higher educational attainment than the other two classes. Those most likely to be Wide-range users were less likely to be heterosexual females, more likely to be gay/bisexual males, dependent on club drugs, had significantly greater drug and sexual sensation-seeking, and were more likely to use when experiencing physical discomfort or pleasant times with others compared to the other two groups. Findings highlight the utility of using person-centered approaches to understand patterns of substance use, as well as highlight several patterns of club drug use among young adults. PMID:19939585

Evaluation of rational nonsteroidal anti-inflammatory drugs and gastro-protective agents use; association rule data mining using outpatient prescription patterns.

PubMed

Pattanaprateep, Oraluck; McEvoy, Mark; Attia, John; Thakkinstian, Ammarin

2017-07-04

Nonsteroidal anti-inflammatory drugs (NSAIDs) and gastro-protective agents should be co-prescribed following a standard clinical practice guideline; however, adherence to this guideline in routine practice is unknown. This study applied an association rule model (ARM) to estimate rational NSAIDs and gastro-protective agents use in an outpatient prescriptions dataset. A database of hospital outpatients from October 1st, 2013 to September 30th, 2015 was searched for any of following drugs: oral antacids (A02A), peptic ulcer and gastro-oesophageal reflux disease drugs (GORD, A02B), and anti-inflammatory and anti-rheumatic products, non-steroids or NSAIDs (M01A). Data including patient demographics, diagnoses, and drug utilization were also retrieved. An association rule model was used to analyze co-prescription of the same drug class (i.e., prescriptions within A02A-A02B, M01A) and between drug classes (A02A-A02B & M01A) using the Apriori algorithm in R. The lift value, was calculated by a ratio of confidence to expected confidence, which gave information about the association between drugs in the prescription. We identified a total of 404,273 patients with 2,575,331 outpatient visits in 2 fiscal years. Mean age was 48 years and 34% were male. Among A02A, A02B and M01A drug classes, 12 rules of associations were discovered with support and confidence thresholds of 1% and 50%. The highest lift was between Omeprazole and Ranitidine (340 visits); about one-third of these visits (118) were prescriptions to non-GORD patients, contrary to guidelines. Another finding was the concomitant use of COX-2 inhibitors (Etoricoxib or Celecoxib) and PPIs. 35.6% of these were for patients aged less than 60 years with no GI complication and no Aspirin, inconsistent with guidelines. Around one-third of occasions where these medications were co-prescribed were inconsistent with guidelines. With the rapid growth of health datasets, data mining methods may help assess quality of care and concordance with guidelines and best evidence.

Cardiovascular Drugs in Avian, Small Mammal, and Reptile Medicine.

PubMed

Fitzgerald, Brenna Colleen; Dias, Sara; Martorell, Jaume

2018-05-01

Cardiovascular disease, including congestive heart failure, pericardial disease, and atherosclerosis, is becoming increasingly better recognized in companion birds, small mammals, and reptiles. A wide range of medications is available to treat these conditions, including diuretics, vasodilators, positive and negative inotropes, antiarrhythmic agents, and pentoxifylline. This review systematically discusses each of these drug classes and their potential applications in exotic species. Although treatment approaches remain largely empirical and extrapolated from small animal and human medicine, the management strategies presented here have the potential to both maintain quality of life and extend survival time for the exotic cardiac patient. Copyright © 2018 Elsevier Inc. All rights reserved.

76 FR 44594 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-26

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-D-0465] Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document... guidance document will serve as the special control for rTMS systems. Section 513(f)(2) of the Federal Food...

Drug Interactions with Lithium: An Update.

PubMed

Finley, Patrick R

2016-08-01

Lithium has been used for the management of psychiatric illnesses for over 50 years and it continues to be regarded as a first-line agent for the treatment and prevention of bipolar disorder. Lithium possesses a narrow therapeutic index and comparatively minor alterations in plasma concentrations can have significant clinical sequelae. Several drug classes have been implicated in the development of lithium toxicity over the years, including diuretics and non-steroidal anti-inflammatory compounds, but much of the anecdotal and experimental evidence supporting these interactions is dated, and many newer medications and medication classes have been introduced during the intervening years. This review is intended to provide an update on the accumulated evidence documenting potential interactions with lithium, with a focus on pharmacokinetic insights gained within the last two decades. The clinical relevance and ramifications of these interactions are discussed.

[Drug management for coronary artery disease in the elderly].

PubMed

Meune, C

2006-11-01

The incidence of side effects increases dramatically with age. It is estimated that almost one third of side effects could be avoided by an appropriate prescription. On the other hand, age is the main factor associated to the non-prescription of major pharmacological classes, which have evidenced their efficacy in younger patients with coronary artery disease. The estimation of the benefit/risk ratio is therefore highly important in the old/very old patient. It seems important to integrate the results of studies and registries including old patients, evidencing the efficacy of the majority of pharmacological classes validated in younger patients, especially antiplatelets, beta-blockers and statins. The assessment of the benefit/risk ratio should also take into account the tolerance profile of the drug and the patient. The prescription should be adapted to the "age-related" changes of pharmacokinetics and pharmacodynamics.

Past 12-month and lifetime comorbidity and poly-drug use of ecstasy users among young adults in the United States: Results from the National Epidemiologic Survey on Alcohol and Related Conditions

PubMed Central

Keyes, Katherine M.; Martins, Silvia S.; Hasin, Deborah S.

2013-01-01

Background Ecstasy use is prevalent among young people and often co-occurs with other drug use, but little is known about the past 12-month and lifetime psychiatric comorbidity and specific additional drug abuse among young adult ecstasy users in the general population. To provide this information, we compared current ecstasy users to former users, other illicit drug users, and non-illicit drug users. Method Data were gathered in a face-to-face survey of the United States conducted in the 2001–2002 (NESARC). Participants were household and group quarters residents aged 18–29 years (n = 8666). We measured current ecstasy use defined as any use in the past year; former ecstasy use as use prior to the past year only; other lifetime drug use included any drug other than ecstasy; lifetime non-illicit drug use as no illicit drug use. Associations were determined for nine other classes of illicit drugs, eight personality disorders, and seven mood and anxiety disorders. Results Of current ecstasy users, 44% used >3 other classes of illicit drugs in the past year, compared to 1.6% of non-ecstasy drug users. Current ecstasy use was associated with current anxiety (OR = 3.7), specifically panic disorder (OR = 7.7) and specific phobia (OR = 4.1), also alcohol abuse (OR = 21.6) and dependence (OR = 4.1) and any personality disorder (OR = 5.1) compared to non-illicit drug users. Conclusions Results indicate important differences in comorbidities of current and former ecstasy users compared to other drug users and lifetime non-illicit drug users that may affect phenotype definitions and etiologic studies. Ecstasy use may represent a distinct population of drug users for which unique treatments may be necessary. PMID:18524499

Polymer therapeutics: concepts and applications.

PubMed

Haag, Rainer; Kratz, Felix

2006-02-13

Polymer therapeutics encompass polymer-protein conjugates, drug-polymer conjugates, and supramolecular drug-delivery systems. Numerous polymer-protein conjugates with improved stability and pharmacokinetic properties have been developed, for example, by anchoring enzymes or biologically relevant proteins to polyethylene glycol components (PEGylation). Several polymer-protein conjugates have received market approval, for example the PEGylated form of adenosine deaminase. Coupling low-molecular-weight anticancer drugs to high-molecular-weight polymers through a cleavable linker is an effective method for improving the therapeutic index of clinically established agents, and the first candidates have been evaluated in clinical trials, including, N-(2-hydroxypropyl)methacrylamide conjugates of doxorubicin, camptothecin, paclitaxel, and platinum(II) complexes. Another class of polymer therapeutics are drug-delivery systems based on well-defined multivalent and dendritic polymers. These include polyanionic polymers for the inhibition of virus attachment, polycationic complexes with DNA or RNA (polyplexes), and dendritic core-shell architectures for the encapsulation of drugs. In this Review an overview of polymer therapeutics is presented with a focus on concepts and examples that characterize the salient features of the drug-delivery systems.

[Design of next generation antibody drug conjugates].

PubMed

Zhu, Gui-Dong; Fu, Yang-Xin

2013-07-01

Chemotherapy remains one of the major tools, along with surgery, radiotherapy, and more recently targeted therapy, in the war against cancer. There have appeared a plethora of highly potent cytotoxic drugs but the poor discriminability between cancerous and healthy cells of these agents limits their broader application in clinical settings. Therapeutic antibodies have emerged as an important class of biological anticancer agents, thanks to their ability in specific binding to tumor-associated antigens. While this important class of biologics can be used as single agents for the treatment of cancer through antibody-dependent cell cytotoxicity (ADCC), their therapeutical efficacy is often limited. Antitumor antibody drug conjugates (ADCs) combine the target-specificity of monoclonal antibody (mAb) and the highly active cell-killing drugs, taking advantages of the best characteristics out of both components. Thus, insufficiency of most naked mAbs in cancer therapy has been circumvented by arming the immunoglobulin with cytotoxic drugs. Here mAbs are used as vehicles to transport potent payloads to tumor cells. ADCs contain three main components: antibody, linker and cytotoxics (also frequently referred as payload). Antibodies can recognize and specifically bind to the tumor-specific antigens, leading to an antibody-assisted internalization, and payload release. While ADC has demonstrated tremendous success, a number of practical challenges limit the broader applications of this new class of anticancer therapy, including inefficient cellular uptake, low cytotoxicity, and off-target effects. This review article aims to cover recent advances in optimizing linkers with increased stability in circulation while allowing efficient payload release within tumor cells. We also attempt to provide some practical strategies in resolving the current challenges in this attractive research area, particularly to those new to the field.

Novel ocular antihypertensive compounds in clinical trials

PubMed Central

Chen, June; Runyan, Stephen A; Robinson, Michael R

2011-01-01

Introduction: Glaucoma is a multifactorial disease characterized by progressive optic nerve injury and visual field defects. Elevated intraocular pressure (IOP) is the most widely recognized risk factor for the onset and progression of open-angle glaucoma, and IOP-lowering medications comprise the primary treatment strategy. IOP elevation in glaucoma is associated with diminished or obstructed aqueous humor outflow. Pharmacotherapy reduces IOP by suppressing aqueous inflow and/or increasing aqueous outflow. Purpose: This review focuses on novel non-FDA approved ocular antihypertensive compounds being investigated for IOP reduction in ocular hypertensive and glaucoma patients in active clinical trials within approximately the past 2 years. Methods: The mode of IOP reduction, pharmacology, efficacy, and safety of these new agents were assessed. Relevant drug efficacy and safety trials were identified from searches of various scientific literature databases and clinical trial registries. Compounds with no specified drug class, insufficient background information, reformulations, and fixed-combinations of marketed drugs were not considered. Results: The investigational agents identified comprise those that act on the same targets of established drug classes approved by the FDA (ie, prostaglandin analogs and β-adrenergic blockers) as well as agents belonging to novel drug classes with unique mechanisms of action. Novel targets and compounds evaluated in clinical trials include an actin polymerization inhibitor (ie, latrunculin), Rho-associated protein kinase inhibitors, adenosine receptor analogs, an angiotensin II type 1 receptor antagonist, cannabinoid receptor agonists, and a serotonin receptor antagonist. Conclusion: The clinical value of novel compounds for the treatment of glaucoma will depend ultimately on demonstrating favorable efficacy and benefit-to-risk ratios relative to currently approved prostaglandin analogs and β-blockers and/or having complementary modes of action. PMID:21629573

Alpha1-adrenergic blockers: current usage considerations.

PubMed

Sica, Domenic A

2005-12-01

Alpha1-adrenergic-blocking drugs are effective in reducing blood pressure and do so in a fashion comparable to most other antihypertensive drug classes. These compounds are most effective in patients in the upright position, reducing systolic and diastolic pressures by 8%-10%. Alpha1-adrenergic-blocking drugs incrementally reduce blood pressure when combined with most drug classes and are the only antihypertensive drug class to improve plasma lipid profiles. Alpha1-adrenergic-blocking drugs are also accepted as important elements of the treatment plan for symptomatic benign prostatic hypertrophy. Dose escalation of an alpha1-adrenergic-blocking drug can trigger renal Na+ retention, and the ensuing volume expansion can attenuate its blood pressure-lowering effect. Orthostatic hypotension can occur with these compounds, particularly when a patient is volume-contracted. Dizziness, headache, and drowsiness are common side effects with alpha1-adrenergic blockers. A modest decline in the use of doxazosin and other alpha1-adrenergic-blocking drugs has occurred coincident to the early termination of the doxazosin treatment arm in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.

PREDICTING DRUG DISPOSITION, ABSORPTION / ELIMINATION / TRANSPORTER INTERPLAY AND THE ROLE OF FOOD ON DRUG ABSORPTION

PubMed Central

Custodio, Joseph M.; Wu, Chi-Yuan; Benet, Leslie Z.

2008-01-01

The ability to predict drug disposition involves concurrent consideration of many chemical and physiological variables and the effect of food on the rate and extent of availability adds further complexity due to postprandial changes in the gastrointestinal (GI) tract. A system that allows for the assessment of the multivariate interplay occurring following administration of an oral dose, in the presence or absence of meal, would greatly benefit the early stages of drug development. This is particularly true in an era when the majority of new molecular entities are highly permeable, poorly soluble, extensively metabolized compounds (BDDCS Class 2), which present the most complicated relationship in defining the impact of transporters due to the marked effects of transporter-enzyme interplay. This review evaluates the GI luminal environment by taking into account the absorption / transport / elimination interplay and evaluates the physiochemical property issues by taking into account the importance of solubility, permeability and metabolism. We concentrate on the BDDCS and its utility in predicting drug disposition. Furthermore, we focus on the effect of food on the extent of drug availability (F), which appears to follow closely what might be expected if a significant effect of high fat meals is inhibition of transporters. That is, high fat meals and lipidic excipients would be expected to have little effect on F for Class 1 drugs; they would increase F of Class 2 drugs, while decreasing F for Class 3 drugs. PMID:18199522

Reimbursement-Based Economics--What Is It and How Can We Use It to Inform Drug Policy Reform?

PubMed

Coyle, Doug; Lee, Karen M; Mamdani, Muhammad; Sabarre, Kelley-Anne; Tingley, Kylie

2015-01-01

In Ontario, approximately $3.8 billion is spent annually on publicly funded drug programs. The annual growth in Ontario Public Drug Program (OPDP) expenditure has been limited to 1.2% over the course of 3 years. Concurrently, the Ontario Drug Policy Research Network (ODPRN) was appointed to conduct drug class review research relating to formulary modernization within the OPDP. Drug class reviews by ODPRN incorporate a novel methodological technique called reimbursement-based economics, which focuses on reimbursement strategies and may be particularly relevant for policy-makers. To describe the reimbursement-based economics approach. Reimbursement-based economics aims to identify the optimal reimbursement strategy for drug classes by incorporating a review of economic literature, comprehensive budget impact analyses, and consideration of cost-effectiveness. This 3-step approach is novel in its focus on the economic impact of alternate reimbursement strategies rather than individual therapies. The methods involved within the reimbursement-based approach are detailed. To facilitate the description, summary methods and findings from a recent application to formulary modernization with respect to the drug class tryptamine-based selective serotonin receptor agonists (triptans) used to treat migraine headaches are presented. The application of reimbursement-based economics in drug policy reforms allows policy-makers to consider the cost-effectiveness and budget impact of different reimbursement strategies allowing consideration of the trade-off between potential cost savings vs increased access to cost-effective treatments. © 2015 American Headache Society.

Analysis of Intra- and Intersubject Variability in Oral Drug Absorption in Human Bioequivalence Studies of 113 Generic Products.

PubMed

Sugihara, Masahisa; Takeuchi, Susumu; Sugita, Masaru; Higaki, Kazutaka; Kataoka, Makoto; Yamashita, Shinji

2015-12-07

In this study, the data of 113 human bioequivalence (BE) studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time-concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (P(eff)). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low P(eff) might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of P(eff)/Do (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (P(eff)/Do < 0.149 × 10(-4) cm/s) showed high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by CYP3A4 while intersubject variability was high for drugs metabolized by CYP2D6. For CYP3A4 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of human BE study, low permeability, solubility-limited absorption, and high affinity to CYP3A4 are identified as risk factors for high intrasubject variability in oral drug absorption. This information is of importance to design the human BE study for oral drug products containing APIs with a risk of large intrasubject variability in oral absorption.

Monitoring of drug intake during pregnancy by questionnaires and LC-MS/MS drug urine screening: evaluation of both monitoring methods.

PubMed

Hoeke, Henrike; Roeder, Stefan; Bertsche, Thilo; Lehmann, Irina; Borte, Michael; von Bergen, Martin; Wissenbach, Dirk K

2015-08-01

Various studies pointed towards a relationship between chronic diseases such as asthma and allergy and environmental risk factors, which are one aspect of the so-called Exposome. These environmental risk factors include also the intake of drugs. One critical step in human development is the prenatal period, in which exposures might have critical impact on the child's health outcome. Thereby, the health effects of drugs taken during gestation are discussed controversially with regard to newborns' disease risk. Due to this, the drug intake of pregnant women in the third trimester was monitored by questionnaire, in addition to biomonitoring using a local birth cohort study, allowing correlations of drug exposure with disease risk. Therefore, 622 urine samples were analyzed by an untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) urine screening and the results were compared to self-administered questionnaires. In total, 48% (n = 296) reported an intake of pharmaceuticals, with analgesics as the most frequent reported drug class in addition to dietary supplements. 182 times compounds were detected by urine screening, with analgesics (42%; n = 66) as the predominantly drug class. A comparison of reported and detected drug intake was performed for three different time spans between completion of the questionnaires and urine sampling. Even if the level of accordance was low in general, similar percentages (~25%, ~19%, and ~ 20%) were found for all groups. This study illustrates that a comprehensive evaluation of drug intake is neither achieved by questionnaires nor by biomonitoring alone. Instead, a combination of both monitoring methods, providing complementary information, should be considered. Copyright © 2014 John Wiley & Sons, Ltd.

Synthesis and potent in vitro activity of novel 1H-benzimidazoles as anti-MRSA agents.

PubMed

Karataş, Hacer; Alp, Mehmet; Yildiz, Sulhiye; Göker, Hakan

2012-08-01

A new class of 1H-benzimidazolecarboxamidines was synthesized and evaluated for in vitro antibacterial and antifungal activities, including drug-resistant bacterial strains. The most potent compound (32) has the same ratio of anti-MRSA activity as Vancomycin (minimal inhibitory concentrations value 0.78 μg/mL). The mechanism of action for 1H-benzimidazolecarboxamidine appears to be different from existing antibacterial agents. These compounds have potential for development as a new class of potent anti-MRSA agent. © 2012 John Wiley & Sons A/S.

Drugs Associated with More Suicidal Ideations Are also Associated with More Suicide Attempts

PubMed Central

Robertson, Henry T.; Allison, David B.

2009-01-01

Context In randomized controlled trials (RCTs), some drugs, including CB1 antagonists for obesity treatment, have been shown to cause increased suicidal ideation. A key question is whether drugs that increase or are associated with increased suicidal ideations are also associated with suicidal behavior, or whether drug–induced suicidal ideations are unlinked epiphenomena that do not presage the more troubling and potentially irrevocable outcome of suicidal behavior. This is difficult to determine in RCTs because of the rarity of suicidal attempts and completions. Objective To determine whether drugs associated with more suicidal ideations are also associated with more suicide attempts in large spontaneous adverse event (AE) report databases. Methodology Generalized linear models with negative binomial distribution were fitted to Food and Drug Administration (FDA) Adverse Event (AE) Reporting System (AERS) data from 2004 to 2008. A total of 1,404,470 AEs from 832 drugs were analyzed as a function of reports of suicidal ideations; other non-suicidal adverse reactions; drug class; proportion of reports from males; and average age of subject for which AE was filed. Drug was treated as the unit of analysis, thus the statistical models effectively had 832 observations. Main Outcome Measures Reported suicide attempts and completed suicides per drug. Results 832 drugs, ranging from abacavir to zopiclone, were evaluated. The 832 drugs, as primary suspect drugs in a given adverse event, accounted for over 99.9% of recorded AERS. Suicidal ideations had a significant positive association with suicide attempts (p<.0001) and had an approximately 131-fold stronger magnitude of association than non-suicidal AERs, after adjusting for drug class, gender, and age. Conclusions In AE reports, drugs that are associated with increased suicidal ideations are also associated with increased suicidal attempts or completions. This association suggests that drug-induced suicidal ideations observed in RCTs plausibly represent harbingers that presage the more serious suicide attempts and completions and should be a cause for concern. PMID:19798416

Psychotropic drug initiation or increased dosage and the acute risk of falls: a prospective cohort study of nursing home residents

PubMed Central

2013-01-01

Background Previous studies suggest that psychotropic drug changes may signal an acute period of time whereby a person is highly vulnerable to fall. It is unknown whether certain classes of psychotropic agents are less safe with respect to the acute risk of falls. Our purpose was to compare fall rates in the 7 days following a change of an antidepressant, antipsychotic, or benzodiazepine. We also identified specific times when residents are at high risk for falls with respect to a psychotropic drug change. Methods Residents in our one-year study included 851 long term care residents from two nursing home facilities in Boston, MA, U.S.A. (May 2010 - May 2011). Drug changes (i.e., new prescriptions or increased dose of a previously used drug) were ascertained using the computerized provider order entry system, whereas falls were ascertained by incident reports. Negative binomial regression was used to compare the rate of falls following a drug change between medication classes. Further, we calculated the rate of falls for each of the 7 days before and 7 days after a psychotropic drug change. Results Forty-eight percent of residents were prescribed a new prescription or increased dose of a psychotropic drug during the study. The rate of falls was similar in the 7 days following a change to a SSRI versus non-SSRI antidepressant (11.9 versus 14.4 falls/1,000 person years; p = 0.58), a typical versus an atypical antipsychotic (25.4 versus 17.1 falls/1,000 person years; p = 0.10), or a short versus long acting benzodiazepine (15.2 versus 13.9 falls/1,000 person years; p = 0.23). Fall risk was highest on day 4 before the drug change (19.0 falls/1,000 person days), on the day of the drug change through 2 days after the drug change (17.6-20.3 falls/1,000 person days), and 5-6 days after the drug change (17.6-19.0 falls/1,000 person days). Conclusions In the nursing home, risk of falls was similar following a psychotropic drug change of any class. We observed higher fall risk in the days before, but mostly after the drug change. We recommend that nursing home residents be closely monitored following a psychotropic drug change in an effort to reduce falls. PMID:23432790

Fall-related injuries in a nursing home setting: is polypharmacy a risk factor?

PubMed

Baranzini, Federico; Diurni, Marcello; Ceccon, Francesca; Poloni, Nicola; Cazzamalli, Sara; Costantini, Chiara; Colli, Cristiano; Greco, Laura; Callegari, Camilla

2009-12-11

Polypharmacy is regarded as an important risk factor for fallingand several studies and meta-analyses have shown an increased fall risk in users of diuretics, type 1a antiarrhythmics, digoxin and psychotropic agents. In particular, recent evidence has shown that fall risk is associated with the use of polypharmacy regimens that include at least one established fall risk-increasing drug, rather than with polypharmacy per se. We studied the role of polypharmacy and the role of well-known fall risk-increasing drugs on the incidence of injurious falls. A retrospective observational study was carried out in a population of elderly nursing home residents. An unmatched, post-stratification design for age class, gender and length of stay was adopted. In all, 695 falls were recorded in 293 residents. 221 residents (75.4%) were female and 72 (24.6%) male, and 133 (45.4%) were recurrent fallers. 152 residents sustained no injuries when they fell, whereas injuries were sustained by 141: minor in 95 (67.4%) and major in 46 (32.6%). Only fall dynamics (p = 0.013) and drugs interaction between antiarrhythmic or antiparkinson class and polypharmacy regimen (> or =7 medications) seem to represent a risk association for injuries (p = 0.024; OR = 4.4; CI 95% 1.21 - 15.36). This work reinforces the importance of routine medication reviews, especially in residents exposed to polypharmacy regimens that include antiarrhythmics or antiparkinson drugs, in order to reduce the risk of fall-related injuries during nursing home stays.

A rational quantitative approach to determine the best dosing regimen for a target therapeutic effect: a unified formalism for antibiotic evaluation.

PubMed

Li, Jun; Nekka, Fahima

2013-02-21

The determination of an optimal dosing regimen is a critical step to enhance the drug efficacy and avoid toxicity. Rational dosing recommendations based on mathematical considerations are increasingly being adopted in the process of drug development and use. In this paper, we propose a quantitative approach to evaluate the efficacy of antibiotic agents. By integrating both pharmacokinetic (PK) and pharmacodynamic (PD) information, this approach gives rise to a unified formalism able to measure the cause-effect of dosing regimens. This new pharmaco-metric allows to cover a whole range of antibiotics, including the two well known concentration and time dependent classes, through the introduction of the Hill-dependency concept. As a direct fallout, our formalism opens a new path toward the bioequivalence evaluation in terms of PK and PD, which associates the in vivo drug concentration and the in vitro drug effect. Using this new approach, we succeeded to reveal unexpected, but relevant behaviors of drug performance when different drug regimens and drug classes are considered. Of particular notice, we found that the doses required to reach the same therapeutic effect, when scheduled differently, exhibit completely different tendencies for concentration and time dependent drugs. Moreover, we theoretically confirmed the previous experimental results of the superiority of the once daily regimen of aminoglycosides. The proposed methodology is appealing for its computational features and can easily be applicable to design fair clinical protocols or rationalize prescription decisions. Copyright © 2012 Elsevier Ltd. All rights reserved.

Various anti-motion sickness drugs and core body temperature changes.

PubMed

Cheung, Bob; Nakashima, Ann M; Hofer, Kevin D

2011-04-01

Blood flow changes and inactivity associated with motion sickness appear to exacerbate the rate of core temperature decrease during subsequent body cooling. We investigated the effects of various classes of anti-motion sickness drugs on core temperature changes. There were 12 healthy male and female subjects (20-35 yr old) who were given selected classes of anti-motion sickness drugs prior to vestibular Coriolis cross coupling induced by graded yaw rotation and periodic pitch-forward head movements in the sagittal plane. All subjects were then immersed in water at 18 degrees C for a maximum of 90 min or until their core temperature reached 35 degrees C. Double-blind randomized trials were administered, including a placebo, a non-immersion control with no drug, and six anti-motion sickness drugs: meclizine, dimenhydrinate, chlorpheniramine, promethazine + dexamphetamine, promethazine + caffeine, and scopolamine + dexamphetamine. A 7-d washout period was observed between trials. Core temperature and the severity of sickness were monitored throughout each trial. A repeated measures design was performed on the severity of sickness and core temperature changes prior to motion provocation, immediately after the motion sickness end point, and throughout the period of cold-water immersion. The most effective anti-motion sickness drugs, promethazine + dexamphetamine (with a sickness score/duration of 0.65 +/- 0.17) and scopolamine + dexamphetamine (with a sickness score/duration of 0.79 +/- 0.17), significantly attenuated the decrease in core temperature. The effect of this attenuation was lower in less effective drugs. Our results suggest that the two most effective anti-motion sickness drugs are also the most effective in attenuating the rate of core temperature decrease.

Predicting when biliary excretion of parent drug is a major route of elimination in humans.

PubMed

Hosey, Chelsea M; Broccatelli, Fabio; Benet, Leslie Z

2014-09-01

Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposition Classification System (BDDCS) characterizes significant routes of drug elimination, identifies potential transporter effects, and is useful in understanding drug-drug interactions. Class 1 and 2 drugs are primarily eliminated in humans via metabolism and will not exhibit significant biliary excretion of parent compound. In contrast, class 3 and 4 drugs are primarily excreted unchanged in the urine or bile. Here, we characterize the significant elimination route of 105 orally administered class 3 and 4 drugs. We introduce and validate a novel model, predicting significant biliary elimination using a simple classification scheme. The model is accurate for 83% of 30 drugs collected after model development. The model corroborates the observation that biliarily eliminated drugs have high molecular weights, while demonstrating the necessity of considering route of administration and extent of metabolism when predicting biliary excretion. Interestingly, a predictor of potential metabolism significantly improves predictions of major elimination routes of poorly metabolized drugs. This model successfully predicts the major elimination route for poorly permeable/poorly metabolized drugs and may be applied prior to human dosing.

[Drug-coated Balloon Angioplasty in Femoropopliteal Arteries - Is There a Class Effect?

PubMed

Teichgräber, Ulf Karl-Martin; Klumb, Christof

2017-10-01

Aim Percutaneous transluminal angioplasty (PTA) is a well-accepted method to re-establish patency in stenotic and reoccluded vessels. One tool to improve results may be to use paclitaxel drug-coated balloon (DCB) catheters. This systematic review investigates whether there is a class effect among different DCBs. Methods The primary endpoint was "Freedom from Target Lesion Revascularisation" (FfTLR) after 12 months. A systematic literature search was performed in PubMed and risk of bias was assessed of the included trials. Efficacy of DCB vs. POBA (plain old balloon angioplasty) in binary outcomes was investigated with relative risks and number needed to treat (NNT). Results Ten trials including 1835 patients and investigating six different DCB were identified. A high risk of bias was found in these studies. There was a lower Late Lumen Loss at six months and a higher FfTLR and primary patency at one year after DCB-treatment. However, results varied greatly with NNTs ranging from three to thirty-three. Overall, there were no differences in ABI- and Rutherford-Outcome as well as incidence of adverse events. Conclusion Tested DCBs were able to improve PTA results at one year. There were large differences in efficacy between different DCB. A class effect cannot be confirmed yet. There is a risk of overestimating the effect of DCBs due to the high risk of bias in the included trials. Georg Thieme Verlag KG Stuttgart · New York.

Benign prostatic hyperplasia (BPH) management in the primary care setting.

PubMed

Kapoor, Anil

2012-10-01

Benign prostate hyperplasia (BPH) occurs in up to 50% of men by age 50, and the incidence increases with age. This common clinical problem is diagnosed by history, including the International Prostate Symptom Score (IPSS) questionnaire, and physical examination by digital rectal examination (DRE). Initial management for BPH includes lifestyle modification, and smooth muscle relaxant alpha blocker therapy. Alpha blockers usually take effect quickly within 3-5 days, and have minimal side effects. Current commonly used alpha blockers include the selective alpha blockers tamsulosin (Flomax), alfusosin (Xatral), and silodosin (Rapaflo). For patients with larger prostates, the 5-alpha reductase inhibitor class (finasteride (Proscar) and dutasteride (Avodart)) work effectively to shrink prostate stroma resulting in improved voiding. The 5-ARI class of drugs, in addition to reducing prostate size, also reduce the need for future BPH-related surgery, and reduce the risk of future urinary retention. Drugs from the phosphodiesterase-5 (PDE-5) inhibitor class may now be considered for treating BPH. Once daily 5 mg tadalafil has been shown to improve BPH-related symptoms and is currently approved to treat patients with BPH. Referral to a urologist can be considered for patients with a rising prostate-specific antigen (PSA), especially while on 5-ARI, failure of urinary symptom control despite maximal medical therapy, suspicion of prostate cancer, hematuria, recurrent urinary infections, urinary retention, or renal failure. Currently the primary care physician is armed with multiple treatment options to effectively treat men with symptomatic BPH.

Effects of landiolol, an ultra-short-acting beta1-selective blocker, on electrical storm refractory to class III antiarrhythmic drugs.

PubMed

Miwa, Yosuke; Ikeda, Takanori; Mera, Hisaaki; Miyakoshi, Mutsumi; Hoshida, Kyoko; Yanagisawa, Ryoji; Ishiguro, Haruhisa; Tsukada, Takehiro; Abe, Atsuko; Yusu, Satoru; Yoshino, Hideaki

2010-05-01

Occasionally it is difficult to inhibit electrical storm (ES) with standard pharmacological treatment. In the present study the effect of landiolol, an ultra-short-acting beta(1)-selective blocker, on ES refractory to class III antiarrhythmic drugs was evaluated. The study group comprised 42 consecutive patients who developed ES for which intravenous class III antiarrhythmic drugs, such as amiodarone and nifekalant, were ineffective. Landiolol was administered intravenously with an initial dose of 2.5 microg x kg(-1) x min(-1), which was doubled if it was ineffective, up to a maximum dose of 80 microg x kg(-1) x min(-1). Landiolol inhibited ES in 33 patients (79%) at a mean dose of 7.5+/-12.2 microg x kg(-1) x min(-1). All patients in whom landiolol was ineffective died of arrhythmia. Of the 33 patients in whom landiolol was effective, 25 survived and were discharged (60% of all patients). Landiolol significantly decreased heart rate (P<0.0001), but did not affect blood pressure. Landiolol was not discontinued for adverse effects in any of the responders. Age, APACHE II score, and pH of arterial blood gas differed significantly between the responders and nonresponders. Landiolol is useful as a life-saving drug for class III antiarrhythmic drug-resistant ES. The main mechanism of ES refractory to class III antiarrhythmic drugs could be abnormal automaticity but not reentry.

Monitoring drug safety in Astrakhan, Russia.

PubMed

Kirilochev, O O; Dorfman, I P; Umerova, A R

2015-01-01

The problem of drug safety will never disappear as new drugs are delivered in increasing numbers. They have high biological activity and adverse drug reactions (ADR) [1]. Currently, adverse drug reactions are the fourth leading cause of death for patients.There are databases of ADRs (Vigibase, Eudravigilance), but we know that ADR manifestations may vary in different countries and regions, due to the demographic, genetic characteristics of the population and the quality of manufactured drugs [2]. In this regard, the study of the ADR at the regional level is very relevant. We aimed to optimize the work on monitoring drug safety in Astrakhan region through pharmacoepidemiological research and development of computer database for analysis of information coming to the center for drug safety monitoring (CDSM). 1. To study the rates of ADR reporting and the structure in the Astrakhan region at the regional center for drug safety monitoring.2. To analyze the outcomes of registered adverse drug reactions.3. To determine the causality of adverse drug reactions.4. To identify reports on the ineffectiveness of drugs.5. To analyze the rates and structure of ADR reporting for drugs prescribed off-label. We studied spontaneous adverse event reporting. The adverse event reports received by the regional CDSM for the period of 2010 to 2014 was analyzed. The groups of drugs were categorized according by Anatomical Therapeutic Chemical classification system. The data were analyzed using Microsoft Office Excel. The likelihood of whether an ADR was actually due to the drugs was assessed with the Naranjo algorithm. The analysis of the results showed that the establishment of the CDSM in September 2010, contributed to improvement of drug safety monitoring in health facilities of the region. Noteworthy was the increasing the number of adverse event reports in 2011 and 2012, compared with the beginning of the year 2010, when the CDSM was not yet functioning.The decrease of adverse event reporting in 2013 and 2014 was due to the fact that doctors in the region had access to better ADR drug information. Along with the increasing number of adverse event reporting we also noted the increase in the number of health facilities that monitored drug safety. The number of health facilities that reported, doubled from 2010 to 2014. We observed the increase in the number of adverse event reports submitted by pharmaceutical companies. General anti-infective drugs for systemic use (class J) were the most common cause of all registered ADRs (44%). Drugs for treatment of tuberculosis (group J04A) were the cause of adverse drug reactions in 34% of reports. ADRs associated with drugs used for treating diseases of cardiovascular system accounted for 16% of case-reports; drugs belonging to the group of Alimentary tract and metabolism (class A) and to the group of Nervous System (class A) were reported to cause ADRs in 10% of cases each. Type A adverse drug reactions, which are usually a consequence of a drug's primary pharmacological effect, were detected in 45% of cases. These reactions were often registered for drugs affecting cardiovascular system (class C), nervous system (class N), dlood and blood forming organs (class B). Type B ADRs were reported in 54% of cases. These were "idiosyncratic" reactions, which could not be predicted on the basis of the drug's main pharmacological action, were not dose-related and were severe [3]. The most frequent cause of type B adverse drug reactions was the General anti-infective medicines for systemic use (Class J). The fatality rate associated with ADRs was 0.3%. Type A adverse drug reactions resulted in death in 38% of cases. Type B ADR (anaphylactic shock) accounted for 62% of the patient's deaths. The Naranjo scale determined the causality of ADRs. The "definite" ADRs were detected in 14% of reports, "probable" - in 47%, and "possible" - in 39% of cases. The rate of reporting associated with ineffectiveness of drugs amounted to 1%. Most often the lack of therapeutic effect was reported in patients receiving drugs of class C (Cardiovascular system, 31% of all cases of inefficiency of drugs). These drugs were used in accordance with their official instructions for use. The proportion of ADR reports for drugs prescribed off-label was 1.4%. The results substantiate the need to continue drug safety monitoring in the Astrakhan region. We plan to further improve the software for ADR analysis.

Drug-drug interactions and adverse drug reactions in polypharmacy among older adults: an integrative review 1

PubMed Central

Rodrigues, Maria Cristina Soares; de Oliveira, Cesar

2016-01-01

ABSTRACT Objective: to identify and summarize studies examining both drug-drug interactions (DDI) and adverse drug reactions (ADR) in older adults polymedicated. Methods: an integrative review of studies published from January 2008 to December 2013, according to inclusion and exclusion criteria, in MEDLINE and EMBASE electronic databases were performed. Results: forty-seven full-text studies including 14,624,492 older adults (≥ 60 years) were analyzed: 24 (51.1%) concerning ADR, 14 (29.8%) DDI, and 9 studies (19.1%) investigating both DDI and ADR. We found a variety of methodological designs. The reviewed studies reinforced that polypharmacy is a multifactorial process, and predictors and inappropriate prescribing are associated with negative health outcomes, as increasing the frequency and types of ADRs and DDIs involving different drug classes, moreover, some studies show the most successful interventions to optimize prescribing. Conclusions: DDI and ADR among older adults continue to be a significant issue in the worldwide. The findings from the studies included in this integrative review, added to the previous reviews, can contribute to the improvement of advanced practices in geriatric nursing, to promote the safety of older patients in polypharmacy. However, more research is needed to elucidate gaps. PMID:27598380

Hepatic transporter drug-drug interactions: an evaluation of approaches and methodologies.

PubMed

Williamson, Beth; Riley, Robert J

2017-12-01

Drug-drug interactions (DDIs) continue to account for 5% of hospital admissions and therefore remain a major regulatory concern. Effective, quantitative prediction of DDIs will reduce unexpected clinical findings and encourage projects to frontload DDI investigations rather than concentrating on risk management ('manage the baggage') later in drug development. A key challenge in DDI prediction is the discrepancies between reported models. Areas covered: The current synopsis focuses on four recent influential publications on hepatic drug transporter DDIs using static models that tackle interactions with individual transporters and in combination with other drug transporters and metabolising enzymes. These models vary in their assumptions (including input parameters), transparency, reproducibility and complexity. In this review, these facets are compared and contrasted with recommendations made as to their application. Expert opinion: Over the past decade, static models have evolved from simple [I]/k i models to incorporate victim and perpetrator disposition mechanisms including the absorption rate constant, the fraction of the drug metabolised/eliminated and/or clearance concepts. Nonetheless, models that comprise additional parameters and complexity do not necessarily out-perform simpler models with fewer inputs. Further, consideration of the property space to exploit some drug target classes has also highlighted the fine balance required between frontloading and back-loading studies to design out or 'manage the baggage'.

Psychotropic drugs and risk of motor vehicle accidents: a population-based case-control study

PubMed Central

Chang, Chia-Ming; Wu, Erin Chia-Hsuan; Chen, Chuan-Yu; Wu, Kuan-Yi; Liang, Hsin-Yi; Chau, Yeuk-Lun; Wu, Chi-Shin; Lin, Keh-Ming; Tsai, Hui-Ju

2013-01-01

Aim To examine comprehensively the relationship between exposure to four classes of psychotropic drugs including antipsychotics, antidepressants, benzodiazepines (BZDs) and Z-drugs, and motor vehicle accidents (MVAs). Method The authors conducted a matched case-control study of 5183 subjects with MVAs and 31 093 matched controls, identified from the claims records of outpatient service visits during the period from 2000 to 2009. Inclusion criteria were defined as subjects aged equal to or more than 18 years and involved in MVAs. Conditional logistic regressions with covariates adjustment (including urbanity, psychiatric and non-psychiatric outpatient visits and Charlson comorbidity score) were applied to examine the effect of four classes of psychotropic drugs on MVAs. Results Significant increased risk of MVAs was found in subjects taking antidepressants within 1 month (adjusted odds ratio (AOR) 1.73, 95% confidence interval (CI) 1.34, 2.22), 1 week (AOR 1.71, 95% CI 1.29, 2.26), and 1 day (AOR 1.70, 95% CI 1.26, 2.29) before MVAs occurred. Similar results were observed in subjects taking benzodiazepines (BZDs) (AOR 1.56, 95% CI 1.38, 1.75 for 1 month; AOR 1.64, 95% CI 1.43, 1.88 for 1 week, and AOR 1.62, 95% CI 1.39, 1.88 for 1 day) and Z-drugs (AOR 1.42, 95% CI 1.14, 1.76 for 1 month, AOR 1.37, 95% CI 1.06, 1.75 for 1 week, AOR 1.34, 95% CI 1.03, 1.75 for 1 day), but not antipsychotics. Moreover, significant dose effects of antidepressants (equal to or more than 0.6–1.0 DDD), BZDs (equal to or more than 0.1–0.5 DDD) and Z-drugs (more than 1 DDD) were observed, respectively, on the risk of experiencing an MVA. Conclusion Taken together, subjects taking antidepressants, BZDs and Z-drugs, separately, should be particularly cautioned for their increasing risk of MVAs. PMID:22971090

Nonimaging detectors in drug development and approval.

PubMed

Wagner, H N

2001-07-01

Regulatory applications for imaging biomarkers will expand in proportion to the validation of specific parameters as they apply to individual questions in the management of disease. This validation is likely to be applicable only to a particular class of drug or a single mechanism of action. Awareness among the world's regulatory authorities of the potential for these emerging technologies is high, but so is the cost to the sponsor (including the logistics of including images in a dossier), and therefore the pharmaceutical industry must evaluate carefully the potential benefit of each technology for its drug development programs, just as the authorities must consider carefully the extent to which the method is valid for the use to which the applicant has put it. For well-characterized tracer systems, it may be possible to design inexpensive cameras that make rapid assessments.

Changing epidemiology of intentional antidepressant drug overdose in Victoria, Australia.

PubMed

Wong, Anselm; Taylor, David McD; Ashby, Karen; Robinson, Jeff

2010-08-01

To determine the epidemiology of intentional antidepressant drug overdose (OD), over an extended time period, in Victoria, Australia. Retrospective epidemiological study of all cases reported to the Victorian Emergency Minimum Dataset (VEMD) January 1998 to December 2007 and calls to the Victorian Poisons Information Centre (VPIC) June 2005 to September 2008. 5467 VEMD cases were analysed. 3169 (57.9%) cases involved selective serotonin reuptake inhibitors (SSRIs) and 1149 (21%) involved tricyclic antidepressants (TCAs). Sertraline (1252, 22.9% cases) was the most common drug. During 2001, the peak year of OD, there were 8.8 OD/100 000 population in the SSRI group and 3.8 OD/100 000 population in the TCA group. Trends over the study period showed increasing SSRI and 'other' newer antidepressant prescription rates and decreases for TCA and monoamine oxidase inhibitors (MAOI). However, the risks of OD in all drug classes were similar and OD/100 000 prescriptions trended downwards for all drug classes over time. 1833 VPIC calls were analysed. Calls relating to SSRIs were the most common yet SSRI OD was associated with significantly fewer symptoms (p < 0.001) and fewer patients with Poisoning Severity Score classifications of moderate or severe (p < 0.01). Antidepressant OD patterns are changing. Antidepressant OD incidence is following prescribing trends. The risk of OD is similar for all drug classes. Absolute numbers of OD and OD/100 000 prescriptions are decreasing for all drug classes.

Biologic agents for IBD: practical insights.

PubMed

Danese, Silvio; Vuitton, Lucine; Peyrin-Biroulet, Laurent

2015-09-01

Six biologic agents are currently approved for the treatment of IBD: four anti-TNF agents (infliximab, adalimumab, golimumab and certolizumab pegol) and two anti-integrin agents (natalizumab and vedolizumab). In Crohn's disease and ulcerative colitis refractory to standard medications, treatment choice among available biologic agents can be challenging. Several parameters should be taken into account to help physicians through the decision-making process, including the comparative effectiveness and long-term safety profile, availability and labelling in the prescriber's country, international guidelines, and cost, as well as patient preferences (such as the route of administration). Herein, we provide practical insights on the use of biologic agents in IBD. The results of head-to-head trials between biologic agents are eagerly awaited to guide decision-making regarding the choice of first-line biologic agents and to determine whether switching within the same drug class or swapping (switching out of the drug class) is preferable after primary or secondary loss of response to the first biologic agent. In the near future, treatment algorithms might evolve with the launch of new drugs (such as ustekinumab, tofacitinib and etrolizumab) and the increased use of biosimilars.

Patient-centered Outcomes with Concomitant Use of Proton Pump Inhibitors and Other Drugs.

PubMed

Shamliyan, Tatyana A; Middleton, Maria; Borst, Clarissa

2017-02-01

We performed a systematic review of patient-centered outcomes after the concomitant use of proton pump inhibitors (PPIs) and other drugs. We searched 4 databases in July 2016 to find studies that reported mortality and morbidity after the concomitant use of PPIs and other drugs. We conducted direct meta-analyses using a random-effects model and graded the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation working group approach. We included data from 17 systematic reviews and meta-analyses, 16 randomized controlled trials, and 16 observational studies that examined the concomitant use of PPIs with medications from 10 drug classes. Low-quality evidence suggests that the use of PPIs is associated with greater morbidity when administered with antiplatelet drugs, bisphosphonates, antibiotics, anticoagulants, metformin, mycophenolate mofetil, or nelfinavir. Concomitant PPIs reduce drug-induced gastrointestinal bleeding and are associated with greater docetaxel and cisplatin response rates in patients with metastatic breast cancer. For demonstrated statistically significant relative risks and benefits from concomitant PPIs, the magnitudes of the effects are small, with <100 attributable events per 1000 patients treated, and the effects are inconsistent among specific drugs. Among individual PPIs, the concomitant use of pantoprazole or esomeprazole, but not omeprazole or lansoprazole, is associated with an increased risk for all-cause mortality, nonfatal myocardial infarction, or stroke. Clopidogrel is associated with a greater risk for myocardial infarction compared with prasugrel. Conflicting results between randomized controlled trials and observational studies and high risk for bias in the body of evidence lessened our confidence in the results. Available evidence suggests a greater risk for adverse patient outcomes after the concomitant use of PPIs and medications from 9 drug classes and warns against inappropriate drug combinations. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Anticancer Properties of Distinct Antimalarial Drug Classes

PubMed Central

Hooft van Huijsduijnen, Rob; Guy, R. Kiplin; Chibale, Kelly; Haynes, Richard K.; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A.; Vennerstrom, Jonathan L.; Yuthavong, Yongyuth; Wells, Timothy N. C.

2013-01-01

We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings. PMID:24391728

Maintaining Fluoroquinolone Class Efficacy: Review of Influencing Factors

PubMed Central

2003-01-01

Previous experience with antimicrobial resistance has emphasized the importance of appropriate stewardship of these pharmacotherapeutic agents. The introduction of fluoroquinolones provided potent new drugs directed primarily against gram-negative pathogens, while the newer members of this class demonstrate more activity against gram-positive species, including Streptococcus pneumoniae. Although these agents are clinically effective against a broad range of infectious agents, emergence of resistance and associated clinical failures have prompted reexamination of their use. Appropriate use revolves around two key objectives: 1) only prescribing antimicrobial therapy when it is beneficial and 2) using the agents(s) with optimal activity against the expected pathogens(s). Pharmacodynamic principles and properties can be applied to achieve the latter objective when prescribing agents belonging to the fluoroquinolone class. A focused approach emphasizing “correct-spectrum” coverage may reduce development of antimicrobial resistance and maintain class efficacy. PMID:12533274

Analytical method for fast screening and confirmation of multi-class veterinary drug residues in fish and shrimp by LC-MS/MS.

PubMed

Kim, Junghyun; Suh, Joon Hyuk; Cho, Hyun-Deok; Kang, Wonjae; Choi, Yong Seok; Han, Sang Beom

2016-01-01

A multi-class, multi-residue analytical method based on LC-MS/MS detection was developed for the screening and confirmation of 28 veterinary drug and metabolite residues in flatfish, shrimp and eel. The chosen veterinary drugs are prohibited or unauthorised compounds in Korea, which were categorised into various chemical classes including nitroimidazoles, benzimidazoles, sulfones, quinolones, macrolides, phenothiazines, pyrethroids and others. To achieve fast and simultaneous extraction of various analytes, a simple and generic liquid extraction procedure using EDTA-ammonium acetate buffer and acetonitrile, without further clean-up steps, was applied to sample preparation. The final extracts were analysed by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The method was validated for each compound in each matrix at three different concentrations (5, 10 and 20 ng g(-1)) in accordance with Codex guidelines (CAC/GL 71-2009). For most compounds, the recoveries were in the range of 60-110%, and precision, expressed as the relative standard deviation (RSD), was in the range of 5-15%. The detection capabilities (CCβs) were below or equal to 5 ng g(-1), which indicates that the developed method is sufficient to detect illegal fishery products containing the target compounds above the residue limit (10 ng g(-1)) of the new regulatory system (Positive List System - PLS).

Best antihypertensive strategies to improve blood pressure control in Latin America: position of the Latin American Society of Hypertension.

PubMed

Coca, Antonio; López-Jaramillo, Patricio; Thomopoulos, Costas; Zanchetti, Alberto

2018-02-01

: Evidence from randomized trials has shown that effective treatment with blood pressure (BP)-lowering medications reduces the risk of cardiovascular morbidity and mortality in patients with hypertension. Therefore, hypertension control and prevention of subsequent morbidity and mortality should be achievable for all patients worldwide. However, many people in Latin America remain undiagnosed, untreated or have inadequately controlled BP, even where this is access to health systems. Barriers to hypertension control in low-income countries include difficulties in transportation to health services; inappropriate opening hours; difficulties in making clinic appointments; inaccessible healthcare facilities, lack of insurance and high treatment costs. After a review of the best recent available evidence on the efficacy and tolerability of antihypertensive drugs and strategies, the Latin American Society of Hypertension experts conclude that all major classes of BP-lowering drugs be available to hypertensive patients, because all have been shown to reduce major cardiovascular outcomes compared with placebo, and have shown to be associated with a comparable risk of major cardiovascular events and mortality when compared between classes. Within each class, no evidence whatsoever is available to show that one compound is more effective than another in outcome prevention. Therefore, the selection of individual drugs may be based mainly on the capacity of Latin American governments to obtain the lowest prices of the different molecules manufactured by companies with high production quality standards.

Effect of cyclodextrin complexation on the aqueous solubility and solubility/dose ratio of praziquantel.

PubMed

Maragos, Stratos; Archontaki, Helen; Macheras, Panos; Valsami, Georgia

2009-01-01

Praziquantel (PZQ), the primary drug of choice in the treatment of schistosomiasis, is a highly lipophilic drug that possesses high permeability and low aqueous solubility and is, therefore, classified as a Class II drug according to the Biopharmaceutics Classification System (BCS). In this work, beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were used in order to determine whether increasing the aqueous solubility of a drug by complexation with CDs, a BCS-Class II compound like PZQ could behave as BCS-Class I (highly soluble/highly permeable) drug. Phase solubility and the kneading and lyophilization techniques were used for inclusion complex preparation; solubility was determined by UV spectroscopy. The ability of the water soluble polymer polyvinylpyrolidone (PVP) to increase the complexation and solubilization efficiency of beta-CD and HP-beta-CD for PZQ was examined. Results showed significant improvement of PZQ solubility in the presence of both cyclodextrins but no additional effect in the presence of PVP. The solubility/dose ratios values of PZQ-cyclodextrin complexes calculated considering the low (150 mg) and the high dose (600 mg) of PZQ, used in practice, indicate that PZQ complexation with CDs may result in drug dosage forms that would behave as a BCS-Class I depending on the administered dose.

Inkjet Printing of Drug-Loaded Mesoporous Silica Nanoparticles-A Platform for Drug Development.

PubMed

Wickström, Henrika; Hilgert, Ellen; Nyman, Johan O; Desai, Diti; Şen Karaman, Didem; de Beer, Thomas; Sandler, Niklas; Rosenholm, Jessica M

2017-11-21

Mesoporous silica nanoparticles (MSNs) have shown great potential in improving drug delivery of poorly water soluble (BCS class II, IV) and poorly permeable (BCS class III, IV) drugs, as well as facilitating successful delivery of unstable compounds. The nanoparticle technology would allow improved treatment by reducing adverse reactions of currently approved drugs and possibly reintroducing previously discarded compounds from the drug development pipeline. This study aims to highlight important aspects in mesoporous silica nanoparticle (MSN) ink formulation development for digital inkjet printing technology and to advice on choosing a method (2D/3D) for nanoparticle print deposit characterization. The results show that both unfunctionalized and polyethyeleneimine (PEI) surface functionalized MSNs, as well as drug-free and drug-loaded MSN-PEI suspensions, can be successfully inkjet-printed. Furthermore, the model BCS class IV drug remained incorporated in the MSNs and the suspension remained physically stable during the processing time and steps. This proof-of-concept study suggests that inkjet printing technology would be a flexible deposition method of pharmaceutical MSN suspensions to generate patterns according to predefined designs. The concept could be utilized as a versatile drug screening platform in the future due to the possibility of accurately depositing controlled volumes of MSN suspensions on various materials.

Nephrogenic systemic fibrosis and class labeling of gadolinium-based contrast agents by the Food and Drug Administration.

PubMed

Yang, Lucie; Krefting, Ira; Gorovets, Alex; Marzella, Louis; Kaiser, James; Boucher, Robert; Rieves, Dwaine

2012-10-01

In 2007, the Food and Drug Administration requested that manufacturers of all approved gadolinium-based contrast agents (GBCAs), drugs widely used in magnetic resonance imaging, use nearly identical text in their product labeling to describe the risk of nephrogenic systemic fibrosis (NSF). Accumulating information about NSF risks led to revision of the labeling text for all of these drugs in 2010. The present report summarizes the basis and purpose of this class-labeling approach and describes some of the related challenges, given the evolutionary nature of the NSF risk evidence. The class-labeling approach for presentation of product risk is designed to decrease the occurrence of NSF and to enhance the safe use of GBCAs in radiologic practice. © RSNA, 2012.

Effect of safety issues with HIV drugs on the approval process of other drugs in the same class: an analysis of European Public Assessment Reports.

PubMed

Arnardottir, Arna H; Haaijer-Ruskamp, Flora M; Straus, Sabine M J; de Graeff, Pieter A; Mol, Peter G M

2011-11-01

Knowledge on the safety of new medicines is limited at the time of market entry. Nearly half of all drugs used to treat HIV registered in the EU required ≥1 Direct Healthcare Professional Communication (DHPC) in the past 10 years for safety issues identified post-approval. The aim was to evaluate the extent to which regulators and industry have addressed the risk of safety issues for HIV drugs based on prior experience with other drugs in the same class and whether doing so impacts development time of these drugs. HIV drugs receiving ≥1 DHPC in the Netherlands between January 1999 and December 2008 were identified. Each drug with a DHPC ('index' drug) was paired with subsequently approved HIV drug(s) in the same class (Anatomical Therapeutic Chemical [ATC] 4th level) ['follow-on' drugs]. Characteristics of safety issues were extracted from the DHPCs of the 'index' drugs. European Public Assessment Reports (EPARs) were reviewed regarding whether the safety issues had been considered during development and approval. Consideration of previously identified safety issues in 'follow-on' drug applications was assessed regarding attention paid to adverse drug reaction (ADR) symptoms in pre-marketing studies, Summary of Product Characteristics (SmPC) and postmarketing commitments, and whether size of the safety population was in accordance with Regulatory guidelines. 'Index' drugs were also paired with drugs in the same class already on the market ('older' drugs). For 'older' drugs, we identified whether the safety issue led to appropriate changes in the current SmPC (January 2011) compared with the SmPC at the time of marketing authorization. Clinical development time was assessed using time from first patent application to market authorization as proxy, and comparison was made between 'index' and 'follow-on' drugs. For 9 (43%) of the 21 centrally authorized HIV drugs, 11 serious safety issues that required a DHPC were identified. Two drugs were excluded from our analysis (DHPCs related to contamination/medication error). Six 'index' drugs were paired, each with one to six 'follow-on' drugs. Three concerned drug-drug interactions (DDIs); the other three were intracranial haemorrhage, neuromuscular weakness and severe skin/hepatic reactions. All but one 'follow-on' drug had information in the EPAR on that specific ADR (i.e. attention was paid to the ADR). The DDIs were addressed in pre-marketing studies and/or the SmPC. Two of the other ADRs were addressed by postmarketing surveillance commitments; intracranial haemorrhage was not addressed. Three safety issues for two 'index' drugs could not be paired with a 'follow-on' drug as no drug in the same class was approved after the corresponding DHPCs were issued. Five of the nine safety issues were added to at least one of the current SmPCs for the 'older' drugs already on the market at the time of DHPC issue. Two safety issues were already in the SmPC of the 'older' drugs at time of market approval and two were not introduced into the SmPC of 'older' drugs. Population size to assess short-term safety complied with the guidelines for four 'index', seven 'follow-on' and three 'older' drugs; population size to assess long-term safety complied for one, three and two drugs, respectively. For five drugs, EPARs did not provide adequate information on population size. No statistically significant difference in development time between 'index' and 'follow-on' drugs was found. Generally, safety issues were taken into account in the approval process of other drugs in the class. The approaches were different and determined by the nature of the ADR. Taking safety issues into account in the approval process did not seem to impact on the time taken to perform the pre-approval clinical programme.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals.

PubMed

Rajabalaya, Rajan; Musa, Muhammad Nuh; Kifli, Nurolaini; David, Sheba R

2017-01-01

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals

PubMed Central

Rajabalaya, Rajan; Musa, Muhammad Nuh; Kifli, Nurolaini; David, Sheba R

2017-01-01

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations. PMID:28243062

Supersaturating drug delivery systems: effect of hydrophilic cyclodextrins and other excipients on the formation and stabilization of supersaturated drug solutions.

PubMed

Brewster, M E; Vandecruys, R; Verreck, G; Peeters, J

2008-03-01

Supersaturating drug delivery systems (SDDS) utilize two important design elements in their preparation including converting the drug of interest into a high energy state or other rapidly dissolving form to facilitate the formation of supersaturated drug solutions and providing a means for stabilizing the formed supersaturated solution such that significant drug absorption is possible from the gastrointestinal tract. This has been referred to as a "spring" and "parachute" approach. The current effort is designed to assess materials which may affect properties in SDDS. To this end, a series of excipients was tested in a co-solvent/solvent quench method to assess their ability to attain and maintain supersaturation for a group of 14 drug development candidates. The approach focussed on hydrophilic cyclodextrins including hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutyl-beta-cyclodextrin (SBEbetaCD). Various rheological polymers and surfactants were also included in the study. Consistent with previous investigations, the pharmaceutical polymers, as a class, had minimal effects on the extent of supersaturation but tended to be good stabilizers while the surfactants tended to provide for the greatest degree of supersaturation but the formed systems were poorly stable. This study found that hydrophilic cyclodextrins, especially SBEbetaCD, gave superior results in terms of attaining and maintaining supersaturation. A knowledge of the behavior and performance of excipients in this context can be useful in designing solid oral dosage forms for difficult-to-formulate drugs and drug candidates.

In silico prediction of drug dissolution and absorption with variation in intestinal pH for BCS class II weak acid drugs: ibuprofen and ketoprofen.

PubMed

Tsume, Yasuhiro; Langguth, Peter; Garcia-Arieta, Alfredo; Amidon, Gordon L

2012-10-01

The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS class III and BCS class II have been proposed, in particular, BCS class II weak acids. However, a discrepancy between the in vivo BE results and in vitro dissolution results for BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH of 6.0. Further the experimental dissolution of ibuprofen tablets in a low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol l (-1) /pH) was dramatically reduced compared with the dissolution in SIF (the average buffer capacity 12.6 mmol l (-1) /pH). Thus these predictions for the oral absorption of BCS class II acids indicate that the absorption patterns depend largely on the intestinal pH and buffer strength and must be considered carefully for a bioequivalence test. Simulation software may be a very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. Copyright © 2012 John Wiley & Sons, Ltd.

In Silico Prediction of Drug Dissolution and Absorption with variation in Intestinal pH for BCS Class II Weak Acid Drugs: Ibuprofen and Ketoprofen§

PubMed Central

Tsume, Yasuhiro; Langguth, Peter; Garcia-Arieta, Alfredo; Amidon, Gordon L.

2012-01-01

The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS Class III and BCS class II have been proposed, particularly, BCS class II weak acids. However, a discrepancy between the in vivo- BE results and in vitro- dissolution results for a BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH=6.0. Further the experimental dissolution of ibuprofen tablets in the low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol L-1/pH) was dramatically reduced compared to the dissolution in SIF (the average buffer capacity 12.6 mmol L -1/pH). Thus these predictions for oral absorption of BCS class II acids indicate that the absorption patterns largely depend on the intestinal pH and buffer strength and must be carefully considered for a bioequivalence test. Simulation software may be very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. PMID:22815122

Assessing measurement error in surveys using latent class analysis: application to self-reported illicit drug use in data from the Iranian Mental Health Survey.

PubMed

Khalagi, Kazem; Mansournia, Mohammad Ali; Rahimi-Movaghar, Afarin; Nourijelyani, Keramat; Amin-Esmaeili, Masoumeh; Hajebi, Ahmad; Sharif, Vandad; Radgoodarzi, Reza; Hefazi, Mitra; Motevalian, Abbas

2016-01-01

Latent class analysis (LCA) is a method of assessing and correcting measurement error in surveys. The local independence assumption in LCA assumes that indicators are independent from each other condition on the latent variable. Violation of this assumption leads to unreliable results. We explored this issue by using LCA to estimate the prevalence of illicit drug use in the Iranian Mental Health Survey. The following three indicators were included in the LCA models: five or more instances of using any illicit drug in the past 12 months (indicator A), any use of any illicit drug in the past 12 months (indicator B), and the self-perceived need of treatment services or having received treatment for a substance use disorder in the past 12 months (indicator C). Gender was also used in all LCA models as a grouping variable. One LCA model using indicators A and B, as well as 10 different LCA models using indicators A, B, and C, were fitted to the data. The three models that had the best fit to the data included the following correlations between indicators: (AC and AB), (AC), and (AC, BC, and AB). The estimated prevalence of illicit drug use based on these three models was 28.9%, 6.2% and 42.2%, respectively. None of these models completely controlled for violation of the local independence assumption. In order to perform unbiased estimations using the LCA approach, the factors violating the local independence assumption (behaviorally correlated error, bivocality, and latent heterogeneity) should be completely taken into account in all models using well-known methods.

An accurate and precise representation of drug ingredients.

PubMed

Hanna, Josh; Bian, Jiang; Hogan, William R

2016-01-01

In previous work, we built the Drug Ontology (DrOn) to support comparative effectiveness research use cases. Here, we have updated our representation of ingredients to include both active ingredients (and their strengths) and excipients. Our update had three primary lines of work: 1) analysing and extracting excipients, 2) analysing and extracting strength information for active ingredients, and 3) representing the binding of active ingredients to cytochrome P450 isoenzymes as substrates and inhibitors of those enzymes. To properly differentiate between excipients and active ingredients, we conducted an ontological analysis of the roles that various ingredients, including excipients, have in drug products. We used the value specification model of the Ontology for Biomedical Investigations to represent strengths of active ingredients and then analyzed RxNorm to extract excipient and strength information and modeled them according to the results of our analysis. We also analyzed and defined dispositions of molecules used in aggregate as active ingredients to bind cytochrome P450 isoenzymes. Our analysis of excipients led to 17 new classes representing the various roles that excipients can bear. We then extracted excipients from RxNorm and added them to DrOn for branded drugs. We found excipients for 5,743 branded drugs, covering ~27% of the 21,191 branded drugs in DrOn. Our analysis of active ingredients resulted in another new class, active ingredient role. We also extracted strengths for all types of tablets, capsules, and caplets, resulting in strengths for 5,782 drug forms, covering ~41% of the 14,035 total drug forms and accounting for ~97 % of the 5,970 tablets, capsules, and caplets in DrOn. We represented binding-as-substrate and binding-as-inhibitor dispositions to two cytochrome P450 (CYP) isoenzymes (CYP2C19 and CYP2D6) and linked these dispositions to 65 compounds. It is now possible to query DrOn automatically for all drug products that contain active ingredients whose molecular grains inhibit or are metabolized by a particular CYP isoenzyme. DrOn is open source and is available at http://purl.obolibrary.org/obo/dron.owl.

Social network analysis of duplicative prescriptions: One-month analysis of medical facilities in Japan.

PubMed

Takahashi, Yoshimitsu; Ishizaki, Tatsuro; Nakayama, Takeo; Kawachi, Ichiro

2016-03-01

Duplicative prescriptions refer to situations in which patients receive medications for the same condition from two or more sources. Health officials in Japan have expressed concern about medical "waste" resulting from this practices. We sought to conduct descriptive analysis of duplicative prescriptions using social network analysis and to report their prevalence across ages. We analyzed a health insurance claims database including 1.24 million people from December 2012. Through social network analysis, we examined the duplicative prescription networks, representing each medical facility as nodes, and individual prescriptions for patients as edges. The prevalence of duplicative prescription for any drug class was strongly correlated with its frequency of prescription (r=0.90). Among patients aged 0-19, cough and colds drugs showed the highest prevalence of duplicative prescriptions (10.8%). Among people aged 65 and over, antihypertensive drugs had the highest frequency of prescriptions, but the prevalence of duplicative prescriptions was low (0.2-0.3%). Social network analysis revealed clusters of facilities connected via duplicative prescriptions, e.g., psychotropic drugs showed clustering due to a few patients receiving drugs from 10 or more facilities. Overall, the prevalence of duplicative prescriptions was quite low - less than 10% - although the extent of the problem varied by drug class and age group. Our approach illustrates the potential utility of using a social network approach to understand these practices. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Adverse drug reactions and drug–drug interactions with over-the-counter NSAIDs

PubMed Central

Moore, Nicholas; Pollack, Charles; Butkerait, Paul

2015-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug–drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available. PMID:26203254

[HIV drug resistance in ART-experienced patients in Cali, Colombia, 2008-2010].

PubMed

Martínez-Cajas, Jorge L; Mueses-Marín, Héctor F; Galindo-Orrego, Pablo; Agudelo, Juan F; Galindo-Quintero, Jaime

2013-01-01

Little has been published in Colombia on HIV drug resistance in patients taking antiretroviral treatment (ART). Currently, the Colombian guidelines do not recommend the use of genotypic antiretroviral resistance tests (GART) for treatment-naive patients or for those experiencing a first therapeutic failure. To determine the frequency of relevant resistance mutations and the degree of susceptibility/ resistance of HIV to antiretroviral drugs (ARVs) in ART-experienced patients. A non-random sample of 170 ART-experienced HIV patients with virologic failure and who underwent GART was recruited. A study of HIV drug resistance was carried out in two groups of patients: one group that underwent early GART and the other group that received late GART testing. The most frequent type of resistance affected the non-nucleoside class (76%). The late-GART group had higher risk of nucleoside analog and protease inhibitor drug resistance, a higher number of resistance mutations and more complex mutational profiles than the early-GART group. A high cross resistance level (30%) was found in the nucleoside analog class. The least affected medications were tenofovir and darunavir. Our results suggest that performing GART late is associated with levels of ARV resistance that could restrict the use of an important number of essential ARV in subsequent regimens. There is a need to revise the current recommendations to include GART prior to start of treatment and after the first virologic failure.

In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans.

PubMed

Chedik, Lisa; Mias-Lucquin, Dominique; Bruyere, Arnaud; Fardel, Olivier

2017-06-30

Intestinal absorption and brain permeation constitute key parameters of toxicokinetics for pesticides, conditioning their toxicity, including neurotoxicity. However, they remain poorly characterized in humans. The present study was therefore designed to evaluate human intestine and brain permeation for a large set of pesticides ( n = 338) belonging to various chemical classes, using an in silico graphical BOILED-Egg/SwissADME online method based on lipophilicity and polarity that was initially developed for drugs. A high percentage of the pesticides (81.4%) was predicted to exhibit high intestinal absorption, with a high accuracy (96%), whereas a lower, but substantial, percentage (38.5%) displayed brain permeation. Among the pesticide classes, organochlorines ( n = 30) constitute the class with the lowest percentage of intestine-permeant members (40%), whereas that of the organophosphorus compounds ( n = 99) has the lowest percentage of brain-permeant chemicals (9%). The predictions of the permeations for the pesticides were additionally shown to be significantly associated with various molecular descriptors well-known to discriminate between permeant and non-permeant drugs. Overall, our in silico data suggest that human exposure to pesticides through the oral way is likely to result in an intake of these dietary contaminants for most of them and brain permeation for some of them, thus supporting the idea that they have toxic effects on human health, including neurotoxic effects.

In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans

PubMed Central

Chedik, Lisa; Mias-Lucquin, Dominique; Bruyere, Arnaud; Fardel, Olivier

2017-01-01

Intestinal absorption and brain permeation constitute key parameters of toxicokinetics for pesticides, conditioning their toxicity, including neurotoxicity. However, they remain poorly characterized in humans. The present study was therefore designed to evaluate human intestine and brain permeation for a large set of pesticides (n = 338) belonging to various chemical classes, using an in silico graphical BOILED-Egg/SwissADME online method based on lipophilicity and polarity that was initially developed for drugs. A high percentage of the pesticides (81.4%) was predicted to exhibit high intestinal absorption, with a high accuracy (96%), whereas a lower, but substantial, percentage (38.5%) displayed brain permeation. Among the pesticide classes, organochlorines (n = 30) constitute the class with the lowest percentage of intestine-permeant members (40%), whereas that of the organophosphorus compounds (n = 99) has the lowest percentage of brain-permeant chemicals (9%). The predictions of the permeations for the pesticides were additionally shown to be significantly associated with various molecular descriptors well-known to discriminate between permeant and non-permeant drugs. Overall, our in silico data suggest that human exposure to pesticides through the oral way is likely to result in an intake of these dietary contaminants for most of them and brain permeation for some of them, thus supporting the idea that they have toxic effects on human health, including neurotoxic effects. PMID:28665355

Comparative modeling and benchmarking data sets for human histone deacetylases and sirtuin families.

PubMed

Xia, Jie; Tilahun, Ermias Lemma; Kebede, Eyob Hailu; Reid, Terry-Elinor; Zhang, Liangren; Wang, Xiang Simon

2015-02-23

Histone deacetylases (HDACs) are an important class of drug targets for the treatment of cancers, neurodegenerative diseases, and other types of diseases. Virtual screening (VS) has become fairly effective approaches for drug discovery of novel and highly selective histone deacetylase inhibitors (HDACIs). To facilitate the process, we constructed maximal unbiased benchmarking data sets for HDACs (MUBD-HDACs) using our recently published methods that were originally developed for building unbiased benchmarking sets for ligand-based virtual screening (LBVS). The MUBD-HDACs cover all four classes including Class III (Sirtuins family) and 14 HDAC isoforms, composed of 631 inhibitors and 24609 unbiased decoys. Its ligand sets have been validated extensively as chemically diverse, while the decoy sets were shown to be property-matching with ligands and maximal unbiased in terms of "artificial enrichment" and "analogue bias". We also conducted comparative studies with DUD-E and DEKOIS 2.0 sets against HDAC2 and HDAC8 targets and demonstrate that our MUBD-HDACs are unique in that they can be applied unbiasedly to both LBVS and SBVS approaches. In addition, we defined a novel metric, i.e. NLBScore, to detect the "2D bias" and "LBVS favorable" effect within the benchmarking sets. In summary, MUBD-HDACs are the only comprehensive and maximal-unbiased benchmark data sets for HDACs (including Sirtuins) that are available so far. MUBD-HDACs are freely available at http://www.xswlab.org/ .

Newer Antibacterial Drugs for a New Century

PubMed Central

Devasahayam, Gina; Scheld, W. Michael; Hoffman, Paul S.

2010-01-01

Antibacterial drug discovery and development has slowed considerably in recent years with novel classes discovered decades ago and regulatory approvals tougher to get. This article describes newer classes of antibacterial drugs introduced or approved after year 2000, their mechanisms of action/ resistance, improved analogs, spectrum of activity and clinical trials. It also discusses new compounds in development with novel mechanisms of action as well as novel unexploited bacterial targets and strategies which may pave the way for combating drug resistance and emerging pathogens in the 21st century. PMID:20053150

Five Antiretroviral Drug Class-Resistant HIV-1 in a Treatment-Naïve Patient Successfully Suppressed with Optimized Antiretroviral Drug Selection.

PubMed

Volpe, Joseph M; Ward, Douglas J; Napolitano, Laura; Phung, Pham; Toma, Jonathan; Solberg, Owen; Petropoulos, Christos J; Walworth, Charles M

2015-01-01

Transmitted HIV-1 exhibiting reduced susceptibility to protease and reverse transcriptase inhibitors is well documented but limited for integrase inhibitors and enfuvirtide. We describe here a case of transmitted 5 drug class-resistance in an antiretroviral (ARV)-naïve patient who was successfully treated based on the optimized selection of an active ARV drug regimen. The value of baseline resistance testing to determine an optimal ARV treatment regimen is highlighted in this case report. © The Author(s) 2015.

O-(Triazolyl)methyl carbamates as a novel and potent class of FAAH inhibitors

PubMed Central

Colombano, Giampiero; Albani, Clara; Ottonello, Giuliana; Ribeiro, Alison; Scarpelli, Rita; Tarozzo, Glauco; Daglian, Jennifer; Jung, Kwang-Mook; Piomelli, Daniele; Bandiera, Tiziano

2015-01-01

Inhibition of fatty acid amide hydrolase (FAAH) activity is under investigation as a valuable strategy for the treatment of several disorders, including pain and drug addiction. A number of potent FAAH inhibitors belonging to different chemical classes have been disclosed. O-aryl carbamates are one of the most representative families. In the search for novel FAAH inhibitors, we synthesized a series of O-(1,2,3-triazol-4-yl)methyl carbamate derivatives exploiting the copper-catalyzed [3 + 2] cycloaddition reaction between azides and alkynes (click chemistry). We explored structure-activity relationships within this new class of compounds and identified potent inhibitors of both rat and human FAAH with IC50 values in the single-digit nanomolar range. PMID:25338703

The Changing Drug Culture: Emerging Drugs of Abuse and Legal Highs.

PubMed

Albertson, Timothy E; Chenoweth, James A; Colby, Daniel K; Sutter, Mark E

2016-02-01

In recent years, there has been a large increase in the number of synthetic drugs used recreationally. One class of drugs is synthetic cannabinoids, which are sprayed onto herbal preparations and marketed under names such as K2 and spice. Others include amphetaminelike compounds, such as cathinones (eg, bath salts) and methylenedioxymethamphetamine (MDMA) (eg, ecstasy, Molly). New hallucinogens, such as Bromo-Dragonfly, and hallucinogens that have been used for centuries, such as Salvia divinorum, also are gaining popularity. Because these substances are sold labeled as not for human consumption and because the chemicals in them frequently change, they often are unregulated, and many users consider them legal, although they are not. Their use often goes undetected because testing for them is not included in routine drug screening. Nonetheless, these substances can be associated with significant toxicities, often because their concentrations are unpredictable. Adverse effects of synthetic cannabinoids include psychosis and other effects. Amphetaminelike drugs have stimulant effects and can cause hyponatremia and seizures. The new hallucinogens can cause serious vasoconstriction with ischemia. Clinicians, especially those working with adolescents and young adults (ie, the main users of these drugs), should be aware of these new substances and counsel patients about their adverse effects. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Investigating the dissolution profiles of amoxicillin, metronidazole, and zidovudine formulations used in Trinidad and Tobago, West Indies.

PubMed

Stuart, Arlene Villarroel; Zuo, Jieyu; Löbenberg, Raimar

2014-10-01

Trinidad and Tobago is a twin-island Republic in the Caribbean and like many developing countries, it has included generic drugs on the national drug formulary to decrease the financial burden of pharmaceutical medications. However, to ensure that medications received by patients are beneficial, generic drugs need to be interchangeable with the innovator which has demonstrated safety, efficacy, and quality. The objective of the study was to compare the dissolution profiles and weight variations for different formulations of amoxicillin, metronidazole, and zidovudine that are on the national drug formulary and marketed in Trinidad and Tobago. All the products investigated are categorized as class 1 drugs according to the Biopharmaceutics Classification System (BCS) and the dissolution profiles were assessed according to the World Health Organization (WHO) criteria for interchangeability between products. The similarity factor, f 2, was used to determine sameness between the products. No generic formulation was found to be similar to Amoxil® 500-mg capsules. The two generic products for metronidazole 200-mg tablets demonstrated more than 85% drug release within 15 min in all three of the buffers; however, their 400-mg counterparts did not fulfill this requirement. The zidovudine 300-mg tablet complied with the requirements in buffer pH 4.5 and simulated gastric fluid (SGF) but not for simulated intestinal fluid (SIF). Some Class 1 pharmaceutical formulations may possess the same active ingredient and amount of drug but may show significant differences to in vitro equivalence requirements. Nevertheless, the dissolution process is suitable to detect these variations.

Restless Legs Syndrome

MedlinePlus

... most cases of RLS can be treated with non-drug therapies and if necessary, medications. top What ... drug pramipexole, suggesting this class of drug offers equivalent benefits. Dopaminergic agents . These drugs, which increase dopamine ...

[Antihistamines in the treatment of allergic rhinitis--update 2008/2009].

PubMed

Kruszewski, Jerzy

2009-09-01

The following paper reviews the latest news on antihistamines used in the treatment of allergic rhinitis. It describes the new results of investigations on clinical application of H3 and H4 receptors in therapy of allergic diseases as well as the effect of emedastine on histamine-induced tissue remodeling. Contemporary clinical research of these drugs fulfills the requirements of placebo-controlled trials, including the comparison with a reference drug, usually cetirizine. The paper discusses efficacy and safety of a new drug--bilastine, and the possibility to improve clinical outcome by combining antihistamine drugs with inhaled glucocorticosteroids and antileukotrienes. It also presents the studies on high efficacy of nasal antihistamines, which most probably results from their high concentration in inflamed tissue, as well as describes the latest news on safe use of antihistamines, including studies of fexofenadine enantiomers in drug interactions with P-glycoprotein, safety of a new antihistamine medication--rupatadine, and psychostimulating effect of some other antihistamines. The review shows that antihistamines, the most frequently used class of anti-allergy medications, have been constantly improved, which is of significant importance for progress of allergic diseases treatment.

Tiered analytics for purity assessment of macrocyclic peptides in drug discovery: Analytical consideration and method development.

PubMed

Qian Cutrone, Jingfang Jenny; Huang, Xiaohua Stella; Kozlowski, Edward S; Bao, Ye; Wang, Yingzi; Poronsky, Christopher S; Drexler, Dieter M; Tymiak, Adrienne A

2017-05-10

Synthetic macrocyclic peptides with natural and unnatural amino acids have gained considerable attention from a number of pharmaceutical/biopharmaceutical companies in recent years as a promising approach to drug discovery, particularly for targets involving protein-protein or protein-peptide interactions. Analytical scientists charged with characterizing these leads face multiple challenges including dealing with a class of complex molecules with the potential for multiple isomers and variable charge states and no established standards for acceptable analytical characterization of materials used in drug discovery. In addition, due to the lack of intermediate purification during solid phase peptide synthesis, the final products usually contain a complex profile of impurities. In this paper, practical analytical strategies and methodologies were developed to address these challenges, including a tiered approach to assessing the purity of macrocyclic peptides at different stages of drug discovery. Our results also showed that successful progression and characterization of a new drug discovery modality benefited from active analytical engagement, focusing on fit-for-purpose analyses and leveraging a broad palette of analytical technologies and resources. Copyright © 2017. Published by Elsevier B.V.

75 FR 68364 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-05

... European Protocol for the Quality Control of the Physical and Technical Aspects of Mammography Screening... entitled ``Physical Laboratory Testing, Breast Compression System'' to follow the Mammography Quality...] Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document...

Maintenance pharmacological immunosuppressive strategies in renal transplantation.

PubMed Central

Vella, J. P.; Sayegh, M. H.

1997-01-01

Current maintenance immunosuppressive regimens for transplantation are based on three classes of drugs: corticosteroids, immunophilin-binding agents (eg, cyclosporin and tacrolimus), and antimetabolites (eg, azathioprine and mycophenolate). Drugs from the various classes inhibit the immune system at different points and are thus synergistic when used in combination. PMID:9338020

76 FR 22906 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-25

...: Topical Oxygen Chamber for Extremities; Availability AGENCY: Food and Drug Administration, HHS. ACTION... entitled, ``Class II Special Controls Guidance Document: Topical Oxygen Chamber for Extremities.'' This guidance document was developed as a special control to support the reclassification of the topical oxygen...

76 FR 64228 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-17

...: External Pacemaker Pulse Generator; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice... entitled ``Class II Special Controls Guidance Document: External Pacemaker Pulse Generator.'' This draft guidance document describes a means by which external pacemaker pulse generators may comply with the...

76 FR 43332 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-20

...: Focused Ultrasound Stimulator System for Aesthetic Use; Availability AGENCY: Food and Drug Administration... the guidance entitled, ``Class II Special Controls Guidance Document: Focused Ultrasound Stimulator System for Aesthetic Use.'' This guidance document describes a means by which focused ultrasound...

Computer-aided drug design for AMP-activated protein kinase activators.

PubMed

Wang, Zhanli; Huo, Jianxin; Sun, Lidan; Wang, Yongfu; Jin, Hongwei; Yu, Hui; Zhang, Liangren; Zhou, Lishe

2011-09-01

AMP-activated protein kinase (AMPK) is an important therapeutic target for the potential treatment of metabolic disorders, cardiovascular disease and cancer. Recently, various classes of compounds that activate AMPK by direct or indirect interactions have been reported. The importance of computer-aided drug design approaches in the search for potent activators of AMPK is now established, including structure-based design, ligand-based design, fragment-based design, as well as structural analysis. This review article highlights the computer-aided drug design approaches utilized to discover of activators targeting AMPK. The principles, advantages or limitation of the different methods are also being discussed together with examples of applications taken from the literatures.

The metabolic score: A decision making tool in diabetes care.

PubMed

Kalra, Sanjay; Gupta, Yashdeep

2015-11-01

The heterogeneity of diabetes mellitus, and the various metabolic abnormalities associated with it, are well known. Current management guidelines used to help choose glucose-lowering drugs in diabetes mellitus describe various drug classes in detail, but do not take the overall metabolic profile into consideration. To help physicians choose appropriate oral therapy, we propose a discrete metabolic score, based upon the presence and absence of metabolic comorbidities included in the definition of metabolic syndrome. This communication describes how to choose an appropriate oral antidiabetic drug using such a score. The metabolic score based decision making aid should be able to prove its utility in all health care settings, especially resource constrained societies.

Are the economics of pharmaceutical research and development changing?: productivity, patents and political pressures.

PubMed

Grabowski, Henry

2004-01-01

Pharmaceutical research and development (R&D) competition in the 1980s and 1990 s was characterised by rising R&D expenditures, favourable returns to innovators and the introduction of many new classes of drugs with high social benefits. However, in the past 3 years, the number of new drug introductions has been well below the historical trend, while the cost per new drug continues to increase. In addition to lagging R&D productivity, the industry has been characterised by other economic and policy uncertainties. These include a wave of early patent challenges and growing political pressure to contain pharmaceutical expenditures. This paper examines the consequences of these developments.

Drug therapeutic failures in emergency department patients. A university hospital experience.

PubMed

Franceschi, Alessandro; Tuccori, Marco; Bocci, Guido; Vannozzi, Francesca; Di Paolo, Antonello; Barbara, Cecilia; Lastella, Marianna; Blandizzi, Corrado; Del Tacca, Mario

2004-01-01

Drug therapeutic failure (DTF) could be considered as an adverse drug reaction in which the expected drug effects do not occur following a prescribed pharmacological treatment, including any clinical event that could be related to a low prescribed dose or lack of compliance. DTFs are responsible for increasing disease length, hospitalisation time and social costs, with the worsening of patient quality of life. The aims of the present study are: (1) to estimate the frequency of DTFs among cases of adverse drug events referred to the emergency department; (2) to identify drug classes implicated in DTFs; (3) to analyse the putative causes underlying DTFs. Data presented in this paper were obtained from the Pronto Soccorso and Adverse Drug Events (PSADE) study carried out to analyse drug-related emergency department admissions in several Italian hospitals. Patients, admitted to the emergency department throughout two periods of 10 days each, were interviewed to gain information on their medical status and drug intake during the last two weeks. The present study analysed the patient questionnaires collected in the emergency department of Pisa University Hospital. Among 123 recorded cases of adverse drug event, 41 cases (19:22 male:female ratio; age range: 17-98 years, median age: 75 years) were identified as suspect DTF, resulting in a frequency of 33.33%. A statistical analysis was performed to evaluate the influence of two variables, class of patient age and number of drugs assumed, on DTFs. In accordance with the present findings, showing that the number of drugs assumed by a patient may increase the risk of DTF more than advanced age (odds ratio: 1.371, P<0.02; 1.295, P<0.03, respectively), the prescription of pharmacological combinations might be proposed as a main risk factor for DTF occurrence. In conclusion, our results suggest that DTFs represent an important cause of emergency department admission, particularly in elderly subjects treated with pharmacological associations.

A method for evaluating nanoparticle transport through the blood-brain barrier in vitro.

PubMed

Guarnieri, Daniela; Muscetti, Ornella; Netti, Paolo A

2014-01-01

Blood-brain barrier (BBB) represents a formidable barrier for many therapeutic drugs to enter the brain tissue. The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous system (CNS) diseases. In this context, nanoparticles are an emerging class of drug delivery systems that can be easily tailored to deliver drugs to various compartments of the body, including the brain. To identify, characterize, and validate novel nanoparticles applicable to brain delivery, in vitro BBB model systems have been developed. In this work, we describe a method to screen nanoparticles with variable size and surface functionalization in order to define the physicochemical characteristics underlying the design of nanoparticles that are able to efficiently cross the BBB.

[Trends in drug-induced liver injury based on reports of adverse reactions to PMDA in Japan].

PubMed

Sudo, Chie; Maekawa, Keiko; Segawa, Katsunori; Hanatani, Tadaaki; Sai, Kimie; Saito, Yoshiro

2012-01-01

Reports on drug-related adverse reactions from manufacturing/distributing pharmaceutical companies or medical institutions/pharmacies are regulated under the Pharmaceutical Affairs Law of Japan, and this system is important for post-marketing safety measures. Although association between the medicine and the adverse event has not been clearly evaluated, and an incidence may be redundantly reported, this information would be useful to roughly grasp the current status of drug-related adverse reactions. In the present study, we analyzed the incidence of drug-induced liver injury by screening the open-source data publicized by the homepage of Pharmaceutical and Medical Devices Agency from 2005 to 2011 fiscal years. Major drug-classes suspected to cause general drug-induced liver injury were antineoplastics, anti-inflammatory agents/common cold drugs, chemotherapeutics including antituberculous drugs, antidiabetics, antiulcers and antiepileptics. In addition, reported cases for fulminant hepatitis were also summarized. We found that antituberculous isoniazid and antineoplastic tegafur-uracil were the top two suspected drugs. These results might deepen understanding of current situations for the drug-induced liver injury in Japan.

Polydrug use typologies and childhood maltreatment in a nationally representative survey of Danish young adults.

PubMed

Armour, Cherie; Shorter, Gillian W; Elhai, Jon D; Elklit, Ask; Christoffersen, Mogens N

2014-01-01

Substance use and childhood maltreatment experience are linked, but little is known about the association with polydrug use patterns. Latent class analyses (LCA) were performed on eight illicit drugs in a random population sample of young Danes separated by sex (males: n = 1,555; females: n = 1,425). Logistic regressions explored associations of polydrug use patterns and childhood maltreatment. A three-class solution best described patterns of polydrug use in both the male and female samples. Across all LCA models, Class 1 was characterized by individuals who represented wide-range polydrug users, endorsing many of the drug types (males = 8%; females = 2%). Class 2 was characterized by amphetamine, cannabis, cocaine, and amyl nitrate users (males = 18%; females = 7%). Class 3 was characterized by individuals who endorsed either low-level use of cannabis only or no drug use (males = 74%; females = 91 %). For males, having been a child-protection case was associated with Classes 1 and 2 and for females with Class 2, compared with Class 3. Alcohol problems were associated with Classes 1 and 2 for both sexes. Sexual abuse was associated with Classes 1 and 2 for females but not males, whereas physical abuse was associated with Classes 1 and 2 for males but not females, as compared with Class 3. Separate sex analyses are important; although patterns of polydrug use are broadly similar, females are less frequently polydrug users. In addition, different relationships exist for the sexes, such that polydrug use patterns are associated with sexual abuse in females, whereas such patterns are associated with physical abuse in young males.

Prevalence and Co-Occurrence of Addictive Behaviors Among Russian and Spanish Youth.

PubMed

Tsai, Jennifer; Huh, Jimi; Idrisov, Bulat; Galimov, Artur; Espada, Jose P; Gonzálvez, María T; Sussman, Steve

2017-01-01

Recently, an addiction matrix measure was assessed among U.S. former alternative high school youth. This presentation seeks to examine the generalizability of findings using this measure among Russian and Spanish high school adolescents. Latent class analysis was used to explore addiction subgroups among adolescents in Russia (average age = 16.27; n = 715) and Spain (average age = 14.9; n = 811). Last 30-day prevalence of one or more of 11 addictions reviewed in the previous work was the primary focus (i.e., cigarettes, alcohol, hard drugs, eating, gambling, Internet, love, sex, exercise, work, and shopping) among Russian youth, and last-30 prevalence of one or more of 8 addictions among Spanish youth (the three drug use items had not been included in the questionnaire for these youths). Results confirmed a two-class model (addicted class and non-addicted class) among both Russian and Spanish adolescents. The mean number of addictions reported was 1.39 ( SD = 1.78) addictions among Russian youth and 1.56 ( SD = 1.68) addictions among Spanish youth. The prevalence of the sample that constituted the "addicted group" in Russia and Spain was 32.2% and 28.6%, respectively. The most prevalent addictions (i.e., love, Internet, exercise) were similar. These results are similar to the findings previously reported for U.S. Latent class structures for addictive behaviors are similar across international adolescent populations. Our results highlight the need to address multiple addictions in health education programming.

Prevalence and characteristics of addictive behaviors in a community sample: A latent class analysis.

PubMed

Deleuze, Jory; Rochat, Lucien; Romo, Lucia; Van der Linden, Martial; Achab, Sophia; Thorens, Gabriel; Khazaal, Yasser; Zullino, Daniele; Maurage, Pierre; Rothen, Stéphane; Billieux, Joël

2015-06-01

While addictions to substances such as alcohol, tobacco, and other drugs have been extensively investigated, interest has been growing in potential non-substance-related addictive behaviors (e.g., excessive gambling, buying or playing video games). In the current study, we sought to determine the prevalence and characteristics of a wide range of addictive behaviors in a general population sample and to identify reliable subgroups of individuals displaying addictive behaviors. Seven hundred seventy participants completed an online survey. The survey screened for the presence and characteristics of the main recognized substance and behavioral addictions (alcohol, tobacco, cannabis, other drugs, gambling, compulsive shopping, intensive exercise, Internet and mobile phone overuse, intensive work involvement, and overeating) in a three-month period. Key aspects of addiction were measured for each reported behavior, including negative outcomes, emotional triggers (positive and negative emotional contexts), search for stimulation or pleasure, loss of control, and cognitive salience. Latent class analysis allowed us to identify three theoretically and clinically relevant subgroups of individuals. The first class groups problematic users, i.e., addiction-prone individuals. The second class groups at-risk users who frequently engage in potentially addictive behaviors to regulate emotional states (especially overinvolvement in common behaviors such as eating, working, or buying). The third class groups individuals who are not prone to addictive behaviors. The existence of different groups in the population sheds new light on the distinction between problematic and non-problematic addiction-like behaviors.

G-protein-coupled receptors: new approaches to maximise the impact of GPCRS in drug discovery.

PubMed

Davey, John

2004-04-01

IBC's Drug Discovery Technology Series is a group of conferences highlighting technological advances and applications in niche areas of the drug discovery pipeline. This 2-day meeting focused on G-protein-coupled receptors (GPCRs), probably the most important and certainly the most valuable class of targets for drug discovery. The meeting was chaired by J Beesley (Vice President, European Business Development for LifeSpan Biosciences, Seattle, USA) and included 17 presentations on various aspects of GPCR activity, drug screens and therapeutic analyses. Keynote Addresses covered two of the emerging areas in GPCR regulation; receptor dimerisation (G Milligan, Professor of Molecular Pharmacology and Biochemistry, University of Glasgow, UK) and proteins that interact with GPCRs (J Bockaert, Laboratory of Functional Genomics, CNRS Montpellier, France). A third Keynote Address from W Thomsen (Director of GPCR Drug Screening, Arena Pharmaceuticals, USA) discussed Arena's general approach to drug discovery and illustrated this with reference to the development of an agonist with potential efficacy in Type II diabetes.

Gender differences in licit and illicit substance use reported by incoming freshman college students.

PubMed

Mostert, Christy Harwell; Eisen, Stan

2008-11-01

College-aged students use both licit and illicit drugs, with adverse physiological and societal effects. The time period when people begin to enter college is known as emerging adulthood, and it offers more opportunities for young people to obtain and use drugs, especially alcohol. However, some drugs are used more often by one gender than the other. This study surveyed 813 students enrolled in a freshman orientation class at Christian Brothers University from 2000-2003. The participants were asked to rank their use of certain drugs on a scale showing how often they have used that drug during their life. A total of 18 licit and illicit drugs were included on the survey. Charts were made for each year depicting the average amount of use of the drugs by males and females. The composite chart showed males tended to use cigarettes, chewing tobacco, beer, hard liquor, marijuana, inhalants, and anabolic steroids more often than women. However, women drank more wine coolers than men.

Surfactant-based drug delivery systems for treating drug-resistant lung cancer.

PubMed

Kaur, Prabhjot; Garg, Tarun; Rath, Goutam; Murthy, R S R; Goyal, Amit K

2016-01-01

Among all cancers, lung cancer is the major cause of deaths. Lung cancer can be categorized into two classes for prognostic and treatment purposes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Both categories of cancer are resistant to certain drugs. Various mechanisms behind drug resistance are over-expression of superficial membrane proteins [glycoprotein (P-gp)], lung resistance-associated proteins, aberration of the intracellular enzyme system, enhancement of the cell repair system and deregulation of cell apoptosis. Structure-performance relationships and chemical compatibility are consequently major fundamentals in surfactant-based formulations, with the intention that a great deal investigation is committed to this region. With the purpose to understand the potential of P-gp in transportation of anti-tumor drugs to cancer cells with much effectiveness and specificity, several surfactant-based delivery systems have been developed which may include microspheres, nanosized drug carriers (nanoparticles, nanoemulsions, stealth liposomes, nanogels, polymer-drug conjugates), novel powders, hydrogels and mixed micellar systems intended for systemic and/or localized delivery.

[The actual incidence of the population in the RF subject: assessment of economic effect (losses)].

PubMed

Ushakov, A A; Saldan, I P; Goleva, O I; Karpova, T N

2013-01-01

In the paper there is presented an analysis and evaluation of the economic losses associated with the actual incidence of the population of the Altai Region on disease classes "Poisoning by drugs, medicaments and biological substances" (T36-T50) and "Toxic effect of substances, mainly non-medical purpose" (T51-T65), including the assessment of the underproduced product in economy of the region in monetary terms, assessment changes in cash flows on the budgets of the Russian Federation (tax receipts). The time period of analysis on disease classes is 5 years (2007-2011).

Polyethylene Glycol Propionaldehydes

NASA Technical Reports Server (NTRS)

Harris, Joe M.; Sedaghat-Herati, Mohammad R.; Karr, Laurel J.

1992-01-01

New class of compounds derived from polyethylene glycol (PEG's) namely, PEG-propionaldehydes, offers two important advantages over other classes of PEG aldehyde derivatives: compounds exhibit selective chemical reactivity toward amino groups and are stable in aqueous environment. PEG's and derivatives used to couple variety of other molecules, such as, to tether protein molecules to surfaces. Biotechnical and biomedical applications include partitioning of two phases in aqueous media; immobilization of such proteins as enzymes, antibodies, and antigens; modification of drugs; and preparation of protein-rejecting surfaces. In addition, surfaces coated with PEG's and derivatives used to control wetting and electroosmosis. Another potential application, coupling to aminated surfaces.

Evaluation of discharge medication orders following automatic therapeutic substitution of commonly exchanged drug classes.

PubMed

Glaholt, Sarah; Hayes, Genevieve L; Wisniewski, Christopher S

2014-04-01

Automatic therapeutic substitution (ATS) is a mechanism that, upon patient hospitalization, prompts the pharmacist to exchange an equivalent formulary drug for a nonformulary medication, typically without prescriber contact. In facilities utilizing ATS, there is the possibility that physicians and patients may be unaware of the substitution, potentially leading to drug-drug interactions, therapeutic duplication, and/or increased patient expense following discharge should the original regimen not be resumed. The purpose of this study was to determine the frequency with which hospitalized patients subjected to an ATS protocol were not returned to outpatient drug therapy. A retrospective chart review of adult patients admitted to an academic medical center between January 1 and June 30, 2011, was conducted. Patients were included if they were admitted on angiotensin-converting enzyme (ACE) inhibitors, antidepressants, nonsedating antihistamines, histamine (H2) receptor antagonists, or proton pump inhibitors (PPIs), and were then prescribed a different agent via ATS. Admission and discharge medication reconciliation documents, dictated discharge summaries, and patient education documentation reports were reviewed for drug therapies and doses, as well as medication counseling evidence. The primary endpoint was the percentage of patients not returned to original outpatient therapy following ATS. Secondary endpoints included prescribing events in patients not returned to original therapy, the rate and source of drug therapy counseling at discharge, and the number of patients discharged on a potentially cost-prohibitive drug, defined as any drug available only as a branded product during the study period. A total of 317 interventions were identified through review of pharmacy records. Of these, 47 patients (15%) were not returned to original outpatient therapy. Within this subsection, 15 patients (32%) were discharged on the substituted drug, eight patients (17%) resumed initial therapy but received a dosage adjustment from previous outpatient therapy, and three patients (6%) were discharged on a drug that was neither the substituted product nor the previous outpatient therapy. The remaining 21 patients had therapy discontinued (n = 12/47, 26%) or lacked documentation of discharge therapy (9/47, 19%). Nursing staff provided medication counseling to 288 of the 317 patients (91%). Overall, 51 patients (16%) were identified as receiving a cost-prohibitive drug. Patients subject to ATS of commonly substituted drug classes were returned to their original outpatient drug therapy more than 85% of the time following inpatient hospitalizations, with similar rates of medication counseling at discharge. The prescribing of cost-prohibitive drugs has been identified as a potential area for pharmacist intervention at discharge.

Progress report on new antiepileptic drugs: A summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII).

PubMed

Bialer, Meir; Johannessen, Svein I; Levy, René H; Perucca, Emilio; Tomson, Torbjörn; White, H Steve

2017-02-01

The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-d-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689). Overall, the results presented at the Conference show that considerable efforts are ongoing into discovery and development of AEDs with potentially improved therapeutic profiles compared with existing agents. Many of the drugs discussed in this report show innovative mechanisms of action and many have shown promising results in patients with pharmacoresistant epilepsies, including previously neglected rare and severe epilepsy syndromes. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Building a drug ontology based on RxNorm and other sources

PubMed Central

2013-01-01

Background We built the Drug Ontology (DrOn) because we required correct and consistent drug information in a format for use in semantic web applications, and no existing resource met this requirement or could be altered to meet it. One of the obstacles we faced when creating DrOn was the difficulty in reusing drug information from existing sources. The primary external source we have used at this stage in DrOn’s development is RxNorm, a standard drug terminology curated by the National Library of Medicine (NLM). To build DrOn, we (1) mined data from historical releases of RxNorm and (2) mapped many RxNorm entities to Chemical Entities of Biological Interest (ChEBI) classes, pulling relevant information from ChEBI while doing so. Results We built DrOn in a modular fashion to facilitate simpler extension and development of the ontology and to allow reasoning and construction to scale. Classes derived from each source are serialized in separate modules. For example, the classes in DrOn that are programmatically derived from RxNorm are stored in a separate module and subsumed by classes in a manually-curated, realist, upper-level module of DrOn with terms such as 'clinical drug role’, 'tablet’, 'capsule’, etc. Conclusions DrOn is a modular, extensible ontology of drug products, their ingredients, and their biological activity that avoids many of the fundamental flaws found in other, similar artifacts and meets the requirements of our comparative-effectiveness research use-case. PMID:24345026

Building a drug ontology based on RxNorm and other sources.

PubMed

Hanna, Josh; Joseph, Eric; Brochhausen, Mathias; Hogan, William R

2013-12-18

We built the Drug Ontology (DrOn) because we required correct and consistent drug information in a format for use in semantic web applications, and no existing resource met this requirement or could be altered to meet it. One of the obstacles we faced when creating DrOn was the difficulty in reusing drug information from existing sources. The primary external source we have used at this stage in DrOn's development is RxNorm, a standard drug terminology curated by the National Library of Medicine (NLM). To build DrOn, we (1) mined data from historical releases of RxNorm and (2) mapped many RxNorm entities to Chemical Entities of Biological Interest (ChEBI) classes, pulling relevant information from ChEBI while doing so. We built DrOn in a modular fashion to facilitate simpler extension and development of the ontology and to allow reasoning and construction to scale. Classes derived from each source are serialized in separate modules. For example, the classes in DrOn that are programmatically derived from RxNorm are stored in a separate module and subsumed by classes in a manually-curated, realist, upper-level module of DrOn with terms such as 'clinical drug role', 'tablet', 'capsule', etc. DrOn is a modular, extensible ontology of drug products, their ingredients, and their biological activity that avoids many of the fundamental flaws found in other, similar artifacts and meets the requirements of our comparative-effectiveness research use-case.

Nonmedical Use of Prescription Medications Among Medical Students in Greece: Prevalence of and Motivation for Use.

PubMed

Papazisis, Georgios; Tsakiridis, Ioannis; Pourzitaki, Chryssa; Apostolidou, Eirini; Spachos, Dimitrios; Kouvelas, Dimitrios

2018-01-02

Non-medical use of prescription medications has risen to unprecedented levels over the past decade worldwide; however, studies assessing misuse across medical students are sparse. The purpose of this study was to1) estimate the lifetime and the past-year prevalence of non-medical use of prescription medications among medical students in Greece 2) identify the motivation for use. 591 medical students completed an anonymous, self-administered, web-based survey assessing lifetime and past-year prevalence of non-medical use of four classes of prescription drugs (opioid painkillers, tranquillizers, sleeping and stimulant medications). According to the motivation to use the responders were classified into three subtypes (selftreatment, recreational, and mixed). The prevalence of lifetime use was 10.7% for at least one of the four prescription drug classes and 9% of the respondents reported lifetime misuse of multiple categories of prescription drugs. The past-year prevalence was approximately 7.7% for at least one of the four prescription drug classes, while the majority misused the drugs "1-2 times per year". Senior students used tranquilizers more than junior students. Self-treatment and mixed subtypes of tranquillizers misuse was more prevalent among women than men while the self-treatment subtype was the most prevalent subtype in all the four drug classes. This is the first study investigating non-medical use of prescription medications among Greek medical students and indicates a high prevalence of misuse of some categories of prescription drugs, mostly for self-treatment purposes.

Antihypertensive adherence and drug class among Asian Pacific Americans.

PubMed

Taira, Deborah A; Gelber, Rebecca P; Davis, James; Gronley, Krista; Chung, Richard S; Seto, Todd B

2007-06-01

Research on adherence has emphasized the need to consider patient ethnicity when developing adherence plans. The objective of this study is to identify predictors of adherence for specific groups, particularly Asian Americans and Pacific Islanders. We examined the factors, including drug class, associated with antihypertensive adherence for 28,395 adults in Hawaii (July 1999-June 2003) using health plan administrative data. The population included Japanese (n=13,836), Filipino (n=3,812), Chinese (n=2,280), Korean (n=450), part-Hawaiian (n=3,746) and white (n=3,920) patients. Members with antihypertensive medication in their possession >or=80% of the time were considered adherent. Multivariable logistic regression models were used to identify factors associated with adherence. Overall adherence rates were less than 65% among all racial/ethnic groups. After adjustment for patient age, gender, morbidity level, health plan type, isle of residence, comorbidities and year of treatment, Japanese were more likely than whites to adhere to antihypertensive therapy [OR=1.21 (1.14-1.29)], whereas Filipino [OR=0.69 (0.64-0.74)], Korean [OR=0.79 (0.67-0.93)] and Hawaiian [OR=0.84 (0.78-0.91)] patients were less likely to adhere. These results were consistent across therapeutic class. Other patient factors associated with lower adherence included younger age, higher morbidity and history of heart disease. Patient factors were also significantly related to adherence, including gender and seeing a sub-specialist. Seeing a physician of the same ethnicity did not appear to improve adherence. Our findings of substantial disparities among Asian Pacific American subgroups highlight the need to examine subgroups separately. Future qualitative research is needed to determine appropriate interventions, particularly for Filipino, Korean and Hawaiian patients.

Coverage and prior authorization of psychotropic drugs under Medicare Part D.

PubMed

Huskamp, Haiden A; Stevenson, David G; Donohue, Julie M; Newhouse, Joseph P; Keating, Nancy L

2007-03-01

This study examined formulary coverage and use of utilization management tools for three classes of psychotropic medications (antidepressants, antipsychotics, and anticonvulsants) among Medicare Part D prescription drug plans serving individuals dually eligible for the Medicare and Medicaid programs. Plans must cover "all or substantially all" molecules (distinct drugs) in these classes. Plans serving "dual eligibles" generally covered at least one formulation of all molecules in the three classes. However, certain product formulations were not covered by a number of plans, and use of prior authorization was common for a minority of plans. The effect of Part D will depend on the restrictiveness of the prior authorization and appeals processes, which is currently unknown.

Hidden costs of HIV treatment in Spain: inefficiency of the antiretroviral drug packaging.

PubMed

Llibre-Codina, Josep M; Andreu-Crespo, Angels; Cardona-Peitx, Gloria; Sala-Piñol, Ferran; Clotet-Sala, Bonaventura; Bonafont-Pujol, Xavier

2014-01-01

Antiretroviral drugs in Spain are delivered by law only in hospital pharmacies. Commercial packages meet variable quality standards when dispensed drugs are returned due to treatment changes or adherence problems Nearly 20-25% of the initial regimens will be changed at 48 weeks for different reasons. We evaluated the economic impact on public health system of the inability of using returned drugs due to inefficient packaging. We defined socially efficient packaging as the best adapted one to being delivered in unit dose to outpatients and classified: Class A - Drug packed in unit doses with complete info (name of drug, dosage in mg, lot, and expiring date) in each unit, maintaining complete information of the drug if returned when the external package is opened. Class B - packed in blisters with complete info in the blister, but not in unit doses, without special conservation conditions (should be re-packed in unit doses in the pharmacy before its dispensation to assure a class A excellence). Class C - packed in plastic containers with complete info written only on a label over the container, would allow repackaging only before its initial delivery, but not when returned. Class D - drug packed in plastic containers with manufacturer's warning that the product cannot be placed outside of the original package due to special conditions of conservation (fridge, humidity) that doesn't allow a unit dose repackaging or reusing an opened container. We analysed a 12-month period (July 2011-June 2012) in a hospital-based HIV outpatient pharmacy that serves 2413 treated individuals. Patients generated 23,574 visits to pharmacy, and received 48,325 drug packages, with 2.529.137 pills delivered. The patients suffered 1051 treatment changes for any reason. A total amount of 122.945€ in treatment were returned to pharmacy in opened packages during the study period. 47.139.91€ would be totally lost, mainly due to being packaged in class C and D boxes, the equivalent of treating 78 patients with rilpivirine/TDF/FTC during 1 month. Class A and B packages in bad condition represented only 1.1% of the cost. However, 75.805€ came from returned packages in good condition that could potentially be reused. Most of the treatment changes were not foreseeable. A significant economic budget is lost through socially inefficient antiretroviral packages. Newer treatments are packaged in C and D categories, therefore maintaining these hidden costs in the near future. Any improvement in the excellence of packaging by the manufacturer, and favouring the choice of drugs supplied through efficient packages (when efficacy, toxicity and convenience are similar) should minimize the treatment expenditures paid by national health budgets.

Prescription drug use during pregnancy in France: a study from the national health insurance permanent sample.

PubMed

Demailly, Romain; Escolano, Sylvie; Quantin, Catherine; Tubert-Bitter, Pascale; Ahmed, Ismaïl

2017-09-01

To provide an up-to-date account of drug prescription during pregnancy in France from 2011 to 2014 using the permanent sample of the French national computerized healthcare database and with a focus on recommended supplementations, fetotoxic drugs and teratogenic drugs. All pregnancies identified by the International Classification of Diseases, 10th Revision codes list in the hospitalization database, lasting more than 9 weeks of amenorrhea and whose delivery occurred between 01/01/2011 and 12/31/2014, were included. Drugs delivered between the trimester before and until the end of the pregnancy were included. Drug exposure prevalence was calculated for each year and according to pregnancy trimesters. The study included 28,491 pregnancies with a median number of 9 [5-13] (median [IQ range]) drugs delivered. The most prescribed drug class was antianemia (in 72.5% of exposed). The prescription rate of recommended vitamins (B9 and D) increased over the study period (+10%). Influenza vaccination also increased but remained at a low rate (1%). Exposure to fetotoxic drugs decreased as pregnancy advanced. Exposure to the main teratogenic antiepileptics was stable over the study period. Low-income pregnant women had a higher average drug consumption except for recommended vitamins. Pregnant French women are among the largest consumers of prescription medications worldwide. Overall, the dispensation trends observed in this study are in line with the recommendations of the French National College of Gynecologists and Obstetricians. Nevertheless, while being low, exposure to fetotoxic drugs, teratogenic drugs or those under safety alerts still occurred. Supplementations and vaccines in low-income pregnant women should also be increased. Copyright © 2017 John Wiley & Sons, Ltd.

Histone deacetylase inhibitors: Potential in cancer therapy.

PubMed

Marks, P A; Xu, W-S

2009-07-01

The role of histone deacetylases (HDAC) and the potential of these enzymes as therapeutic targets for cancer, neurodegenerative diseases and a number of other disorders is an area of rapidly expanding investigation. There are 18 HDACs in humans. These enzymes are not redundant in function. Eleven of the HDACs are zinc dependent, classified on the basis of homology to yeast HDACs: Class I includes HDACs 1, 2, 3, and 8; Class IIA includes HDACs 4, 5, 7, and 9; Class IIB, HDACs 6 and 10; and Class IV, HDAC 11. Class III HDACs, sirtuins 1-7, have an absolute requirement for NAD(+), are not zinc dependent and generally not inhibited by compounds that inhibit zinc dependent deacetylases. In addition to histones, HDACs have many nonhistone protein substrates which have a role in regulation of gene expression, cell proliferation, cell migration, cell death, and angiogenesis. HDAC inhibitors (HDACi) have been discovered of different chemical structure. HDACi cause accumulation of acetylated forms of proteins which can alter their structure and function. HDACi can induce different phenotypes in various transformed cells, including growth arrest, apoptosis, reactive oxygen species facilitated cell death and mitotic cell death. Normal cells are relatively resistant to HDACi induced cell death. Several HDACi are in various stages of development, including clinical trials as monotherapy and in combination with other anti-cancer drugs and radiation. The first HDACi approved by the FDA for cancer therapy is suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza), approved for treatment of cutaneous T-cell lymphoma. 2009 Wiley-Liss, Inc.

The Tuberculosis Drug Discovery and Development Pipeline and Emerging Drug Targets

PubMed Central

Mdluli, Khisimuzi; Kaneko, Takushi; Upton, Anna

2015-01-01

The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal. PMID:25635061

21 CFR 809.30 - Restrictions on the sale, distribution and use of analyte specific reagents.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Restrictions on the sale, distribution and use of... Requirements for Manufacturers and Producers § 809.30 Restrictions on the sale, distribution and use of analyte... include the statement for class I exempt ASR's: “Analyte Specific Reagent. Analytical and performance...

Natural product-based 6-hydroxy-2 3 4 6-tetrahydropyrrolo[1 2-a]pyrimidinium Scaffold as a new antifungal template

USDA-ARS?s Scientific Manuscript database

Synthetic analogues of the marine-derived class of natural products phloeodictines have been prepared and exhibited potent in vitro fungicidal activities against a broad array of fungal pathogens including drug-resistant strains. The 6-hydroxy-2,3,4,6-tetrahydropyrrolo[1,2-a] pyrimidinium structura...

Substance Abuse in the Workingplace: Readings in the Labor-Management Issues.

ERIC Educational Resources Information Center

Hogler, Raymond L., Ed.

This document contains a collection of readings offering a broad overview of the subject of drug and alcohol abuse in the workplace. Included are: (1) "'Miller Time' in Antebellum America: An Historical Appraisal of the Drinking Habits of the Working Class" (John C. McWilliams); (2) "The Impact of Substance Abuse at the…

Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates

PubMed Central

Donaghy, Heather

2016-01-01

ABSTRACT Antibody-drug conjugates (ADCs) represent a new class of cancer therapeutics. Their design involves a tumor-specific antibody, a linker and a cytotoxic payload. They were designed to allow specific targeting of highly potent cytotoxic agents to tumor cells whilst sparing normal cells. Frequent toxicities that may be driven by any of the components of an ADC have been reported. There are currently more than 50 ADCs in active clinical development, and a further ∼20 that have been discontinued. For this review, the reported toxicities of ADCs were analysed, and the mechanisms for their effects are explored in detail. Methods to reduce toxicities, including dosing strategies and drug design, are discussed. The toxicities reported for active and discontinued drugs are important to drive the rational design and improve the therapeutic index of ADCs of the future. PMID:27045800

Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?

PubMed

Gopalakrishnan, Ranganath; Frolov, Andrey I; Knerr, Laurent; Drury, William J; Valeur, Eric

2016-11-10

Over the past decade, foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino acid based backbones, have been the most studied from a therapeutic perspective, while polyaromatic foldamers have barely evolved from their nascency and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targets or provide chemical biology tools. The potential of foldamer drug candidates reaching the clinic is still a stretch. Nevertheless, advances in the field have demonstrated their potential for the discovery of next generation therapeutics. In this perspective, the current knowledge of foldamers is reviewed in a drug discovery context. Recent advances in the early phases of drug discovery including hit finding, target validation, and optimization and molecular modeling are discussed. In addition, challenges and focus areas are debated and gaps highlighted.

Patient-Reported Outcomes Labeling for Products Approved by the Office of Hematology and Oncology Products of the US Food and Drug Administration (2010-2014).

PubMed

Gnanasakthy, Ari; DeMuro, Carla; Clark, Marci; Haydysch, Emily; Ma, Esprit; Bonthapally, Vijayveer

2016-06-01

To review the use of patient-reported outcome (PRO) data in medical product labeling granted by the US Food and Drug Administration (FDA) for new molecular entities and biologic license applications by the FDA Office of Hematology and Oncology Products (OHOP) between January 2010 and December 2014, to elucidate challenges faced by OHOP for approving PRO labeling, and to understand challenges faced by drug manufacturers to include PRO end points in oncology clinical trials. FDA Drug Approval Reports by Month were reviewed to obtain the number of new molecular entities and biologic license applications approved from 2010 to 2014. Drugs approved by the FDA OHOP during this period were selected for further review, focusing on brand and generic name; approval date; applicant; indication; PRO labeling describing treatment benefit, measures, end point status, and significant results; FDA reviewer feedback on PRO end points; and study design of registration trials. First in class, priority review, fast track, orphan drug, or accelerated approval status was retrieved for selected oncology drugs from 2011 to 2014. Descriptive analyses were performed by using Microsoft Excel 2010. Of 160 drugs approved by the FDA (2010-2014), 40 were approved by OHOP. Three (7.5%) of the 40 received PRO-related labeling (abiraterone acetate, ruxolitinib phosphate, and crizotinib). Compared with nononcology drugs (2011-2014), oncology drugs were more likely to be orphan and first in class. The majority of oncology drug reviews by FDA were fast track, priority, or accelerated. Although symptoms and functional decrements are common among patients with cancer, PRO labeling is rare in the United States, likely because of logistical hurdles and oncology study design. Recent developments within the FDA OHOP to capture PROs in oncology studies for the purpose of product labeling are encouraging. © 2016 by American Society of Clinical Oncology.

Factors associated with patterns of mobile technology use among persons who inject drugs.

PubMed

Collins, Kelly M; Armenta, Richard F; Cuevas-Mota, Jazmine; Liu, Lin; Strathdee, Steffanie A; Garfein, Richard S

2016-01-01

New and innovative methods of delivering interventions are needed to further reduce risky behaviors and increase overall health among persons who inject drugs (PWID). Mobile health (mHealth) interventions have potential for reaching PWID; however, little is known about mobile technology use (MTU) in this population. In this study, the authors identify patterns of MTU and identified factors associated with MTU among a cohort of PWID. Data were collected through a longitudinal cohort study examining drug use, risk behaviors, and health status among PWID in San Diego, California. Latent class analysis (LCA) was used to define patterns of MTU (i.e., making voice calls, text messaging, and mobile Internet access). Multinomial logistic regression was then used to identify demographic characteristics, risk behaviors, and health indicators associated with mobile technology use class. In LCA, a 4-class solution fit the data best. Class 1 was defined by low MTU (22%, n = 100); class 2, by PWID who accessed the Internet using a mobile device but did not use voice or text messaging (20%, n = 95); class 3, by primarily voice, text, and connected Internet use (17%, n = 91); and class 4, by high MTU (41%, n = 175). Compared with low MTU, high MTU class members were more likely to be younger, have higher socioeconomic status, sell drugs, and inject methamphetamine daily. The majority of PWID in San Diego use mobile technology for voice, text, and/or Internet access, indicating that rapid uptake of mHealth interventions may be possible in this population. However, low ownership and use of mobile technology among older and/or homeless individuals will need to be considered when implementing mHealth interventions among PWID.

Effects of blood-pressure-lowering treatment on outcome incidence in hypertension: 10 - Should blood pressure management differ in hypertensive patients with and without diabetes mellitus? Overview and meta-analyses of randomized trials.

PubMed

Thomopoulos, Costas; Parati, Gianfranco; Zanchetti, Alberto

2017-05-01

Type 2 diabetes mellitus is associated with an increased risk of hypertension, and cardiovascular and renal disease, and it has been recommended that management of hypertension should be more aggressive in presence than in absence of diabetes mellitus, but the matter is controversial at present. Meta-analysing all available randomized controlled trials (RCTs) to compare the effects on cardiovascular and renal outcomes of blood pressure BP lowering to different systolic BP (SBP) and diastolic BP (DBP) levels or by different drug classes in patients with and without diabetes mellitus. The database consisted of 72 BP-lowering RCTs (260 210 patients) and 50 head-to-head drug comparison RCTs (247 006). Among these two sets, RCTs or RCT subgroups separately reporting data from patients with and without diabetes mellitus were identified, and stratified by in-treatment achieved SBP and DBP, by drug class compared with placebo, and drug class compared with all other classes. Risk ratios and 95% confidence intervals, and absolute risk reductions of six fatal and non-fatal cardiovascular outcomes, all-cause death, and end-stage renal disease (ESRD) were calculated (random-effects model) separately for diabetes mellitus and no diabetes mellitus, and compared by interaction analysis. We identified 41 RCTs providing data on 61 772 patients with diabetes mellitus and 40 RCTs providing data on 191 353 patients without diabetes mellitus. For achieved SBP at least 140 mmHg, relative and absolute reductions of most cardiovascular outcomes were significantly greater in diabetes mellitus than no diabetes mellitus, whereas for achieved SBP below 130 mmHg, the difference disappeared or reversed (greater outcome reduction in no diabetes mellitus). Significant ESRD reduction was found only in diabetes mellitus, but it was greatest when achieved SBP was at least 140 mmHg, and no further effect was found at SBP below 140 mmHg. All antihypertensive drug classes reduced cardiovascular risk vs. placebo in diabetes mellitus and no diabetes mellitus, but angiotensin-converting enzyme inhibitors were the only class more effective in diabetes mellitus than in no diabetes mellitus. When compared to other classes, renin-angiotensin system blockers were equally effective in cardiovascular prevention in no diabetes mellitus, but moderately, though significantly, more effective in diabetes mellitus. BP-lowering treatment significantly and importantly reduces cardiovascular risk both in diabetes mellitus and no diabetes mellitus, but evidence for reduced ESRD risk is available only in diabetes. Contrary to past recommendations, in diabetes mellitus there is little or no further benefit in lowering SBP below 130 mmHg, whereas continuing benefit is seen in no diabetes mellitus also at SBP below 130 mmHg. Although all BP-lowering drugs can beneficially be prescribed in hypertensive patients with diabetes mellitus, the current recommendation to initiate or include a renin-angiotensin system blocker is supported by the evidence here presented.

Clinical Applications of Hallucinogens: A Review

PubMed Central

Garcia-Romeu, Albert; Kersgaard, Brennan; Addy, Peter H.

2016-01-01

Hallucinogens fall into several different classes, as broadly defined by pharmacological mechanism of action, and chemical structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the molecular to the behavioral level, and presenting the most up-to-date information on clinically oriented research with these substances, with important ramifications for their potential therapeutic value. PMID:27454674

76 FR 20992 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-14

...: Low Level Laser System for Aesthetic Use; Availability AGENCY: Food and Drug Administration, HHS... guidance entitled ``Class II Special Controls Guidance Document: Low Level Laser System for Aesthetic Use.'' This guidance document describes a means by which low level laser systems for aesthetic use may comply...

21 CFR 870.4200 - Cardiopulmonary bypass accessory equipment.

Code of Federal Regulations, 2010 CFR

2010-04-01

....4200 Section 870.4200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... class I if it does not involve an electrical connection to the patient. The device is exempt from the... (special controls). The device is classified as class II if it involves an electrical connection to the...

21 CFR 870.4200 - Cardiopulmonary bypass accessory equipment.

Code of Federal Regulations, 2011 CFR

2011-04-01

....4200 Section 870.4200 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... class I if it does not involve an electrical connection to the patient. The device is exempt from the... (special controls). The device is classified as class II if it involves an electrical connection to the...

76 FR 69040 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-07

...: In Vitro Diagnostic Devices for Yersinia Species Detection; Availability AGENCY: Food and Drug... availability of a draft guidance entitled ``Class II Special Controls Guidance Document: In Vitro Diagnostic Devices for Yersinia Species Detection.'' This draft guidance document describes a means by which in vitro...

76 FR 6622 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-07

...: Contact Cooling System for Aesthetic Use; Availability AGENCY: Food and Drug Administration, HHS. ACTION... entitled ``Class II Special Controls Guidance Document: Contact Cooling System for Aesthetic Use.'' This guidance document describes a means by which contact cooling systems for aesthetic use may comply with the...

Patent life of antiretroviral drugs approved in the US from 1987 to 2007.

PubMed

Rodriguez-Monguio, Rosa; Seoane-Vazquez, Enrique

2009-06-01

This study analyzes the effective patent life of antiretroviral (ARV) new molecular entities (NMEs) approved for marketing in the United States (US) between 1987 and 2007. The study includes all NMEs approved during the study period with at least one patent listed in the Orange Book (OB). Drugs discontinued from the market were excluded from the analysis. Data sources are the US Food and Drug Administration (FDA) and the US Patent and Trademark Office. A comparison between the effective patent life of ARV NMEs and NMEs from other therapeutic classes was performed. The first and last patents were used to estimate the minimum and maximum effective patent life of NMEs. Group differences were assessed using group comparison t-tests, Chi-Square and Fishers' exact tests. The FDA approved 547 NMEs during the study period; 153 NMEs did not have a patent listed in the OB or were discontinued from the US market. The patent analysis included 22 ARV NMEs and 372 other NMEs. ARV MNEs had a range from 1 to 15 patents listed in the OB. The FDA new drug application (NDA) review time was shorter for ARVs (5.8+/-2.3 months) than for other NMEs (23.6+/-18.7 months). ARV NMEs had an average of 13.2+/-3.8 years of effective patent life for the first patent versus 11.0+/-4.2 years for other NMEs. ARV NMEs had an average of 17.5+/-3.6 years of effective patent life for the last patent versus the 14.8+/-4.8 years for other NMEs. The effective patent life listed for the last patent of seven ARV NMEs (31.8%) exceeded 20 years. Shortening the drug approval process increased the effective patent life of ARVs and facilitated faster entry of new drugs into the market. ARVs had an average of 2-3 more years of effective patent life than other therapeutic classes and, therefore, a longer period without generic competition.

Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability.

PubMed

Alhalaweh, Amjad; Alzghoul, Ahmad; Mahlin, Denny; Bergström, Christel A S

2015-11-10

Amorphous materials are inherently unstable and tend to crystallize upon storage. In this study, we investigated the extent to which the physical stability and inherent crystallization tendency of drugs are related to their glass-forming ability (GFA), the glass transition temperature (Tg) and thermodynamic factors. Differential scanning calorimetry was used to produce the amorphous state of 52 drugs [18 compounds crystallized upon heating (Class II) and 34 remained in the amorphous state (Class III)] and to perform in situ storage for the amorphous material for 12h at temperatures 20°C above or below the Tg. A computational model based on the support vector machine (SVM) algorithm was developed to predict the structure-property relationships. All drugs maintained their Class when stored at 20°C below the Tg. Fourteen of the Class II compounds crystallized when stored above the Tg whereas all except one of the Class III compounds remained amorphous. These results were only related to the glass-forming ability and no relationship to e.g. thermodynamic factors was found. The experimental data were used for computational modeling and a classification model was developed that correctly predicted the physical stability above the Tg. The use of a large dataset revealed that molecular features related to aromaticity and π-π interactions reduce the inherent physical stability of amorphous drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Identification of a better Homo sapiens Class II HDAC inhibitor through binding energy calculations and descriptor analysis

PubMed Central

2010-01-01

Human papillomaviruses (HPVs) are the most common on sexually transmitted viruses in the world. HPVs are responsible for a large spectrum of deseases, both benign and malignant. The certain types of HPV are involved in the development of cervical cancer. In attemps to find additional drugs in the treatment of cervical cancer, inhibitors of the histone deacetylases (HDAC) have received much attention due to their low cytotoxic profiles and the E6/E7 oncogene function of human papilomavirus can be completely by passed by HDAC inhibition. The histone deacetylase inhibitors can induce growth arrest, differentiation and apoptosis of cancer cells. HDAC class I and class II are considered the main targets for cancer. Therefore, the six HDACs class II was modeled and about two inhibitors (SAHA and TSA) were docked using AutoDock4.2, to each of the inhibitor in order to identify the pharmacological properties. Based on the results of docking, SAHA and TSA were able to bind with zinc ion in HDACs models as a drug target. SAHA was satisfied almost all the properties i.e., binding affinity, the Drug-Likeness value and Drug Score with 70% oral bioavailability and the carbonyl group of these compound fits well into the active site of the target where the zinc is present. Hence, SAHA could be developed as potential inhibitors of class II HDACs and valuable cervical cancer drug candidate. PMID:21106123

Identification of a better Homo sapiens Class II HDAC inhibitor through binding energy calculations and descriptor analysis.

PubMed

Tambunan, Usman Sumo Friend; Wulandari, Evi Kristin

2010-10-15

Human papillomaviruses (HPVs) are the most common on sexually transmitted viruses in the world. HPVs are responsible for a large spectrum of deseases, both benign and malignant. The certain types of HPV are involved in the development of cervical cancer. In attemps to find additional drugs in the treatment of cervical cancer, inhibitors of the histone deacetylases (HDAC) have received much attention due to their low cytotoxic profiles and the E6/E7 oncogene function of human papilomavirus can be completely by passed by HDAC inhibition. The histone deacetylase inhibitors can induce growth arrest, differentiation and apoptosis of cancer cells. HDAC class I and class II are considered the main targets for cancer. Therefore, the six HDACs class II was modeled and about two inhibitors (SAHA and TSA) were docked using AutoDock4.2, to each of the inhibitor in order to identify the pharmacological properties. Based on the results of docking, SAHA and TSA were able to bind with zinc ion in HDACs models as a drug target. SAHA was satisfied almost all the properties i.e., binding affinity, the Drug-Likeness value and Drug Score with 70% oral bioavailability and the carbonyl group of these compound fits well into the active site of the target where the zinc is present. Hence, SAHA could be developed as potential inhibitors of class II HDACs and valuable cervical cancer drug candidate.

Therapeutic Duplicates in a Cohort of Hospitalized Elderly Patients: Results from the REPOSI Study.

PubMed

Pasina, Luca; Astuto, Sarah; Cortesi, Laura; Tettamanti, Mauro; Franchi, Carlotta; Marengoni, Alessandra; Mannucci, Pier Mannuccio; Nobili, Alessandro

2016-09-01

Explicit criteria for potentially inappropriate prescriptions in the elderly are recommended to avoid prescriptions of duplicate drug classes and to optimize monotherapy within a single drug class before a new agent is considered. Duplicate drug class prescription (or therapeutic duplicates) puts the patient at increased risk of adverse drug reactions with no additional therapeutic benefits. To our knowledge, the prevalence of elderly inpatients receiving therapeutic duplicates has never been studied. Our objective was to assess the prevalence of therapeutic duplicates at admission, discharge, and 3-month follow-up of hospitalized elderly patients. This cross-sectional prospective study was conducted in 97 Italian internal medicine and geriatric wards. Therapeutic duplicates were defined as at least two drugs of the same therapeutic class prescribed simultaneously to a patient. A patient's drug therapy at admission relates to prescriptions from general practitioners, whereas prescriptions at discharge are those from hospital internists or geriatricians. The study sample comprised 5821 admitted and 4983 discharged patients. In all, 143 therapeutic duplicates were found at admission and 170 at discharge. The prevalence of patients exposed to at least one therapeutic duplicate rose significantly from hospital admission (2.5 %) to discharge (3.4 %; p = 0.0032). Psychotropic drugs and drugs for peptic ulcer or gastroesophageal reflux disease were the most frequently involved. A total of 86.8 % of patients discharged with at least one therapeutic duplicate were still receiving them at 3-month follow-up. Hospitalization and drugs prescribed by internists and geriatricians are both factors associated with a small but definite increase in overall therapeutic duplicates in elderly patients admitted to internal medicine and geriatric wards. More attention should be paid to the indications for each drug prescribed, because therapeutic duplicates are not supported by evidence and increase both the risk of adverse drug reactions and costs. Identification of unnecessary therapeutic duplicates is essential for the optimization of polypharmacy.

Substance Use Profiles of Urban American Indian Adolescents: A Latent Class Analysis.

PubMed

Kulis, Stephen S; Jager, Justin; Ayers, Stephanie L; Lateef, Husain; Kiehne, Elizabeth

2016-07-28

A growing majority of American Indian adolescents now live in cities and are at high risk of early and problematic substance use and its negative health effects. This study used latent class analysis to empirically derive heterogeneous patterns of substance use among urban American Indian adolescents, examined demographic correlates of the resulting latent classes, and tested for differences among the latent classes in other risk behavior and prosocial outcomes. The study employed a representative sample of 8th, 10th, and 12th grade American Indian adolescents (n = 2,407) in public or charter schools in metropolitan areas of Arizona in 2012. Latent class analysis examined eight types of last 30 day substance use. Four latent classes emerged: a large group of "nonusers" (69%); a substantial minority using alcohol, tobacco, and/or marijuana [ATM] (17%); a smaller group of polysubstance users consuming, alcohol, tobacco, marijuana, other illicit drugs, and prescription or OTC drugs in combination (6%); and a "not alcohol" group reporting combinations of tobacco, marijuana, and prescription drug use, but rarely alcohol use (4%). The latent classes varied by age and grade level, but not by other demographic characteristics, and aligned in highly consistent patterns on other non-substance use outcomes. Polysubstance users reported the most problematic and nonusers the least problematic outcomes, with ATM and "not alcohol" users in the middle. Urban AI adolescent substance use occurs in three somewhat distinctive patterns of combinations of recent alcohol and drug consumption, covarying in systematic ways with other problematic risk behaviors and attitudes.

Resistance to echinocandin-class antifungal drugs

PubMed Central

Perlin, David S.

2009-01-01

Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandins drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking β-1,3-D-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two “hot-spot” regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by one thousand-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom. PMID:17569573

High drug-loading nanomedicines: progress, current status, and prospects

PubMed Central

Shen, Shihong; Wu, Youshen; Liu, Yongchun; Wu, Daocheng

2017-01-01

Drug molecules transformed into nanoparticles or endowed with nanostructures with or without the aid of carrier materials are referred to as “nanomedicines” and can overcome some inherent drawbacks of free drugs, such as poor water solubility, high drug dosage, and short drug half-life in vivo. However, most of the existing nanomedicines possess the drawback of low drug-loading (generally less than 10%) associated with more carrier materials. For intravenous administration, the extensive use of carrier materials might cause systemic toxicity and impose an extra burden of degradation, metabolism, and excretion of the materials for patients. Therefore, on the premise of guaranteeing therapeutic effect and function, reducing or avoiding the use of carrier materials is a promising alternative approach to solve these problems. Recently, high drug-loading nanomedicines, which have a drug-loading content higher than 10%, are attracting increasing interest. According to the fabrication strategies of nanomedicines, high drug-loading nanomedicines are divided into four main classes: nanomedicines with inert porous material as carrier, nanomedicines with drug as part of carrier, carrier-free nanomedicines, and nanomedicines following niche and complex strategies. To date, most of the existing high drug-loading nanomedicines belong to the first class, and few research studies have focused on other classes. In this review, we investigate the research status of high drug-loading nanomedicines and discuss the features of their fabrication strategies and optimum proposal in detail. We also point out deficiencies and developing direction of high drug-loading nanomedicines. We envision that high drug-loading nanomedicines will occupy an important position in the field of drug-delivery systems, and hope that novel perspectives will be proposed for the development of high drug-loading nanomedicines. PMID:28615938

Multi-residue determination of 210 drugs in pork by ultra-high-performance liquid chromatography-tandem mass spectrometry.

PubMed

Yin, Zhiqiang; Chai, Tingting; Mu, Pengqian; Xu, Nana; Song, Yue; Wang, Xinlu; Jia, Qi; Qiu, Jing

2016-09-09

This paper presents a multi-residue analytical method for 210 drugs in pork using ultra-high-performance liquid chromatography-Q-Trap tandem mass spectrometry (UPLC-MS/MS) within 20min via positive ESI in scheduled multi-reaction monitoring (MRM) mode. The 210 drugs, belonging to 21 different chemical classes, included macrolides, sulfonamides, tetracyclines, β-lactams, β-agonists, aminoglycosides, antiviral drugs, glycosides, phenothiazine, protein anabolic hormones, non-steroidal anti-inflammatory drugs (NSAIDs), quinolones, antifungal drugs, corticosteroids, imidazoles, piperidines, piperazidines, insecticides, amides, alkaloids and others. A rapid and simple preparation method was applied to process the animal tissues, including solvent extraction with an acetonitrile/water mixture (80/20, v/v), defatting and clean-up processes. The recoveries ranged from 52% to 130% with relative standard deviations (RSDs)<20% for spiked concentrations of 10, 50 and 250μg/kg. More than 90% of the analytes achieved low limits of quantification (LOQs)<10μg/kg. The decision limit (CCα), detection capability (CCβ) values were in the range of 2-502μg/kg and 4-505μg/kg, respectively. This method is significant for food safety monitoring and controlling veterinary drug use. Copyright © 2016 Elsevier B.V. All rights reserved.

Changes in Retail Prices of Prescription Dermatologic Drugs From 2009 to 2015.

PubMed

Rosenberg, Miranda E; Rosenberg, Steven P

2016-02-01

Physicians from many specialties as well as primary care prescribe dermatologic medications; as insurance formularies become increasingly restrictive and more patients are covered with high-deductible insurance plans, many patients are forced to pay high retail prices to obtain their medications. To determine the changes in the prices of commonly prescribed dermatologic medications since 2009 and to identify trends in price increases for different classes of drugs. Four national chain pharmacies received surveys requesting price data on commonly prescribed dermatologic drugs in 2009, 2011, 2014, and 2015. The initial survey requested information on 72 brand-name drugs. Subsequent surveys increased to eventually include 120 additional brand-name drugs and their generic alternatives when available. Owing to the frequency of prescription, diseases treated, or unusual price increases, 19 brand-name drugs surveyed in all 4 years were selected for final price trend analysis, which was conducted from August 1 to 15, 2015. Retail prices of topical and systemic drugs for the treatment of various dermatologic conditions. Prices of surveyed brand-name drugs increased rapidly between 2009 and 2015. Of the 19 brand-name drugs analyzed, the retail prices of 7 drugs more than quadrupled during the study period. Among these 19 drugs, the mean price increase was 401% during the 6-year survey period, with the majority of the price increases occurring after 2011. Prices of topical antineoplastic drugs had the greatest mean absolute and percentage increase ($10,926.58 [1240%]). Prices of drugs in the antiinfective class had the smallest mean absolute increase ($333.99); prices of psoriasis medications had the smallest mean percentage increase (180%). Prices of acne and rosacea medications increased a mean of 195%, and prices of topical corticosteroids increased a mean of 290% during the study period. Selected generic drugs surveyed in 2011 and 2014 also increased a mean of 279% during the 3-year period. The price of prescription dermatologic drugs rose considerably from 2009 to 2015, with the vast majority of price increases occurring after 2011. Percent increases for multiple, frequently prescribed medications greatly outpaced inflation, national health expenditure growth, and increases in reimbursements for physician services.

Clozapine and GABA transmission in schizophrenia disease models: establishing principles to guide treatments.

PubMed

O'Connor, William T; O'Shea, Sean D

2015-06-01

Schizophrenia disease models are necessary to elucidate underlying changes and to establish new therapeutic strategies towards a stage where drug efficacy in schizophrenia (against all classes of symptoms) can be predicted. Here we summarise the evidence for a GABA dysfunction in schizophrenia and review the functional neuroanatomy of five pathways implicated in schizophrenia, namely the mesocortical, mesolimbic, ventral striopallidal, dorsal striopallidal and perforant pathways including the role of local GABA transmission and we describe the effect of clozapine on local neurotransmitter release. This review also evaluates psychotropic drug-induced, neurodevelopmental and environmental disease models including their compatibility with brain microdialysis. The validity of disease models including face, construct, etiological and predictive validity and how these models constitute theories about this illness is also addressed. A disease model based on the effect of the abrupt withdrawal of clozapine on GABA release is also described. The review concludes that while no single animal model is entirely successful in reproducing schizophreniform symptomatology, a disease model based on an ability to prevent and/or reverse the abrupt clozapine discontinuation-induced changes in GABA release in brain regions implicated in schizophrenia may be useful for hypothesis testing and for in vivo screening of novel ligands not limited to a single pharmacological class. Copyright © 2015 Elsevier Inc. All rights reserved.

Evaluation and management of the patient with difficult-to-control or resistant hypertension.

PubMed

Viera, Anthony J; Hinderliter, Alan L

2009-05-15

High blood pressure is often difficult to control. Resistant hypertension is blood pressure above goal despite adherence to a combination of at least three antihypertensive medications of different classes, optimally dosed and usually including a diuretic. The approach to blood pressure that is apparently difficult to control begins with an assessment of the patient's adherence to the management plan, including lifestyle modifications and medications. White-coat hypertension may need to be ruled out. Suboptimal therapy is the most common reason for failure to reach the blood pressure goal. Once-daily fixed-dose combination pills may improve control through the synergism of antihypertensive agents from different classes and improved adherence. Truly drug-resistant hypertension is commonly caused by chronic kidney disease, obstructive sleep apnea, or hyperaldosteronism, all of which can lead to fluid retention. Higher doses of diuretics (or a change to a loop diuretic) are usually needed. Other strategies include adding an alpha blocker, alpha-beta blocker, clonidine, or an aldosterone antagonist (e.g., spironolactone). Particularly in patients with diabetes or renal disease, combining a long-acting nondihydropyridine with a dihydropyridine calcium channel . blocker can also be considered. Obesity, heavy alcohol intake, high levels of dietary sodium, and interfering substances (especially nonsteroidal anti-inflammatory drugs) contribute to hypertension that is resistant or difficult to control.

Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors?

PubMed

Clark, David W J; Strandell, Johanna

2006-06-01

Polymyositis occurring in patients treated with omeprazole has been signalled as a possible adverse drug reaction (ADR) by the New Zealand Intensive Medicines Monitoring Programme (IMMP) and the WHO Collaborating Centre for International Drug Monitoring: the Uppsala Monitoring Centre (UMC). Polymyositis and other myopathies have also been reported in post-marketing data and in the medical literature in association with proton pump inhibitor (PPI) use. We wished to follow-up these signals and investigate the evidence of causality for the association of polymyositis and other myopathy with PPI use. Spontaneously reported ADRs from national monitoring centres are sent to the WHO ADR database (VigiBase). VigiBase was searched for case reports of the PPIs, omeprazole, pantoprazole, lansoprazole, esomeprazole and rabeprazole, with terms indicative of myopathy, and further information was elicited from the national centres to help establish causality. Literature sources were reviewed for the occurrence of the above terms in combination with PPIs. In total, there were 292 reports of various myopathies with PPIs, excluding 868 cases of 'myalgia'. In this analysis, 69 patients recovered when the drug was withdrawn and, in 15 patients, the reaction re-occurred when the drug was reinstated. In one-third of the 292 cases, the PPI was the single administered drug, and the PPI was the single suspected drug by the reporter in 57% of reports where concomitant medication was used. In this analysis, three index cases are documented. One involves the same patient taking three different PPIs (lansoprazole, esomeprazole and rabeprazole) at different time periods, with myalgia and muscle weakness occurring with all three drugs. In the two other index cases, myopathies with esomeprazole and omeprazole were reported with positive rechallenge, and causality was assessed as 'possible' and 'certain' by the reporting centres. In 27 cases myositis or polymyositis was reported. Other myopathies were reported, including 35 cases with rhabdomyolysis. In 9 of these cases, the PPI was withdrawn and the reaction abated. The PPI was reinstated in one patient, but the reaction did not re-occur. Time to onset was given in 17 of the rhabdomyolysis cases, rhabdomyolysis occurred with the first week in 9 cases, and in 3 cases the reaction occurred between 14 days to 3 months of treatment. In 12 of these patients, an HMG-CoA reductase inhibitor (statin) was taken concomitantly. Case reports from the WHO ADR database, including index cases involving four out of five PPIs, along with evidence of a possible mechanism, provide compelling evidence that there is a causal association between members of the PPI drug class and myopathy including polymyositis. Evidence was also obtained to support the view that PPI use may be associated with occurrence of other myopathies, including the serious reaction rhabdomyolysis.

Major adverse cardiovascular event reduction with GLP-1 and SGLT2 agents: evidence and clinical potential

PubMed Central

Røder, Michael E.

2017-01-01

Treatment of patients with type 2 diabetes is directed against treating symptoms of hyperglycemia, minimizing the risk of hypoglycemia, and the risk of microvascular and macrovascular complications. The majority of patients with type 2 diabetes die from cardiovascular or cerebrovascular disease. Future therapies should therefore focus on reducing cardiovascular morbidity in this high-risk population. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are two drug classes with proven antihyperglycemic effect in type 2 diabetes. However, these drugs seem to have other effects such as weight reduction, low risk of hypoglycemia, and blood pressure reduction. Emerging evidence suggests pleiotropic effects, which potentially could be important in reducing cardiovascular risk. Prompted by regulatory authorities demanding cardiovascular outcome trials (CVOTs) assessing the cardiovascular safety of new antihyperglycemic drug candidates, many CVOTs are ongoing and a few of these are finalized. Somewhat surprising recent CVOTs in both drug classes have shown promising data on cardiovascular morbidity and mortality in patients with a very high risk of cardiovascular events. It is uncertain whether this is a class effect of the two drug classes, and it is yet unproven whether long-term cardiovascular benefits of these drugs can be extrapolated to populations at lower risk of cardiovascular disease. The aim of the present review is to give an overview of our current knowledge of the GLP-1RA and SGLT2-i classes, with specific focus on mechanisms of action, effects on cardiovascular risk factors and cardiovascular morbidity and mortality from the CVOTs presently available. The clinical potential of these data is discussed. PMID:29344329

Psychotropic medication patterns among youth in foster care.

PubMed

Zito, Julie M; Safer, Daniel J; Sai, Devadatta; Gardner, James F; Thomas, Diane; Coombes, Phyllis; Dubowski, Melissa; Mendez-Lewis, Maria

2008-01-01

Studies have revealed that youth in foster care covered by Medicaid insurance receive psychotropic medication at a rate > 3 times that of Medicaid-insured youth who qualify by low family income. Systematic data on patterns of medication treatment, particularly concomitant drugs, for youth in foster care are limited. The purpose of this work was to describe and quantify patterns of psychotropic monotherapy and concomitant therapy prescribed to a randomly selected, 1-month sample of youth in foster care who had been receiving psychotropic medication. METHODS. Medicaid data were accessed for a July 2004 random sample of 472 medicated youth in foster care aged 0 through 19 years from a southwestern US state. Psychotropic medication treatment data were identified by concomitant pattern, frequency, medication class, subclass, and drug entity and were analyzed in relation to age group; gender; race or ethnicity; International Classification of Diseases, Ninth Revision, psychiatric diagnosis; and physician specialty. Of the foster children who had been dispensed psychotropic medication, 41.3% received > or = 3 different classes of these drugs during July 2004, and 15.9% received > or = 4 different classes. The most frequently used medications were antidepressants (56.8%), attention-deficit/hyperactivity disorder drugs (55.9%), and antipsychotic agents (53.2%). The use of specific psychotropic medication classes varied little by diagnostic grouping. Psychiatrists prescribed 93% of the psychotropic medication dispensed to youth in foster care. The use of > or = 2 drugs within the same psychotropic medication class was noted in 22.2% of those who were given prescribed drugs concomitantly. Concomitant psychotropic medication treatment is frequent for youth in foster care and lacks substantive evidence as to its effectiveness and safety.

Study on the association between drug‑resistance and gene mutations of the active efflux pump acrAB‑tolC gene and its regulatory genes.

PubMed

Ma, Quan-Ping; Su, Liang; Liu, Jing-Wen; Yao, Ming-Xiao; Yuan, Guang-Ying

2018-06-01

The aim of the present study was to investigate the correlation between the multi‑drug resistance of Shigella flexneri and the drug‑resistant gene cassette carried by integrons; in the meanwhile, to detect the associations between drug‑resistance and gene mutations of the active efflux pump acrAB‑tolC gene and its regulatory genes, including marOR, acrR and soxS. A total of 158 isolates were isolated from the stool samples of 1,026 children with diarrhoea aged 14 years old between May 2012 and October 2015 in Henan. The K‑B method was applied for the determination of drug resistance of Shigella flexneri, and polymerase chain reaction amplification was used for class 1, 2 and 3 integrase genes. Enzyme digestion and sequence analysis were performed for the variable regions of positive strains. Based on the drug sensitivity assessment, multi‑drug resistant strains that were resistant to five or more antibiotics, and sensitive strains were selected for amplification. Their active efflux pump genes, acrA and acrB, and regulatory genes, marOR, acrR and soxS, were selected for sequencing. The results revealed that 91.1% of the 158 strains were multi‑resistant to ampicillin, chloramphenicol, tetracycline and streptomycin, and 69.6% of the strains were multi‑resistant to sulfamethoxazole/trimethoprim. The resistance to ceftazidime, ciprofloxacin and levofloxacin was <32.9%. All strains (100%) were sensitive to cefoxitin, cefoperazone/sulbactam and imipenem. The rate of the class 1 integron positivity was 91.9% (144/158). Among these class 1 integron‑positive strains, 18 strains exhibited the resistance gene cassette dfrV in the variable region of the strain, four strains exhibited dfrA17‑aadA5 in the variable region and 140 strains exhibited blaOXA‑30‑aadA1 in the variable region. Four strains showed no resistance gene in the variable regions. The rate of class 2 integron positivity was 86.1% (136/158), and all positive strains harboured the dfrA1‑sat1‑aadA resistance gene cassette in the variable region. The class 3 integrase gene was not detected in these strains. The gene sequencing showed the deletion of base CATT in the 36, 37, 38, 39 site in the marOR gene, which is a regulatory gene of the active efflux pump, AcrAB‑TolC. Taken together, the multi‑drug resistance of Shigella flexneri was closely associated with gene mutations of class 1 and 2 integrons and the marOR gene.

Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin-Deficient Cells.

PubMed

Telford, Bryony J; Chen, Augustine; Beetham, Henry; Frick, James; Brew, Tom P; Gould, Cathryn M; Single, Andrew; Godwin, Tanis; Simpson, Kaylene J; Guilford, Parry

2015-05-01

The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein-coupled receptor (GPCR) signaling proteins were highly enriched among the synthetic lethal candidates. Diverse families of cytoskeletal proteins were also frequently represented. These broad classes of E-cadherin synthetic lethal hits were validated using both lentiviral-mediated shRNA knockdown and specific antagonists, including the JAK inhibitor LY2784544, Pertussis toxin, and the aurora kinase inhibitors alisertib and danusertib. Next, we conducted a 4,057 known drug screen and time course studies on the CDH1 isogenic MCF10A cell lines and identified additional drug classes with linkages to GPCR signaling and cytoskeletal function that showed evidence of E-cadherin synthetic lethality. These included multiple histone deacetylase inhibitors, including vorinostat and entinostat, PI3K inhibitors, and the tyrosine kinase inhibitors crizotinib and saracatinib. Together, these results demonstrate that E-cadherin loss creates druggable vulnerabilities that have the potential to improve the management of both sporadic and familial LBC and DGC. ©2015 American Association for Cancer Research.

Pharmacotherapy of focal epilepsy in children: a systematic review of approved agents.

PubMed

Arya, Ravindra; Glauser, Tracy A

2013-04-01

Partial-onset seizures contribute the bulk of seizure burden in childhood epilepsy. The therapeutic decision making involves consideration of factors specific to drug, patient and socioeconomic situation. This paper systematically reviews the available efficacy/effectiveness evidence for various anti-epileptic drugs (AED) as monotherapy and adjunctive therapy for partial-onset seizures in children. Relevant randomized clinical trials (RCTs) were identified by a structured PubMed search, supplemented by an additional hand search of reference lists and authors' files. Eligible studies were reviewed and data extracted into tables. Included RCTs were classified based on accepted published criteria. Only efficacy and effectiveness outcome measures were evaluated since there is little scientifically rigorous comprehensive AED adverse effects data. Oxcarbazepine is the only AED with Class I evidence for efficacy/effectiveness as initial monotherapy for partial-onset seizures in children. Carbamazepine, clobazam, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, vigabatrin and zonisamide have, at best, Class III efficacy/effectiveness evidence for monotherapy of partial-onset seizures in children. For adjunctive therapy, gabapentin, lamotrigine, levetiracetam, oxcarbazepine and topiramate have Class I efficacy/effectiveness evidence for treatment of pediatric partial-onset seizures. This efficacy/effectiveness analysis must not be used in isolation when selecting therapy. AED selection for a specific child needs to integrate a drug's efficacy/effectiveness data with its safety and tolerability profile, pharmacokinetic properties, available formulations, and patient specific characteristics. It is critical that physicians and patients incorporate all these relevant variables when choosing AED therapy.

21 CFR 25.33 - Animal drugs.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Animal drugs. 25.33 Section 25.33 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.33 Animal drugs. The classes of actions listed in this section are...

21 CFR 25.33 - Animal drugs.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Animal drugs. 25.33 Section 25.33 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.33 Animal drugs. The classes of actions listed in this section are...

21 CFR 25.33 - Animal drugs.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Animal drugs. 25.33 Section 25.33 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.33 Animal drugs. The classes of actions listed in this section are...

21 CFR 25.33 - Animal drugs.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Animal drugs. 25.33 Section 25.33 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.33 Animal drugs. The classes of actions listed in this section are...

21 CFR 25.33 - Animal drugs.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Animal drugs. 25.33 Section 25.33 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.33 Animal drugs. The classes of actions listed in this section are...

21 CFR 25.31 - Human drugs and biologics.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Human drugs and biologics. 25.31 Section 25.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.31 Human drugs and biologics. The classes of...

21 CFR 25.31 - Human drugs and biologics.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Human drugs and biologics. 25.31 Section 25.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.31 Human drugs and biologics. The classes of...

21 CFR 25.31 - Human drugs and biologics.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Human drugs and biologics. 25.31 Section 25.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.31 Human drugs and biologics. The classes of...

21 CFR 25.31 - Human drugs and biologics.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Human drugs and biologics. 25.31 Section 25.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ENVIRONMENTAL IMPACT CONSIDERATIONS Categorical Exclusions § 25.31 Human drugs and biologics. The classes of...

78 FR 69133 - Drug Enforcement Administration

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-18

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., California 94085, made application by renewal to the Drug Enforcement Administration (DEA) to be registered as a bulk manufacturer of the following basic classes of controlled substances: Drug Schedule...

Medicare Part D Claims Rejections for Nursing Home Residents, 2006 to 2010

PubMed Central

Stevenson, David G.; Keohane, Laura M.; Mitchell, Susan L.; Zarowitz, Barbara J.; Huskamp, Haiden A.

2013-01-01

Objectives Much has been written about trends in Medicare Part D formulary design and consumers’ choice of plans, but little is known about the magnitude of claims rejections or their clinical and administrative implications. Our objective was to study the overall rate at which Part D claims are rejected, whether these rates differ across plans, drugs, and medication classes, and how these rejection rates and reasons have evolved over time. Study Design and Methods We performed descriptive analyses of data on paid and rejected Part D claims submitted by 1 large national long-term care pharmacy from 2006 to 2010. In each of the 5 study years, data included approximately 450,000 Medicare beneficiaries living in long-term care settings with approximately 4 million Part D drug claims. Claims rejection rates and reasons for rejection are tabulated for each study year at the plan, drug, and class levels. Results Nearly 1 in 6 drug claims was rejected during the first 5 years of the Medicare Part D program, and this rate has increased over time. Rejection rates and reasons for rejection varied substantially across drug products and Part D plans. Moreover, the reasons for denials evolved over our study period. Coverage has become less of a factor in claims rejections than it was initially and other formulary tools such as drug utilization review, quantity-related coverage limits, and prior authorization are increasingly used to deny claims. Conclusions Examining claims rejection rates can provide important supplemental information to assess plans’ generosity of coverage and to identify potential areas of concern. PMID:23145808

Protocol of GLUcose COntrol Safety and Efficacy in type 2 DIabetes, a NETwork meta-analysis: GLUCOSE DINET protocol-Rational and design.

PubMed

Grenet, Guillaume; Lajoinie, Audrey; Ribault, Shams; Nguyen, Gia Bao; Linet, Thomas; Metge, Augustin; Cornu, Catherine; Cucherat, Michel; Moulin, Philippe; Gueyffier, François

2017-06-01

The aim of this study was to propose a ranking of the currently available antidiabetic drugs, regarding vascular clinical outcomes, in patients with type 2 diabetes, through a network meta-analysis approach. Randomized clinical trials, regardless of the blinding design, testing contemporary antidiabetic drugs, and considering clinically relevant outcomes in patients with type 2 diabetes mellitus will be included. The primary outcomes of this analysis will be overall mortality, cardiovascular mortality, and major cardiovascular events. Diabetic microangiopathy will be a secondary outcome. Adverse events, hypoglycemia, weight evolution, bariatric surgery, and discontinuation of the treatment will also be recorded. Each drug will be analyzed according to its therapeutic class: biguanide, alpha-glucosidase inhibitors, sulfonylureas, glitazones, glinides, insulin, DPP-4 inhibitors, GLP-1 analogs, and gliflozins. The treatment effect of each drug class will be compared using pairwise meta-analysis and a Bayesian random model network meta-analysis. Sensitivity analyses will be conducted according to the quality of the studies and the glycemic control. The report will follow the PRISMA checklist for network meta-analysis. Results of the search strategy and of the study selection will be presented in a PRISMA compliant flowchart. The treatment effects will be summarized with odds ratio (OR) estimates and their 95% credible intervals. A ranking of the drugs will be proposed. Our network meta-analysis should allow a clinically relevant ranking of the contemporary antidiabetic drugs. © 2016 Société Française de Pharmacologie et de Thérapeutique.

49 CFR 40.85 - What drugs do laboratories test for?

Code of Federal Regulations, 2013 CFR

2013-10-01

... WORKPLACE DRUG AND ALCOHOL TESTING PROGRAMS Drug Testing Laboratories § 40.85 What drugs do laboratories test for? As a laboratory, you must test for the following five drugs or classes of drugs in a DOT drug... 49 Transportation 1 2013-10-01 2013-10-01 false What drugs do laboratories test for? 40.85 Section...

49 CFR 40.85 - What drugs do laboratories test for?

Code of Federal Regulations, 2014 CFR

2014-10-01

... WORKPLACE DRUG AND ALCOHOL TESTING PROGRAMS Drug Testing Laboratories § 40.85 What drugs do laboratories test for? As a laboratory, you must test for the following five drugs or classes of drugs in a DOT drug... 49 Transportation 1 2014-10-01 2014-10-01 false What drugs do laboratories test for? 40.85 Section...

49 CFR 40.85 - What drugs do laboratories test for?

Code of Federal Regulations, 2011 CFR

2011-10-01

... WORKPLACE DRUG AND ALCOHOL TESTING PROGRAMS Drug Testing Laboratories § 40.85 What drugs do laboratories test for? As a laboratory, you must test for the following five drugs or classes of drugs in a DOT drug... 49 Transportation 1 2011-10-01 2011-10-01 false What drugs do laboratories test for? 40.85 Section...

49 CFR 40.85 - What drugs do laboratories test for?

Code of Federal Regulations, 2012 CFR

2012-10-01

... WORKPLACE DRUG AND ALCOHOL TESTING PROGRAMS Drug Testing Laboratories § 40.85 What drugs do laboratories test for? As a laboratory, you must test for the following five drugs or classes of drugs in a DOT drug... 49 Transportation 1 2012-10-01 2012-10-01 false What drugs do laboratories test for? 40.85 Section...

49 CFR 40.85 - What drugs do laboratories test for?

Code of Federal Regulations, 2010 CFR

2010-10-01

... WORKPLACE DRUG AND ALCOHOL TESTING PROGRAMS Drug Testing Laboratories § 40.85 What drugs do laboratories test for? As a laboratory, you must test for the following five drugs or classes of drugs in a DOT drug... 49 Transportation 1 2010-10-01 2010-10-01 false What drugs do laboratories test for? 40.85 Section...

Antibody–Drug Conjugates for Cancer Therapy

PubMed Central

Parslow, Adam C.; Parakh, Sagun; Lee, Fook-Thean; Gan, Hui K.; Scott, Andrew M.

2016-01-01

Antibody–drug conjugates (ADCs) take advantage of the specificity of a monoclonal antibody to deliver a linked cytotoxic agent directly into a tumour cell. The development of these compounds provides exciting opportunities for improvements in patient care. Here, we review the key issues impacting on the clinical success of ADCs in cancer therapy. Like many other developing therapeutic classes, there remain challenges in the design and optimisation of these compounds. As the clinical applications for ADCs continue to expand, key strategies to improve patient outcomes include better patient selection for treatment and the identification of mechanisms of therapy resistance. PMID:28536381

Antibody-drug conjugates for cancer therapy: The technological and regulatory challenges of developing drug-biologic hybrids.

PubMed

Hamilton, Gregory S

2015-09-01

Antibody-drug conjugates (ADCs) are a new class of therapeutic agents that combine the targeting ability of monoclonal antibodies (mAbs) with small molecule drugs. The combination of a mAb targeting a cancer-specific antigen with a cytotoxin has tremendous promise as a new type of targeted cancer therapy. Two ADCs have been approved and many more are in clinical development, suggesting that this new class of drugs is coming to the forefront. Because of their unique nature as biologic-small drug hybrids, ADCs are challenging to develop, from both the scientific and regulatory perspectives. This review discusses both these aspects in current practice, and surveys the current state of the art of ADC drug development. Copyright © 2015 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Combinations of Macrolide Resistance Determinants in Field Isolates of Mannheimia haemolytica and Pasteurella multocida▿

PubMed Central

Desmolaize, Benoit; Rose, Simon; Wilhelm, Cornelia; Warrass, Ralf; Douthwaite, Stephen

2011-01-01

Respiratory tract infections in cattle are commonly associated with the bacterial pathogens Mannheimia haemolytica and Pasteurella multocida. These infections can generally be successfully treated in the field with one of several groups of antibiotics, including macrolides. A few recent isolates of these species exhibit resistance to veterinary macrolides with phenotypes that fall into three distinct classes. The first class has type I macrolide, lincosamide, and streptogramin B antibiotic resistance and, consistent with this, the 23S rRNA nucleotide A2058 is monomethylated by the enzyme product of the erm(42) gene. The second class shows no lincosamide resistance and lacks erm(42) and concomitant 23S rRNA methylation. Sequencing of the genome of a representative strain from this class, P. multocida 3361, revealed macrolide efflux and phosphotransferase genes [respectively termed msr(E) and mph(E)] that are arranged in tandem and presumably expressed from the same promoter. The third class exhibits the most marked drug phenotype, with high resistance to all of the macrolides tested, and possesses all three resistance determinants. The combinations of erm(42), msr(E), and mph(E) are chromosomally encoded and intermingled with other exogenous genes, many of which appear to have been transferred from other members of the Pasteurellaceae. The presence of some of the exogenous genes explains recent reports of resistance to additional drug classes. We have expressed recombinant versions of the erm(42), msr(E), and mph(E) genes within an isogenic Escherichia coli background to assess their individually contributions to resistance. Our findings indicate what types of compounds might have driven the selection for these resistance determinants. PMID:21709086

Microbial contamination of syringes during preparation: the direct influence of environmental cleanliness and risk manipulations on end-product quality.

PubMed

Stucki, Cyril; Sautter, Anna-Maria; Favet, Jocelyne; Bonnabry, Pascal

2009-11-15

The direct influence of environmental cleanliness and risk manipulations on prepared syringes was evaluated. Media-fill testing was used to estimate potential microbial contamination. Syringes were prepared in three different environments using four different uncontrolled high-risk manipulations. The three environments included an International Organization for Standardization (ISO) class 5 horizontal laminar-airflow hood in an ISO class 6 cleanroom (in accordance with United States Pharmacopeia [USP] chapter 797), an ISO class 7 drug preparation area of an operating room, and an uncontrolled decentralized pharmacy in a ward. For each combination of environment and manipulation, 100 syringes were filled by a single operator. The four high-risk manipulations used included simple filling of syringes with trypticase soy broth, three-second contact by the ungloved fingers of the operator with the hub of the syringe, three-second contact between an object and the hub of the syringe, and exposure of the filled syringes to ambient air for 10 minutes. Of the 1500 syringes prepared in three different environments, none produced within the cleanroom contained microorganisms, 6% were contaminated in the operating room, and 16% were contaminated in the ward (p < 0.0001). Certain high-risk manipulations were associated with a significant increase in the contamination of the surrogate syringes, including exposure to nonsterile ambient air and nonsterile objects or fingers (p < 0.0001). High contamination rates were measured when the hub of syringes touched nonsterile environmental surfaces and fingers, whereas the drawn-air manipulation was associated with a lower risk of contamination. Working within a properly operating unidirectional airflow primary engineering control in an ISO class 5 cleanroom in accordance with USP chapter 797 requirements was demonstrated to be the best way to avoid bacterial or fungal contamination of injectable drugs directly resulting in patient infections.

Adolescent Drug Use in a Southern, Middle-Class Metropolitan High School.

ERIC Educational Resources Information Center

Chandler, Joyce; Page, Richard

1991-01-01

Examined patterns of drug use among southern, metropolitan, middle to upper-middle class high school students (n=240). Found that alcohol use was much more prevalent than was marijuana use. There was little evidence that many students had ever used cocaine in any form, depressants, phencyclidine (PCP), or lysergic acid diethylamide (LSD).(NB)

Highlights from Drugs and the Class of '78: Behaviors, Attitudes, and Recent National Trends.

ERIC Educational Resources Information Center

Johnston, Lloyd D.; And Others

The current prevalence of drug use among American high school seniors (classes of 1975 through 1978) was investigated through a program entitled "Monitoring the Future: A Continuing Study of the Lifestyles and Values of Youth," conducted by the University of Michigan's Institute for Social Research and funded by the National Institute on Drug…

Therapeutic drug monitoring of antimetabolic cytotoxic drugs

PubMed Central

Lennard, L

1999-01-01

Therapeutic drug monitoring is not routinely used for cytotoxic agents. There are several reasons, but one major drawback is the lack of established therapeutic concentration ranges. Combination chemotherapy makes the establishment of therapeutic ranges for individual drugs difficult, the concentration-effect relationship for a single drug may not be the same as that when the drug is used in a drug combination. Pharmacokinetic optimization protocols for many classes of cytotoxic compounds exist in specialized centres, and some of these protocols are now part of large multicentre trials. Nonetheless, methotrexate is the only agent which is routinely monitored in most treatment centres. An additional factor, especially in antimetabolite therapy, is the existence of pharmacogenetic enzymes which play a major role in drug metabolism. Monitoring of therapy could include assay of phenotypic enzyme activities or genotype in addition to, or instead of, the more traditional measurement of parent drug or drug metabolites. The cytotoxic activities of mercaptopurine and fluorouracil are regulated by thiopurine methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD), respectively. Lack of TPMT functional activity produces life-threatening mercaptopurine myelotoxicity. Very low DPD activity reduces fluorouracil breakdown producing severe cytotoxicity. These pharmacogenetic enzymes can influence the bioavailability, pharmacokinetics, toxicity and efficacy of their substrate drugs. PMID:10190647

Predicting Drug-Target Interactions for New Drug Compounds Using a Weighted Nearest Neighbor Profile.

PubMed

van Laarhoven, Twan; Marchiori, Elena

2013-01-01

In silico discovery of interactions between drug compounds and target proteins is of core importance for improving the efficiency of the laborious and costly experimental determination of drug-target interaction. Drug-target interaction data are available for many classes of pharmaceutically useful target proteins including enzymes, ion channels, GPCRs and nuclear receptors. However, current drug-target interaction databases contain a small number of drug-target pairs which are experimentally validated interactions. In particular, for some drug compounds (or targets) there is no available interaction. This motivates the need for developing methods that predict interacting pairs with high accuracy also for these 'new' drug compounds (or targets). We show that a simple weighted nearest neighbor procedure is highly effective for this task. We integrate this procedure into a recent machine learning method for drug-target interaction we developed in previous work. Results of experiments indicate that the resulting method predicts true interactions with high accuracy also for new drug compounds and achieves results comparable or better than those of recent state-of-the-art algorithms. Software is publicly available at http://cs.ru.nl/~tvanlaarhoven/drugtarget2013/.

Polydrug Use and HIV Risk Among People Who Inject Heroin in Tijuana, Mexico: A Latent Class Analysis.

PubMed

Meacham, Meredith C; Rudolph, Abby E; Strathdee, Steffanie A; Rusch, Melanie L; Brouwer, Kimberly C; Patterson, Thomas L; Vera, Alicia; Rangel, Gudelia; Roesch, Scott C

2015-01-01

Although most people who inject drugs (PWID) in Tijuana, Mexico, primarily inject heroin, injection and non-injection use of methamphetamine and cocaine is common. We examined patterns of polydrug use among heroin injectors to inform prevention and treatment of drug use and its health and social consequences. Participants were PWID residing in Tijuana, aged ≥18 years who reported heroin injection in the past six months and were recruited through respondent-driven sampling (n = 1,025). Latent class analysis was conducted to assign individuals to classes on a probabilistic basis, using four indicators of past six-month polydrug and polyroute use: cocaine injecting, cocaine smoking or snorting, methamphetamine injecting, and methamphetamine smoking or snorting. Latent class membership was regressed onto covariates in a multinomial logistic regression. Latent class analyses testing 1, 2, 3, and 4 classes were fit, with the 3-class solution fitting best. Class 1 was defined by predominantly heroin use (50.2%, n = 515); class 2 by methamphetamine and heroin use (43.7%, n = 448), and class 3 by methamphetamine, cocaine, and heroin use (6.0%, n = 62). Bivariate and multivariate analyses indicated a group of methamphetamine and cocaine users that exhibited higher-risk sexual practices and lower heroin injecting frequency, and a group of methamphetamine users who were younger and more likely to be female. Discrete subtypes of heroin PWID were identified based on methamphetamine and cocaine use patterns. These findings have identified subtypes of heroin injectors who require more tailored interventions to reduce the health and social harms of injecting drug use.

Polydrug use and HIV risk among people who inject heroin in Tijuana, Mexico: A Latent class analysis

PubMed Central

Meacham, M.C.; Rudolph, A.E.; Strathdee, S.A.; Rusch, M.L.; Brouwer, K.C.; Patterson, T.L.; Vera, A.; Rangel, G.; Roesch, S.C.

2016-01-01

Background Although most people who inject drugs (PWID) in Tijuana, Mexico, primarily inject heroin, injection and non-injection use of methamphetamine and cocaine is common. We examined patterns of polydrug use among heroin injectors to inform prevention and treatment of drug use and its health and social consequences. Methods Participants were PWID residing in Tijuana aged ≥ 18 years who reported heroin injection in the past 6 months and were recruited through respondent driven sampling (n=1025). Latent class analysis was conducted to assign individuals to classes on a probabilistic basis, using four indicators of past 6 month polydrug and polyroute use: cocaine injecting, cocaine smoking or snorting, methamphetamine injecting, methamphetamine smoking or snorting. Latent class membership was regressed onto covariates in a multinomial logistic regression. Results Latent class analyses testing 1, 2, 3, and 4 classes were fit, with the 3-class solution fitting best. Class 1 was defined by predominantly heroin use (50.2%, n=515); class 2 by methamphetamine and heroin use (43.7%, n=448), and class 3 by methamphetamine, cocaine, and heroin use (6.0%, n=62). Bivariate and multivariate analyses indicated a group of methamphetamine and cocaine users that exhibited higher risk sexual practices and lower heroin injecting frequency, and a group of methamphetamine users who were younger and more likely to be female. Conclusions Discrete subtypes of heroin PWID were identified based on methamphetamine and cocaine use patterns. These findings have identified subtypes of heroin injectors who require more tailored interventions to reduce the health and social harms of injecting drug use. PMID:26444185

Multi-class multi-residue analysis of veterinary drugs in meat using enhanced matrix removal lipid cleanup and liquid chromatography-tandem mass spectrometry.

PubMed

Zhao, Limian; Lucas, Derick; Long, David; Richter, Bruce; Stevens, Joan

2018-05-11

This study presents the development and validation of a quantitation method for the analysis of multi-class, multi-residue veterinary drugs using lipid removal cleanup cartridges, enhanced matrix removal lipid (EMR-Lipid), for different meat matrices by liquid chromatography tandem mass spectrometry detection. Meat samples were extracted using a two-step solid-liquid extraction followed by pass-through sample cleanup. The method was optimized based on the buffer and solvent composition, solvent additive additions, and EMR-Lipid cartridge cleanup. The developed method was then validated in five meat matrices, porcine muscle, bovine muscle, bovine liver, bovine kidney and chicken liver to evaluate the method performance characteristics, such as absolute recoveries and precision at three spiking levels, calibration curve linearity, limit of quantitation (LOQ) and matrix effect. The results showed that >90% of veterinary drug analytes achieved satisfactory recovery results of 60-120%. Over 97% analytes achieved excellent reproducibility results (relative standard deviation (RSD) < 20%), and the LOQs were 1-5 μg/kg in the evaluated meat matrices. The matrix co-extractive removal efficiency by weight provided by EMR-lipid cartridge cleanup was 42-58% in samples. The post column infusion study showed that the matrix ion suppression was reduced for samples with the EMR-Lipid cartridge cleanup. The reduced matrix ion suppression effect was also confirmed with <15% frequency of compounds with significant quantitative ion suppression (>30%) for all tested veterinary drugs in all of meat matrices. The results showed that the two-step solid-liquid extraction provides efficient extraction for the entire spectrum of veterinary drugs, including the difficult classes such as tetracyclines, beta-lactams etc. EMR-Lipid cartridges after extraction provided efficient sample cleanup with easy streamlined protocol and minimal impacts on analytes recovery, improving method reliability and consistency. Copyright © 2018 Elsevier B.V. All rights reserved.

Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs.

PubMed

Devarbhavi, Harshad; Andrade, Raúl J

2014-05-01

Antimicrobial agents including antituberculosis (anti-TB) agents are the most common cause of idiosyncratic drug-induced liver injury (DILI) and drug-induced liver failure across the world. Better molecular and genetic biomarkers are acutely needed to help identify those at risk of liver injury particularly for those needing antituberculosis therapy. Some antibiotics such as amoxicillin-clavulanate and isoniazid consistently top the lists of agents in retrospective and prospective DILI databases. Central nervous system agents, particularly antiepileptics, account for the second most common class of agents implicated in DILI registries. Hepatotoxicity from older antiepileptics such as carbamazepine, phenytoin, and phenobarbital are often associated with hypersensitivity features, whereas newer antiepileptic drugs have a more favorable safety profile. Antidepressants and nonsteroidal anti-inflammatory drugs carry very low risk of significant liver injury, but their prolific use make them important causes of DILI. Early diagnosis and withdrawal of the offending agent remain the mainstays of minimizing hepatotoxicity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Chemistry challenges in lead optimization: silicon isosteres in drug discovery.

PubMed

Showell, Graham A; Mills, John S

2003-06-15

During the lead optimization phase of drug discovery projects, the factors contributing to subsequent failure might include poor portfolio decision-making and a sub-optimal intellectual property (IP) position. The pharmaceutical industry has an ongoing need for new, safe medicines with a genuine biomedical benefit, a clean IP position and commercial viability. Inherent drug-like properties and chemical tractability are also essential for the smooth development of such agents. The introduction of bioisosteres, to improve the properties of a molecule and obtain new classes of compounds without prior art in the patent literature, is a key strategy used by medicinal chemists during the lead optimization process. Sila-substitution (C/Si exchange) of existing drugs is an approach to search for new drug-like candidates that have beneficial biological properties and a clear IP position. Some of the fundamental differences between carbon and silicon can lead to marked alterations in the physicochemical and biological properties of the silicon-containing analogues and the resulting benefits can be exploited in the drug design process.

Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids.

PubMed

Mor, Visesato; Rella, Antonella; Farnoud, Amir M; Singh, Ashutosh; Munshi, Mansa; Bryan, Arielle; Naseem, Shamoon; Konopka, James B; Ojima, Iwao; Bullesbach, Erika; Ashbaugh, Alan; Linke, Michael J; Cushion, Melanie; Collins, Margaret; Ananthula, Hari Krishna; Sallans, Larry; Desai, Pankaj B; Wiederhold, Nathan P; Fothergill, Annette W; Kirkpatrick, William R; Patterson, Thomas; Wong, Lai Hong; Sinha, Sunita; Giaever, Guri; Nislow, Corey; Flaherty, Patrick; Pan, Xuewen; Cesar, Gabriele Vargas; de Melo Tavares, Patricia; Frases, Susana; Miranda, Kildare; Rodrigues, Marcio L; Luberto, Chiara; Nimrichter, Leonardo; Del Poeta, Maurizio

2015-06-23

Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N'-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N'-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals. Copyright © 2015 Mor et al.

Sildenafil (Viagra) and club drug use in gay and bisexual men: the role of drug combinations and context.

PubMed

Halkitis, Perry N; Green, Kelly A

2007-06-01

Data ascertained in a study of club drug use among 450 gay and bisexual men indicate that at least one class of PDE-5 (phosphodiesterase type 5 inhibitor, sildenafil [Viagra]) is used frequently in combination with club drugs such as methamphetamine, MDMA (3,4 methylenedioxymethamphetamine [ecstasy]), ketamine, cocaine, and GHB (gamma hydroxy butyrate). Patterns of sildenafil use in combination with each of the club drugs differ among key demographics including race and age. Multivariate models, controlling for demographic factors, suggest that contextual factors are key to understanding why men mix sildenafil with club drugs, although age may still be an important issue to consider. Of particular importance is the fact that use of club drugs in combination with sildenafil is strongly associated with circuit and sex parties, where a centerpiece of these environments focuses on sexual exchange. These models imply interplay between person-level and contextual factors in explaining drug use patterns and further indicate that interventions aimed at addressing illicit substance use must carefully consider the role of environmental factors in explaining behavior.

Ontology-based systematic representation and analysis of traditional Chinese drugs against rheumatism.

PubMed

Liu, Qingping; Wang, Jiahao; Zhu, Yan; He, Yongqun

2017-12-21

Rheumatism represents any disease condition marked with inflammation and pain in the joints, muscles, or connective tissues. Many traditional Chinese drugs have been used for a long time to treat rheumatism. However, a comprehensive information source for these drugs is still missing, and their anti-rheumatism mechanisms remain unclear. An ontology for anti-rheumatism traditional Chinese drugs would strongly support the representation, analysis, and understanding of these drugs. In this study, we first systematically collected reported information about 26 traditional Chinese decoction pieces drugs, including their chemical ingredients and adverse events (AEs). By mostly reusing terms from existing ontologies (e.g., TCMDPO for traditional Chinese medicines, NCBITaxon for taxonomy, ChEBI for chemical elements, and OAE for adverse events) and making semantic axioms linking different entities, we developed the Ontology of Chinese Medicine for Rheumatism (OCMR) that includes over 3000 class terms. Our OCMR analysis found that these 26 traditional Chinese decoction pieces are made from anatomic entities (e.g., root and stem) from 3 Bilateria animals and 23 Mesangiospermae plants. Anti-inflammatory and antineoplastic roles are important for anti-rheumatism drugs. Using the total of 555 unique ChEBI chemical entities identified from these drugs, our ChEBI-based classification analysis identified 18 anti-inflammatory, 33 antineoplastic chemicals, and 9 chemicals (including 3 diterpenoids and 3 triterpenoids) having both anti-inflammatory and antineoplastic roles. Furthermore, our study detected 22 diterpenoids and 23 triterpenoids, including 16 pentacyclic triterpenoids that are likely bioactive against rheumatism. Six drugs were found to be associated with 184 unique AEs, including three AEs (i.e., dizziness, nausea and vomiting, and anorexia) each associated with 5 drugs. Several chemical entities are classified as neurotoxins (e.g., diethyl phthalate) and allergens (e.g., eugenol), which may explain the formation of some TCD AEs. The OCMR could be efficiently queried for useful information using SPARQL scripts. The OCMR ontology was developed to systematically represent 26 traditional anti-rheumatism Chinese drugs and their related information. The OCMR analysis identified possible anti-rheumatism and AE mechanisms of these drugs. Our novel ontology-based approach can also be applied to systematic representation and analysis of other traditional Chinese drugs.

Molecular mechanisms in therapy of acid-related diseases

PubMed Central

Shin, J. M.; Vagin, O.; Munson, K.; Kidd, M.; Modlin, I. M.; Sachs, G.

2011-01-01

Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists. PMID:17928953

Antimalarial activity of compounds comprising a primary benzene sulfonamide fragment.

PubMed

Andrews, Katherine T; Fisher, Gillian M; Sumanadasa, Subathdrage D M; Skinner-Adams, Tina; Moeker, Janina; Lopez, Marie; Poulsen, Sally-Ann

2013-11-15

Despite the urgent need for effective antimalarial drugs with novel modes of action no new chemical class of antimalarial drug has been approved for use since 1996. To address this, we have used a rational approach to investigate compounds comprising the primary benzene sulfonamide fragment as a potential new antimalarial chemotype. We report the in vitro activity against Plasmodium falciparum drug sensitive (3D7) and resistant (Dd2) parasites for a panel of fourteen primary benzene sulfonamide compounds. Our findings provide a platform to support the further evaluation of primary benzene sulfonamides as a new antimalarial chemotype, including the identification of the target of these compounds in the parasite. Copyright © 2013 Elsevier Ltd. All rights reserved.

Accurate and Reliable Prediction of the Binding Affinities of Macrocycles to Their Protein Targets.

PubMed

Yu, Haoyu S; Deng, Yuqing; Wu, Yujie; Sindhikara, Dan; Rask, Amy R; Kimura, Takayuki; Abel, Robert; Wang, Lingle

2017-12-12

Macrocycles have been emerging as a very important drug class in the past few decades largely due to their expanded chemical diversity benefiting from advances in synthetic methods. Macrocyclization has been recognized as an effective way to restrict the conformational space of acyclic small molecule inhibitors with the hope of improving potency, selectivity, and metabolic stability. Because of their relatively larger size as compared to typical small molecule drugs and the complexity of the structures, efficient sampling of the accessible macrocycle conformational space and accurate prediction of their binding affinities to their target protein receptors poses a great challenge of central importance in computational macrocycle drug design. In this article, we present a novel method for relative binding free energy calculations between macrocycles with different ring sizes and between the macrocycles and their corresponding acyclic counterparts. We have applied the method to seven pharmaceutically interesting data sets taken from recent drug discovery projects including 33 macrocyclic ligands covering a diverse chemical space. The predicted binding free energies are in good agreement with experimental data with an overall root-mean-square error (RMSE) of 0.94 kcal/mol. This is to our knowledge the first time where the free energy of the macrocyclization of linear molecules has been directly calculated with rigorous physics-based free energy calculation methods, and we anticipate the outstanding accuracy demonstrated here across a broad range of target classes may have significant implications for macrocycle drug discovery.

Short communication: cheminformatics analysis to identify predictors of antiviral drug penetration into the female genital tract.

PubMed

Thompson, Corbin G; Sedykh, Alexander; Nicol, Melanie R; Muratov, Eugene; Fourches, Denis; Tropsha, Alexander; Kashuba, Angela D M

2014-11-01

The exposure of oral antiretroviral (ARV) drugs in the female genital tract (FGT) is variable and almost unpredictable. Identifying an efficient method to find compounds with high tissue penetration would streamline the development of regimens for both HIV preexposure prophylaxis and viral reservoir targeting. Here we describe the cheminformatics investigation of diverse drugs with known FGT penetration using cluster analysis and quantitative structure-activity relationships (QSAR) modeling. A literature search over the 1950-2012 period identified 58 compounds (including 21 ARVs and representing 13 drug classes) associated with their actual concentration data for cervical or vaginal tissue, or cervicovaginal fluid. Cluster analysis revealed significant trends in the penetrative ability for certain chemotypes. QSAR models to predict genital tract concentrations normalized to blood plasma concentrations were developed with two machine learning techniques utilizing drugs' molecular descriptors and pharmacokinetic parameters as inputs. The QSAR model with the highest predictive accuracy had R(2)test=0.47. High volume of distribution, high MRP1 substrate probability, and low MRP4 substrate probability were associated with FGT concentrations ≥1.5-fold plasma concentrations. However, due to the limited FGT data available, prediction performances of all models were low. Despite this limitation, we were able to support our findings by correctly predicting the penetration class of rilpivirine and dolutegravir. With more data to enrich the models, we believe these methods could potentially enhance the current approach of clinical testing.

Prodrugs as self-assembled hydrogels: a new paradigm for biomaterials.

PubMed

Vemula, Praveen Kumar; Wiradharma, Nikken; Ankrum, James A; Miranda, Oscar R; John, George; Karp, Jeffrey M

2013-12-01

Prodrug-based self-assembled hydrogels represent a new class of active biomaterials that can be harnessed for medical applications, in particular the design of stimuli responsive drug delivery devices. In this approach, a promoiety is chemically conjugated to a known-drug to generate an amphiphilic prodrug that is capable of forming self-assembled hydrogels. Prodrug-based self-assembled hydrogels are advantageous as they alter the solubility of the drug, enhance drug loading, and eliminate the use of harmful excipients. In addition, self-assembled prodrug hydrogels can be designed to undergo controlled drug release or tailored degradation in response to biological cues. Herein we review the development of prodrug-based self-assembled hydrogels as an emerging class of biomaterials that overcome several common limitations encountered in conventional drug delivery. Published by Elsevier Ltd.

Elastin-Like Recombinamers As Smart Drug Delivery Systems.

PubMed

Arias, F Javier; Santos, Mercedes; Ibanez-Fonseca, Arturo; Pina, Maria Jesus; Serrano, Sofía

2018-02-19

Drug delivery systems that are able to control the release of bioactive molecules and designed to carry drugs to target sites are of particular interest for tissue therapy. Moreover, systems comprising materials that can respond to environmental stimuli and promote self-assembly and higher order supramolecular organization are especially useful in the biomedical field. Objetive: This review focuses on biomaterials suitable for this purpose and that include elastin-like recombinamers (ELRs), a class of proteinaceous polymers bioinspired by natural elastin, designed using recombinant technologies. The self-assembly and thermoresponsive behaviour of these systems, along with their biodegradability, biocompatibility and well-defined composition as a result of their tailormade design, make them particularly attractive for controlled drug delivery. ELR-based delivery systems that allow targeted delivery are reviewed, especially ELR-drug recombinant fusion constructs, ELR-drug systems chemically bioconjugated in their monomeric and soluble forms, and drug encapsulation by nanoparticle-forming ELRs. Subsequently, the review focuses on those drug carriers in which smart release is triggered by pH or temperature with a particular focus on cancer treatments. Systems for controlled drug release based on depots and hydrogels that act as both a support and reservoir in which drugs can be stored will be described, and their applications in drug delivery discussed. Finally, smart drug-delivery systems not based on ELRs, including those comprising proteins, synthetic polymers and non-polymeric systems, will also be briefly discussed. Several different constructions based on ELRs are potential candidates for controlled drug delivery to be applied in advanced biomedical treatments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Students who developed logical reasoning skills reported improved confidence in drug dose calculation: Feedback from remedial maths classes.

PubMed

Shelton, Chris

2016-06-01

The safe administration of drugs is a focus of attention in healthcare. It is regarded as acceptable that a formula card or mnemonic can be used to find the correct dose and fill a prescription even though this removes any requirement for performing the underlying computation. Feedback and discussion in class reveal that confidence in arithmetic skills can be low even when students are able to pass the end of semester drug calculation exam. To see if confidence in the understanding and performance of arithmetic for drug calculations can be increased by emphasising student's innate powers of logical reasoning after reflection. Remedial classes offered for students who have declared a dislike or lack of confidence in arithmetic have been developed from student feedback adopting a reasoning by logical step methodology. Students who gave up two hours of their free learning time were observed to engage seriously with the learning methods, focussing on the innate ability to perform logical reasoning necessary for drug calculation problems. Working in small groups allowed some discussion of the route to the answer and this was followed by class discussion and reflection. The results were recorded as weekly self-assessment scores for confidence in calculation. A self-selecting group who successfully completed the end of semester drug calculation exam reported low to moderate confidence in arithmetic. After four weeks focussing on logical skills a significant increase in self-belief was measured. This continued to rise in students who remained in the classes. Many students hold a negative belief regarding their own mathematical abilities. This restricts the learning of arithmetic skills making alternate routes using mnemonics and memorised steps an attractive alternative. Practising stepwise logical reasoning skills consolidated by personal reflection has been effective in developing student's confidence and awareness of their innate powers of deduction supporting an increase in competence in drug administration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Personalized Drug Therapy in Cystic Fibrosis: From Fiction to Reality.

PubMed

de Lima Marson, Fernando Augusto; Bertuzzo, Carmen Silvia; Ribeiro, Jose Dirceu

2015-01-01

Personalized drug therapy for cystic fibrosis (CF) is a long-term dream for CF patients, caregivers, physicians and researchers. After years of study, the fiction of personalized treatment has turned to hope. Basic information about CFTR mutations classes and new treatments is needed if we are to deal properly with the new CF era. The problems involved in this issue, however, should be evaluated with greater care and attention. VX-770 is a new drug available to treat CF patients with some class III CFTR mutations and other drugs are being studied regarding other classes. The scientific literature has constantly given information about each therapy, both in vitro and in vivo. The hope is increasing. Nevertheless the "scientific world" still lacks information about patients' reality and daily health related practical needs. Clinical trials have showed good evaluation of some drugs so far, but clinical response is a wide spectrum yet to be analyzed: CFTR mutations spectrum, costs related to the treatment with new drugs (for VX-770 therapy), variability of CF clinical expression, limitations to test in vitro drugs, absence of good clinical markers to evaluate drug response, absence of long-term studies and with patients below six years old, multidrug treatment used to improve the expression response, and finally, the most important problem, who will benefit from the new drugs therapy, are issues that constitute a barrier that should be overcome. Personalized drug therapy may not be a fiction anymore, but it is not yet a reality for all CF patients.

Comparative Modeling and Benchmarking Data Sets for Human Histone Deacetylases and Sirtuin Families

PubMed Central

Xia, Jie; Tilahun, Ermias Lemma; Kebede, Eyob Hailu; Reid, Terry-Elinor; Zhang, Liangren; Wang, Xiang Simon

2015-01-01

Histone Deacetylases (HDACs) are an important class of drug targets for the treatment of cancers, neurodegenerative diseases and other types of diseases. Virtual screening (VS) has become fairly effective approaches for drug discovery of novel and highly selective Histone Deacetylases Inhibitors (HDACIs). To facilitate the process, we constructed the Maximal Unbiased Benchmarking Data Sets for HDACs (MUBD-HDACs) using our recently published methods that were originally developed for building unbiased benchmarking sets for ligand-based virtual screening (LBVS). The MUBD-HDACs covers all 4 Classes including Class III (Sirtuins family) and 14 HDACs isoforms, composed of 631 inhibitors and 24,609 unbiased decoys. Its ligand sets have been validated extensively as chemically diverse, while the decoy sets were shown to be property-matching with ligands and maximal unbiased in terms of “artificial enrichment” and “analogue bias”. We also conducted comparative studies with DUD-E and DEKOIS 2.0 sets against HDAC2 and HDAC8 targets, and demonstrate that our MUBD-HDACs is unique in that it can be applied unbiasedly to both LBVS and SBVS approaches. In addition, we defined a novel metric, i.e. NLBScore, to detect the “2D bias” and “LBVS favorable” effect within the benchmarking sets. In summary, MUBD-HDACs is the only comprehensive and maximal-unbiased benchmark data sets for HDACs (including Sirtuins) that is available so far. MUBD-HDACs is freely available at http://www.xswlab.org/. PMID:25633490

The risks of polypharmacy following spinal cord injury

PubMed Central

Kitzman, Patrick; Cecil, Darrin; Kolpek, Jimmi Hatton

2017-01-01

Objective The purpose of this study was to examine the overall prevalence of polypharmacy within the spinal cord injury (SCI) population, the level of polypharmacy with respect to seven classes of high-risk drugs commonly used to treat secondary conditions in the SCI population, and the overall risks for drug-related problems (DRP) related to polypharmacy. Design A retrospective case–control design. Setting A commercially available claims dataset that included patient cases from 4800 hospitals in the USA between 2007 and 2009. Participants Individuals with tetraplegia, paraplegia, and those with SCI but not specified as either tetraplegia or paraplegia as well as a control population of randomly selected, age- and sex-matched individuals without a diagnosis of SCI. Outcome measures The overall prevalence of polypharmacy, the prevalence of commonly prescribed high-risk medications, and the prevalence of reported DRPs. Results Overall, the patients in the SCI population were prescribed significantly more medications than their control counterparts. There was a higher rate of individuals being prescribed medications from multiple high-risk classes (e.g. analgesic-narcotics, anticonvulsant, antidepressant, and skeletal muscle relaxer), as well as multiple medications within each class (e.g. multiple analgesic-narcotics). The SCI group had a higher incidence of DRPs. Conclusion Our results are some of the first to demonstrate the extent of polypharmacy in individuals with SCI, including commonly prescribed high-risk medications, leading to a higher rate of DPRs. The higher rate of polypharmacy and DRPs can impact rehabilitation goals and community integration following neurologic injury. PMID:24970339

The risks of polypharmacy following spinal cord injury.

PubMed

Kitzman, Patrick; Cecil, Darrin; Kolpek, Jimmi Hatton

2017-03-01

The purpose of this study was to examine the overall prevalence of polypharmacy within the spinal cord injury (SCI) population, the level of polypharmacy with respect to seven classes of high-risk drugs commonly used to treat secondary conditions in the SCI population, and the overall risks for drug-related problems (DRP) related to polypharmacy. A retrospective case-control design. A commercially available claims dataset that included patient cases from 4800 hospitals in the USA between 2007 and 2009. Individuals with tetraplegia, paraplegia, and those with SCI but not specified as either tetraplegia or paraplegia as well as a control population of randomly selected, age- and sex-matched individuals without a diagnosis of SCI. The overall prevalence of polypharmacy, the prevalence of commonly prescribed high-risk medications, and the prevalence of reported DRPs. Overall, the patients in the SCI population were prescribed significantly more medications than their control counterparts. There was a higher rate of individuals being prescribed medications from multiple high-risk classes (e.g. analgesic-narcotics, anticonvulsant, antidepressant, and skeletal muscle relaxer), as well as multiple medications within each class (e.g. multiple analgesic-narcotics). The SCI group had a higher incidence of DRPs. Our results are some of the first to demonstrate the extent of polypharmacy in individuals with SCI, including commonly prescribed high-risk medications, leading to a higher rate of DPRs. The higher rate of polypharmacy and DRPs can impact rehabilitation goals and community integration following neurologic injury.

Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

PubMed Central

Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

2017-01-01

Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening. PMID:28691103

Optimizing solubility and permeability of a biopharmaceutics classification system (BCS) class 4 antibiotic drug using lipophilic fragments disturbing the crystal lattice.

PubMed

Tehler, Ulrika; Fagerberg, Jonas H; Svensson, Richard; Larhed, Mats; Artursson, Per; Bergström, Christel A S

2013-03-28

Esterification was used to simultaneously increase solubility and permeability of ciprofloxacin, a biopharmaceutics classification system (BCS) class 4 drug (low solubility/low permeability) with solid-state limited solubility. Molecular flexibility was increased to disturb the crystal lattice, lower the melting point, and thereby improve the solubility, whereas lipophilicity was increased to enhance the intestinal permeability. These structural changes resulted in BCS class 1 analogues (high solubility/high permeability) emphasizing that simple medicinal chemistry may improve both these properties.

Contemporary clinical trials in ventricular tachycardia and fibrillation: implications of ESVEM, CASCADE, and CASH for clinical management.

PubMed

Anderson, J L

1995-10-01

Recent clinical trials in patients with ventricular tachycardia (VT) or fibrillation (VF) have occurred in the setting of the disappointing results of postinfarction secondary prevention studies using Class I antiarrhythmics (e.g., CAST). ESVEM addressed in a randomized trial whether electrophysiologic study (EPS) or Holter monitoring (HM) is a more accurate predictor of long-term antiarrhythmic drug efficacy in VT/VF patients (N=486) and what the relative efficacy of various antiarrhythmic agents is for VT/VF. Surprisingly, arrhythmia recurrence rates were not significantly different by the method of determining an efficacy prediction. However, arrhythmia recurrence and mortality were lower (by about 50% at 1 year) in patients treated with sotalol (a mixed Class II/III agent) than with other drugs (Class I). CASCADE evaluated empiric amiodarone versus guided (EPS or HM) standard (Class I) therapy in survivors of out-of-hospital cardiac arrest due to VF. The primary endpoint of cardiac death, resuscitated VF, or syncopal shock (in ICD patients) was reduced by amiodarone compared with conventional therapy (9% vs 23% at 1 year). An interim report of the ongoing CASH study suggested in 230 survivors of cardiac arrest that propafenone (Class IC) provided less effective prophylaxis (approximately 20% 1-year mortality) compared with randomly assigned therapies with amiodarone, metoprolol, or an ICD (approximately 14% mortality rates) and was excluded from further study. These studies have led to a paradigm shift in the approach to antiarrhythmic therapy of VT/VF: drugs with antisympathetic plus Class III (refractoriness prolonging) action (i.e., sotalol, amiodarone) are superior to traditional drugs with Class I( conduction slowing) effects, even when guided by EPS or HM.

Targeted polymeric therapeutic nanoparticles: design, development and clinical translation†

PubMed Central

Kamaly, Nazila; Xiao, Zeyu; Valencia, Pedro M.; Radovic-Moreno, Aleksandar F.; Farokhzad, Omid C.

2013-01-01

Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges associated with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochemical properties. Additionally, we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 references). PMID:22388185

Application of the BCS biowaiver approach to assessing bioequivalence of orally disintegrating tablets with immediate release formulations.

PubMed

Ono, Asami; Sugano, Kiyohiko

2014-11-20

The aim of this study was to compare the dissolution profiles of oral disintegrating tablets (ODTs) and immediate release (IR) formulations in order to experimentally validate the regulatory biowaiver scheme (BWS) for biopharmaceutical classification system (BCS) class III drugs. We examined six drugs that show clinical bioequivalence between the ODTs and IR formulations: taltirelin, olopatadine, droxidopa, famotidine, fexofenadine, and hydrochlorothiazide. The dissolution profiles of these drugs were evaluated using the compendium paddle apparatus at pH 1.2 and 6.8. Taltirelin and olopatadine showed very rapid dissolution and met the dissolution criteria in the BWS, whereas droxidopa, famotidine, fexofenadine, and hydrochlorothiazide did not. Furthermore, in the case of famotidine, fexofenadine, and hydrochlorothiazide, the ODTs and IR formulations showed dissimilar dissolution profiles. The dose-to-solubility ratio (D:S) of these drugs was larger than that of the other drugs. The results of this study suggest that extension of the BCS-BWS to ODTs and IR formulations of BCS class III drugs is appropriate. Furthermore, for BCS class III drugs with relatively high D:S, clinical bioequivalence would be achievable even when two formulations showed different dissolution profiles in vitro. Copyright © 2014 Elsevier B.V. All rights reserved.

Trends in prescriptions and costs of drugs for mental disorders in England, 1998-2010.

PubMed

Ilyas, Stephen; Moncrieff, Joanna

2012-05-01

Increasing rates of prescriptions for antidepressants, antipsychotics and stimulants have been reported from various countries. To examine trends in prescriptions and the costs of all classes of psychiatric medication in England. Data from the Prescription Cost Analysis 1998-2010 was examined, using linear regression analysis to examine trends. Prescriptions of drugs used for mental disorders increased by 6.8% (95% CI 6.3-7.4) per year on average, in line with other drugs, but made up an increasing proportion of all prescription drug costs (P = 0.001). There were rising trends in prescriptions of all classes of psychiatric drugs, except anxiolytics and hypnotics (which did not change). Antidepressant prescriptions increased by 10% (95% CI 9.0-11) per year on average, and antipsychotics by 5.1% (95% CI 4.3-5.9). Antipsychotics overtook antidepressants as the most costly class of psychiatric medication, with costs rising 22% (95% CI 17-27) per year. Rising prescriptions may be partly explained by longer-term treatment and increasing population. Nevertheless, it appears that psychiatric drugs make an increasing contribution to total prescription drug costs, with antipsychotics becoming the most costly. Low-dose prescribing of some antipsychotics is consistent with other evidence that their use may not be restricted to those with severe mental illness.

Calcium channel blockers in hypertension. Is there still a controversy?

PubMed

Izzo, Joseph L

2005-08-01

There are several reasons why no single antihypertensive drug class is ideal in all clinical situations. First, pathophysiologic heterogeneity in hypertension and diversity of mechanisms of antihypertensive drugs dictate that no single drug class can be optimally effective in all subpopulations. Second, sustained blood pressure control generally requires combination therapy to block the reflex stimulation of physiologic mechanisms that attempt to restore blood pressure to pretreatment levels. Third, while effective blood pressure control is more important than choice of initial drug in the prevention of hypertension-related morbidity and mortality, specific drug classes are indicated for optimal treatment of complications of hypertension (e.g. heart failure, kidney disease). Fourth, although antihypertensive drug side effects are uncommon, alternative strategies are required in some patients. Given these principles, past controversies regarding whether calcium channel blockers (CCBs) should be used in the treatment of hypertension become moot. CCBs are extremely effective in lowering blood pressure and in preventing stroke and cardiovascular disease. When additional blood pressure lowering is necessary to meet strict targets, CCBs may be added, even in heart failure or chronic kidney disease, where CCBs alone may not achieve optimal outcomes. Combinations of CCBs with "anti-neurohumoral" drugs such as ACE inhibitors are particularly useful to achieve sustained blood pressure control, reduce adverse effects such as edema, and improve outcomes.

Quantification of Drug Choice with the Generalized Matching Law in Rhesus Monkeys

ERIC Educational Resources Information Center

Koffarnus, Mikhail N.; Woods, James H.

2008-01-01

The generalized matching law provides precise descriptions of choice, but has not been used to characterize choice between different doses of drugs or different classes of drugs. The current study examined rhesus monkeys' drug self-administration choices between identical drug doses, different doses, different drugs (cocaine, remifentanil, and…

Cocaine use trajectories of club drug-using young adults recruited using time-space sampling

PubMed Central

Ramo, Danielle E.; Grov, Christian; Delucchi, Kevin; Kelly, Brian C.; Parsons, Jeffrey T.

2011-01-01

Cocaine is the most widely used club drug. Yet, little is known about how patterns of cocaine use vary over time among young adults of diverse gender and sexual identities. This study used latent class growth analysis to identify trajectories of cocaine use over a year and explored individual and substance use factors associated with these trajectories. A sample of 400 young adults (mean age = 23.9 years) with recent club drug use were recruited from New York City bars and nightclubs using time-space sampling. Participants completed quantitative measures at baseline, 4-, 8- and 12-months follow-up. A 4-class model fit the data best. Patterns were: Consistent use (48%), Inconsistent use (14%), Decreasing Likelihood of use (28%), and Consistent non-use (11%). Those most likely to be in the Consistent use class had the highest frequency of baseline club drug dependence (χ2 (3, 397) = 15.1, p < .01), cocaine dependence (χ2 (3, 397) = 18.9, p < .01), recent alcohol use (χ2 (3, 397) = 12.48, p < .01), and drug sensation-seeking (χ2 (3, 397) = 9.03, p < .01). Those most likely to be in the Consistent Non-use class had the highest frequency of baseline marijuana use (χ2 (3, 397) = 2.71, p < .05). Contrary to hypotheses, there were no differences in most-likely trajectory class by gender/sexual-orientation, age, ethnicity, education, employment status, or income. Findings highlight the diversity of cocaine use patterns over time among young adults, and the personal and substance use characteristics that are associated with each. PMID:21907497

Electrospun Fibers as a Dressing Material for Drug and Biological Agent Delivery in Wound Healing Applications

PubMed Central

Gizaw, Mulugeta; Thompson, Jeffrey; Faglie, Addison; Lee, Shih-Yu; Neuenschwander, Pierre; Chou, Shih-Feng

2018-01-01

Wound healing is a complex tissue regeneration process that promotes the growth of new tissue to provide the body with the necessary barrier from the outside environment. In the class of non-healing wounds, diabetic wounds, and ulcers, dressing materials that are available clinically (e.g., gels and creams) have demonstrated only a slow improvement with current available technologies. Among all available current technologies, electrospun fibers exhibit several characteristics that may provide novel replacement dressing materials for the above-mentioned wounds. Therefore, in this review, we focus on recent achievements in electrospun drug-eluting fibers for wound healing applications. In particular, we review drug release, including small molecule drugs, proteins and peptides, and gene vectors from electrospun fibers with respect to wound healing. Furthermore, we provide an overview on multifunctional dressing materials based on electrospun fibers, including those that are capable of achieving wound debridement and wound healing simultaneously as well as multi-drugs loading/types suitable for various stages of the healing process. Our review provides important and sufficient information to inform the field in development of fiber-based dressing materials for clinical treatment of non-healing wounds. PMID:29382065

The Drug Facts Box: Improving the communication of prescription drug information.

PubMed

Schwartz, Lisa M; Woloshin, Steven

2013-08-20

Communication about prescription drugs ought to be a paragon of public science communication. Unfortunately, it is not. Consumers see $4 billion of direct-to-consumer advertising annually, which typically fails to present data about how well drugs work. The professional label--the Food and Drug Administration's (FDA) mechanism to get physicians information needed for appropriate prescribing--may also fail to present benefit data. FDA labeling guidance, in fact, suggests that industry omit benefit data for new drugs in an existing class and for drugs approved on the basis of unfamiliar outcomes (such as depression rating scales). The medical literature is also problematic: there is selective reporting of favorable trials, favorable outcomes within trials, and "spinning" unfavorable results to maximize benefit and minimize harm. In contrast, publicly available FDA reviews always include the phase 3 trial data on benefit and harm, which are the basis of drug approval. However, these reviews are practically inaccessible: lengthy, poorly organized, and weakly summarized. To improve accessibility, we developed the Drug Facts Box: a one-page summary of benefit and harm data for each indication of a drug. A series of studies--including national randomized trials--demonstrates that most consumers understand the Drug Facts Box and that it improves decision-making. Despite calls from their own Risk Communication Advisory Committee and Congress (in the Affordable Care Act) to consider implementing boxes, the FDA announced it needs at least 3-5 y more to make a decision. Given its potential public health impact, physicians and the public should not have to wait that long for better drug information.

The Drug Facts Box: Improving the communication of prescription drug information

PubMed Central

Schwartz, Lisa M.; Woloshin, Steven

2013-01-01

Communication about prescription drugs ought to be a paragon of public science communication. Unfortunately, it is not. Consumers see $4 billion of direct-to-consumer advertising annually, which typically fails to present data about how well drugs work. The professional label—the Food and Drug Administration's (FDA) mechanism to get physicians information needed for appropriate prescribing—may also fail to present benefit data. FDA labeling guidance, in fact, suggests that industry omit benefit data for new drugs in an existing class and for drugs approved on the basis of unfamiliar outcomes (such as depression rating scales). The medical literature is also problematic: there is selective reporting of favorable trials, favorable outcomes within trials, and “spinning” unfavorable results to maximize benefit and minimize harm. In contrast, publicly available FDA reviews always include the phase 3 trial data on benefit and harm, which are the basis of drug approval. However, these reviews are practically inaccessible: lengthy, poorly organized, and weakly summarized. To improve accessibility, we developed the Drug Facts Box: a one-page summary of benefit and harm data for each indication of a drug. A series of studies—including national randomized trials—demonstrates that most consumers understand the Drug Facts Box and that it improves decision-making. Despite calls from their own Risk Communication Advisory Committee and Congress (in the Affordable Care Act) to consider implementing boxes, the FDA announced it needs at least 3–5 y more to make a decision. Given its potential public health impact, physicians and the public should not have to wait that long for better drug information. PMID:23942130

Field evaluation of the Los Angeles Police Department drug detection procedure.

DOT National Transportation Integrated Search

1986-12-01

The Los Angeles Police Department (LAPD) has developed a drug recognition program designed to provide trained officers the ability to detect drug-impaired drivers and to identify the responsible drug class (e.g., stimulant, depressant, etc. ). As par...

Medical management of levodopa-associated motor complications in patients with Parkinson's disease.

PubMed

Jankovic, Joseph; Stacy, Mark

2007-01-01

Parkinson's disease is a neurodegenerative disorder that affects approximately 1% of people over the age of 60 years. Levodopa is standard, and often initial, therapy for patients with this condition; however, with continued treatment and as the disease progresses, up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications. These levodopa-associated problems may become disabling and profoundly affect quality of life. Medications commonly used to manage these symptoms include monoamine oxidase type B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, the NMDA receptor antagonist amantadine and dopamine receptor agonists. Agents that block MAO-B, such as rasagiline and selegiline, are used as both initial and adjunctive therapy in patients with Parkinson's disease. These medications increase concentrations of dopamine in the brain by blocking its reuptake from the synaptic cleft, a mechanism that can slow motor decline, increase 'on' time and improve symptoms of Parkinson's disease. Adverse events with these agents can include confusion, hallucination and orthostatic hypotension. MAO-B inhibition may elicit drug-drug interactions if administered with TCAs, SSRIs or SNRIs. Conventional oral selegiline is associated with potentially harmful plasma concentrations of three major amphetamine metabolites, although metabolite concentrations are significantly lower with a new orally disintegrating tablet (ODT) selegiline formulation. Selegiline ODT is also absorbed more efficiently and shows less pharmacokinetic variability than conventional oral selegiline.COMT mediates peripheral catabolism of levodopa. Therefore, agents that block COMT, such as tolcapone and entacapone, increase the elimination half-life of levodopa. Given adjunctively with levodopa, COMT inhibitors can decrease 'off' time and increase 'on' time, as well as lower the daily levodopa dose. Although more potent than entacapone, tolcapone requires monitoring for hepatotoxicity. Amantadine is a noncompetitive NMDA receptor antagonist shown to lower dyskinesia scores and improve motor complications in patients with Parkinson's disease when given adjunctively with levodopa. Dopamine agonists, also used as initial and adjunctive therapy in Parkinson's disease, improve motor response and decrease 'off' time purportedly through direct stimulation of dopamine receptors. Current dopamine agonists include bromocriptine, pergolide, cabergoline, lisuride, apomorphine, pramipexole, ropinirole and rotigotine. Although effective, this class of medications can be associated with cardiovascular and psychiatric adverse effects that can limit their utility. All medications used to manage levodopa-associated motor complications in patients with Parkinson's disease have had differing degrees of success. Although head-to-head comparisons of drugs within classes are rare, some differences have emerged related to effects on motor fluctuations, dyskinesias and on/off times, as well as to adverse effects. When choosing a drug to treat levodopa-induced complications, it is important to consider the risks and benefits of the different classes and of the specific agents within each class, given the different efficacy and safety profiles of each.

Proteases as therapeutics

PubMed Central

Craik, Charles S.; Page, Michael J.; Madison, Edwin L.

2015-01-01

Proteases are an expanding class of drugs that hold great promise. The U.S. FDA (Food and Drug Administration) has approved 12 protease therapies, and a number of next generation or completely new proteases are in clinical development. Although they are a well-recognized class of targets for inhibitors, proteases themselves have not typically been considered as a drug class despite their application in the clinic over the last several decades; initially as plasma fractions and later as purified products. Although the predominant use of proteases has been in treating cardiovascular disease, they are also emerging as useful agents in the treatment of sepsis, digestive disorders, inflammation, cystic fibrosis, retinal disorders, psoriasis and other diseases. In the present review, we outline the history of proteases as therapeutics, provide an overview of their current clinical application, and describe several approaches to improve and expand their clinical application. Undoubtedly, our ability to harness proteolysis for disease treatment will increase with our understanding of protease biology and the molecular mechanisms responsible. New technologies for rationally engineering proteases, as well as improved delivery options, will expand greatly the potential applications of these enzymes. The recognition that proteases are, in fact, an established class of safe and efficacious drugs will stimulate investigation of additional therapeutic applications for these enzymes. Proteases therefore have a bright future as a distinct therapeutic class with diverse clinical applications. PMID:21406063

Identification of Microorganisms Isolated From Counterfeit and Unapproved Decorative Contact Lenses.

PubMed

Land, Adrian D; Penno, Katie L; Brzezinski, Jennifer L

2018-03-01

All contact lenses (corrective/noncorrective) are considered Class II or Class III medical devices under the Federal Food, Drug, and Cosmetic Act, which also states that contact lenses can only be obtained with a prescription. The Forensic Chemistry Center of the US Food & Drug Administration has examined over 300 decorative, noncorrective contact lenses obtained without a prescription. Our observations indicate that 60% of the counterfeit lenses and 27% of the unapproved lenses examined were positive for microbial contamination. Twenty-nine different brands of noncorrective contact lenses were examined, and 48% of them had at least one sample positive for microbial contamination. Each microorganism was further identified using DNA sequencing. Contaminated contact lenses are associated with numerous health risks, including ocular infections and conjunctivitis leading to permanent visual impairment or blindness. These results support the contention that acquiring contact lenses without a prescription is a considerable threat to consumer health and safety. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Use of a Classroom Jury Trial To Increase Student Perception of Science as Part of Their Lives

NASA Astrophysics Data System (ADS)

Jones, Marjorie A.

1997-05-01

The concept of a jury trial in the classroom setting was used to present and discuss a current, controversial topic, the drug mifepristone (RU486). This drug is used as an abortion inducing agent although it has other clinical uses. The major goal was for students to see that science is a very important part of their lives. The class project involved discussions of the scientific, sociological, moral, ethical, religious, legal, as well as financial aspects of a real trial which involved a major science issue. Students were involved in role playing which included obtaining information and then participating in the mock trial. Student roles in this activity were as judges, defendant, jury, witnesses, lawyers, and court reporters. This four week project involved both verbal and written participation. Grades were based on both their oral and written on this project. The students found this a very interesting activity as evidenced by their enthusiasm. This class activity could be adapted to a variety of timely topics.

The design of drugs for HIV and HCV.

PubMed

De Clercq, Erik

2007-12-01

Since the discovery of the human immunodeficiency virus (HIV) in 1983, dramatic progress has been made in the development of novel antiviral drugs. The HIV epidemic fuelled the development of new antiviral drug classes, which are now combined to provide highly active antiretroviral therapies. The need for the treatment of hepatitis C virus (HCV), which was discovered in 1989, has also provided considerable impetus for the development of new classes of antiviral drugs, and future treatment strategies for chronic HCV might involve combination regimens that are analogous to those currently used for HIV. By considering the drug targets in the different stages of the life cycle of these two viruses, this article presents aspects of the history, medicinal chemistry and mechanisms of action of approved and investigational drugs for HIV and HCV, and highlights general lessons learned from anti-HIV-drug design that could be applied to HCV.

Duloxetine

MedlinePlus

... www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/UCM096273.No matter your age, before you take an antidepressant, you, ... abdomen itching yellowing of the skin or eyes dark colored urine loss of appetite extreme tiredness or ...

Clomipramine

MedlinePlus

... www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/UCM096273.No matter your age, before you take an antidepressant, you, ... blue discoloration of the skin fever widened pupils (dark circles in the center of the eye) decreased ...

Nortriptyline

MedlinePlus

... www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/UCM096273.No matter what your age, before you take an antidepressant, ... seeing things that do not exist) widened pupils (dark circles in the middle of the eyes) drowsiness ...

Nefazodone

MedlinePlus

... www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/UCM096273.No matter what your age, before you take an antidepressant, ... the skin or eyes, unusual bleeding or bruising, dark-colored urine, pain in the upper right part ...

The impact of supersaturation level for oral absorption of BCS class IIb drugs, dipyridamole and ketoconazole, using in vivo predictive dissolution system: Gastrointestinal Simulator (GIS).

PubMed

Tsume, Yasuhiro; Matsui, Kazuki; Searls, Amanda L; Takeuchi, Susumu; Amidon, Gregory E; Sun, Duxin; Amidon, Gordon L

2017-05-01

The development of formulations and the assessment of oral drug absorption for Biopharmaceutical Classification System (BCS) class IIb drugs is often a difficult issue due to the potential for supersaturation and precipitation in the gastrointestinal (GI) tract. The physiological environment in the GI tract largely influences in vivo drug dissolution rates of those drugs. Thus, those physiological factors should be incorporated into the in vitro system to better assess in vivo performance of BCS class IIb drugs. In order to predict oral bioperformance, an in vitro dissolution system with multiple compartments incorporating physiologically relevant factors would be expected to more accurately predict in vivo phenomena than a one-compartment dissolution system like USP Apparatus 2 because, for example, the pH change occurring in the human GI tract can be better replicated in a multi-compartmental platform. The Gastrointestinal Simulator (GIS) consists of three compartments, the gastric, duodenal and jejunal chambers, and is a practical in vitro dissolution apparatus to predict in vivo dissolution for oral dosage forms. This system can demonstrate supersaturation and precipitation and, therefore, has the potential to predict in vivo bioperformance of oral dosage forms where this phenomenon may occur. In this report, in vitro studies were performed with dipyridamole and ketoconazole to evaluate the precipitation rates and the relationship between the supersaturation levels and oral absorption of BCS class II weak base drugs. To evaluate the impact of observed supersaturation levels on oral absorption, a study utilizing the GIS in combination with mouse intestinal infusion was conducted. Supersaturation levels observed in the GIS enhanced dipyridamole and ketoconazole absorption in mouse, and a good correlation between their supersaturation levels and their concentration in plasma was observed. The GIS, therefore, appears to represent in vivo dissolution phenomena and demonstrate supersaturation and precipitation of dipyridamole and ketoconazole. We therefore conclude that the GIS has been shown to be a good biopredictive tool to predict in vivo bioperformance of BCS class IIb drugs that can be used to optimize oral formulations. Copyright © 2017. Published by Elsevier B.V.

Multisite cost analysis of a school-based voluntary alcohol and drug prevention program.

PubMed

Kilmer, Beau; Burgdorf, James R; D'Amico, Elizabeth J; Miles, Jeremy; Tucker, Joan

2011-09-01

This article estimates the societal costs of Project CHOICE, a voluntary after-school alcohol and other drug prevention program for adolescents. To our knowledge, this is the first cost analysis of an after-school program specifically focused on reducing alcohol and other drug use. The article uses microcosting methods based on the societal perspective and includes a number of sensitivity analyses to assess how the results change with alternative assumptions. Cost data were obtained from surveys of participants, facilitators, and school administrators; insights from program staff members; program expenditures; school budgets; the Bureau of Labor Statistics; and the National Center for Education Statistics. From the societal perspective, the cost of implementing Project CHOICE in eight California schools ranged from $121 to $305 per participant (Mdn = $238). The major cost drivers included labor costs associated with facilitating Project CHOICE, opportunity costs of displaced class time (because of in-class promotions for Project CHOICE and consent obtainment), and other efforts to increase participation. Substituting nationally representative cost information for wages and space reduced the range to $100-$206 (Mdn = $182), which is lower than the Substance Abuse and Mental Health Services Administration's estimate of $262 per pupil for the "average effective school-based program in 2002." Denominating national Project CHOICE costs by enrolled students instead of participants generates a median per-pupil cost of $21 (range: $14-$28). Estimating the societal costs of school-based prevention programs is crucial for efficiently allocating resources to reduce alcohol and other drug use. The large variation in Project CHOICE costs across schools highlights the importance of collecting program cost information from multiple sites.

Multisite Cost Analysis of a School-Based Voluntary Alcohol and Drug Prevention Program*

PubMed Central

Kilmer, Beau; Burgdorf, James R.; D'amico, Elizabeth J.; Miles, Jeremy; Tucker, Joan

2011-01-01

Objective: This article estimates the societal costs of Project CHOICE, a voluntary after-school alcohol and other drug prevention program for adolescents. To our knowledge, this is the first cost analysis of an after-school program specifically focused on reducing alcohol and other drug use. Method: The article uses microcosting methods based on the societal perspective and includes a number of sensitivity analyses to assess how the results change with alternative assumptions. Cost data were obtained from surveys of participants, facilitators, and school administrators; insights from program staff members; program expenditures; school budgets; the Bureau of Labor Statistics; and the National Center for Education Statistics. Results: From the societal perspective, the cost of implementing Project CHOICE in eight California schools ranged from $121 to $305 per participant (Mdn = $238). The major cost drivers included labor costs associated with facilitating Project CHOICE, opportunity costs of displaced class time (because of in-class promotions for Project CHOICE and consent obtainment), and other efforts to increase participation. Substituting nationally representative cost information for wages and space reduced the range to $100–$206 (Mdn = $182), which is lower than the Substance Abuse and Mental Health Services Administration's estimate of $262 per pupil for the "average effective school-based program in 2002." Denominating national Project CHOICE costs by enrolled students instead of participants generates a median per-pupil cost of $21 (range: $14—$28). Conclusions: Estimating the societal costs of school-based prevention programs is crucial for efficiently allocating resources to reduce alcohol and other drug use. The large variation in Project CHOICE costs across schools highlights the importance of collecting program cost information from multiple sites. PMID:21906509

78 FR 76059 - New Animal Drugs for Use in Animal Feeds; Bambermycins

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-16

.... FDA-2012-N-0002] New Animal Drugs for Use in Animal Feeds; Bambermycins AGENCY: Food and Drug... amending the animal drug regulations to remove dairy replacement heifers from the pasture cattle class for....gov . SUPPLEMENTARY INFORMATION: FDA has noticed that the animal drug regulations for bambermycins...

The effect of a three-tier formulary on antidepressant utilization and expenditures.

PubMed

Hodgkin, Dominic; Parks Thomas, Cindy; Simoni-Wastila, Linda; Ritter, Grant A; Lee, Sue

2008-06-01

Health plans in the United States are struggling to contain rapid growth in their spending on medications. They have responded by implementing multi-tiered formularies, which label certain brand medications 'non-preferred' and require higher patient copayments for those medications. This multi-tier policy relies on patients' willingness to switch medications in response to copayment differentials. The antidepressant class has certain characteristics that may pose problems for implementation of three-tier formularies, such as differences in which medication works for which patient, and high rates of medication discontinuation. To measure the effect of a three-tier formulary on antidepressant utilization and spending, including decomposing spending allocations between patient and plan. We use claims and eligibility files for a large, mature nonprofit managed care organization that started introducing its three-tier formulary on January 1, 2000, with a staggered implementation across employer groups. The sample includes 109,686 individuals who were continuously enrolled members during the study period. We use a pretest-posttest quasi-experimental design that includes a comparison group, comprising members whose employer had not adopted three-tier as of March 1, 2000. This permits some control for potentially confounding changes that could have coincided with three-tier implementation. For the antidepressants that became nonpreferred, prescriptions per enrollee decreased 11% in the three-tier group and increased 5% in the comparison group. The own-copay elasticity of demand for nonpreferred drugs can be approximated as -0.11. Difference-in-differences regression finds that the three-tier formulary slowed the growth in the probability of using antidepressants in the post-period, which was 0.3 percentage points lower than it would have been without three-tier. The three-tier formulary also increased out-of-pocket payments while reducing plan payments and total spending. The results indicate that the plan enrollees were somewhat responsive to the changed incentives, shifting away from the drugs that became nonpreferred. However, the intervention also resulted in cost-shifting from plan to enrollees, indicating some price-inelasticity. The reduction in the proportion of enrollees filling any prescriptions contrasts with results of prior studies for non-psychotropic drug classes. Limitations include the possibility of confounding changes coinciding with three-tier implementation (if they affected the two groups differentially); restriction to continuous enrollees; and lack of data on rebates the plan paid to drug manufacturers. The results of this study suggest that the impact of the three-tier formulary approach may be somewhat different for antidepressants than for some other classes. Policymakers should monitor the effects of three-tier programs on utilization in psychotropic medication classes. Future studies should seek to understand the reasons for patients' limited response to the change in incentives, perhaps using physician and/or patient surveys. Studies should also examine the effects of three-tier programs on patient adherence, quality of care, and clinical and economic outcomes.

Age-Related Inducibility of Carboxylesterases by the Antiepileptic Agent Phenobarbital and Implications in Drug Metabolism and Lipid Accumulation 1, 2

PubMed Central

Xiao, Da; Chen, Yi-Tzai; Yang, Dongfang; Yan, Bingfang

2014-01-01

Carboxylesterases (CES) constitute a class of hydrolytic enzymes that play critical roles in drug metabolism and lipid mobilization. Previous studies with a large number of human liver samples have suggested that the inducibility of carboxylesterases is inversely related with age. To directly test this possibility, neonatal (10 days of age) and adult mice were treated with the antiepileptic agent phenobarbital. The expression and hydrolytic activity were determined on six major carboxylesterases including ces1d, the ortholog of human CES1. Without exception, all carboxylesterases tested were induced to a greater extent in neonatal than adult mice. The induction was detected at mRNA, protein and catalytic levels. Ces1d was greatly induced and found to rapidly hydrolyze the antiplatelet agent clopidogrel and support the accumulation of neutral lipids. Phenobarbital represents a large number of therapeutic agents that induce drug metabolizing enzymes and transporters in a species-conserved manner. The higher inducibility of carboxylesterases in the developmental age likely represents a general phenomenon cross species including human. Consequently, individuals in the developmental age may experience greater drug-drug interactions. The greater induction of ces1d also provides a molecular explanation to the clinical observation that children on antiepileptic drugs increase plasma lipids. PMID:22513142

Hypertension Update: Resistant Hypertension.

PubMed

Viera, Anthony J

2018-06-01

Resistant hypertension is a blood pressure (BP) level that remains above the goal level despite adherence to at least three appropriately dosed antihypertensive drugs of different classes, one of which is a diuretic. Evaluation of suspected resistant hypertension starts with confirming adherence to the drug regimen. White coat hypertension should be ruled out with out-of-office BP level measurements, ideally using 24-hour ambulatory BP monitoring. Obesity, significant alcohol intake, and interfering drugs and other substances can contribute to resistant hypertension. Lifestyle modifications, including exercise and dietary sodium restriction, can be useful in management. Resistant hypertension may be due to secondary etiologies (eg, parenchymal kidney disease, obstructive sleep apnea, hyperaldosteronism). Adequate diuretic treatment is a key part of therapy. In addition to a diuretic, patients with resistant hypertension should take a dihydropyridine calcium channel blocker and an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. Spironolactone is an effective fourth drug. Other drug options include a beta blocker, a long-acting nondihydropyridine calcium channel blocker, or clonidine or guanfacine. When the BP level is not controlled despite adherence to a four-drug regimen, referral to a hypertension subspecialist should be considered. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms

PubMed Central

Soderstrom, Ken; Soliman, Eman; Van Dross, Rukiyah

2017-01-01

Cannabinoids include the active constituents of Cannabis or are molecules that mimic the structure and/or function of these Cannabis-derived molecules. Cannabinoids produce many of their cellular and organ system effects by interacting with the well-characterized CB1 and CB2 receptors. However, it has become clear that not all effects of cannabinoid drugs are attributable to their interaction with CB1 and CB2 receptors. Evidence now demonstrates that cannabinoid agents produce effects by modulating activity of the entire array of cellular macromolecules targeted by other drug classes, including: other receptor types; ion channels; transporters; enzymes, and protein- and non-protein cellular structures. This review summarizes evidence for these interactions in the CNS and in cancer, and is organized according to the cellular targets involved. The CNS represents a well-studied area and cancer is emerging in terms of understanding mechanisms by which cannabinoids modulate their activity. Considering the CNS and cancer together allow identification of non-cannabinoid receptor targets that are shared and divergent in both systems. This comparative approach allows the identified targets to be compared and contrasted, suggesting potential new areas of investigation. It also provides insight into the diverse sources of efficacy employed by this interesting class of drugs. Obtaining a comprehensive understanding of the diverse mechanisms of cannabinoid action may lead to the design and development of therapeutic agents with greater efficacy and specificity for their cellular targets. PMID:29066974

Solid dispersions, part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs.

PubMed

Bikiaris, Dimitrios N

2011-12-01

The absorption of poorly water-soluble drugs, when presented in the crystalline state to the gastrointestinal tract, is typically dissolution rate-limited, and according to BCS these drugs belong mainly to class II. Both dissolution kinetics and solubility are particle size dependent. Nowadays, various techniques are available to the pharmaceutical industry for dissolution rate enhancement of such drugs. Among such techniques, nanosuspensions and drug formulation in solid dispersions are those with the highest interest. This review discusses strategies undertaken over the last 10 years, which have been applied for the dissolution enhancement of poorly water-soluble drugs; such processes include melt mixing, electrospinning, microwave irradiation and the use of inorganic nanoparticles. Many problems in this field still need to be solved, mainly the use of toxic solvents, and for this reason the use of innovative new procedures and materials will increase over the coming years. Melt mixing remains extremely promising for the preparation of SDs and will probably become the most used method in the future for the preparation of solid drug dispersions.

Weekly active-learning activities in a drug information and literature evaluation course.

PubMed

Timpe, Erin M; Motl, Susannah E; Eichner, Samantha F

2006-06-15

To incorporate learning activities into the weekly 2-hour Drug Information and Literature Evaluation class sessions to improve student ability and confidence in performing course objectives, as well as to assess student perception of the value of these activities. In-class activities that emphasized content and skills taught within class periods were created and implemented. Three different surveys assessing student ability and confidence in completing drug information and literature retrieval and evaluation tasks were administered prior to and following the appropriate class sessions. At the completion of the course, an additional evaluation was administered to assess the students' impressions of the value of the learning activities. Students reported increased ability and confidence in all course objectives. The teaching activities were also stated to be useful in students' learning of the material. Incorporation of weekly learning activities resulted in an improvement in student ability and confidence to perform course objectives. Students considered these activities to be beneficial and to contribute to the completion of course objectives.

Drugs in hair. Part I. Metabolisms of major drug classes.

PubMed

White, R M

2017-01-01

Currently, hair can be reliably tested for the presence of drugs. However, one major drawback to the use of parent drugs is the question of potential external or environmental contamination. The analysis of metabolites to confirm the use of the parent drugs was proposed in this short review. The development of hair as a test matrix and the incorporation of xenobiotics, in general, into the hair matrix were discussed. What constitutes an appropriate metabolite for drug testing to mirror the use of a parent drug was proposed and discussed. The use of metabolites rather than parent drugs to indicate unequivocal use rather than external exposure was also discussed for amphetamines, cannabinoids, cocaine, opiates (codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone), phencyclidine, fentanyl, benzodiazepines, and ethanol. This, however, was discussed in terms of class and/or individual drug. In addition, selection or potential selection of appropriate metabolites was reviewed. The actual incorporation of drug metabolites into hair versus the metabolism of drugs which was incorporated into hair were also considered. Copyright © 2017 Central Police University.

The effects of rurality on substance use disorder diagnosis: A multiple-groups latent class analysis.

PubMed

Brooks, Billy; McBee, Matthew; Pack, Robert; Alamian, Arsham

2017-05-01

Rates of accidental overdose mortality from substance use disorder (SUD) have risen dramatically in the United States since 1990. Between 1999 and 2004 alone rates increased 62% nationwide, with rural overdose mortality increasing at a rate 3 times that seen in urban populations. Cultural differences between rural and urban populations (e.g., educational attainment, unemployment rates, social characteristics, etc.) affect the nature of SUD, leading to disparate risk of overdose across these communities. Multiple-groups latent class analysis with covariates was applied to data from the 2011 and 2012 National Survey on Drug Use and Health (n=12.140) to examine potential differences in latent classifications of SUD between rural and urban adult (aged 18years and older) populations. Nine drug categories were used to identify latent classes of SUD defined by probability of diagnosis within these categories. Once the class structures were established for rural and urban samples, posterior membership probabilities were entered into a multinomial regression analysis of socio-demographic predictors' association with the likelihood of SUD latent class membership. Latent class structures differed across the sub-groups, with the rural sample fitting a 3-class structure (Bootstrap Likelihood Ratio Test P value=0.03) and the urban fitting a 6-class model (Bootstrap Likelihood Ratio Test P value<0.0001). Overall the rural class structure exhibited less diversity in class structure and lower prevalence of SUD in multiple drug categories (e.g. cocaine, hallucinogens, and stimulants). This result supports the hypothesis that different underlying elements exist in the two populations that affect SUD patterns, and thus can inform the development of surveillance instruments, clinical services, and prevention programming tailored to specific communities. Copyright © 2017 Elsevier Ltd. All rights reserved.

Changes in Body Weight and Psychotropic Drugs: A Systematic Synthesis of the Literature

PubMed Central

Dent, Robert; Blackmore, Angelique; Peterson, Joan; Habib, Rami; Kay, Gary Peter; Gervais, Alan; Taylor, Valerie; Wells, George

2012-01-01

Introduction Psychotropic medication use is associated with weight gain. While there are studies and reviews comparing weight gain for psychotropics within some classes, clinicians frequently use drugs from different classes to treat psychiatric disorders. Objective To undertake a systematic review of all classes of psychotropics to provide an all encompassing evidence-based tool that would allow clinicians to determine the risks of weight gain in making both intra-class and interclass choices of psychotropics. Methodology and Results We developed a novel hierarchical search strategy that made use of systematic reviews that were already available. When such evidence was not available we went on to evaluate randomly controlled trials, followed by cohort and other clinical trials, narrative reviews, and, where necessary, clinical opinion and anecdotal evidence. The data from the publication with the highest level of evidence based on our hierarchical classification was presented. Recommendations from an expert panel supplemented the evidence used to rank these drugs within their respective classes. Approximately 9500 articles were identified in our literature search of which 666 citations were retrieved. We were able to rank most of the psychotropics based on the available evidence and recommendations from subject matter experts. There were few discrepancies between published evidence and the expert panel in ranking these drugs. Conclusion Potential for weight gain is an important consideration in choice of any psychotropic. This tool will help clinicians select psychotropics on a case-by-case basis in order to minimize the impact of weight gain when making both intra-class and interclass choices. PMID:22719834

Translating data on antihypertensive drugs into clinical practice.

PubMed

Weber, M A

1998-06-01

Two problems in the treatment of hypertension continue to be largely unsolved. The first, and more simple, is our inability to adequately control blood pressure in the majority of hypertensive patients. This not only reflects the difficulty of retaining patients in effective treatment programs, but also of convincing physicians to strive for optimal blood pressure levels. There is a continuing need for new antihypertensive drugs and combinations to help accomplish these goals. The second major problem is that the major clinical endpoints, including coronary events and renal failure, have not been adequately reduced by traditional therapies. Standard regimens, particularly those including diuretics, have protected against strokes and heart failure. Our improved understanding of vascular biology in hypertension has directed interest to the mechanisms in hypertensive patients that might accelerate atherosclerosis and vascular events in these individuals. This involves addressing the concomitant metabolic risk factors that comprise the "Hypertension Syndrome," and, perhaps of equal importance, finding therapies that directly inhibit unwanted types of growth and proliferative activities within the walls of critical arteries. Many substances within the endothelium and the vascular wall may participate as initiators or mediators of pathology, but most information thus far has focused on the renin-angiotensin system. Angiotensin converting enzyme inhibitors (and potentially angiotensin receptor blockers) have provided coronary and renal protection in various cardiovascular conditions, though not yet in formal hypertension trials. Calcium channel blockers have also shown promise, including recent stroke and cardiovascular benefits in patients with isolated systolic hypertension, but, again, definitive coronary data in hypertension are awaited. Unless concomitant conditions mandate the selection of a particular antihypertensive drug class, physicians currently have a dilemma: should they choose drugs from older classes that have not provided full protection? Or, should they prescribe newer agents with exciting potential but with, as yet, unproved endpoint benefits in hypertension? Until currently ongoing prospective trials of antihypertensive therapy are completed, physicians must be guided by their own interpretations of the available data.

Drug-induced seizures in children and adolescents presenting for emergency care: current and emerging trends.

PubMed

Finkelstein, Y; Hutson, J R; Freedman, S B; Wax, P; Brent, J

2013-01-01

Seizures may be the presenting manifestation of acute poisoning in children. Knowledge of the etiologic agent, or likely drug-class exposure, is crucial to minimize morbidity and optimize care. To describe the agents most commonly responsible for pediatric drug-induced seizures, whose evaluation included a medical toxicology consultation in the United States. Using the 37 participating sites of the Toxicology Investigators Consortium (ToxIC) Case Registry, a cross-country surveillance tool, we conducted an observational study of a prospectively collected cohort. We identified all pediatric (younger than 18 years) reports originating from an Emergency Department (ED) which included a chemical or drug-induced seizure, and required a medical toxicology consultation between April 1, 2010 and March 31, 2012. Results. We identified 142 pediatric drug-induced seizure cases (56% male), which represent nearly 5% of pediatric cases requiring bedside consultation by medical toxicologists. One-hundred and seven cases (75%) occurred in children aged 13-18 years, and 86 (61%) resulted from intentional ingestions. Antidepressants were the most commonly identified agents ingested (n = 61; 42%), of which bupropion was the leading drug (n = 30; 50% of antidepressants), followed by anticholinergics/antihistamines (n = 31; 22%). All antidepressant-induced seizures in teenagers were intentional and represented self-harm behavior. Sympathomimetic agents, including street drugs, represent the most common agents in children younger than 2 years (n = 4/19). Antidepressants, and specifically bupropion, are presently the most common medications responsible for pediatric drug-induced seizures requiring medical toxicology consultation in the United States. In teenagers presenting with new-onset seizures of unknown etiology, the possibility of deliberate self-poisoning should be explored, since most drug-induced seizures in this age group resulted from intentional ingestion.

Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development

PubMed Central

Wolk, Omri; Agbaria, Riad; Dahan, Arik

2014-01-01

The main objective of this work was to investigate in-silico predictions of physicochemical properties, in order to guide oral drug development by provisional biopharmaceutics classification system (BCS). Four in-silico methods were used to estimate LogP: group contribution (CLogP) using two different software programs, atom contribution (ALogP), and element contribution (KLogP). The correlations (r2) of CLogP, ALogP and KLogP versus measured LogP data were 0.97, 0.82, and 0.71, respectively. The classification of drugs with reported intestinal permeability in humans was correct for 64.3%–72.4% of the 29 drugs on the dataset, and for 81.82%–90.91% of the 22 drugs that are passively absorbed using the different in-silico algorithms. Similar permeability classification was obtained with the various in-silico methods. The in-silico calculations, along with experimental melting points, were then incorporated into a thermodynamic equation for solubility estimations that largely matched the reference solubility values. It was revealed that the effect of melting point on the solubility is minor compared to the partition coefficient, and an average melting point (162.7°C) could replace the experimental values, with similar results. The in-silico methods classified 20.76% (±3.07%) as Class 1, 41.51% (±3.32%) as Class 2, 30.49% (±4.47%) as Class 3, and 6.27% (±4.39%) as Class 4. In conclusion, in-silico methods can be used for BCS classification of drugs in early development, from merely their molecular formula and without foreknowledge of their chemical structure, which will allow for the improved selection, engineering, and developability of candidates. These in-silico methods could enhance success rates, reduce costs, and accelerate oral drug products development. PMID:25284986

Dendrimeric Systems and Their Applications in Ocular Drug Delivery

PubMed Central

Yavuz, Burçin; Bozdağ Pehlivan, Sibel; Ünlü, Nurşen

2013-01-01

Ophthalmic drug delivery is one of the most attractive and challenging research area for pharmaceutical scientists and ophthalmologists. Absorption of an ophthalmic drug in conventional dosage forms is seriously limited by physiological conditions. The use of nonionic or ionic biodegradable polymers in aqueous solutions and colloidal dosage forms such as liposomes, nanoparticles, nanocapsules, microspheres, microcapsules, microemulsions, and dendrimers has been studied to overcome the problems mentioned above. Dendrimers are a new class of polymeric materials. The unique nanostructured architecture of dendrimers has been studied to examine their role in delivery of therapeutics and imaging agents. Dendrimers can enhance drug's water solubility, bioavailability, and biocompatibility and can be applied for different routes of drug administration successfully. Permeability enhancer properties of dendrimers were also reported. The use of dendrimers can also reduce toxicity versus activity and following an appropriate application route they allow the delivery of the drug to the targeted site and provide desired pharmacokinetic parameters. Therefore, dendrimeric drug delivery systems are of interest in ocular drug delivery. In this review, the limitations related to eye's unique structure, the advantages of dendrimers, and the potential applications of dendrimeric systems to ophthalmology including imaging, drug, peptide, and gene delivery will be discussed. PMID:24396306

Immediate-type hypersensitivity drug reactions

PubMed Central

Stone, Shelley F; Phillips, Elizabeth J; Wiese, Michael D; Heddle, Robert J; Brown, Simon G A

2014-01-01

Hypersensitivity reactions including anaphylaxis have been reported for nearly all classes of therapeutic reagents and these reactions can occur within minutes to hours of exposure. These reactions are unpredictable, not directly related to dose or the pharmacological action of the drug and have a relatively high mortality risk. This review will focus on the clinical presentation, immune mechanisms, diagnosis and prevention of the most serious form of immediate onset drug hypersensitivity reaction, anaphylaxis. The incidence of drug-induced anaphylaxis deaths appears to be increasing and our understanding of the multiple and complex reasons for the unpredictable nature of anaphylaxis to drugs is also expanding. This review highlights the importance of enhancing our understanding of the biology of the patient (i.e. immune response, genetics) as well as the pharmacology and chemistry of the drug when investigating, diagnosing and treating drug hypersensitivity. Misdiagnosis of drug hypersensitivity leads to substantial patient risk and cost. Although oral provocation is often considered the gold standard of diagnosis, it can pose a potential risk to the patient. There is an urgent need to improve and standardize diagnostic testing and desensitization protocols as other diagnostic tests currently available for assessment of immediate drug allergy are not highly predictive. PMID:24286446

Immediate-type hypersensitivity drug reactions.

PubMed

Stone, Shelley F; Phillips, Elizabeth J; Wiese, Michael D; Heddle, Robert J; Brown, Simon G A

2014-07-01

Hypersensitivity reactions including anaphylaxis have been reported for nearly all classes of therapeutic reagents and these reactions can occur within minutes to hours of exposure. These reactions are unpredictable, not directly related to dose or the pharmacological action of the drug and have a relatively high mortality risk. This review will focus on the clinical presentation, immune mechanisms, diagnosis and prevention of the most serious form of immediate onset drug hypersensitivity reaction, anaphylaxis. The incidence of drug-induced anaphylaxis deaths appears to be increasing and our understanding of the multiple and complex reasons for the unpredictable nature of anaphylaxis to drugs is also expanding. This review highlights the importance of enhancing our understanding of the biology of the patient (i.e. immune response, genetics) as well as the pharmacology and chemistry of the drug when investigating, diagnosing and treating drug hypersensitivity. Misdiagnosis of drug hypersensitivity leads to substantial patient risk and cost. Although oral provocation is often considered the gold standard of diagnosis, it can pose a potential risk to the patient. There is an urgent need to improve and standardize diagnostic testing and desensitization protocols as other diagnostic tests currently available for assessment of immediate drug allergy are not highly predictive. © 2013 The British Pharmacological Society.

The Metabolism of the Volatile Amines

PubMed Central

Tobe, Barry A.; Goldman, Bernard S.

1963-01-01

The effects of certain drugs on metabolism of ammonia by the liver and kidneys in dogs were investigated by a technique in which both hepatic inflow and outflow bloods could be repeatedly sampled in unanesthetized healthy animals. Specific representatives of the classes of the drugs studied included thiopental (barbiturates), morphine (opiates and analgesics), promazine (tranquillizers), and chlorothiazide (oral diuretics). The three drugs commonly used as sedatives were all found to impair the ability of the liver to metabolize ammonia. The diuretic, by contrast, increased the amount of ammonia put into the systemic system by the kidneys. Ethanol appeared to have little or no direct effect on ammonia metabolism. The possibility exists that the occurrence of acute hepatic encephalopathy in patients with severe liver disease may be avoided in many cases if these drugs are administered with proper care. Results also indicated that current concepts of the pharmacological action of sedatives, opiates and tranquillizers may require revision. ImagesFig. 2 PMID:14069611

Targeting bacterial central metabolism for drug development.

PubMed

Murima, Paul; McKinney, John D; Pethe, Kevin

2014-11-20

Current antibiotics, derived mainly from natural sources, inhibit a narrow spectrum of cellular processes, namely DNA replication, protein synthesis, and cell wall biosynthesis. With the worldwide explosion of drug resistance, there is renewed interest in the investigation of alternate essential cellular processes, including bacterial central metabolic pathways, as a drug target space for the next generation of antibiotics. However, the validation of targets in central metabolism is more complex, as essentiality of such targets can be conditional and/or contextual. Bearing in mind our enhanced understanding of prokaryotic central metabolism, a key question arises: can central metabolism be bacteria's Achilles' heel and a therapeutic target for the development of new classes of antibiotics? In this review, we draw lessons from oncology and attempt to address some of the open questions related to feasibility of targeting bacterial central metabolism as a strategy for developing new antibacterial drugs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Thiolated chitosans: useful excipients for oral drug delivery.

PubMed

Werle, Martin; Bernkop-Schnürch, Andreas

2008-03-01

To improve the bioavailability of orally administered drugs, formulations based on polymers are of great interest for pharmaceutical technologists. Thiolated chitosans are multifunctional polymers that exhibit improved mucoadhesive, cohesive and permeation-enhancing as well as efflux-pump-inhibitory properties. They can be synthesized by derivatization of the primary amino groups of chitosan with coupling reagents bearing thiol functions. Various data gained in-vitro as well as in-vivo studies clearly demonstrate the potential of thiolated chitosans for oral drug delivery. Within the current review, the synthesis and characterization of thiolated chitosans so far developed is summarized. Features of thiolated chitosans important for oral drug delivery are discussed as well. Moreover, different formulation approaches, such as matrix tablets and micro-/nanoparticles, as well as the applicability of thiolated chitosans for the oral delivery of various substance classes including peptides and efflux pump substrates, are highlighted.

Drug development from the bench to the pharmacy: with special reference to dipeptidyl peptidase-4 inhibitor development.

PubMed

Carr, R D

2016-06-01

The dipeptidyl peptidase-4 (DPP-4) inhibitor concept is an example of prospective drug design and development based upon a distinct endocrine hypothesis. The design of enzyme inhibitors is a pragmatic approach to drug design; being compatible with the identification and optimization of small molecules that have properties commensurate with oral administration, as well as acceptable drug metabolism, distribution and elimination characteristics. Glucagon-like peptide 1 (GLP-1), a hormone with a spectrum of favourable metabolic actions, including glucose-dependent stimulation of insulin and inhibition of glucagon secretion, provided the endocrine basis from which the idea of using DPP-4 inhibitors as anti-diabetic agents was developed. The origin of the DPP-4 inhibitor concept was inspired by the angiotensin-converting enzyme inhibitor approach, which succeeded in establishing a class of extensively used therapeutic agents for the treatment of cardiovascular disorders. © 2016 Diabetes UK.

Patterns and Correlates of Drug Use Among Urban High School Students

ERIC Educational Resources Information Center

Mc Killip, Jack; And Others

1973-01-01

A drug-use survey was administered in a large metropolitan, middle class high school to test two hypotheses: a. drug users can be divided according to the types of drugs used (tobacco, alcohol, and marijuana vs. opiates, LSD, amphetamines, etc.); and, b. respondents' drug use is significantly related to their peers drug use. Both hypotheses were…

Prospects for new antibacterials: can we do better?

PubMed

Georgopapadakou, Nafsika H

2014-02-01

Bacterial resistance to antibacterial drugs has been increasing relentlessly over the past two decades. This includes common residents of the human body: Staphylococcus aureus (methicillin resistant or MRSA) Enteroccus faecalis and E. faecium (vancomycin resistant or VRE): Enterobacteriaceae (multiresistant, carbapenems included or CRE). It also includes environmental, opportunistic, but intrinsically multiresistant species: Pseudomonas aeruginosa and Acinetobacter baumannii. Financial considerations have curtailed R&D activity in the antibacterial field in all, but a couple of large pharmaceutical companies and small biotech companies have largely been unable to fill the drug discovery gap. Antibacterials currently under development have targeted, almost exclusively, Gram-positive bacteria; hence, greater effort must be directed against Gram-negative bacteria, particularly enterobacteria. There also has to be more transparency and care in clinical development. To get ahead of the problem of resistance, we must look for first-in-class antibacterials and new targets. The need to innovate is best addressed through partnerships between drug-makers and public institutions. Such partnerships would provide a long-term view and stability to projects, but also balance the interests of corporate and public stakeholders.

Different classes of antibiotics given to women routinely for preventing infection at caesarean section.

PubMed

Gyte, Gillian M I; Dou, Lixia; Vazquez, Juan C

2014-11-17

Caesarean section increases the risk of postpartum infection for women and prophylactic antibiotics have been shown to reduce the incidence; however, there are adverse effects. It is important to identify the most effective class of antibiotics to use and those with the least adverse effects. To determine, from the best available evidence, the balance of benefits and harms between different classes of antibiotic given prophylactically to women undergoing caesarean section. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2014) and reference lists of retrieved papers. We included randomised controlled trials comparing different classes of prophylactic antibiotics given to women undergoing caesarean section. We excluded trials that compared drugs with placebo or drugs within a specific class; these are assessed in other Cochrane reviews. Two review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. We included 35 studies of which 31 provided data on 7697 women. For the main comparison between cephalosporins versus penicillins, there were 30 studies of which 27 provided data on 7299 women. There was a lack of good quality data and important outcomes often included only small numbers of women.For the comparison of a single cephalosporin versus a single penicillin (Comparison 1 subgroup 1), we found no significant difference between these classes of antibiotics for our chosen most important seven outcomes namely: maternal sepsis - there were no women with sepsis in the two studies involving 346 women; maternal endometritis (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.81 to 1.52, nine studies, 3130 women, random effects, moderate quality of the evidence); maternal wound infection (RR 0.83, 95% CI 0.38 to 1.81, nine studies, 1497 women, random effects, low quality of the evidence), maternal urinary tract infection (RR 1.48, 95% CI 0.89 to 2.48, seven studies, 1120 women, low quality of the evidence) and maternal composite adverse effects (RR 2.02, 95% CI 0.18 to 21.96, three studies, 1902 women, very low quality of the evidence). None of the included studies looked for infant sepsis nor infant oral thrush.This meant we could only conclude that the current evidence shows no overall difference between the different classes of antibiotics in terms of reducing maternal infections after caesarean sections. However, none of the studies reported on infections diagnosed after the initial postoperative hospital stay. We were unable to assess what impact, if any, the use of different classes of antibiotics might have on bacterial resistance. Based on the best currently available evidence, cephalosporins and penicillins have similar efficacy at caesarean section when considering immediate postoperative infections. We have no data for outcomes on the baby, nor on late infections (up to 30 days) in the mother. Clinicians need to consider bacterial resistance and women's individual circumstances.

Antidepressants, antimicrobials or both? Gut microbiota dysbiosis in depression and possible implications of the antimicrobial effects of antidepressant drugs for antidepressant effectiveness.

PubMed

Macedo, Danielle; Filho, Adriano José Maia Chaves; Soares de Sousa, Caren Nádia; Quevedo, João; Barichello, Tatiana; Júnior, Hélio Vitoriano Nobre; Freitas de Lucena, David

2017-01-15

The first drug repurposed for the treatment of depression was the tuberculostatic iproniazid. At present, drugs belonging to new classes of antidepressants still have antimicrobial effects. Dysbiosis of gut microbiota was implicated in the development or exacerbation of mental disorders, such as major depressive disorder (MDD). Based on the current interest in the gut-brain axis, the focus of this narrative review is to compile the available studies regarding the influences of gut microbiota in behavior and depression and to show the antimicrobial effect of antidepressant drugs. A discussion regarding the possible contribution of the antimicrobial effect of antidepressant drugs to its effectiveness/resistance is included. The search included relevant articles from PubMed, SciELO, LILACS, PsycINFO, and ISI Web of Knowledge. MDD is associated with changes in gut permeability and microbiota composition. In this respect, antidepressant drugs present antimicrobial effects that could also be related to the effectiveness of these drugs for MDD treatment. Conversely, some antimicrobials present antidepressant effects. Both antidepressants and antimicrobials present neuroprotective/antidepressant and antimicrobial effects. Further studies are needed to evaluate the participation of antimicrobial mechanisms of antidepressants in MDD treatment as well as to determine the contribution of this effect to antidepressant resistance. Copyright © 2016 Elsevier B.V. All rights reserved.

Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection

PubMed Central

Dyall, Julie; Coleman, Christopher M.; Hart, Brit J.; Venkataraman, Thiagarajan; Holbrook, Michael R.; Kindrachuk, Jason; Johnson, Reed F.; Olinger, Gene G.; Jahrling, Peter B.; Laidlaw, Monique; Johansen, Lisa M.; Lear-Rooney, Calli M.; Glass, Pamela J.; Hensley, Lisa E.

2014-01-01

Outbreaks of emerging infections present health professionals with the unique challenge of trying to select appropriate pharmacologic treatments in the clinic with little time available for drug testing and development. Typically, clinicians are left with general supportive care and often untested convalescent-phase plasma as available treatment options. Repurposing of approved pharmaceutical drugs for new indications presents an attractive alternative to clinicians, researchers, public health agencies, drug developers, and funding agencies. Given the development times and manufacturing requirements for new products, repurposing of existing drugs is likely the only solution for outbreaks due to emerging viruses. In the studies described here, a library of 290 compounds was screened for antiviral activity against Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Selection of compounds for inclusion in the library was dependent on current or previous FDA approval or advanced clinical development. Some drugs that had a well-defined cellular pathway as target were included. In total, 27 compounds with activity against both MERS-CoV and SARS-CoV were identified. The compounds belong to 13 different classes of pharmaceuticals, including inhibitors of estrogen receptors used for cancer treatment and inhibitors of dopamine receptor used as antipsychotics. The drugs identified in these screens provide new targets for in vivo studies as well as incorporation into ongoing clinical studies. PMID:24841273

New drugs of abuse.

PubMed

Rech, Megan A; Donahey, Elisabeth; Cappiello Dziedzic, Jacqueline M; Oh, Laura; Greenhalgh, Elizabeth

2015-02-01

Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and have become increasingly popular. Recognition and treatment of new drugs of abuse pose many challenges for health care providers due to lack of quantitative reporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinical and adverse effects and purported pharmacology of several new classes of drugs of abuse including synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of these substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases. © 2014 Pharmacotherapy Publications, Inc.

A survey of the administration of drugs to young infants. The Alspac Survey Team. Avon Longitudinal Study of Pregnancy and Childhood.

PubMed Central

Hawkins, N; Golding, J

1995-01-01

Medication which is given to young infants during the first months of life, an important period of development, may have effects on development which would not be observed in adults receiving the same drugs. The aim of this study was to estimate the numbers of children receiving various types of medication, including both prescription and non-prescription drugs, during the first 6 months of life. Self-completion questionnaires were posted to mothers participating in the Avon Longitudinal Study of Pregnancy & Childhood (ALSPAC) when their children were 6 months of age. These questionnaires included enquiries about the administration of drugs to the study children. The study was based in the three Bristol-based health districts of Avon in the United Kingdom. The study population comprised of 6973 children born in the 12 month period between the 1st July 1991 and the 30th June 1992. The majority of mothers, 96%, reported that their children had received medication, excluding vaccines, during the first 6 months of life. 35% had been given drugs from four or more different classes. Paracetamol had been given to 84% of the children, antibiotics to 30%. In view of potential effects of drug exposure on long term development, it is important that drugs which are administered to children are carefully assessed to ensure that they are not harmful. PMID:8527273

Association of medication errors with drug classifications, clinical units, and consequence of errors: Are they related?

PubMed

Muroi, Maki; Shen, Jay J; Angosta, Alona

2017-02-01

Registered nurses (RNs) play an important role in safe medication administration and patient safety. This study examined a total of 1276 medication error (ME) incident reports made by RNs in hospital inpatient settings in the southwestern region of the United States. The most common drug class associated with MEs was cardiovascular drugs (24.7%). Among this class, anticoagulants had the most errors (11.3%). The antimicrobials was the second most common drug class associated with errors (19.1%) and vancomycin was the most common antimicrobial that caused errors in this category (6.1%). MEs occurred more frequently in the medical-surgical and intensive care units than any other hospital units. Ten percent of MEs reached the patients with harm and 11% reached the patients with increased monitoring. Understanding the contributing factors related to MEs, addressing and eliminating risk of errors across hospital units, and providing education and resources for nurses may help reduce MEs. Copyright © 2016 Elsevier Inc. All rights reserved.

Solving the Conflict in Southern Thailand

DTIC Science & Technology

2009-03-25

includes allegations of police brutality, criminal activity , disrespect of Islam, the presence of culturally insensitive businesses such as bars, drug...the advocacy of cultural , ethnic, tribal, religious, racial or gender separation from the larger group, often with demands for greater political...countries would be studied as possible models for the south. Moreover, Brigadier General Kanid Utitsarn, a US Army War College student in the Class of 2007

Clinical applications of hallucinogens: A review.

PubMed

Garcia-Romeu, Albert; Kersgaard, Brennan; Addy, Peter H

2016-08-01

Hallucinogens fall into several different classes, as broadly defined by pharmacological mechanism of action, and chemical structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the molecular to the behavioral level, and presenting the most up-to-date information on clinically oriented research with these substances, with important ramifications for their potential therapeutic value. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Structure-based drug design for G protein-coupled receptors.

PubMed

Congreve, Miles; Dias, João M; Marshall, Fiona H

2014-01-01

Our understanding of the structural biology of G protein-coupled receptors has undergone a transformation over the past 5 years. New protein-ligand complexes are described almost monthly in high profile journals. Appreciation of how small molecules and natural ligands bind to their receptors has the potential to impact enormously how medicinal chemists approach this major class of receptor targets. An outline of the key topics in this field and some recent examples of structure- and fragment-based drug design are described. A table is presented with example views of each G protein-coupled receptor for which there is a published X-ray structure, including interactions with small molecule antagonists, partial and full agonists. The possible implications of these new data for drug design are discussed. © 2014 Elsevier B.V. All rights reserved.

Fragment-based design of kinase inhibitors: a practical guide.

PubMed

Erickson, Jon A

2015-01-01

Fragment-based drug design has become an important strategy for drug design and development over the last decade. It has been used with particular success in the development of kinase inhibitors, which are one of the most widely explored classes of drug targets today. The application of fragment-based methods to discovering and optimizing kinase inhibitors can be a complicated and daunting task; however, a general process has emerged that has been highly fruitful. Here a practical outline of the fragment process used in kinase inhibitor design and development is laid out with specific examples. A guide to the overall process from initial discovery through fragment screening, including the difficulties in detection, to the computational methods available for use in optimization of the discovered fragments is reported.

Bath salts and synthetic cathinones: An emerging designer drug phenomenon

PubMed Central

German, Christopher L.; Fleckenstein, Annette E.; Hanson, Glen R.

2014-01-01

The synthetic cathinones are an emerging class of designer drugs abused for psychostimulant and hallucinogenic effects similar to cocaine, methylenedioxymethamphetamine (MDMA), or other amphetamines. Abuse of synthetic cathinones, frequently included in products sold as ‘bath salts’, became prevalent in early 2009, leading to legislative classification throughout Europe in 2010 and schedule I classification within the United States in 2011. Recent pre-clinical and clinical studies indicate dysregulation of central monoamine systems are a principal mechanism of synthetic cathinone action and presumably underlie the behavioral effects and abuse liability associated with these drugs. This review provides insight into the development of synthetic cathinones as substances of abuse, current patterns of their abuse, known mechanisms of their action and toxicology, and the benefits and drawbacks of their classification. PMID:23911668

Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery

PubMed Central

Kesharwani, Prashant; Iyer, Arun K.

2015-01-01

Advances in the application of nanotechnology in medicine have given rise to multifunctional smart nanocarriers that can be engineered with tunable physicochemical characteristics to deliver one or more therapeutic agent(s) safely and selectively to cancer cells, including intracellular organelle-specific targeting. Dendrimers having properties resembling biomolecules, with well-defined 3D nanopolymeric architectures, are emerging as a highly attractive class of drug and gene delivery vector. The presence of numerous peripheral functional groups on hyperbranched dendrimers affords efficient conjugation of targeting ligands and biomarkers that can recognize and bind to receptors overexpressed on cancer cells for tumor-cell-specific delivery. The present review compiles the recent advances in dendrimer-mediated drug and gene delivery to tumors by passive and active targeting principles with illustrative examples. PMID:25555748

Association of Reference Pricing with Drug Selection and Spending

PubMed Central

Robinson, James C.; Whaley, Christopher M.; Brown, Timothy T.

2017-01-01

BACKGROUND In the United States, prices for therapeutically similar drugs vary widely, which has prompted efforts by public and private insurers to steer patients toward the lower-priced options. Under reference pricing, the insurer or employer establishes a maximum contribution it will make toward the price of a drug or procedure, and the patient pays the remainder. METHODS We used difference-in-differences multivariable regression methods to analyze changes in prescriptions and pricing for 1302 drugs in 78 therapeutic classes in the United States, before and after implementation of reference pricing by an alliance of private employers. We assessed trends for the study group relative to those for an employee group that was not subject to reference pricing. The study included 1,122,741 prescriptions that were reimbursed during the period from 2010 through 2014. RESULTS Implementation of reference pricing was associated with a higher percentage of prescriptions that were filled for the lowest-priced reference drug within its therapeutic class (difference in probability, 7.0 percentage points; 95% confidence interval [CI], 4.0 to 9.9), a lower average price paid per prescription (−13.9%; 95% CI, −23.8 to −2.7), and a higher rate of copayment by patients (5.2%; 95% CI, 0.2 to 10.4) than in the comparison group. During the first 18 months after implementation, spending for employers was $1.34 million lower and the amount of copayments for employees was $0.12 million higher than in the comparison group. CONCLUSIONS Implementation of reference pricing was associated with significant changes in drug selection and spending for a population of patients covered by employment-based insurance in the United States. (Funded by the Agency for Healthcare Research and Quality and the Genentech Foundation.) PMID:28813219

Multidrug resistance in fungi: regulation of transporter-encoding gene expression

PubMed Central

Paul, Sanjoy; Moye-Rowley, W. Scott

2014-01-01

A critical risk to the continued success of antifungal chemotherapy is the acquisition of resistance; a risk exacerbated by the few classes of effective antifungal drugs. Predictably, as the use of these drugs increases in the clinic, more resistant organisms can be isolated from patients. A particularly problematic form of drug resistance that routinely emerges in the major fungal pathogens is known as multidrug resistance. Multidrug resistance refers to the simultaneous acquisition of tolerance to a range of drugs via a limited or even single genetic change. This review will focus on recent progress in understanding pathways of multidrug resistance in fungi including those of most medical relevance. Analyses of multidrug resistance in Saccharomyces cerevisiae have provided the most detailed outline of multidrug resistance in a eukaryotic microorganism. Multidrug resistant isolates of S. cerevisiae typically result from changes in the activity of a pair of related transcription factors that in turn elicit overproduction of several target genes. Chief among these is the ATP-binding cassette (ABC)-encoding gene PDR5. Interestingly, in the medically important Candida species, very similar pathways are involved in acquisition of multidrug resistance. In both C. albicans and C. glabrata, changes in the activity of transcriptional activator proteins elicits overproduction of a protein closely related to S. cerevisiae Pdr5 called Cdr1. The major filamentous fungal pathogen, Aspergillus fumigatus, was previously thought to acquire resistance to azole compounds (the principal antifungal drug class) via alterations in the azole drug target-encoding gene cyp51A. More recent data indicate that pathways in addition to changes in the cyp51A gene are important determinants in A. fumigatus azole resistance. We will discuss findings that suggest azole resistance in A. fumigatus and Candida species may share more mechanistic similarities than previously thought. PMID:24795641

A tale of two approaches: complementary mechanisms of cytotoxic and targeted therapy resistance may inform next-generation cancer treatments

PubMed Central

Masui, Kenta; Gini, Beatrice; Wykosky, Jill; Zanca, Ciro; Cavenee, Webster K.

2013-01-01

Chemotherapy and molecularly targeted approaches represent two very different modes of cancer treatment and each is associated with unique benefits and limitations. Both types of therapy share the overarching limitation of the emergence of drug resistance, which prevents these drugs from eliciting lasting clinical benefit. This review will provide an overview of the various mechanisms of resistance to each of these classes of drugs and examples of drug combinations that have been tested clinically. This analysis supports the contention that understanding modes of resistance to both chemotherapy and molecularly targeted therapies may be very useful in selecting those drugs of each class that will have complementing mechanisms of sensitivity and thereby represent reasonable combination therapies. PMID:23455378

Perspectives on zebrafish models of hallucinogenic drugs and related psychotropic compounds.

PubMed

Neelkantan, Nikhil; Mikhaylova, Alina; Stewart, Adam Michael; Arnold, Raymond; Gjeloshi, Visar; Kondaveeti, Divya; Poudel, Manoj K; Kalueff, Allan V

2013-08-21

Among different classes of psychotropic drugs, hallucinogenic agents exert one of the most prominent effects on human and animal behaviors, markedly altering sensory, motor, affective, and cognitive responses. The growing clinical and preclinical interest in psychedelic, dissociative, and deliriant hallucinogens necessitates novel translational, sensitive, and high-throughput in vivo models and screens. Primate and rodent models have been traditionally used to study cellular mechanisms and neural circuits of hallucinogenic drugs' action. The utility of zebrafish ( Danio rerio ) in neuroscience research is rapidly growing due to their high physiological and genetic homology to humans, ease of genetic manipulation, robust behaviors, and cost effectiveness. Possessing a fully characterized genome, both adult and larval zebrafish are currently widely used for in vivo screening of various psychotropic compounds, including hallucinogens and related drugs. Recognizing the growing importance of hallucinogens in biological psychiatry, here we discuss hallucinogenic-induced phenotypes in zebrafish and evaluate their potential as efficient preclinical models of drug-induced states in humans.

Preferred supplier contracts in post-patent prescription drug markets.

PubMed

Blankart, Carl Rudolf; Stargardt, Tom

2016-02-22

In recent years, the expiration of patents for large drug classes has increased the importance of post-patent drug markets. However, previous research has focused solely on patent drug markets. In this study, the authors evaluate the influence of preferred supplier contracts, the German approach to tendering, in post-patent drug markets using a hierarchical market share attraction model. The authors find that preferred supplier contracts are a powerful strategic instrument for generic manufacturers in a highly competitive environment. They quantify the effects of signing a preferred supplier contract and show that brand-name manufacturers are vulnerable to tendering. Therefore, brand-name manufacturers should readjust their strategies and consider including preferred supplier contracts in their marketing mix. In addition, the authors employ a simulation to demonstrate that a first-mover advantage might be gained from signing a preferred supplier contract. Furthermore, their results can be used as a blueprint for decision makers in the pharmaceutical industry to assess the market share effects of different contracting strategies regarding preferred supplier contracts.

Synthesis and biochemical analysis of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-N-hydroxy-octanediamides as inhibitors of human histone deacetylases.

PubMed

Henkes, Leonhard M; Haus, Patricia; Jäger, Felix; Ludwig, Joachim; Meyer-Almes, Franz-Josef

2012-01-15

Inhibition of human histone deacetylases (HDACs) has emerged as a novel concept in the chemotherapeutic treatment of cancer. Two chemical entities, SAHA (ZOLINZA, Merck) and romidepsin (Istodax, Celgene) have been recently approved by the FDA as first-in-class drugs against cutaneous T-cell lymphoma. Clinical use of these drugs revealed several side effects including gastro-intestinal symptoms, fatigue, thrombocytopenia, thrombosis. Romidepsin is associated with an yet unresolved cardiotoxicity issue. A general hypothesis for the diminishment of unwanted adverse effects and an improved therapeutical window suggests the development of more isotype selective inhibitors. In this study the first time HDAC inhibitors with perfluorinated spacers between the zinc chelating moiety and the aromatic capping group were synthesized and tested against representatives of HDAC classes I, IIa and IIb. Competitive binding assays and a combined approach by using blind docking and molecular dynamics support binding of the perfluorinated analogs of SAHA to the active site of the HDAC-like amidohydrolase from Bordetella/Alcaligenes and presumably also to human HDACs. In contrast to the alkyl spacer of SAHA and derivatives, the perfluorinated alkyl spacer seems to contribute to or facilitate the induction of selectivity for class II, particularly class IIa, HDACs even though the overall potency of the perfluorinated SAHA analogs in this study against human HDACs remained still rather moderate in the micromolar range. Copyright © 2011 Elsevier Ltd. All rights reserved.

Postgenomic strategies in antibacterial drug discovery.

PubMed

Brötz-Oesterhelt, Heike; Sass, Peter

2010-10-01

During the last decade the field of antibacterial drug discovery has changed in many aspects including bacterial organisms of primary interest, discovery strategies applied and pharmaceutical companies involved. Target-based high-throughput screening had been disappointingly unsuccessful for antibiotic research. Understanding of this lack of success has increased substantially and the lessons learned refer to characteristics of targets, screening libraries and screening strategies. The 'genomics' approach was replaced by a diverse array of discovery strategies, for example, searching for new natural product leads among previously abandoned compounds or new microbial sources, screening for synthetic inhibitors by targeted approaches including structure-based design and analyses of focused libraries and designing resistance-breaking properties into antibiotics of established classes. Furthermore, alternative treatment options are being pursued including anti-virulence strategies and immunotherapeutic approaches. This article summarizes the lessons learned from the genomics era and describes discovery strategies resulting from that knowledge.