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Sample records for b-adrenergic drugs improves

  1. Molecular characterization of an. alpha. sub 2B -adrenergic receptor

    SciTech Connect

    Harrison, J.K.; Dewan Zeng; D'Angelo, D.D.; Tucker, A.L.; Zhihong Lu; Barber, C.M.; Lynch, K.R. )

    1990-02-26

    {alpha}{sub 2}-Adrenergic receptors comprise a heterogeneous population based on pharmacologic and molecular evidence. The authors have isolated a cDNA clone (pRNG{alpha}2) encoding a previously undescribed third subtype of an {alpha}{sub 2}-adrenergic receptor from a rat kidney cDNA library. The library was screened with an oligonucleotide encoding a highly conserved region found in all biogenic amine receptors described to date. The deduced amino acid sequence displays many features of G-protein coupled receptors with exception of the absence of the consensus N-linked glycosylation site at the amino terminus. Membranes prepared from COS-1 cells transfected with pRNG{alpha}2 display high affinity and saturable binding to {sup 3}H-rauwolscine (K{sub d}=2 nM).Competition curve data analysis shows that pRNG{alpha}2 protein binds to a variety of adrenergic drugs with the following rank order of potency: yohimbine {ge} cholorpromazine > prazosin {ge} clonidine > norepinephrine {ge} oxymetazoline. pRNG{alpha}2 RNA accumulates in both adult rat kidney and rat neonatal lung (predominant species is 4.0 kb). They conclude that pRNG{alpha}2 likely represents a cDNA for the {alpha}{sub 2B}-adrenergic receptor.

  2. Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates.

    PubMed

    Drouin, Candice; Darracq, Laurent; Trovero, Fabrice; Blanc, Gérard; Glowinski, Jacques; Cotecchia, Susanna; Tassin, Jean-Pol

    2002-04-01

    Drugs of abuse, such as psychostimulants and opiates, are generally considered as exerting their locomotor and rewarding effects through an increased dopaminergic transmission in the nucleus accumbens. Noradrenergic transmission may also be implicated because most psychostimulants increase norepinephrine (NE) release, and numerous studies have indicated interactions between noradrenergic and dopaminergic neurons through alpha1-adrenergic receptors. However, analysis of the effects of psychostimulants after either destruction of noradrenergic neurons or pharmacological blockade of alpha1-adrenergic receptors led to conflicting results. Here we show that the locomotor hyperactivities induced by d-amphetamine (1-3 mg/kg), cocaine (5-20 mg/kg), or morphine (5-10 mg/kg) in mice lacking the alpha1b subtype of adrenergic receptors were dramatically decreased when compared with wild-type littermates. Moreover, behavioral sensitizations induced by d-amphetamine (1-2 mg/kg), cocaine (5-15 mg/kg), or morphine (7.5 mg/kg) were also decreased in knock-out mice when compared with wild-type. Ruling out a neurological deficit in knock-out mice, both strains reacted similarly to novelty, to intraperitoneal saline, or to the administration of scopolamine (1 mg/kg), an anti-muscarinic agent. Finally, rewarding properties could not be observed in knock-out mice in an oral preference test (cocaine and morphine) and conditioned place preference (morphine) paradigm. Because catecholamine tissue levels, autoradiography of D1 and D2 dopaminergic receptors, and of dopamine reuptake sites and locomotor response to a D1 agonist showed that basal dopaminergic transmission was similar in knock-out and wild-type mice, our data indicate a critical role of alpha1b-adrenergic receptors and noradrenergic transmission in the vulnerability to addiction.

  3. α1B-Adrenergic Receptors Differentially Associate with Rab Proteins during Homologous and Heterologous Desensitization

    PubMed Central

    Castillo-Badillo, Jean A.; Sánchez-Reyes, Omar B.; Alfonzo-Méndez, Marco A.; Romero-Ávila, M. Teresa; Reyes-Cruz, Guadalupe; García-Sáinz, J. Adolfo

    2015-01-01

    Internalization of G protein-coupled receptors can be triggered by agonists or by other stimuli. The process begins within seconds of cell activation and contributes to receptor desensitization. The Rab GTPase family controls endocytosis, vesicular trafficking, and endosomal fusion. Among their remarkable properties is the differential distribution of its members on the surface of various organelles. In the endocytic pathway, Rab 5 controls traffic from the plasma membrane to early endosomes, whereas Rab 4 and Rab 11 regulate rapid and slow recycling from early endosomes to the plasma membrane, respectively. Moreover, Rab 7 and Rab 9 regulate the traffic from late endosomes to lysosomes and recycling to the trans-Golgi. We explore the possibility that α1B-adrenergic receptor internalization induced by agonists (homologous) and by unrelated stimuli (heterologous) could involve different Rab proteins. This possibility was explored by Fluorescence Resonance Energy Transfer (FRET) using cells coexpressing α1B-adrenergic receptors tagged with the red fluorescent protein, DsRed, and different Rab proteins tagged with the green fluorescent protein. It was observed that when α1B-adrenergic receptors were stimulated with noradrenaline, the receptors interacted with proteins present in early endosomes, such as the early endosomes antigen 1, Rab 5, Rab 4, and Rab 11 but not with late endosome markers, such as Rab 9 and Rab 7. In contrast, sphingosine 1-phosphate stimulation induced rapid and transient α1B-adrenergic receptor interaction of relatively small magnitude with Rab 5 and a more pronounced and sustained one with Rab 9; interaction was also observed with Rab 7. Moreover, the GTPase activity of the Rab proteins appears to be required because no FRET was observed when dominant-negative Rab mutants were employed. These data indicate that α1B-adrenergic receptors are directed to different endocytic vesicles depending on the desensitization type (homologous vs

  4. The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence

    PubMed Central

    Trovero, Fabrice; David, Sabrina; Bernard, Philippe; Puech, Alain; Bizot, Jean-Charles; Tassin, Jean-Pol

    2016-01-01

    Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs. PMID:26968030

  5. The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence.

    PubMed

    Trovero, Fabrice; David, Sabrina; Bernard, Philippe; Puech, Alain; Bizot, Jean-Charles; Tassin, Jean-Pol

    2016-01-01

    Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.

  6. Overexpression of the alpha1B-adrenergic receptor causes apoptotic neurodegeneration: multiple system atrophy.

    PubMed

    Zuscik, M J; Sands, S; Ross, S A; Waugh, D J; Gaivin, R J; Morilak, D; Perez, D M

    2000-12-01

    Progress toward elucidating the function of alpha1B-adrenergic receptors (alpha1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate alpha1B-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active alpha1BARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in alpha1B-expressing domains of the brain and progressing with age to encompass all areas. The degeneration was apoptotic and did not occur in non-transgenic mice. Correspondingly, transgenic mice showed an age-progressive hindlimb disorder that was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degeneration in the substantia nigra. Transgenic mice also had a grand mal seizure disorder accompanied by a corresponding dysplasia and neurodegeneration of the cerebral cortex. Both behavioral phenotypes (locomotor impairment and seizure) could be partially rescued with the alpha1AR antagonist terazosin, indicating that alpha1AR signaling participated directly in the pathology. Our results indicate that overstimulation of alpha1BAR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown.

  7. Bronchodilatory and B-adrenergic effects of methanolic and aqueous extracts of Althaea root on isolated tracheobronchial smooth rat muscle

    PubMed Central

    Alani, Behrang; Zare, Mohammad; Noureddini, Mahdi

    2015-01-01

    Background: The smooth muscle contractions of the tracheobronchial airways are mediated through the balance of adrenergic, cholinergic and peptidergic nervous mechanisms. This research was designed to determine the bronchodilatory and B-adrenergic effects of methanolic and aqueous extracts of root Althaea on the isolated tracheobronchial smooth muscle of the rat. Materials and Methods: In this experimental study, 116 tracheobronchial sections (5 mm) from 58 healthy male Sprague-Dawley rats were dissected and divided into 23 groups. The effect of methanolic and aqueous extracts of the root Althaea was assayed at different concentrations (0.2, 0.6, 2.6, 6.6, 14.6 μg/ml) and epinephrine (5 μm) in the presence and absence of propranolol (1 μM) under one g tension based on the isometric method. This assay was recorded in an organ bath containing Krebs-Henseleit solution for tracheobronchial smooth muscle contractions using potassium chloride (KCl) (60 mM) induction. Results: Epinephrine (5 μm) alone and root methanolic and aqueous extract concentrations (0.6-14.6 μg/ml) reduced tracheobronchial smooth muscle contractions induced using KCl (60 mM) in a dose dependent manner. Propranolol inhibited the antispasmodic effect of epinephrine on tracheobronchial smooth muscle contractions, but could not reduce the antispasmodic effect of the root extract concentrations. Conclusion: The methanolic and aqueous extracts of Althaea root inhibited the tracheobronchial smooth muscle contractions of rats in a dose dependent manner, but B-adrenergic receptors do not appear to engage in this process. Understanding the mechanism of this process can be useful in the treatment of pulmonary obstructive diseases like asthma. PMID:25879003

  8. Psychoactive Drugs: Improving Prescribing Practices.

    ERIC Educational Resources Information Center

    Ghodse, Hamid, Ed.; Khan, Inayat, Ed.

    This book presents a wide-ranging analysis of what can be done to reduce the misuse of psychoactive drugs without compromising appreciation for their therapeutic value. Emphasis is placed on the need to give physicians guidelines for deciding to whom to prescribe, what to prescribe, how much, and for how long. Chapter 1 provides an introduction…

  9. Regulation of α2B-Adrenergic Receptor Cell Surface Transport by GGA1 and GGA2

    PubMed Central

    Zhang, Maoxiang; Huang, Wei; Gao, Jie; Terry, Alvin V.; Wu, Guangyu

    2016-01-01

    The molecular mechanisms that control the targeting of newly synthesized G protein-coupled receptors (GPCRs) to the functional destinations remain poorly elucidated. Here, we have determined the role of Golgi-localized, γ-adaptin ear domain homology, ADP ribosylation factor-binding proteins 1 and 2 (GGA1 and GGA2) in the cell surface transport of α2B-adrenergic receptor (α2B-AR), a prototypic GPCR, and studied the underlying mechanisms. We demonstrated that knockdown of GGA1 and GGA2 by shRNA and siRNA significantly reduced the cell surface expression of inducibly expressed α2B-AR and arrested the receptor in the perinuclear region. Knockdown of each GGA markedly inhibited the dendritic expression of α2B-AR in primary cortical neurons. Consistently, depleting GGA1 and GGA2 attenuated receptor-mediated signal transduction measured as ERK1/2 activation and cAMP inhibition. Although full length α2B-AR associated with GGA2 but not GGA1, its third intracellular loop was found to directly interact with both GGA1 and GGA2. More interestingly, further mapping of interaction domains showed that the GGA1 hinge region and the GGA2 GAE domain bound to multiple subdomains of the loop. These studies have identified an important function and revealed novel mechanisms of the GGA family proteins in the forward trafficking of a cell surface GPCR. PMID:27901063

  10. Improving drug addiction treatment in China.

    PubMed

    Tang, Yi-Lang; Hao, Wei

    2007-07-01

    To illustrate the current situation and problems of drug addiction in treatment China and propose suggestions. A descriptive study based on literature searched from Medline and the China National Knowledge Infrastructure database (1996-2007) and hand-picked references. Since the re-emergence of drug addiction in China in the early 1990s, there has been tremendous progress in drug addiction treatments in China, especially treatments for opiate addiction. However, many problems and challenges remain for improvement, including widespread negative attitudes towards drug abuse and drug-dependent individuals, the lack of evidence-based data on the efficacy of Chinese traditional medicine and the lack of a comprehensive and integrated system to organize all treatment resources and monitor treatment progress. The authors discuss the challenges that impede effective treatments of drug addiction and some suggestions are proposed. Implementing these suggestions can improve the outcome of treatment of drug-dependent individuals and benefit the whole society. China faces substantial drug addiction problems that appear to be worsening with time. Although much progress in drug addiction treatment has been made, improvement in many aspects is needed urgently.

  11. Improved candidate drug mining for Alzheimer's disease.

    PubMed

    Cheng, Yu-Huei; Chuang, Li-Yeh; Chang, Hsueh-Wei; Yang, Cheng-Hong

    2014-01-01

    Alzheimer's disease (AD) is the main cause of dementia for older people. Although several antidementia drugs such as donepezil, rivastigmine, galantamine, and memantine have been developed, the effectiveness of AD drug therapy is still far from satisfactory. Recently, the single nucleotide polymorphisms (SNPs) have been chosen as one of the personalized medicine markers. Many pharmacogenomics databases have been developed to provide comprehensive information by associating SNPs with drug responses, disease incidence, and genes that are critical in choosing personalized therapy. However, we found that some information from different sets of pharmacogenomics databases is not sufficient and this may limit the potential functions for pharmacogenomics. To address this problem, we used approximate string matching method and data mining approach to improve the searching of pharmacogenomics database. After computation, we can successfully identify more genes linked to AD and AD-related drugs than previous online searching. These improvements may help to improve the pharmacogenomics of AD for personalized medicine.

  12. Overview on gastroretentive drug delivery systems for improving drug bioavailability.

    PubMed

    Lopes, Carla M; Bettencourt, Catarina; Rossi, Alessandra; Buttini, Francesca; Barata, Pedro

    2016-08-20

    In recent decades, many efforts have been made in order to improve drug bioavailability after oral administration. Gastroretentive drug delivery systems are a good example; they emerged to enhance the bioavailability and effectiveness of drugs with a narrow absorption window in the upper gastrointestinal tract and/or to promote local activity in the stomach and duodenum. Several strategies are used to increase the gastric residence time, namely bioadhesive or mucoadhesive systems, expandable systems, high-density systems, floating systems, superporous hydrogels and magnetic systems. The present review highlights some of the drugs that can benefit from gastroretentive strategies, such as the factors that influence gastric retention time and the mechanism of action of gastroretentive systems, as well as their classification into single and multiple unit systems.

  13. Cloning, characterisation and identification of several polymorphisms in the promoter region of the human alpha2B-adrenergic receptor gene.

    PubMed

    Cayla, Cécile; Heinonen, Paula; Viikari, Liisa; Schaak, Stéphane; Snapir, Amir; Bouloumié, Anne; Karvonen, Matti K; Pesonen, Ullamari; Scheinin, Mika; Paris, Hervé

    2004-02-01

    Screening of a foetal brain genomic DNA library allowed to isolate a 10-kb fragment of the gene encoding the human alpha2B-adrenergic receptor, that contained 5.5 kb of the 5'-flanking region, the open reading frame and 2.9 kb of the 3'-flanking region. The 1-kb fragment upstream from the start codon was rich in GC, lacked consensus TATA or CAAT box, but contained several Sp1-binding sites. Other potential cis-regulatory elements found in the 5'-flanking region included AP2, USF, Stat-6, NFkappaB and Olf-1. A single canonical polyadenylation signal (AATAAA) was found at position +3252/+3257 and the polyadenylation site was 3274 nucleotides downstream from ATG. Transfection experiments with chimeric luciferase constructs containing various truncated fragments of the 5'-region showed that the fragment -3160/+3 exhibited promoter activity in all tested cell lines and permitted the definition of a minimal 200-bp promoter (-603/-411) containing three putative Sp1-binding sites and two initiator elements. Transcriptional activity of this region was inhibited by the addition of mithramycin, a specific inhibitor of Sp1 binding to GC-rich sequences. The search for sequence variants within a fragment covering 1.7 kb of 5'-flanking region and the coding region allowed us to identify five novel single nucleotide polymorphisms. Interestingly, the G/C substitution at position -98 relative to the start codon was common and in complete linkage with a previously identified insertion/deletion polymorphism in the coding region which was showed to affect alpha2B-adrenergic receptor function. Based on transfection data and computer-assisted sequence analysis, the -98 G/C single nucleotide polymorphism was located within a portion of the 5'-UTR (-127/+3) affecting luciferase activity and it created additional putative binding site for Sp1. However, G/C substitution had no significant incidence on promoter activity in BHK-21 or HeLa cells.

  14. α1A- and α1B-Adrenergic Receptors Differentially Modulate Antidepressant-Like Behavior in the Mouse

    PubMed Central

    Doze, Van A.; Handel, Evelyn M.; Jensen, Kelly A.; Darsie, Belle; Luger, Elizabeth J.; Haselton, James R.; Talbot, Jeffery N.; Rorabaugh, Boyd R.

    2009-01-01

    Tricyclic antidepressant (TCA) drugs are used for the treatment of chronic depression, obsessive compulsive disorder (OCD), and anxiety-related disorders. Chronic use of TCA drugs increases the expression of α1-adrenergic receptors (α1-ARs). Yet, it is unclear whether increased α1-AR expression contributes to the antidepressant effects of these drugs or if this effect is unrelated to their therapeutic benefit. In this study, mice expressing constitutively active mutant α1A-ARs (CAM α1A-AR) or CAM α1B-ARs were used to examine the effects of α1A- and α1B-AR signaling on rodent behavioral models of depression, OCD, and anxiety. CAM α1A-AR mice, but not CAM α1B-AR mice, exhibited antidepressant-like behavior in the tail suspension test and forced swim test. This behavior was reversed by prazosin, a selective α1-AR inverse agonist, and mimicked by chronically treating wild type mice with cirazoline, an α1A-AR agonist. Marble burying behavior, commonly used to model OCD in rodents, was significantly decreased in CAM α1A-AR mice but not in CAM α1B-AR mice. In contrast, no significant differences in anxiety-related behavior were observed between wild type, CAM α1A-AR, and CAM α1B-AR animals in the elevated plus maze and light/dark box. This is the first study to demonstrate that α1A- and α1B-ARs differentially modulate antidepressant-like behavior in the mouse. These data suggest that α1A-ARs may be a useful therapeutic target for the treatment of depression. PMID:19540213

  15. alpha(1A)- and alpha(1B)-adrenergic receptors differentially modulate antidepressant-like behavior in the mouse.

    PubMed

    Doze, Van A; Handel, Evelyn M; Jensen, Kelly A; Darsie, Belle; Luger, Elizabeth J; Haselton, James R; Talbot, Jeffery N; Rorabaugh, Boyd R

    2009-08-18

    Tricyclic antidepressant (TCA) drugs are used for the treatment of chronic depression, obsessive-compulsive disorder (OCD), and anxiety-related disorders. Chronic use of TCA drugs increases the expression of alpha(1)-adrenergic receptors (alpha(1)-ARs). Yet, it is unclear whether increased alpha(1)-AR expression contributes to the antidepressant effects of these drugs or if this effect is unrelated to their therapeutic benefit. In this study, mice expressing constitutively active mutant alpha(1A)-ARs (CAM alpha(1A)-AR) or CAM alpha(1B)-ARs were used to examine the effects of alpha(1A)- and alpha(1B)-AR signaling on rodent behavioral models of depression, OCD, and anxiety. CAM alpha(1A)-AR mice, but not CAM alpha(1B)-AR mice, exhibited antidepressant-like behavior in the tail suspension test and forced swim test. This behavior was reversed by prazosin, a selective alpha(1)-AR inverse agonist, and mimicked by chronically treating wild type mice with cirazoline, an alpha(1A)-AR agonist. Marble burying behavior, commonly used to model OCD in rodents, was significantly decreased in CAM alpha(1A)-AR mice but not in CAM alpha(1B)-AR mice. In contrast, no significant differences in anxiety-related behavior were observed between wild type, CAM alpha(1A)-AR, and CAM alpha(1B)-AR animals in the elevated plus maze and light/dark box. This is the first study to demonstrate that alpha(1A)- and alpha(1B)-ARs differentially modulate antidepressant-like behavior in the mouse. These data suggest that alpha(1A)-ARs may be a useful therapeutic target for the treatment of depression.

  16. [Suggestions on improving administration of local crude drug quality standards].

    PubMed

    Zhao, Yu-Xin; Ma, Guang-Lin; Yu, Jiang-Yong

    2017-07-01

    To improve the administration of local crude drug quality standard, the administration history, and current administration situation of local crude drugs were reviewed, the legal orientation and positive effect of local crude drugs were analyzed, and the existing problems were summarized. It was found that many problems existed in the administration of local crude drug quality standards, especially the phenomenon of homonym and synonym on their names. The suggestions on improving the administration of local crude drug quality standards were proposed. First of all, the construction of legal system should be strengthened to improve the administration methods. Secondly, the coordination mechanism should be developed to solve the outstanding problems. Thirdly, the basic research should be enhanced to resolve the general technical problems. Lastly, the channels to transfer the local crude drugs into pharmacopeia standards should be developed to achieve dynamic administration. Copyright© by the Chinese Pharmaceutical Association.

  17. Augmenting drug-carrier compatibility improves tumour nanotherapy efficacy

    NASA Astrophysics Data System (ADS)

    Zhao, Yiming; Fay, François; Hak, Sjoerd; Manuel Perez-Aguilar, Jose; Sanchez-Gaytan, Brenda L.; Goode, Brandon; Duivenvoorden, Raphaël; de Lange Davies, Catharina; Bjørkøy, Astrid; Weinstein, Harel; Fayad, Zahi A.; Pérez-Medina, Carlos; Mulder, Willem J. M.

    2016-04-01

    A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug-carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug-carrier compatibility affects drug release in a tumour mouse model. We found the drug's hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, we applied these findings to improve chemotherapeutic delivery by augmenting the parent drug's compatibility; as a result, we achieved better antitumour efficacy. Our results help elucidate nanomedicines' in vivo fate and provide guidelines for efficient drug delivery.

  18. Salt formation to improve drug solubility.

    PubMed

    Serajuddin, Abu T M

    2007-07-30

    Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. In this article, physicochemical principles of salt solubility are presented, with special reference to the influence of pH-solubility profiles of acidic and basic drugs on salt formation and dissolution. Non-ideality of salt solubility due to self-association in solution is also discussed. Whether certain acidic or basic drugs would form salts and, if salts are formed, how easily they would dissociate back into their free acid or base forms depend on interrelationships of several factors, such as S0 (intrinsic solubility), pH, pKa, Ksp (solubility product) and pHmax (pH of maximum solubility). The interrelationships of these factors are elaborated and their influence on salt screening and the selection of optimal salt forms for development are discussed. Factors influencing salt dissolution under various pH conditions, and especially in reactive media and in presence of excess common ions, are discussed, with practical reference to the development of solid dosage forms.

  19. Synergistic drug combinations improve therapeutic selectivity

    PubMed Central

    Lehàr, Joseph; Krueger, Andrew S.; Avery, William; Heilbut, Adrian M.; Johansen, Lisa M.; Price, E. Roydon; Rickles, Richard J.; Short, Glenn F.; Staunton, Jane E.; Jin, Xiaowei; Lee, Margaret S.; Zimmermann, Grant R.; Borisy, Alexis A.

    2009-01-01

    Prevailing drug discovery approaches focus on compounds with molecular selectivity, inhibiting disease-relevant targets over others in vitro. However in vivo, many such agents are not therapeutically selective, either because of undesirable activity at effective doses or because the biological system responds to compensate. In theory, drug combinations should permit increased control of such complex biology, but there is a common concern that therapeutic synergy will generally be mirrored by synergistic side-effects. Here we provide evidence, from 94,110 multi-dose combination experiments representing diverse disease areas and large scale flux balance simulations of inhibited bacterial metabolism, that multi-target synergies are more specific than single agent activities to particular cellular contexts. Using an anti-inflammatory combination, we show how multi-target synergy can achieve therapeutic selectivity in animals through differential target expression. Synergistic combinations can increase the number of selective therapies using the current pharmacopeia, and offer opportunities for more precise control of biological systems. PMID:19581876

  20. Improving Alcohol/Drug Education in Illinois Schools.

    ERIC Educational Resources Information Center

    Illinois State Board of Education, Springfield.

    This paper lists guidelines approved by the Illinois State Board of Education for improving alcohol and drug education in the schools. Statistics point out the seriousness of alcohol and drug abuse in terms of human costs to the victim, his/her family, and associates, and the economic costs of health care, accident losses, crime, social programs,…

  1. The Prodrug Approach: A Successful Tool for Improving Drug Solubility.

    PubMed

    Jornada, Daniela Hartmann; dos Santos Fernandes, Guilherme Felipe; Chiba, Diego Eidy; de Melo, Thais Regina Ferreira; dos Santos, Jean Leandro; Chung, Man Chin

    2015-12-29

    Prodrug design is a widely known molecular modification strategy that aims to optimize the physicochemical and pharmacological properties of drugs to improve their solubility and pharmacokinetic features and decrease their toxicity. A lack of solubility is one of the main obstacles to drug development. This review aims to describe recent advances in the improvement of solubility via the prodrug approach. The main chemical carriers and examples of successful strategies will be discussed, highlighting the advances of this field in the last ten years.

  2. From Local Quality Improvement to National Drug Recall

    PubMed Central

    Herzer, Kurt R.; Lim, Christine; Li, Matthew; Xie, Yanjun; Doyle, Peter A.; Cover, Renee; Mark, Lynette J.

    2014-01-01

    Medication errors due to look-alike drugs put patients at risk and can be fatal. Neuromuscular blocking agents, such as vecuronium, can cause awake-paralysis in patients if administered as a single agent. Recent literature reported six cases in which vecuronium was inadvertently administered instead of the antibiotic drug cefazolin. This article describes a standardized quality improvement process used at The Johns Hopkins Hospital that was locally implemented following an adverse drug event and culminated in a nationwide FDA-mandated drug recall of vecuronium. PMID:23508529

  3. Improving drug manufacturing with process analytical technology.

    PubMed

    Rodrigues, Licinia O; Alves, Teresa P; Cardoso, Joaquim P; Menezes, José C

    2006-01-01

    Within the process analytical technology (PAT) framework, as presented in the US Food and Drug Administration guidelines, the aim is to design, develop and operate processes consistently to ensure a pre-defined level of quality at the end of the manufacturing process. Three PAT implementation scenarios can be envisaged. Firstly, PAT could be used in its most modest version (in an almost non-PAT manner) to simply replace an existing quality control protocol (eg, using near-infrared spectroscopy for an in-process quality control, such as moisture content). Secondly, the use of in-process monitoring and process analysis could be integrated to enhance process understanding and operation for an existing industrial process. Thirdly, PAT could be used extensively and exclusively throughout development, scale-up and full-scale production of a new product and process. Although the first type of implementations are well known, reports of the second and third types remain scarce. Herein, results obtained from PAT implementations of the second and third types are described for two industrial processes for preparing bulk active pharmaceutical ingredients, demonstrating the benefits in terms of increased process understanding and process control.

  4. Improving Care for the Treatment of Alcohol and Drug Disorders

    PubMed Central

    McCarty, Dennis; Gustafson, David; Capoccia, Victor A.; Cotter, Frances

    2008-01-01

    The Network for the Improvement of Addiction Treatment (NIATx) teaches alcohol and drug treatment programs to apply process improvement strategies and make organizational changes that improve quality of care. Participating programs reduce days to admission, increase retention in care and spread the application of process improvement within their treatment centers. More generally, NIATx provides a framework for addressing the Institute of Medicine’s six dimensions of quality care (i.e., safe, effective, patient-centered, efficient, timely and equitable) in treatments for alcohol, drug and mental health disorders. NIATx and its extensions illustrate how the behavioral health field can respond to the demand for higher quality treatment services. PMID:18259871

  5. Overcoming limitations in nanoparticle drug delivery: triggered, intravascular release to improve drug penetration into tumors

    PubMed Central

    Manzoor, Ashley A.; Lindner, Lars H.; Landon, Chelsea D.; Park, Ji-Young; Simnick, Andrew J.; Dreher, Matthew R.; Das, Shiva; Hanna, Gabi; Park, Won; Chilkoti, Ashutosh; Koning, Gerben A.; Hagen, Timo L.M. ten; Needham, David; Dewhirst, Mark W.

    2012-01-01

    Traditionally, the goal of nanoparticle-based chemotherapy has been to decrease normal tissue toxicity by improving drug specificity to tumors. The EPR effect (Enhanced Permeability and Retention) can permit passive accumulation into tumor interstitium. However, suboptimal delivery is achieved with most nanoparticles because of heterogeneities of vascular permeability, which limits nanoparticle penetration. Further, slow drug release limits bioavailability. We developed a fast drug-releasing liposome triggered by local heat that has already shown substantial anti-tumor efficacy and is in human trials. Here, we demonstrate that thermally sensitive liposomes release doxorubicin inside the tumor vasculature. Real-time confocal imaging of doxorubicin delivery to murine tumors in window chambers and histologic analysis of flank tumors illustrates that intravascular drug release increases free drug in the interstitial space. This increases both the time that tumor cells are exposed to maximum drug levels and the drug penetration distance, compared with free drug or traditional pegylated liposomes. These improvements in drug bioavailability establish a new paradigm in drug delivery: rapidly triggered drug release in the tumor bloodstream. PMID:22952218

  6. Multitask learning improves prediction of cancer drug sensitivity

    PubMed Central

    Yuan, Han; Paskov, Ivan; Paskov, Hristo; González, Alvaro J.; Leslie, Christina S.

    2016-01-01

    Precision oncology seeks to predict the best therapeutic option for individual patients based on the molecular characteristics of their tumors. To assess the preclinical feasibility of drug sensitivity prediction, several studies have measured drug responses for cytotoxic and targeted therapies across large collections of genomically and transcriptomically characterized cancer cell lines and trained predictive models using standard methods like elastic net regression. Here we use existing drug response data sets to demonstrate that multitask learning across drugs strongly improves the accuracy and interpretability of drug prediction models. Our method uses trace norm regularization with a highly efficient ADMM (alternating direction method of multipliers) optimization algorithm that readily scales to large data sets. We anticipate that our approach will enhance efforts to exploit growing drug response compendia in order to advance personalized therapy. PMID:27550087

  7. Aptamer-based liposomes improve specific drug loading and release.

    PubMed

    Plourde, Kevin; Derbali, Rabeb Mouna; Desrosiers, Arnaud; Dubath, Céline; Vallée-Bélisle, Alexis; Leblond, Jeanne

    2017-04-10

    Aptamer technology has shown much promise in cancer therapeutics for its targeting abilities. However, its potential to improve drug loading and release from nanocarriers has not been thoroughly explored. In this study, we employed drug-binding aptamers to actively load drugs into liposomes. We designed a series of DNA aptamer sequences specific to doxorubicin, displaying multiple binding sites and various binding affinities. The binding ability of aptamers was preserved when incorporated into cationic liposomes, binding up to 15equivalents of doxorubicin per aptamer, therefore drawing the drug into liposomes. Optimization of the charge and drug/aptamer ratios resulted in ≥80% encapsulation efficiency of doxorubicin, ten times higher than classical passively-encapsulating liposomal formulations and similar to a pH-gradient active loading strategy. In addition, kinetic release profiles and cytotoxicity assay on HeLa cells demonstrated that the release and therapeutic efficacy of liposomal doxorubicin could be controlled by the aptamer's structure. Our results suggest that the aptamer exhibiting a specific intermediate affinity is the best suited to achieve high drug loading while maintaining efficient drug release and therapeutic activity. This strategy was successfully applied to tobramycin, a hydrophilic drug suffering from low encapsulation into liposomes, where its loading was improved six-fold using aptamers. Overall, we demonstrate that aptamers could act, in addition to their targeting properties, as multifunctional excipients for liposomal formulations.

  8. Management for improving patients’ knowledge and understanding about drug allergy

    PubMed Central

    Jarernsiripornkul, Narumol; Chaipichit, Nataporn; Chumworathayi, Pansu; Krska, Janet

    2014-01-01

    Background: Drug allergy a serious adverse drug reaction commonly concerned in healthcare practice. Inadequate documentation and communication between health providers, and limited health literacy and knowledge in patients could contribute to the re-occurrence of allergic reactions. Objective: To evaluate the effectiveness of initiatives aiming to improve patients’ knowledge, understanding and behavior in preventing recurrent drug allergy. Methods: A before-and-after study was conducted at an 800-bed university teaching hospital, involving patients with a history of drug allergy. Questionnaires, completed at baseline and one month after receiving information were used to compare knowledge and understanding of drug allergy and behaviors in relation to drug allergy cards. Patients in Group 1 received a brochure only, but patients in Group 2 also received a pharmacist counseling intervention in addition to the brochure. Outcomes were evaluated within intervention group and between intervention groups. Results: The study included 299 (30.4%) and 100 patients (100.0%) in Groups 1 and 2 respectively who completed the baseline questionnaire, of whom 179 (59.8%) and 96 (96.0%) completed the follow-up questionnaire. At baseline, higher educational levels and possession of a drug allergy card were significantly associated with better knowledge about drug allergy. After intervention, Group 2 had significantly greater increases in mean overall knowledge scores than Group 1 (p<0.01) and also greater increases in the proportions self-reporting carrying and presenting drug allergy cards (p<0.05 and p<0.01). Conclusions: Pharmacist counseling plus brochure may be more effective than brochure alone in promoting patients’ knowledge of drug allergy and drug allergy card importance. PMID:25883688

  9. Improving drug delivery to solid tumors: priming the tumor microenvironment.

    PubMed

    Khawar, Iftikhar Ali; Kim, Jung Ho; Kuh, Hyo-Jeong

    2015-03-10

    Malignant transformation and growth of the tumor mass tend to induce changes in the surrounding microenvironment. Abnormality of the tumor microenvironment provides a driving force leading not only to tumor progression, including invasion and metastasis, but also to acquisition of drug resistance, including pharmacokinetic (drug delivery-related) and pharmacodynamic (sensitivity-related) resistance. Drug delivery systems exploiting the enhanced permeability and retention (EPR) effect and active targeting moieties were expected to be able to cope with delivery-related drug resistance. However, recent evidence supports a considerable barrier role of tumors via various mechanisms, which results in imperfect or inefficient EPR and/or targeting effect. The components of the tumor microenvironment such as abnormal tumor vascular system, deregulated composition of the extracellular matrix, and interstitial hypertension (elevated interstitial fluid pressure) collectively or cooperatively hinder the drug distribution, which is prerequisite to the efficacy of nanoparticles and small-molecule drugs used in cancer medicine. Hence, the abnormal tumor microenvironment has recently been suggested to be a promising target for the improvement of drug delivery to improve therapeutic efficacy. Strategies to modulate the abnormal tumor microenvironment, referred to here as "solid tumor priming" (vascular normalization and/or solid stress alleviation leading to improvement in blood perfusion and convective molecular movement), have shown promising results in the enhancement of drug delivery and anticancer efficacy. These strategies may provide a novel avenue for the development of new chemotherapeutics and combination chemotherapeutic regimens as well as reassessment of previously ineffective agents. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Improving Viral Protease Inhibitors to Counter Drug Resistance

    PubMed Central

    Yilmaz, Nese Kurt; Swanstrom, Ronald; Schiffer, Celia A.

    2016-01-01

    Drug resistance is a major problem in health care, undermining therapy outcomes and necessitating novel approaches to drug design. Extensive studies on resistance to viral protease inhibitors, particularly those of HIV-1 and hepatitis C virus (HCV) protease, revealed a plethora of information on the structural and molecular mechanisms underlying resistance. These insights led to several strategies to improve viral protease inhibitors to counter resistance, such as exploiting the essential biological function and leveraging evolutionary constraints. Incorporation of these strategies into structure-based drug design can minimize vulnerability to resistance, not only for viral proteases but for other quickly evolving drug targets as well, toward designing inhibitors one step ahead of evolution to counter resistance with more intelligent and rational design. PMID:27090931

  11. Drug delivery systems improve pharmaceutical profile and facilitate medication adherence.

    PubMed

    Wertheimer, Albert I; Santella, Thomas M; Finestone, Albert J; Levy, Richard A

    2005-01-01

    Innovations in dosage forms and dose delivery systems across a wide range of medications offer substantial clinical advantages, including reduced dosing frequency and improved patient adherence; minimized fluctuation of drug concentrations and maintenance of blood levels within a desired range; localized drug delivery; and the potential for reduced adverse effects and increased safety. The advent of new large-molecule drugs for previously untreatable or only partially treatable diseases is stimulating the development of suitable delivery systems for these agents. Although advanced formulations may be more expensive than conventional dosage forms, they often have a more favorable pharmacologic profile and can be cost-effective. Inclusion of these dosage forms on drug formulary lists may help patients remain on therapy and reduce the economic and social burden of care.

  12. Strategies to improve drug delivery in bladder cancer therapy.

    PubMed

    Wirth, M; Plattner, V E; Gabor, F

    2009-07-01

    Bladder cancer is the ninth most common malignancy in the world featuring very high gender variability in occurrence. Current options for bladder cancer therapy include surgery, immunotherapy, chemotherapy and radiotherapy with a trend towards multimodal treatments. However, successful management remains a challenge for urologists and oncologists because of the high risk for recurrence and progression. Particularly in the field of bladder cancer chemotherapy, efficacy of treatment might be improved by advanced drug delivery strategies aimed at prolonged residence time within the bladder cavity and increased permeability of the bladder wall during intravesical instillation. Moreover, a deeper understanding of the biology of bladder carcinogenesis and malignant progression stimulated the development of a new generation of anticancer drugs for targeted therapies that might result in increased treatment specificity together with lower toxic potential and higher therapeutic indices. This review discusses the available strategies for 'targeted therapy', focusing on molecular targets, and for 'controlled delivery', comprising all other approaches towards improved drug delivery.

  13. Asthma improved by nonsteroidal anti-inflammatory drugs.

    PubMed

    Kordansky, D; Adkinson, N F; Norman, P S; Rosenthal, R R

    1978-04-01

    A patient who claimed benefit from aspirin for her reversible bronchospasm was challenged orally in a placebo-controlled study with aspirin and other aspirin-like drugs. Specific airways conductance and spirometry were monitored for up to 150 minutes after oral challenge. Aspirin, mefenamic acid, and ibuprofen administration resulted in marked (45% to 80%) improvement in forced expiratory volume in 1 second (FEV1) compared to lactose placebo. Indomethacin, sodium salicylate, and tartrazine resulted in modest (15% to 25%) FEV1 improvement, while phenylbutazone produced a 25% decrease. These results are discussed here in terms of the ability of these drugs to inhibit the prostaglandin synthetase enzyme system. This case suggests that aspirin and other nonsteroidal anti-inflammatory drugs may be beneficial rather than harmful in some asthmatic patients.

  14. 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.

  15. Stealth Properties to Improve Therapeutic Efficacy of Drug Nanocarriers

    PubMed Central

    Caliceti, Paolo

    2013-01-01

    Over the last few decades, nanocarriers for drug delivery have emerged as powerful tools with unquestionable potential to improve the therapeutic efficacy of anticancer drugs. Many colloidal drug delivery systems are underdevelopment to ameliorate the site specificity of drug action and reduce the systemic side effects. By virtue of their small size they can be injected intravenously and disposed into the target tissues where they release the drug. Nanocarriers interact massively with the surrounding environment, namely, endothelium vessels as well as cells and blood proteins. Consequently, they are rapidly removed from the circulation mostly by the mononuclear phagocyte system. In order to endow nanosystems with long circulation properties, new technologies aimed at the surface modification of their physicochemical features have been developed. In particular, stealth nanocarriers can be obtained by polymeric coating. In this paper, the basic concept underlining the “stealth” properties of drug nanocarriers, the parameters influencing the polymer coating performance in terms of opsonins/macrophages interaction with the colloid surface, the most commonly used materials for the coating process and the outcomes of this peculiar procedure are thoroughly discussed. PMID:23533769

  16. Improved drug therapy: triangulating phenomics with genomics and metabolomics

    PubMed Central

    2014-01-01

    Embracing the complexity of biological systems has a greater likelihood to improve prediction of clinical drug response. Here we discuss limitations of a singular focus on genomics, epigenomics, proteomics, transcriptomics, metabolomics, or phenomics—highlighting the strengths and weaknesses of each individual technique. In contrast, ‘systems biology’ is proposed to allow clinicians and scientists to extract benefits from each technique, while limiting associated weaknesses by supplementing with other techniques when appropriate. Perfect predictive modeling is not possible, whereas modeling of intertwined phenomic responses using genomic stratification with metabolomic modifications may greatly improve predictive values for drug therapy. We thus propose a novel-integrated approach to personalized medicine that begins with phenomic data, is stratified by genomics, and ultimately refined by metabolomic pathway data. Whereas perfect prediction of efficacy and safety of drug therapy is not possible, improvements can be achieved by embracing the complexity of the biological system. Starting with phenomics, the combination of linking metabolomics to identify common biologic pathways and then stratifying by genomic architecture, might increase predictive values. This systems biology approach has the potential, in specific subsets of patients, to avoid drug therapy that will be either ineffective or unsafe. PMID:25181945

  17. A Cooperative Model to Improve Hospital Equipments and Drugs Management

    NASA Astrophysics Data System (ADS)

    Baffo, Ilaria; Confessore, Giuseppe; Liotta, Giacomo; Stecca, Giuseppe

    The cost of services provided by public and private healthcare systems is nowadays becoming critical. This work tackles the criticalities of hospital equipments and drugs management by emphasizing its implications on the whole healthcare system efficiency. The work presents a multi-agent based model for decisional cooperation in order to address the problem of integration of departments, wards and personnel for improving equipments, and drugs management. The proposed model faces the challenge of (i) gaining the benefits deriving from successful collaborative models already used in industrial systems and (ii) transferring the most appropriate industrial management practices to healthcare systems.

  18. Intracochlear drug injections through the round window membrane: Measures to improve drug retention

    PubMed Central

    Plontke, Stefan K.; Hartsock, Jared J.; Gill, Ruth M.; Salt, Alec N.

    2016-01-01

    The goal of this study was to develop appropriate methodology to apply drugs quantitatively to perilymph of the ear. Intratympanic applications of drugs to the inner ear often result in variable drug levels in perilymph and can only be used for molecules that readily permeate the round window (RW) membrane. Direct intracochlear and intralabyrinthine application procedures for drugs, genes or cell-based therapies by-pass the tight boundaries at the round window, oval window, otic capsule and the blood-labyrinth barrier. However, perforations can release inner ear pressure, allowing cerebrospinal fluid to enter through the cochlear aqueduct, displacing the injected drug solution into the middle ear. Two markers, fluorescein or fluorescein isothiocyanate (FITC)-labeled dextran, were used to quantify how much of an injected substance was retained in cochlear perilymph following an intracochlear injection. We evaluated whether procedures to mitigate fluid leaks improved marker retention in perilymph. Almost all procedures to reduce volume efflux, including the use of gel for internal sealing and glue for external sealing of the injection site, resulted in improved retention of the marker in perilymph. Adhesive on the RW membrane effectively prevented leaks but also influenced fluid exchange between CSF and perilymph. We conclude that drugs can be delivered to the ear in a consistent, quantitative manner using intracochlear injections if care is taken to control the fluid leaks that result from cochlear perforation. PMID:26905306

  19. Improving the odds in discriminating "drug-like" from "non drug-like" compounds.

    PubMed

    Frimurer, T M; Bywater, R; Naerum, L; Lauritsen, L N; Brunak, S

    2000-01-01

    We have used a feed-forward neural network technique to classify chemical compounds into potentially "drug-like" and "non drug-like" candidates. The neural network was trained to distinguish between a set of "drug-like" and "non drug-like" chemical compounds taken from the MACCS-II Drug Data Report (MDDR) and the Available Chemicals Directory (ACD). The 2D atom types (of the full atomic representation) were assigned and applied as descriptors to encode numerically each compound. There are four main conclusions: First the method performs well, correctly assigning 88% of the compounds in both MDDR and ACD. Improved discrimination was achieved by a more critical selection of training sets. Second, the method gives much better prediction performance than the widely used "Rule of Five", which accepts as many as 74% of the ACD compounds but only 66% of those in MDDR, resulting in a correlation coefficient which is effectively zero, compared to a value of 0.63 for the neural network prediction. Third, based on a standard Tanimoto similarity search the selection of drug-like compounds in the evaluation set is not biased toward compounds similar to those in the training set. Fourth, the trained neural network was applied to evaluate the drug-likeness of 136 GABA uptake inhibitors with impressive results. The implications of applying a neural network to characterize chemical compounds are discussed.

  20. New forms of old drugs: improving without changing.

    PubMed

    Domingos, Sofia; André, Vânia; Quaresma, Sílvia; Martins, Inês C B; Minas da Piedade, M Fátima; Duarte, Maria Teresa

    2015-06-01

    In a short approach, we want to present the improvements that have recently been done in the world of new solid forms of known active pharmaceutical ingredients (APIs). The different strategies will be addressed, and successful examples will be given. This overview presents a possible step to overcome the 10-15 years of hard work involved in launching a new drug in the market: the use of new forms of well-known APIs, and improve their efficiency by enhancing their bioavailability and pharmacokinetics. It discusses some of the latest progresses. We want to present, in a brief overview, what recently has been done to improve the discovery of innovative methods of using well-known APIs, and improve their efficiency. Multicomponent crystal forms have shown to be the most promising achievements to accomplish these aims, by altering API physico-chemical properties, such as solubility, thermal stability, shelf life, dissolution rate and compressibility. API-ionic liquids (ILs) and their advantages will be briefly referred. An outline of what has recently been achieved in metal drug coordination and in drug storage and delivery using bio-inspired metal-organic frameworks (BioMOFs) will also be addressed. © 2015 Royal Pharmaceutical Society.

  1. Computerized advice on drug dosage to improve prescribing practice.

    PubMed

    Durieux, Pierre; Trinquart, Ludovic; Colombet, Isabelle; Niès, Julie; Walton, Rt; Rajeswaran, Anand; Rège Walther, Myriam; Harvey, Emma; Burnand, Bernard

    2008-07-16

    Maintaining therapeutic concentrations of drugs with a narrow therapeutic window is a complex task. Several computer systems have been designed to help doctors determine optimum drug dosage. Significant improvements in health care could be achieved if computer advice improved health outcomes and could be implemented in routine practice in a cost effective fashion. This is an updated version of an earlier Cochrane systematic review, by Walton et al, published in 2001. To assess whether computerised advice on drug dosage has beneficial effects on the process or outcome of health care. We searched the Cochrane Effective Practice and Organisation of Care Group specialized register (June 1996 to December 2006), MEDLINE (1966 to December 2006), EMBASE (1980 to December 2006), hand searched the journal Therapeutic Drug Monitoring (1979 to March 2007) and the Journal of the American Medical Informatics Association (1996 to March 2007) as well as reference lists from primary articles. Randomized controlled trials, controlled trials, controlled before and after studies and interrupted time series analyses of computerized advice on drug dosage were included. The participants were health professionals responsible for patient care. The outcomes were: any objectively measured change in the behaviour of the health care provider (such as changes in the dose of drug used); any change in the health of patients resulting from computerized advice (such as adverse reactions to drugs). Two reviewers independently extracted data and assessed study quality. Twenty-six comparisons (23 articles) were included (as compared to fifteen comparisons in the original review) including a wide range of drugs in inpatient and outpatient settings. Interventions usually targeted doctors although some studies attempted to influence prescriptions by pharmacists and nurses. Although all studies used reliable outcome measures, their quality was generally low. Computerized advice for drug dosage gave

  2. Overcoming cellular and tissue barriers to improve liposomal drug delivery

    NASA Astrophysics Data System (ADS)

    Kohli, Aditya G.

    Forty years of liposome research have demonstrated that the anti-tumor efficacy of liposomal therapies is, in part, driven by three parameters: 1) liposome formulation and lipid biophysics, 2) accumulation and distribution in the tumor, and 3) release of the payload at the site of interest. This thesis outlines three studies that improve on each of these delivery steps. In the first study, we engineer a novel class of zwitterlipids with an inverted headgroup architecture that have remarkable biophysical properties and may be useful for drug delivery applications. After intravenous administration, liposomes accumulate in the tumor by the enhanced permeability and retention effect. However, the tumor stroma often limits liposome efficacy by preventing distribution into the tumor. In the second study, we demonstrate that depletion of hyaluronan in the tumor stroma improves the distribution and efficacy of DoxilRTM in murine 4T1 tumors. Once a liposome has distributed to the therapeutic site, it must release its payload over the correct timescale. Few facile methods exist to quantify the release of liposome therapeutics in vivo. In the third study, we outline and validate a simple, robust, and quantitative method for tracking the rate and extent of release of liposome contents in vivo. This tool should facilitate a better understanding of the pharmacodynamics of liposome-encapsulated drugs in animals. This work highlights aspects of liposome behavior that have prevented successful clinical translation and proposes alternative approaches to improve liposome drug delivery.

  3. Deploying continuous improvement across the drug discovery value chain.

    PubMed

    Walker, Stephen M; Davies, Barry J

    2011-06-01

    In addressing the challenges facing pharmaceutical R&D one question is frequently asked: how can continuous improvement (CI), delivered through a Lean Sigma approach, be applied in a research environment to deliver overall benefit? We show that taking a value chain approach to improvement projects in a discovery research organization, initially focusing on the drug discovery project delivery level (i.e. middle layer of the value chain), provides the foundation for an effective CI programme. The adaptation of Lean Sigma principles and methodology, combined with the tenacity and creativity of scientists, enabled the delivery of significant improvements in challenging areas, including target selection, project decision making and the compound design-make-test-analyse (DMTA) cycle. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. Adaptive Programming Improves Outcomes in Drug Court: An Experimental Trial

    PubMed Central

    Marlowe, Douglas B.; Festinger, David S.; Dugosh, Karen L.; Benasutti, Kathleen M.; Fox, Gloria; Croft, Jason R.

    2011-01-01

    Prior studies in Drug Courts reported improved outcomes when participants were matched to schedules of judicial status hearings based on their criminological risk level. The current experiment determined whether incremental efficacy could be gained by periodically adjusting the schedule of status hearings and clinical case-management sessions in response to participants’ ensuing performance in the program. The adjustments were made pursuant to a priori criteria specified in an adaptive algorithm. Results confirmed that participants in the full adaptive condition (n = 62) were more than twice as likely as those assigned to baseline-matching only (n = 63) to be drug-abstinent during the first 18 weeks of the program; however, graduation rates and the average time to case resolution were not significantly different. The positive effects of the adaptive program appear to have stemmed from holding noncompliant participants more accountable for meeting their attendance obligations in the program. Directions for future research and practice implications are discussed. PMID:22923854

  5. Improvement of Pediatric Drug Development: Regulatory and Practical Frameworks.

    PubMed

    Tsukamoto, Katusra; Carroll, Kelly A; Onishi, Taku; Matsumaru, Naoki; Brasseur, Daniel; Nakamura, Hidefumi

    2016-03-01

    A dearth in pediatric drug development often leaves pediatricians with no alternative but to prescribe unlicensed or off-label drugs with a resultant increased risk of adverse events. We present the current status of pediatric drug development and, based on our data analysis, clarify the problems in this area. Further action is proposed to improve the drug development that has pediatric therapeutic orphan status. We analyzed all Phase II/III and Phase III trials in ClinicalTrials.gov that only included pediatric participants (<18 years old) between 2006 and 2014. Performance index, an indicator of pediatric drug development, was calculated by dividing the annual number of pediatric clinical trials by million pediatric populations acquired from Census.gov. Effects of the 2 Japanese premiums introduced in 2010, for the enhancement of pediatric drug development, were analyzed by comparing mean performance index prepremiums (2006-2009) and postpremiums (2010-2014) among Japan, the European Union, and the United States. The European Union Clinical Trials Register and published reports from the European Medicines Agency were also surveyed to investigate the Paediatric Committee effect on pediatric clinical trials in the European Union. Mean difference of the performance index in prepremiums and postpremiums between Japan and the European Union were 0.296 (P < 0.001) and 0.066 (P = 0.498), respectively. Those between Japan and the United States were 0.560 (P < 0.001) and 0.281 (P = 0.002), indicating that pediatric drug development in Japan was more active after the introduction of these premiums, even reaching the level of the European Union. The Pediatric Regulation and the Paediatric Committee promoted pediatric drug development in the European Union. The registered number of clinical trials that includes at least 1 participants <18 years old in the European Union Clinical Trials Register increased by 247 trials (from 672) in the 1000 days after regulation. The ratio

  6. Improving and Accelerating Drug Development for Nervous System Disorders

    PubMed Central

    Pankevich, Diana E.; Altevogt, Bruce M.; Dunlop, John; Gage, Fred H.; Hyman, Steve E.

    2014-01-01

    Advances in the neurosciences have placed the field in the position where it is poised to significantly reduce the burden of nervous system disorders. However, drug discovery, development and translation for nervous system disorders still pose many unique challenges. The key scientific challenges can be summarized as follows: mechanisms of disease, target identification and validation, predictive models, biomarkers for patient stratification and as endpoints for clinical trials, clear regulatory pathways, reliability and reproducibility of published data, and data sharing and collaboration. To accelerate nervous system drug development the Institute of Medicine’s Forum on Neuroscience and Nervous System Disorders has hosted a series of public workshops that brought together representatives of industry, government (including both research funding and regulatory agencies), academia, and patient groups to discuss these challenges and offer potential strategies to improve the translational neuroscience. PMID:25442933

  7. Adaptive Programming Improves Outcomes in Drug Court: An Experimental Trial.

    PubMed

    Marlowe, Douglas B; Festinger, David S; Dugosh, Karen L; Benasutti, Kathleen M; Fox, Gloria; Croft, Jason R

    2012-04-01

    Prior studies in Drug Courts reported improved outcomes when participants were matched to schedules of judicial status hearings based on their criminological risk level. The current experiment determined whether incremental efficacy could be gained by periodically adjusting the schedule of status hearings and clinical case-management sessions in response to participants' ensuing performance in the program. The adjustments were made pursuant to a priori criteria specified in an adaptive algorithm. Results confirmed that participants in the full adaptive condition (n = 62) were more than twice as likely as those assigned to baseline-matching only (n = 63) to be drug-abstinent during the first 18 weeks of the program; however, graduation rates and the average time to case resolution were not significantly different. The positive effects of the adaptive program appear to have stemmed from holding noncompliant participants more accountable for meeting their attendance obligations in the program. Directions for future research and practice implications are discussed.

  8. Improving Patient Understanding of Prescription Drug Label Instructions

    PubMed Central

    Davis, Terry C.; Federman, Alex D.; Bass, Pat F.; Jackson, Robert H.; Middlebrooks, Mark; Parker, Ruth M.

    2008-01-01

    Background Patient misunderstanding of instructions on prescription drug labels is common and a likely cause of medication error and less effective treatment. Objective To test whether the use of more explicit language to describe dose and frequency of use for prescribed drugs could improve comprehension, especially among patients with limited literacy. Design Cross-sectional study using in-person, structured interviews. Patients Three hundred and fifty-nine adults waiting for an appointment in two hospital-based primary care clinics and one federally qualified health center in Shreveport, Louisiana; Chicago, Illinois; and New York, New York, respectively. Measurement Correct understanding of each of ten label instructions as determined by a blinded panel review of patients’ verbatim responses. Results Patient understanding of prescription label instructions ranged from 53% for the least understood to 89% for the most commonly understood label. Patients were significantly more likely to understand instructions with explicit times periods (i.e., morning) or precise times of day compared to instructions stating times per day (i.e., twice) or hourly intervals (89%, 77%, 61%, and 53%, respectively,  < 0.001). In multivariate analyses, dosage instructions with specific times or time periods were significantly more likely to be understood compared to instructions stating times per day (time periods — adjusted relative risk ratio (ARR) 0.42, 95% Confidence Interval (CI) 0.34–0.52; specific times — ARR 0.60, 95% CI 0.49–0.74). Low and marginal literacy remained statistically significant independent predictors of misinterpreting instructions (low - ARR 2.70, 95% CI 1.81–4.03; marginal -ARR 1.66, 95% CI 1.18–2.32). Conclusions Use of precise wording on prescription drug label instructions can improve patient comprehension. However, patients with limited literacy were more likely to misinterpret instructions despite use of more explicit language. PMID

  9. Encapsulation of poorly water-soluble drugs into organic nanotubes for improving drug dissolution.

    PubMed

    Moribe, Kunikazu; Makishima, Takashi; Higashi, Kenjirou; Liu, Nan; Limwikrant, Waree; Ding, Wuxiao; Masuda, Mitsutoshi; Shimizu, Toshimi; Yamamoto, Keiji

    2014-07-20

    Hydrocortisone (HC), a poorly water-soluble drug, was encapsulated within organic nanotubes (ONTs), which were formed via the self-assembly of N-{12-[(2-α,β-d-glucopyranosyl) carbamoyl]dodecanyl}-glycylglycylglycine acid. The stability of the ONTs was evaluated in ten organic solvents, of differing polarities, by field emission transmission electron microscopy. The ONTs maintained their stable tubular structure in the highly polar solvents, such as ethanol and acetone. Furthermore, solution-state (1)H-NMR spectroscopy confirmed that they were practically insoluble in acetone at 25°C (0.015 mg/mL). HC-loaded ONTs were prepared by solvent evaporation using acetone. A sample with a 3/7 weight ratio of HC/ONT was analyzed by powder X-ray diffraction, which confirmed the presence of a halo pattern and the absence of any crystalline HC peak. HC peak broadening, observed by solid-state (13)C-NMR measurements of the evaporated sample, indicated the absence of HC crystals. These results indicated that HC was successfully encapsulated in ONT as an amorphous state. Improvements of the HC dissolution rate were clearly observed in aqueous media at both pH 1.2 and 6.8, probably due to HC amorphization in the ONTs. Phenytoin, another poorly water-soluble drug, also showed significant dissolution improvement upon ONT encapsulation. Therefore, ONTs can serve as an alternative pharmaceutical excipient to enhance the bioavailability of poorly water-soluble drugs.

  10. Improving drug safety: From adverse drug reaction knowledge discovery to clinical implementation.

    PubMed

    Tan, Yuxiang; Hu, Yong; Liu, Xiaoxiao; Yin, Zhinan; Chen, Xue-Wen; Liu, Mei

    2016-11-01

    Adverse drug reactions (ADRs) are a major public health concern, causing over 100,000 fatalities in the United States every year with an annual cost of $136 billion. Early detection and accurate prediction of ADRs is thus vital for drug development and patient safety. Multiple scientific disciplines, namely pharmacology, pharmacovigilance, and pharmacoinformatics, have been addressing the ADR problem from different perspectives. With the same goal of improving drug safety, this article summarizes and links the research efforts in the multiple disciplines into a single framework from comprehensive understanding of the interactions between drugs and biological system and the identification of genetic and phenotypic predispositions of patients susceptible to higher ADR risks and finally to the current state of implementation of medication-related decision support systems. We start by describing available computational resources for building drug-target interaction networks with biological annotations, which provides a fundamental knowledge for ADR prediction. Databases are classified by functions to help users in selection. Post-marketing surveillance is then introduced where data-driven approach can not only enhance the prediction accuracy of ADRs but also enables the discovery of genetic and phenotypic risk factors of ADRs. Understanding genetic risk factors for ADR requires well organized patient genetics information and analysis by pharmacogenomic approaches. Finally, current state of clinical decision support systems is presented and described how clinicians can be assisted with the integrated knowledgebase to minimize the risk of ADR. This review ends with a discussion of existing challenges in each of disciplines with potential solutions and future directions.

  11. Nanotechnology versus other techniques in improving drug dissolution.

    PubMed

    Kwok, Philip Chi Lip; Chan, Hak-Kim

    2014-01-01

    Many newly discovered drug molecules have low aqueous solubility, which results in low bioavailability. One way to improve their dissolution is to formulate them as nanoparticles, which have high specific surface areas, consequently increasing the dissolution rate and solubility. Nanoparticles can be produced via top-down or bottom-up methods. Top-down techniques such as wet milling and high pressure homogenisation involve reducing large particles to nano-sizes. Some pharmaceutical products made by these processes have been marketed. Bottom-up methods such as precipitation and controlled droplet evaporation form nanoparticles from molecules in solution. To minimise aggregation upon drying and promote redispersion of the nanoparticles upon reconstitution or administration, hydrophilic matrix formers are added to the formulation. However, the nanoparticles will eventually agglomerate together after dispersing in the liquid and hinders dissolution. Currently there is no pharmacopoeial method specified for nanoparticles. Amongst the current dissolution apparatus available for powders, the flow-through cell has been shown to be the most suitable. Regulatory and pharmacopoeial standards should be established in the future to standardise the dissolution testing of nanoparticles. More nanoparticle formulations of new hydrophobic drugs are expected to be developed in the future with the advancement of nanotechnology. However, the agglomeration problem is inherent and difficult to overcome. Thus the benefit of dissolution enhancement often cannot be fully realised. On the other hand, chemical strategies such as modifying the parent drug molecule to form a more soluble salt form, prodrug, or cyclodextrin complexation are well established and have been shown to be effective in enhancing dissolution. Thus the value of nanoformulations needs to be interpreted in the light of their limitations. Chemical approaches should also be considered in new product development.

  12. Recommendations to improve the usability of drug-drug interaction clinical decision support alerts.

    PubMed

    Payne, Thomas H; Hines, Lisa E; Chan, Raymond C; Hartman, Seth; Kapusnik-Uner, Joan; Russ, Alissa L; Chaffee, Bruce W; Hartman, Christian; Tamis, Victoria; Galbreth, Brian; Glassman, Peter A; Phansalkar, Shobha; van der Sijs, Heleen; Gephart, Sheila M; Mann, Gordon; Strasberg, Howard R; Grizzle, Amy J; Brown, Mary; Kuperman, Gilad J; Steiner, Chris; Sullins, Amanda; Ryan, Hugh; Wittie, Michael A; Malone, Daniel C

    2015-11-01

    To establish preferred strategies for presenting drug-drug interaction (DDI) clinical decision support alerts. A DDI Clinical Decision Support Conference Series included a workgroup consisting of 24 clinical, usability, and informatics experts representing academia, health information technology (IT) vendors, healthcare organizations, and the Office of the National Coordinator for Health IT. Workgroup members met via web-based meetings 12 times from January 2013 to February 2014, and two in-person meetings to reach consensus on recommendations to improve decision support for DDIs. We addressed three key questions: (1) what, how, where, and when do we display DDI decision support? (2) should presentation of DDI decision support vary by clinicians? and (3) how should effectiveness of DDI decision support be measured? Our recommendations include the consistent use of terminology, visual cues, minimal text, formatting, content, and reporting standards to facilitate usability. All clinicians involved in the medication use process should be able to view DDI alerts and actions by other clinicians. Override rates are common but may not be a good measure of effectiveness. Seven core elements should be included with DDI decision support. DDI information should be presented to all clinicians. Finally, in their current form, override rates have limited capability to evaluate alert effectiveness. DDI clinical decision support alerts need major improvements. We provide recommendations for healthcare organizations and IT vendors to improve the clinician interface of DDI alerts, with the aim of reducing alert fatigue and improving patient safety. © The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Opening Pandora's pillbox: using modern information tools to improve drug safety.

    PubMed

    Gottlieb, Scott

    2005-01-01

    How the Food and Drug Administration (FDA) responds to criticism of its drug safety process will determine whether drug safety actually improves. Propping up the Office of Drug Safety with more bureaucratic prominence or adding new requirements to the preapproval process will add to the cost of drug development and not make drugs safer. New information tools can dramatically improve postmarketing surveillance and collection of data on safety. This information could then be used to reach more definitive regulatory conclusions sooner. New incentives will be needed to entice payers and product developers to work on building a broader, more robust system for collecting data on drug safety.

  14. Targeting drug sensitivity predictors: New potential strategies to improve pharmacotherapy of human brain disorders.

    PubMed

    Kalueff, Allan V; Stewart, Adam Michael; Nguyen, Michael; Song, Cai; Gottesman, Irving I

    2015-12-03

    One of the main challenges in medicine is the lack of efficient drug therapies for common human disorders. For example, although depressed patients receive powerful antidepressants, many often remain resistant to psychopharmacotherapy. The growing recognition of complex interplay between the drug targets and the predictors of drug sensitivity requires an improved understanding of these two key aspects of drug action and their potentially shared molecular networks. Here, we apply the concept of endophenotypes and their interplay to drug action and sensitivity. Based on these analyses, we postulate that novel drugs may be developed by targeting specific molecular pathways that integrate drug targets with drug sensitivity predictors.

  15. Reimbursed Price of Orphan Drugs: Current Strategies and Potential Improvements.

    PubMed

    Mincarone, Pierpaolo; Leo, Carlo Giacomo; Sabina, Saverio; Sarriá-Santamera, Antonio; Taruscio, Domenica; Serrano-Aguilar, Pedro Guillermo; Kanavos, Panos

    2017-01-01

    The pricing and reimbursement policies for pharmaceuticals are relevant to balance timely and equitable access for all patients, financial sustainability, and reward for valuable innovation. The proliferation of high-cost specialty medicines is particularly true in rare diseases (RDs) where the pricing mechanism is characterised by a lack of transparency. This work provides an overall picture of current strategies for the definition of the reimbursed prices of orphan drugs (ODs) and highlights some potential improvements. Current strategies and suggestions are presented along 4 dimensions: (1) comprehensive value assessment, (2) early dialogs among relevant stakeholders, (3) innovative reimbursement approaches, and (4) societal participation in producing ODs. Comprehensive value assessment could be achieved by clarifying the approach of distributive justice to adopt, ensuring a representative participation of stakeholders, and with a broad consideration of value-bearing factors. With respect to early dialogs, cross-border cooperation can be determinant to companies and agencies. The cost-benefit ratio of early dialogs needs to be demonstrated and the "regulatory capture" effect should be monitored. Innovative reimbursement approaches were developed to balance the need for evidence-based decisions with the timely access to innovative drugs. The societal participation in producing ODs needs to be recognised in a collaborating framework where adaptive agreements can be developed with mutual satisfaction. Such agreements could also impact on coverage and reimbursement decisions as additional elements for the determination of a comprehensive societal value of ODs. Further research is needed to investigate the highlighted open challenges so that RDs will not remain, in practical terms, orphan diseases. © 2017 S. Karger AG, Basel.

  16. Improving postapproval drug safety surveillance: getting better information sooner.

    PubMed

    Hennessy, Sean; Strom, Brian L

    2015-01-01

    Adverse drug events (ADEs) are an important public health concern, accounting for 5% of all hospital admissions and two-thirds of all complications occurring shortly after hospital discharge. There are often long delays between when a drug is approved and when serious ADEs are identified. Recent and ongoing advances in drug safety surveillance include the establishment of government-sponsored networks of population databases, the use of data mining approaches, and the formal integration of diverse sources of drug safety information. These advances promise to reduce delays in identifying drug-related risks and in providing reassurance about the absence of such risks.

  17. Improving Detection of Arrhythmia Drug-Drug Interactions in Pharmacovigilance Data through the Implementation of Similarity-Based Modeling.

    PubMed

    Vilar, Santiago; Lorberbaum, Tal; Hripcsak, George; Tatonetti, Nicholas P

    2015-01-01

    Identification of Drug-Drug Interactions (DDIs) is a significant challenge during drug development and clinical practice. DDIs are responsible for many adverse drug effects (ADEs), decreasing patient quality of life and causing higher care expenses. DDIs are not systematically evaluated in pre-clinical or clinical trials and so the FDA U. S. Food and Drug Administration relies on post-marketing surveillance to monitor patient safety. However, existing pharmacovigilance algorithms show poor performance for detecting DDIs exhibiting prohibitively high false positive rates. Alternatively, methods based on chemical structure and pharmacological similarity have shown promise in adverse drug event detection. We hypothesize that the use of chemical biology data in a post hoc analysis of pharmacovigilance results will significantly improve the detection of dangerous interactions. Our model integrates a reference standard of DDIs known to cause arrhythmias with drug similarity data. To compare similarity between drugs we used chemical structure (both 2D and 3D molecular structure), adverse drug side effects, chemogenomic targets, drug indication classes, and known drug-drug interactions. We evaluated the method on external reference standards. Our results showed an enhancement of sensitivity, specificity and precision in different top positions with the use of similarity measures to rank the candidates extracted from pharmacovigilance data. For the top 100 DDI candidates, similarity-based modeling yielded close to twofold precision enhancement compared to the proportional reporting ratio (PRR). Moreover, the method helps in the DDI decision making through the identification of the DDI in the reference standard that generated the candidate.

  18. Physicochemical Properties of Solid Phospholipid Particles as a Drug Delivery Platform for Improving Oral Absorption of Poorly Soluble Drugs.

    PubMed

    Kawakami, Kohsaku; Miyazaki, Aoi; Fukushima, Mayuko; Sato, Keiko; Yamamura, Yuko; Mohri, Kohta; Sakuma, Shinji

    2017-01-01

    A novel drug delivery platform, mesoporous phospholipid particle (MPP), is introduced. Its physicochemical properties and ability as a carrier for enhancing oral absorption of poorly soluble drugs are discussed. MPP was prepared through freeze-drying a cyclohexane/t-butyl alcohol solution of phosphatidylcholine. Its basic properties were revealed using scanning electron microscopy, x-ray diffraction, thermal analysis, hygroscopicity measurement, and so on. Fenofibrate was loaded to MPP as a poorly soluble model drug, and effect of MPP on the oral absorption behavior was observed. MPP is spherical in shape with a diameter typically in the range of 10-15 μm and a wide surface area that exceeds 10 m(2)/g. It has a bilayer structure that may accommodate hydrophobic drugs in the acyl chain region. When fenofibrate was loaded in MPP as a model drug, it existed partially in a crystalline state and improvement in the dissolution behavior was achieved in the presence of a surfactant, because of the formation of mixed micelles composed of phospholipids and surfactants in the dissolution media. MPP greatly improved the oral absorption of fenofibrate compared to that of the crystalline drug and its efficacy was almost equivalent to that of an amorphous drug dispersion. MPP is a promising option for improving the oral absorption of poorly soluble drugs based on the novel mechanism of dissolution improvement.

  19. Active drug safety surveillance: a tool to improve public health.

    PubMed

    Platt, Richard; Madre, Leanne; Reynolds, Robert; Tilson, Hugh

    2008-12-01

    Ensuring that drugs have an acceptable safety profile and are used safely is a major public health priority. The Centers for Education and Research on Therapeutics (CERTs) convened experts from academia, government, and industry to assess strategies to increase the speed and predictive value of generating and evaluating safety signals, and to identify next steps to improve the US system for identifying and evaluating potential safety signals. The CERTs convened a think tank comprising representatives of the groups noted above to address these goals. Participants observed that, with the increasing availability of electronic health data, opportunities have emerged to more accurately characterize and confirm potential safety issues. The gain for public health from a highly coordinated network of population-based databases for active surveillance is great and within reach, although operational questions remain. A collaborative network must create a working definition of a safety signal, screening algorithms, and criteria and strategies to confirm or refute a signal once identified through screening. Guidelines are needed for when and how to communicate a signal exists and is being evaluated, as well as the outcome of that evaluation. A public-private partnership to create a network of government and private databases to routinely evaluate and prioritize safety questions is in the public interest. Better methods are needed, and a knowledgeable workforce is required to conduct the surveillance and understand how to interpret the results. The international community will benefit from the availability of better methods and more experts. Copyright (c) 2008 John Wiley & Sons, Ltd.

  20. Gold-mediated drug delivery for improved outcome in chemotherapy

    NASA Astrophysics Data System (ADS)

    Yang, C.; Chithrani, B. D.

    2017-02-01

    Nanoparticles can be used to overcome the side effects due to poor distribution of anticancer drugs. Among other NPs, colloidal gold nanoparticles (GNPs) offer the possibility of transporting major quantities of drugs due to their large surface-to volume ratio while confining anticancer drugs as closely as possible to their biological targets through passive and active targeting ensuring limited harmful systemic distribution. In this study, we chose bleomycin (BLM) as the anticancer drug since its therapeutic efficiency is severely limited because of its side effects. Bleomycin was conjugated to GNPs through a thiol bond. The effectiveness of the chemotherapeutic drug, bleomycin, is observed by visualizing DNA double strand breaks and calculating the survival fraction. The action of the drug is known to be in the nucleus and our experiments have shown GNPs in the nucleus along with bleomycin. Use of GNPs to deliver bleomycin increased the therapeutic efficacy of the drug. Having a better understanding of the interaction of GNPs and drugs will establish a more successful NP-based platform for combined therapeutic approach in cancer research since GNPs can be used as radiation dose enhancers.

  1. Integrating translational neuroscience to improve drug abuse treatment for adolescents.

    PubMed

    Boyce, Cheryl Anne; Lynne-Landsman, Sarah D

    2013-06-01

    Adolescence is an exciting and challenging period of maturation, rapid brain development, and developmental changes in neurobiological, neurocognitive, and neurobehavioral processes. Although behavioral therapies available for adolescent substance abuse have increased, effectiveness research in this area lags considerably behind that of clinical research on treatment for drug-abusing adults. Behavioral treatment approaches show significant promise for treating drug-abusing adolescents, but many have not incorporated innovations in neuroscience on brain development, cognitive processes, and neuroimaging. Linking developmental neuroscience with behavioral treatments can create novel drug abuse interventions and increase the effectiveness of existing interventions for substance-abusing adolescents. Contemporary research on brain development, cognition, and neuroscience is ripe for translation to inform developmentally sensitive drug abuse treatments for adolescents. Neuroscientists and interventionists are challenged to build mutual collaborations for integration of neuroscience and drug abuse treatment for adolescents. 2013 APA, all rights reserved

  2. Improving Drugs Administration Safety in Pediatric Resuscitation Using Mobile Technology.

    PubMed

    Hagberg, Hamdi; Siebert, Johan; Gervaix, Alain; Daehne, Peter; Lovis, Christian; Manzano, Sergio; Ehrler, Frederic

    2016-01-01

    The fast preparation of drugs during pediatric resuscitation is of utmost importance. The influence of the patient's weight on the drug doses requires to perform complex calculations and is a source of errors. A technological solution could be a real help in avoiding these kinds of mistakes. Relying on a user centered approach we have developed an application supporting drug preparation. It has been tested in simulations with predefined scenario. The developed tool consists of a screen displaying a list of drug that can be administered. When the user select a drug, the instructions regarding its preparation are displayed with all dosage precisely calculated. The tool has demonstrated a significant reduction of errors associated to administration, a speeding up the overall process and has been well received by the nurses.

  3. 78 FR 8446 - Center for Drug Evaluation and Research; Prescription Drug Labeling Improvement and Enhancement...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-06

    ... prescription drug products and reducing the likelihood of medication errors. FDA implemented standardized... voluntarily converts to PLR format. \\4\\ Data obtained from http://labels.fda.gov . Generic drugs approved... show that only 10 percent of generic drug labeling has been converted to the PLR format.\\5\\ Since...

  4. Herb-drug interactions: challenges and opportunities for improved predictions.

    PubMed

    Brantley, Scott J; Argikar, Aneesh A; Lin, Yvonne S; Nagar, Swati; Paine, Mary F

    2014-03-01

    Supported by a usage history that predates written records and the perception that "natural" ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb-drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb-drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb-drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb-drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens.

  5. Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions

    PubMed Central

    Brantley, Scott J.; Argikar, Aneesh A.; Lin, Yvonne S.; Nagar, Swati

    2014-01-01

    Supported by a usage history that predates written records and the perception that “natural” ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb–drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb–drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb–drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb–drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens. PMID:24335390

  6. Improving Drug Sensitivity Prediction Using Different Types of Data

    PubMed Central

    Hejase, HA; Chan, C

    2015-01-01

    The algorithms and models used to address the two subchallenges that are part of the NCI-DREAM (Dialogue for Reverse Engineering Assessments and Methods) Drug Sensitivity Prediction Challenge (2012) are presented. In subchallenge 1, a bidirectional search algorithm is introduced and optimized using an ensemble scheme and a nonlinear support vector machine (SVM) is then applied to predict the effects of the drug compounds on breast cancer cell lines. In subchallenge 2, a weighted Euclidean distance method is introduced to predict and rank the drug combinations from the most to the least effective in reducing the viability of a diffuse large B-cell lymphoma (DLBCL) cell line. PMID:26225231

  7. Improving attrition rates in Ebola virus drug discovery.

    PubMed

    Glisic, Sanja; Paessler, Slobodan; Veljkovic, Nevena; Perovic, Vladimir R; Prljic, Jelena; Veljkovic, Veljko

    2015-01-01

    The Ebola 2014/2015 outbreak has had devastating effects on the people living in West Africa. The spread of the disease in endemic countries and the potential introduction of sporadic cases in other continents points out the global health threat of Ebola virus disease (EVD). Despite the urgent need for treating EVD, there are no approved treatments. Given the lack of treatments available, alternative therapeutic strategies have had to be used. This article summarizes the unregistered therapeutics that were used to treat patients during the Ebola 2014/2015 outbreak, in addition to approaches used for the selection of candidate drugs. The article also proposes potential theoretical criterion for use in virtual screening of molecular libraries for candidate Ebola drugs. In the absence of approved therapeutics for EVD, experimental drugs have had to be used. The repurposing of approved drugs for the treatment of EVD, as an alternative therapeutic strategy, has also been suggested. Screening in vitro- and in silico-approved drugs revealed several promising candidates but further testing is required to test their efficacy. All these therapeutic approaches are, however, only short-term solutions and there is still an urgent need for the development of specific drugs for the current and future outbreaks.

  8. Improving Detection of Arrhythmia Drug-Drug Interactions in Pharmacovigilance Data through the Implementation of Similarity-Based Modeling

    PubMed Central

    Vilar, Santiago; Lorberbaum, Tal; Hripcsak, George; Tatonetti, Nicholas P.

    2015-01-01

    Identification of Drug-Drug Interactions (DDIs) is a significant challenge during drug development and clinical practice. DDIs are responsible for many adverse drug effects (ADEs), decreasing patient quality of life and causing higher care expenses. DDIs are not systematically evaluated in pre-clinical or clinical trials and so the FDA U. S. Food and Drug Administration relies on post-marketing surveillance to monitor patient safety. However, existing pharmacovigilance algorithms show poor performance for detecting DDIs exhibiting prohibitively high false positive rates. Alternatively, methods based on chemical structure and pharmacological similarity have shown promise in adverse drug event detection. We hypothesize that the use of chemical biology data in a post hoc analysis of pharmacovigilance results will significantly improve the detection of dangerous interactions. Our model integrates a reference standard of DDIs known to cause arrhythmias with drug similarity data. To compare similarity between drugs we used chemical structure (both 2D and 3D molecular structure), adverse drug side effects, chemogenomic targets, drug indication classes, and known drug-drug interactions. We evaluated the method on external reference standards. Our results showed an enhancement of sensitivity, specificity and precision in different top positions with the use of similarity measures to rank the candidates extracted from pharmacovigilance data. For the top 100 DDI candidates, similarity-based modeling yielded close to twofold precision enhancement compared to the proportional reporting ratio (PRR). Moreover, the method helps in the DDI decision making through the identification of the DDI in the reference standard that generated the candidate. PMID:26068584

  9. Pure drug and polymer based nanotechnologies for the improved solubility, stability, bioavailability and targeting of anti-HIV drugs.

    PubMed

    Sharma, Puneet; Garg, Sanjay

    2010-03-18

    The impact of human immunodeficiency virus (HIV) infection has been devastating with nearly 7400 new infections every day. Although, the advent of highly active antiretroviral therapy (HAART) has made a tremendous contribution in reducing the morbidity and mortality in developed countries, the situation in developing countries is still grim with millions of people being infected by this disease. The new advancements in the field of nanotechnology based drug delivery systems hold promise to improve the situation. These nanoscale systems have been successfully employed in other diseases such as cancer, and therefore, we now have a better understanding of the practicalities and technicalities associated with their clinical development. Nanotechnology based approaches offer some unique opportunities specifically for the improvement of water solubility, stability, bioavailability and targeting of antiretroviral drugs. This review presents discussion on the contribution of pure drug and polymer based nanotechnologies for the delivery anti-HIV drugs. Copyright 2009 Elsevier B.V. All rights reserved.

  10. Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.

    PubMed

    Zhou, Jiangbing; Patel, Toral R; Sirianni, Rachael W; Strohbehn, Garth; Zheng, Ming-Qiang; Duong, Nha; Schafbauer, Thomas; Huttner, Anita J; Huang, Yiyun; Carson, Richard E; Zhang, Ying; Sullivan, David J; Piepmeier, Joseph M; Saltzman, W Mark

    2013-07-16

    Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

  11. Integrating Drug's Mode of Action into Quantitative Structure-Activity Relationships for Improved Prediction of Drug-Induced Liver Injury.

    PubMed

    Wu, Leihong; Liu, Zhichao; Auerbach, Scott; Huang, Ruili; Chen, Minjun; McEuen, Kristin; Xu, Joshua; Fang, Hong; Tong, Weida

    2017-04-24

    Drug-induced liver injury (DILI) is complex in mechanism. Different drugs could undergo different mechanisms but result in the same DILI type, while the same drug could lead to different DILI types via different mechanisms. Therefore, predicting a drug's potential for DILI should take its underlying mechanisms into consideration. To achieve that, we constructed a novel approach by incorporating the drug's Mode of Action (MOA) into Quantitative Structure-Activity Relationship (QSAR) modeling. This MOA-DILI approach was examined using a data set of 333 drugs. The drugs were first grouped according to their MOA profiles (positive or negative in each MOA) based on the Tox21 qHTS assays. QSAR models for individual MOA assays were developed and subsequently combined to obtain the MOA-DILI model. A hold-out testing strategy (222 drugs for training and 111 drugs as a test set) was employed, which yielded a predictive accuracy of 0.711. The MOA-DILI model was directly compared with the standard QSAR approach using the same hold-out strategy, and the QSAR model yielded an accuracy of 0.662. To minimize the random chance in splitting training/test sets, the hold-out testing process was repeated 1000 times, and the observed difference in prediction accuracy between MOA-DILI and QSARs was statistically significant (P value <0.0001). Out of 17 MOAs used, four assays (i.e., antioxidant response elements, PPAR-gamma, estrogen receptor, and thyroid receptor assays) contributed most to the improved prediction of the MOA-DILI model over QSARs. In conclusion, the MOA-DILI approach has the potential to significantly improve predictive outcomes and to reveal complex relationships between MOAs and DILI, all of which would be helpful in developing DILI predictive models in drug screening and for risk assessment of industrial chemicals.

  12. Development of a salt drug with improved solubility: Ethionamide nitrate

    NASA Astrophysics Data System (ADS)

    Diniz, Luan F.; Carvalho, Paulo S.; de Melo, Cristiane C.; Ellena, Javier

    2017-06-01

    To avoid drug resistance, an adequate tuberculosis treatment should include not only a first-line drug but also at least one second-line drug such as, for example, Ethionamide (ETH). However, the dissolution rate and oral absorption of ETH is highly limited by its low aqueous solubility. Considering that a salt is in general more soluble than its parent compound, herein we depicted a new supramolecular modification of ETH, an Ethionamide nitrate salt (ETHNO3). This salt is the first ETH structure that has been crystallized with four independent ionic pairs (ETH+NO3-) in the asymmetric unit. In addition to the structural study, the salt formation was also identified on the FT-IR and FT-Raman spectra. The thermal behavior of ETHNO3 was also investigated here together with its solubility profile in three dissolution media (purified water, pH 4.0 and 7.0).

  13. Triangulating Syndemic Services and Drug Treatment Policy: Improving Drug Treatment Portal Locations in Baltimore City.

    PubMed

    Furr-Holden, Debra M; Milam, Adam J; Nesoff, Elizabeth D; Garoon, Joshua; Smart, Mieka J; Duncan, Alexandra; Warren, Gregory C

    2016-01-01

    The prevalence of injection drug use (IDU) and incidence of human immunodeficiency virus (HIV) remain high in Baltimore, where IDU is a primary HIV risk factor. Substance use disorders and HIV are related syndemically--their causes and consequences interact synergistically. Baltimore is increasingly considering the syndemic relationship of substance use disorders, IDU, and HIV in making decisions about drug treatment funding and location. Our goal was to empirically identify the optimal location of new drug treatment programs through the development and application of a novel, practical tool. Syndemic triangles were constructed to measure and visualize unmet need for drug treatment services. These data were used to determine priority zones for new treatment centers. The application of this tool helped inform strategies for locating drug treatment services in Baltimore, and its successful use suggests its potential value in other metropolitan areas.

  14. Pediatric status epilepticus: improved management with new drug therapies?

    PubMed

    Verrotti, Alberto; Ambrosi, Michela; Pavone, Piero; Striano, Pasquale

    2017-06-01

    Status Epilepticus (SE) is the most common neurological emergency of childhood. It requires prompt administration of appropriately selected anti-seizure medications. Areas covered: Following a distinction between estabilished and emergent drugs, we present pharmacological treatment options and their clinical utility in children, with a short mention on alternatives to drug treatment. We also propose an algorithm for the management of pediatric SE. For this review a Pubmed, Medline and Embase search was performed. Expert opinion: In early SE in children, in the prehospital setting, rectal diazepam or buccal midazolam are efficacious drugs; whereas in the hospital setting, intravenous lorazepam or diazepam are indicated. As regard estabilished stage of SE, in addition to the 'classic' compounds, such as phenytoin and phenobarbital, other drugs such as valproic acid, levetiracetam and lacosamide have been demonstrated efficacious. Treatment recommendations of refractory SE depend on retrospective case series and uncontrolled studies. We reported experiences about the use of midazolam, propofol, ketamine and lidocaine. They could be a valid option, but further prospective studies are necessary. Over the last few decades, important advances in basic mechanisms underlying refractory SE have been achieved, but few data are available regarding management of these stages.

  15. Improved management of drugs, hormones and pesticides in Africa.

    PubMed

    Mitema, E S

    2009-03-01

    Drugs, hormones and pesticides are chemical compounds used for alleviation of various diseases in animals. There are many classes of drugs which have been used and in the case of natural steroid hormones these have been used to increase mass gain by stimulating protein anabolism. Pesticides have been used for many years in the control of ectoparasites which transmit important human and livestock diseases. The purpose of the present article is to review procedures for management of veterinary products to facilitate national and international trade. These compounds and/or their metabolites have the potential to cause undesirable health effects to either target animals or consumers. Most African countries do not have competent authorities to conduct risk analysis for veterinary drug and pesticide residues in edible tissues. Because of the possible undesirable health effects from residues of veterinary compounds, the FAO/WHO established expert groups to establish acceptable daily intake and maximum residue levels (MRLs) for each drug or pesticide. In the case of natural steroids like oestradiol, progesterone and testosterone implants, no withdrawal period is required since there is no risk to the consumer. Bulls can have levels of testosterone ranging from 535-10,950 pg/g, heifers 92-250 and treated steers 100 pg/g, respectively. Data to enable approval of drugs and pesticides is to a large extent similar and include toxicity studies, reproductive studies, stability studies, safety, efficacy, tissue residue depletion studies and environmental impact. Good practice in the use of acaricides as indicated on the label is inevitable so that residue levels of these compounds remain below the specified MRL. Enactment and enforcement of legislations by various countries for the control of registration, sale, distribution and usage of ethical products should be enforced including use of prescriptions by veterinarians. Good practice in the use of veterinary drugs is the

  16. Improved measurement of drug exposure in the brain using drug-specific correction for residual blood

    PubMed Central

    Fridén, Markus; Ljungqvist, Helena; Middleton, Brian; Bredberg, Ulf; Hammarlund-Udenaes, Margareta

    2010-01-01

    A major challenge associated with the determination of the unbound brain-to-plasma concentration ratio of a drug (Kp,uu,brain), is the error associated with correction for the drug in various vascular spaces of the brain, i.e., in residual blood. The apparent brain vascular spaces of plasma water (Vwater, 10.3 μL/g brain), plasma proteins (Vprotein, 7.99 μL/g brain), and the volume of erythrocytes (Ver, 2.13 μL/g brain) were determined and incorporated into a novel, drug-specific correction model that took the drug-unbound fraction in the plasma (fu,p) into account. The correction model was successfully applied for the determination of Kp,uu,brain for indomethacin, loperamide, and moxalactam, which had potential problems associated with correction. The influence on correction of the drug associated with erythrocytes was shown to be minimal. Therefore, it is proposed that correction for residual blood can be performed using an effective plasma space in the brain (Veff), which is calculated from the measured fu,p of the particular drug as well as from the estimates of Vwater and Vprotein, which are provided in this study. Furthermore, the results highlight the value of determining Kp,uu,brain with statistical precision to enable appropriate interpretation of brain exposure for drugs that appear to be restricted to the brain vascular spaces. PMID:19756019

  17. Assessing the Potential for Drug-Nanoparticle Surface Interactions To Improve Drug Penetration into the Skin.

    PubMed

    Cai, X J; Woods, A; Mesquida, P; Jones, S A

    2016-04-04

    There is continued debate as to how nanomaterials enhance the passive diffusion of drugs through the skin. This study examined if drug-nanoparticle surface interactions, which occurred during topical application, had the capability to enhance percutaneous penetration. Atomic force microscopy force adhesion measurements were used to demonstrate that a model drug, tetracaine, strongly adsorbed to the surface of a negatively charged carboxyl-modified polystyrene nanoparticle (NanoPSCOOH) through both its methyl and amine functionalities (up to a 6- and 16-fold greater adhesion force respectively compared with the CH3-CH3 control). These drug-particle adhesion forces were significantly reduced (p < 0.05) to values that were lower than the CH3-CH3 control measurements when tetracaine interacted with a silica nanoparticle (NanoSiO2). This reduction in adhesion was attributed to the lower surface charge of the NanoSiO2 (ca. -23 mV) compared to the NanoPSCOOH (ca. -40 mV), which diminished the electrostatic interactions between positive amine of tetracaine and the negative particle. Mixing NanoPSCOOH with tetracaine on the skin retarded percutaneous drug penetration compared to the control (tetracaine saturated solution without nanoparticles), but the NanoSiO2, which still adsorbed the tetracaine, produced a 3.6-fold enhancement in percutaneous penetration compared to the same control. These data demonstrated the capability of moderate nanoparticle surface interactions that occurred within the application vehicle to promote drug percutaneous penetration.

  18. [Preparation of two poor water soluble drugs - nanoporous ZnO solid dispersions and the mechanism of drug dissolution improvement].

    PubMed

    Gao, Bei; Sun, Chang-shan; Zhi, Zhuang-zhi; Wang, Yan; Chang, Di; Wang, Si-ling; Jiang, Tong-ying

    2011-11-01

    Nanoporous ZnO was used as a carrier to prepare drug solid dispersion, the mechanism of which to improve the drug dissolution was also studied. Nanoporous ZnO, obtained through chemical deposition method, was used as a carrier to prepare indomethacin and cilostazol solid dispersions by melt-quenching method, separately. The results of scanning electron microscope, surface area analyzer, fourier transform infra-red spectroscopy, differential scanning calorimeter and X-ray diffraction showed that drugs were implanted into nanopores of ZnO by physical adsorption effect and highly dispersed into nanopores of ZnO in amorphous form, moreover, these nanopores strongly inhibited amorphous recrystallization in the condition of 45 degrees C and 75% RH. In addition, the results of the dissolution tested in vitro exhibited that the accumulated dissolutions of indomethacin and cilostazol solid dispersions achieved about 90% within 5 min and approximately 80% within 30 min. It was indicated in this study that the mechanism of drug dissolution improvement was associated with the effects of nanoporous ZnO carrier on increasing drug dispersion, controlling drug in nanopores as amorphous form and inhibiting amorphous recrystallization.

  19. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    PubMed

    Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Betancourt-Conde, Irene; Aguirre-Raudry, Miriam; Vázquez-Raygoza, Alejandra; Luevano-De la Cruz, Artemisa; Favela-Candia, Alejandro; Sarabia-Sanchez, Marie; Ríos-Soto, Lluvia; Méndez-Hernández, Edna; Cisneros-Martínez, Jorge; Palacio-Gastélum, Marcelo Gómez; Valdez-Solana, Mónica; Hernández-Rivera, Jessica; De Lira-Sánchez, Jaime; Campos-Almazán, Mara; Téllez-Valencia, Alfredo

    2016-01-01

    Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria.

  20. Improving pediatric drug safety: need for more efficient clinical translation of pharmacovigilance knowledge.

    PubMed

    Castro-Pastrana, Lucila I; Carleton, Bruce C

    2011-01-01

    There is an urgency to improve the evaluation of pediatric drug safety in the pre-market and post-market phases of drug evaluation. The need to improve pharmacovigilance methods concerns not only new drugs but also existing drugs that have been used for many years in an off-label manner in children. Effective methods for early detection of adverse drug reactions (ADRs) and drug safety epidemiologic studies are a pressing need in pediatrics. Moreover, the nature and severity of an ADR as well as the extent to which the suspected drug is being used, will determine how quickly the information about risk needs to be made available to users and what would be the most appropriate method of communication. Based on our experience through the Genotype-specific Approaches to Therapy in Children study, an active ADR surveillance network of pediatric hospitals across Canada, we present five strategic elements that should be included in pharmacovigilance initiatives in pediatrics: active ADR surveillance; drug or ADR targeted pharmacovigilance; trained surveillance clinicians; case-control methodology and standardized procedures for recognition; reporting and evaluating drug-induced harm. In addition, linking pharmacovigilance with pharmacogenomics to find drug safety solutions is presented as a promising strategy for knowledge generation. Finally, we discuss the importance of an efficient translation of the pharmacovigilance knowledge into clinical practice to achieve safer drug therapy in children.

  1. Smart nanoparticles improve therapy for drug-resistant tumors by overcoming pathophysiological barriers

    PubMed Central

    Liu, Jian-ping; Wang, Ting-ting; Wang, Dang-ge; Dong, An-jie; Li, Ya-ping; Yu, Hai-jun

    2017-01-01

    The therapeutic outcome of chemotherapy is severely limited by intrinsic or acquired drug resistance, the most common causes of chemotherapy failure. In the past few decades, advancements in nanotechnology have provided alternative strategies for combating tumor drug resistance. Drug-loaded nanoparticles (NPs) have several advantages over the free drug forms, including reduced cytotoxicity, prolonged circulation in the blood and increased accumulation in tumors. Currently, however, nanoparticulate drugs have only marginally improved the overall survival rate in clinical trials because of the various pathophysiological barriers that exist in the tumor microenvironment, such as intratumoral distribution, penetration and intracellular trafficking, etc. Smart NPs with stimulus-adaptable physico-chemical properties have been extensively developed to improve the therapeutic efficacy of nanomedicine. In this review, we summarize the recent advances of employing smart NPs to treat the drug-resistant tumors by overcoming the pathophysiological barriers in the tumor microenvironment. PMID:27569390

  2. Quality Standards for Herbal Drugs and Herbal Drug Preparations - Appropriate or Improvements Necessary?

    PubMed

    Länger, Reinhard; Stöger, Erich; Kubelka, Wolfgang; Helliwell, Keith

    2017-08-29

    Standards for quality control as defined in the European Pharmacopoeia contribute significantly to a consistent and high quality of herbal drugs, herbal drug preparations, and herbal medicinal products. The minimum content of single plant constituents is considered of high relevance. Therefore, nearly all monographs on herbal drugs or herbal drug preparations contain an obligatory assay.However, a critical evaluation of the data published for such assayed constituents reveals that in most cases these constituents have to be considered as purely analytical markers without correlation to quality or efficacy. Examples where the assay does not meet its objective support the need to adapt current quality standards. Moreover, the trend to increase the content of certain constituents may lead to significant modifications to traditional manufacturing processes.In order to initiate a scientific discussion, the role of the assay in the context of quality requirements, quality documentation in the manufacturing process, safety, and efficacy is discussed and possible alternatives to the single marker assay are examined. Georg Thieme Verlag KG Stuttgart · New York.

  3. Improvement of drug safety by the use of lipid-based nanocarriers.

    PubMed

    Lim, Sok Bee; Banerjee, Amrita; Önyüksel, Hayat

    2012-10-10

    Drug toxicity is an important factor that contributes significantly to adverse drug events in current healthcare practice. Application of lipid-based nanocarriers in drug formulation is one approach to improve drug safety. Lipid-based delivery systems include micelles, liposomes, solid lipid nanoparticles, nanoemulsions and nanosuspensions. These carriers are generally composed of physiological lipids well tolerated by human body. Delivery of water-insoluble drugs in these formulations increases their solubility and stability in aqueous media and eliminates the need for toxic co-solvents or pH adjustment to solubilize hydrophobic drugs. Association or encapsulation of peptides/proteins within lipid-based carriers protects the labile biologics against enzymatic degradation, hence reducing the therapeutic dose required and risk of dose-dependent toxicity. Most importantly, lipid-based nanocarriers alter the pharmacokinetics and biodistribution of drugs through passive and active targeting, leading to increased drug accumulation at target sites while significantly decreasing non-specific distribution to other tissues. Furthermore, surface modification of these nanocarriers reduces immunogenicity of drug-carrier complexes, imparts stealth by preventing opsonization and removal by phagocytes and minimizes interaction with circulating blood components. In view of heightening attention on drug safety in patient treatment, lipid-based nanocarrier is therefore an important and promising option for formulation of pharmaceutical products to improve treatment safety and efficacy.

  4. Application of gold nanoparticles for improved drug efficiency

    NASA Astrophysics Data System (ADS)

    Shittu, K. O.; Bankole, M. T.; Abdulkareem, A. S.; Abubakre, O. K.; Ubaka, A. U.

    2017-09-01

    Due to increasing resistance of microorganisms towards current antibiotics, there is a need for new or enhanced antibiotics. Nanotechnology is a technology that enhances the use of gold nanoparticles (AuNP) in area of medical applications, especially as a drug carrier for targeted drug delivery. In this research, AuNPs was synthesized using biological method via bioreduction of Piper guineense aqueous leaf extract on tetra gold chloride, characterized using UV-Vis spectrophometer, DLS, TEM/EDS and FTIR. The synthesized AuNPs was covalently functionalized with polyethylene glycol and encapsulated with Lincomycin and in vitro dissolution methods was used to evaluate the potential performance of the formulated nanodrug. The nanodrug has highest release efficiency at the 9th minutes (23.4 mg ml-1 for 40 °C) and (29.5 mg ml-1 for 60 °C) compared with the non-nanodrug. The antibacterial potential of the nanodrug was seen on the gram-positive bacteria of Staphylococcus aureus and Streptococcus pyogenes with highest inhibitions of 18 mm (at 40 °C) and 16 mm (at 60 °C) for S. aureus, and 16 mm for S. pyogenes (both at 40 °C and 60 °C). The bacteria growth inhibition continued and lasted for 15 min, while that of non-nanodrug lasted for 9 min with lesser growth inhibition compared to the formulated nanodrug. This work shows that the presence of the AuNPs increased the release efficiency of lincomycin even at a lower concentration and also bacteria growth inhibition thereby suggesting the effectiveness of the nanodrug formulation.

  5. Pathways and Progress in Improving Drug Delivery through the Intestinal Mucosa and Blood-Brain Barriers

    PubMed Central

    Laksitorini, Marlyn; Prasasty, Vivitri D.; Kiptoo, Paul K.; Siahaan, Teruna J.

    2015-01-01

    One of the major hurdles in developing therapeutic agents is the difficulty in delivering drugs through the intestinal mucosa and blood-brain barriers (BBB). The goal here is to describe the general structures of the biological barriers and the strategies to enhance drug delivery across these barriers. Prodrug methods used to improve drug penetration via the transcellular pathway have been successfully developed, and some prodrugs have been used to treat patients. The use of transporters to improve absorption of some drugs (e.g., antiviral agents) has also been successful in treating patients. Other methods, including (a) blocking the efflux pumps to improve transcellular delivery and (b) modulation of cell-cell adhesion in the intercellular junctions to improve paracellular delivery across biological barriers are still in the investigational stage. PMID:25418271

  6. Improvement in Language Function Correlates with Gait Improvement in Drug-naïve Parkinson's Disease Patients Taking Dopaminergic Medication.

    PubMed

    Murakami, Hidetomo; Momma, Yutaro; Nohara, Tetsuhito; Mori, Yukiko; Futamura, Akinori; Sugita, Toshihisa; Ishigaki, Seiichiro; Katoh, Hirotaka; Kezuka, Machiko; Ono, Kenjiro; Miller, Michael W; Kawamura, Mitsuru

    2016-01-01

    Dopaminergic drugs, the gold standard for motor symptoms, are known to affect cognitive function in Parkinson's disease (PD) patients. We compared the effects of dopaminergic treatment on motor and cognitive function in drug-naïve patients. Dopaminergic medication (levodopa, dopamine agonist, selegiline) was given to 27 drug-naïve PD patients and increased to a dose optimal for improved motor symptoms. Patients were tested prior to, and 4-7 months after, drug initiation. Motor function was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS). Cognitive function was assessed using both the Japanese version of the Montreal Cognitive Assessment (MoCA-J) and the Neurobehavioral Cognitive Status Examination (COGNISTAT-J). Improvements from baseline for both motor and cognitive assessment were compared. Mean score of all motor assessments (UPDRS total score of Parts II and III, and sub-scores of tremor, rigidity, bradykinesia, gait, and postural instability) and certain cognitive assessments (MoCA-J total score and subscore of delayed recall) significantly improved with dopaminergic medication. Gait score improvement showed significant positive correlation with improvement in MoCA-J language domain and in language-comprehension subtests of COGNISTAT-J using Spearman's correlation coefficients. Furthermore, multiple regression analysis showed gait score improvement significantly correlated with improvements in the subtests of language-comprehension in COGNISTAT-J. There is correlated improvement in both gait and language function in de novo PD patients in response to dopaminergic drugs. Gait and language dysfunction in these patients may share a common pathophysiology linked to dopamine deficits.

  7. Student nurses need more than maths to improve their drug calculating skills.

    PubMed

    Wright, Kerri

    2007-05-01

    Nurses need to be able to calculate accurate drug calculations in order to safely administer drugs to their patients (NMC, 2002). Studies have shown however that nurses do not always have the necessary skills to calculate accurate drug dosages and are potentially administering incorrect dosages of drugs to their patients (Hutton, M. 1998. Nursing Mathematics: the importance of application. Nursing Standard 13(11), 35-38; Kapborg, I. 1994. Calculation and administration of drug dosage by Swedish nurses, Student Nurses and Physicians. International Journal for Quality in Health Care 6(4), 389-395; O'Shea, E. 1999. Factors contributing to medication errors: a literature review. Journal of Advanced Nursing 8, 496-504; Wilson, A. 2003. Nurses maths: researching a practical approach. Nursing Standard 17(47), 33-36). The literature indicates that in order to improve drug calculations strategies need to focus on both the mathematical skills and conceptual skills of student nurses so they can interpret clinical data into drug calculations to be solved. A study was undertaken to investigate the effectiveness of implementing several strategies which focussed on developing the mathematical and conceptual skills of student nurses to improve their drug calculation skills. The study found that implementing a range of strategies which addressed these two developmental areas significantly improved the drug calculation skills of nurses. The study also indicates that a range of strategies has the potential ensuring that the skills taught are retained by the student nurses. Although the strategies significantly improved the drug calculation skills of student nurses, the fact that only 2 students were able to achieve 100% in their drug calculation test indicates a need for further research into this area.

  8. Targeting receptors, transporters and site of absorption to improve oral drug delivery.

    PubMed

    Hamman, J H; Demana, P H; Olivier, E I

    2007-01-01

    Although the oral route of drug administration is the most acceptable way of self-medication with a high degree of patient compliance, the intestinal absorption of many drugs is severely hampered by different biological barriers. These barriers comprise of biochemical and physical components. The biochemical barrier includes enzymatic degradation in the gastrointestinal lumen, brush border and in the cytoplasm of the epithelial cells as well as efflux transporters that pump drug molecules from inside the epithelial cell back to the gastrointestinal lumen. The physical barrier consists of the epithelial cell membranes, tight junctions and mucus layer. Different strategies have been applied to improve the absorption of drugs after oral administration, which range from chemical modification of drug molecules and formulation technologies to the targeting of receptors, transporters and specialized cells such as the gut-associated lymphoid tissues. This review focuses specifically on the targeting of receptor-mediated endocytosis, transporters and the absorption-site as methods of optimizing intestinal drug absorption. Intestinal epithelial cells express several nutrient transporters that can be targeted by modifying the drug molecule in such a way that it is recognized as a substrate. Receptor-mediated endocytosis is a transport mechanism that can be targeted for instance by linking a receptor substrate to the drug molecule of interest. Many formulation strategies exist for enhancing drug absorption of which one is to deliver drugs at a specific site in the gastrointestinal tract where optimum drug absorption takes place.

  9. Targeting Receptors, Transporters and Site of Absorption to Improve Oral Drug Delivery

    PubMed Central

    Hamman, J.H.; Demana, P.H.; Olivier, E.I.

    2007-01-01

    Although the oral route of drug administration is the most acceptable way of self-medication with a high degree of patient compliance, the intestinal absorption of many drugs is severely hampered by different biological barriers. These barriers comprise of biochemical and physical components. The biochemical barrier includes enzymatic degradation in the gastrointestinal lumen, brush border and in the cytoplasm of the epithelial cells as well as efflux transporters that pump drug molecules from inside the epithelial cell back to the gastrointestinal lumen. The physical barrier consists of the epithelial cell membranes, tight junctions and mucus layer. Different strategies have been applied to improve the absorption of drugs after oral administration, which range from chemical modification of drug molecules and formulation technologies to the targeting of receptors, transporters and specialized cells such as the gut-associated lymphoid tissues. This review focuses specifically on the targeting of receptor-mediated endocytosis, transporters and the absorption-site as methods of optimizing intestinal drug absorption. Intestinal epithelial cells express several nutrient transporters that can be targeted by modifying the drug molecule in such a way that it is recognized as a substrate. Receptor-mediated endocytosis is a transport mechanism that can be targeted for instance by linking a receptor substrate to the drug molecule of interest. Many formulation strategies exist for enhancing drug absorption of which one is to deliver drugs at a specific site in the gastrointestinal tract where optimum drug absorption takes place. PMID:21901064

  10. [The importance of clinical data management in improvement of drug evaluation].

    PubMed

    Huang, Qin; Wang, Jun

    2015-11-01

    Although the importance of clinical data is drawing more attention in drug development in China, the clinical data management is not good enough in the clinical trials right now. With the development of internet and progress of information technology, especially with the setup of the state innovation strategy for drug development, it is necessary and urgent to improve the clinical data quality. Good data quality is the primary basis of technical evaluation of drug at the marketing authorization. So Center for Drug Evaluation of CFDA has made some endeavors to enhance data management in the clinical trials in recent years. This article is focused on these aspects of data managment.

  11. Confidentiality laws and secrecy in medical research: improving public access to data on drug safety.

    PubMed

    Kesselheim, Aaron S; Mello, Michelle M

    2007-01-01

    Pharmaceutical manufacturers have long considered results collected from drugs' clinical trials to be confidential information or trade secrets, even after submission to the Food and Drug Administration (FDA). We describe FDA policies regarding disclosure of clinical trial data and evaluate how courts have interpreted the Freedom of Information Act in cases seeking access to unreleased information. Recent examples of approved drugs later found to have dangerous side effects show the importance of complete dissemination of safety information. We suggest regulatory and legislative policy changes regarding how the FDA handles confidential information that can improve understanding of the risks of prescription drugs.

  12. Scattered light: improving photoacoustic spectral measurement with a drug tablet

    NASA Astrophysics Data System (ADS)

    Yu, Rong; Jiang, Yue-song; Yu, Lan; Wen, Dong-hai; Hua, Hou-qiang; Wu, Xiao-fang

    2013-08-01

    Photoacoustic spectroscopy (PAS) is a powerful tool for the study of the absorption spectra of solid samples. Scattered light, which used to be a main error source in conventional absorption spectroscopy, is not a problem for PAS, and furthermore, in this paper it is helpful for photoacoustic spectroscopy measurement. In this work, the photoacoustic spectra of an olanzapine tablet and its powder have been investigated. Differential analysis was used to eliminate the background signal generated by the photoacoustic cell. It is found that the photoacoustic spectrum of olanzapine in the powdered olanzapine tablet has the same spectral features as that of the pure olanzapine powder, while the photoacoustic spectrum of the olanzapine tablet does not have, although the ingredients in both are completely the same. This phenomenon can be interpreted as the light scattering effects in the powdered olanzapine tablet. The light scattering effects in a solid mixture amplify the photoacoustic spectral features of the main light-absorbing ingredient in the mixture, rather than enhance the measured photoacoustic signal over the whole measured wavelength range, which is different from the influence of light scattering effects on a single-ingredient solid powder. Based on this work, a method is proposed to preliminarily fast identify the light-absorbing ingredient in a solid mixture. Using the method, a drug tablet can be measured directly in solid state and hardly need sample preprocessing, and thus the time for composition analyses will be reduced significantly.

  13. Pharmaceutical pricing: a review of proposals to improve access and affordability of prescription drugs.

    PubMed

    Tironi, Paula

    2010-01-01

    This article discusses how pharmaceutical innovation achieves remarkable improvements in human health but a significant portion of the U.S. population cannot afford prescription drugs. The author examines ways that patent protection, generics, supply chain complexity, and the cost of innovation and promotion affect access and affordability. The author then looks at the influences of marketing strategies and industry trends such as the patent cliff and pipeline for new drugs, innovations in biotechnology and genomics, comparative effectiveness analysis, and payor and employer strategies on drug prices. An analysis of reform proposals in the context of industry trends suggests that promoting generic drug use and availability through education, prohibiting authorized generics, and restricting the practice of developing follow-on drugs and discontinuing the original formulations upon patent expiration could improve access and affordability most quickly and significantly.

  14. Systems biology-embedded target validation: improving efficacy in drug discovery.

    PubMed

    Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

    2014-01-01

    The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment.

  15. Bioavailability Improvement Strategies for Poorly Water-Soluble Drugs Based on the Supersaturation Mechanism: An Update.

    PubMed

    Yang, Meiyan; Gong, Wei; Wang, Yuli; Shan, Li; Li, Ying; Gao, Chunsheng

    2016-01-01

    The formulation development for poorly soluble drugs still remains a challenge. Supersaturating drug delivery systems (SDDS) or drug delivery systems based on supersaturating provide a promising way to improve the oral bioavailability of poorly water-soluble drugs. In supersaturable formulations, drug concentration exceeds the equilibrium solubility when exposed to gastrointestinal fluids, and the supersaturation state is maintained long enough to be absorbed, resulting in compromised bioavailability. In this article, the mechanism of generating and maintaining supersaturation and the evaluation methods of supersaturation assays are discussed. Recent advances in different drug delivery systems based on supersaturating are the focus and are discussed in detail.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

  16. Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment

    PubMed Central

    Tzvetkov, Mladen V.

    2008-01-01

    Variation in the human genome is a most important cause of variable response to drugs and other xenobiotics. Susceptibility to almost all diseases is determined to some extent by genetic variation. Driven by the advances in molecular biology, pharmacogenetics has evolved within the past 40 years from a niche discipline to a major driving force of clinical pharmacology, and it is currently one of the most actively pursued disciplines in applied biomedical research in general. Nowadays we can assess more than 1,000,000 polymorphisms or the expression of more than 25,000 genes in each participant of a clinical study – at affordable costs. This has not yet significantly changed common therapeutic practices, but a number of physicians are starting to consider polymorphisms, such as those in CYP2C9, CYP2C19, CYP2D6, TPMT and VKORC1, in daily medical practice. More obviously, pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research; large clinical trials without a pharmacogenomic add-on appear to have become the minority. This review is about how the discipline of pharmacogenetics has evolved from the analysis of single proteins to current approaches involving the broad analyses of the entire genome and of all mRNA species or all metabolites and other approaches aimed at trying to understand the entire biological system. Pharmacogenetics and genomics are becoming substantially integrated fields of the profession of clinical pharmacology, and education in the relevant methods, knowledge and concepts form an indispensable part of the clinical pharmacology curriculum and the professional life of pharmacologists from early drug discovery to pharmacovigilance. PMID:18224312

  17. Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement.

    PubMed

    Stuurman, Frederik E; Nuijen, Bastiaan; Beijnen, Jos H; Schellens, Jan H M

    2013-06-01

    The use of oral anticancer drugs has increased during the last decade, because of patient preference, lower costs, proven efficacy, lack of infusion-related inconveniences, and the opportunity to develop chronic treatment regimens. Oral administration of anticancer drugs is, however, often hampered by limited bioavailability of the drug, which is associated with a wide variability. Since most anticancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in the bioavailability can have a negative impact on treatment outcome. This review discusses mechanisms of low bioavailability of oral anticancer drugs and strategies for improvement. The extent of oral bioavailability depends on many factors, including release of the drug from the pharmaceutical dosage form, a drug's stability in the gastrointestinal tract, factors affecting dissolution, the rate of passage through the gut wall, and the pre-systemic metabolism in the gut wall and liver. These factors are divided into pharmaceutical limitations, physiological endogenous limitations, and patient-specific limitations. There are several strategies to reduce or overcome these limitations. First, pharmaceutical adjustment of the formulation or the physicochemical characteristics of the drug can improve the dissolution rate and absorption. Second, pharmacological interventions by combining the drug with inhibitors of transporter proteins and/or pre-systemic metabolizing enzymes can overcome the physiological endogenous limitations. Third, chemical modification of a drug by synthesis of a derivative, salt form, or prodrug could enhance the bioavailability by improving the absorption and bypassing physiological endogenous limitations. Although the bioavailability can be enhanced by various strategies, the development of novel oral products with low solubility or cell membrane permeability remains cumbersome and is often unsuccessful. The main reasons are

  18. Improvement of drug loading onto ion exchange resin by cyclodextrin inclusion complex.

    PubMed

    Samprasit, Wipada; Rojanarata, Theerasak; Akkaramongkolporn, Prasert; Ngawhirunpat, Tanasait; Sila-on, Warisada; Opanasopit, Praneet

    2013-11-01

    Ion exchange resins have ability to exchange their counter ions for ionized drug in the surrounding medium, yielding "drug resin complex." Cyclodextrin can be applied for enhancement of drug solubility and stability. Cyclodextrin inclusion complex of poorly water-soluble NSAIDs, i.e. meloxicam and piroxicam, was characterized and its novel application for improving drug loading onto an anionic exchange resin, i.e. Dowex® 1×2, was investigated. β-Cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrin (HP-β-CD) were used for the preparation of inclusion complex with drugs in solution state at various pH. The inclusion complex was characterized by phase solubility, continuous variation, spectroscopic and electrochemistry methods. Then, the drug with and without cyclodextrin were equilibrated with resin at 1:1 and 1:2 weight ratio of drug and resin. Solubility of the drugs was found to increase with increasing cyclodextrin concentration and pH. The increased solubility was explained predominantly due to the formation of inclusion complex at low pH and the increased ionization of drug at high pH. According to characterization studies, the inclusion complex was successfully formed with a 1:1 stoichiometry. The presence of cyclodextrin in the loading solution resulted in the improvement of drug loading onto resin. Enhancing drug loading onto ion-exchange resin via the formation of cyclodextrin inclusion complex is usable in the development of ion-exchange based drug delivery systems, which will beneficially reduce the use of harmful acidic or basic and organic chemicals.

  19. Prodrug design to improve pharmacokinetic and drug delivery properties: challenges to the discovery scientists.

    PubMed

    Jana, S; Mandlekar, S; Marathe, P

    2010-01-01

    The prodrug design is a versatile, powerful method that can be applied to a wide range of parent drug molecules, administration routes, and formulations. Clinically, the majority of prodrugs are used with the aim of enhancing drug permeation by increasing lipophilicity, or by improving aqueous solubility. Prodrug design may improve the bioavailability of parent molecule, and thus can be integrated into the iterative process of lead optimization, rather than employing it as a post-hoc approach. The purpose of this review is to provide an update of advances and progress in the knowledge of current strategic approaches of prodrug design, along with their real-world utility in drug discovery and development. The review covers the type of prodrugs and functional groups that are amenable to prodrug design. Various prodrug approaches for improving oral drug delivery are discussed, with numerous examples of marketed prodrugs, including improved aqueous solubility, improved lipophilicity, transporter-mediated absorption, and prodrug design to achieve site-specific delivery. Tools employed for prodrug screening, and specific challenges in prodrug research and development are also elaborated. This article is intended to encourage discovery scientists to be creative and consider a rationally designed prodrug approach during the lead optimization phase of drug discovery programs, when the structure activity relationship (SAR) for the drug target is incompatible with pharmacokinetic or biopharmaceutical objectives.

  20. Toward improved anti-cryptococcal drugs: Novel molecules and repurposed drugs.

    PubMed

    Krysan, Damian J

    2015-05-01

    Cryptococcosis is one of the most important fungal infections of humans. It primarily, but not exclusively, afflicts people with compromised immune function. Cryptococcosis is most commonly caused by Cryptococcus neoformans var. grubii with C. neoformans var. neoformans and C. gatti also contributing to the disease. Cryptococcosis is primarily manifested as meningoencephalitis although pneumonia occurs frequently as well. Globally, the burden of disease is highest among those living with HIV/AIDS and is one of the most common causes of death in this patient population. Cryptococcal meningitisis almost invariably fatal if untreated. The current gold standard therapy is amphotericin B combined with 5-flucytosine. Unfortunately, this therapy has significant toxicity and is not widely available in resource-limited regions. Fluconazole, which is associated with poorer outcomes, is frequently as an alternative. Here, I present the characteristics of an ideal anti-cryptococcal agent and review recent progress toward identifying both novel and repurposed drugs as potential new therapies.

  1. Improving the quality of adverse drug reaction reporting by 4th-year medical students.

    PubMed

    Rosebraugh, Curtis J; Tsong, Yi; Zhou, Feng; Chen, Min; Mackey, Ann Corken; Flowers, Charlene; Toyer, Denise; Flockhart, David A; Honig, Peter K

    2003-03-01

    Evaluate whether a 15-minute lecture intervention will improve adverse drug reaction reporting quality on standard MedWatch forms. Seventy-eight 4th-year medical students were randomized to intervention 'Group-A' or non-intervention 'Group-B' on the first day of a required five-day clinical pharmacology rotation. Group-A participants attended a 15-minute lecture on completing a MedWatch form with quality information considered by the Food and Drug Administration as critical to adequate adverse drug reaction reporting. Group-B participants did not attend this lecture. Both groups then watched a standardized patient interview of a recognizable adverse drug reaction and completed MedWatch forms. Four Safety Evaluators from the Food and Drug Administration (FDA) rated student responses in a blinded fashion for the primary efficacy variable of Overall Impression and six informational domins using a standardized data quality analysis form that was developed within the Office of Postmarketing Drug Risk Assessment of the FDA. Seventy-eight MedWatch forms were evaluated (Group-A = 40, Group B = 38). Overall MedWatch information quality scores for the intervention group were significantly higher than the non-intervention group (p < 0.004). As little as a 15-minute intervention can significantly improve the quality of adverse drug reaction reporting by 4th-year medical students. Academic medical centers should consider incorporating adverse drug reaction reporting curriculum into the clinical training of medical students.

  2. 3D Pharmacophoric Similarity improves Multi Adverse Drug Event Identification in Pharmacovigilance

    NASA Astrophysics Data System (ADS)

    Vilar, Santiago; Tatonetti, Nicholas P.; Hripcsak, George

    2015-03-01

    Adverse drugs events (ADEs) detection constitutes a considerable concern in patient safety and public health care. For this reason, it is important to develop methods that improve ADE signal detection in pharmacovigilance databases. Our objective is to apply 3D pharmacophoric similarity models to enhance ADE recognition in Offsides, a pharmacovigilance resource with drug-ADE associations extracted from the FDA Adverse Event Reporting System (FAERS). We developed a multi-ADE predictor implementing 3D drug similarity based on a pharmacophoric approach, with an ADE reference standard extracted from the SIDER database. The results showed that the application of our 3D multi-type ADE predictor to the pharmacovigilance data in Offsides improved ADE identification and generated enriched sets of drug-ADE signals. The global ROC curve for the Offsides ADE candidates ranked with the 3D similarity score showed an area of 0.7. The 3D predictor also allows the identification of the most similar drug that causes the ADE under study, which could provide hypotheses about mechanisms of action and ADE etiology. Our method is useful in drug development, screening potential adverse effects in experimental drugs, and in drug safety, applicable to the evaluation of ADE signals selected through pharmacovigilance data mining.

  3. 3D pharmacophoric similarity improves multi adverse drug event identification in pharmacovigilance.

    PubMed

    Vilar, Santiago; Tatonetti, Nicholas P; Hripcsak, George

    2015-03-06

    Adverse drugs events (ADEs) detection constitutes a considerable concern in patient safety and public health care. For this reason, it is important to develop methods that improve ADE signal detection in pharmacovigilance databases. Our objective is to apply 3D pharmacophoric similarity models to enhance ADE recognition in Offsides, a pharmacovigilance resource with drug-ADE associations extracted from the FDA Adverse Event Reporting System (FAERS). We developed a multi-ADE predictor implementing 3D drug similarity based on a pharmacophoric approach, with an ADE reference standard extracted from the SIDER database. The results showed that the application of our 3D multi-type ADE predictor to the pharmacovigilance data in Offsides improved ADE identification and generated enriched sets of drug-ADE signals. The global ROC curve for the Offsides ADE candidates ranked with the 3D similarity score showed an area of 0.7. The 3D predictor also allows the identification of the most similar drug that causes the ADE under study, which could provide hypotheses about mechanisms of action and ADE etiology. Our method is useful in drug development, screening potential adverse effects in experimental drugs, and in drug safety, applicable to the evaluation of ADE signals selected through pharmacovigilance data mining.

  4. Generalized enrichment analysis improves the detection of adverse drug events from the biomedical literature.

    PubMed

    Winnenburg, Rainer; Shah, Nigam H

    2016-06-23

    Identification of associations between marketed drugs and adverse events from the biomedical literature assists drug safety monitoring efforts. Assessing the significance of such literature-derived associations and determining the granularity at which they should be captured remains a challenge. Here, we assess how defining a selection of adverse event terms from MeSH, based on information content, can improve the detection of adverse events for drugs and drug classes. We analyze a set of 105,354 candidate drug adverse event pairs extracted from article indexes in MEDLINE. First, we harmonize extracted adverse event terms by aggregating them into higher-level MeSH terms based on the terms' information content. Then, we determine statistical enrichment of adverse events associated with drug and drug classes using a conditional hypergeometric test that adjusts for dependencies among associated terms. We compare our results with methods based on disproportionality analysis (proportional reporting ratio, PRR) and quantify the improvement in signal detection with our generalized enrichment analysis (GEA) approach using a gold standard of drug-adverse event associations spanning 174 drugs and four events. For single drugs, the best GEA method (Precision: .92/Recall: .71/F1-measure: .80) outperforms the best PRR based method (.69/.69/.69) on all four adverse event outcomes in our gold standard. For drug classes, our GEA performs similarly (.85/.69/.74) when increasing the level of abstraction for adverse event terms. Finally, on examining the 1609 individual drugs in our MEDLINE set, which map to chemical substances in ATC, we find signals for 1379 drugs (10,122 unique adverse event associations) on applying GEA with p < 0.005. We present an approach based on generalized enrichment analysis that can be used to detect associations between drugs, drug classes and adverse events at a given level of granularity, at the same time correcting for known dependencies among

  5. Measures Such As Interstate Cooperation Would Improve The Efficacy Of Programs To Track Controlled Drug Prescriptions

    PubMed Central

    Deyo, Richard A.; Irvine, Jessica; Millet, Lisa; Beran, Todd; O'Kane, Nicole; Wright, Dagan; McCarty, Dennis

    2013-01-01

    In response to increasing abuse of prescription drugs, 44 states have implemented -- and five more states will soon adopt -- monitoring programs to track prescriptions of controlled medications. Although these programs are primarily designed to help law enforcement officials and regulatory agencies spot possible illegal activity, health care providers have begun to use data from them to help improve patient safety and quality of care. We reviewed government documents, expert white papers, articles from the peer reviewed medical literature, and reports of the experiences of local health officials. Although we found some evidence that prescription drug monitoring programs are a benefit to both law enforcement and health care delivery, the programs have strengths and weaknesses, and their overall impact on drug abuse and illegal activity remains unclear. We believe that improving the efficacy of prescription drug monitoring programs will require such changes as more standardization and interstate cooperation, better training of providers, more secure funding, and further evaluation. PMID:23406570

  6. Amorphous solid dispersion technique for improved drug delivery: basics to clinical applications.

    PubMed

    Mishra, Dinesh Kumar; Dhote, Vinod; Bhargava, Arpit; Jain, Dinesh Kumar; Mishra, Pradyumna Kumar

    2015-12-01

    Solid dispersion has emerged as a method of choice and has been extensively investigated to ascertain the in vivo improved performance of many drug formulations. It generally involves dispersion of drug in amorphous particles (clusters) or in crystalline particles. Comparatively, in the last decade, amorphous drug-polymer solid dispersion has evolved into a platform technology for delivering poorly water-soluble small molecules. However, the success of this technique in the pharmaceutical industry mainly relies on different drug-polymer attributes like physico-chemical stability, bioavailability and manufacturability. The present review showcases the efficacy of amorphous solid dispersion technique in the research and evolution of different drug formulations particularly for those with poor water soluble properties. Apart from the numerous mechanisms of action involved, a comprehensive summary of different key parameters required for the solubility enhancement and their translational efficacy to clinics is also emphasized.

  7. [Drug release of coated dental implant neck region to improve tissue integration].

    PubMed

    Wolf, Jens; Sternberg, Katrin; Behrend, Detlef; Schmitz, Klaus-Peter; von Schwanewede, Heinrich

    2009-08-01

    In order to improve tissue integration, the neck region of dental implants was coated with the biodegradable polymer poly (L-lactide) incorporating tetracycline, ibuprofen and the combination of both drugs using a solvent dip-coating process. Metallographic analysis, light microscopy and electron microscopy were used to detect the thickness range and the surface characteristics of the coatings. Cytotoxicity was evaluated using the tetrazolium colorimetric method with the fibroblast cell line L929. The in vitro drug release was measured in isotonic sodium chloride solution by UV spectroscopy. To explore if drug release is concentration-dependent, the total amount of drug was varied in the coating (20% wt, 30% wt and 40% wt). The results showed a continuous release of the embedded drugs in relevant dosage over a period of 6 months. In contrast to high tetracycline concentrations, high ibuprofen concentrations resulted in a decreased metabolic activity of the L929 fibroblasts.

  8. Spherical agglomerates of pure drug nanoparticles for improved pulmonary delivery in dry powder inhalers

    NASA Astrophysics Data System (ADS)

    Hu, Jun; Dong, Yuancai; Pastorin, Giorgia; Ng, Wai Kiong; Tan, Reginald B. H.

    2013-04-01

    The aim of this study was to produce micron-sized spherical agglomerates of pure drug nanoparticles to achieve improved aerosol performance in dry powder inhalers (DPIs). Sodium cromoglicate was chosen as the model drug. Pure drug nanoparticles were prepared through a bottom-up particle formation process, liquid antisolvent precipitation, and then rapidly agglomerated into porous spherical microparticles by immediate (on-line) spray drying. Nonporous spherical drug microparticles with similar geometric size distribution were prepared by conventional spray drying of the aqueous drug solution, which together with the mechanically micronized drug particles were used as the control samples. The three samples were characterized by field emission scanning electron microscopy, laser diffraction, Brunauer-Emmett-Teller analysis, density measurement, powder X-ray diffraction, and in vitro aerosol deposition measurement with a multistage liquid impinger. It was found that drug nanoparticles with a diameter of 100 nm were precipitated and agglomerated into highly porous spherical microparticles with a volume median diameter ( D 50 %) of 2.25 ± 0.08 μm and a specific surface area of 158.63 ± 3.27 m2/g. In vitro aerosol deposition studies showed the fine particle fraction of such spherical agglomerates of drug nanoparticles was increased by more than 50 % in comparison with the control samples, demonstrating significant improvements in aerosol performance. The results of this study indicated the potential of the combined particle engineering process of liquid antisolvent precipitation followed by immediate (on-line) spray drying in the development of novel DPI drug products with improved aerosol performance.

  9. Improving drug-therapy decisions through educational outreach. A randomized controlled trial of academically based "detailing".

    PubMed

    Avorn, J; Soumerai, S B

    1983-06-16

    Improving precision and economy in the prescribing of drugs is a goal whose importance has increased with the proliferation of new and potent agents and with growing economic pressures to contain health-care costs. We implemented an office-based physician education program to reduce the excessive use of three drug groups: cerebral and peripheral vasodilators, an oral cephalosporin, and propoxyphene. A four-state sample of 435 prescribers of these drugs was identified through Medicaid records and randomly assigned to one of three groups. Physicians who were offered personal educational visits by clinical pharmacists along with a series of mailed "unadvertisements" reduced their prescribing of the target drugs by 14 per cent as compared with controls (P = 0.0001). A comparable reduction in the number of dollars reimbursed for these drugs was also seen between the two groups, resulting in substantial cost savings. No such change was seen in physicians who received mailed print materials only. The effect persisted for at least nine months after the start of the intervention, and no significant increase in the use of expensive substitute drugs was found. Academically based "detailing" may represent a useful and cost-effective way to improve the quality of drug-therapy decisions and reduce unnecessary expenditures.

  10. Assembling nanoparticle coatings to improve the drug delivery performance of lipid based colloids

    NASA Astrophysics Data System (ADS)

    Simovic, Spomenka; Barnes, Timothy J.; Tan, Angel; Prestidge, Clive A.

    2012-02-01

    Lipid based colloids (e.g. emulsions and liposomes) are widely used as drug delivery systems, but often suffer from physical instabilities and non-ideal drug encapsulation and delivery performance. We review the application of engineered nanoparticle layers at the interface of lipid colloids to improve their performance as drug delivery systems. In addition we focus on the creation of novel hybrid nanomaterials from nanoparticle-lipid colloid assemblies and their drug delivery applications. Specifically, nanoparticle layers can be engineered to enhance the physical stability of submicron lipid emulsions and liposomes, satbilise encapsulated active ingredients against chemical degradation, control molecular transport and improve the dermal and oral delivery characteristics, i.e. increase absorption, bioavailability and facilitate targeted delivery. It is feasible that hybrid nanomaterials composed of nanoparticles and colloidal lipids are effective encapsulation and delivery systems for both poorly soluble drugs and biological drugs and may form the basis for the next generation of medicines. Additional pre-clinical research including specific animal model studies are required to advance the peptide/protein delivery systems, whereas the silica lipid hybrid systems have now entered human clinical trials for poorly soluble drugs.

  11. Pleiotropic drug-resistance attenuated genomic library improves elucidation of drug mechanisms.

    PubMed

    Coorey, Namal V C; Matthews, James H; Bellows, David S; Atkinson, Paul H

    2015-11-01

    Identifying Saccharomyces cerevisiae genome-wide gene deletion mutants that confer hypersensitivity to a xenobiotic aids the elucidation of its mechanism of action (MoA). However, the biological activities of many xenobiotics are masked by the pleiotropic drug resistance (PDR) network which effluxes xenobiotics that are PDR substrates. The PDR network in S. cerevisiae is almost entirely under the control of two functionally homologous transcription factors Pdr1p and Pdr3p. Herein we report the construction of a PDR-attenuated haploid non-essential DMA (PA-DMA), lacking PDR1 and PDR3, which permits the MoA elucidation of xenobiotics that are PDR substrates at low concentrations. The functionality of four key cellular processes commonly activated in response to xenobiotic stress: oxidative stress response, general stress response, unfolded stress response and calcium signalling pathways were assessed in the absence of PDR1 and PDR3 genes and were found to unaltered, therefore, these key chemogenomic signatures are not lost when using the PA-DMA. Efficacy of the PA-DMA was demonstrated using cycloheximide and latrunculin A at low nanomolar concentrations to attain chemical genetic profiles that were more specific to their known main mechanisms. We also found a two-fold increase in the number of compounds that are bioactive in the pdr1Δpdr3Δ compared to the wild type strain in screening the commercially available LOPAC(1280) library. The PA-DMA should be particularly applicable to mechanism determination of xenobiotics that have limited availability, such as natural products.

  12. Hybrid systems based on "drug - in cyclodextrin - in nanoclays" for improving oxaprozin dissolution properties.

    PubMed

    Mura, Paola; Maestrelli, Francesca; Aguzzi, Carola; Viseras, César

    2016-07-25

    A combined approach based on drug complexation with cyclodextrins, and complex entrapment in nanoclays has been investigated, to join in a single delivery system the benefits of these carriers and potentiate their ability to improve the dissolution properties of oxaprozin (OXA), a poorly water-soluble anti-inflammatory drug. Based on previous studies, randomly methylated ß-cyclodextrin (RAMEB) was chosen as the most effective cyclodextrin for OXA complexation. Adsorption equilibrium studies performed on three different clays (sepiolite, attapulgite, bentonite) allowed selection of sepiolite (SV) for its greater adsorption power towards OXA. DSC and XRPD studies indicated drug amorphization in both binary OXA-RAMEB coground and OXA-SV cofused products, due to its complexation or very fine dispersion in the clay structure, respectively. The drug amorphous state was maintained also in the ternary OXA-RAMEB-SV cofused system. Dissolution studies evidenced a clear synergistic effect of RAMEB complexation and clay nanoencapsulation in improving the OXA dissolution properties, with an almost 100% increase in percent dissolved and dissolution efficiency compared to the OXA-RAMEB coground system. Therefore, the proposed combined approach represents an interesting tool for improving the therapeutic effectiveness of poorly soluble drugs, and reducing the CD amount necessary for obtaining the desired drug solubility and dissolution rate increase. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Modified-chitosan nanoparticles: Novel drug delivery systems improve oral bioavailability of doxorubicin.

    PubMed

    Khdair, Ayman; Hamad, Islam; Alkhatib, Hatim; Bustanji, Yasser; Mohammad, Mohammad; Tayem, Rabab; Aiedeh, Khaled

    2016-10-10

    The efficacy of most anticancer drugs is highly limited in vivo due mainly to poor pharmacokinetics behavior including poor bioavailability after extravascular administration. We have developed novel chitosan-modified polymeric nanoparticles for oral as well as i.v. administration. Nanoparticles were developed utilizing the double emulsion solvent evaporation technique for sustained delivery of various anticancer drugs. Chitosan diacetate (CDA) and chitosan triacetate (CTA) polymers were previously modified in our laboratory and used as novel matrix. Nanoparticles, loaded with various anticancer drugs, were characterized for particle size using dynamic light scattering as well as transmission electron microscopy and net surface charge using dynamic light scattering. Particles size was below 100nm in diameter and zeta potential ranged - (25-30). Encapsulation efficiency of anticancer drugs varied considerably and was dependent on the physicochemical characteristics of the encapsulated drug. However, chitosan triacetate nanoparticles showed relatively higher encapsulation efficiency than chitosan diacetate nanoparticles. In vitro release of encapsulated drugs was sustained over a period of 14days. Nanoparticles enhanced cellular accumulation of encapsulated drugs, compared to the free drugs, in vitro in MCF-7 and Caco-II tumor cell lines. In conclusion, diacetate and triacetate chitosan are novel polymers that can be used to formulate nanoparticles which efficiently encapsulated anticancer drugs, and sustained the release and enhanced tumor cellular uptake of these drugs. Further, chitosan triacetate nanoparticles enhanced oral bioavailability of doxorubicin. CDA and CTA nanoparticles can be used to efficiently deliver anticancer drugs and improve their in vivo profile. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Improved release of triamcinolone acetonide from medicated soft contact lenses loaded with drug nanosuspensions.

    PubMed

    García-Millán, Eva; Quintáns-Carballo, Mónica; Otero-Espinar, Francisco Javier

    2017-06-15

    Drug nanosuspensions (NSs) show a significant potential to improve loading and release properties of the poorly water soluble drug triamcinolone acetonide (TA) from poly(hydroxyethyl methacrylate) (pHEMA) soft contact lenses. In this work, TA NSs were developed by a controlled precipitation method using a fractional factorial Plackett-Burmann design. Poloxamer 407 (PL) and polyvinyl alcohol (PVA) as stabilizing agents were selected. NSs were characterized in terms of their drug content, particle size and morphology. Results indicate that all studied factors, except homogenization speed and sonication, have significant influence on the drug incorporation yield into NSs. Drug nanoparticles showed an interesting size that may be suitable for their incorporation into topical ocular drug delivery systems, as hydrogels. pHEMA hydrogels and daily-wear Hilafilcon B commercial contact lenses (SCLs) were employed to study TA loading capacity and drug release properties using NSs as loading system. Hydrogels have been synthesised by copolymerization of 2-hydroxyethyl methacrylate (HEMA) with methacrylic acid (MA) in accordance with a previous work (García-Millán et al., 2015). Both synthesised hydrogels and SCLs were characterized in terms of their mechanical and physical properties and TA loading and release properties. Selected TA NS was further characterized by studying its physical-chemical stability during the loading process. Results show that the use of TA NSs as loading medium significantly increases drug loading capacity and release of soft contact lenses in comparison with drug saturated solution. Synthesised pHEMA hydrogels and SCLs lenses have good properties as ophthalmic drug delivery systems, but SCLs load higher quantities of drug and release TA in shorter time periods than synthesised pHEMA hydrogel. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety.

    PubMed

    Meanwell, Nicholas A

    2011-09-19

    The development of small molecule drug candidates from the discovery phase to a marketed product continues to be a challenging enterprise with very low success rates that have fostered the perception of poor productivity by the pharmaceutical industry. Although there have been significant advances in preclinical profiling that have improved compound triaging and altered the underlying reasons for compound attrition, the failure rates have not appreciably changed. As part of an effort to more deeply understand the reasons for candidate failure, there has been considerable interest in analyzing the physicochemical properties of marketed drugs for the purpose of comparing with drugs in discovery and development as a means capturing recent trends in drug design. The scenario that has emerged is one in which contemporary drug discovery is thought to be focused too heavily on advancing candidates with profiles that are most easily satisfied by molecules with increased molecular weight and higher overall lipophilicity. The preponderance of molecules expressing these properties is frequently a function of increased aromatic ring count when compared with that of the drugs launched in the latter half of the 20th century and may reflect a preoccupation with maximizing target affinity rather than taking a more holistic approach to drug design. These attributes not only present challenges for formulation and absorption but also may influence the manifestation of toxicity during development. By providing some definition around the optimal physicochemical properties associated with marketed drugs, guidelines for drug design have been developed that are based largely on calculated parameters and which may readily be applied by medicinal chemists as an aid to understanding candidate quality. The physicochemical properties of a molecule that are consistent with the potential for good oral absorption were initially defined by Lipinski, with additional insights allowing further

  16. Improving the prediction of the brain disposition for orally administered drugs using BDDCS

    PubMed Central

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

    2012-01-01

    In modeling blood–brain barrier (BBB) passage, in silico models have yielded ~80% prediction accuracy, and are currently used in early drug discovery. Being derived from molecular structural information only, these models do not take into account the biological factors responsible for the in vivo outcome. Passive permeability and P-glycoprotein (Pgp, ABCB1) efflux have been successfully recognized to impact xenobiotic extrusion from the brain, as Pgp is known to play a role in limiting the BBB penetration of oral drugs in humans. However, these two properties alone fail to explain the BBB penetration for a significant number of marketed central nervous system (CNS) agents. The Biopharmaceutics Drug Disposition Classification System (BDDCS) has proved useful in predicting drug disposition in the human body, particularly in the liver and intestine. Here we discuss the value of using BDDCS to improve BBB predictions of oral drugs. BDDCS class membership was integrated with in vitro Pgp efflux and in silico permeability data to create a simple 3-step classification tree that accurately predicted CNS disposition for more than 90% of 153 drugs in our data set. About 98% of BDDCS class 1 drugs were found to markedly distribute throughout the brain; this includes a number of BDDCS class 1 drugs shown to be Pgp substrates. This new perspective provides a further interpretation of how Pgp influences the sedative effects of H1-histamine receptor antagonists. PMID:22261306

  17. Improving anticancer drug development begins with cell culture: misinformation perpetrated by the misuse of cytotoxicity assays.

    PubMed

    Eastman, Alan

    2017-01-31

    The high failure rate of anticancer drug discovery and development has consumed billions of dollars annually. While many explanations have been provided, I believe that misinformation arising from inappropriate cell-based screens has been completely over-looked. Most cell culture experiments are irrelevant to how drugs are subsequently administered to patients. Usually, drug development focuses on growth inhibition rather than cell killing. Drugs are selected based on continuous incubation of cells, then frequently administered to the patient as a bolus. Target identification and validation is often performed by gene suppression that inevitably mimics continuous target inhibition. Drug concentrations in vitro frequently far exceed in vivo concentrations. Studies of drug synergy are performed at sub-optimal concentrations. And the focus on a limited number of cell lines can misrepresent the potential efficacy in a patient population. The intent of this review is to encourage more appropriate experimental design and data interpretation, and to improve drug development in the area of cell-based assays. Application of these principles should greatly enhance the successful translation of novel drugs to the patient.

  18. Improving anticancer drug development begins with cell culture: misinformation perpetrated by the misuse of cytotoxicity assays

    PubMed Central

    Eastman, Alan

    2017-01-01

    The high failure rate of anticancer drug discovery and development has consumed billions of dollars annually. While many explanations have been provided, I believe that misinformation arising from inappropriate cell-based screens has been completely over-looked. Most cell culture experiments are irrelevant to how drugs are subsequently administered to patients. Usually, drug development focuses on growth inhibition rather than cell killing. Drugs are selected based on continuous incubation of cells, then frequently administered to the patient as a bolus. Target identification and validation is often performed by gene suppression that inevitably mimics continuous target inhibition. Drug concentrations in vitro frequently far exceed in vivo concentrations. Studies of drug synergy are performed at sub-optimal concentrations. And the focus on a limited number of cell lines can misrepresent the potential efficacy in a patient population. The intent of this review is to encourage more appropriate experimental design and data interpretation, and to improve drug development in the area of cell-based assays. Application of these principles should greatly enhance the successful translation of novel drugs to the patient. PMID:27750219

  19. Can Functional Magnetic Resonance Imaging Improve Success Rates in CNS Drug Discovery?

    PubMed Central

    Borsook, David; Hargreaves, Richard; Becerra, Lino

    2011-01-01

    Introduction The bar for developing new treatments for CNS disease is getting progressively higher and fewer novel mechanisms are being discovered, validated and developed. The high costs of drug discovery necessitate early decisions to ensure the best molecules and hypotheses are tested in expensive late stage clinical trials. The discovery of brain imaging biomarkers that can bridge preclinical to clinical CNS drug discovery and provide a ‘language of translation’ affords the opportunity to improve the objectivity of decision-making. Areas Covered This review discusses the benefits, challenges and potential issues of using a science based biomarker strategy to change the paradigm of CNS drug development and increase success rates in the discovery of new medicines. The authors have summarized PubMed and Google Scholar based publication searches to identify recent advances in functional, structural and chemical brain imaging and have discussed how these techniques may be useful in defining CNS disease state and drug effects during drug development. Expert opinion The use of novel brain imaging biomarkers holds the bold promise of making neuroscience drug discovery smarter by increasing the objectivity of decision making thereby improving the probability of success of identifying useful drugs to treat CNS diseases. Functional imaging holds the promise to: (1) define pharmacodynamic markers as an index of target engagement (2) improve translational medicine paradigms to predict efficacy; (3) evaluate CNS efficacy and safety based on brain activation; (4) determine brain activity drug dose-response relationships and (5) provide an objective evaluation of symptom response and disease modification. PMID:21765857

  20. The use of nationwide on-line prescription records improves the drug history in hospitalized patients.

    PubMed

    Glintborg, Bente; Poulsen, Henrik E; Dalhoff, Kim P

    2008-02-01

    Structured medication interviews improve the medication history upon hospitalization. Pharmacy records are valid lists of the prescribed medications available to individual patients. In Denmark, treating doctors now have access to their patients' pharmacy records through a real-time online electronic database What this study adds: Omission errors are frequent among hospitalized patients despite structured drug interviews and home visits. Pharmacy records may be used to minimize patients' recall bias and improve the medication lists. Structured medication interviews improve the medication history in hospitalized patients. In Denmark, a nationwide electronic version of individual pharmacy records (PR) has recently been introduced. Use of these records could improve the medication lists in hospitalized patients. We prospectively included 500 patients admitted to an acute medical department. In individual patients, the PR was compared with (i) the medication list written in the patient chart and (ii) drug information provided by the patient during a structured drug interview upon admission and during a home visit after discharge. Median patient age was 72 years. Upon admission, patients reported using 1958 prescription-only medications (POM) (median four drugs per patient, range 0-14), of which 114 (6%) were not registered in PR. In PR, 1153 POM (median one per patient, range 0-11) were registered during the month preceding admission. The patients did not report 309 (27%) of these upon admission. Home visits were performed in a subgroup of 115 patients. During home visits, 18% of POM registered in PR during the preceding month were not reported. Drug type was predictive of reporting irrespective of patient sex or age. Cardiovascular drugs were reported most and dermatological were reported less frequently. Underreporting might be due to recall bias, non-adherence or discontinuation of drugs. Omission errors are frequent despite structured medication interviews

  1. Mesoporous silica-based dosage forms improve release characteristics of poorly soluble drugs: case example fenofibrate.

    PubMed

    Dressman, Jennifer B; Herbert, Elisabeth; Wieber, Alena; Birk, Gudrun; Saal, Christoph; Lubda, Dieter

    2016-05-01

    Mesoporous silica-based dosage forms offer the potential for improving the absorption of poorly soluble drugs after oral administration. In this investigation, fenofibrate was used as a model drug to study the ability of monomodal ('PSP A') and bimodal ('PSP B') porous silica to improve release by a 'spring' effect in in vitro biorelevant dissolution tests. Also investigated was the addition of various polymers to provide a 'parachute' effect, that is, to keep the drug in solution after its release. Loading fenofibrate onto PSP A or PSP B porous silica substantially improved the dissolution profile of fenofibrate under fasted state conditions compared with both pure drug and the marketed product, TriCor® 145 mg. Adding a polymer such as hydroxypropyl methylcellulose acetate succinate, polyvinylpyrrolidone or copovidon (HPMCAS, PVP or PVPVA) sustains the higher release of fenofibrate from the PSP A silica, resulting in a combination 'spring and parachute' effect - loading the drug onto the silica causes a 'spring' effect while the polymer enhances the spring effect (HPMCAS, PVP) and adds a sustaining 'parachute'. Interestingly, a silica to polymer ratio of 4:1 w/w appears to have an optimal effect for fenofibrate (HPMCAS, PVP). Dissolution results under conditions simulating the fasted state in the small intestine with the PSP A or the PSP B silica with HPMCAS added in a 4:1 w/w ratio show very substantial improvement over the marketed, nanosized product (TriCor® 145 mg). Further experiments to determine whether the highly positive effects on fenofibrate release observed with the silica prototypes investigated to date can be translated to further poorly soluble drugs and to what extent they translate into improved in-vivo performance are warranted. © 2015 Royal Pharmaceutical Society.

  2. Chitosan microparticles for oral bioavailability improvement of the hydrophobic drug curcumin.

    PubMed

    Wan, Shuxin; Sun, Yingqian; Sun, Li; Tan, Fengping

    2012-06-01

    The aim of this study was to assess the feasibility of microparticles for dissolution enhancement and oral bioavailability of curcumin (Cur). Microparticles were prepared by the ionic crosslinking interaction with the use of tripolyphosphate (TPP) and chitosan (Cs). The physicochemical characteristics of microparticles were investigated. The in vivo performance was assessed by a pharmacokinetic study. The microparticles had an average diameter of 58.50 microm. Acceptable drug loading and encapsulation efficiency of microparticles were obtained to be 33.5% and 85.2%, respectively. Dissolution of Cur enhanced in the microparticles in comparison with pure drug. Drug release profile of Cur from microparticles fitted the first-order model. Microparticles provided improved pharmacokinetic parameters (Cmax 270.24 ng/ml, T(max) 1.30 h) in rats as compared with pure drug (C(max) 87.06 nglml, Tmax 0.66 h). The AUC value of microparticles was 8.4 fold that of the pure drug. The information from this study suggests that the developed microparticles successfully enhanced dissolution of the poorly water-soluble drug Cur, and eventually, improved its oral bioavailability effectively.

  3. An educational intervention on drug use in nursing homes improves health outcomes resource utilization and reduces inappropriate drug prescription.

    PubMed

    García-Gollarte, Fermín; Baleriola-Júlvez, José; Ferrero-López, Isabel; Cuenllas-Díaz, Álvaro; Cruz-Jentoft, Alfonso J

    2014-12-01

    Inappropriate drug prescription is a common problem in people living in nursing homes and is linked to adverse health outcomes. This study assessed the effect of an educational intervention directed to nursing home physicians in reducing inappropriate prescription and improving health outcomes and resource utilization. Prospective, randomized, multicenter study. A private organization of nursing homes in Spain. Sixty nursing home physicians caring for approximately 3900 nursing home residents in 37 centers were randomized to receive an educational intervention (30) or as a control group (30). 10 hours educational program, followed by on demand support by phone. Outcomes were assessed in 1018 randomly selected nursing home residents. Appropriateness of drug use [measured by the Screening Tool of Older Persons Prescriptions (STOPP) and Screening Tool to Alert Doctors to Right Treatment (START) criteria], incidence of selected geriatric syndromes (falls, delirium) and health resource utilization (visits to physicians and nursing homes, visits to the emergency room, days of hospitalization) were recorded for 3 months before the intervention started and 3 months after the intervention finished. O total of 716 residents finished the study (344 cared for by the intervention group physicians, 372 cared for by control physicians). Mean age was 84.4 ± 12.7 years; 73% were women. The mean number of inappropriate drugs (STOPP criteria) was higher at the end of the study in the control than in the intervention group (1.29 ± 1.56 vs 0.81 ± 1.13), as was the number of residents on 6 or more drugs (76.5% vs.67.0%), using antipsychotics (9.1% vs 3.2%) or duplicate medications (32.5% vs 9.2%). The number of fallers increased in the control group (from 19.3% to 28%) and did not significantly change in the intervention group (from 25.3% to 23.9%); the number of residents with delirium increased in the control group (from 3.8% to 9.1%) and decreased in the intervention group (from 6

  4. Nanostructured lipid carriers: An emerging platform for improving oral bioavailability of lipophilic drugs

    PubMed Central

    Khan, Saba; Baboota, Sanjula; Ali, Javed; Khan, Sana; Narang, Ramandeep Singh; Narang, Jasjeet Kaur

    2015-01-01

    Nowadays exploration of novel lipid-based formulations is akin to a magnet for researchers worldwide for improving the in vivo performance of highly lipophilic drugs. Over the last few years, new compositions of lipids have been developed, and the probable bioavailability enhancement has been investigated. We reviewed the most recent data dealing with backlogs of conventional lipid-based formulations such as physical instability, limited drug loading capacities, drug expulsion during storage along with all the possible hindrances resulting in poor absorption of highly lipophilic drugs such as P-glycoprotein efflux, extensive metabolism by cytochrome P450 etc. In tandem with these aspects, an exclusive formulation approach has been discussed in detail in this paper. Therefore, this review focuses on resolving the concerned ambiguity with successful oral administration of highly lipophilic drugs through designing novel lipidic formulations (nanostructured lipid carriers [NLC]) that constitute a blend of solid and liquid lipids. The article highlights the potential role of such formulation in normalizing the in vivo fate of poorly soluble drugs. Finally, the present manuscript discusses the dominance of NLC over other lipid-based formulations and provides a perspective of how they defeat and overcome the barriers that lead to the poor bioavailability of hydrophobic drugs. PMID:26682188

  5. Preclinical models for pediatric solid tumor drug discovery: current trends, challenges and the scopes for improvement.

    PubMed

    Kumar, Sushil; Mokhtari, Reza Bayat; Yeger, Herman; Baruchel, Sylvain

    2012-11-01

    The enhancement in pediatric cancer survival achieved in the past few decades has been confined to low- and moderate-risk cancers, whereas no notable improvement in survival was observed in high-risk and advanced-stage childhood cancers. High attrition rate of candidate drugs in clinical trials is a major hurdle in the development of effective therapies for pediatric solid tumors. In order to reduce the failure rate of candidate drugs in clinical trials, more effective strategies are needed to enhance the predictability of preclinical testing. The authors have described the current trends in preclinical drug development for treating pediatric solid tumors. Furthermore, the authors review their limitations and the available remedies, with regards to choice of models, pharmacokinetic considerations and the criteria for assessing the long-term efficacy of a candidate drug. In many solid tumors, common differences between pediatric and adult cancers have been observed, and therefore, clinical trials for pediatric solid tumors must be conducted on the basis of preclinical observations in pediatric solid tumor models. There is a need to invest in extensive preclinical testing on pediatric solid tumor models. None of the preclinical models can fully recapitulate the human cancers. Therefore, these limitations must be considered while conducting a preclinical trial. The dose and schedule of drugs used for preclinical testing must be clinically relevant. While testing the efficacy of drugs, the markers of apoptosis, drug resistance, hypoxia and tumor-initiating cells can inform us about the long-term therapeutic response of a cancer.

  6. Improved Therapeutic Efficacy in Bone and Joint Disorders by Targeted Drug Delivery to Bone.

    PubMed

    Takahashi, Tatsuo

    2016-01-01

     Site-specific drug delivery to bone is considered achievable using acidic amino acid (L-Asp or L-Glu) homopeptides known as acidic oligopeptides. We found that fluorescence-labeled acidic oligopeptides containing six or more residues bound strongly to hydroxyapatite, which is a major component of bone, and were selectively delivered to and retained in bone after systemic administration. We explored the applicability of this result for drug delivery by conjugation of estradiol and levofloxacin with an L-Asp hexapeptide. We also similarly tagged enzymes (tissue-nonspecific alkaline phosphatase, β-glucuronidase, and N-acetylgalactosamine-6-sulfate sulfatase) and decoy receptors (endogenous secretory receptor for advanced glycation end products and etanercept) to assess whether these would improve therapeutic efficacy. The L-Asp hexapeptide-tagged drugs, including enzymes and decoy receptors, were efficiently delivered to bone in comparison with the untagged drugs. An in vivo experiment confirmed the efficacy of L-Asp hexapeptide-tagged drugs on bone and joint disorders, although there was some loss of bioactivity of estradiol and levofloxacin in vitro, suggesting that the acidic hexapeptide was partly removed by hydrolysis in the body after delivery to bone. It was expected that the ester linkage to the hexapeptide would be susceptible to hydrolysis in situ, releasing the drug from the acidic oligopeptide. These results support the usefulness of acidic oligopeptides as bone-targeting carriers for therapeutic agents. We present some pharmacokinetic and pharmacological properties of the L-Asp hexapeptide-tagged drugs.

  7. Improving Predictive Modeling in Pediatric Drug Development: Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling

    SciTech Connect

    Slikker, William; Young, John F.; Corley, Rick A.; Dorman, David C.; Conolly, Rory B.; Knudsen, Thomas; Erstad, Brian L.; Luecke, Richard H.; Faustman, Elaine M.; Timchalk, Chuck; Mattison, Donald R.

    2005-07-26

    A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

  8. Information Technology-Based Interventions to Improve Drug-Drug Interaction Outcomes: A Systematic Review on Features and Effects.

    PubMed

    Nabovati, Ehsan; Vakili-Arki, Hasan; Taherzadeh, Zhila; Saberi, Mohammad Reza; Medlock, Stephanie; Abu-Hanna, Ameen; Eslami, Saeid

    2017-01-01

    The purpose of this systematic review was to identify features and effects of information technology (IT)-based interventions on outcomes related to drug-drug interactions (DDI outcomes). A literature search was conducted in Medline, EMBASE, and the Cochrane Library for published English-language studies. Studies were included if a main outcome was related to DDIs, the intervention involved an IT-based system, and the study design was experimental or observational with controls. Study characteristics, including features and effects of IT-based interventions, were extracted. Nineteen studies comprising five randomized controlled trials (RCT), five non-randomized controlled trials (NRCT) and nine observational studies with controls (OWC) were included. Sixty-four percent of prescriber-directed interventions, and all non-prescriber interventions, were effective. Each of the following characteristics corresponded to groups of studies of which a majority were effective: automatic provision of recommendations within the providers' workflow, intervention at the time of decision-making, integration into other systems, and requiring the reason for not following the recommendations. Only two studies measured clinical outcomes: an RCT that showed no significant improvement and an OWC that showed improvement, but did not statistically assess the effect. Most studies that measured surrogate outcomes (e.g. potential DDIs) and other outcomes (e.g. adherence to alerts) showed improvements. IT-based interventions improve surrogate clinical outcomes and adherence to DDI alerts. However, there is lack of robust evidence about their effectiveness on clinical outcomes. It is recommended that researchers consider the identified features of effective interventions in the design of interventions and evaluate the effectiveness on DDI outcomes, particularly clinical outcomes.

  9. Self-microemulsifying drug-delivery system for improved oral bioavailability of probucol: preparation and evaluation

    PubMed Central

    Sha, Xianyi; Wu, Juan; Chen, Yanzuo; Fang, Xiaoling

    2012-01-01

    The objective of our investigation was to design a self-microemulsifying drug-delivery system (SMEDDS) to improve the bioavailability of probucol. SMEDDS was composed of probucol, olive oil, Lauroglycol FCC, Cremophor EL, Tween-80, and PEG-400. Droplet sizes were determined. In vitro release was investigated. Pharmacokinetics and bioavailability of probucol suspension, oil solution, and SMEDDS were evaluated and compared in rats. Plasma drug concentration was determined by high-performance liquid chromatography. After administration of probucol suspension, plasma drug concentration was very low. Relative bioavailability of SMEDDS was dramatically enhanced in an average of 2.15- and 10.22-fold that of oil solution and suspension, respectively. It was concluded that bioavailability of probucol was enhanced greatly by SMEDDS. Improved solubility and lymphatic transport may contribute to the enhancement of bioavailability. PMID:22359449

  10. Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy

    PubMed Central

    Chen, Helen HW; Chen, Wen-Chung; Liang, Zhang-Dong; Tsai, Wen-Bin; Long, Yan; Aiba, Isamu; Fu, Siqing; Broaddus, Russell; Liu, Jinsong; Feun, Lynn G; Savaraj, Niramol; Kuo, Macus Tien

    2016-01-01

    Introduction Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy. Area covered Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated. Expert opinion While both transcriptional and posttranslational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed. PMID:26004625

  11. Improving treatment adherence in drug abusers who are HIV-positive.

    PubMed

    Malone, S B; Osborne, J J

    2000-01-01

    This article discusses the complex dual diagnosis of HIV/AIDS (Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome) and substance abuse, which affects a growing number of individuals worldwide. A brief review of HIV/AIDS is provided and the connection between HIV/AIDS and substance abuse is described. Substance abuse complicates both HIV/AIDS and its management because of the effects that illicit drugs have on various body systems and because of the behavioral disturbances that accompany substance use. For a variety of reasons adherence to treatment is poor in this population and several factors that negatively impact adherence are outlined. Treatment of drug abusers who are HIV-positive requires more flexibility than treating drug abuse and HIV separately. Because medication regimens can be complicated and demanding and nonadherence to treatment can cause mutation of the virus resulting in drug-resistant strains, it is essential to get the patient committed to treatment The goals of treatment are abstinence from illicit drugs, adherence to a treatment regimen, suppression of viral load, improved CD4 count, and improved quality of life. The role of the case manager is critical to improving treatment adherence. Essential attributes include knowledge of disease processes, critical thinking, and the ability to navigate the healthcare system. Case management interventions to improve treatment adherence should be directed at the patient, the regimen, the client-patient relationship, and the healthcare system. Because HIV/AIDS is now classified as a chronic disease and is no longer viewed as a death sentence, people who are HIV-positive have hope for longevity and a cure. It is this hope for a longer life and possible cure that can be used to motivate substance abusers who are HIV-infected to improve their treatment adherence and quality of life.

  12. pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs.

    PubMed

    Wang, Xue-Qing; Zhang, Qiang

    2012-10-01

    pH-sensitive polymeric nanoparticles are promising for oral drug delivery, especially for peptide/protein drugs and poorly water-soluble medicines. This review describes current status of pH-sensitive polymeric nanoparticles for oral drug delivery and introduces the mechanisms of drug release from them as well as possible reasons for absorption improvement, with emphasis on our contribution to this field. pH-sensitive polymeric nanoparticles are prepared mainly with polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of drug release are the result of carriers' dissolution, swelling or both of them at specific pH. The possible reasons for improvement of oral bioavailability include the following: improve drug stability, enhance mucoadhesion, prolong resident time in GI tract, ameliorate intestinal permeability and increase saturation solubility and dissolution rate for poorly water-soluble drugs. As for the advantages of pH-sensitive nanoparticles over conventional nanoparticles, we conclude that (1) most carriers used are enteric-coating materials and their safety has been approved. (2) The rapid dissolution or swelling of carriers at specific pH results in quick drug release and high drug concentration gradient, which is helpful for absorption. (3) At the specific pH carriers dissolve or swell, and the bioadhesion of carriers to mucosa becomes high because nanoparticles turn from solid to gel, which can facilitate drug absorption.

  13. A comparative study on the nanoparticles for improved drug delivery systems.

    PubMed

    Mahmoodi, Nosrat O; Ghavidast, Atefeh; Amirmahani, Najmeh

    2016-09-01

    Nanoparticles have attracted considerable recent interest for diverse biomedical applications because of the unique properties of the nanomaterials. It is already known that one of the major advances in the relative application of nanoparticles is the recognition of the steric stabilization which can increase the particle stability in the biological environment and provide the opportunities of the application of nanoparticles in the development of drug delivery systems (DDSs) for achieving drug targeting and controlled drug release. To facilitate their use in such applications, the appropriate design of surface ligands on these nanoparticles is necessary. In view of these, functionalized nanoparticles through surface modification can be utilized to specifically interact with the target molecules on the cell membrane or intracellular ones. This review briefly presents self-assembled nanoparticles with molecules of therapeutic significance with two strategies. The first strategy attempts to improve the placement of the drugs using conjugating the appropriate ligands or adding targeting moieties to the DDS. The second strategy utilizes trigger-controlled drug-release, which restricts drug release at the targeted site to kill cancer cells by externally controlled mechanisms. Among external stimulations, conveniently light has attracted much interest because it, as an orthogonal external stimulus, gives spatiotemporal control of payload release.

  14. Market access of cancer drugs in European countries: improving resource allocation.

    PubMed

    Pauwels, Kim; Huys, Isabelle; Casteels, Minne; De Nys, Katelijne; Simoens, Steven

    2014-06-01

    Public health systems need to make well-founded choices in order to distribute their scarce resources in the most efficient way. Given the number of cancer patients, public/private investments in oncology research, the growing number of new anti-cancer agents and consequent budget impact of cancer care, market access of cancer drugs has become delicate over the last decade. Furthermore, decision makers are challenged by ethical objections and endeavour to provide fair and equal access to treatments for cancer patients. The aim of this study is to generate an overview of market access procedures for cancer drugs in eight European countries and formulate advice for improvement of resource allocation. Results are obtained through a literature review and a qualitative questionnaire and validated by experts with proven knowledge about procedures for price setting and reimbursement of drugs. Diverse measures are applied in the studied countries to optimize reimbursement of cancer drugs such as adjusted cost-effectiveness threshold, regulations for off-label use and new market access agreements. Additionally, innovative cancer drugs are excluded from explicit cost control measures such as payback of budget excess by pharmaceutical companies and lump-sum payments per diagnostic related groups (DRG) in the hospital. The results suggest that cancer is prioritized above other disease areas. Further research is necessary to address the question if society attaches higher value to cancer drugs than to treatments for other diseases.

  15. A new and improved method for the preparation of drug nanosuspension formulations using acoustic mixing technology.

    PubMed

    Leung, Dennis H; Lamberto, David J; Liu, Lina; Kwong, Elizabeth; Nelson, Todd; Rhodes, Timothy; Bak, Annette

    2014-10-01

    Drug discovery and development is a challenging area. During the drug optimization process, available drug compounds often have poor physicochemical and biopharmaceutical properties, making the proper in vivo evaluation of these compounds difficult. To address these challenges, drug nanoparticles of poorly soluble compounds have emerged as a promising formulation approach. Herein, we report on a new drug sparing technology utilizing low shear acoustic mixing to rapidly identify optimized nanosuspension formulations for a wide range of compounds with dramatically improved material and time efficiencies. This approach has several key advantages over typical methods of preparing nanoparticles, including miniaturization of the milling process, the ability to evaluate multiple formulation conditions in a high throughput manner, and direct translation to optimized formulation scale-up for in vivo studies. Furthermore, there are additional benefits obtained with this new approach resulting in nanosuspension formulations with significant stability and physical property enhancements over those obtained using traditional media milling techniques. These advantages make this approach highly suitable for the rapid evaluation of potential drug candidates in the discovery and development space. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. DrugE-Rank: improving drug–target interaction prediction of new candidate drugs or targets by ensemble learning to rank

    PubMed Central

    Yuan, Qingjun; Gao, Junning; Wu, Dongliang; Zhang, Shihua; Mamitsuka, Hiroshi; Zhu, Shanfeng

    2016-01-01

    Motivation: Identifying drug–target interactions is an important task in drug discovery. To reduce heavy time and financial cost in experimental way, many computational approaches have been proposed. Although these approaches have used many different principles, their performance is far from satisfactory, especially in predicting drug–target interactions of new candidate drugs or targets. Methods: Approaches based on machine learning for this problem can be divided into two types: feature-based and similarity-based methods. Learning to rank is the most powerful technique in the feature-based methods. Similarity-based methods are well accepted, due to their idea of connecting the chemical and genomic spaces, represented by drug and target similarities, respectively. We propose a new method, DrugE-Rank, to improve the prediction performance by nicely combining the advantages of the two different types of methods. That is, DrugE-Rank uses LTR, for which multiple well-known similarity-based methods can be used as components of ensemble learning. Results: The performance of DrugE-Rank is thoroughly examined by three main experiments using data from DrugBank: (i) cross-validation on FDA (US Food and Drug Administration) approved drugs before March 2014; (ii) independent test on FDA approved drugs after March 2014; and (iii) independent test on FDA experimental drugs. Experimental results show that DrugE-Rank outperforms competing methods significantly, especially achieving more than 30% improvement in Area under Prediction Recall curve for FDA approved new drugs and FDA experimental drugs. Availability: http://datamining-iip.fudan.edu.cn/service/DrugE-Rank Contact: zhusf@fudan.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307615

  17. Improved medication use in long-term care: building on the consultant pharmacist's drug regimen review.

    PubMed

    Harjivan, Chandresh; Lyles, Alan

    2002-04-01

    Elderly and long-term care (LTC) patients often require complex medication regimens that increase their risk of adverse drug events or suboptimal pharmacotherapy. Currently, oversight of medication use in LTC facilities consists of a federally mandated monthly audit, the drug regimen review (DRR), performed by a consultant pharmacist, and yearly onsite government surveys. Although the DRR's purpose is to improve drug use and to avoid adverse drug events, the Centers for Medicare and Medicaid Services's (CMS) current DRR guidelines focus on a limited selection of medications and indications rather than on patient outcomes. An expanded model building on CMS's survey guidelines and the American Society of Consultant Pharmacists' Fleetwood Model is proposed to improve oversight of medication use. The proposed model includes using consultant pharmacists with demonstrated geriatric pharmacotherapy expertise, direct patient assessments by the pharmacist, increased interaction among healthcare professionals, evidence-based practices, and explicit patient outcome assessments. It is both feasible and timely: (1) the LTC prospective payment system aligns financial incentives between payers and providers; and (2) the Institute of Medicine has made quality improvement and error reduction a priority.

  18. Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D

    PubMed Central

    Ke, Zhongcheng; Hou, Xuefeng; Jia, Xiao-bin

    2016-01-01

    Background The main purpose of this research was to design a self-nanoemulsifying drug delivery system (SNEDDS) for improving the bioavailability of cyclovirobuxine D as a poorly water-soluble drug. Materials and methods Solubility trials, emulsifying studies, and pseudo-ternary phase diagrams were used to screen the SNEDDS formulations. The optimized drug-loaded SNEDDS was prepared at a mass ratio of 3:24:38:38 for cyclovirobuxine D, oleic acid, Solutol SH15, and propylene glycol, respectively. The optimized formulation was characterized in terms of physicochemical and pharmacokinetic parameters compared with marketed cyclovirobuxine D tablets. Results The optimized cyclovirobuxine-D-loaded SNEDDS was spontaneously dispersed to form a nanoemulsion with a globule size of 64.80±3.58 nm, which exhibited significant improvement of drug solubility, rapid absorption rate, and enhanced area under the curve, together with increased permeation and decreased efflux. Fortunately, there was a nonsignificant cytotoxic effect toward Caco-2 cells. The relative bioavailability of SNEDDS was 200.22% in comparison with market tablets, in rabbits. Conclusion SNEDDS could be a potential candidate for an oral dosage form of cyclovirobuxine D with improved bioavailability. PMID:27418807

  19. Improved Diagnosis of Pleural Tuberculosis Using the Microscopic-Observation Drug-Susceptibility Technique

    PubMed Central

    Tovar, Marco; Siedner, Mark J.; Gilman, Robert H.; Santillan, Carlos; Caviedes, Luz; Valencia, Teresa; Jave, Oswaldo; Rod Escombe, A.; Moore, David A. J.; Evans, Carlton A.

    2010-01-01

    Tests for pleural tuberculosis are insensitive and expensive. We compared nonproprietary microscopic-observation drug-susceptibility (MODS) culture with Löwenstein-Jensen culture for evaluation of pleural specimens. MODS culture was associated with greatly increased diagnostic sensitivity and shorter time to diagnosis, compared with Löwenstein-Jensen culture (sensitivity of culture of biopsy specimens, 81% vs. 51%; time to diagnosis, 11 days vs. 24 days; P < .001). The MODS technique is inexpensive, allows drug-susceptibility testing, and is a considerably improved diagnostic method for pleural tuberculosis. PMID:18300380

  20. Comprehensive summary--Predict-IV: A systems toxicology approach to improve pharmaceutical drug safety testing.

    PubMed

    Mueller, Stefan O; Dekant, Wolfgang; Jennings, Paul; Testai, Emanuela; Bois, Frederic

    2015-12-25

    This special issue of Toxicology in Vitro is dedicated to disseminating the results of the EU-funded collaborative project "Profiling the toxicity of new drugs: a non animal-based approach integrating toxicodynamics and biokinetics" (Predict-IV; Grant 202222). The project's overall aim was to develop strategies to improve the assessment of drug safety in the early stage of development and late discovery phase, by an intelligent combination of non animal-based test systems, cell biology, mechanistic toxicology and in silico modeling, in a rapid and cost effective manner. This overview introduces the scope and overall achievements of Predict-IV. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Potential of Non-aqueous Microemulsions to Improve the Delivery of Lipophilic Drugs to the Skin.

    PubMed

    Carvalho, Vanessa F; de Lemos, Debora P; Vieira, Camila S; Migotto, Amanda; Lopes, Luciana B

    2017-07-01

    In this study, non-aqueous microemulsions were developed because of the challenges associated with finding pharmaceutically acceptable solvents for topical delivery of drugs sparingly soluble in water. The formulation irritation potential and ability to modulate the penetration of lipophilic compounds (progesterone, α-tocopherol, and lycopene) of interest for topical treatment/prevention of skin disorders were evaluated and compared to solutions and aqueous microemulsions of similar composition. The microemulsions (ME) were developed with BRIJ, vitamin E-TPGS, and ethanol as surfactant-co-surfactant blend and tributyrin, isopropyl myristate, and oleic acid as oil phase. As polar phase, propylene glycol (MEPG) or water (MEW) was used (26% w/w). The microemulsions were isotropic and based on viscosity and conductivity assessment, bicontinuous. Compared to drug solutions in lipophilic vehicles, MEPG improved drug delivery into viable skin layers by 2.5-38-fold; the magnitude of penetration enhancement mediated by MEPG into viable skin increased with drug lipophilicity, even though the absolute amount of drug delivered decreased. Delivery of progesterone and tocopherol, but not lycopene (the most lipophilic compound), increased up to 2.5-fold with MEW, and higher amounts of these two drugs were released from MEW (2-2.5-fold). Both microemulsions were considered safe for topical application, but MEPG-mediated decrease in the viability of reconstructed epidermis was more pronounced, suggesting its higher potential for irritation. We conclude that MEPG is a safe and suitable nanocarrier to deliver a variety of lipophilic drugs into viable skin layers, but the use of MEW might be more advantageous for drugs in the lower range of lipophilicity.

  2. Improvement on dissolution rate of inclusion complex of Rifabutin drug with β-cyclodextrin.

    PubMed

    Shanmuga Priya, Arumugam; Sivakamavalli, Jeyachandran; Vaseeharan, Baskaralingam; Stalin, Thambusamy

    2013-11-01

    The effect of β-cyclodextrin (β-CD) on the improvement of solubility and antimicrobial activity of poorly water soluble drug Rifabutin (RFB) was studied. The solid inclusion complex is prepared under different methods and it is characterized by FT-IR, XRD, DSC and SEM methods. Solubility type, stability constant, stoichiometric ratio were investigated from phase solubility diagram of inclusion complex (RFB with β-CD). The dissolution profiles of the inclusion complexes were carried out and obvious increase in dissolution rate was observed when compared with pure RFB drug. Inclusion complexation process was further confirmed by molecular docking studies using PatchDock server. The in vitro antimicrobial and antibiofilm activity of RFB sensible microorganisms was significantly increased by on inclusion complexation process. This trend of inclusion complexation of poorly water soluble drugs is highly recognized as a successful and useful approach for the application in pharmaceutical field. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Improvement of some pharmaceutical properties of drugs by cyclodextrin complexation. 4. Chlorpromazine hydrochloride.

    PubMed

    Ammar, H O; Ghorab, M; el-Nahhas, S A; Omar, S M; Ghorab, M M

    1995-12-01

    The potentiality of interaction of chlorpromazine hydrochloride (CPZ) with beta-cyclodextrin (beta-CD) was investigated by spectrophotometry, vapour pressure osmometry and DSC thermograms. The results revealed a very strong evidence for molecular interaction between CPZ and beta-CD. The continuous variation method was used to elucidate the stoichiometry of such interaction by spectrophotometric as well as vapour pressure measurements. Both types of data revealed the formation of a 1:1 complex. The stability constant of the complex was determined at different temperatures by the vapour pressure osmometric method. The enthalpy and entropy of interaction were evaluated and the results indicate that the interaction is exothermic. The CPZ/beta-CD complex was prepared, lyophilized and photochemical stability of the drug, its physical mixture with beta-CD as well as the prepared complex was investigated at different pH-values in presence of different buffer systems. The results revealed that the stability of the drug is greatly improved in presence of beta-CD and the great dependency of stability on the pH of the solution is decreased in presence of beta-CD. The partition coefficient of CPZ and its complex with beta-CD was determined. The data reveal a higher p.c. of the complex compared to the parent drug. The effect of beta-CD on the bioavailability of CPZ was investigated by measuring the miotic response intensity in volunteers receiving a single oral dose of the drug, drug/beta-CD physical mixture or complex. The results revealed a distinct improvement of the biological performance of CPZ by beta-CD as evidenced by an increased intensity of drug action and its duration as well as augmenting its bioavailability without affecting the time for maximum effect.

  4. The use of nationwide on-line prescription records improves the drug history in hospitalized patients

    PubMed Central

    Glintborg, Bente; Poulsen, Henrik E; Dalhoff, Kim P

    2008-01-01

    Background Structured medication interviews improve the medication history in hospitalized patients. In Denmark, a nationwide electronic version of individual pharmacy records (PR) has recently been introduced. Use of these records could improve the medication lists in hospitalized patients. Methods We prospectively included 500 patients admitted to an acute medical department. In individual patients, the PR was compared with (i) the medication list written in the patient chart and (ii) drug information provided by the patient during a structured drug interview upon admission and during a home visit after discharge. Results Median patient age was 72 years. Upon admission, patients reported using 1958 prescription-only medications (POM) (median four drugs per patient, range 0–14), of which 114 (6%) were not registered in PR. In PR, 1153 POM (median one per patient, range 0–11) were registered during the month preceding admission. The patients did not report 309 (27%) of these upon admission. Home visits were performed in a subgroup of 115 patients. During home visits, 18% of POM registered in PR during the preceding month were not reported. Drug type was predictive of reporting irrespective of patient sex or age. Cardiovascular drugs were reported most and dermatologicals were reported less frequently. Underreporting might be due to recall bias, non-adherence or discontinuation of drugs. Conclusions Omission errors are frequent despite structured medication interviews. Pharmacy records or medication lists from all treating doctors must be included in medication reviews in order to reduce recall bias. What is already known about this subject Structured medication interviews improve the medication history upon hospitalizationPharmacy records are valid lists of the prescribed medications available to individual patientsIn Denmark, treating doctors now have access to their patients' pharmacy records through a real-time online electronic database What this study adds

  5. Synergetic effects of doxycycline-loaded chitosan nanoparticles for improving drug delivery and efficacy

    PubMed Central

    Cover, Natasha F; Lai-Yuen, Susana; Parsons, Anna K; Kumar, Arun

    2012-01-01

    Introduction Doxycycline, a broad-spectrum antibiotic, is the most commonly prescribed antibiotic worldwide for treating infectious diseases. It may be delivered orally or intravenously but can lead to gastrointestinal irritation and local inflammation. For treatment of uterine infections, transcervical administration of doxycycline encapsulated in nanoparticles made of biodegradable chitosan may improve sustained delivery of the drug, thereby minimizing adverse effects and improving drug efficacy. Methods and materials As a first step toward assessing this potential, we used an ionic gelation method to synthesize blank and doxycycline-loaded chitosan nanoparticles (DCNPs), which we then characterized in terms of several properties relevant to clinical efficacy: particle size, shape, encapsulation efficiency, antibacterial activity, and in vitro cytotoxicity. Two particle formulations were examined, with one (named DCNP6) containing approximately 1.5 times the crosslinker concentration of the other (DCNP4). Results The two formulations produced spherically shaped drug-loaded nanoparticles. The spheres ranged in size from 30 to 220 nm diameter for DCNP4 and 200 to 320 nm diameter for DCNP6. Average encapsulation yield was 53% for DCNP4 and 56% for DCNP6. In terms of drug release, both formulations showed a burst effect within the first 4 to 5 hours, followed by a slow, sustained release for the remainder of the 24-hour monitoring period. The in vitro antibacterial activity against Escherichia coli was high, with both formulations achieving more than 90% inhibition of 4-hour bacterial growth. Cytotoxic effects of the DCNPs on normal human ovarian surface epithelial cells were significantly lower than those of unencapsulated doxycycline. After 5 days, cultures exposed to the unencapsulated antibiotic showed a 61% decrease in cell viability, while cultures exposed to the DCNPs exhibited less than a 10% decrease. Conclusion These laboratory results suggest that DCNPs

  6. Self-emulsifying drug delivery systems as a tool to improve solubility and bioavailability of resveratrol.

    PubMed

    Balata, Gehan F; Essa, Ebtessam A; Shamardl, Hanan A; Zaidan, Samira H; Abourehab, Mohammed As

    2016-01-01

    Resveratrol is a nonflavonoid polyphenolic compound which has a broad range of desirable biological actions which include antioxidant, anti-inflammatory, antidiabetic, cardioprotective, and antitumor activities. However, there is concern that the bioavailability of resveratrol may limit some of its clinical utility. So, the aim of this study was to enhance the dissolution rate and oral hypoglycemic and hypolipidemic effect of resveratrol. This was achieved using self-emulsifying drug delivery system. The solubility of resveratrol was determined in various oils, surfactants, and cosurfactants. Phase diagram was plotted to identify the efficient self-emulsification regions using olive oil, Tween 80, and propylene glycol. The prepared self-emulsifying drug delivery system formulations were tested for thermodynamic stability, emulsification efficiency, droplet size, zeta potential, and in vitro drug release. Self-emulsification time averaged 17-99 seconds without precipitation and the mean droplet sizes ranged from 285 to 823 nm with overall zeta potential of -2.24 to -15.4 mv. All formulations improved drug dissolution in relation to unprocessed drug with a trend of decreased dissolution parameters with increasing oil content. The optimized formula, F19, with dissolution efficiency of 94% compared to only 42% of pure drug was used to study the in vivo hypoglycemic and hypolipidemic effects of resveratrol in diabetic-induced albino rats and comparing these effects with that of pure resveratrol in different doses. Treatment with the optimized formula, F19, at 10 mg/kg had significant hypoglycemic and hypolipidemic effects in diabetic-induced albino rats which were nearly similar to the high dose (20 mg/kg) of unprocessed resveratrol. From the study, it was concluded that formulation F19 has good emulsification property with uniform globule size, satisfactory in vitro drug release profile, and significant in vivo hypoglycemic effects which identify future opportunities

  7. Self-emulsifying drug delivery systems as a tool to improve solubility and bioavailability of resveratrol

    PubMed Central

    Balata, Gehan F; Essa, Ebtessam A; Shamardl, Hanan A; Zaidan, Samira H; Abourehab, Mohammed AS

    2016-01-01

    Resveratrol is a nonflavonoid polyphenolic compound which has a broad range of desirable biological actions which include antioxidant, anti-inflammatory, antidiabetic, cardioprotective, and antitumor activities. However, there is concern that the bioavailability of resveratrol may limit some of its clinical utility. So, the aim of this study was to enhance the dissolution rate and oral hypoglycemic and hypolipidemic effect of resveratrol. This was achieved using self-emulsifying drug delivery system. The solubility of resveratrol was determined in various oils, surfactants, and cosurfactants. Phase diagram was plotted to identify the efficient self-emulsification regions using olive oil, Tween 80, and propylene glycol. The prepared self-emulsifying drug delivery system formulations were tested for thermodynamic stability, emulsification efficiency, droplet size, zeta potential, and in vitro drug release. Self-emulsification time averaged 17–99 seconds without precipitation and the mean droplet sizes ranged from 285 to 823 nm with overall zeta potential of −2.24 to −15.4 mv. All formulations improved drug dissolution in relation to unprocessed drug with a trend of decreased dissolution parameters with increasing oil content. The optimized formula, F19, with dissolution efficiency of 94% compared to only 42% of pure drug was used to study the in vivo hypoglycemic and hypolipidemic effects of resveratrol in diabetic-induced albino rats and comparing these effects with that of pure resveratrol in different doses. Treatment with the optimized formula, F19, at 10 mg/kg had significant hypoglycemic and hypolipidemic effects in diabetic-induced albino rats which were nearly similar to the high dose (20 mg/kg) of unprocessed resveratrol. From the study, it was concluded that formulation F19 has good emulsification property with uniform globule size, satisfactory in vitro drug release profile, and significant in vivo hypoglycemic effects which identify future

  8. Use of amino acids as counterions improves the solubility of the BCS II model drug, indomethacin.

    PubMed

    ElShaer, Amr; Khan, Sheraz; Perumal, Dhaya; Hanson, Peter; Mohammed, Afzal R

    2011-07-01

    The number of new chemical entities (NCE) is increasing every day after the introduction of combinatorial chemistry and high throughput screening to the drug discovery cycle. One third of these new compounds have aqueous solubility less than 20µg/mL [1]. Therefore, a great deal of interest has been forwarded to the salt formation technique to overcome solubility limitations. This study aims to improve the drug solubility of a Biopharmaceutical Classification System class II (BCS II) model drug (Indomethacin; IND) using basic amino acids (L-arginine, L-lysine and L-histidine) as counterions. Three new salts were prepared using freeze drying method and characterised by FT-IR spectroscopy, proton nuclear magnetic resonance ((1)HNMR), Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). The effect of pH on IND solubility was also investigated using pH-solubility profile. Both arginine and lysine formed novel salts with IND, while histidine failed to dissociate the free acid and in turn no salt was formed. Arginine and lysine increased IND solubility by 10,000 and 2296 fold, respectively. An increase in dissolution rate was also observed for the novel salts. Since these new salts have improved IND solubility to that similar to BCS class I drugs, IND salts could be considered for possible waivers of bioequivalence.

  9. Solid Dispersion Approach Improving Dissolution Rate of Stiripentol: a Novel Antiepileptic Drug

    PubMed Central

    Afifi, Samar

    2015-01-01

    Some drugs have low bioavailability due to their poor aqueous solubility and/or slow dissolution rate in biological fluids. Stiripentol (STP) is a novel anticonvulsant drug that is structurally unrelated to the currently available antiepileptics. It has poor aqueous solubility and its solubility has to be enhanced accordingly. Polyethyleneglycol 6000 (PEG-6000) is commonly utilized as a hydrophilic carrier for poorly water soluble drugs in order to improve their bioavailability. STP and PEG-6000 binary system was obtained by physical mixture, solvent evaporation, co-evaporation and melting methods using different weight ratios. The properties of the prepared binary systems were evaluated using dissolution rate, phase solubility, Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and scanning electron microscope (SEM) studies. The FTIR spectroscopic studies showed the stability of STP and absence of STP-PEG-6000 interaction. The DSC and SEM studies indicated the amorphous state of STP in its binary systems with PEG-6000. Dissolution profile of STP was significantly improved via complexation with PEG-6000 as compared with the pure drug. The binary system which was prepared using melting method showed the highest dissolution rate. The promising results of the prepared binary systems open the avenue for further oral formulation of STP. PMID:26664367

  10. Solid Dispersion Approach Improving Dissolution Rate of Stiripentol: a Novel Antiepileptic Drug.

    PubMed

    Afifi, Samar

    2015-01-01

    Some drugs have low bioavailability due to their poor aqueous solubility and/or slow dissolution rate in biological fluids. Stiripentol (STP) is a novel anticonvulsant drug that is structurally unrelated to the currently available antiepileptics. It has poor aqueous solubility and its solubility has to be enhanced accordingly. Polyethyleneglycol 6000 (PEG-6000) is commonly utilized as a hydrophilic carrier for poorly water soluble drugs in order to improve their bioavailability. STP and PEG-6000 binary system was obtained by physical mixture, solvent evaporation, co-evaporation and melting methods using different weight ratios. The properties of the prepared binary systems were evaluated using dissolution rate, phase solubility, Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and scanning electron microscope (SEM) studies. The FTIR spectroscopic studies showed the stability of STP and absence of STP-PEG-6000 interaction. The DSC and SEM studies indicated the amorphous state of STP in its binary systems with PEG-6000. Dissolution profile of STP was significantly improved via complexation with PEG-6000 as compared with the pure drug. The binary system which was prepared using melting method showed the highest dissolution rate. The promising results of the prepared binary systems open the avenue for further oral formulation of STP.

  11. Doxorubicin-loaded platelets as a smart drug delivery system: An improved therapy for lymphoma

    PubMed Central

    Xu, Peipei; Zuo, Huaqin; Chen, Bing; Wang, Ruju; Ahmed, Arsalan; Hu, Yong; Ouyang, Jian

    2017-01-01

    Chemotherapy is majorly used for the treatment of many cancers, including lymphoma. However, cytotoxic drugs, utilized in chemotherapy, can induce various side effects on normal tissues because of their non-specific distribution in the body. Natural platelets are used as drug carriers because of their biocompatibility and specific targeting to vascular disorders, such as cancer, inflammation, and thrombosis. In this work, doxorubicin (DOX) was loaded in natural platelets for treatment of lymphoma. Results showed that DOX was loaded into platelets with high drug loading and encapsulation efficiency. DOX did not significantly induce morphological and functional changes in platelets. DOX-platelet facilitated intracellular drug accumulation through “tumor cell-induced platelet aggregation” and released DOX into the medium in a pH-controlled manner. This phenomenon reduced the adverse effects and enhanced the therapeutic efficacy. The growth inhibition of lymphoma Raji cells was enhanced, and the cardiotoxicity of DOX was reduced when DOX was loaded in platelets. DOX-platelet improved the anti-tumor activity of DOX by regulating the expression of apoptosis-related genes. Thus, platelets can serve as potential drug carriers to deliver DOX for clinical treatment of lymphoma. PMID:28198453

  12. [Improvement of intestinal absorption of poorly absorbable drugs by various sugar esters].

    PubMed

    Yamamoto, Akira; Katsumi, Hidemasa; Kusamori, Kosuke; Sakane, Toshiyasu

    2014-01-01

    Effects of sucrose fatty acid esters (sugar esters) on the intestinal absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. 5(6)-Carboxyfluorescein (CF) and fluorescein isothiocyanate-dextrans (FDs) with various molecular weights were used as model drugs of poorly absorbable drugs. The absorption of CF from the rat small intestine was significantly enhanced in the presence of various sugar esters and a maximal absorption enhancing effect was observed in the presence of 0.5%(w/v) S-1670. The absorption enhancing effect of S-1670 in the small intestine decreased as the molecular weights of drugs increased. Moreover, we evaluated the intestinal membrane damage with or without various sugar esters. These sugar esters (0.5%(w/v)) did not increase the activities of lactate dehydrogenase (LDH), suggesting that these sugar esters did not cause serious membrane damage to the intestinal epithelium. Furthermore, these sugar esters increased membrane fluidity of lipid layers of the intestinal brush border membranes and decreased the transepithelial electrical resistance (TEER) of Caco-2 cells. Therefore, these findings suggested that these sugar esters might improve the intestinal absorption of poorly absorbable drugs via a transcellular and a paracellular pathways.

  13. Controlled release drug delivery systems to improve post-operative pharmacotherapy.

    PubMed

    Bhusal, Prabhat; Harrison, Jeff; Sharma, Manisha; Jones, David S; Hill, Andrew G; Svirskis, Darren

    2016-10-01

    Over 230 million surgical procedures are conducted worldwide each year with numbers increasing. Pain, undesirable inflammation and infection are common complications experienced by patients following surgery. Opioids, non-steroidal anti-inflammatory drugs (NSAIDs), local anaesthetics (LAs) and antibiotics are the commonly administered drugs peri-operatively to manage these complications. Post-operative pharmacotherapy is typically achieved using immediate-release dosage forms of drugs, which lead to issues around fluctuating plasma concentrations, systemic adverse effects and poor patient adherence. Controlled release (CR) systems for certain medicines including opioids, NSAIDs and antibiotics have demonstrably enhanced treatment efficacy in the post-surgical setting. However, challenges remain to ensure patient safety while achieving individual therapeutic needs. Newer CR systems in the research and development pipeline have a high level of control over medicine release, which can be initiated, tuned or stopped on-demand. Future systems will self-regulate drug release in response to biological markers providing precise individualized therapy. In this review, we cover currently adopted CR systems in post-operative pharmacotherapy, including drug eluting medical devices, and highlight a series of examples of novel CR technologies that have the potential for translation into post-surgical settings to improve medication efficacy and enhance post-surgical recovery.

  14. Improved prediction of drug-target interactions using regularized least squares integrating with kernel fusion technique.

    PubMed

    Hao, Ming; Wang, Yanli; Bryant, Stephen H

    2016-02-25

    Identification of drug-target interactions (DTI) is a central task in drug discovery processes. In this work, a simple but effective regularized least squares integrating with nonlinear kernel fusion (RLS-KF) algorithm is proposed to perform DTI predictions. Using benchmark DTI datasets, our proposed algorithm achieves the state-of-the-art results with area under precision-recall curve (AUPR) of 0.915, 0.925, 0.853 and 0.909 for enzymes, ion channels (IC), G protein-coupled receptors (GPCR) and nuclear receptors (NR) based on 10 fold cross-validation. The performance can further be improved by using a recalculated kernel matrix, especially for the small set of nuclear receptors with AUPR of 0.945. Importantly, most of the top ranked interaction predictions can be validated by experimental data reported in the literature, bioassay results in the PubChem BioAssay database, as well as other previous studies. Our analysis suggests that the proposed RLS-KF is helpful for studying DTI, drug repositioning as well as polypharmacology, and may help to accelerate drug discovery by identifying novel drug targets.

  15. Overcoming intratumor heterogeneity of polygenic cancer drug resistance with improved biomarker integration.

    PubMed

    Rehemtulla, Alnawaz

    2012-12-01

    Improvements in technology and resources are helping to advance our understanding of cancer-initiating events as well as factors involved with tumor progression, adaptation, and evasion of therapy. Tumors are well known to contain diverse cell populations and intratumor heterogeneity affords neoplasms with a diverse set of biologic characteristics that can be used to evolve and adapt. Intratumor heterogeneity has emerged as a major hindrance to improving cancer patient care. Polygenic cancer drug resistance necessitates reconsidering drug designs to include polypharmacology in pursuit of novel combinatorial agents having multitarget activity to overcome the diverse and compensatory signaling pathways in which cancer cells use to survive and evade therapy. Advances will require integration of different biomarkers such as genomics and imaging to provide for more adequate elucidation of the spatially varying location, type, and extent of diverse intratumor signaling molecules to provide for a rationale-based personalized cancer medicine strategy.

  16. Pyrimethamine-loaded lipid-core nanocapsules to improve drug efficacy for the treatment of toxoplasmosis.

    PubMed

    Pissinate, Kenia; dos Santos Martins-Duarte, Érica; Schaffazick, Scheila Rezende; de Oliveira, Catiúscia Padilha; Vommaro, Rossiane Cláudia; Guterres, Sílvia Stanisçuaski; Pohlmann, Adriana Raffin; de Souza, Wanderley

    2014-02-01

    We propose an innovative product based on the nanoencapsulation of pyrimethamine (PYR), aiming an improvement of drug efficacy for the treatment of toxoplasmosis. The in vitro cytotoxicity effect of encapsulated PYR and PYR-colloidal suspension was concomitantly evaluated against LLC-MK2 lineage and mouse peritoneal macrophage showing that the cells had similar tolerance for both PYR encapsulated or in the aqueous suspension. CF1 mice acutely infected with tachyzoites of Toxoplasma gondii RH strain treated with different doses (5.0-10 mg/kg/day) of PYR-nanocapsules had survival rate higher than the animals treated with the same doses of non-encapsulated PYR. Thus, encapsulation of PYR improved the efficacy of this drug against an acute model of toxoplasmosis in mice and can be considered an alternative for reducing the dose of PYR, which, in turn, could also reduce the side effects associated to the treatment.

  17. Overcoming Intratumor Heterogeneity of Polygenic Cancer Drug Resistance with Improved Biomarker Integration1

    PubMed Central

    Rehemtulla, Alnawaz

    2012-01-01

    Improvements in technology and resources are helping to advance our understanding of cancer-initiating events as well as factors involved with tumor progression, adaptation, and evasion of therapy. Tumors are well known to contain diverse cell populations and intratumor heterogeneity affords neoplasms with a diverse set of biologic characteristics that can be used to evolve and adapt. Intratumor heterogeneity has emerged as a major hindrance to improving cancer patient care. Polygenic cancer drug resistance necessitates reconsidering drug designs to include polypharmacology in pursuit of novel combinatorial agents having multitarget activity to overcome the diverse and compensatory signaling pathways in which cancer cells use to survive and evade therapy. Advances will require integration of different biomarkers such as genomics and imaging to provide for more adequate elucidation of the spatially varying location, type, and extent of diverse intratumor signaling molecules to provide for a rationale-based personalized cancer medicine strategy. PMID:23308059

  18. Improvement of bone marrow fibrosis with ruxolitinib: will this finding change our perception of the drug?

    PubMed

    Breccia, Massimo; Molica, Matteo; Colafigli, Gioia; Alimena, Giuliana

    2015-08-01

    Ruxolitinib, a JAK1 and JAK2 inhibitor, has been tested and approved for the treatment of primary and secondary myelofibrosis. Reduction of spleen volume and improvement of constitutional symptoms and quality of life have been reported as the major findings in sponsored randomized clinical trials. Recent data indicated that the drug improves bone marrow fibrosis and that different targets may be involved in this response. These new data, which require confirmation in prospective trials, may change our perspectives and therapeutic strategies for this disease.

  19. Hypothesis driven drug design: improving quality and effectiveness of the design-make-test-analyse cycle.

    PubMed

    Plowright, Alleyn T; Johnstone, Craig; Kihlberg, Jan; Pettersson, Jonas; Robb, Graeme; Thompson, Richard A

    2012-01-01

    In drug discovery, the central process of constructing and testing hypotheses, carefully conducting experiments and analysing the associated data for new findings and information is known as the design-make-test-analyse cycle. Each step relies heavily on the inputs and outputs of the other three components. In this article we report our efforts to improve and integrate all parts to enable smooth and rapid flow of high quality ideas. Key improvements include enhancing multi-disciplinary input into 'Design', increasing the use of knowledge and reducing cycle times in 'Make', providing parallel sets of relevant data within ten working days in 'Test' and maximising the learning in 'Analyse'.

  20. Improvement of dissolution property of poorly water-soluble drug by supercritical freeze granulation.

    PubMed

    Sonoda, Ryoichi; Hara, Yuko; Iwasaki, Tomohiro; Watano, Satoru

    2009-10-01

    The dissolution property of the poorly water-soluble drug, flurbiprofen (FP) was improved by a novel supercritical freeze granulation using supercritical carbon dioxide. Supercritical freeze granulation was defined as a production method of the granulated substances by using the dry ice to generate intentionally for the rapid atomization of the supercritical carbon dioxide to the atmospheric pressure. This process utilized a rapid expansion of supercritical solutions (RESS) process with the mixture of the drug and lactose. In the supercritical freeze granulation, needle-like FP fine particles were obtained which adhered to the surface of lactose particles, which did not dissolve in supercritical carbon dioxide. The number of FP particles that adhered to the surface of particles decreased with an increase in the ratio of lactose added, leading to markedly improve the dissolution rate. This improvement was caused not only by the increase in the specific surface area but also the improvement of the dispersibility of FP in water. It is thus concluded that the supercritical freeze granulation is a useful technique to improve the dissolution property of the poorly water-soluble flurbiprofen.

  1. Improvement in Hemodynamics After Methylene Blue Administration in Drug-Induced Vasodilatory Shock: A Case Report.

    PubMed

    Laes, JoAn R; Williams, David M; Cole, Jon B

    2015-12-01

    The purpose of this study is to describe a case where methylene blue improved hemodynamics in a poisoned patient. This is a single case report where a poisoned patient developed vasodilatory shock following ingestion of atenolol, amlodipine, and valsartan. Shock persisted after multiple therapies including vasopressors, high-dose insulin, hemodialysis, and 20% intravenous fat emulsion. Methylene blue (2 mg/kg IV over 30 min) was administered in the ICU with temporal improvement as measured by pulmonary artery catheter hemodynamic data pre- and post-methylene blue administration. Within 1 h of methylene blue administration, systemic vascular resistance improved (240 dyn s/cm5 increased to 1204 dyn s/cm5), and vasopressor requirements decreased with maintenance of mean arterial pressure 60 mmHg. Methylene blue may improve hemodynamics in drug-induced vasodilatory shock and should be considered in critically ill patients poisoned with vasodilatory medications refractory to standard therapies.

  2. Antihypertensive drug prescribing and persistence among new elderly users: implications for persistence improvement interventions.

    PubMed

    Tu, Karen; Anderson, Laura N; Butt, Debra A; Quan, Hude; Hemmelgarn, Brenda R; Campbell, Norm R; McAlister, Finlay A

    2014-06-01

    The objective of this study was to examine persistence rates and factors influencing persistence for new elderly users of antihypertensive drugs. We conducted a population-based cohort study in Ontario of adults aged 66 years or older to identify new users of antihypertensive medications between 1999 and 2010. Two-year therapy and class persistence were defined as persistence on any antihypertensive medication and persistence only on the same antihypertensive medication class, respectively. From 1999-2010, the prevalence of antihypertensive drug use increased from 47.8%-60.5% (P < 0.0001). Persistence was evaluated in 420,148 new users of antihypertensive drugs. After 2 years, therapy persistence was 58.9% and varied according to initial class prescribed, from 52.3% for diuretics to 64.1% for angiotensin-converting enzyme inhibitors. Class persistence ranged from 25.3% for diuretics to 35.8% for angiotensin II receptor blockers. Therapy persistence rates were greater in new users from more recent years (adjusted odds ratio [aOR], 1.24; 95% confidence interval [CI], 1.21-1.27). Subgroups that demonstrated poorer persistence included patients older than 75 years (aOR, 0.95; 95% CI, 0.94-0.96), those with lowest neighbourhood income quintile (aOR, 0.81; 95% CI, 0.80-0.83 compared with the highest quintile), those from urban vs rural areas (aOR, 0.83; 95% CI, 0.81-0.84), and those who started on diuretics as initial monotherapy compared with all other drug classes. Although 2-year therapy and class persistence were low for new users of antihypertensive drugs, improvements have occurred over the past decade. Our data highlight subgroups to target for future persistence improvement interventions. Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

  3. PPO/PEO modified hollow fiber membranes improved sensitivity of 3D cultured hepatocytes to drug toxicity via suppressing drug adsorption on membranes.

    PubMed

    Shen, Chong; Meng, Qin; He, Wenjuan; Wang, Qichen; Zhang, Guoliang

    2014-11-01

    The three dimensional (3D) cell culture in polymer-based micro system has become a useful tool for in vitro drug discovery. Among those polymers, polysulfone hollow fiber membrane (PSf HFM) is commonly used to create a microenvironment for cells. However, the target drug may adsorb on the polymeric surface, and this elicits negative impacts on cell exposure due to the reduced effective drug concentration in culture medium. In order to reduce the drug adsorption, PSf membrane were modified with hydrophilic Pluronic (PEO-b-PPO-b-PEO) copolymers, L121, P123 and F127 (PEO contents increase from 10%, 30% to 70%), by physical adsorption. As a result, the hydrophilicity of HFMs increased at an order of PSfF127>P123>L121 HFMs. The three modified membrane all showed significant resistance to adsorption of acid/neutral drugs. More importantly, the adsorption of base drugs were largely reduced to an average value of 11% on the L121 HFM. The improved resistance to drug adsorption could be attributed to the synergy of hydrophobic/neutrally charged PPO and hydrophilic PEO. The L121 HFM was further assessed by evaluating the drug hepatotoxicity in 3D culture of hepatocytes. The base drugs, clozapine and doxorubicin, showed more sensitive hepatotoxicity on hepatocytes in L121 HFM than in PSf HFM, while the acid drug, salicylic acid, showed the similar hepatotoxicity to hepatocytes in both HFMs. Our finding suggests that PSf HFM modified by PEO-b-PPO-b-PEO copolymers can efficiently resist the drug adsorption onto polymer membrane, and consequently improve the accuracy and sensitivity of in vitro hepatotoxic drug screening. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Dissolution rate improvement of poorly water-soluble drugs obtained by adsorbing solutions of drugs in hydrophilic solvents onto high surface area carriers.

    PubMed

    Friedrich, Heike; Fussnegger, Bernd; Kolter, Karl; Bodmeier, Roland

    2006-02-01

    The dissolution rate of the model drugs carbamazepine and nifedipine was improved by adsorbing solutions of the drugs in hydrophilic non-volatile or volatile solvents onto carriers with a large surface area. This was accomplished by dissolving the drug in methanol or the non-toxic hydrophilic liquids PEG 400 or 2-pyrrolidone, and adsorbing these solutions onto the surface of silica (Aerosil) or crosslinked polyvinylpyrrolidone (Kollidon CL-M). The solvent binding capacities decreased in the order of methanol, PEG 400, 2-pyrrolidone for Aerosil 200, 300, 380 and for Kollidon CL-M. Kollidon bound less liquid than Aerosil because of the smaller surface area. Differential scanning calorimetry measurements showed higher interactions between drugs and Kollidon compared to Aerosil, suggesting a low aggregation of precipitated drug particles. The drug release from the adsorbent systems was enhanced when compared to micronized drug and independent of the drug loading in the investigated range. The drugs were also dissolved in various liquid, paste-like or solid solubilisers (polyoxyl-40-hydrogenated castor oil (Cremophor RH 40), macrogol-15-hydroxystearate (Solutol HS), poloxamers (Lutrol F68, Pluronic F87NF and Pluronic L44NF) and adsorbed onto Kollidon. These adsorbent systems also exhibited an increased dissolution rate when compared to pure drug.

  5. Co-encapsulation of a drug with a protein in erythrocytes for improved drug loading and release: phenytoin and bovine serum albumin (BSA).

    PubMed

    Hamidi, Mehrdad; Azimi, Kourosh; Mohammadi-Samani, Soliman

    2011-01-01

    The aim of the present study was to use a novel protein co-encapsulation method to prepare phenytoin-loaded human erythrocytes with improved loading parameters and release profiles. Carrier erythrocytes were prepared using the hypotonic pre-swelling method. A series of in vitro characterization tests were carried out on the carrier cells, including loading parameters, drug and hemoglobin release, hematological indices, particle size analysis, osmotic fragility, turbulence fragility, and scanning electron microscopy (SEM). Co-encapsulation with bovine serum albumin (BSA) resulted in about 8-times higher drug loading in erythrocytes, with biphasic release trend instead of triphasic in the case of drug alone loading. In comparison to the normal unloaded cells, MCH and MCHC indices were decreased in the case of both drug and drug/protein loading, apparent cell sizes were unchanged, cell shapes were changed to spherical rather than biconcave discoid, and the osmotic as well as turbulence fragilities were higher in the case of drug/protein but were unchanged in the case of drug alone loading. The most profound finding of this study was the possibility of achieving remarkably higher drug loading and more controllable drug release profile in the case of drug/protein loading, with no unwanted in vitro characteristics change.

  6. Distinguishing between the Permeability Relationships with Absorption and Metabolism To Improve BCS and BDDCS Predictions in Early Drug Discovery

    PubMed Central

    2015-01-01

    The biopharmaceutics classification system (BCS) and biopharmaceutics drug distribution classification system (BDDCS) are complementary classification systems that can improve, simplify, and accelerate drug discovery, development, and regulatory processes. Drug permeability has been widely accepted as a screening tool for determining intestinal absorption via the BCS during the drug development and regulatory approval processes. Currently, predicting clinically significant drug interactions during drug development is a known challenge for industry and regulatory agencies. The BDDCS, a modification of BCS that utilizes drug metabolism instead of intestinal permeability, predicts drug disposition and potential drug–drug interactions in the intestine, the liver, and most recently the brain. Although correlations between BCS and BDDCS have been observed with drug permeability rates, discrepancies have been noted in drug classifications between the two systems utilizing different permeability models, which are accepted as surrogate models for demonstrating human intestinal permeability by the FDA. Here, we recommend the most applicable permeability models for improving the prediction of BCS and BDDCS classifications. We demonstrate that the passive transcellular permeability rate, characterized by means of permeability models that are deficient in transporter expression and paracellular junctions (e.g., PAMPA and Caco-2), will most accurately predict BDDCS metabolism. These systems will inaccurately predict BCS classifications for drugs that particularly are substrates of highly expressed intestinal transporters. Moreover, in this latter case, a system more representative of complete human intestinal permeability is needed to accurately predict BCS absorption. PMID:24628254

  7. Improving pharmaceutical innovation by building a more comprehensive database on drug development and use.

    PubMed

    Daniel, Gregory W; Cazé, Alexis; Romine, Morgan H; Audibert, Céline; Leff, Jonathan S; McClellan, Mark B

    2015-02-01

    New drugs and biologics have had a tremendous impact on the treatment of many diseases. However, available measures suggest that pharmaceutical innovation has remained relatively flat, despite substantial growth in research and development spending. We review recent literature on pharmaceutical innovation to identify limitations in measuring and assessing innovation, and we describe the framework and collaborative approach we are using to develop more comprehensive, publicly available metrics for innovation. Our research teams at the Brookings Institution and Deerfield Institute are collaborating with experts from multiple areas of drug development and regulatory review to identify and collect comprehensive data elements related to key development and regulatory characteristics for each new molecular entity approved over the past several decades in the United States and the European Union. Subsequent phases of our effort will add data on downstream product use and patient outcomes and will also include drugs that have failed or been abandoned in development. Such a database will enable researchers to better analyze the drivers of drug innovation, trends in the output of new medicines, and the effect of policy efforts designed to improve innovation.

  8. A new Strategy to Improve Drug Delivery to the Maxillary Sinuses: The Frequency Sweep Acoustic Airflow.

    PubMed

    El Merhie, Amira; Navarro, Laurent; Delavenne, Xavier; Leclerc, Lara; Pourchez, Jérémie

    2016-05-01

    Enhancement of intranasal sinus deposition involves nebulization of a drug superimposed by an acoustic airflow. We investigated the impact of fixed frequency versus frequency sweep acoustic airflow on the improvement of aerosolized drug penetration into maxillary sinuses. Fixed frequency and frequency sweep acoustic airflow were generated using a nebulizing system of variable frequency. The effect of sweep cycle and intensity variation was studied on the intranasal sinus deposition. We used a nasal replica created from CT scans using 3D printing. Sodium fluoride and gentamicin were chosen as markers. Studies performed using fixed frequency acoustic airflow showed that each of maxillary sinuses of the nasal replica required specific frequency for the optimal aerosol deposition. Intranasal sinus drug deposition experiments under the effect of the frequency sweep acoustic airflow showed an optimal aerosol deposition into both maxillary sinus of the nasal replica. Studies on the effect of the duration of the sweep cycle showed that the shorter the cycle the better the deposition. We demonstrate the benefit of frequency sweep acoustic airflow on drug deposition into maxillary sinuses. However further in vivo studies have to be conducted since delivery rates cannot be obviously determined from a nasal replica.

  9. AC and DC electrospinning of hydroxypropylmethylcellulose with polyethylene oxides as secondary polymer for improved drug dissolution.

    PubMed

    Balogh, Attila; Farkas, Balázs; Verreck, Geert; Mensch, Jürgen; Borbás, Enikő; Nagy, Brigitta; Marosi, György; Nagy, Zsombor Kristóf

    2016-05-30

    Alternating current electrospinning (ACES) capable to reach multiple times higher specific productivities than widely used direct current electrospinning (DCES) was investigated and compared with DCES to prepare drug-loaded formulations based on one of the most widespread polymeric matrix used for commercialized pharmaceutical solid dispersions, hydroxypropylmethylcellulose 2910 (HPMC). In order to improve the insufficient spinnability of HPMC (both with ACES and DCES) polyethylene oxide (PEO) as secondary polymer with intense ACES activity was introduced into the electrospinning solution. Different grades of this polymer used at as low concentrations in the fibers as 0.1% or less enabled the production of high quality HPMC-based fibrous mats without altering its physicochemical properties remarkably. Increasing concentrations of higher molecular weight PEOs led to the thickening of fibers from submicronic diameters to several microns of thickness. ACES fibers loaded with the poorly water-soluble model drug spironolactone were several times thinner than drug-loaded fibers prepared with DCES in spite of the higher feeding rates applied. The amorphous HPMC-based fibers with large surface area enhanced the dissolution of spironolactone significantly, the presence of small amounts of PEO did not affect the dissolution rate. The presented results confirm the diverse applicability of ACES, a novel technique to prepare fibrous drug delivery systems.

  10. Improved therapeutic entities derived from known generics as an unexplored source of innovative drug products.

    PubMed

    Stegemann, Sven; Klebovich, Imre; Antal, István; Blume, Henning H; Magyar, Kálmán; Németh, György; Paál, Tamás L; Stumptner, Willibald; Thaler, György; Van de Putte, Armand; Shah, Vinod P

    2011-11-20

    With a New Drug Application (NDA) innovative drug therapies are reaching the market in a specific dosage form for one or more clinically proven indications of which after expiration of the patent or the data exclusivity copies are launched using Abbreviated New Drug Applications (ANDA). Advanced therapies that emerged from launched molecules during their product life-cycle have gained considerable attention as clinical practice provides evidence for additional therapeutic values, patient centric delivery systems show improved therapeutic outcomes or emerging technologies offer efficiency gains in manufacturing or access to emerging markets. The USA and European regulatory framework has set reasonable regulations in place for these "Supergenerics" or "hybrid" applications. While these regulations are relatively recent the pharmaceutical industry is just starting to use this route for their product development and life-cycle management. From a clinical perspective the potential for advanced product development have been demonstrated. Yet, there is still a lag of common understanding between the different stakeholders regarding the development, application process and commercial incentive in developing enhanced therapeutic entities based on existing drug products for the market.

  11. Drugs.

    ERIC Educational Resources Information Center

    Hurst, Hunter, Ed.; And Others

    1984-01-01

    This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

  12. Engineered particles demonstrate improved flow properties at elevated drug loadings for direct compression manufacturing.

    PubMed

    Trementozzi, Andrea N; Leung, Cheuk-Yui; Osei-Yeboah, Frederick; Irdam, Erwin; Lin, Yiqing; MacPhee, J Michael; Boulas, Pierre; Karki, Shyam B; Zawaneh, Peter N

    2017-03-08

    Optimizing powder flow and compaction properties are critical for ensuring a robust tablet manufacturing process. The impact of flow and compaction properties of the active pharmaceutical ingredient (API) becomes progressively significant for higher drug load formulations, and for scaling up manufacturing processes. This study demonstrated that flow properties of a powder blend can be improved through API particle engineering, without critically impacting blend tabletability at elevated drug loadings. In studying a jet milled API (D50=24μm) and particle engineered wet milled API (D50=70μm and 90μm), flow functions of all API lots were similarly poor despite the vast difference in average particle size (ffc<4). This finding strays from the common notion that powder flow properties are directly correlated to particle size distribution. Upon adding excipients, however, clear trends in flow functions based on API particle size were observed. Wet milled API blends had a much improved flow function (ffc>10) compared with the jet milled API blends. Investigation of the compaction properties of both wet and jet milled powder blends also revealed that both jet and wet milled material produced robust tablets at the drug loadings used. The ability to practically demonstrate this uncommon observation that similarly poor flowing APIs can lead to a marked difference upon blending is important for pharmaceutical development. It is especially important in early phase development during API selection, and is advantageous particularly when material-sparing techniques are utilized.

  13. Cocrystallization and amorphization induced by drug-excipient interaction improves the physical properties of acyclovir.

    PubMed

    Masuda, Takaaki; Yoshihashi, Yasuo; Yonemochi, Etsuo; Fujii, Kotaro; Uekusa, Hidehiro; Terada, Katsuhide

    2012-01-17

    Although acyclovir is one of the most important antiviral drugs used today, there are several problems with its physical properties. The aim of this study is to prepare cocrystals or amorphous complex of acyclovir using drug-excipient interactions to improve the physical properties of the drug, especially its dissolution rate and transdermal absorption. Screening for formation of cocrystals and the presence of amorphous acyclovir was conducted with various pharmaceutical excipinents, with the use of the solution-crystallization method and liquid-assisted cogrinding. The potential cocrystalline phase and the amorphized complex were characterized by PXRD, TG/DTA, IR, DSC and HPLC techniques. The screening indicated that acyclovir formed novel cocrystals with tartaric acid and was amorphized with citric acid. The acyclovir-tartaric acid cocrystal (ACV-TA cocrystal) structure was determined from synchrotron X-ray powder diffraction data. T(g) of the amorphous acyclovir-citric acid compound (ACV-CA amorphous) was determined by DSC. The initial dissolution rate of the ACV-TA cocrystals was considerably faster than that of anhydrous acyclovir. In vitro skin permeation of ACV-CA amorphous from polyethylene glycol (PEG) ointment was remarkably higher than that of the crystalline acyclovir. We successfully improved the physical properties of acyclovir by the cocrystallization and amorphization techniques, using pharmaceutical excipients.

  14. Microemulsions as drug delivery systems to improve the solubility and the bioavailability of poorly water-soluble drugs.

    PubMed

    He, Cai-Xia; He, Zhong-Gui; Gao, Jian-Qing

    2010-04-01

    Microemulsions have been studied extensively as potential drug delivery vehicles for poorly water-soluble drugs. An understanding of the physicochemical and biopharmaceutical characteristics of the microemulsions according to administration routes will provide guidance for designing the formulations of microemulsions. In this paper, the use and the characteristics of microemulsions as drug delivery vehicles are reviewed. As the formulations of the microemulsion always include a great amount of surfactant and co-surfactant, which may cause hemolysis or histopathological alterations of the tissue, the potential toxicity or the irritancy of microemulsions is also discussed in this paper. Developments of microemulsions for poorly water-soluble drugs in recent years are included in this review. Several factors limiting the commercial or clinical use of microemulsions are also discussed. Considering the potential in enhanced drug uptake/permeation and facing the limitations, their unique properties make microemulsions a promising vehicle for poorly water-soluble drugs.

  15. Improving the quality of antimicrobial drug use can result in cost containment.

    PubMed

    Gyssens, I C; Kullberg, B J

    1995-09-22

    Antibiotic policies are implemented to optimize patient care, to limit antimicrobial resistance and to reduce costs. Before improving the use of antimicrobial drugs by monitoring, it is of primary importance to conduct a general utilization review to document problem areas within the hospital and to evaluate quality and costs. Subsequently, limited targets for an intervention can be defined. For the evaluation of quality, established criteria can be used to classify prescriptions into categories of appropriate use. Several classification systems are described in the literature. We have developed a classification method which allows evaluation of each relevant parameter associated with antimicrobial drug use and global (true) cost calculation. Data are processed in a computer program for Apple or Windows. Surgical prophylaxis is a target of choice to analyse at a hospital pharmacy level. Important cost savings can be obtained by implementing well-accepted standards of good antimicrobial prophylaxis.

  16. [Effectiveness of interventions for improving drug prescribing in Primary Health Care].

    PubMed

    Zavala-González, Marco Antonio; Cabrera-Pivaral, Carlos Enrique; Orozco-Valerio, María de Jesús; Ramos-Herrera, Igor Martín

    2017-01-01

    To determine the effectiveness of interventions for improving drug prescribing in Primary Health Care units. Systematic review and meta-analysis. Searches were made in MedLine(©), ScienceDirect(©), Springer(©), SciELO(©), Dialnet(©), RedALyC(©) and Imbiomed(©), in Spanish, English and Portuguese, using keywords "drug prescribing", "intervention studies" and "primary health care", indexed in each data base up to August 2014. Experimental and quasi-experimental studies were included that had a CASP-score>5 and that evaluated effect of any type intervention on the quality of drug prescription in Primary Health Care. A total of 522 articles were found, and an analysis was performed on 12 that reported 17 interventions: 64.7% educational, 23.5% incorporating pharmacists into the health team, and 11.8% on the use of computer applications. The strong "intervention/improvement" associations were educational interventions OR=2.47 (95% CI; 2.28 - 2.69), incorporation of pharmacists OR=3.28 (95% CI; 2.58 4.18), and use of computer applications OR=10.16 (95% CI; 8.81 -11.71). The use of interventions with computer applications showed to be more effective than educational interventions and incorporation pharmacists into the health team. Future studies are required that include economic variables such as, implementation costs, drug costs and other expenses associated with health care and treatment of diseases. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  17. Transglycosylated stevia and hesperidin as pharmaceutical excipients: dramatic improvement in drug dissolution and bioavailability.

    PubMed

    Uchiyama, Hiromasa; Tozuka, Yuichi; Imono, Masaaki; Takeuchi, Hirofumi

    2010-10-01

    The capability of transglycosylated materials, α-glycosyltransferase-treated stevia (Stevia-G) and α-glycosyl hesperidin (Hsp-G), to enhance the bioavailability of poorly water-soluble drugs was investigated. Spray-dried particles (SDPs) of drug/transglycosylated material, such as, flurbiprofen (FP)/Stevia-G, probucol (PRO)/Stevia-G, FP/Hsp-G, and PRO/Hsp-G were prepared. All SDPs showed pronounced improvement in both dissolution rate and apparent drug solubility. The amount of dissolved PRO was significantly improved to that of untreated PRO crystals when prepared as SDPs of PRO/Stevia-G or PRO/Hsp-G. There was no cytotoxicity to Caco-2 cells at levels of 10% Stevia-G or Hsp-G solution. Values for the area under the plasma concentration-time curve (AUC) of untreated PRO, SDPs of PRO/Hsp-G and PRO/Stevia-G after oral administration to rats were 4.94±2.06, 26.08±4.52 and 48.79±9.97μgh/mL, respectively. Interestingly, AUC values in cases of the FP system were in the order of untreated FPdrug absorption enhancement may depend on the type of transglycosylated materials used. Stevia-G, a newly investigated material for this purpose, was found to have good potential for use as a pharmaceutical excipient. Copyright © 2010 Elsevier B.V. All rights reserved.

  18. New generation antiepileptic drugs: what do they offer in terms of improved tolerability and safety?

    PubMed Central

    Gazzola, Deana M.

    2011-01-01

    Over the last two decades a total of 11 antiepileptic drugs (AEDs) have been introduced to the US market. Randomized, placebo-controlled trials have yielded information about each drug’s efficacy, tolerability, and safety profile; however, few studies have compared the newer generation AEDs directly with the older generation. Comparative studies are not always straightforward in their interpretation, as many characteristics of drugs, both favorable and unfavorable, may not be highlighted by such studies. In general, findings from the literature suggest that the newer generation AEDs (including vigabatrin, felbamate, gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, zonisamide, pregabalin, rufinamide, and lacosamide) enjoy both improved tolerability and safety compared with older agents such as phenobarbital, phenytoin, carbamazepine, and valproate. This is partially supported by some of the findings of the QSS and the TTA Committee of the American Academy of Neurology (AAN), whose review of four AEDs (gabapentin, lamotrigine, topiramate, and tiagabine) is discussed. Briefly, when compared with carbamazepine, lamotrigine was better tolerated; topiramate adverse events (AEs) were fairly comparable to carbamazepine and valproate; and tiagabine compared with placebo was associated with a higher discontinuation rate due to AEs. The findings of the SANAD trial are also presented; when administered to patients with partial epilepsy, carbamazepine was most likely to fail due to AEs, and lamotrigine and gabapentin were least likely to fail due to AEs. When administered to patients with idiopathic generalized epilepsy, topiramate was most frequently associated with AE-related discontinuation, followed by valproate; and while valproate was the most efficacious drug in this arm of the study, lamotrigine was more tolerable. What makes the SANAD study valuable and somewhat unique is its head-to-head comparison of one drug with another. Such

  19. Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

    PubMed Central

    Richey, Elizabeth A.; Lyons, E. Alison; Nebeker, Jonathan R.; Shankaran, Veena; McKoy, June M.; Luu, Thanh Ha; Nonzee, Narissa; Trifilio, Steven; Sartor, Oliver; Benson, Al B.; Carson, Kenneth R.; Edwards, Beatrice J.; Gilchrist-Scott, Douglas; Kuzel, Timothy M.; Raisch, Dennis W.; Tallman, Martin S.; West, Dennis P.; Hirschfeld, Steven; Grillo-Lopez, Antonio J.; Bennett, Charles L.

    2009-01-01

    Purpose Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. Methods We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Results Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non–orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non–orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. Conclusion AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs. PMID:19636013

  20. Withdrawal of antiepileptic drugs improves psychomotor speed after childhood epilepsy surgery.

    PubMed

    van Schooneveld, Monique M J; van Erp, Nicole; Boshuisen, Kim; Meekes, Joost; Braun, Kees P J

    2013-11-01

    This retrospective study evaluates the impact of postoperative antiepileptic drug (AED) withdrawal on psychomotor speed in seizure-free children, operated for medically refractory epilepsy. Post-surgical medication policy and neuropsychological assessments (performed shortly before and 6, 12 and 24 months after surgery), were evaluated in 57 children (32 female, median age at surgery 13 years). Patients were divided into a withdrawal (n=29) and a no-withdrawal group (n=28). Scores of four psychomotor tests performed at 12 and 24 months after surgery were compared with those of postoperative baseline measurements, performed 6 months after surgery. At 24 months, the withdrawal group had improved significantly more than the no-withdrawal group on three of four tests; reaction time to light (p=0.031), reaction time to sound (p=0.045) and tapping (p=0.003). At 12 months, a non-significant tendency in the same direction was found for both reaction time tests. Drug withdrawal after surgery improves psychomotor speed and may unleash the potential for cognitive improvement. Copyright © 2013 Elsevier B.V. All rights reserved.

  1. Improving Drug Loading of Mucosal Solvent Cast Films Using a Combination of Hydrophilic Polymers with Amoxicillin and Paracetamol as Model Drugs

    PubMed Central

    Kianfar, Farnoosh

    2013-01-01

    Solvent cast mucosal films with improved drug loading have been developed by combining carboxymethyl cellulose (CMC), sodium alginate (SA), and carrageenan (CAR) using paracetamol and amoxicillin as model drugs and glycerol (GLY) as plasticizer. Films were characterized using X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), folding resilience, swelling capacity, mucoadhesivity, and drug dissolution studies. SA, CMC, and GLY (5 : 3 : 6) films showed maximum amoxicillin loading of 26.3% whilst CAR, CMC, and GLY (1 : 2 : 3) films had a maximum paracetamol loading of 40%. XRPD analysis showed different physical forms of the drugs depending on the amount loaded. Films containing 29.4% paracetamol and 26.3% amoxicillin showed molecular dispersion of the drugs while excess paracetamol was observed on the film surface when the maximum 40% was loaded. Work of adhesion was similar for blank films with slightly higher cohesiveness for CAR and CMC based films, but the differences were significant between paracetamol and amoxicillin containing films. The stickiness and cohesiveness for drug loaded films were generally similar with no significant differences. The maximum percentage cumulative drug release was 84.65% and 70.59% for paracetamol and amoxicillin, respectively, with anomalous case two transport mechanism involving both drug diffusion and polymer erosion. PMID:23841056

  2. A Comparative Examination of two Fmoc Removal Reagents for Process Improvement to Produce Peptide Drugs

    NASA Astrophysics Data System (ADS)

    Srivastava, K.; Davis, M.

    The importance of peptides as therapeutics has been recognized since they were found responsible for a wide variety of biological functions. The recent approval of peptide drugs such as Byetta® (Amylin Pharmaceuticals, Inc.), Fuzeon® (Hoffman-LaRoche Inc.), Integrelin™ (CDR Therapeutics, Inc.), Natrecor® (SCIOS Inc.), Symlin® (Amylin), Teriparatide, and Ziconotide, etc., which demonstrated applications for treatment of such problems as bone metabolism disorders, cardiovascular diseases, diabetes, viral infections and severe chronic pain control, has further endorsed the growing interest in peptides as a potential drug. This growing trend for peptide drugs has drawn our attention for their production in a cost-effective manner. To do so, the improvement in the quality of crude peptides during synthesis, the most critical parameter in the process, is important to prevent yield losses during the more expensive purification step. To accomplish it, we decided to examine the efficacy of the commonly used nucleophilic base piperidine and non-neucleophilic base DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene) for the complete removal of Fmoc group during the synthesis of peptides. According to our investigation, application of piperidine was found more effective than DBU in solid phase synthesis. Details of the investigation will be discussed.

  3. Improving on Nature: The Role of Nanomedicine in the Development of Clinical Natural Drugs.

    PubMed

    Bilia, Anna Rita; Piazzini, Vieri; Guccione, Clizia; Risaliti, Laura; Asprea, Martina; Capecchi, Giada; Bergonzi, Maria Camilla

    2017-03-01

    Natural products have been used as a major source of drugs for millennia, and about half of the pharmaceuticals in use today are derived from natural products. However, their efficacy can be limited because of their low hydrophilicity and intrinsic dissolution rate(s), or physical/chemical instability. In addition, they can present scarce absorption, poor pharmacokinetics and bioavailability, scarce biodistribution, first-pass metabolism, trivial penetration and accumulation in the organs of the body, or low targeting efficacy. Novel nanoformulations based on drug delivery systems, namely nanoparticles, micelles, and vesicles, offer significant promise in overcoming these limitations. Nowadays, nanomedicine is crucial in developing appropriate therapeutic treatments of essential drugs, specifically antitumor and antiparasistic agents (i.e., Taxol, vincristine, camptothecin, doxorubicin, artemisinin) and other emerging molecules with pleiotropic functions (i.e., resveratrol, curcumin, salvianolic acid B, honokiol). Additionally, the number of nanoformulations developed with flavonoids, in particular rutin, quercetin, silymarin, and green tea catechins, is constantly increasing, and a significant number of publications have appeared in the last decade pertaining to nanoformulations based on extracts and essential oils. Most of these studies report very promising nanoformulations with sustained release and improved bioavailability at much lower doses than conventional preparations, and in many cases, also a better safety profile.

  4. Developmental effects of antiepileptic drugs and the need for improved regulations

    PubMed Central

    Loring, David W.

    2016-01-01

    Antiepileptic drugs (AEDs) are among the most common teratogenic drugs prescribed to women of childbearing age. AEDs can induce both anatomical (malformations) and behavioral (cognitive/behavioral deficits) teratogenicity. Only in the last decade have we begun to truly discriminate differential AED developmental effects. Fetal valproate exposure carries a special risk for both anatomical and behavioral teratogenic abnormalities, but the mechanisms and reasons for individual variability are unknown. Intermediate anatomical risks exist for phenobarbital and topiramate. Several AEDs (e.g., lamotrigine and levetiracetam) appear to possess low risks for both anatomical and behavioral teratogenesis. Despite advances in the past decade, our knowledge of the teratogenic risks for most AEDs and the underlying mechanisms remain inadequate. Further, the long-term effects of AEDs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently. Our recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of AED prescription practices for women, routine preclinical testing of all new AEDs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential AED cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for AED-induced anatomical and behavioral teratogenesis. PMID:26519545

  5. Systematic Development of Self-Emulsifying Drug Delivery Systems of Atorvastatin with Improved Bioavailability Potential

    PubMed Central

    Khan, Fariba; Islam, Md. Saiful; Roni, Monzurul Amin; Jalil, Reza-Ul

    2012-01-01

    The aim of this study was to prepare and characterize a self-emulsifying drug delivery system (SEDDS) with a high drug load of poorly water-soluble atorvastatin for the enhancement of dissolution and oral bioavailability. Solubility of atorvastatin in oil, surfactant, and cosurfactant was determined. Pseudo-ternary phase diagrams were constructed by the aqueous titration method, and formulations were developed based on the optimum excipient combinations. A high drug load (10% w/w) was achieved with a combination of oleic acid, Tween 80, and polyethylene glycol 400, ensuring the maximum dissolution property (in the case of SES6). Effects of lipids and surfactants on physical properties of SEDDS such as in vitro emulsification efficiency in terms of self-emulsification time, emulsion droplet size, and percent transmittance were measured. Multiple regression analysis revealed that a higher amount of surfactants significantly increased dissolution of ATV while decreasing emulsion droplet size and emulsification time. About a four-fold increase in dissolution was achieved by SEDDS compared to pure ATV powder. Overall, this study suggests that dissolution and oral bioavailability of ATV could be improved by SEDDS technology. PMID:23264948

  6. User-centered design improves the usability of drug-drug interaction alerts: Experimental comparison of interfaces.

    PubMed

    Luna, Daniel R; Rizzato Lede, Daniel A; Otero, Carlos M; Risk, Marcelo R; González Bernaldo de Quirós, Fernán

    2017-02-01

    Clinical Decision Support Systems can alert health professionals about drug interactions when they prescribe medications. The Hospital Italiano de Buenos Aires in Argentina developed an electronic health record with drug-drug interaction alerts, using traditional software engineering techniques and requirements. Despite enhancing the drug-drug interaction knowledge database, the alert override rate of this system was very high. We redesigned the alert system using user-centered design (UCD) and participatory design techniques to enhance the drug-drug interaction alert interface. This paper describes the methodology of our UCD. We used crossover method with realistic, clinical vignettes to compare usability of the standard and new software versions in terms of efficiency, effectiveness, and user satisfaction. Our study showed that, compared to the traditional alert system, the UCD alert system was more efficient (alerts faster resolution), more effective (tasks completed with fewer errors), and more satisfying. These results indicate that UCD techniques that follow ISO 9241-210 can generate more usable alerts than traditional design. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Improving aerosolization of drug powders by reducing powder intrinsic cohesion via a mechanical dry coating approach.

    PubMed

    Zhou, Qi Tony; Qu, Li; Larson, Ian; Stewart, Peter J; Morton, David A V

    2010-07-15

    The aim of this study was to investigate the effect of coating on the aerosolization of three model micronized powders. Three model powder materials (salbutamol sulphate, salmeterol xinafoate, triamcinolone acetonide) were chosen not only for their different chemical properties but also for their different physical properties such as shape and size distribution. Each powder was coated with 5% (w/w) magnesium stearate using two different dry mechanofusion approaches. After mechanofusion, both poured and tapped densities for all three model drug powders significantly increased. There were significant improvements in aerosolization behavior from an inhaler device for all model powders after mechanofusion. Such improvements in aerosolization were attributed to the reduction in agglomerate strength caused by decreasing powder intrinsic cohesion via surface modification. The work also indicated that the effect of the coating was dependant on the initial particle properties.

  8. Improving aerosol drug delivery during invasive mechanical ventilation with redesigned components.

    PubMed

    Longest, P Worth; Azimi, Mandana; Golshahi, Laleh; Hindle, Michael

    2014-05-01

    Patients receiving invasive mechanical ventilation with an endotracheal tube (ETT) can often benefit from pharmaceutical aerosols; however, drug delivery through the ventilator circuit is known to be very inefficient. The objective of this study was to improve the delivery of aerosol through an invasive mechanical ventilation system by redesigning circuit components using a streamlining approach. Redesigned components were the T-connector interface between the nebulizer and ventilator line and the Y-connector leading to the ETT. The streamlining approach seeks to minimize aerosol deposition and loss by eliminating sharp changes in flow direction and tubing diameter that lead to flow disruption. Both in vitro experiments and computational fluid dynamic (CFD) simulations were applied to analyze deposition and emitted dose of drug for multiple droplet size distributions, flows, and ETT sizes used in adults. The experimental results demonstrated that the streamlined components improved delivery through the circuit by factors ranging from 1.3 to 1.5 compared with a commercial system for adult ETT sizes of 8 and 9 mm. The overall delivery efficiency was based on the bimodal aspect of the aerosol distributions and could not be predicted by median diameter alone. CFD results indicated a 20-fold decrease in turbulence in the junction region for the streamlined Y resulting in a maximum 9-fold decrease in droplet deposition. The relative effectiveness of the streamlined designs was found to increase with increasing particle size and increasing flow, with a maximum improvement in emitted dose of 1.9-fold. Streamlined components can significantly improve the delivery of pharmaceutical aerosols during mechanical ventilation based on an analysis of multiple aerosol generation devices, ETT sizes, and flows.

  9. Evaluating an approach to improving the adoption rate of wireless drug library updates for smart pumps.

    PubMed

    Poppe, Lindsey B; Eckel, Stephen F

    2011-01-15

    An academic medical center's approach to improving the adoption rate of wireless drug library updates for smart pumps was evaluated. A multidisciplinary team composed of pharmacy, nursing, medical engineering, materials management, and patient equipment personnel at an academic medical center collaborated to update the drug libraries of more than 1800 smart pumps via a wireless control system. Two pilot tests were completed to identify and resolve issues before the live wireless update was attempted. The second pilot test, a passive approach, produced an adoption rate of 42% of 1804 pumps at the end of one week and a rate of 56% on day 10. The goal of 80% was not achieved until day 22. The change to an active multidisciplinary process three months later produced an adoption rate of 80% for 1869 pumps on day 10, resulting in a 45.4% increase in the adoption rate between the two trials on day 10 (p < 0.001). Communication regarding the updates was disseminated via e-mail to the entire organization, with fliers posted on all patient care units, and verbally during staff meetings. Patient equipment personnel manually tagged each pump with a blue zip tie after verifying the update to easily identify which pumps had been updated. Areas for improvement include increasing communication to the staff detailing when the update will occur and changing the day of the week the update is performed. A multidisciplinary team actively engaged in the updating of wireless i.v. smart pump drug libraries reduced the amount of time required to reach a goal adoption rate of 80%.

  10. Compulsory Licenses for Cancer Drugs: Does Circumventing Patent Rights Improve Access to Oncology Medications?

    PubMed Central

    Bognar, Cinthia Leite Frizzera Borges; Bychkovsky, Brittany L.

    2016-01-01

    Worldwide, there are enormous inequities in cancer control that cause poor outcomes among patients with cancer who live in low- and middle-income countries (LMICs). One of the biggest challenges that oncology faces today is how to increase patient access to expensive, but life-saving, therapies in LMICs. Access to cancer medications in LMICs is a major problem, especially in recent years, as the costs of these therapies continue to rise exponentially. One mechanism available to LMICs to improve access to cancer medications allows a country to pursue a compulsory license for a given drug. Here, we will review how the legal framework in the World Trade Organization's Trade-Related Aspects of Intellectual Property Rights Agreement and the Doha Declaration supports countries to circumvent patent laws and acquire compulsory licenses for essential medicines. We will also discuss the current and future role of compulsory licenses in oncology and how compulsory licenses may improve access to cancer drugs in LMICs. PMID:28717715

  11. Colloidal silver nanoparticles improve anti-leukemic drug efficacy via amplification of oxidative stress.

    PubMed

    Guo, Dawei; Zhang, Junren; Huang, Zhihai; Jiang, Shanxiang; Gu, Ning

    2015-02-01

    Recently, increased reactive oxygen species (ROS) levels and altered redox status in cancer cells have become a novel therapeutic strategy to improve cancer selectivity over normal cells. It has been known that silver nanoparticles (AgNPs) display anti-leukemic activity via ROS overproduction. Hence, we hypothesized that AgNPs could improve therapeutic efficacy of ROS-generating agents against leukemia cells. In the current study, N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid, was used as a drug model of ROS induction to investigate its synergistic effect with AgNPs. The data exhibited that AgNPs with uniform size prepared by an electrochemical method could localize in the lysosomes, mitochondria and cytoplasm of SHI-1 cells. More importantly, AgNPs together with 4-HPR could exhibit more cytotoxicity and apoptosis via overproduction of ROS in comparison with that alone. Taken together, these results reveal that AgNPs combined with ROS-generating drugs could potentially enhance therapeutic efficacy against leukemia cells, thereby providing a novel strategy for AgNPs in leukemia therapy.

  12. Avoidable interruptions during drug administration in an intensive rehabilitation ward: improvement project.

    PubMed

    Buchini, Sara; Quattrin, Rosanna

    2012-04-01

    To record the frequency of interruptions and their causes, to identify 'avoidable' interruptions and to build an improvement project to reduce 'avoidable' interruptions. In Italy each year 30,000-35,000 deaths per year are attributed to health-care system errors, of which 19% are caused by medication errors. The factors that contribute to drug management error also include interruptions and carelessness during treatment administration. A descriptive study design was used to record the frequency of interruptions and their causes and to identify 'avoidable' interruptions in an intensive rehabilitation ward in Northern Italy. A data collection grid was used to record the data over a 6-month period. A total of 3000 work hours were observed. During the study period 1170 interruptions were observed. The study identified 14 causes of interruption. The study shows that of the 14 cases of interruptions at least nine can be defined as 'avoidable'. An improvement project has been proposed to reduce unnecessary interruptions and distractions to avoid making errors. An additional useful step to reduce the incidence of treatment errors would be to implement the use of a single patient medication sheet for the recording of drug prescription, preparation and administration and also the incident reporting. © 2011 Blackwell Publishing Ltd.

  13. Efficient nuclear drug translocation and improved drug efficacy mediated by acidity-responsive boronate-linked dextran/cholesterol nanoassembly.

    PubMed

    Zhu, Jing-Yi; Lei, Qi; Yang, Bin; Jia, Hui-Zhen; Qiu, Wen-Xiu; Wang, Xuli; Zeng, Xuan; Zhuo, Ren-Xi; Feng, Jun; Zhang, Xian-Zheng

    2015-06-01

    The present study reported a lysosome-acidity-targeting bio-responsive nanovehicle self-assembled from dextran (Dex) and phenylboronic acid modified cholesterol (Chol-PBA), aiming at the nucleus-tropic drug delivery. The prominent advantage of this assembled nanoconstruction arose from its susceptibility to acidity-labile dissociation concurrently accompanied with the fast liberation of encapsulated drugs, leading to efficient nuclear drug translocation and consequently favorable drug efficacy. By elaborately exploiting NH4Cl pretreatment to interfere with the cellular endosomal acidification progression, this study clearly evidenced at a cellular level the strong lysosomal-acidity dependency of nuclear drug uptake efficiency, which was shown to be the main factor influencing the drug efficacy. The boronate-linked nanoassembly displayed nearly no cytotoxicity and can remain structural stability under the simulated physiological conditions including 10% serum and the normal blood sugar concentration. The cellular exposure to cholesterol was found to bate the cellular uptake of nanoassembly in a dose-dependent manner, suggesting a cholesterol-associated mechanism of the intracellular internalization. The in vivo antitumor assessment in xenograft mouse models revealed the significant superiority of DOX-loaded Dex/Chol-PBA nanoassembly over the controls including free DOX and the DOX-loaded non-sensitive Dex-Chol, as reflected by the more effective tumor-growth inhibition and the better systematic safety. In terms of the convenient preparation, sensitive response to lysosomal acidity and efficient nuclear drug translocation, Dex/Chol-PBA nanoassembly derived from natural materials shows promising potentials as the nanovehicle for nucleus-tropic drug delivery especially for antitumor agents. More attractively, this study offers a deeper insight into the mechanism concerning the contribution of acidity-responsive delivery to the enhanced chemotherapy performance.

  14. Best practices: an electronic drug alert program to improve safety in an accountable care environment.

    PubMed

    Griesbach, Sara; Lustig, Adam; Malsin, Luanne; Carley, Blake; Westrich, Kimberly D; Dubois, Robert W

    2015-04-01

    The accountable care organization (ACO), one of the most promising and talked about new models of care, focuses on improving communication and care transitions by tying potential shared savings to specific clinical and financial benchmarks. An important factor in meeting these benchmarks is an ACO's ability to manage medications in an environment where medical and pharmacy care has been integrated. The program described in this article highlights the critical components of Marshfield Clinic's Drug Safety Alert Program (DSAP), which focuses on prioritizing and communicating safety issues related to medications with the goal of reducing potential adverse drug events. Once the medication safety concern is identified, it is reviewed to evaluate whether an alert warrants sending prescribers a communication that identifies individual patients or a general communication to all physicians describing the safety concern. Instead of basing its decisions regarding clinician notification about drug alerts on subjective criteria, the Marshfield Clinic's DSAP uses an internally developed scoring system. The scoring system includes criteria developed from previous drug alerts, such as level of evidence, size of population affected, severity of adverse event identified or targeted, litigation risk, available alternatives, and potential for duration of medication use. Each of the 6 criteria is assigned a weight and is scored based upon the content and severity of the alert received.  In its first 12 months, the program targeted 6 medication safety concerns involving the following medications: topiramate, glyburide, simvastatin, citalopram, pioglitazone, and lovastatin. Baseline and follow-up prescribing data were gathered on the targeted medications. Follow-up review of prescribing data demonstrated that the DSAP provided quality up-to-date safety information that led to changes in drug therapy and to decreases in potential adverse drug events. In aggregate, nearly 10,000 total

  15. Increasing the use of 'smart' pump drug libraries by nurses: a continuous quality improvement project.

    PubMed

    Harding, Andrew D

    2012-01-01

    The use of infusion pumps that incorporate "smart" technology (smart pumps) can reduce the risks associated with receiving IV therapies. Smart pump technology incorporates safeguards such as a list of high-alert medications, soft and hard dosage limits, and a drug library that can be tailored to specific patient care areas. Its use can help to improve patient safety and to avoid potentially catastrophic harm associated with medication errors. But when one independent community hospital in Massachusetts switched from older mechanical pumps to smart pumps, it neglected to assign an "owner" to oversee the implementation process. One result was that nurses were using the smart pump library for only 37% of all infusions.To increase pump library usage percentage-thereby reducing the risks associated with infusion and improving patient safety-the hospital undertook a continuous quality improvement project over a four-month period in 2009. With the involvement of direct care nurses, and using quantitative data available from the smart pump software, the nursing quality and pharmacy quality teams identified ways to improve pump and pump library use. A secondary goal was to calculate the hospital's return on investment for the purchase of the smart pumps. Several interventions were developed and, on the first of each month, implemented. By the end of the project, pump library usage had nearly doubled; and the hospital had completely recouped its initial investment.

  16. An improved relaxed complex scheme for receptor flexibility in computer-aided drug design

    NASA Astrophysics Data System (ADS)

    Amaro, Rommie E.; Baron, Riccardo; McCammon, J. Andrew

    2008-09-01

    The interactions among associating (macro)molecules are dynamic, which adds to the complexity of molecular recognition. While ligand flexibility is well accounted for in computational drug design, the effective inclusion of receptor flexibility remains an important challenge. The relaxed complex scheme (RCS) is a promising computational methodology that combines the advantages of docking algorithms with dynamic structural information provided by molecular dynamics (MD) simulations, therefore explicitly accounting for the flexibility of both the receptor and the docked ligands. Here, we briefly review the RCS and discuss new extensions and improvements of this methodology in the context of ligand binding to two example targets: kinetoplastid RNA editing ligase 1 and the W191G cavity mutant of cytochrome c peroxidase. The RCS improvements include its extension to virtual screening, more rigorous characterization of local and global binding effects, and methods to improve its computational efficiency by reducing the receptor ensemble to a representative set of configurations. The choice of receptor ensemble, its influence on the predictive power of RCS, and the current limitations for an accurate treatment of the solvent contributions are also briefly discussed. Finally, we outline potential methodological improvements that we anticipate will assist future development.

  17. Improving the drug dispensing process at the National Institute of respiratory diseases by applying the six sigma methodology.

    PubMed

    Pimentel-Aguilar, A B; Aguilar-Adaya, M K; Sánchez-Castillo, E I; Ortiz-Posadas, M R

    2011-01-01

    The purpose of this work was to improve the drug dispensing process at the National Institute of Respiratory Diseases of Mexico by applying the six sigma methodology, identifying the non-value added activities as well as the areas of opportunity, in order to make proposals to ensure the supply of prescription drugs to the patient in a timely manner. Seven variables were defined and three indicators were generated, which were implemented in three clinical services of the Institute to measure the current performance of the drug distribution process. With the obtained results, a proposed set of eight improvements were subsequently implemented in a pilot program.

  18. The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes.

    PubMed

    Gribkoff, Valentin K; Kaczmarek, Leonard K

    2016-03-12

    An important goal of biomedical research is to translate basic research findings into useful medical advances. In the field of neuropharmacology this requires understanding disease mechanisms as well as the effects of drugs and other compounds on neuronal function. Our hope is that this information will result in new or improved treatment for CNS disease. Despite great progress in our understanding of the structure and functions of the CNS, the discovery of new drugs and their clinical development for many CNS disorders has been problematic. As a result, CNS drug discovery and development programs have been subjected to significant cutbacks and eliminations over the last decade. While there has been recent resurgence of interest in CNS targets, these past changes in priority of the pharmaceutical and biotech industries reflect several well-documented realities. CNS drugs in general have higher failure rates than non-CNS drugs, both preclinically and clinically, and in some areas, such as the major neurodegenerative diseases, the clinical failure rate for disease-modifying treatments has been 100%. The development times for CNS drugs are significantly longer for those drugs that are approved, and post-development regulatory review is longer. In this introduction we review some of the reasons for failure, delineating both scientific and technical realities, some unique to the CNS, that have contributed to this. We will focus on major neurodegenerative disorders, which affect millions, attract most of the headlines, and yet have witnessed the fewest successes. We will suggest some changes that, when coupled with the approaches discussed in the rest of this special volume, may improve outcomes in future CNS-targeted drug discovery and development efforts.

  19. Improvement in transdermal drug delivery performance by graphite oxide/temperature-responsive hydrogel composites with micro heater.

    PubMed

    Yun, Jumi; Lee, Dae Hoon; Im, Ji Sun; Kim, Hyung-Il

    2012-08-01

    Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater.

  20. Flavonoids and polymer derivatives as CYP3A4 inhibitors for improved oral drug bioavailability.

    PubMed

    Fasinu, Pius; Choonara, Yahya E; Khan, Riaz A; Du Toit, Lisa C; Kumar, Pradeep; Ndesendo, Valence M K; Pillay, Viness

    2013-02-01

    Molecular modeling computations were utilized to generate pharmaceutical grade CYP3A4-enzyme inhibitors. In vitro metabolism of felodipine in human intestinal and liver microsomes (HLM and HIM) was optimized yielding a Michaelis-Menten plot from where the K(m) and V(max) values were estimated by nonlinear regression. The flavonoids, naringin, naringenin, and quercetin, were subsequently incubated with felodipine at the determined K(m) value in HLM. Comparing results obtained from a known CYP3A4 inhibitor, verapamil, the flavonoids inhibited felodipine metabolism. In-depth computational analysis of these flavonoids in terms of CYP3A4 binding, sequencing, and affinity, computational biomimetism was employed to validate the potential CYP3A4 inhibitors. The modeled compounds were comparatively evaluated by incubation with felodipine in both HLM and HIM. Results showed that the polymers 8-arm-PEG, o-(2-aminoethyl)-o-methyl-PEG, 4-arm-PEG (molecular weight = 10,000 g/mol and 20,000 g/mol, respectively), and poly(l-lysine) were able to inhibit the felodipine metabolism with the half maximal inhibitory concentration (IC(50)) values ranging from 7.22 to 30.0 μM (HLM) and 5.78 to 41.03 μM (HIM). Molecular docking confirmed drug-enzyme interactions by computing the free energies of binding (ΔE) and inhibition constants (K(i)) of the docked compounds utilizing a Lamarckian Genetic Algorithm. Comparative correlations between the computed and experimental K(i) values were obtained. Computational modeling of CYP3A4 inhibitors provided a suitable strategy to screen pharmaceutical grade compounds that may potentially inhibit presystemic CYP3A4-dependent drug metabolism with the prospect of improving oral drug bioavailability. Copyright © 2012 Wiley Periodicals, Inc.

  1. Computer-assisted interventions to improve QTc documentation in patients receiving QT-prolonging drugs.

    PubMed

    Sandau, Kristin E; Sendelbach, Sue; Fletcher, Linda; Frederickson, Joel; Drew, Barbara J; Funk, Marjorie

    2015-03-01

    Many medications commonly used in hospitals can cause prolonged corrected QT interval (QTc), putting patients at risk for torsade de pointes (TdP), a potentially fatal arrhythmia. However, documentation of QTc for hospitalized patients receiving QT-prolonging medications is often not consistent with American Heart Association standards. To examine effects of education and computerized documentation enhancements on QTc documentation. A quasi-experimental multisite study among 4011 cardiac-monitored patients receiving QTc-prolonging medications within a 10-hospital health care system was conducted to compare QTc documentation before (n=1517), 3 months after (n = 1301), and 4 to 6 months after (n = 1193) an intervention. The intervention included (1) online education for 3232 nurses, (2) electronic notifications to alert nurses when a patient received at least 2 doses of a QT-prolonging medication, and (3) computerized calculation of QTc in electronic health records after nurses had documented heart rate and QT interval. QTc documentation for inpatients receiving QTc-prolonging drugs increased significantly from baseline (17.3%) to 3 months after the intervention (58.2%; P < .001) within the 10 hospitals and had increased further 4 to 6 months after the intervention (62.1%, P = .75). Patients at larger hospitals were significantly more likely to have their QTc documented (46.4%) than were patients at smaller hospitals (26.2%; P < .001). A 3-step system-wide intervention was associated with an increase in QTc documentation for patients at risk for drug-induced TdP, and improvements persisted over time. Further study is needed to assess whether increased QTc documentation decreases occurrence of drug-induced TdP. (American Journal of Critical Care. 2015;24:e6-e15). ©2015 American Association of Critical-Care Nurses.

  2. Amorphous ternary cyclodextrin nanocomposites of telmisartan for oral drug delivery: improved solubility and reduced pharmacokinetic variability.

    PubMed

    Sangwai, Mayur; Vavia, Pradeep

    2013-09-10

    Despite of advancements in dosage form design and use of multifunctional excipients, improvement in dissolution characteristics of molecules like Telmisartan (TEL) having exceedingly pH dependent and poor solubility profile is still challenging. The present research work explores an innovative particle engineering approach which synergistically coalesce two principally different solubility enhancement strategies namely ternary β-cyclodextrin complexation and top-down nanonization in a unit process. The research was aimed to improve solubility and reduce in vivo variability in pharmacokinetic parameters of TEL irrespective to physiological pH conditions. Ternary β-cyclodextrin nanocomposites of TEL were prepared with high pressure homogenization using meglumine as ternary component. TEL nanocomposites were thoroughly characterized for particle size, surface topology, surface charge, inclusion complexation, crystalinity, dissolution and in vivo pharmacokinetic performance in male wistar rats at fed and fasted state. TEL nanocomposites exhibited average particle size of 698 ± 23 nm. Remarkable improvement in in vitro dissolution characteristics in multimedia and biorelevant media was observed in comparison with plain drug and marketed formulation. Results of in vivo pharmacokinetic studies revealed that, nanocomposites effectively bypass variation in pharmacokinetic parameters at fed and fasted states with 346%, 315%, 301% and 321% increase in relative bioavailability compared to marketed formulation and pure TEL in fed and fasted conditions respectively.

  3. Improvement of pyrazolo[3,4-d]pyrimidines pharmacokinetic properties: nanosystem approaches for drug delivery

    PubMed Central

    Vignaroli, Giulia; Calandro, Pierpaolo; Zamperini, Claudio; Coniglio, Federica; Iovenitti, Giulia; Tavanti, Matteo; Colecchia, David; Dreassi, Elena; Valoti, Massimo; Schenone, Silvia; Chiariello, Mario; Botta, Maurizio

    2016-01-01

    Pyrazolo[3,4-d]pyrimidines are a class of compounds with a good activity against several cancer cell lines. Despite the promising anticancer activity, these molecules showed a poor aqueous solubility. This issue could threat the future development of pyrazolo[3,4-d]pyrimidines as clinical drug candidates. With the aim of improving their solubility profile and consequently their pharmacokinetic properties, we have chosen four compounds (1–4) on the base of their anti-neuroblastoma activity and we have developed albumin nanoparticles and liposomes for the selected candidates. Albumin nanoparticles and liposomes were prepared and characterized regarding size and ζ-potential distribution, polidispersity index, entrapment efficiency and activity against SH-SY5Y human neuroblastoma cell line. The most promising nanosystem, namely LP-2, was chosen to perform further studies: confocal microscopy, stability and drug release in physiological conditions, and biodistribution. Altogether, the obtained data strongly indicate that the encapsulation of pyrazolo[3,4-d]pyrimidines in liposomes represent an effective method to overcome the poor water solubility. PMID:26898318

  4. Diphenylether-Modified 1,2-Diamines with Improved Drug Properties for Development against Mycobacterium tuberculosis.

    PubMed

    Foss, Marie H; Pou, Sovitj; Davidson, Patrick M; Dunaj, Jennifer L; Winter, Rolf W; Pou, Sovijja; Licon, Meredith H; Doh, Julia K; Li, Yuexin; Kelly, Jane X; Dodean, Rozalia A; Koop, Dennis R; Riscoe, Michael K; Purdy, Georgiana E

    2016-07-08

    New treatments for tuberculosis infection are critical to combat the emergence of multidrug- and extensively drug-resistant Mycobacterium tuberculosis (Mtb). We report the characterization of a diphenylether-modified adamantyl 1,2-diamine that we refer to as TBL-140, which has a minimal inhibitory concentration (MIC99) of 1.2 μg/mL. TBL-140 is effective against drug-resistant Mtb and nonreplicating bacteria. In addition, TBL-140 eliminates expansion of Mtb in cell culture infection assays at its MIC. To define the mechanism of action of this compound, we performed a spontaneous mutant screen and biochemical assays. We determined that TBL-140 treatment affects the proton motive force (PMF) by perturbing the transmembrane potential (ΔΨ), consistent with a target in the electron transport chain (ETC). As a result, treated bacteria have reduced intracellular ATP levels. We show that TBL-140 exhibits greater metabolic stability than SQ109, a structurally similar compound in clinical trials for treatment of MDR-TB infections. Combined, these results suggest that TBL-140 should be investigated further to assess its potential as an improved therapeutic lead against Mtb.

  5. Neuroblastoma-targeted nanocarriers improve drug delivery and penetration, delay tumor growth and abrogate metastatic diffusion.

    PubMed

    Cossu, Irene; Bottoni, Gianluca; Loi, Monica; Emionite, Laura; Bartolini, Alice; Di Paolo, Daniela; Brignole, Chiara; Piaggio, Francesca; Perri, Patrizia; Sacchi, Angelina; Curnis, Flavio; Gagliani, Maria Cristina; Bruno, Silvia; Marini, Cecilia; Gori, Alessandro; Longhi, Renato; Murgia, Daniele; Sementa, Angela Rita; Cilli, Michele; Tacchetti, Carlo; Corti, Angelo; Sambuceti, Gianmario; Marchiò, Serena; Ponzoni, Mirco; Pastorino, Fabio

    2015-11-01

    Selective tumor targeting is expected to enhance drug delivery and to decrease toxicity, resulting in an improved therapeutic index. We have recently identified the HSYWLRS peptide sequence as a specific ligand for aggressive neuroblastoma, a childhood tumor mostly refractory to current therapies. Here we validated the specific binding of HSYWLRS to neuroblastoma cell suspensions obtained either from cell lines, animal models, or Schwannian-stroma poor, stage IV neuroblastoma patients. Binding of the biotinylated peptide and of HSYWLRS-functionalized fluorescent quantum dots or liposomal nanoparticles was dose-dependent and inhibited by an excess of free peptide. In animal models obtained by the orthotopic implant of either MYCN-amplified or MYCN single copy human neuroblastoma cell lines, treatment with HSYWLRS-targeted, doxorubicin-loaded Stealth Liposomes increased tumor vascular permeability and perfusion, enhancing tumor penetration of the drug. This formulation proved to exert a potent antitumor efficacy, as evaluated by bioluminescence imaging and micro-PET, leading to (i) delay of tumor growth paralleled by decreased tumor glucose consumption, and (ii) abrogation of metastatic spreading, accompanied by absence of systemic toxicity and significant increase in the animal life span. Our findings are functional to the design of targeted nanocarriers with potentiated therapeutic efficacy towards the clinical translation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Exploiting the Immunomodulatory Properties of Chemotherapeutic Drugs to Improve the Success of Cancer Immunotherapy

    PubMed Central

    Kersten, Kelly; Salvagno, Camilla; de Visser, Karin E.

    2015-01-01

    Cancer immunotherapy is gaining momentum in the clinic. The current challenge is to understand why a proportion of cancer patients do not respond to cancer immunotherapy, and how this can be translated into the rational design of combinatorial cancer immunotherapy strategies aimed at maximizing success of immunotherapy. Here, we discuss how tumors orchestrate an immunosuppressive microenvironment, which contributes to their escape from immune attack. Relieving the immunosuppressive networks in cancer patients is an attractive strategy to extend the clinical success of cancer immunotherapy. Since the clinical availability of drugs specifically targeting immunosuppressive cells or mediators is still limited, an alternative strategy is to use conventional chemotherapy drugs with immunomodulatory properties to improve cancer immunotherapy. We summarize the preclinical and clinical studies that illustrate how the anti-tumor T cell response can be enhanced by chemotherapy-induced relief of immunosuppressive networks. Treatment strategies aimed at combining chemotherapy-induced relief of immunosuppression and T cell-boosting checkpoint inhibitors provide an attractive and clinically feasible approach to overcome intrinsic and acquired resistance to cancer immunotherapy, and to extend the clinical success of cancer immunotherapy. PMID:26500653

  7. Improving access to high-cost cancer drugs in Latin America: Much to be done.

    PubMed

    Ruiz, Rossana; Strasser-Weippl, Kathrin; Touya, Diego; Herrero Vincent, Carmen; Hernandez-Blanquisett, Abraham; St Louis, Jessica; Bukowski, Alexandra; Goss, Paul E

    2017-04-15

    Lack of access to high-cost medications is a complex issue at the intersection of economics, medicine, politics, and ethics, and it poses a significant threat to global health care. The problem is even more significant in low- and middle-income countries, such as those in Latin America, where governments and individuals struggle to pay for products that are priced at several times the level of their per capita gross domestic product. In this review, we examine the determinants for increasing drug costs and how Latin American countries face this burgeoning crisis. We emphasize that a number of opportunities and strategies to reduce costs and improve access exist and should be identified and implemented, ideally within a regional approach with multiple stakeholders involved and based on systematic and transparent cost-effectiveness analyses. Cancer 2017;123:1313-1323. © 2016 American Cancer Society. © 2017 American Cancer Society.

  8. Factors affecting the stability of drug-loaded polymeric micelles and strategies for improvement

    NASA Astrophysics Data System (ADS)

    Zhou, Weisai; Li, Caibin; Wang, Zhiyu; Zhang, Wenli; Liu, Jianping

    2016-09-01

    Polymeric micelles (PMs) self-assembled by amphiphilic block copolymers have been used as promising nanocarriers for tumor-targeted delivery due to their favorable properties, such as excellent biocompatibility, prolonged circulation time, favorable particle sizes (10-100 nm) to utilize enhanced permeability and retention effect and the possibility for functionalization. However, PMs can be easily destroyed due to dilution of body fluid and the absorption of proteins in system circulation, which may induce drug leakage from these micelles before reaching the target sites and compromise the therapeutic effect. This paper reviewed the factors that influence stability of micelles in terms of thermodynamics and kinetics consist of the critical micelle concentration of block copolymers, glass transition temperature of hydrophobic segments and polymer-polymer and polymer-cargo interaction. In addition, some effective strategies to improve the stability of micelles were also summarized.

  9. Validity of Psoriatic Arthritis and Capture of Disease Modifying Antirheumatic Drugs in The Health Improvement Network

    PubMed Central

    Ogdie, Alexis; Alehashemi, Sara; Jon Love, Thorvardur; Jiang, Yihui; Haynes, Kevin; Hennessy, Sean; Choi, Hyon; Gelfand, Joel M.

    2014-01-01

    Purpose To examine the validity of diagnostic codes for psoriatic arthritis in The Health Improvement Network (THIN) and to examine the agreement between General Practitioner (GP) report and prescription records for Disease Modifying Antirheumatic Drugs (DMARDs). Methods Questionnaires were sent to the GPs of 100 randomly selected patients with at least one medical record code for psoriatic arthritis. The positive predictive value (PPV) for a GP confirmed diagnosis was calculated and alternative algorithms were examined to determine which method resulted in the highest PPV. Results The PPV for a single code for psoriatic arthritis was 85% (95%CI: 75.8–91.7%). Adding a prescription for a DMARD increased the PPV to 91% but with a substantial loss in sensitivity. Agreement between GPs and prescription data for use of an oral DMARD was 69%. Conclusions The diagnosis codes for psoriatic arthritis used in THIN are valid. All prescriptions for DMARDs may not be accounted for in THIN. PMID:25044030

  10. Can pharmaco-electroencephalography help improve survival of central nervous system drugs in early clinical development?

    PubMed

    Wilson, Frederick J; Leiser, Steven C; Ivarsson, Magnus; Christensen, Søren R; Bastlund, Jesper F

    2014-03-01

    Pharmaco-electroencephalography has significant yet unrealised promise as a translatable intermediate biomarker of central pharmacodynamic activity that could help reduce Phase 2 attrition in the development of central nervous system drugs. In an effort to understand its true potential, a framework for decision-making was proposed and the utility of pharmaco-electroencephalography was assessed through several case studies. A key finding was that lack of standardisation reduces the value of data pooling and meta-analyses and renders assessment of translatability difficult, limiting utility in all but simple cases. Pre-competitive collaboration is essential both to improving understanding of translation and developing modern signal processing techniques. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Synergistic role of solid lipid and porous silica in improving the oral delivery of weakly basic poorly water soluble drugs.

    PubMed

    Yasmin, Rokhsana; Rao, Shasha; Bremmell, Kristen; Prestidge, Clive

    2017-01-01

    Oral absorption of weakly basic drugs (e.g. cinnarizine (CIN)) is limited by their pH dependent precipitation in intestinal conditions. To overcome this challenge, a novel drug delivery system composed of solid lipid and porous silica, namely silica encapsulated solid lipid (SESL) particles, was developed via hot homogenization of melted lipid dispersion, followed by ultra-sonication of the silica stabilized homogenized melted lipid dispersion. Scanning electron microscope (SEM) images of the SESL formulation revealed non-spherical and aggregated hybrid particles, with rough exterior and structured nanoparticles visible on the surface. A 1.5, 2.2 and 7-fold improvement in the dissolution of CIN was observed for the SESL particles, under simulated intestinal non-digesting conditions, in comparison to the drug loaded in solid lipid (CIN-SL) matrix, drug loaded in porous silica (CIN-PS) and pure drug powder. Under simulated intestinal digestive condition, significant improvement in the drug solubilization was reported for the SESL formulation in compared to the individual drug loaded systems i.e. CIN-PS and CIN-SL. Thereby, silica encapsulated solid lipid system provides a promising oral delivery approach for poorly water soluble weakly basic drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Melt dispersion granules: formulation and evaluation to improve oral delivery of poorly soluble drugs - a case study with valsartan.

    PubMed

    Chella, Naveen; Tadikonda, Ramarao

    2015-06-01

    Solid dispersion (SD) technique is a promising strategy to improve the solubility and dissolution of BCS class II drugs. However, only few products are marketed till today based on SD technology due to poor flow properties and stability. The present work was intended to solve these problems by using combination approach, melt dispersion and surface adsorption technologies. The main aim of the present work is to improve the absorption in the stomach (at lower pH) where the absorption window exists for the drug by improving the dissolution, resulting in the enhancement of oral bioavailability of poorly soluble, weakly acidic drug with pH dependant solubility, i.e. valsartan. Melt dispersion granules were prepared in different ratios using different carriers (Gelucire 50/13, PEG 8000 and Pluronic F-68) and lactose as an adsorbent. Similarly, physical mixtures were also prepared at corresponding ratios. The prepared dispersion granules and physical mixtures were characterized by FTIR, DSC and in vitro dissolution studies. DSC studies revealed reduction in the crystallinity with a possibility of presence of amorphous character of drug in the dispersion granules. From dissolution studies, valsartan Gelucire dispersion (GSD4; 1:4 ratio) showed complete drug release in 30 min against the plain drug which showed only 11.31% of drug release in 30 min. Pharmacokinetic studies of optimized formulation in male Wistar rats showed 2.65-fold higher bioavailability and 1.47-fold higher Cmax compared to pure drug. The melt dispersion technology has the potential to improve dissolution and the bioavailability of BCS class II drugs.

  13. Changeovers of vasoactive drug infusion pumps: impact of a quality improvement program.

    PubMed

    Argaud, Laurent; Cour, Martin; Martin, Olivier; Saint-Denis, Marc; Ferry, Tristan; Goyatton, Agnes; Robert, Dominique

    2007-01-01

    Hemodynamic instability following the changeover of vasoactive infusion pump (CVIP) is a common problem in the intensive care unit. Several empiric methods are used to achieve CVIP. We hypothesized that the variation in these procedures could generate some morbidity. We sought to assess the effects of the standardization of practice, as a quality improvement program, on the CVIP-induced incidents. We performed a prospective before-and-after intervention study including all adult patients with a diagnosis of cardiovascular failure who received a continuous infusion of vasoactive drugs or inotropic drugs. After a baseline preimplementation period (phase 1), a standardized 'quick change method' of CVIP using two syringe drivers was implemented in our intensive care unit (phase 2). Endpoints (rate and distribution of incidents: variations of systolic blood pressure >20 mmHg or heart rate >20 beats/min, and arrhythmias) were registered in both 3-month phases. We studied a total of 913 CVIP events (phase 1, 435 events; phase 2, 478 events) from 43 patients. Patient characteristics were not significantly different among phases, with a majority of the patients having septic shock. The frequency of incidents was significantly (P < 0.0001) reduced in phase 2 (5.9%, n = 28) versus phase 1 (17.8%, n = 78). This effect was observed whichever catecholamine was used. More than 98% of incidents were blood pressure variations, with a similar distribution of the nature of incidents in both phases. The present study illustrates that adverse events are common following CVIP, and illustrates the positive impact of a quality improvement program to enhance inpatient safety related to this current process of care.

  14. Changeovers of vasoactive drug infusion pumps: impact of a quality improvement program

    PubMed Central

    Argaud, Laurent; Cour, Martin; Martin, Olivier; Saint-Denis, Marc; Ferry, Tristan; Goyatton, Agnes; Robert, Dominique

    2007-01-01

    Background Hemodynamic instability following the changeover of vasoactive infusion pump (CVIP) is a common problem in the intensive care unit. Several empiric methods are used to achieve CVIP. We hypothesized that the variation in these procedures could generate some morbidity. We sought to assess the effects of the standardization of practice, as a quality improvement program, on the CVIP-induced incidents. Materials and methods We performed a prospective before-and-after intervention study including all adult patients with a diagnosis of cardiovascular failure who received a continuous infusion of vasoactive drugs or inotropic drugs. After a baseline preimplementation period (phase 1), a standardized 'quick change method' of CVIP using two syringe drivers was implemented in our intensive care unit (phase 2). Endpoints (rate and distribution of incidents: variations of systolic blood pressure >20 mmHg or heart rate >20 beats/min, and arrhythmias) were registered in both 3-month phases. Results We studied a total of 913 CVIP events (phase 1, 435 events; phase 2, 478 events) from 43 patients. Patient characteristics were not significantly different among phases, with a majority of the patients having septic shock. The frequency of incidents was significantly (P < 0.0001) reduced in phase 2 (5.9%, n = 28) versus phase 1 (17.8%, n = 78). This effect was observed whichever catecholamine was used. More than 98% of incidents were blood pressure variations, with a similar distribution of the nature of incidents in both phases. Conclusion The present study illustrates that adverse events are common following CVIP, and illustrates the positive impact of a quality improvement program to enhance inpatient safety related to this current process of care. PMID:18163908

  15. Bioerodable PLGA-Based Microparticles for Producing Sustained-Release Drug Formulations and Strategies for Improving Drug Loading

    PubMed Central

    Han, Felicity Y.; Thurecht, Kristofer J.; Whittaker, Andrew K.; Smith, Maree T.

    2016-01-01

    Poly(lactic-co-glycolic acid) (PLGA) is the most widely used biomaterial for microencapsulation and prolonged delivery of therapeutic drugs, proteins and antigens. PLGA has excellent biodegradability and biocompatibility and is generally recognized as safe by international regulatory agencies including the United States Food and Drug Administration and the European Medicines Agency. The physicochemical properties of PLGA may be varied systematically by changing the ratio of lactic acid to glycolic acid. This in turn alters the release rate of microencapsulated therapeutic molecules from PLGA microparticle formulations. The obstacles hindering more widespread use of PLGA for producing sustained-release formulations for clinical use include low drug loading, particularly of hydrophilic small molecules, high initial burst release and/or poor formulation stability. In this review, we address strategies aimed at overcoming these challenges. These include use of low-temperature double-emulsion methods to increase drug-loading by producing PLGA particles with a small volume for the inner water phase and a suitable pH of the external phase. Newer strategies for producing PLGA particles with high drug loading and the desired sustained-release profiles include fabrication of multi-layered microparticles, nanoparticles-in-microparticles, use of hydrogel templates, as well as coaxial electrospray, microfluidics, and supercritical carbon dioxide methods. Another recent strategy with promise for producing particles with well-controlled and reproducible sustained-release profiles involves complexation of PLGA with additives such as polyethylene glycol, poly(ortho esters), chitosan, alginate, caffeic acid, hyaluronic acid, and silicon dioxide. PMID:27445821

  16. Solely abluminal drug release from coronary stents could possibly improve reendothelialization.

    PubMed

    Zhang, Haijun; Deng, Wei; Wang, Xiangfei; Wang, Shenguo; Ge, Junbo; Toft, Egon

    2016-09-01

    To compare a new stent with an asymmetric coating, eluting the drug to the abluminal surface, to a stent with a conventional coating eluting the drug both to the luminal and the abluminal side. Stents with asymmetric coating, eluting the drug to the vessel wall (BPSES-A), could potentially give faster reendothelialization after percutaneous coronary interventions (PCI) and decrease in in-stent thrombosis and late restenosis. BPSES-A, conventional coated stents (BPSES-C), biodegradable polymer stents without drug (BPS, for control), and bare metal stents (BMS, for control) were implanted into the coronary arteries of 38 pigs (75 stents). Pigs were sacrificed after 4, 12, and 24 weeks. Quantitative coronary angiography was used to compare in-stent late lumen loss (LLL) and electron microscopy was used to reveal levels of reendothelialization. The stents were all successfully implanted. LLL of BPSES-A, BPSES-C, BMS, and BPS were 0.56 ± 0.51, 0.60 ± 0.58, 0.89 ± 0.43, and 1.68 ± 0.30 mm, respectively, after 4 weeks. LLL of BPSES-A and BPSES-C were 0.63 ± 0.53 and 0.69 ± 0.24 mm, respectively, after 12 weeks. LLL of BPSES-A, BPSES-C, and BMS were 0.42 ± 0.15 m, 0.56 ± 0.28 mm, and 0.99 ± 0.13 mm, respectively, after 24 weeks. The scaling of reendothelialization was as follows: after 4 weeks BMS > = BPS > BPSES-A > BPSES-C, after 12 weeks BPSES-A > BPSES-C, and after 24 weeks BMS > BPSES-A > BPSES-C. Reendothelialization was better in BPSES-A than BPSES-C (P < 0.05). There was no correlation between LLL and reendothelialization (P = 0.42). Asymmetric coating of coronary stents might be helpful to improve reendothelialization. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Improving toxicity screening and drug development by using genetically defined strains.

    PubMed

    Festing, Michael F W

    2010-01-01

    According to the US Food and Drugs Administration (Food and Drug Administration (2004) Challenge and opportunity on the critical path to new medical products.) "The inability to better assess and predict product safety leads to failures during clinical development and, occasionally, after marketing". This increases the cost of new drugs as clinical trials are even more expensive than pre-clinical testing.One relatively easy way of improving toxicity testing is to improve the design of animal experiments. A fundamental principle when designing an experiment is to control all variables except the one of interest: the treatment. Toxicologist and pharmacologists have widely ignored this principle by using genetically heterogeneous "outbred" rats and mice, increasing the chance of false-negative results. By using isogenic (inbred or F1 hybrid, see Note 1) rats and mice instead of outbred stocks the signal/noise ratio and the power of the experiments can be increased at little extra cost whilst using no more animals. Moreover, the power of the experiment can be further increased by using more than one strain, as this reduces the chance of selecting one which is resistant to the test chemical. This can also be done without increasing the total number of animals by using a factorial experimental design, e.g. if the ten outbred animals per treatment group in a 28-day toxicity test were replaced by two animals of each of five strains (still ten animals per treatment group) selected to be as genetically diverse as possible, this would increase the signal/noise ratio and power of the experiment. This would allow safety to be assessed using the most sensitive strain.Toxicologists should also consider making more use of the mouse instead of the rat. They are less costly to maintain, use less test substance, there are many inbred and genetically modified strains, and it is easier to identify gene loci controlling variation in response to xenobiotics in this species.We demonstrate

  18. The upright posture improves plantar stepping and alters responses to serotonergic drugs in spinal rats

    PubMed Central

    Sławińska, Urszula; Majczyński, Henryk; Dai, Yue; Jordan, Larry M

    2012-01-01

    Recent studies on the restoration of locomotion after spinal cord injury have employed robotic means of positioning rats above a treadmill such that the animals are held in an upright posture and engage in bipedal locomotor activity. However, the impact of the upright posture alone, which alters hindlimb loading, an important variable in locomotor control, has not been examined. Here we compared the locomotor capabilities of chronic spinal rats when placed in the horizontal and upright postures. Hindlimb locomotor movements induced by exteroceptive stimulation (tail pinching) were monitored with video and EMG recordings. We found that the upright posture alone significantly improved plantar stepping. Locomotor trials using anaesthesia of the paws and air stepping demonstrated that the cutaneous receptors of the paws are responsible for the improved plantar stepping observed when the animals are placed in the upright posture. We also tested the effectiveness of serotonergic drugs that facilitate locomotor activity in spinal rats in both the horizontal and upright postures. Quipazine and (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) improved locomotion in the horizontal posture but in the upright posture either interfered with or had no effect on plantar walking. Combined treatment with quipazine and 8-OH-DPAT at lower doses dramatically improved locomotor activity in both postures and mitigated the need to activate the locomotor CPG with exteroceptive stimulation. Our results suggest that afferent input from the paw facilitates the spinal CPG for locomotion. These potent effects of afferent input from the paw should be taken into account when interpreting the results obtained with rats in an upright posture and when designing interventions for restoration of locomotion after spinal cord injury. PMID:22351637

  19. A novel approach to enhance the mucoadhesion of lipid drug nanocarriers for improved drug delivery to the buccal mucosa.

    PubMed

    Du, Joanne D; Liu, Qingtao; Salentinig, Stefan; Nguyen, Tri-Hung; Boyd, Ben J

    2014-08-25

    Targeted drug delivery to the buccal mucosa offers distinct advantages over oral delivery to the gastrointestinal tract including by-passing hepatic first-pass metabolism. However, the buccal route is often limited by low bioavailability, low drug loading and reduced residence time due to salivary excretion and clearance. To overcome these limitations, a novel mucoadhesive formulation based on liquid crystalline nanoparticles was designed. Utilising a pH induced in situ transition from a stable vesicle formulation to dispersed inverse hexagonal phase nanoparticles (hexosomes) enhanced adsorption onto the mucosal surface was enabled. Firstly, the phase behaviour of the amphiphilic lipid phytantriol (PHY) and oleic acid (OA) was assessed from pH 2-9 using small-angle X-ray scattering (SAXS) and cryo-transmission electron microscopy (cryo-TEM) to determine the appropriate composition for the vesicle to hexosome transition. The colloidal stability of the formulation was determined using turbidity studies. Dispersions comprising 30% w/w OA in PHY were able to form stable vesicles at pH 8 and transition to hexosomes when exposed to pH<7 (as encountered on the buccal mucosal surface). Subsequent ex vivo studies utilising excised porcine buccal tissue indicated significant retention of the in situ-formed PHY/OA hexosomes when compared to control DOPC vesicles (p<0.005), confirmed independently using confocal fluorescence microscopy, radioactive scintillation counting and HPLC analysis for incorporated drug. Thus, a novel approach providing a stable vesicle formulation, with in situ transformation to mucoadhesive hexosomes has been identified with the potential to enhance drug delivery to mucosal surfaces.

  20. Improving the therapeutic index in cancer therapy by using antibody-drug conjugates designed with a moderately cytotoxic drug.

    PubMed

    Govindan, Serengulam V; Cardillo, Thomas M; Rossi, Edmund A; Trisal, Preeti; McBride, William J; Sharkey, Robert M; Goldenberg, David M

    2015-06-01

    The antibody-drug conjugate (ADC), IMMU-130, of the moderately cytotoxic topoisomerase I inhibitor, SN-38, and the CEACAM5-targeted humanized antibody (mAb), labetuzumab, was evaluated in model systems of human colon carcinoma and in phase I clinical trials of heavily pretreated patients with metastatic colorectal cancer. The conjugate, designed with a near-homogeneous drug substitution of 7-8 SN-38/mAb and with a linker that released 50% of the drug in ∼20 h, showed significant antitumor effects compared to a nontargeted ADC in human tumor xenografts, which could be augmented in combination with bevacizumab. The advantage of fractionated dosing was demonstrated, with potential implications for the clinical dosing schedule. Biodistribution comparing IMMU-130 with labetuzumab showed that the conjugate cleared somewhat faster from the blood, but this did not affect tumor uptake and retention. The use of an ultrastable linker in the conjugate design abrogated antitumor effects. A tolerability study in rabbits showed a high safety margin, with no-observed-adverse-effect level (NOAEL) corresponding to a cumulative human-equivalent protein dose of 40-60 mg/kg. The preclinical findings appear to be corroborated in two phase I clinical trials, with high tolerability and evidence of antitumor activity, including objective responses. The impact of the ADC design on the utility of IMMU-130, tailored to a poorly internalizing target, is discussed.

  1. Improvement of physicochemical properties of an antiepileptic drug by salt engineering.

    PubMed

    Rahman, Ziyaur; Zidan, Ahmed S; Samy, Raghu; Sayeed, Vilayat A; Khan, Mansoor A

    2012-09-01

    The focus of the present investigation was to evaluate the feasibility of using cyclamic salt of lamotrigine in order to improve its solubility and intrinsic dissolution rate (IDR). The salt was prepared by solution crystallization method and characterized chemically by fourier transform infrared spectroscopy (FTIR), proton ((1)H) and carbon ((13)C) nuclear magnetic resonance (liquid and solid, NMR) spectroscopy, physically by powder X-ray diffraction (PXRD), thermally by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), physicochemically for solubility, IDR, solution and solid-state stability, and polymorphism by solution recrystallization and slurry conversion studies. The FTIR, NMR, PXRD, DSC, and TGA spectra and thermograms indicated the salt formation. The salt formation increased lamotrigine solubility by 19-fold and IDR by 4.9-fold in water. The solution and solid-state stability were similar to parent molecule and were resistant to polymorphic transformation. In conclusion, cyclamic salt of lamotrigine provides another potential avenue for the pharmaceutical development of lamotrigine with improved physicochemical properties especially for pediatric population. It is also possible that appropriate dosage forms can be formulated with much lower drug amount and better safety profile than existing products.

  2. An educational intervention to improve nurses' knowledge, attitude, and practice toward reporting of adverse drug reactions.

    PubMed

    Hanafi, Somayeh; Torkamandi, Hassan; Hayatshahi, Alireza; Gholami, Kheirollah; Shahmirzadi, Nikinaz Ashrafi; Javadi, Mohammad Reza

    2014-01-01

    The reporting of adverse drug reactions (ADRs) by nurses in hospitals is very important. This study was aimed at investigating the impact of an educational intervention to improve ADR reporting and whether trained nurses had better knowledge, attitude, and practice toward ADR reporting. A total of 300 nurses in a tertiary care teaching hospital in Tehran, Iran were evaluated with a knowledge, attitude, and practice (KAP) questionnaire regarding ADR reporting in March 2010. After this, an educational program about ADR was provided to nurses. Then the nurses were re-evaluated by the same questionnaire. Comparisons were made of the attitude and knowledge within nurses, before and after education. Data were analyzed using SPSS software. P < 0.05 was considered as significant level. Independent-sample t-test was used to measure the intervention effect. The response rate was 61.3% (N = 184). Knowledge of nurses before the intervention was significantly less than the knowledge after the intervention (P = 0.001). Also, there was a significant effect on attitude (P = 0.002). During the follow-up period of 4 months after the intervention, 26 spontaneous reports were received. Continuous ADR educational program, training, and integration of ADRs' reporting into the activities of the nurses would likely improve ADR reporting.

  3. A pilot randomized controlled clinical trial to improve antiepileptic drug adherence in young children with epilepsy.

    PubMed

    Modi, Avani C; Guilfoyle, Shanna M; Mann, Krista A; Rausch, Joseph R

    2016-03-01

    The primary aim was to examine the preliminary efficacy of a family tailored problem-solving intervention to improve antiepileptic drug (AED) adherence in families of children with new-onset epilepsy. Secondary aims were to assess changes in targeted mechanisms and treatment feasibility and acceptability. Fifty families (M(age) = 7.6 ± 3.0; 80% Caucasian; 42% idiopathic localization related) completed baseline questionnaires and were given an electronic monitor to observe daily AED adherence. If adherence was ≤ 95% in the first 7 months of the study, families were randomized (Supporting Treatment Adherence Regimens (STAR): n = 11; Treatment as Usual (TAU): n = 12). Twenty-one families were not randomized due to adherence being ≥95%. The STAR intervention included four face-to-face and two telephone problem-solving sessions over 8 weeks. Significant group differences in adherence were found during active intervention (weeks 4-6; TAU = -12.0 vs. STAR = 18.1, p < 0.01; and weeks session 6-8: TAU = -9.7 vs. STAR = 15.3, p < 0.05). Children who received the STAR intervention exhibited improved adherence compared to children in the TAU group during active treatment. Significant changes in epilepsy knowledge and management were noted for the STAR group. Families expressed benefitting from the STAR intervention. Future studies should include a larger sample size and booster intervention sessions to maintain treatment effects over time.

  4. Drug resistance marker-aided genome shuffling to improve acetic acid tolerance in Saccharomyces cerevisiae.

    PubMed

    Zheng, Dao-Qiong; Wu, Xue-Chang; Wang, Pin-Mei; Chi, Xiao-Qin; Tao, Xiang-Lin; Li, Ping; Jiang, Xin-Hang; Zhao, Yu-Hua

    2011-03-01

    Acetic acid existing in a culture medium is one of the most limiting constraints in yeast growth and viability during ethanol fermentation. To improve acetic acid tolerance in Saccharomyces cerevisiae strains, a drug resistance marker-aided genome shuffling approach with higher screen efficiency of shuffled mutants was developed in this work. Through two rounds of genome shuffling of ultraviolet mutants derived from the original strain 308, we obtained a shuffled strain YZ2, which shows significantly faster growth and higher cell viability under acetic acid stress. Ethanol production of YZ2 (within 60 h) was 21.6% higher than that of 308 when 0.5% (v/v) acetic acid was added to fermentation medium. Membrane integrity, higher in vivo activity of the H+-ATPase, and lower oxidative damage after acetic acid treatment are the possible reasons for the acetic acid-tolerance phenotype of YZ2. These results indicated that this novel genome shuffling approach is powerful to rapidly improve the complex traits of industrial yeast strains.

  5. Countering imbalanced datasets to improve adverse drug event predictive models in labor and delivery.

    PubMed

    Taft, L M; Evans, R S; Shyu, C R; Egger, M J; Chawla, N; Mitchell, J A; Thornton, S N; Bray, B; Varner, M

    2009-04-01

    The IOM report, Preventing Medication Errors, emphasizes the overall lack of knowledge of the incidence of adverse drug events (ADE). Operating rooms, emergency departments and intensive care units are known to have a higher incidence of ADE. Labor and delivery (L&D) is an emergency care unit that could have an increased risk of ADE, where reported rates remain low and under-reporting is suspected. Risk factor identification with electronic pattern recognition techniques could improve ADE detection rates. The objective of the present study is to apply Synthetic Minority Over Sampling Technique (SMOTE) as an enhanced sampling method in a sparse dataset to generate prediction models to identify ADE in women admitted for labor and delivery based on patient risk factors and comorbidities. By creating synthetic cases with the SMOTE algorithm and using a 10-fold cross-validation technique, we demonstrated improved performance of the Naïve Bayes and the decision tree algorithms. The true positive rate (TPR) of 0.32 in the raw dataset increased to 0.67 in the 800% over-sampled dataset. Enhanced performance from classification algorithms can be attained with the use of synthetic minority class oversampling techniques in sparse clinical datasets. Predictive models created in this manner can be used to develop evidence based ADE monitoring systems.

  6. An internal quality improvement collaborative significantly reduces hospital-wide medication error related adverse drug events.

    PubMed

    McClead, Richard E; Catt, Charline; Davis, J Terrance; Morvay, Shelly; Merandi, Jenna; Lewe, Dorcas; Stewart, Barbara; Brilli, Richard J

    2014-12-01

    To reduce the rate of harmful adverse drug events (ADEs) of severity level D-I from a baseline peak of 0.24 ADE/1000 doses to 0.08 ADE/1000 doses. A hospital-wide, quasi-experimental time series quality improvement (QI) initiative to reduce ADEs was implemented. High-reliability concepts, microsystem-based multidisciplinary teams, and QI science methods were used. ADEs were detected through a combination of voluntary reporting, trigger tool analysis, reversal agent review, and pharmacy interventions. A multidisciplinary ADE Quality Collaborative focused on medication use processes, not on specific classes of medications. Effective interventions included huddles and an ADE prevention bundle. The rate of harmful ADEs initially increased by >65% because of increased error reporting, temporally associated with the implementation of a program focused on high reliability and an improved safety culture. The quarterly rate was 0.17 ADE/1000 dispensed doses in Q1 2010. By the end of Q2 2013, the rate had decreased by 76.5%, to 0.04 ADE/1000 dispensed doses (P < .001). Using an internal collaborative model and QI methodologies focused on medication use processes, harmful ADEs were reduced hospital-wide by 76.5%. The concurrent implementation of a high-reliability, safety-focused program was important as well. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Quercetin-containing self-nanoemulsifying drug delivery system for improving oral bioavailability.

    PubMed

    Tran, Thanh Huyen; Guo, Yi; Song, Donghui; Bruno, Richard S; Lu, Xiuling

    2014-03-01

    Quercetin is a dietary flavonoid with potential chemoprotective effects, but has low bioavailability because of poor aqueous solubility and low intestinal absorption. A quercetin-containing self-nanoemulsifying drug delivery system (Q-SNEDDS) was developed to form oil-in-water nanoemulsions in situ for improving quercetin oral bioavailability. On the basis of the quercetin solubility, emulsifying ability, and stability after dispersion in an aqueous phase, an optimal SNEDDS consisting of castor oil, Tween® 80, Cremophor® RH 40, and PEG 400 (20:16:34:30, w/w) was identified. Upon mixing with water, Q-SNEDDS formed a nanoemulsion having a droplet size of 208.8 ± 4.5 nm and zeta potential of -26.3 ± 1.2 mV. The presence of Tween® 80 and PEG 400 increased quercetin solubility and maintained supersaturated quercetin concentrations (5 mg/mL) for >1 month. The optimized Q-SNEDDS significantly improved quercetin transport across a human colon carcinoma (Caco-2) cell monolayer. Fluorescence imaging demonstrated rapid absorption of the Q-SNEDDS within 40 min of oral ingestion. Following oral administration of Q-SNEDDS in rats (15 mg/kg), the area under the concentration curve and maximum concentration of plasma quercetin after 24 h increased by approximately twofold and threefold compared with the quercetin control suspension. These data suggest that this Q-SNEDDS formulation can enhance the solubility and oral bioavailability of quercetin for appropriate clinical application.

  8. Mobile phone text messaging improves antihypertensive drug adherence in the community.

    PubMed

    Varleta, Paola; Acevedo, Mónica; Akel, Carlos; Salinas, Claudia; Navarrete, Carlos; García, Ana; Echegoyen, Carolina; Rodriguez, Daniel; Gramusset, Lissette; Leon, Sandra; Cofré, Pedro; Retamal, Raquel; Romero, Katerine

    2017-09-21

    Antihypertensive drug adherence (ADA) is a mainstay in blood pressure control. Education through mobile phone short message system (SMS) text messaging could improve ADA. The authors conducted a randomized study involving 314 patients with hypertension with <6 months of antihypertensive treatment from the Preventive Health Program of 12 different primary care centers in Santiago, Chile. Patients were randomly assigned to receive or not receive SMS related to ADA and healthy lifestyle. Adherence was assessed by the self-reported four-item scale Morisky-Green-Levine questionnaire at baseline and after 6 months of follow-up, with four of four positive questions classified as good adherence. Group comparison for adherence was performed by means of a logistic regression model, adjusting by baseline adherence, age older than 60 years, and sex. A total of 163 patients were randomized to receive and 151 to not receive SMS. After 6 months of follow-up, ADA in the non-SMS group decreased from 59.3% to 51.4% (P=.1). By contrast, adherence increased from 49% to 62.3% (P=.01) in the SMS group. Text messaging intervention improved ADA (risk ratio, 1.3; 95% confidence interval, 1.0-1.6 [P<.05]). At 6-month follow-up, text messaging resulted in an increase in reporting ADA in this hypertensive Latino population. This approach could become an effective tool to overcome poor medication adherence in the community. ©2017 Wiley Periodicals, Inc.

  9. The First Decade of the National Drug Abuse Treatment Clinical Trials Network: Bridging the Gap Between Research and Practice to Improve Drug Abuse Treatment

    PubMed Central

    Tai, Betty; Straus, Michele M.; Liu, David; Sparenborg, Steven; Jackson, Ron; McCarty, Dennis

    2010-01-01

    The National Institute on Drug Abuse established the National Drug Abuse Treatment Clinical Trials Network (CTN) in 1999 to improve the quality of addiction treatment using science as the vehicle. The network brings providers from community-based drug abuse treatment programs and scientists from university-based research centers together in an alliance that fosters bi-directional communication and collaboration. Collaboration enhanced the relevance of research to practice and facilitated the development and implementation of evidence-based treatments in community practice settings. The CTN’s 20 completed trials tested pharmacological, behavioral, and integrated treatment interventions for adolescents and adults; more than 11,000 individuals participated in the trials. This paper reviews the rationale for the CTN, describes the translation of its guiding principles into research endeavors, and anticipates the future evolution of clinical research within the Network. PMID:20307794

  10. Rapid improvement of icterus and pruritus by the oral administration of colestimide in two cases of drug-induced hepatitis.

    PubMed

    Tani, M; Hayashi, Y; Okamoto, S; Yokohama, S; Inaba, M; Kubota, H; Nakamura, K

    2001-11-01

    We report two cases of drug-induced hepatitis refractory to therapy of ursodeoxycholic acid and prednisolone, who were relieved of icterus and pruritus immediately by the oral administration of colestimide. Their liver dysfunction was not improved, by withdrawal of causative drugs or by treatment with prednisolone and ursodeoxycholic acid. Colestimide (3.0 g/day), a strong basic anion-exchange resin, was orally taken before breakfast and evening meal, leading to rapid and complete relief of icterus and pruritus. These cases suggested that colestimide would be useful for patients with cholestasis in drug-induced hepatitis, because this agent has few side effects and it is easy to take.

  11. Improving the reporting of adverse drug reactions in the hospital setting.

    PubMed

    Pushkin, Richard; Frassetto, Lynda; Tsourounis, Candy; Segal, Eleanor S; Kim, Stephanie

    2010-11-01

    The US Food and Drug Administration (FDA) is perceived by the public as having a substantial responsibility to ensure drug safety; however, the FDA has limited resources for active surveillance and relies on voluntary reporting of adverse events and potential adverse drug reactions. Studies have shown that underreporting of adverse events and adverse drug reactions is widespread. Furthermore, a review of several studies demonstrates that most adverse drug reactions are reported by pharmacists and nurses, with physicians reporting the fewest. The hospital setting, with its clearly defined patient population observed around the clock, is an ideal setting in which to identify potential adverse drug reaction signals and to report them to either the drug manufacturer or the FDA. In this article we describe the present system for addressing adverse events, obstacles to reporting them, and the important role any hospital physician could play in reporting adverse events and potential adverse drug reactions.

  12. An Analysis of Mathematical Models to Improve Counter-Drug Smuggling Operations

    DTIC Science & Technology

    2014-09-01

    drugs smuggled directly into the United States (National Drug Intelligence Center, 2011). They typically smuggle cocaine, heroin , and marijuana into...and heroin to Mexican and Caribbean traffickers for distribution in the United States. Dominican TCOs in the United States have long-standing...National Drug Intelligence Center, 2011). The Dominican TCOs obtain cocaine and heroin from TCOs in Colombia and smuggle the drugs into the United

  13. Disease-modifying antirheumatic drugs improve cardiovascular autonomic neuropathy in psoriatic arthritis

    PubMed Central

    Syngle, Ashit; Verma, Inderjeet; Krishan, Pawan; Syngle, Vijaita

    2016-01-01

    Background: Cardiovascular autonomic neuropathy (CAN) is a significant risk predictor for sudden cardiac death in autoimmune rheumatic diseases. As yet, there is no therapeutic treatment of CAN in psoriatic arthritis (PsA). Even now, the impact of the most commonly employed disease-modifying antirheumatic drug (DMARD) therapy on CAN in PsA is not known. Hence, we investigated the impact of DMARDs on CAN in PsA. Methods: In this prospective, cross-sectional study, 20 patients of PsA and 20 age- and sex-matched healthy controls were recruited. CAN was diagnosed by applying the five cardiovascular reflex tests according to Ewing. Parasympathetic dysfunction was established by performing three tests: heart-rate response to deep breathing, standing, and Valsalva tests. Sympathetic dysfunction was examined by applying two tests: blood pressure response to standing, and handgrip tests. Disease severity was assessed by the 28-joint-count disease activity score (DAS-28) and the disease activity score in psoriatic arthritis (DAPSA). Results: Cardiovascular reflex tests were impaired significantly among the PsA patients compared with well-matched healthy subjects (p < 0.05). Parasympathetic dysfunction was more prominent than sympathetic dysfunction. After 12 weeks treatment, parasympathetic dysfunction (heart rate response to deep breath and standing) significantly (p < 0.05) improved in patients with PsA, while there was no significant improvement in sympathetic function. Conclusion: These study results suggests parasympathetic autonomic dysfunction is more prominent than sympathetic dysfunction in PsA. Synthetic DMARDs improved parasympathetic dysfunction in PsA. PMID:27047572

  14. Production of Inhalable Submicrometer Aerosols from Conventional Mesh Nebulizers for Improved Respiratory Drug Delivery

    PubMed Central

    Longest, P. Worth; Spence, Benjamin M.; Holbrook, Landon T.; Mossi, Karla M.; Son, Yoen-Ju; Hindle, Michael

    2012-01-01

    Submicrometer and nanoparticle aerosols may significantly improve the delivery efficiency, dissolution characteristics, and bioavailability of inhaled pharmaceuticals. The objective of this study was to explore the formation of submicrometer and nanometer aerosols from mesh nebulizers suitable for respiratory drug delivery using experiments and computational fluid dynamics (CFD) modeling. Mesh nebulizers were coupled with add-on devices to promote aerosol drying and the formation of submicrometer particles, as well as to control the inhaled aerosol temperature and relative humidity. Cascade impaction experiments were used to determine the initial mass median aerodynamic diameters of 0.1% albuterol aerosols produced by the AeroNeb commercial (4.69 μm) and lab (3.90 μm) nebulizers and to validate the CFD model in terms of droplet evaporation. Through an appropriate selection of flow rates, nebulizers, and model drug concentrations, submicrometer and nanometer aerosols could be formed with the three devices considered. Based on CFD simulations, a wire heated design was shown to overheat the airstream producing unsafe conditions for inhalation if the aerosol was not uniformly distributed in the tube cross-section or if the nebulizer stopped producing droplets. In comparison, a counter-flow heated design provided sufficient thermal energy to produce submicrometer particles, but also automatically limited the maximum aerosol outlet temperature based on the physics of heat transfer. With the counter-flow design, submicrometer aerosols were produced at flow rates of 5, 15, and 30 LPM, which may be suitable for various forms of oral and nasal aerosol delivery. Thermodynamic conditions of the aerosol stream exiting the counter-flow design were found be in a range of 21-45 °C with relative humidity greater than 40% in some cases, which was considered safe for direct inhalation and advantageous for condensational growth delivery. PMID:22707794

  15. Production of Inhalable Submicrometer Aerosols from Conventional Mesh Nebulizers for Improved Respiratory Drug Delivery.

    PubMed

    Longest, P Worth; Spence, Benjamin M; Holbrook, Landon T; Mossi, Karla M; Son, Yoen-Ju; Hindle, Michael

    2012-09-01

    Submicrometer and nanoparticle aerosols may significantly improve the delivery efficiency, dissolution characteristics, and bioavailability of inhaled pharmaceuticals. The objective of this study was to explore the formation of submicrometer and nanometer aerosols from mesh nebulizers suitable for respiratory drug delivery using experiments and computational fluid dynamics (CFD) modeling. Mesh nebulizers were coupled with add-on devices to promote aerosol drying and the formation of submicrometer particles, as well as to control the inhaled aerosol temperature and relative humidity. Cascade impaction experiments were used to determine the initial mass median aerodynamic diameters of 0.1% albuterol aerosols produced by the AeroNeb commercial (4.69 μm) and lab (3.90 μm) nebulizers and to validate the CFD model in terms of droplet evaporation. Through an appropriate selection of flow rates, nebulizers, and model drug concentrations, submicrometer and nanometer aerosols could be formed with the three devices considered. Based on CFD simulations, a wire heated design was shown to overheat the airstream producing unsafe conditions for inhalation if the aerosol was not uniformly distributed in the tube cross-section or if the nebulizer stopped producing droplets. In comparison, a counter-flow heated design provided sufficient thermal energy to produce submicrometer particles, but also automatically limited the maximum aerosol outlet temperature based on the physics of heat transfer. With the counter-flow design, submicrometer aerosols were produced at flow rates of 5, 15, and 30 LPM, which may be suitable for various forms of oral and nasal aerosol delivery. Thermodynamic conditions of the aerosol stream exiting the counter-flow design were found be in a range of 21-45 °C with relative humidity greater than 40% in some cases, which was considered safe for direct inhalation and advantageous for condensational growth delivery.

  16. Progress in the development of early diagnosis and a drug with unique pharmacology to improve cancer therapy

    PubMed Central

    Lehotzky, A.; Tőkési, N.; Gonzalez-Alvarez, I.; Merino, V.; Bermejo, M.; Orosz, F.; Lau, P.; Kovacs, G.G.; Ovádi, J.

    2008-01-01

    Cancer continues to be one of the major health and socio-economic problems worldwide, despite considerable efforts to improve its early diagnosis and treatment. The identification of new constituents as biomarkers for early diagnosis of neoplastic cells and the discovery of new type of drugs with their mechanistic actions are crucial to improve cancer therapy. New drugs have entered the market, thanks to industrial and legislative efforts ensuring continuity of pharmaceutical development. New targets have been identified, but cancer therapy and the anti-cancer drug market still partly depend on anti-mitotic agents. The objective of this paper is to show the effects of KAR-2, a potent anti-mitotic compound, and TPPP/p25, a new unstructured protein, on the structural and functional characteristics of the microtubule system. Understanding the actions of these two potential effectors on the microtubule system could be the clue for early diagnosis and improvement of cancer therapy. PMID:18644768

  17. Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs.

    PubMed

    Dahan, Arik; Hoffman, Amnon

    2008-07-02

    As a consequence of modern drug discovery techniques, there has been a consistent increase in the number of new pharmacologically active lipophilic compounds that are poorly water soluble. A great challenge facing the pharmaceutical scientist is making these molecules into orally administered medications with sufficient bioavailability. One of the most popular approaches to improve the oral bioavailability of these molecules is the utilization of a lipid based drug delivery system. Unfortunately, current development strategies in the area of lipid based delivery systems are mostly empirical. Hence, there is a need for a simplified in vitro method to guide the selection of a suitable lipidic vehicle composition and to rationalize the delivery system design. To address this need, a dynamic in vitro lipolysis model, which provides a very good simulation of the in vivo lipid digestion process, has been developed over the past few years. This model has been extensively used for in vitro assessment of different lipid based delivery systems, leading to enhanced understanding of the suitability of different lipids and surfactants as a delivery system for a given poorly water soluble drug candidate. A key goal in the development of the dynamic in vitro lipolysis model has been correlating the in vitro data of various drug-lipidic delivery system combinations to the resultant in vivo drug profile. In this paper, we discuss and review the need for this model, its underlying theory, practice and limitations, and the available data accumulated in the literature. Overall, the dynamic in vitro lipolysis model seems to provide highly useful initial guidelines in the development process of oral lipid based drug delivery systems for poorly water soluble drugs, and it predicts phenomena that occur in the pre-enterocyte stages of the intestinal absorption cascade.

  18. Improving Post-Approval Drug Safety Surveillance: Getting Better Information Sooner

    PubMed Central

    Hennessy, Sean; Strom, Brian L.

    2015-01-01

    Adverse drug events (ADEs) are an important public health concern, accounting for 5% of all hospital admissions and two-thirds of all complications occurring shortly after hospital discharge. There are often long delays between when a drug is approved and when serious ADEs are identified. Recent and ongoing advances in drug safety surveillance include establishment of government-sponsored networks of population databases, use of data mining approaches, and formal integration of diverse sources of drug safety information. These advances promise to reduce delays in identifying drug-related risks, allowing earlier identification of risks as well as reassurance about the absence of specific risks. PMID:25292435

  19. Creating a unique, multi-stakeholder Paediatric Oncology Platform to improve drug development for children and adolescents with cancer.

    PubMed

    Vassal, Gilles; Rousseau, Raphaël; Blanc, Patricia; Moreno, Lucas; Bode, Gerlind; Schwoch, Stefan; Schrappe, Martin; Skolnik, Jeffrey; Bergman, Lothar; Bradley-Garelik, Mary Brigid; Saha, Vaskar; Pearson, Andy; Zwierzina, Heinz

    2015-01-01

    Seven years after the launch of the European Paediatric Medicine Regulation, limited progress in paediatric oncology drug development remains a major concern amongst stakeholders - academics, industry, regulatory authorities, parents, patients and caregivers. Restricted increases in early phase paediatric oncology trials, legal requirements and regulatory pressure to propose early Paediatric Investigation Plans (PIPs), missed opportunities to explore new drugs potentially relevant for paediatric malignancies, lack of innovative trial designs and no new incentives to develop drugs against specific paediatric targets are some unmet needs. Better access to new anti-cancer drugs for paediatric clinical studies and improved collaboration between stakeholders are essential. The Cancer Drug Development Forum (CDDF), previously Biotherapy Development Association (BDA), with Innovative Therapy for Children with Cancer Consortium (ITCC), European Society for Paediatric Oncology (SIOPE) and European Network for Cancer Research in Children and Adolescents (ENCCA) has created a unique Paediatric Oncology Platform, involving multiple stakeholders and the European Union (EU) Commission, with an urgent remit to improve paediatric oncology drug development. The Paediatric Oncology Platform proposes to recommend immediate changes in the implementation of the Regulation and set the framework for its 2017 revision; initiatives to incentivise drug development against specific paediatric oncology targets, and repositioning of drugs not developed in adults. Underpinning these changes is a strategy for mechanism of action and biology driven selection and prioritisation of potential paediatric indications rather than the current process based on adult cancer indications. Pre-competitive research and drug prioritisation, early portfolio evaluation, cross-industry cooperation and multi-compound/sponsor trials are being explored, from which guidance for innovative trial designs will be

  20. Polyelectrolyte Complex Based Interfacial Drug Delivery System with Controlled Loading and Improved Release Performance for Bone Therapeutics

    PubMed Central

    Vehlow, David; Schmidt, Romy; Gebert, Annett; Siebert, Maximilian; Lips, Katrin Susanne; Müller, Martin

    2016-01-01

    An improved interfacial drug delivery system (DDS) based on polyelectrolyte complex (PEC) coatings with controlled drug loading and improved release performance was elaborated. The cationic homopolypeptide poly(l-lysine) (PLL) was complexed with a mixture of two cellulose sulfates (CS) of low and high degree of substitution, so that the CS and PLL solution have around equal molar charged units. As drugs the antibiotic rifampicin (RIF) and the bisphosphonate risedronate (RIS) were integrated. As an important advantage over previous PEC systems this one can be centrifuged, the supernatant discarded, the dense pellet phase (coacervate) separated, and again redispersed in fresh water phase. This behavior has three benefits: (i) Access to the loading capacity of the drug, since the concentration of the free drug can be measured by spectroscopy; (ii) lower initial burst and higher residual amount of drug due to removal of unbound drug and (iii) complete adhesive stability due to the removal of polyelectrolytes (PEL) excess component. It was found that the pH value and ionic strength strongly affected drug content and release of RIS and RIF. At the clinically relevant implant material (Ti40Nb) similar PEC adhesive and drug release properties compared to the model substrate were found. Unloaded PEC coatings at Ti40Nb showed a similar number and morphology of above cultivated human mesenchymal stem cells (hMSC) compared to uncoated Ti40Nb and resulted in considerable production of bone mineral. RIS loaded PEC coatings showed similar effects after 24 h but resulted in reduced number and unhealthy appearance of hMSC after 48 h due to cell toxicity of RIS.

  1. Probiotic B420 and prebiotic polydextrose improve efficacy of antidiabetic drugs in mice.

    PubMed

    Stenman, Lotta K; Waget, Aurélie; Garret, Céline; Briand, François; Burcelin, Rémy; Sulpice, Thierry; Lahtinen, Sampo

    2015-01-01

    Gut microbiota is now known to control glucose metabolism. Previous studies have shown that probiotics and prebiotics may improve glucose metabolism, but their effects have not been studied in combination with drug therapy. The aim of this study was to investigate whether probiotics and prebiotics combined with drug therapy affect diabetic outcomes. Two different study designs were used to test gut microbiota modulating treatments with metformin (MET) or sitagliptin (SITA) in male C57Bl/6J mice. In Design 1, diabetes was induced with four-week feeding with a ketogenic, 72 kcal% fat diet with virtually no carbohydrates. Mice were then randomly divided into four groups (n = 10 in each group): (1) vehicle, (2) Bifidobacterium animalis ssp. lactis 420 (B420) (10(9) CFU/day), (3) MET (2 mg/mL in drinking water), or (4) MET + B420 (same doses as in the MET and B420 groups). After another 4 weeks, glucose metabolism was assessed with a glucose tolerance test. Fasting glucose, fasting insulin and HOMA-IR were also assessed. In Design 2, mice were fed the same 72 kcal% fat diet to induce diabetes, but they were simultaneously treated within their respective groups (n = 8 in each group): (1) non-diabetic healthy control, (2) vehicle, (3) SITA [3 mg/(kg*day)] (4) SITA with prebiotic polydextrose (PDX) (0.25 g/day), (5) SITA with B420 (10(9) CFU/day), and (6) SITA + PDX + B420. Glucose metabolism was assessed at 4 weeks, and weight development was monitored for 6 weeks. In Design 1, with low-dose metformin, mice treated with B420 had a significantly lower glycemic response (area under the curve) (factorial experiment, P = 0.002) and plasma glucose concentration (P = 0.02) compared to mice not treated with B420. In Design 2, SITA + PDX reduced glycaemia in the oral glucose tolerance test significantly more than SITA only (area under the curve reduced 28 %, P < 0.0001). In addition, B420, PDX or B420+PDX, together with SITA, further decreased fasting

  2. Lipid nanoparticles with no surfactant improve oral absorption rate of poorly water-soluble drug.

    PubMed

    Funakoshi, Yuka; Iwao, Yasunori; Noguchi, Shuji; Itai, Shigeru

    2013-07-15

    A pharmacokinetic study was performed in rats to evaluate the oral absorption ratios of nanoparticle suspensions containing the poorly water-soluble compound nifedipine (NI) and two different types of lipids, including hydrogenated soybean phosphatidylcholine and dipalmitoylphosphatidylglycerol. NI-lipid nanoparticle (LN) suspensions with a mean particle size of 48.0 nm and a zeta potential of -57.2 mV were prepared by co-grinding combined with a high-pressure homogenization process. The oral administration of NI-LN suspensions to rats led to a significant increase in the NI plasma concentration, and the area under the curve (AUC) value was found to be 108 min μg mL⁻¹, indicating a 4-fold increase relative to the NI suspensions. A comparison of the pharmacokinetic parameters of the NI-LN suspensions with those of the NI solution prepared using only the surfactant polysorbate 80 revealed that although the AUC and bioavailability (59%) values were almost identical, a rapid absorption rate was still observed in the NI-LN suspensions. These results therefore indicated that lipid nanoparticles prepared using only two types of phospholipid with a mean particle size of less than 50 nm could improve the absorption of the poorly water-soluble drug. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Therapeutic strategies to improve drug delivery across the blood-brain barrier

    PubMed Central

    Azad, Tej D.; Pan, James; Connolly, Ian D.; Remington, Austin; Wilson, Christy M.; Grant, Gerald A.

    2015-01-01

    Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB’s physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it. PMID:25727231

  4. Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug-bile interaction.

    PubMed

    Takemura, Shigeo; Kondo, Hiromu; Watanabe, Shunsuke; Sako, Kazuhiro; Ogawara, Ken-Ichi; Higaki, Kazutaka

    2013-09-01

    The aim of this study was to find out polymeric compounds that can inhibit the interaction between YM466, a novel anticoagulant, and bile to improve its oral bioavailability. In vitro ultrafiltration method using extract gall powder was useful to detect the formation of insoluble complex of YM466 with bile and also used to select a polymer that can inhibit the interaction between YM466 and bile. The in vitro studies revealed that aminoalkylmethacrylate (AAM) copolymer E, a polymethacrylate, dose-dependently inhibited the interaction between YM466 and bile and that this polymer could interact with bile salt, but not with YM466, possibly by electrostatic and/or hydrophobic interactions. The coadministration of AAM copolymer E with YM466 to rats dose-dependently increased the plasma concentration of YM466 and it was found that the oral dose of the polymer three times of YM466 (polymer to drug ratio in weight, P-D ratio, 3) significantly increased AUC0-1 h of YM466 to 2.6-fold of that of YM466 alone. Considering the condition of therapeutic use of YM466 and the maximum tolerated dose of the polymer, the formulation of P-D ratio 3 would be clinically practical and promising from the viewpoint of safety.

  5. Neural basis for the ability of atypical antipsychotic drugs to improve cognition in schizophrenia.

    PubMed

    Sumiyoshi, Tomiki; Higuchi, Yuko; Uehara, Takashi

    2013-10-16

    Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of schizophrenia. It is noteworthy that atypical antipsychotic drugs (AAPDs), e.g., clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. A novel strategy for cognitive enhancement in psychosis may be benefited by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT1A agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g., event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some AAPDs acting directly or indirectly on 5-HT1A receptors. These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia.

  6. Neural Basis for the Ability of Atypical Antipsychotic Drugs to Improve Cognition in Schizophrenia

    PubMed Central

    Sumiyoshi, Tomiki; Higuchi, Yuko; Uehara, Takashi

    2013-01-01

    Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of schizophrenia. It is noteworthy that atypical antipsychotic drugs (AAPDs), e.g., clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. A novel strategy for cognitive enhancement in psychosis may be benefited by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT1A agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g., event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some AAPDs acting directly or indirectly on 5-HT1A receptors. These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia. PMID:24137114

  7. Nanoparticle Drug Delivery Systems Designed to Improve Cancer Vaccines and Immunotherapy

    PubMed Central

    Fan, Yuchen; Moon, James J.

    2015-01-01

    Recent studies have demonstrated great therapeutic potential of educating and unleashing our own immune system for cancer treatment. However, there are still major challenges in cancer immunotherapy, including poor immunogenicity of cancer vaccines, off-target side effects of immunotherapeutics, as well as suboptimal outcomes of adoptive T cell transfer-based therapies. Nanomaterials with defined physico-biochemical properties are versatile drug delivery platforms that may address these key technical challenges facing cancer vaccines and immunotherapy. Nanoparticle systems have been shown to improve targeted delivery of tumor antigens and therapeutics against immune checkpoint molecules, amplify immune activation via the use of new stimuli-responsive or immunostimulatory materials, and augment the efficacy of adoptive cell therapies. Here, we review the current state-of-the-art in nanoparticle-based strategies designed to potentiate cancer immunotherapies, including cancer vaccines with subunit antigens (e.g., oncoproteins, mutated neo-antigens, DNA and mRNA antigens) and whole-cell tumor antigens, dendritic cell-based vaccines, artificial antigen-presenting cells, and immunotherapeutics based on immunogenic cell death, immune checkpoint blockade, and adoptive T-cell therapy. PMID:26350600

  8. The economics of direct-to-consumer advertising of prescription-only drugs: prescribed to improve consumer welfare?

    PubMed

    Morgan, Steven; Mintzes, Barbara; Barer, Morris

    2003-10-01

    According to economic theory, one might expect that the informational content of direct-to-consumer advertising of prescription-only drugs would improve consumers' welfare. However, contrasting the models of consumer and market behaviour underlying this theory with the realities of the prescription-only drug market reveals that this market is distinct in ways that render it unlikely that advertising will serve an unbiased and strictly informative function. A review of qualitative evidence regarding the informational content of drug advertising supports this conclusion. Direct-to-consumer prescription drug advertising concentrates on particular products, and features of those products, to the exclusion of others, and the information provided has frequently been found to be biased or misleading in regulatory and academic evaluations. Governments that have so far resisted direct-to-consumer advertising should invest in independent sources of evidence that could help consumers and professionals to better understand the risks and benefits of treating disease with alternative drug and non-drug therapies, rather than permitting direct-to-consumer prescription drug advertising.

  9. Simple PCR Assays Improve the Sensitivity of HIV-1 Subtype B Drug Resistance Testing and Allow Linking of Resistance Mutations

    PubMed Central

    Johnson, Jeffrey A.; Li, Jin-Fen; Wei, Xierong; Lipscomb, Jonathan; Bennett, Diane; Brant, Ashley; Cong, Mian-er; Spira, Thomas; Shafer, Robert W.; Heneine, Walid

    2007-01-01

    Background The success of antiretroviral therapy is known to be compromised by drug-resistant HIV-1 at frequencies detectable by conventional bulk sequencing. Currently, there is a need to assess the clinical consequences of low-frequency drug resistant variants occurring below the detection limit of conventional genotyping. Sensitive detection of drug-resistant subpopulations, however, requires simple and practical methods for routine testing. Methodology We developed highly-sensitive and simple real-time PCR assays for nine key drug resistance mutations and show that these tests overcome substantial sequence heterogeneity in HIV-1 clinical specimens. We specifically used early wildtype virus samples from the pre-antiretroviral drug era to measure background reactivity and were able to define highly-specific screening cut-offs that are up to 67-fold more sensitive than conventional genotyping. We also demonstrate that sequencing the mutation-specific PCR products provided a direct and novel strategy to further detect and link associated resistance mutations, allowing easy identification of multi-drug-resistant variants. Resistance mutation associations revealed in mutation-specific amplicon sequences were verified by clonal sequencing. Significance Combined, sensitive real-time PCR testing and mutation-specific amplicon sequencing provides a powerful and simple approach that allows for improved detection and evaluation of HIV-1 drug resistance mutations. PMID:17653265

  10. Nanoparticle-based drug delivery to improve the efficacy of antiretroviral therapy in the central nervous system

    PubMed Central

    Gomes, Maria João; Neves, José das; Sarmento, Bruno

    2014-01-01

    Antiretroviral drug therapy plays a cornerstone role in the treatment of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome patients. Despite obvious advances over the past 3 decades, new approaches toward improved management of infected individuals are still required. Drug distribution to the central nervous system (CNS) is required in order to limit and control viral infection, but the presence of natural barrier structures, in particular the blood–brain barrier, strongly limits the perfusion of anti-HIV compounds into this anatomical site. Nanotechnology-based approaches may help providing solutions for antiretroviral drug delivery to the CNS by potentially prolonging systemic drug circulation, increasing the crossing and reducing the efflux of active compounds at the blood–brain barrier, and providing cell/tissue-targeting and intracellular drug delivery. After an initial overview on the basic features of HIV infection of the CNS and barriers to active compound delivery to this anatomical site, this review focuses on recent strategies based on antiretroviral drug-loaded solid nanoparticles and drug nanosuspensions for the potential management of HIV infection of the CNS. PMID:24741312

  11. Improvement of drug delivery by hyperthermia treatment using magnetic cubic cobalt ferrite nanoparticles

    NASA Astrophysics Data System (ADS)

    Dey, Chaitali; Baishya, Kaushik; Ghosh, Arup; Goswami, Madhuri Mandal; Ghosh, Ajay; Mandal, Kalyan

    2017-04-01

    In this study, we report a novel synthesis method, characterization and application of a new class of ferromagnetic cubic cobalt ferrite magnetic nanoparticles (MNPs) for hyperthermia therapy and temperature triggered drug release. The MNPs are characterized by XRD, TEM, FESEM, AC magnetic hysteresis and VSM. These MNPs were coated with folic acid and loaded with an anticancer drug. The drug release studies were done at two different temperatures (37 °C and 44 °C) with progress of time. It was found that higher release of drug took place at elevated temperature (44 °C). We have developed a temperature sensitive drug delivery system which releases the heat sensitive drug selectively as the particles are heated up under AC magnetic field and controlled release is possible by changing the external AC magnetic field.

  12. A modified emulsion gelation technique to improve buoyancy of hydrogel tablets for floating drug delivery systems.

    PubMed

    Yom-Tov, Ortal; Seliktar, Dror; Bianco-Peled, Havazelet

    2015-10-01

    The use of buoyant or floating hydrogel tablets is of particular interest in the sustained release of drugs to the stomach. They have an ability to slow the release rates of drugs by prolonging their absorption window in the upper part of the gastrointestinal (GI) tract. In this study we synthesized bioactive hydrogels that have sustainable release rates for drugs in the stomach based on a hydrogel preparation technique that employs emulsifying surfactants. The emulsion gelation technique, which encapsulates oil droplets within the hydrogels during crosslinking, was used to decrease their specific gravity in aqueous environments, resulting in floating drug release depots. Properties such as swelling, buoyancy, density and drug release were manipulated by changing the polymer concentrations, surfactant percentages and the oil:polymer ratios. The relationship between these properties and the hydrogel's floating lag time was documented. The potential for this material to be used as a floating drug delivery system was demonstrated.

  13. Quantitative evaluation and optimization of co-drugging to improve anti-HIV latency therapy

    PubMed Central

    Wong, Victor C.; Fong, Linda E.; Adams, Nicholas M.; Xue, Qiong; Dey, Siddharth S.; Miller-Jensen, Kathryn

    2014-01-01

    Human immunodeficiency virus 1 (HIV) latency remains a significant obstacle to curing infected patients. One promising therapeutic strategy is to purge the latent cellular reservoir by activating latent HIV with latency-reversing agents (LRAs). In some cases, co-drugging with multiple LRAs is necessary to activate latent infections, but few studies have established quantitative criteria for determining when co-drugging is required. Here we systematically quantified drug interactions between histone deacetylase inhibitors and transcriptional activators of HIV and found that the need for co-drugging is determined by the proximity of latent infections to the chromatin-regulated viral gene activation threshold at the viral promoter. Our results suggest two classes of latent viral integrations: those far from the activation threshold that benefit from co-drugging, and those close to the threshold that are efficiently activated by a single drug. Using a primary T cell model of latency, we further demonstrated that the requirement for co-drugging was donor dependent, suggesting that the host may set the level of repression of latent infections. Finally, we showed that single drug or co-drugging doses could be optimized, via repeat stimulations, to minimize unwanted side effects while maintaining robust viral activation. Our results motivate further study of patient-specific latency-reversing strategies. PMID:26191086

  14. Effectiveness of combinations of Ayurvedic drugs in alleviating drug toxicity and improving quality of life of cancer patients treated with chemotherapy.

    PubMed

    Deshmukh, Vineeta; Kulkarni, Arvind; Bhargava, Sudhir; Patil, Tushar; Ramdasi, Vijay; Gangal, Sudha; Godse, Vasanti; Datar, Shrinivas; Gujar, Shweta; Sardeshmukh, Sadanand

    2014-11-01

    This study was conducted to assess the effectiveness of combinations of Ayurvedic drugs in alleviating the toxicity of chemotherapy and improving the quality of life of cancer patients. The following was the research question: Can Ayurvedic drugs be used to alleviate the side effects of chemotherapy and improve the quality of life of cancer patients? Random patients with malignancies of different tissues, grades, and stages were divided into two groups according to their treatment modality. Group 1 consisted of 15 patients treated with six cycles of chemotherapy alone and who did not receive any Ayurvedic drugs (control group). Group 2 consisted of patients (divided into three arms) who received Ayurvedic drugs during chemotherapy and after chemotherapy. Nineteen patients in arm 1 received the Ayurvedic drugs Mauktikyukta Kamdudha (MKD) and Mauktikyukta Praval Panchamruta (MPP) along with a full course of chemotherapy. Fifteen patients in arm 2 received the same Ayurvedic treatment, but the treatment was started after completing the sixth cycle of chemotherapy. Eighteen patients in arm 3 received the Suvarnabhasmadi formulation (SBD) in addition to MKD and MPP after completing the sixth cycle of chemotherapy. Treatment was given for 16 weeks in all three arms. Patients from both groups were observed for a period of 6 months. The assessment criteria depended on Common Toxicity Criteria (CTC designed by NIH and NCI): haemogram; weight; physical examination including Quality of Life Questionnaire (QLQ designed by the European Organization of Research and Treatment of Cancer (EORTC)) for functional, symptom and global scores; and Karnofsky score for assessment of general well-being and activities of daily life. ECOG (Eastern Cooperation Oncology Group) score was also additionally included for assessment of symptoms. From amongst the symptomatic criteria, there was significant improvement in all the three arms compared with the control group in nausea, loss of appetite

  15. Design and evaluation of novel interferon lambda analogs with enhanced antiviral activity and improved drug attributes

    PubMed Central

    Yu, Debin; Zhao, Mingzhi; Dong, Liwei; Zhao, Lu; Zou, Mingwei; Sun, Hetong; Zhang, Mengying; Liu, Hongyu; Zou, Zhihua

    2016-01-01

    Type III interferons (IFNs) (also called IFN-λ: IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4) are critical players in the defense against viral infection of mucosal epithelial cells, where the activity of type I IFNs is weak, and unlike type I IFNs that are associated with severe and diverse side effects, type III IFNs cause minimal side effects due to the highly restricted expression of their receptors, and thus appear to be promising agents for the treatment and prevention of respiratory and gastrointestinal viral infection. However, the antiviral potency of natural type III IFNs is weak compared to type I and, although IFN-λ3 possesses the highest bioactivity among the type III IFNs, IFN-λ1, instead of IFN-λ3, is being developed as a therapeutic drug due to the difficulty to express IFN-λ3 in the prokaryotic expression system. Here, to develop optimal IFN-λ molecules with improved drug attributes, we designed a series of IFN-λ analogs by replacing critical amino acids of IFN-λ1 with the IFN-λ3 counterparts, and vice versa. Four of the designed analogs were successfully expressed in Escherichia coli with high yield and were easily purified from inclusion bodies. Interestingly, all four analogs showed potent activity in inducing the expression of the antiviral genes MxA and OAS and two of them, analog-6 and -7, displayed an unexpected high potency that is higher than that of type I IFN (IFN-α2a) in activating the IFN-stimulated response element (ISRE)-luciferase reporter. Importantly, both analog-6 and -7 effectively inhibited replication of hepatitis C virus in Huh-7.5.1 cells, with an IC50 that is comparable to that of IFN-α2a; and consistent with the roles of IFN-λ in mucosal epithelia, both analogs potently inhibited replication of H3N2 influenza A virus in A549 cells. Together, these studies identified two IFN-λ analogs as candidates to be developed as novel antiviral biologics. PMID:26792983

  16. A Guided Interview Process to Improve Student Pharmacists' Identification of Drug Therapy Problems

    PubMed Central

    Miller, Michael J.; Koenigsfeld, Carrie; Haack, Sally; Hegge, Karly; McCleeary, Erin

    2011-01-01

    Objective To measure agreement between advanced pharmacy practice experience students using a guided interview process and experienced clinical pharmacists using standard practices to identify drug therapy problems. Methods Student pharmacists enrolled in an advanced pharmacy practice experience (APPE) and clinical pharmacists conducted medication therapy management interviews to identify drug therapy problems in elderly patients recruited from the community. Student pharmacists used a guided interview tool, while clinical pharmacists' interviews were conducted using their usual and customary practices. Student pharmacists also were surveyed to determine their perceptions of the interview tool. Results Fair to moderate agreement was observed on student and clinical pharmacists' identification of 4 of 7 drug therapy problems. Of those, agreement was significantly higher than chance for 3 drug therapy problems (adverse drug reaction, dosage too high, and needs additional drug therapy) and not significant for 1 (unnecessary drug therapy). Students strongly agreed that the interview tool was useful but agreed less strongly on recommending its use in practice. Conclusions The guided interview process served as a useful teaching aid to assist student pharmacists to identify drug therapy problems. PMID:21451770

  17. Optimization of drug loading to improve physical stability of paclitaxel-loaded long-circulating liposomes.

    PubMed

    Kannan, Vinayagam; Balabathula, Pavan; Divi, Murali K; Thoma, Laura A; Wood, George C

    2015-01-01

    The effect of formulation and process parameters on drug loading and physical stability of paclitaxel-loaded long-circulating liposomes was evaluated. The liposomes were prepared by hydration-extrusion method. The formulation parameters such as total lipid content, cholesterol content, saturated-unsaturated lipid ratio, drug-lipid ratio and process parameters such as extrusion pressure and number of extrusion cycles were studied and their impact on drug loading and physical stability was evaluated. A proportionate increase in drug loading was observed with increase in the total phospholipid content. Cholesterol content and saturated lipid content in the bilayer showed a negative influence on drug loading. The short-term stability evaluation of liposomes prepared with different drug-lipid ratios demonstrated that 1:60 as the optimum drug-lipid ratio to achieve a loading of 1-1.3 mg/mL without the risk of physical instability. The vesicle size decreased with an increase in the extrusion pressure and number of extrusion cycles, but no significant trends were observed for drug loading with changes in process pressure or number of cycles. The optimization of formulation and process parameters led to a physically stable formulation of paclitaxel-loaded long-circulating liposomes that maintain size, charge and integrity during storage.

  18. Risk Management Plans: are they a tool for improving drug safety?

    PubMed

    Frau, Serena; Font Pous, Maria; Luppino, Maria Rosa; Conforti, Anita

    2010-08-01

    In 2005, new European legislation authorised Regulatory Agencies to require drug companies to submit a risk management plan (RMP) comprising detailed commitments for post-marketing pharmacovigilance. The aim of the study is to describe the characteristics of RMP for 15 drugs approved by the European Medicines Agency (EMA) and their impact on post-marketing safety issues. Of the 90 new Chemical Entities approved through a centralised procedure by the EMA during 2006 and 2007, 15 of them were selected and their safety aspects and relative RMPs analysed. All post-marketing communications released for safety reasons related to these drugs were also considered. A total of 157 safety specifications were established for the drugs assessed. Risk minimisation activities were foreseen for 5 drugs as training activities. Post-marketing safety issues emerged for 12 of them, leading to 39 type II variations in Summary of Product Characteristics (SPC). Nearly half of such variations, 19 (49%), concerned safety aspects not envisaged by the RMPs. Besides this, 9 Safety Communications were published for 6 out of 15 drugs assessed. The present study reveals several critical points on the way RMPs have been implemented. Several activities proposed by the RMPs do not appear to be adequate in dealing with the potential risks of drugs. Poor communication of risk to practitioners and to the public, and above all limited transparency for the total assessment of risk, seem to transform RMPs into a tool to reassure the public when inadequately evaluated drugs are granted premature marketing authorisation.

  19. Improvement of the bitter taste of drugs by complexation with cyclodextrins: applications, evaluations and mechanisms.

    PubMed

    Arima, Hidetoshi; Higashi, Taishi; Motoyama, Keiichi

    2012-05-01

    Drugs having bitter tastes cause low patient compliance. Many taste-masking techniques such as physical barrier coatings, chemical modification and sensory masking have been developed. Among chemical modification, the inclusion complexation of drugs with cyclodextrins (CyDs) can provide the effective bitter taste-masking effects without complicated formulation and/or delayed dissolution of drugs. Herein, we describe some quantitative methods to evaluate the taste-masking effects of CyD complexes with drugs in solution and the solid state. In addition, we introduce the recent applications of CyDs to excipients for taste masking against various bitter-taste drugs, as well as discuss the possible mechanisms for the taste-masking effect of CyD complexation.

  20. Strategies to improve delivery of anticancer drugs across the blood–brain barrier to treat glioblastoma

    PubMed Central

    Oberoi, Rajneet K.; Parrish, Karen E.; Sio, Terence T.; Mittapalli, Rajendar K.; Elmquist, William F.; Sarkaria, Jann N.

    2016-01-01

    Glioblastoma (GBM) is a lethal and aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. Molecularly targeted agents hold great promise in treating these genetically heterogeneous tumors, yet have produced disappointing results. One reason for the clinical failure of these novel therapies can be the inability of the drugs to achieve effective concentrations in the invasive regions beyond the bulk tumor. In this review, we describe the influence of the blood–brain barrier on the distribution of anticancer drugs to both the tumor core and infiltrative regions of GBM. We further describe potential strategies to overcome these drug delivery limitations. Understanding the key factors that limit drug delivery into brain tumors will guide future development of approaches for enhanced delivery of effective drugs to GBM. PMID:26359209

  1. Strategies for improving adherence to antiepileptic drug treatment in people with epilepsy.

    PubMed

    Al-Aqeel, Sinaa; Gershuni, Olga; Al-Sabhan, Jawza; Hiligsmann, Mickael

    2017-02-03

    Poor adherence to antiepileptic medication is associated with increased mortality, morbidity and healthcare costs. In this review, we focus on interventions designed and tested in randomised controlled trials and quasi-randomised controlled trials to assist people with adherence to antiepileptic medication. This is an updated version of the original Cochrane review published in the Cochrane Library, Issue 1, 2010. To determine the effectiveness of interventions aimed at improving adherence to antiepileptic medication in adults and children with epilepsy. For the latest update, on 4 February 2016 we searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 4 February 2016), CINAHL Plus (EBSCOhost 1937 to 4 February 2016), PsycINFO (EBSCOhost 1887 to 4 February 2016), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. We also searched the reference lists of relevant articles. Randomised and quasi-randomised controlled trials of adherence-enhancing interventions aimed at people with a clinical diagnosis of epilepsy (as defined in individual studies), of any age and treated with antiepileptic drugs in a primary care, outpatient or other community setting. All review authors independently assessed lists of potentially relevant citations and abstracts. At least two review authors independently extracted data and performed quality assessment of each study according to the Cochrane tool for assessing risk of bias. We graded the level of evidence for each outcome according to the GRADE working group scale.The studies differed widely according to the type of intervention and measures of adherence; therefore combining data was not appropriate. We included 12 studies reporting data on 1642 participants (intervention = 833, control = 809). Eight studies targeted adults with epilepsy, one study included participants

  2. Next generation sequencing improves detection of drug resistance mutations in infants after PMTCT failure.

    PubMed

    Fisher, Randall G; Smith, Davey M; Murrell, Ben; Slabbert, Ruhan; Kirby, Bronwyn M; Edson, Clair; Cotton, Mark F; Haubrich, Richard H; Kosakovsky Pond, Sergei L; Van Zyl, Gert U

    2015-01-01

    Next generation sequencing (NGS) allows the detection of minor variant HIV drug resistance mutations (DRMs). However data from new NGS platforms after Prevention-of-Mother-to-Child-Transmission (PMTCT) regimen failure are limited. To compare major and minor variant HIV DRMs with Illumina MiSeq and Life Technologies Ion Personal Genome Machine (PGM) in infants infected despite a PMTCT regimen. We conducted a cross-sectional study of NGS for detecting DRMs in infants infected despite a zidovudine (AZT) and Nevirapine (NVP) regimen, before initiation of combination antiretroviral therapy. Sequencing was performed on PCR products from plasma samples on PGM and MiSeq platforms. Bioinformatic analyses were undertaken using a codon-aware version of the Smith-Waterman mapping algorithm and a mixture multinomial error filtering statistical model. Of 15 infants, tested at a median age of 3.4 months after birth, 2 (13%) had non-nucleoside reverse transcriptase inhibitor (NNRTI) DRMs (K103N and Y181C) by bulk sequencing, whereas PGM detected 4 (26%) and MiSeq 5 (30%). NGS enabled the detection of additional minor variant DRMs in the infant with K103N. Coverage and instrument quality scores were higher with MiSeq, increasing the confidence of minor variant calls. NGS followed by bioinformatic analyses detected multiple minor variant DRMs in HIV-1 RT among infants where PMTCT failed. The high coverage of MiSeq and high read quality improved the confidence of identified DRMs and may make this platform ideal for minor variant detection. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Advent of Novel Phosphatidylcholine-Associated Nonsteroidal Anti-Inflammatory Drugs with Improved Gastrointestinal Safety

    PubMed Central

    Lim, Yun Jeong; Dial, Elizabeth J.

    2013-01-01

    The mucosa of the gastrointestinal (GI) tract exhibits hydrophobic, nonwettable properties that protect the underlying epithelium from gastric acid and other luminal toxins. These biophysical characteristics appear to be attributable to the presence of an extracellular lining of surfactant-like phospholipids on the luminal aspects of the mucus gel layer. Phosphatidylcholine (PC) represents the most abundant and surface-active form of gastric phospholipids. PC protected experimental rats from a number of ulcerogenic agents and/or conditions including nonsteroidal anti-inflammatory drugs (NSAIDs), which are chemically associated with PC. Moreover, preassociating a number of the NSAIDs with exogenous PC prevented a decrease in the hydrophobic characteristics of the mucus gel layer and protected rats against the injurious GI side effects of NSAIDs while enhancing and/or maintaining their therapeutic activity. Bile plays an important role in the ability of NSAIDs to induce small intestinal injury. NSAIDs are rapidly absorbed from the GI tract and, in many cases, undergo enterohepatic circulation. Thus, NSAIDs with extensive enterohepatic cycling are more toxic to the GI tract and are capable of attenuating the surface hydrophobic properties of the mucosa of the lower GI tract. Biliary PC plays an essential role in the detoxification of bile salt micelles. NSAIDs that are secreted into the bile injure the intestinal mucosa via their ability to chemically associate with PC, which forms toxic mixed micelles and limits the concentration of biliary PC available to interact with and detoxify bile salts. We have worked to develop a family of PC-associated NSAIDs that appear to have improved GI safety profiles with equivalent or better therapeutic efficacy in both rodent model systems and pilot clinical trials. PMID:23423874

  4. Improving cancer treatment with cyclotron produced radionuclides. [Multiple Drug Resistance (MDR)

    SciTech Connect

    Larson, S.M.; Finn, R.D.

    1990-10-15

    The overall objective of this work was to promote nuclear medicine applications in oncology. This is being done by improving the scientific basis of diagnosis, treatment and treatment follow-up with cyclotron-produced tracers. For diagnostic use, positron-emitting isotopes such as Ga-66 and I-124 are being used. Initial studies on the characterization of He-4 particle energies required for Ga-66 production have been completed. Parameters for I-124 radiolabelling of monoclonal antibodies have been determined; the labelled antibodies have been used in animal studies using positron emission tomography (PET) to quantify antibody concentration within tumors in vivo. Imaging physics studies have demonstrated that I-124 can be quantitatively imaged by PET, even in the presence of 100-told greater concentrations of I-131. Measurement of concentrations of label in vivo has been accomplished in nuclei mice bearing neuroblastoma tumors and nude rats bearing human ovarian cancer cells. These studies have major implications for both the quantification of dosimetry and quantification kinetic assessment of anti-tumor antibody localization in vivo. For treatment of tumors, F-18 has been incorporated in 2-fluoro-2-deoxy glucose and 5-fluoro uridine, and O-15 labelled water has been produced. Reagents incorporating C-11 and N-13 are under development. In a related area, C-14 labelled colchicine is being studied as a means of assaying cells for multiple drug resistance (MDR). Cells expressing MDR are shown to retain significantly less C-14 colchiene. This suggest that colchiene retention may be of useful probe in modelling and studying MDR development in human tumors. The precursor required for producing C-11 colchicine has also been synthesized. 11 refs. (MHB)

  5. An injectable hybrid nanoparticle-in-oil-in-water submicron emulsion for improved delivery of poorly soluble drugs.

    PubMed

    Wang, Shuo; Wang, Hua; Liang, Wenquan; Huang, Yongzhuo

    2012-04-13

    Poor drugability problems are commonly seen in a class of chemical entities with poor solubility in water and oil, and moreover, physicochemical instability of these compounds poses extra challenges in design of dosage forms. Such problems contribute a significant high failure rate in new drug development. A hybrid nanoparicle-in-oil-in-water (N/O/W) submicron emulsion was proposed for improved delivery of poorly soluble and unstable drugs (e.g., dihydroartemisinin (DHA)). DHA is known for its potent antimalarial effect and antitumor activity. However, its insolubility and instability impose big challenges for formulations, and so far, no injectable dosage forms are clinically available yet. Therefore, an injectable DHA N/O/W system was developed. Unlike other widely-explored systems (e.g., liposomes, micelles, and emulsions), in which low drug load and only short-term storage are often found, the hybrid submicron emulsion possesses three-fold higher drug-loading capacity than the conventional O/W emulsion. Of note, it can be manufactured into a freeze-drying form and can render its storage up to 6 months even in room temperature. The in vivo studies demonstrated that the PK profiles were significantly improved, and this injectable system was effective in suppressing tumor growth. The strategy provides a useful solution to effective delivery of such a class of drugs.

  6. Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons.

    PubMed

    Chokshi, Rina J; Zia, Hossein; Sandhu, Harpreet K; Shah, Navnit H; Malick, Waseem A

    2007-01-01

    The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.

  7. An injectable hybrid nanoparticle-in-oil-in-water submicron emulsion for improved delivery of poorly soluble drugs

    NASA Astrophysics Data System (ADS)

    Wang, Shuo; Wang, Hua; Liang, Wenquan; Huang, Yongzhuo

    2012-04-01

    Poor drugability problems are commonly seen in a class of chemical entities with poor solubility in water and oil, and moreover, physicochemical instability of these compounds poses extra challenges in design of dosage forms. Such problems contribute a significant high failure rate in new drug development. A hybrid nanoparicle-in-oil-in-water (N/O/W) submicron emulsion was proposed for improved delivery of poorly soluble and unstable drugs (e.g., dihydroartemisinin (DHA)). DHA is known for its potent antimalarial effect and antitumor activity. However, its insolubility and instability impose big challenges for formulations, and so far, no injectable dosage forms are clinically available yet. Therefore, an injectable DHA N/O/W system was developed. Unlike other widely-explored systems (e.g., liposomes, micelles, and emulsions), in which low drug load and only short-term storage are often found, the hybrid submicron emulsion possesses three-fold higher drug-loading capacity than the conventional O/W emulsion. Of note, it can be manufactured into a freeze-drying form and can render its storage up to 6 months even in room temperature. The in vivo studies demonstrated that the PK profiles were significantly improved, and this injectable system was effective in suppressing tumor growth. The strategy provides a useful solution to effective delivery of such a class of drugs.

  8. Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery.

    PubMed

    Boshuisen, Kim; van Schooneveld, Monique M J; Uiterwaal, Cuno S P M; Cross, J Helen; Harrison, Sue; Polster, Tilman; Daehn, Marion; Djimjadi, Sarina; Yalnizoglu, Dilek; Turanli, Guzide; Sassen, Robert; Hoppe, Christian; Kuczaty, Stefan; Barba, Carmen; Kahane, Philippe; Schubert-Bast, Susanne; Reuner, Gitta; Bast, Thomas; Strobl, Karl; Mayer, Hans; de Saint-Martin, Anne; Seegmuller, Caroline; Laurent, Agathe; Arzimanoglou, Alexis; Braun, Kees P J

    2015-07-01

    Antiepileptic drugs (AEDs) have cognitive side effects that, particularly in children, may affect intellectual functioning. With the TimeToStop (TTS) study, we showed that timing of AED withdrawal does not majorly influence long-term seizure outcomes. We now aimed to evaluate the effect of AED withdrawal on postoperative intelligence quotient (IQ), and change in IQ (delta IQ) following pediatric epilepsy surgery. We collected IQ scores of children from the TTS cohort with both pre- and postoperative neuropsychological assessments (NPAs; n = 301) and analyzed whether reduction of AEDs prior to the latest NPA was related to postoperative IQ and delta IQ, using linear regression analyses. Factors previously identified as independently relating to (delta) IQ, and currently identified predictors of (delta) IQ, were considered possible confounders and used for adjustment. Additionally, we adjusted for a compound propensity score that contained previously identified determinants of timing of AED withdrawal. Mean interval to the latest NPA was 19.8 ± 18.9 months. Reduction of AEDs at the latest NPA significantly improved postoperative IQ and delta IQ (adjusted regression coefficient [RC] = 3.4, 95% confidence interval [CI] = 0.6-6.2, p = 0.018 and RC = 4.5, 95% CI = 1.7-7.4, p = 0.002), as did complete withdrawal (RC = 4.8, 95% CI = 1.4-8.3, p = 0.006 and RC = 5.1, 95% CI = 1.5-8.7, p = 0.006). AED reduction also predicted ≥ 10-point IQ increase (p = 0.019). The higher the number of AEDs reduced, the higher was the IQ (gain) after surgery (RC = 2.2, 95% CI = 0.6-3.7, p = 0.007 and RC = 2.6, 95% CI = 1.0-4.2, p = 0.001, IQ points per AED reduced). Start of AED withdrawal, number of AEDs reduced, and complete AED withdrawal were associated with improved postoperative IQ scores and gain in IQ, independent of other determinants of cognitive outcome. © 2015 American Neurological Association.

  9. Improved prediction of salvage antiretroviral therapy outcomes using ultrasensitive HIV-1 drug resistance testing.

    PubMed

    Pou, Christian; Noguera-Julian, Marc; Pérez-Álvarez, Susana; García, Federico; Delgado, Rafael; Dalmau, David; Álvarez-Tejado, Miguel; Gonzalez, Dimitri; Sayada, Chalom; Chueca, Natalia; Pulido, Federico; Ibáñez, Laura; Rodríguez, Cristina; Casadellà, Maria; Santos, José R; Ruiz, Lidia; Clotet, Bonaventura; Paredes, Roger

    2014-08-15

    The clinical relevance of ultrasensitive human immunodeficiency virus type 1 (HIV-1) genotypic resistance testing in antiretroviral treatment (ART)-experienced individuals remains unknown. This was a retrospective, multicentre, cohort study in ART-experienced, HIV-1-infected adults who initiated salvage ART including, at least 1 ritonavir-boosted protease inhibitor, raltegravir or etravirine. Presalvage ART Sanger and 454 sequencing of plasma HIV-1 were used to generate separate genotypic sensitivity scores (GSS) using the HIVdb, ANRS, and REGA algorithms. Virological failure (VF) was defined as 2 consecutive HIV-1 RNA levels ≥200 copies/mL at least 12 weeks after salvage ART initiation, whereas subjects remained on the same ART. The ability of Sanger and 454-GSS to predict VF was assessed by receiver operating characteristic (ROC) curves and survival analyses. The study included 132 evaluable subjects; 28 (21%) developed VF. Using HIVdb, 454 predicted VF better than Sanger sequencing in the ROC curve analysis (area under the curve: 0.69 vs 0.60, Delong test P = .029). Time to VF was shorter for subjects with 454-GSS < 3 vs 454-GSS ≥ 3 (Log-rank P = .003) but not significantly different between Sanger-GSS < 3 and ≥3. Factors independently associated with increased risk of VF in multivariate Cox regression were a 454-GSS < 3 (HR = 4.6, 95 CI, [1.5, 14.0], P = .007), and the number of previous antiretrovirals received (HR = 1.2 per additional drug, 95 CI, [1.1, 1.3], P = .001). Equivalent findings were obtained with the ANRS and REGA algorithms. Ultrasensitive HIV-1 genotyping improves GSS-based predictions of virological outcomes of salvage ART relative to Sanger sequencing. This may improve the clinical management of ART-experienced subjects living with HIV-1. NCT01346878. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. Polyamidoamine dendrimers as novel potential absorption enhancers for improving the small intestinal absorption of poorly absorbable drugs in rats.

    PubMed

    Lin, Yulian; Fujimori, Takeo; Kawaguchi, Naoko; Tsujimoto, Yuiko; Nishimi, Mariko; Dong, Zhengqi; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

    2011-01-05

    Effects of polyamidoamine (PAMAM) dendrimers on the intestinal absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. 5(6)-Carboxyfluorescein (CF), fluorescein isothiocyanate-dextrans (FDs) with various molecular weights, calcitonin and insulin were used as model drugs of poorly absorbable drugs. The absorption of CF, FD4 and calcitonin from the rat small intestine was significantly enhanced in the presence of PAMAM dendrimers. The absorption-enhancing effects of PAMAM dendrimers for improving the small intestinal absorption of CF were concentration and generation dependent and a maximal absorption-enhancing effect was observed in the presence of 0.5% (w/v) G2 PAMAM dendrimer. However, G2 PAMAM dendrimer had almost no absorption-enhancing effect on the small intestinal absorption of macromolecular drugs including FD10 and insulin. Overall, the absorption-enhancing effects of G2 PAMAM dendrimer in the small intestine decreased as the molecular weights of drug increased. However, G2 PAMAM dendrimer did not enhance the intestinal absorption of these drugs with different molecular weights in the large intestine. Furthermore, we evaluated the intestinal membrane damage with or without G2 PAMAM dendrimer. G2 PAMAM dendrimer (0.5% (w/v)) significantly increased the activities of lactate dehydrogenase (LDH) and the amounts of protein released from the intestinal membranes, but the activities and amounts of these toxic markers were less than those in the presence of 3% Triton X-100 used as a positive control. Moreover, G2 PAMAM dendrimer at concentrations of 0.05% (w/v) and 0.1% (w/v) did not increase the activities and amounts of these toxic markers. These findings suggested that PAMAM dendrimers at lower concentrations might be potential and safe absorption enhancers for improving absorption of poorly absorbable drugs from the small intestine.

  11. Measuring Adverse Drug Events on Hospital Medicine Units with the Institute for Healthcare Improvement Trigger Tool: A Chart Review

    PubMed Central

    Lau, Iris; Kirkwood, Allison

    2014-01-01

    Background: An adverse drug event (ADE) is a noxious, unintended response to a drug, occurring at doses used in humans for prophylaxis, diagnosis, or treatment of disease or for modification of physiological function. ADEs account for about one-quarter of all adverse events in Canadian hospitals. Canadian data on specific types of ADEs and commonly implicated drugs are lacking. In particular, there is a paucity of data on ADEs that occur during hospital admissions. Objectives: The primary objective was to identify the incidence of ADEs in a sample of adult general medicine inpatients over a 1-year period. The secondary objective was to identify the 5 drugs most frequently responsible for ADEs in this setting. Methods: A retrospective chart analysis was conducted for general medicine patients discharged from St Paul’s Hospital in Vancouver, British Columbia, from January to December 2011. ADEs were identified using the Institute for Healthcare Improvement (IHI) Trigger Tool for Measuring Adverse Drug Events. The Naranjo criteria were applied to assess causality, and a physician independently authenticated the ADEs for preventability and harm using the categories of harm set out by the US National Coordinating Council for Medication Error Reporting and Prevention. Results: Of the 204 patient encounters reviewed, 15 involved ADEs, which represented an incidence of 7% over the 1-year study period. The 5 drugs most frequently implicated in ADEs were vancomycin, ciprofloxacin, ceftriaxone, piperacillin–tazobactam, and moxifloxacin. Conclusions: The rate of ADEs during hospital admissions was substantial. These events may necessitate additional investigations and interventions and may prolong the hospital stay. The authors do not recommend the IHI Trigger Tool for Measuring Adverse Drug Events for efficient prospective detection of ADEs in manual chart reviews. Possible modifications to improve the utility of this tool might include incorporating it into a compatible

  12. Improving the detection limits of antispasmodic drugs electrodes by using modified membrane sensors with inner solid contact.

    PubMed

    Ibrahim, Hosny; Issa, Y M; Abu-Shawish, Hazem M

    2007-05-09

    Three coated wire electrodes (CWEs) for the antispasmodic drugs; dicyclomine (Dc), mebeverine (Mv) and drotaverine (Dv) hydrochlorides were developed. Each electrode based on ion-associate of a heteropoly anion with the drug cation incorporated in membrane sensor modified with graphite and deposited on silver internal solid contact. The influence of addition of graphite to the membranes and the type of the internal solid contact on the potentiometric responses of the electrodes was investigated. The characteristics of the new electrodes were compared to the characteristics of previously reported traditional liquid inner contact electrodes of the same drugs. The lower detection limits of the proposed electrodes were somewhat better than those observed with the corresponding liquid contact ISEs and reached (1.2-2.0)x10(-7)M. The potentiometric selectivity of the CWEs revealed a significant improvement and much faster response times compared to the liquid contact ISEs. The practical utility of each electrode has been demonstrated by using it successfully in potentiometric determination of its respective drug in pharmaceutical preparations both in batch and flow injection conditions. Each electrode was also used as an indicator electrode in the potentiometric titration of the drug against standard silicotungstic acid and in potentiometric determination of the drug concentration in urine samples.

  13. Improving the dissolution rate of hydrophobic drugs through encapsulation in porous lactose as a new biocompatible porous carrier.

    PubMed

    Ebrahimi, Amirali; Saffari, Morteza; Langrish, Timothy

    2017-04-15

    T he dissolution rates of indomethacin (IMC) and nifedipine (NIF) as poorly water-soluble model drugs have been significantly improved by encapsulating their molecules in the porous structure of engineered-particles of lactose as a new biocompatible porous carrier. The formulation method used in this study utilized a template-based spray-drying technique for in-situ production of porous lactose followed by two solvent-based drug-loading methods: (i) adsorption from organic solution, and (ii) incipient wetness impregnation to incorporate the drugs inside the porous lactose. In both cases, the results of DSC and XRD have revealed the deposition of nano-sized crystals of drugs inside the nanopores due to the nanoconfinement phenomenon. Greater extents of drug loadings have been achieved during the indomethacin adsorption due to the hydrogen-bonding interaction with the surface of lactose, as determined by FTIR spectroscopy. The in vitro release studies in simulated gastric fluid (SGF) have shown faster release rates for the impregnated particles compared with drug-loaded particles via the adsorption method. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Preparation and characterization of TAM-loaded HPMC/PAN composite fibers for improving drug-release profiles.

    PubMed

    Shen, Xiaxia; Yu, Dengguang; Zhang, Xiaofei; Branford-White, Christopher; Zhu, Limin

    2011-01-01

    The present paper reports the preparation and characterization of composite hydroxypropyl methylcellulose/polyacrylonitrile (HPMC/PAN)-medicated fibers via a wet spinning technique. Tamoxifen (TAM) was selected as a model drug. Numerous analyses were conducted to characterize the mechanical, structure and morphology properties of the composite fibers. The drug content and in vitro dissolution behavior were also investigated. SEM images showed that the TAM-loaded HPMC/PAN composite fibers had a finger-like outer skin and a porous structure. FT-IR spectra demonstrated that there was a good compatibility between polymer and drug. Results from X-ray diffraction and DSC suggested that most of the incorporated TAM was evenly distributed in the fiber matrix in an amorphous state, except for a minority that aggregated on the surface of fibers. The drug content in the fibers was lower than that in the spinning solution and about 10% of TAM was lost during spinning process. In vitro dissolution results indicated that, compared to TAM-PAN fibers, HPMC/PAN composite systems had weaker initial burst release effects and more drug-loading. The combination of hydrophilic polymer HPMC with PAN could improve the performance of polymer matrix composite fibers in regulating the drug-release profiles.

  15. Ursodeoxycholic Acid Can Improve Liver Transaminase Quantities in Children with Anticonvulsant Drugs Hepatotoxicity: a Pilot Study.

    PubMed

    Asgarshirazi, Masoumeh; Shariat, Mamak; Dalili, Hosein; Keihanidoost, Zarrin

    2015-01-01

    The present study has been directed to investigate Ursodeoxycholic Acid (UDCA) effect in children, to reduce the high Liver transaminases induced by Anticonvulsant drugs (drug induced hepatitis). This idea has been driven from Cytoprotective and antioxidant properties of UDCA to be used in drug induced inflammation in Liver. Twenty two epileptic patients aged between 4 mo - 3 yr whom were under anticonvulsant therapy with drugs such as valperoic acid, primidone, levetiracetam, Phenobarbital or any combination of them and had shown Liver transaminases rise , after rule out of Viral-Autoimmune, Metabolic and Anatomic causes, have been prescribed UDCA in dose of 10-15 mg/kg/day, at least for 6 months. Any patient who have shown confusing factors such as genetic disorders with liver involvement or spontaneous decline in enzymes or had not treatment compliance has been excluded from the study. Transaminases range changes as well as Probable side effects of the drug have been monitored. The results indicated that UDCA is effective and well tolerable in the children with drug induced hyper transaminasemia. No side effect has been seen and recorded in this study. Based on this study and its results, we recommend UDCA as a safe and effective choice in drug induced hepatotoxicities.

  16. Modulation of electrostatic interactions to improve controlled drug delivery from nanogels.

    PubMed

    Mauri, Emanuele; Chincarini, Giulia M F; Rigamonti, Riccardo; Magagnin, Luca; Sacchetti, Alessandro; Rossi, Filippo

    2017-03-01

    The synthesis of nanogels as devices capable to maintain the drug level within a desired range for a long and sustained period of time is a leading strategy in controlled drug delivery. However, with respect to the good results obtained with antibodies and peptides there are a lot of problems related to the quick and uncontrolled diffusion of small hydrophilic molecules through polymeric network pores. For these reasons research community is pointing toward the use of click strategies to reduce release rates of the linked drugs to the polymer chains. Here we propose an alternative method that considers the electrostatic interactions between polymeric chains and drugs to tune the release kinetics from nanogel network. The main advantage of these systems lies in the fact that the carried drugs are not modified and no chemical reactions take place during their loading and release. In this work we synthesized PEG-PEI based nanogels with different protonation degrees and the release kinetics with charged and uncharged drug mimetics (sodium fluorescein, SF, and rhodamine B, RhB) were studied. Moreover, also the effect of counterion used to induce protonation was taken into account in order to build a tunable drug delivery system able to provide multiple release rates with the same device.

  17. Preparation and Characterization of Self-Microemulsifying Drug Delivery System of Olmesartan Medoxomil for Bioavailability Improvement

    PubMed Central

    Prajapati, Shailesh T.; Joshi, Harsh A.; Patel, Chhaganbhai N.

    2013-01-01

    Olmesartan medoxomil (OLM) is an angiotensin II receptor blocker (ARB) antihypertensive agent administered orally that has absolute bioavailability of only 26% due to the poor aqueous solubility (7.75 μg/ml). The aim of the present investigation was to develop a self-microemulsifying drug delivery system (SMEDDS) to enhance the oral absorption of OLM. The solubility of OLM in various oils, surfactants, and cosurfactants was determined. Pseudoternary phase diagrams were constructed using Acrysol EL 135, Tween 80, Transcutol P, and distilled water to identify the efficient self-microemulsification region. Prepared SMEDDS was further evaluated for its emulsification time, drug content, optical clarity, droplet size, zeta potential, in vitro dissolution, and in vitro and ex vivo drug diffusion study. The optimized formulation S2 contained OLM (20 mg), Tween 80 (33%v/v), Transcutol P (33%v/v), and Acrysol EL 135 (34%v/v) had shown the smallest particle size, maximum solubility, less emulsification time, good optical clarity, and in vitro release. The in vitro and ex vivo diffusion rate of the drug from the SMEDDS was significantly higher than that of the plain drug suspension. It was concluded that SMEDDS would be a promising drug delivery system for poorly water-soluble drugs by the oral route. PMID:26555991

  18. Using multiple cause-of-death data to improve surveillance of drug-related mortality

    PubMed Central

    Nordstrom, David L.; Yokoi-Shelton, Mieko L.; Zosel, Amy

    2015-01-01

    Context Many state and local areas are affected by the national epidemic of drug-related mortality, which recently has shown signs of a rising licit-to-illicit drug death ratio. Appropriate local public health surveillance can help to monitor and control this epidemic. Objective Using our state as an example, we sought to illustrate how to describe the changes in drug death rates, causes, and circumstances. In contrast to most other surveillance reports, our approach includes both drug-induced and drug-related deaths and both demographic and socioeconomic decedent characteristics. Design Cross-sectional study. Setting All residents of the State of Wisconsin. Participants Decedents from 1999–2008. Main outcome measure Annual numbers and population-based rates of deaths due to drugs, including both identified and unidentified drugs. Information was obtained from death certificates with any of approximately 270 underlying, immediate, or contributing cause of death codes from the International Classification of Diseases 10th Revision. Results Drug-related death rates increased during much of the 10-year study period, and the ratio of male to female deaths rose. The median age at death from drug-related causes was 43 years. Opioid analgesic poisoning surpassed cocaine and heroin poisoning as the most frequent type of fatal drug poisoning. Of all 4828 deaths from drug-related causes--virtually all of which were certified by a county medical examiner or coroner--3,410 (71%) were unintentional, and 1,053 (22%) were suicide. The unintentional-to-suicide death rate ratio grew from 1.6 to 3.5 during the study period. Methadone-related deaths increased from 10 in 1999 to 118 in 2008 (1080%), while benzodiazepine-related deaths rose from 23 to 106 (361%). Conclusions Although premature deaths from drug use and abuse continue to rise, in some states even surpassing motor vehicle crash deaths, multiple cause of death information from death certificates is available to monitor

  19. Improving drug discovery with high-content phenotypic screens by systematic selection of reporter cell lines

    PubMed Central

    Wu, Qi; Liu, Shanshan; Coster, Adam D.; Posner, Bruce A.; Altschuler, Steven J.; Wu, Lani F.

    2015-01-01

    High-content, image-based screens enable the identification of compounds that induce cellular responses similar to those of known drugs but through different chemical structures or targets. A central challenge in designing phenotypic screens is choosing suitable imaging biomarkers. Here we present a method for systematically identifying optimal reporter cell lines for annotating compound libraries (ORACLs), whose phenotypic profiles most accurately classify a training set of known drugs. We generate a library of fluorescently tagged reporter cell lines, and let analytical criteria determine which among them—the ORACL—best classifies compounds into multiple, diverse drug classes. We demonstrate that an ORACL can functionally annotate large compound libraries across diverse drug classes in a single-pass screen and confirm high prediction accuracy via orthogonal, secondary validation assays. Our approach will increase the efficiency, scale and accuracy of phenotypic screens by maximizing their discriminatory power. PMID:26655497

  20. Molecular Aspects of Mucoadhesive Carrier Development for Drug Delivery and Improved Absorption

    PubMed Central

    Peppas, Nicholas A; Thomas, J. Brock; McGinity, James

    2011-01-01

    Although the oral route remains the most favored route of drug administration, major scientific obstacles prevent the effective and efficient delivery of low-molecular-mass drugs, peptides and proteins that exhibit poor solubility and permeability. Mucoadhesive dosage forms and the associated drug carriers have the ability to interact at a molecular level with the mucus gel layer that lines the epithelial surfaces of the major absorptive regions of the body. This interaction provides an increased residence time of the therapeutic formulation while localizing the drug at the site of administration. Such local, non-specific targeting leads to an increase in both oral absorption and bioavailability. Fundamental understanding of the biological processes encountered along the gastrointestinal tract can provide a sufficient engineer of carriers that are capable to provide this increase in residence time. Here we discuss the theoretical framework for achieving mucoadhesive systems as related to biomaterials science and the structure of the biomaterials used. PMID:19105897

  1. Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

    PubMed Central

    2014-01-01

    Background The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. Results We use this approach to prioritize genes as drug target candidates in a set of ER + breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER + breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. Conclusions Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use. PMID:24495353

  2. Improving the assessment of heart toxicity for all new drugs through translational regulatory science.

    PubMed

    Johannesen, L; Vicente, J; Gray, R A; Galeotti, L; Loring, Z; Garnett, C E; Florian, J; Ugander, M; Stockbridge, N; Strauss, D G

    2014-05-01

    Fourteen drugs have been removed from the market worldwide because they cause torsade de pointes. Most drugs that cause torsade can be identified by assessing whether they block the human ether à gogo related gene (hERG) potassium channel and prolong the QT interval on the electrocardiogram. In response, regulatory agencies require new drugs to undergo "thorough QT" studies. However, some drugs block hERG potassium channels and prolong QT with minimal torsade risk because they also block calcium and/or sodium channels. Through analysis of clinical and preclinical data from 34 studies submitted to the US Food and Drug Administration and by computer simulations, we demonstrate that by dividing the QT interval into its components of depolarization (QRS), early repolarization (J-Tpeak), and late repolarization (Tpeak-Tend), along with atrioventricular conduction delay (PR), it may be possible to determine which hERG potassium channel blockers also have calcium and/or sodium channel blocking activity. This translational regulatory science approach may enable innovative drugs that otherwise would have been labeled unsafe to come to market.

  3. Improving the translation in Europe of nanomedicines (a.k.a. drug delivery) from academia to industry.

    PubMed

    Eaton, Michael A W

    2012-12-28

    Over the last decade the involvement of European academic scientists in the translation of Nanomedicines and Drug Delivery into useful therapeutics has been modest. Funders have become increasingly concerned and some attempts have been made in Europe to improve impact. While the consequences are minimal at present for stakeholders, the eventual impact at national and political levels could be serious and is likely to lead to reverse innovation - the import of healthcare products from developing economies - if not addressed. Some knowledge of industrial drug development is critical for innovation in this regulated sector - this information being not easily obtained outside Pharma. While peer review has failings, more important is project inception, since once started research takes on a life of its own. This paper aims to encourage healthcare researchers to take a more translational approach to selecting (applied) drug delivery projects.

  4. Nanosuspension for improving the bioavailability of a poorly soluble drug and screening of stabilizing agents to inhibit crystal growth.

    PubMed

    Ghosh, Indrajit; Bose, Sonali; Vippagunta, Radha; Harmon, Ferris

    2011-05-16

    The purpose of this study was to develop a nanosuspension of a poorly soluble drug by nanomilling process using wet media milling to achieve superior in vitro dissolution and high in vivo exposure in pharmacokinetic studies. A promising nanosuspension was developed with Vitamin E TPGS based formulation with particle size in the nano range. Although the formulation showed significant improvement during in vitro dissolution and in vivo plasma level, probably due to the strong hydrophobic interaction between Vitamin TPGS and the drug molecule, crystal growth was observed during stability studies. A systematic study was done with different combinations of solubilizer/stabilizer system in order to obtain a more stable nanosuspension. Hydroxypropyl methylcellulose (HPMC 3 cps) was found to stabilize the nanosuspension by better surface coverage due to stronger interaction with the drug as compared to other stabilizers used in this study.

  5. Particle size reduction to the nanometer range: a promising approach to improve buccal absorption of poorly water-soluble drugs

    PubMed Central

    Rao, Shasha; Song, Yunmei; Peddie, Frank; Evans, Allan M

    2011-01-01

    Poorly water-soluble drugs, such as phenylephrine, offer challenging problems for buccal drug delivery. In order to overcome these problems, particle size reduction (to the nanometer range) and cyclodextrin complexation were investigated for permeability enhancement. The apparent solubility in water and the buccal permeation of the original phenylephrine coarse powder, a phenylephrine–cyclodextrin complex and phenylephrine nanosuspensions were characterized. The particle size and particle surface properties of phenylephrine nanosuspensions were used to optimize the size reduction process. The optimized phenylephrine nanosuspension was then freeze dried and incorporated into a multi-layered buccal patch, consisting of a small tablet adhered to a mucoadhesive film, yielding a phenylephrine buccal product with good dosage accuracy and improved mucosal permeability. The design of the buccal patch allows for drug incorporation without the need to change the mucoadhesive component, and is potentially suited to a range of poorly water-soluble compounds. PMID:21753876

  6. A novel clinical pharmacy management system in improving the rational drug use in department of general surgery.

    PubMed

    Bao, L; Wang, Y; Shang, T; Ren, X; Ma, R

    2013-01-01

    Hospital information system is widely used to improve work efficiency of hospitals in China. However, it is lack of the function providing pharmaceutical information service for clinical pharmacists. A novel clinical pharmacy management system developed by our hospital was introduced to improve the work efficiency of clinical pharmacists in our hospital and to carry out large sample statistical analyzes by providing pharmacy information services and promoting rational drug use. Clinical pharmacy management system was developed according to the actual situation. Taking prescription review in the department of general surgery as the example, work efficiency of clinical pharmacists, quality and qualified rates of prescriptions before and after utilizing clinical pharmacy management system were compared. Statistics of 48,562 outpatient and 5776 inpatient prescriptions of the general surgical department were analyzed. Qualified rates of both the inpatient and outpatient prescriptions of the general surgery department increased, and the use of antibiotics decreased. This system apparently improved work efficiency, standardized the level and accuracy of drug use, which will improve the rational drug use and pharmacy information service in our hospital. Meanwhile, utilization of prophylactic antibiotics for the aseptic operations also reduced.

  7. The Last State to Grant Nurse Practitioners DEA Licensure: An Education Improvement Initiative on the Florida Prescription Drug Monitoring Program.

    PubMed

    Kellams, Joni R; Maye, John P

    Nurse practitioners (NPs) now have prescriptive authority for controlled substances in all 50 states in the United States. Florida, the last state to grant NPs DEA licensure, has been wrought with prescription diversion practices for a number of years as pill mills, doctor shopping, and overprescribing proliferated. Prescription Drug Monitoring Programs (PDMPs) help curb drug diversion activity and play a key role in reducing the abuse of controlled substances. The primary objective of this education improvement initiative was to increase knowledge of actively licensed NPs in the state of Florida regarding the state's PDMP. The main themes included the drug abuse problem, description and progression of the PDMP, and how to use the Florida PDMP. Upon approval from the institutional review board, this education improvement initiative gauged NP knowledge of the PDMP and main themes before and after an educational PowerPoint intervention. A pretest/posttest questionnaire was administered for assessment of all knowledge questions. One hundred forty-five NPs with active advanced registered NP licenses in Florida completed both the pretest and posttest questionnaires. Descriptive statistics and paired t tests were used for statistical significance testing. Knowledge of the PDMP and the main themes of the education improvement initiative significantly increased (p < .001) from pretest to posttest results. This education improvement initiative had positive effects for NPs on the knowledge of the Florida PDMP and the main themes. This indicated that Florida NPs are able to acquire greater comprehension of the PDMP by an education intervention.

  8. Effectiveness of the behavior change intervention to improve harm reduction self-efficacy among people who inject drugs in Thailand.

    PubMed

    Pawa, Duangta; Areesantichai, Chitlada

    2016-01-01

    People who inject drugs (PWID) in Thailand reported unsafe injection practices resulting in injection-related health consequences. Harm reduction self-efficacy plays an important role and could be improved to reduce harm associated with injecting drugs. Evidence-based interventions targeting PWID are needed. This study sought to evaluate the effectiveness of the behavior change intervention within the PWID population. The behavior change intervention, Triple-S, was designed to improve harm reduction self-efficacy among PWID. This quasi-experimental study was a pre- and post-comparison with a control group design. Participants were PWID, aged 18-45 years, and located in Bangkok. Changes in harm reduction self-efficacy of the intervention group were compared with the control group using paired and independent t-test. Most of PWID were male (84%), had a secondary school and lower education (71%), were single, and had a mean age of 41 years. They had been injecting drugs for an average of 20 years, and the median of drug injections per week was ten times in the past month. Pre- and post-intervention effects were measured and results showed that the intervention group reported improvement in harm reduction self-efficacy in negative emotional conditions (P=0.048). Our findings suggest that Triple-S intervention can significantly improve harm reduction self-efficacy in negative emotional conditions. The results may suggest the importance of behavior change intervention, especially when integrated with services provided by drop-in centers. The intervention can be further developed to cover other harm reduction behaviors and improve harm reduction self-efficacy.

  9. Effectiveness of the behavior change intervention to improve harm reduction self-efficacy among people who inject drugs in Thailand

    PubMed Central

    Pawa, Duangta; Areesantichai, Chitlada

    2016-01-01

    Background People who inject drugs (PWID) in Thailand reported unsafe injection practices resulting in injection-related health consequences. Harm reduction self-efficacy plays an important role and could be improved to reduce harm associated with injecting drugs. Evidence-based interventions targeting PWID are needed. This study sought to evaluate the effectiveness of the behavior change intervention within the PWID population. Methods The behavior change intervention, Triple-S, was designed to improve harm reduction self-efficacy among PWID. This quasi-experimental study was a pre- and post-comparison with a control group design. Participants were PWID, aged 18–45 years, and located in Bangkok. Changes in harm reduction self-efficacy of the intervention group were compared with the control group using paired and independent t-test. Results Most of PWID were male (84%), had a secondary school and lower education (71%), were single, and had a mean age of 41 years. They had been injecting drugs for an average of 20 years, and the median of drug injections per week was ten times in the past month. Pre- and post-intervention effects were measured and results showed that the intervention group reported improvement in harm reduction self-efficacy in negative emotional conditions (P=0.048). Conclusion Our findings suggest that Triple-S intervention can significantly improve harm reduction self-efficacy in negative emotional conditions. The results may suggest the importance of behavior change intervention, especially when integrated with services provided by drop-in centers. The intervention can be further developed to cover other harm reduction behaviors and improve harm reduction self-efficacy. PMID:27660503

  10. Sugars as solid dispersion carrier to improve solubility and dissolution of the BCS class II drug: clotrimazole.

    PubMed

    Madgulkar, Ashwini; Bandivadekar, Mithun; Shid, Tanaji; Rao, Shivani

    2016-01-01

    Solid dispersion of poorly soluble BCS class II drug, clotrimazole, was prepared with the aim of enhancing its dissolution profile. Solid dispersions were prepared using various sugars as carriers at different weight ratio to drug-like d-mannitol, d-fructose, d-dextrose and d-maltose by fusion method. The solubility of plain clotrimazole in different percent of sugar solutions was measured. Also, its solubility in solid dispersion and their physical mixture were assessed. The dissolution of all the prepared SD tablets, direct compressed clotrimazole tablet and plain drug were tested using the U.S. Pharmacopeia convention (USP) apparatus II. The dissolution profiles were characterized by parameters like area under curve (AUC), mean residence time (MRT), mean dissolution time (MDT) and percent dissolution efficiency (% DE). The release kinetics study was performed using DD Solver TM software. The selected solid dispersions (SDs) were evaluated for antifungal activity. A 100% solution of mannitol showed 806-fold increases in solubility as compared with plain clotrimazole in water. It was observed that the dissolution profile of clotrimazole was improved by mannitol SD at drug to sugar ration of 1:3. The percent DE value for mannitol SD tablet was found to be 77.3516% as against plain drug and directly compressed tablet of clotrimazole at 50.9439% and 31.33%, respectively. Also the antifungal activity indicated by inhibition zone was found to be 54 mm indicating enhance activity against Candida albicans as compared with plain CTZ at 6.6 mm. Thus, it can be concluded that the sugar alcohol, that is, mannitol is a more promising hydrophilic carrier for solid dispersion preparation to improve the solubility and dissolution of poorly soluble drugs.

  11. Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy.

    PubMed

    Kaminskas, Lisa M; McLeod, Victoria M; Ryan, Gemma M; Kelly, Brian D; Haynes, John M; Williamson, Mark; Thienthong, Neeranat; Owen, David J; Porter, Christopher J H

    2014-06-10

    Direct administration of chemotherapeutic drugs to the lungs significantly enhances drug exposure to lung resident cancers and may improve chemotherapy when compared to intravenous administration. Direct inhalation of uncomplexed or unencapsulated cytotoxic drugs, however, leads to bolus release and unacceptable lung toxicity. Here, we explored the utility of a 56kDa PEGylated polylysine dendrimer, conjugated to doxorubicin, to promote the controlled and prolonged exposure of lung-resident cancers to cytotoxic drug. After intratracheal instillation to rats, approximately 60% of the dendrimer was rapidly removed from the lungs (within 24h) via mucociliary clearance and absorption into the blood. This was followed by a slower clearance phase that reflected both absorption from the lungs (bioavailability 10-13%) and biodegradation of the dendrimer scaffold. After 7days, approximately 15% of the dose remained in the lungs. A syngeneic rat model of lung metastasised breast cancer was subsequently employed to compare the anticancer activity of the dendrimer with a doxorubicin solution formulation after intravenous and pulmonary administration. Twice weekly intratracheal instillation of the dendrimer led to a >95% reduction in lung tumour burden after 2weeks in comparison to IV administration of doxorubicin solution which reduced lung tumour burden by only 30-50%. Intratracheal instillation of an equivalent dose of doxorubicin solution led to extensive lung-related toxicity and death withinseveral days of a single dose. The data suggest that PEGylated dendrimers have potential as inhalable drug delivery systems to promote the prolonged exposure of lung-resident cancers to chemotherapeutic drugs and to improve anti-cancer activity.

  12. Improved oral absorption of dutasteride via Soluplus®-based supersaturable self-emulsifying drug delivery system (S-SEDDS).

    PubMed

    Lee, Dong Hoon; Yeom, Dong Woo; Song, Ye Seul; Cho, Ha Ra; Choi, Yong Seok; Kang, Myung Joo; Choi, Young Wook

    2015-01-15

    A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to improve the oral absorption of dutasteride (DTS), a 5α-reductase inhibitor that is poorly water-soluble. A supersaturable system was prepared by employing Soluplus(®) (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) as a precipitation inhibitor with a conventional SEDDS vehicle consisted of Capryol™ 90, Cremophor(®) EL and Transcutol(®) HP (DTS:SEDDS vehicle:Soluplus(®)=1.0:67.6:10.0 w/v/w). In an in vitro dissolution test in a non-sink condition, the drug dissolution rate from SEDDS was rapidly increased to 72% for an initial period of 5min, but underwent rapid drug precipitation within 2h, decreasing the amount of drug dissolved to one-seventh of its original amount. On the other hand, S-SEDDS resulted in a slower crystallization of DTS by virtue of a precipitation inhibitor, maintaining a 3 times greater dissolution rate after 2h compared to SEDDS. In an in vivo pharmacokinetic study in rats, the S-SEDDS formulation exhibited 3.9-fold greater area-under-curve value than that of the drug suspension and 1.3-fold greater than that of SEDDS. The maximum plasma concentration of S-SEDDS was 5.6- and 2.0-fold higher compared to drug suspension and SEDDS, respectively. The results of this study suggest that the novel supersaturable system may be a promising tool for improving the physicochemical property and oral absorption of the 5α-reductase inhibitor.

  13. A thermosensitive liposome prepared with a Cu²⁺ gradient demonstrates improved pharmacokinetics, drug delivery and antitumor efficacy.

    PubMed

    Tagami, Tatsuaki; May, Jonathan P; Ernsting, Mark J; Li, Shyh-Dar

    2012-07-10

    Here we report the development of an enhanced thermosensitive formulation composed of DPPC and Brij78, loaded with doxorubicin (DOX) using a Cu²⁺ gradient and post-inserted with an additional amount of Brij78. This optimal formulation (HaT-II: Hyperthermia-activated cytoToxic) displayed significantly improved stability in serum at 37 °C, and enhanced drug release rates at 41-42 °C, compared to LTSL (lyso-lipid temperature sensitive liposomes, DPPC/MSPC/DSPE-PEG₂₀₀₀=86/10/4, pH gradient drug loading). HaT-II released 100% DOX within 15-40s at 40-42 °C, with only 5% drug leakage at 37 °C after 30 min in serum, while LTSL lost 30% of its drug content at 37 °C and exhibited ~2-fold decreased release rate constants at 41-42 °C under the same conditions. The pharmacokinetics of DOX was significantly improved in non-heated HaT-II treated healthy mice with 2.5-fold increased area under the curve and 2-fold prolonged circulation half life compared to LTSL. This led to 2-fold improved drug delivery to the heated tumor by HaT-II (~20% injected dose/g tissue), relative to LTSL and significantly enhanced antitumor efficacy with complete inhibition of tumor growth after a single dose of HaT-II. Finally, HaT-II exhibited little toxicity in mice, inducing no body weight loss and no abnormality in the blood chemistry (10 mg DOX/kg). Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.

    PubMed

    Goldring, Christopher; Antoine, Daniel J; Bonner, Frank; Crozier, Jonathan; Denning, Chris; Fontana, Robert J; Hanley, Neil A; Hay, David C; Ingelman-Sundberg, Magnus; Juhila, Satu; Kitteringham, Neil; Silva-Lima, Beatriz; Norris, Alan; Pridgeon, Chris; Ross, James A; Young, Rowena Sison; Tagle, Danilo; Tornesi, Belen; van de Water, Bob; Weaver, Richard J; Zhang, Fang; Park, B Kevin

    2017-02-01

    Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2017;65:710-721).

  15. The influence of aqueous content in small scale salt screening--improving hit rate for weakly basic, low solubility drugs.

    PubMed

    Tarsa, Peter B; Towler, Christopher S; Woollam, Grahame; Berghausen, Jörg

    2010-09-11

    Salt screening and selection is a well established approach for improving the properties of drug candidates, including dissolution rate and bioavailability. Typically during early development only small amounts of compound are available for solid state profiling, including salt screening. In order to probe large areas of experimental space, high-throughput screening is utilized and is often designed in a way to search for suitable crystallization parameters within hundreds or even thousands of conditions. However, the hit rate in these types of screens can be very low. In order to allow for selection of a salt form early within the drug development process whilst using smaller amounts of compounds, a screening procedure taking into account the compounds properties and the driving forces for salt formation is described. Experiments were carried out on the model compounds clotrimazole, cinnarizine itraconazole and atropine. We found an increase in crystalline hit rate for water-insoluble drugs crystallized from solutions that included at least 10% aqueous content. Conversely it was observed that compounds with greater water solubility did not benefit from aqueous content in salt screening, instead organic solvents lead to more crystalline screening hits. Results from four model compounds show that the inclusion of an aqueous component to the salt reaction can enhance the chance of salt formation and significantly improve the crystalline hit rate for low water soluble drugs.

  16. Novel polyvinylpyrrolidones to improve delivery of poorly water-soluble drugs: from design to synthesis and evaluation.

    PubMed

    Niemczyk, Anna I; Williams, Adrian C; Rawlinson-Malone, Clare F; Hayes, Wayne; Greenland, Barnaby W; Chappell, David; Khutoryanskaya, Olga; Timmins, Peter

    2012-08-06

    Polyvinylpyrrolidone is widely used in tablet formulations with the linear form acting as a wetting agent and disintegrant, whereas the cross-linked form is a superdisintegrant. We have previously reported that simply mixing the commercial cross-linked polymer with ibuprofen disrupted drug crystallinity with consequent improvements in drug dissolution behavior. In this study, we have designed and synthesized novel cross-linking agents containing a range of oligoether moieties that have then been polymerized with vinylpyrrolidone to generate a suite of novel excipients with enhanced hydrogen-bonding capabilities. The polymers have a porous surface and swell in the most common solvents and in water, properties that suggest their value as disintegrants. The polymers were evaluated in simple physical mixtures with ibuprofen as a model poorly water-soluble drug. The results show that the novel PVPs induce the drug to become "X-ray amorphous", which increased dissolution to a greater extent than that seen with commercial cross-linked PVP. The polymers stabilize the amorphous drug with no evidence for recrystallization seen after 20 weeks of storage.

  17. Dual-drug delivery by porous silicon nanoparticles for improved cellular uptake, sustained release, and combination therapy.

    PubMed

    Wang, Chang-Fang; Mäkilä, Ermei M; Kaasalainen, Martti H; Hagström, Marja V; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

    2015-04-01

    Dual-drug delivery of antiangiogenic and chemotherapeutic drugs can enhance the therapeutic effect for cancer therapy. Conjugation of methotrexate (MTX) to porous silicon (PSi) nanoparticles (MTX-PSi) with positively charged surface can improve the cellular uptake of MTX and inhibit the proliferation of cancer cells. Herein, MTX-PSi conjugates sustained the release of MTX up to 96 h, and the released fragments including MTX were confirmed by mass spectrometry. The intracellular distribution of the MTX-PSi nanoparticles was confirmed by transmission electron microscopy. Compared to pure MTX, the MTX-PSi achieved similar inhibition of cell proliferation in folate receptor (FR) over-expressing U87 MG cancer cells, and a higher effect in low FR-expressing EA.hy926 cells. Nuclear fragmentation analysis demonstrated programmed cell apoptosis of MTX-PSi in the high/low FR-expressing cancer cells, whereas PSi alone at the same dose had a minor effect on cell apoptosis. Finally, the porous structure of MTX-PSi enabled a successful concomitant loading of another anti-angiogenic hydrophobic drug, sorafenib, and considerably enhanced the dissolution rate of sorafenib. Overall, the MTX-PSi nanoparticles can be used as a platform for combination chemotherapy by simultaneously enhancing the dissolution rate of a hydrophobic drug and sustaining the release of a conjugated chemotherapeutic drug. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  18. Need for an improved submission process for listing drugs for reimbursement in Canadian provinces.

    PubMed

    West, Roy; Borden, E Keith; Collet, Jean-Paul; Rawson, Nigel S B; Tonks, Robert S

    2003-01-01

    To have a drug listed in a province's formulary, manufacturers must submit an application providing data required by the provincial rules and guidelines. The procedures for the scientific evaluation of drugs considered for listing for reimbursement in five provinces have been examined previously. The present study investigates the clarity of the same five provinces' rules and guidelines about effectiveness and cost data that should be included in listing submissions from the perspective of the pharmaceutical company. The manufacturers of five recently introduced drugs selected by the investigators received questionnaires asking about the departments within their companies that are responsible for the submission, the data required by each of the five provinces and the clarity of each province's requirements for submission. Each company was also asked similar questions about its own submission experience with its drug. Investigators visited each manufacturer to review the questionnaires and answer questions. The manufacturers perceived the rules and guidelines on effectiveness and economic data of several provinces as being neither clear nor consistent. Consequently, information that companies submit in their attempts at compliance with the rules and guidelines varies substantially. The manufacturers' perceptions of the information required by the provinces on effectiveness and cost information were inconsistent. Previous work indicated that the provinces make significant decisions about listings based on inadequate information resulting in a scientifically flawed system that contributes to considerable inequality in access to new drugs between provinces. The findings of the present work reinforce this conclusion.

  19. Dual Drug Loaded Biodegradable Nanofibrous Microsphere for Improving Anti-Colon Cancer Activity

    PubMed Central

    Fan, Rangrang; Li, Xiaoling; Deng, Jiaojiao; Gao, Xiang; Zhou, Liangxue; Zheng, Yu; Tong, Aiping; Zhang, Xiaoning; You, Chao; Guo, Gang

    2016-01-01

    One of the approaches being explored to increase antitumor activity of chemotherapeutics is to inject drug-loaded microspheres locally to specific anatomic sites, providing for a slow, long term release of a chemotherapeutic while minimizing systemic exposure. However, the used clinically drug carriers available at present have limitations, such as their low stability, renal clearance and residual surfactant. Here, we report docetaxel (DOC) and curcumin (CUR) loaded nanofibrous microspheres (DOC + CUR/nanofibrous microspheres), self-assembled from biodegradable PLA-PEO-PPO-PEO-PLA polymers as an injectable drug carrier without adding surfactant during the emulsification process. The obtained nanofibrous microspheres are composed entirely of nanofibers and have an open hole on the shell without the assistance of a template. It was shown that these DOC + CUR/nanofibrous microspheres could release curcumin and docetaxel slowly in vitro. The slow, sustained release of curcumin and docetaxel in vivo may help maintain local concentrations of active drug. The mechanism by which DOC + CUR/nanofibrous microspheres inhibit colorectal peritoneal carcinomatosis might involve increased induction of apoptosis in tumor cells and inhibition of tumor angiogenesis. In vitro and in vivo evaluations demonstrated efficacious synergistic antitumor effects against CT26 of curcumin and docetaxel combined nanofibrous microspheres. In conclusion, the dual drug loaded nanofibrous microspheres were considered potentially useful for treating abdominal metastases of colorectal cancer. PMID:27324595

  20. Novel application of hydrophobin in medical science: a drug carrier for improving serum stability

    PubMed Central

    Zhao, Liqiang; Xu, Haijin; Li, Ying; Song, Dongmin; Wang, Xiangxiang; Qiao, Mingqiang; Gong, Min

    2016-01-01

    Multiple physiological properties of glucagon-like peptide-1 (GLP-1) ensure that it is a promising drug candidate for the treatment of type 2 diabetes. However, the in vivo half-life of GLP-1 is short because of rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The poor serum stability of GLP-1 has significantly limited its clinical utility, although many studies are focused on extending the serum stability of this molecule. Hydrophobin, a self-assembling protein, was first applied as drug carrier to stabilize GLP-1 against protease degradation by forming a cavity. The glucose tolerance test clarified that the complex retained blood glucose clearance activity for 72 hours suggesting that this complex might be utilized as a drug candidate administered every 2–3 days. Additionally, it was found that the mutagenesis of hydrophobin preferred a unique pH condition for self-assembly. These findings suggested that hydrophobin might be a powerful tool as a drug carrier or a pH sensitive drug-release compound. The novel pharmaceutical applications of hydrophobin might result in future widespread interest in hydrophobin. PMID:27212208

  1. Dual Drug Loaded Biodegradable Nanofibrous Microsphere for Improving Anti-Colon Cancer Activity

    NASA Astrophysics Data System (ADS)

    Fan, Rangrang; Li, Xiaoling; Deng, Jiaojiao; Gao, Xiang; Zhou, Liangxue; Zheng, Yu; Tong, Aiping; Zhang, Xiaoning; You, Chao; Guo, Gang

    2016-06-01

    One of the approaches being explored to increase antitumor activity of chemotherapeutics is to inject drug-loaded microspheres locally to specific anatomic sites, providing for a slow, long term release of a chemotherapeutic while minimizing systemic exposure. However, the used clinically drug carriers available at present have limitations, such as their low stability, renal clearance and residual surfactant. Here, we report docetaxel (DOC) and curcumin (CUR) loaded nanofibrous microspheres (DOC + CUR/nanofibrous microspheres), self-assembled from biodegradable PLA-PEO-PPO-PEO-PLA polymers as an injectable drug carrier without adding surfactant during the emulsification process. The obtained nanofibrous microspheres are composed entirely of nanofibers and have an open hole on the shell without the assistance of a template. It was shown that these DOC + CUR/nanofibrous microspheres could release curcumin and docetaxel slowly in vitro. The slow, sustained release of curcumin and docetaxel in vivo may help maintain local concentrations of active drug. The mechanism by which DOC + CUR/nanofibrous microspheres inhibit colorectal peritoneal carcinomatosis might involve increased induction of apoptosis in tumor cells and inhibition of tumor angiogenesis. In vitro and in vivo evaluations demonstrated efficacious synergistic antitumor effects against CT26 of curcumin and docetaxel combined nanofibrous microspheres. In conclusion, the dual drug loaded nanofibrous microspheres were considered potentially useful for treating abdominal metastases of colorectal cancer.

  2. Nanocarriers and their Actions to Improve Skin Permeability and Transdermal Drug Delivery.

    PubMed

    Khan, Nauman R; Harun, Mohd S; Nawaz, Asif; Harjoh, Nurulaini; Wong, Tin W

    2015-01-01

    Transdermal drug delivery is impeded by the natural barrier of epidermis namely stratum corneum. This limits the route to transport of drugs with a log octanol-water partition coefficient of 1 to 3, molecular weight of less than 500 Da and melting point of less than 200°C. Nanotechnology has received widespread investigation as nanocarriers are deemed to be able to fluidize the stratum corneum as a function of size, shape, surface charges, and hydrophilicity-hydrophobicity balance, while delivering drugs across the skin barrier. This review provides an overview and update on the latest designs of liposomes, ethosomes, transfersomes, niosomes, magnetosomes, oilin- water nanoemulsions, water-in-oil nanoemulsions, bicontinuous nanoemulsions, covalently crosslinked polysaccharide nanoparticles, ionically crosslinked polysaccharide nanoparticles, polyelectrolyte coacervated nanoparticles and hydrophobically modified polysaccharide nanoparticles with respect to their ability to fuse or fluidize lipid/protein/tight junction regimes of skin, and effect changes in skin permeability and drug flux. Universal relationships of nanocarrier size, zeta potential and chemical composition on transdermal permeation characteristics of drugs will be developed and discussed.

  3. Nanotechnology applications for improved delivery of antiretroviral drugs to the brain.

    PubMed

    Wong, Ho Lun; Chattopadhyay, Niladri; Wu, Xiao Yu; Bendayan, Reina

    2010-03-18

    Human immunodeficiency virus (HIV) can gain access to the central nervous system during the early course of primary infection. Once in the brain compartment the virus actively replicates to form an independent viral reservoir, resulting in debilitating neurological complications, latent infection and drug resistance. Current antiretroviral drugs (ARVs) often fail to effectively reduce the HIV viral load in the brain. This, in part, is due to the poor transport of many ARVs, in particular protease inhibitors, across the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSBF). Studies have shown that nanocarriers including polymeric nanoparticles, liposomes, solid lipid nanoparticles (SLN) and micelles can increase the local drug concentration gradients, facilitate drug transport into the brain via endocytotic pathways and inhibit the ATP-binding cassette (ABC) transporters expressed at the barrier sites. By delivering ARVs with nanocarriers, significant increase in the drug bioavailability to the brain is expected to be achieved. Recent studies show that the specificity and efficiency of ARVs delivery can be further enhanced by using nanocarriers with specific brain targeting, cell penetrating ligands or ABC-transporters inhibitors. Future research should focus on achieving brain delivery of ARVs in a safe, efficient, and yet cost-effective manner. Copyright 2009 Elsevier B.V. All rights reserved.

  4. The effect of HPMCAS functional groups on drug crystallization from the supersaturated state and dissolution improvement.

    PubMed

    Ueda, Keisuke; Higashi, Kenjirou; Yamamoto, Keiji; Moribe, Kunikazu

    2014-04-10

    The inhibitory effect on drug crystallization in aqueous solution was evaluated using various forms of hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS suppressed crystallization of carbamazepine (CBZ), nifedipine (NIF), mefenamic acid, and dexamethasone. The inhibition of drug crystallization mainly derived from molecular level hydrophobic interactions between the drug and HPMCAS. HPMCAS with a lower succinoyl substituent ratio strongly suppressed drug crystallization. The inhibition of crystallization was affected by pH, with the CBZ crystallization being inhibited at a higher pH due to the hydrophilization of HPMCAS derived from succinoyl ionization. The molecular mobility of CBZ in an HPMCAS solution was evaluated by 1D-(1)H NMR and relaxation time measurements. CBZ mobility was strongly suppressed in the HPMCAS solutions where strong inhibitory effects on CBZ crystallization were observed. The mobility suppression of CBZ in the HPMCAS solution was derived from intermolecular interactions between CBZ and HPMCAS leading to an inhibition of crystallization. The effect of HPMCAS on the drug dissolution rate was evaluated using an NIF/HPMCAS solid dispersion. The dissolution rate of NIF was increased when HPMCAS with a higher succinoyl substituent ratio was used. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. A community effort to assess and improve drug sensitivity prediction algorithms

    PubMed Central

    Costello, James C; Heiser, Laura M; Georgii, Elisabeth; Gönen, Mehmet; Menden, Michael P; Wang, Nicholas J; Bansal, Mukesh; Ammad-ud-din, Muhammad; Hintsanen, Petteri; Khan, Suleiman A; Mpindi, John-Patrick; Kallioniemi, Olli; Honkela, Antti; Aittokallio, Tero; Wennerberg, Krister; Collins, James J; Gallahan, Dan; Singer, Dinah; Saez-Rodriguez, Julio; Kaski, Samuel; Gray, Joe W; Stolovitzky, Gustavo

    2015-01-01

    Predicting the best treatment strategy from genomic information is a core goal of precision medicine. Here we focus on predicting drug response based on a cohort of genomic, epigenomic and proteomic profiling data sets measured in human breast cancer cell lines. Through a collaborative effort between the National Cancer Institute (NCI) and the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we analyzed a total of 44 drug sensitivity prediction algorithms. The top-performing approaches modeled nonlinear relationships and incorporated biological pathway information. We found that gene expression microarrays consistently provided the best predictive power of the individual profiling data sets; however, performance was increased by including multiple, independent data sets. We discuss the innovations underlying the top-performing methodology, Bayesian multitask MKL, and we provide detailed descriptions of all methods. This study establishes benchmarks for drug sensitivity prediction and identifies approaches that can be leveraged for the development of new methods. PMID:24880487

  6. Gastroretentive Formulations for Improving Oral Bioavailability of Drugs-Focus on Microspheres and their Production.

    PubMed

    Alzaher, Woroud; Shaw, John; Al-Kassas, Raida

    2016-01-01

    Oral administration is the most commonly used drug delivery route for the majority of conditions. Given its advantages over other routes, such as convenience and cost, its use is increasing every year despite the major advances in drug delivery. Nevertheless, oral formulations are limited and challenged by physicochemical barriers and highly variable residence times. Gastric retention is a strategy that can overcome the highly variable gastric residence time by designing formulations that remain in the stomach longer than would otherwise be expected. This is especially beneficial for drugs that have an absorption window in the stomach and proximal intestine. Various techniques are discussed and include gasgenerating tablets, floating microspheres, hydrodynamically balanced systems, bioadhesive particles, rafts and modified shape systems. Microspheres having the advantages of being multi-unit are further discussed with regard to their production methods and characterisation. Further, a summary of microsphere studies is presented that looks at methods used and key results.

  7. Nanoparticle Drug Loading as a Design Parameter to Improve Docetaxel Pharmacokinetics and Efficacy

    PubMed Central

    Chu, Kevin S.; Schorzman, Allison N.; Finniss, Mathew C.; Bowerman, Charles J.; Peng, Lei; Luft, J. Christopher; Madden, Andrew; Wang, Andrew Z.; Zamboni, William C.; DeSimone, Joseph M.

    2013-01-01

    Nanoparticle (NP) drug loading is one of the key defining characteristics of a NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT®), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel. PMID:23899444

  8. Thermal treatment of galactose-branched polyelectrolyte microcapsules to improve drug delivery with reserved targetability.

    PubMed

    Zhang, Fu; Wu, Qi; Liu, Li-Jun; Chen, Zhi-Chun; Lin, Xian-Fu

    2008-06-05

    A novel multilayered drug delivery system by LbL assembly of galactosylated polyelectrolyte, which is possible to have the potential in hepatic targeting by the presence of galactose residues at the microcapsule's surface, is designed. Thermal treatment was performed on the capsules and a dramatic thermal shrinkage up to 60% decrease of capsule diameter above 50 degrees C was observed. This thermal behavior was then used to manipulate drug loading capacity and release rate. Heating after drug loading could seal the capsule shell, enhancing the loading capacity and reducing the release rate significantly. Excellent affinity between galactose-binding lectin and heated galactose-containing microcapsules were observed, indicating a stable targeting potential even after high temperature elevating up to 90 degrees C.

  9. Achieving a Dream: Meeting Policy Goals Related to Improving Drug Access

    PubMed Central

    Zakus, David; Kohler, Jillian Clare; Zakriova, Venera; Yarmoshuk, Aaron

    2010-01-01

    International experts recognize that significant inequities exist in the accessibility of life-saving medicines among poor and vulnerable populations, especially in developing countries. This article highlights that drug access even for relatively cheap medicines is out of reach for the vast numbers of global poor. This badly affects people living with HIV/AIDS who face serious obstacles in accessing ARVs. The same concerns are attributed to neglected diseases. Despite international meetings, promises from the pharmaceutical industry and a lot of media attention little has changed in the past 20 years. The accessibility gap to life-saving drugs could be reduced by the UNITAID initiative to pool patents for the many different ARVs, but the reality is that UNITAID is still a promise. To surmount this global problem of inequity requires a rethinking of traditional models of drug access and health objectives that should not be compromised by commercial interests. PMID:20148088

  10. A community effort to assess and improve drug sensitivity prediction algorithms.

    PubMed

    Costello, James C; Heiser, Laura M; Georgii, Elisabeth; Gönen, Mehmet; Menden, Michael P; Wang, Nicholas J; Bansal, Mukesh; Ammad-ud-din, Muhammad; Hintsanen, Petteri; Khan, Suleiman A; Mpindi, John-Patrick; Kallioniemi, Olli; Honkela, Antti; Aittokallio, Tero; Wennerberg, Krister; Collins, James J; Gallahan, Dan; Singer, Dinah; Saez-Rodriguez, Julio; Kaski, Samuel; Gray, Joe W; Stolovitzky, Gustavo

    2014-12-01

    Predicting the best treatment strategy from genomic information is a core goal of precision medicine. Here we focus on predicting drug response based on a cohort of genomic, epigenomic and proteomic profiling data sets measured in human breast cancer cell lines. Through a collaborative effort between the National Cancer Institute (NCI) and the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we analyzed a total of 44 drug sensitivity prediction algorithms. The top-performing approaches modeled nonlinear relationships and incorporated biological pathway information. We found that gene expression microarrays consistently provided the best predictive power of the individual profiling data sets; however, performance was increased by including multiple, independent data sets. We discuss the innovations underlying the top-performing methodology, Bayesian multitask MKL, and we provide detailed descriptions of all methods. This study establishes benchmarks for drug sensitivity prediction and identifies approaches that can be leveraged for the development of new methods.

  11. Trimethyl chitosan improves Anti-HIV effects of Atripla as a new nano-formulated drug.

    PubMed

    Shohani, Sepideh; Abdoli, Asghar; Khansarinejad, Behzad; Ardestani, Mehdi Shafiee; Salimi-Asl, Mohammad; Ghanbari, Maryam; Haj, Mehrdad Sadeghi; Zabihollahi, Rezvan; Mondanizadeh, Mahdieh

    2016-12-16

    Background; highly active antiretroviral therapy (HAART) has been commonly used for HIV treatment. Its main drawbacks like drug resistance and side effects raised researcher's interest to find new approaches for its treatment. Trimethyl chitosan is one of the drug carriers which was introduced recently. Materials and Methods; the conjugated atripla-trimethyl chitosan was designed and characterized by zetasizer, AFM and FTIR techniques. The drug conjugation with trimethyl chitosan and cellular uptake of nano-conjugate were determined by spectrophotometry. XTT test was used to measure the cytotoxicity. Anti-retroviral efficiency was studied by ELISA test. Results; Zetasizer Results proved that the average size of nano-conjugate particles agglomeration was 493.4±24.6 nm but the size of the majority of the particles was 177.2±7.8 nm with the intensity of 87.9%. AFM technique revealed that the size of nano-conjugate and trimethyl chitosan were 129 nm and 59.78 nm, respectively. Zeta potential was -1.35±0.04 mv for nano-conjugate and -7.69±0.3 mv for drug. Conjugation efficiency of atripla with trimethyl chitosan was 5.27%. Measured cellular uptake with spectrophotometry for nano-conjugate was about twice of the free drug in examined concentrations (P=0.007). Compared to atripla, the nano-conjugate showed a higher inhibitory effect on HIV replication (P=0.0001). Conclusion; The result showed that atripla-TMC conjugate does not have a significant cytotoxicity effect. Due to the higher inhibitory effect of nano-conjugate on viral replication, it can be used in lower concentration for antiviral treatment, which resulted in reduction of drug resistance and other side effects.

  12. Improving lead generation success through integrated methods: transcending 'drug discovery by numbers'.

    PubMed

    Campbell, James B

    2010-12-01

    Key methodologies such as HTS and combinatorial chemistry have allowed pharmaceutical discovery to focus on identifying promising drug candidates through the use of statistics. Thus, amassing large data sets from large-scale screening campaigns of ever-increasing corporate compound collections was expected to deliver unprecedented success for the pharmaceutical industry. This feature review explores aspects of how the reliance on using numbers to drive discovery has gone awry. Building knowledge equity from the integration of multiple parallel screening assays, workstreams and data sources provides an alternative to driving discovery through statistics. Thus, a more rational approach to creating and inventing new leads and drug opportunities may be pursued.

  13. Drug-eluting coronary stents – focus on improved patient outcomes

    PubMed Central

    Jaffery, Zehra; Prasad, Amit; Lee, John H; White, Christopher J

    2011-01-01

    The development of stent has been a major advance in the treatment of obstructive coronary artery disease since the introduction of balloon angioplasty. Subsequently, neointimal hyperplasia within the stent leading to in-stent restenosis emerged as a major obstacle in long-term success of percutaneous coronary intervention. Recent introduction of drug-eluting stents is a major breakthrough to tackle this problem. This review article summarizes stent technology, reviews progress of drug-eluting stents and discusses quality of life, patient satisfaction, and acceptability of percutaneous coronary intervention. PMID:22915977

  14. Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules.

    PubMed

    Luker, Tim; Alcaraz, Lilian; Chohan, Kamaldeep K; Blomberg, Niklas; Brown, Dearg S; Butlin, Roger J; Elebring, Thomas; Griffin, Andrew M; Guile, Simon; St-Gallay, Stephen; Swahn, Britt-Marie; Swallow, Steve; Waring, Michael J; Wenlock, Mark C; Leeson, Paul D

    2011-10-01

    A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.

  15. Improving the effect of FDA-mandated drug safety alerts with Internet-based continuing medical education.

    PubMed

    Kraus, Carl N; Baldwin, Alan T; McAllister, R G

    2013-02-01

    The US Food and Drug Administration (FDA) requires risk communication as an element of Risk Evaluation and Mitigation Strategies (REMS) to alert and educate healthcare providers about severe toxicities associated with approved drugs. The educational effectiveness of this approach has not been evaluated. To support the communication plan element of the ipilimumab REMS, a Medscape Safe Use Alert (SUA) letter was distributed by Medscape via email and mobile device distribution to clinicians specified in the REMS. This alert contained the FDA-approved Dear Healthcare Provider (DHCP) letter mandated for distribution. A continuing medical education (CME) activity describing ipilimumab toxicities and the appropriate management was simultaneously posted on the website and distributed to Medscape members. Data were collected over a 6-month period regarding the handling of the letter and the responses to pre- and post-test questions for those who participated in the CME activity. Analysis of the answers to the pre- and posttest questions showed that participation in the CME activity resulted in an improvement in correct answer responses of 47%. Our experience shows that there are likely distinct information sources that are utilized by different HCP groups. The ready availability of a brief CME activity was utilized by 24,063 individuals, the majority of whom showed enhanced understanding of ipilimumab toxicity by improvement in post-test scores, educational data that are not available via implementation of standard safety alert communications. These results demonstrate that improvement in understanding of specific drug toxicities is enhanced by a CME intervention.

  16. Have VET Reforms Resulted in Improvements in Quality? Illustrations from the Alcohol and Other Drugs Sector

    ERIC Educational Resources Information Center

    Roche, Ann; Kostadinov, Victoria; White, Michael

    2014-01-01

    Australian vocational education and training (VET) has undergone major reforms since the 1990s, including the introduction of competency based training (CBT) and the "streamlining" of qualifications. This paper examines the impact of these reforms, using the alcohol and other drugs sector as a case illustration. A survey of alcohol and…

  17. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index.

    PubMed

    Junutula, Jagath R; Raab, Helga; Clark, Suzanna; Bhakta, Sunil; Leipold, Douglas D; Weir, Sylvia; Chen, Yvonne; Simpson, Michelle; Tsai, Siao Ping; Dennis, Mark S; Lu, Yanmei; Meng, Y Gloria; Ng, Carl; Yang, Jihong; Lee, Chien C; Duenas, Eileen; Gorrell, Jeffrey; Katta, Viswanatham; Kim, Amy; McDorman, Kevin; Flagella, Kelly; Venook, Rayna; Ross, Sarajane; Spencer, Susan D; Lee Wong, Wai; Lowman, Henry B; Vandlen, Richard; Sliwkowski, Mark X; Scheller, Richard H; Polakis, Paul; Mallet, William

    2008-08-01

    Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding. When conjugated to monomethyl auristatin E, an antibody against the ovarian cancer antigen MUC16 is as efficacious as a conventional conjugate in mouse xenograft models. Moreover, it is tolerated at higher doses in rats and cynomolgus monkeys than the same conjugate prepared by conventional approaches. The favorable in vivo properties of the near-homogenous composition of this conjugate suggest that our strategy offers a general approach to retaining the antitumor efficacy of antibody-drug conjugates, while minimizing their systemic toxicity.

  18. Food incentives improve adherence to tuberculosis drug treatment among homeless patients in Russia.

    PubMed

    Gärden, Bodil; Samarina, Arina; Stavchanskaya, Irina; Alsterlund, Rolf; Övregaard, Amanda; Taganova, Olga; Shpakovskaya, Ludmilla; Zjemkov, Vladimir; Ridell, Malin; Larsson, Lars-Olof

    2013-03-01

    The aim of the study was to evaluate the impact of food incentives on adherence to tuberculosis (TB) drug treatment among homeless patients with TB. Food packages were thus given as a part of directly observed therapy to 142 homeless patients with TB at a dispensary in Saint Petersburg, Russian Federation. In addition, a social worker provided the patients with information and legal assistance, for example help with internal passports. Among the 142 patients, 66 were included in the study at the dispensary during their entire treatment period, while 76 patients were included in the study during shorter periods mainly because of transfer to inpatient care. In the first group, 59% of the patients continued the TB drug treatment without interruption in contrast to 31% in a control group. In the second group, that is those studied during shorter periods, 95% continued the TB drug treatment without interruption while attached to the dispensary. Food was introduced in the TB programme of the City of St. Petersburg as a consequence of this study. In conclusion, it can be stated that the food incentive had a strong positive impact on the adherence to TB drug treatment among these socially marginalized patients. The social support contributed in all probability also to the positive results.

  19. Improvement of the Prediction of Drugs Demand Using Spatial Data Mining Tools.

    PubMed

    Ramos, M Isabel; Cubillas, Juan José; Feito, Francisco R

    2016-01-01

    The continued availability of products at any store is the major issue in order to provide good customer service. If the store is a drugstore this matter reaches a greater importance, as out of stock of a drug when there is high demand causes problems and tensions in the healthcare system. There are numerous studies of the impact this issue has on patients. The lack of any drug in a pharmacy in certain seasons is very common, especially when some external factors proliferate favoring the occurrence of certain diseases. This study focuses on a particular drug consumed in the city of Jaen, southern Andalucia, Spain. Our goal is to determine in advance the Salbutamol demand. Advanced data mining techniques have been used with spatial variables. These last have a key role to generate an effective model. In this research we have used the attributes that are associated with Salbutamol demand and it has been generated a very accurate prediction model of 5.78% of mean absolute error. This is a very encouraging data considering that the consumption of this drug in Jaen varies 500% from one period to another.

  20. Pyridoxine improves drug-induced parkinsonism and psychosis in a schizophrenic patient.

    PubMed

    Sandyk, R; Pardeshi, R

    1990-06-01

    Drug-induced Parkinsonism is a common serious side-effect of neuroleptic therapy. In cases of irreversible drug-induced Parkinsonism, pharmacological management is notoriously difficult. A schizophrenic patient with severe neuroleptic-induced Parkinsonism and Tardive Dyskinesia is presented in whom administration of pyridoxine (vitamin B6) (100 mg/d) resulted in dramatic and persistent attenuation of the movement disorders as well as reduction of psychotic behavior. Since pyridoxine deficiency is associated with marked reduction of cerebral serotonin concentrations and pineal melatonin production in rats, the effects of pyridoxine on the movement disorder and psychosis may have been mediated largely by enhancing serotonin and melatonin functions. An additional effect of excess pyridoxine administration on GABA and dopamine activity cannot be excluded. Pyridoxine has been reported to attenuate the severity of levodopa-induced dyskinesias in patients with Parkinson's disease and it is suggested that pyridoxine supplementation should be considered in psychiatric patients with drug-induced movement disorders including persistent Parkinsonism. An underlying pyridoxine deficiency in these patients may exacerbate the psychotic behavior and additionally, potentially increase the risk of drug-induced movement disorders.

  1. Mixed micelles loaded with silybin-polyene phosphatidylcholine complex improve drug solubility

    PubMed Central

    Duan, Rui-ling; Sun, Xun; Liu, Jie; Gong, Tao; Zhang, Zhi-rong

    2011-01-01

    Aim: To prepare a novel formulation of phosphatidylcholine (PC)-bile salts (BS)-mixed micelles (MMs) loaded with silybin (SLB)-PC complex for parenteral applications. Methods: SLB-PC-BS-MMs were prepared using the co-precipitation method. Differential scanning calorimetry (DSC) analysis was used to confirm the formation of the complex and several parameters were optimized to obtain a high quality formulation. The water-solubility, drug loading, particle size, zeta potential, morphology and in vivo properties of the SLB-PC-BS-MMs were determined. Results: The solubility of SLB in water was increased from 40.83±1.18 μg/mL to 10.14±0.36 mg/mL with a high drug loading (DL) of 14.43%±0.44% under optimized conditions. The SLB-PC-BS-MMs were observed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and showed spherical shapes. The particle size and zeta potential, as measured by photon correlation spectroscopy (PCS), were about 30±4.8 nm and −39±5.0 mV, respectively. In vivo studies showed that incorporation of the SLB-PC complex into PC-BS-MMs led to a prolonged circulation time of the drug. Conclusion: This novel formulation appears to be a good candidate for drug substances that exhibit poor solubility for parenteral administration. PMID:21170082

  2. [Improving drug prescribing in the elderly: a new edition of STOPP/START criteria].

    PubMed

    Delgado Silveira, E; Montero Errasquín, B; Muñoz García, M; Vélez-Díaz-Pallarés, M; Lozano Montoya, I; Sánchez-Castellano, C; Cruz-Jentoft, A J

    2015-01-01

    Inappropriate use of drugs in older patients may have an adverse impact on several individual health outcomes, such as increasing the prevalence of adverse drug reactions, morbidity and mortality, and geriatric syndromes, as well as on health care systems, such as increased costs and longer hospital stays. Explicit criteria of drug appropriateness are increasingly used to detect and prevent inappropriate use of drugs, either within a comprehensive geriatric assessment or as tool used by different multidisciplinary geriatric teams. STOPP-START criteria, first published in 2008 (in Spanish in 2009), are being adopted as reference criteria throughout Europe. The Spanish version of the new 2014 edition (recently published in English) of the STOPP-START criteria is presented here. A review of all the papers published in Spain using the former version of these criteria is also presented, with the intention of promoting their use and for research in different health care levels. Copyright © 2014 SEGG. Published by Elsevier Espana. All rights reserved.

  3. Outcome of Drug Abuse Treatment and Self Concept Improvement for Mass Transit Workers.

    ERIC Educational Resources Information Center

    Biase, D. Vincent; Sullivan, Arthur P.

    Because of increasing concern about drug use in the work place and its impact on public safety, an urban mass transit agency formed a collaborative treatment link with Daytop Village to provide treatment for "impaired" transportation workers. Effective counseling approaches in the residential setting were adapted for ambulatory use and…

  4. Medicinal chemistry based approaches and nanotechnology-based systems to improve CNS drug targeting and delivery.

    PubMed

    Vlieghe, Patrick; Khrestchatisky, Michel

    2013-05-01

    The central nervous system (CNS) is protected by various barriers, which regulate nervous tissue homeostasis and control the selective and specific uptake, efflux, and metabolism of endogenous and exogenous molecules. Among these barriers is the blood-brain barrier (BBB), a physical and physiological barrier that filters very efficiently and selectively the entry of compounds from the blood to the brain and protects nervous tissue from harmful substances and infectious agents present in the bloodstream. The BBB also prevents the entry of potential drugs. As a result, various drug targeting and delivery strategies are currently being developed to enhance the transport of drugs from the blood to the brain. Following a general introduction, we briefly overview in this review article the fundamental physiological properties of the BBB. Then, we describe current strategies to bypass the BBB (i.e., invasive methods, alternative approaches, and temporary opening) and to cross it (i.e., noninvasive approaches). This section is followed by a chapter addressing the chemical and technological solutions developed to cross the BBB. A special emphasis is given to prodrug-targeting approaches and targeted nanotechnology-based systems, two promising strategies for BBB targeting and delivery of drugs to the brain.

  5. Crosslinked chitosan-dextran sulfate nanoparticle for improved topical ocular drug delivery

    PubMed Central

    Chaiyasan, Wanachat; Srinivas, Sangly P.

    2015-01-01

    Purpose To examine the benefits of chitosan-dextran sulfate nanoparticles (CDNs) as a topical ocular delivery system with lutein as a model drug. Methods CDNs were developed by polyelectrolyte complexation of positively charged chitosan (CS) and negatively charged dextran sulfate (DS). 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and polyethylene glycol 400 (PEG400) were used as co-crosslinking and stabilizing agents, respectively. The influence of these on the properties of CDNs, including drug release and mucoadhesiveness, was examined. The chemical stability of lutein in CDNs (LCDNs) was also examined. Results Typically, LCDNs showed a spherical shape, possessing a mean size of ~400 nm with a narrow size distribution. The entrapment efficiency of lutein was in the range of 60%–76%. LCDNs possessing a positive surface charge (+46 mV) were found to be mucoadhesive. The release profile of LCDNs followed Higuchi’s square root model, suggesting drug release by diffusion from the polymer matrix. Lutein in LCDNs showed increased chemical stability during storage compared to its solution form. Conclusions These characteristics of CDNs make them suitable for drug delivery to the ocular surface. PMID:26604662

  6. Dried Blood Spot sampling in psychiatry: Perspectives for improving therapeutic drug monitoring.

    PubMed

    Martial, Lisa C; Aarnoutse, Rob E; Mulder, Martina; Schellekens, Arnt; Brüggemann, Roger J M; Burger, David M; Schene, Aart H; Batalla, Albert

    2017-03-01

    Assessment of drug concentrations is indicated to guide dosing of a selected number of drugs used in psychiatry. Conventionally this is done by vena puncture. Novel sampling strategies such as dried blood spot (DBS) sampling have been developed for various drugs, including antipsychotics, antidepressants and mood-stabilizers. DBS sampling is typically performed by means of a finger prick. This method allows for remote sampling, which means that patients are not required to travel to a health care facility. The number of DBS assays for drugs used in psychiatry has increased over the last decade and includes antidepressants (tricyclic and serotonin and/or norepinephrine reuptake inhibitors), mood stabilizers and first- and second-generation antipsychotics. Available assays often comply with analytical validation criteria but are seldom used in routine clinical care. Little attention has been paid to the clinical validation and implementation processes of home sampling. Ideally, not only medicines but also clinical chemistry parameters should be measured within the same sample. This article reflects on the position of DBS remote sampling in psychiatry and provides insight in the requisites of making such a sampling tool successful. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

  7. Drug Resistance and the Role of Combination Chemotherapy in Improving Patient Outcomes

    PubMed Central

    Yardley, Denise A.

    2013-01-01

    Resistance to cancer chemotherapy is a common phenomenon especially in metastatic breast cancer (MBC), a setting in which patients typically have had exposure to multiple lines of prior therapy. The subsequent development of drug resistance can result in rapid disease progression during or shortly after completion of treatment. Moreover, cross-class multidrug resistance limits patient treatment choices, particularly in a setting where treatments options are few. One attempt to minimize the impact of drug resistance has been the concurrent use of two or more chemotherapy agents with unrelated mechanisms of action and differing modes of drug resistance, with the intent of blocking the development of multiple intracellular escape pathways essential for tumor survival. Within the past decade, an array of mechanistically diverse agents has augmented the list of combination regimens that may be both synergistic and efficacious in pretreated MBC. The aim of this paper is to review mechanisms of resistance to common chemotherapy agents and to consider current combination treatment options for heavily pretreated and/or drug-resistant patients with MBC. PMID:23864953

  8. 3-aminopropyl functionalized magnesium phyllosilicate as an organoclay based drug carrier for improving the bioavailability of flurbiprofen

    PubMed Central

    Yang, Liang; Choi, Soo-Kyung; Shin, Hyun-Jae; Han, Hyo-Kyung

    2013-01-01

    This study aimed to develop an oral delivery system using clay-based organic–inorganic hybrid materials to improve the bioavailability of the drug, flurbiprofen, which is poorly soluble in water. 3-aminopropyl functionalized magnesium phyllosilicate (AMP clay) was synthesized by a one-pot direct sol-gel method, and then flurbiprofen (FB) was incorporated into AMP clay (FB-AMP) at different drug/clay ratios. The structural characteristics of AMP and FB-AMP formulation were confirmed by X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy. Among tested formulations, FB-AMP(3), dramatically increased the dissolution of FB and achieved rapid and complete drug release within 2 hours. More than 60% of FB was released from FB-AMP(3) after 30 minutes; the drug was completely dissolved in the water within 2 hours. Under the acidic condition (pH 1.2), FB-AMP(3) also increased the dissolution of FB by up to 47.1% within 1 hour, which was three-fold higher than that of untreated FB. Furthermore, following an oral administration of FB-AMP(3) to Sprague-Dawley rats, the peak plasma concentration and area under the plasma concentration-time curve of FB increased two-fold, and the time to reach the peak plasma concentration was shortened compared with that in the untreated FB. This result suggests that the oral drug delivery system using clay-based organic–inorganic hybrid material might be useful to improve the bioavailability of FB. PMID:24204143

  9. QbD-Oriented Development of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) of Valsartan with Improved Biopharmaceutical Performance.

    PubMed

    Bandyopadhyay, Shantanu; Beg, Sarwar; Katare, O P; Sharma, Gajanand; Singh, Bhupinder

    2015-01-01

    The objectives of the present studies were to develop the systematically optimized selfnanoemulsifying drug delivery systems (SNEDDS) of valsartan employing the holistic QbD approach. The quality profile target product (QTPP) was defined and critical quality attributes (CQAs) earmarked. Preformulation studies including the equilibrium solubility and pseudoternary phase titration studies facilitated the selection of suitable lipids and emulgents for formulation of SNEDDS. Risk assessment and factor screening studies facilitated the selection of Lauroglycol FCC and Capmul MCM L8 (i.e., lipid), Tween 40 and Tween 80 (i.e., emulgent) as the critical material attributes (CMAs) for SNEDDS prepared using medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs). A central composite design (CCD) was employed for systematic optimization of SNEDDS, taking globule size (Dnm), drug release in 10 min (Q10min) and amount permeated in 45 min (%Perm45min) as the CQAs. Design space was generated using apt mathematical models to embark upon the optimized formulations and validation of the QbD. In situ SPIP studies revealed significant improvement in the absorptivity and permeability parameters of SNEDDS owing to the inhibition of P-gp/MRP2 efflux vis-à-vis the conventional marketed formulation and pure drug. In vivo pharmacokinetic studies corroborated marked enhancement in the oral bioavailability drug from SNEDDS vis-à-vis the marketed formulation. Establishment of various levels of in vitro/in vivo correlations (IVIVC) indicated excellent goodness of fit between the in vitro drug release data with the in vivo absorption parameters. In a nutshell, the present studies report successful QbD-based development of MCT and LCT-SNEDDS of valsartan with improved biopharmaceutical performance.

  10. Initiatives to improve prescribing efficiency for drugs to treat Parkinson's disease in Croatia: influence and future directions.

    PubMed

    Brkicic, Ljiljana Sovic; Godman, Brian; Voncina, Luka; Sovic, Slavica; Relja, Maja

    2012-06-01

    Parkinson's disease (PD) is the second most common neurological disease affecting older adults. Consequently, this disease should be a focus among payers, with increasing utilization of newer premium-priced patent-protected add-on therapies to stabilize or even improve motor function over time. However, expenditure can be moderated by reforms. Consequently, there is a need to assess the influence of these reforms on the prescribing efficiency for drugs to treat PD in Croatia before proposing additional measures. Prescribing efficiency is defined as increasing the use of add-on therapies for similar expenditure. An observational retrospective study of the Croatian Institute for Health Insurance database of drugs to treat patients with PD in Croatia from 2000 to 2010 was carried out, with utilization measured in defined daily doses (defined as the average maintenance dose of a drug when used in its major indication in adults). The study years were chosen to reflect recent reforms. Only reimbursed expenditure is measured from a health insurance perspective. Utilization of drugs to treat PD increased by 218% between 2000 and 2010. Reimbursed expenditure increased by 360%, principally driven by increasing utilization of premium-priced patent-protected add-on therapies, including ropinirole and pramipexole. However, following recent reforms, reducing expenditure/defined daily dose for the different drugs, as well as overall expenditure, stabilized reimbursed expenditure between 2005 and 2010. Treatment of PD is complex, and add-on therapies are needed to improve care. Reimbursed expenditure should now fall following stabilization, despite increasing volumes, as successive add-on therapies lose their patents, further increasing prescribing efficiency.

  11. Generic drug prices and policy in Australia: room for improvement? a comparative analysis with England.

    PubMed

    Mansfield, Sarah J

    2014-02-01

    To assess the degree to which reimbursement prices in Australia and England differ for a range of generic drugs, and to analyse the supply- and demand-side factors that may contribute to these differences. Australian and English reimbursement prices were compared for a range of generic drugs using pricing information obtained from government websites. Next, a literature review was conducted to identify supply- and demand-side factors that could affect generic prices in Australia and England. Various search topics were identified addressing potential supply-side (e.g. market approval, intellectual property protection of patented drugs, generic pricing policy, market size, generic supply chain and discounting practices) and demand-side (consumers, prescribers and pharmacists) factors. Related terms were searched in academic databases, official government websites, national statistical databases and internet search engines. Analysis of drug reimbursement prices for 15 generic molecules (representing 45 different drug presentations) demonstrated that Australian prices were on average over 7-fold higher than in England. Significant supply-side differences included aspects of pricing policy, the relative size of the generics markets and the use of clawback policies. Major differences in demand-side policies related to generic prescribing, pharmacist substitution and consumer incentives. Despite recent reforms, the Australian Government continues to pay higher prices than its English counterpart for many generic medications. The results suggest that particular policy areas may benefit from review in Australia, including the length of the price-setting process, the frequency of subsequent price adjustments, the extent of price competition between originators and generics, medical professionals' knowledge about generic medicines and incentives for generic prescribing. WHAT IS KNOWN ABOUT THE TOPIC? Prices of generic drugs have been the subject of much scrutiny over recent

  12. Joint medicine-information and pharmacovigilance services could improve detection and communication about drug-safety problems

    PubMed Central

    Schjøtt, Jan; Bergman, Jenny

    2014-01-01

    Background RELIS is a Norwegian network of four regional medicine-information and pharmacovigilance centers where pharmacists and clinical pharmacologists provide feedback to health care professionals in spontaneous drug-related questions and adverse drug-reaction (ADR) reports published in a question–answer pair (QAP) database (the RELIS database) and the Norwegian ADR database, respectively. Objective To describe the potential of RELIS’s dual service to improve detection and communication of drug-safety problems. Materials and methods We searched the RELIS database for QAPs about ADRs with use of the Norwegian ADR database as a reference. We also searched the Norwegian ADR database for reports that used the RELIS database as a reference. Both searches were limited to the years 2003–2012. We then selected the example of pregabalin and drug abuse after the marketing of Lyrica in Norway in September 2004 to illustrate RELIS’s potential to detect new drug-safety information through a limited number of QAPs and ADR reports. Results A total of 5,427 (26%) of 21,071 QAPs in the RELIS database concerned ADRs. QAPs from this database were used as references in 791 (4%) of a total of 22,090 reports in the Norwegian ADR database. The Norwegian ADR database was used as a reference in 363 (7%) of 5,427 QAPs that concerned ADRs. Between September 2004 and September 2008, RELIS received eleven questions and 13 ADR reports about suspicion of Lyrica (pregabalin) and different aspects of abuse. Conclusion RELIS processes data through two databases that facilitate communication about ADRs. Our service also has the potential to detect new drug-safety problems with a limited number of questions and ADR reports. PMID:25061339

  13. Stem cell-derived models to improve mechanistic understanding and prediction of human drug induced liver injury

    PubMed Central

    Goldring, Christopher; Antoine, Daniel J.; Bonner, Frank; Crozier, Jonathan; Denning, Chris; Fontana, Robert J.; Hanley, Neil A.; Hay, David C.; Ingelman-Sundberg, Magnus; Juhila, Satu; Kitteringham, Neil; Silva-Lima, Beatriz; Norris, Alan; Pridgeon, Chris; Ross, James A.; Sison Young, Rowena; Tagle, Danilo; Tornesi, Belen; van de Water, Bob; Weaver, Richard J.; Zhang, Fang; Park, B. Kevin

    2016-01-01

    Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalised toxicology to determine inter-individual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury (DILI) means that no current single cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human DILI. Nevertheless, a single cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment, and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally-differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. PMID:27775817

  14. Merits of using color and shape differentiation to improve the speed and accuracy of drug strength identification on over-the-counter medicines by laypeople.

    PubMed

    Hellier, Elizabeth; Tucker, Mike; Kenny, Natalie; Rowntree, Anna; Edworthy, Judy

    2010-09-01

    This study aimed to examine the utility of using color and shape to differentiate drug strength information on over-the-counter medicine packages. Medication errors are an important threat to patient safety, and confusions between drug strengths are a significant source of medication error. A visual search paradigm required laypeople to search for medicine packages of a particular strength from among distracter packages of different strengths, and measures of reaction time and error were recorded. Using color to differentiate drug strength information conferred an advantage on search times and accuracy. Shape differentiation did not improve search times and had only a weak effect on search accuracy. Using color to differentiate drug strength information improves drug strength identification performance. Color differentiation of drug strength information may be a useful way of reducing medication errors and improving patient safety.

  15. Design and evaluation of mPEG-PLA micelles functionalized with drug-interactive domains as improved drug carriers for docetaxel delivery.

    PubMed

    Qi, Dingqing; Gong, Feirong; Teng, Xin; Ma, Mingming; Wen, Huijing; Yuan, Weihao; Cheng, Yi; Lu, Chong

    2017-10-01

    Polymeric micelles are very attractive drug delivery systems for hydrophobic agents, owing to their readily tailorable chemical structure and ease for scale-up preparation. However, the intrinsic poor stability of drug-loaded micelles presents one of the major challenges for most micellar systems in the translation to clinical applications. In this study, a simple, well-defined, and easy-to-scale up 9-Fluorenylmethoxycarbonyl (Fmoc) and tert-butoxycarbonyl (Boc) containing lysine dendronized mPEG-PLA (mPEG-PLA-Lys(FB)2) micellar formulation was designed and prepared for docetaxel (DTX) delivery, in an effort to improve the stability of the micelles, and its physicochemical properties, pharmacokinetics, and anti-tumor efficacy against SKOV-3 ovarian cancer were evaluated. MPEG-PLA-Lys(FB)2 was synthesized via a three-step synthetic route, and it actively interacted with DTX in aqueous media to form stable micelles with small particle sizes (~17-19 nm) and narrow size distribution (PI < 0.1), which can be lyophilized and easily reconstituted in saline without significant change in particle size distribution. In vitro drug-release study demonstrated that mPEG-PLA-Lys(FB)2 micelles achieved delayed and sustained release manner of DTX in comparison with mPEG-PLA micelles. Further in vivo xenograft tumor model in nude mice DTX/mPEG-PLA-Lys(FB)2 micelles demonstrated significantly higher inhibitory effect on tumor growth than the marketed formulation Taxotere. Thus, our system may hold promise as a simple and effective delivery system for DTX with a potential for translation into clinical study.

  16. Dissolution improvement of solid self-emulsifying drug delivery systems of fenofibrate using an inorganic high surface adsorption material.

    PubMed

    Shazly, Gamal; Mohsin, Kazi

    2015-03-01

    Solidification of lipid formulations using adsorbents is a recent technique attracting great interest due to its favourable properties including flexibility in dose division, reduction of intra-subject and inter-subject variability, improvement in efficacy/safety profile and enhancement of physical/ chemical stability. The current study aims to convert liquid self-emulsifying/nanoemulsifying drug delivery systems (SEDDS/SNEDDS) into solid SEDDS/SNEDDS and to assess how adsorption of the drug onto an inorganic high surface area material, NeusilinR grade US2 (NUS2), affects its in vitro dissolution performance. Lipid formulation classification systems (LFCS) Type III formulations were designed for the model anti-cholesterol drug fenofibrate. NUS2 was used to solidify the SEDDS/SNEDDS. Particle size and SEM analyses of solid SEDDS/SNEDDS powder were carried out to investigate the adsorption efficiency. In vitro dissolution studies were conducted to compare the developed formulations with the marketed product. The results of characterization studies showed that the use of 50% (m/m) adsorbent resulted in superior flowability and kept the drug stable is amorphous state. Dissolution studies allow the conclusion that the formulation containing a surfactant of higher water solubility (particularly, Type IIIB SNEDDS) has comparably faster and higher release profiles than Type IIIA (SEDDS) and marketed product.

  17. Improved Release of Celecoxib from High Drug Loading Amorphous Solid Dispersions Formulated with Polyacrylic Acid and Cellulose Derivatives.

    PubMed

    Xie, Tian; Taylor, Lynne S

    2016-03-07

    Amorphous solid dispersions (ASDs) have been extensively exploited as a strategy for improving the dissolution performance of poorly water-soluble drugs. However, factors underpinning the observed dissolution profiles are not clearly understood, and the choice of polymeric carriers is largely empirical. In the current study, the dissolution performance of a high drug loading ASD containing the poorly water-soluble, anti-inflammatory agent, celecoxib, was optimized by using binary polymers combinations. Polyacrylic acid (PAA), a highly water-soluble polymer, was used to substantially increase the dissolution rate of the drug, while hydroxypropyl methyl cellulose (HPMC) or HPMC acetate succinate (HPMCAS) were added to stabilize the solid amorphous matrix against crystallization upon hydration, as well as to maintain supersaturation. Quantitative measurements of the impact of the polymers on the solution nucleation and growth rates of celecoxib revealed that, while the cellulose derivatives are effective nucleation inhibitors, it is more difficult to completely prevent crystal growth in solutions containing seed crystals, in particular at high supersaturations. Therefore, it is critical to prevent the formation of crystals in the dissolving matrix during dissolution. By using certain ratios of HPMC and PAA, both rapid release as well as crystallization inhibition could be achieved, even at high drug loadings. Utilizing combinations of polymers may therefore be useful to tailor release profiles while providing optimized crystallization inhibition.

  18. Evaluation of current methods used to analyze the expression profiles of ABC transporters yields an improved drug-discovery database

    PubMed Central

    Orina, Josiah N.; Calcagno, Anna Maria; Wu, Chung-Pu; Varma, Sudhir; Shih, Joanna; Lin, Min; Eichler, Gabriel; Weinstein, John N.; Pommier, Yves; Ambudkar, Suresh V.; Gottesman, Michael M.; Gillet, Jean-Pierre

    2009-01-01

    The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anti-cancer drug and can develop by multiple mechanisms. These mechanisms can act individually or synergistically, leading to multidrug resistance (MDR), in which the cell becomes resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered. Although extensive work has been done to characterize MDR mechanisms in vitro, the translation of this knowledge to the clinic has not been successful. Therefore, identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing highly homologous genes from small amounts of tissue is fundamental to achieving any significant enhancement in our understanding of multidrug resistance mechanisms and could lead to treatments designed to circumvent it. In this study, we use a previously established database that allows the identification of lead compounds in the early stages of drug discovery that are not ABC transporter substrates. We believe this can serve as a model for appraising the accuracy and sensitivity of current methods used to analyze the expression profiles of ABC transporters. We found two platforms to be superior methods for the analysis of expression profiles of highly homologous gene superfamilies. This study also led to an improved database by revealing previously unidentified substrates for ABCB1, ABCC1 and ABCG2, transporters that contribute to multidrug resistance. PMID:19584229

  19. Drug discovery and beyond: the role of public-private partnerships in improving access to new malaria medicines.

    PubMed

    Nwaka, Solomon

    2005-10-01

    Traditional pharmaceutical research and development (R&D) strategy has failed to address the desperate need for new antimalarial drugs. The populations affected are too poor to attract commercially-driven R&D. Over the last few years, a new model, the public-private partnership for product development, has radically changed the antimalarial R&D landscape. The partnerships bring together academic and industry expertise with funding from governmental, philanthropic and charitable sources. The Medicines for Malaria Venture, a not-for-profit foundation based in Geneva, aims to develop new antimalarials for developing countries through public-private partnership. It is currently managing a portfolio of around 20 projects at various stages of development. However, as in all drug R&D, some of these projects will fail. The portfolio approach helps to maximize the chances of success, but there are obvious challenges, including financial and managerial ones. Proactive management of the two vital interfaces in the drug supply chain is important for success. Upstream, basic research must be aligned with translational research in order to ensure a continuous supply of leads into the development pipeline. Meanwhile, downstream, drug discovery and development must be aligned with access to ensure optimal health impact. All stages require partnership, sustainable financing and the engagement of disease-endemic countries. The recent G8 report on Africa has lent support to mechanisms aimed at improving health and achieving the Millenium Development Goals.

  20. Diclofenac acid nanocrystals as an effective strategy to reduce in vivo skin inflammation by improving dermal drug bioavailability.

    PubMed

    Pireddu, Rosa; Caddeo, Carla; Valenti, Donatella; Marongiu, Francesca; Scano, Alessandra; Ennas, Guido; Lai, Francesco; Fadda, Anna Maria; Sinico, Chiara

    2016-07-01

    In this work a diclofenac acid nanosuspension formulation was produced as a novel approach for the treatment of skin inflammation. Drug nanocrystals, prepared by the wet media milling technique and stabilized using Poloxamer 188, were characterized by different techniques: scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry, Fourier transform infrared spectroscopy and photon correlation spectroscopy. The ability of nanocrystals to improve dermal drug bioavailability was investigated ex vivo by using Franz diffusion vertical cells and mouse skin, in comparison with both diclofenac acid coarse suspensions and a commercial formulation. The topical anti-inflammatory activity of the drug nanosuspension was assessed in vivo by testing its effect compared to common inflammatory endpoints: i.e. the inhibition of chemically induced oedema and leucocyte infiltration (reflected in myeloperoxidase activity). Following the milling procedure, diclofenac nanocrystals exhibited a mean diameter of approximately 279nm, a low polydispersity index (∼0.17) and maintained the same polymorphic form of the starting bulk powder. When the drug nanosuspension was applied on the mouse skin it produced a higher accumulation of diclofenac in the skin compared to both the coarse suspensions and the commercial formulation, as demonstrated by ex vivo transdermal delivery experiments. Moreover, the nanosuspension provided an in vivo oedema inhibition of 50%, which was not statistically different from the commercial formulation. On the contrary, the nanosuspension showed a higher inhibition of myeloperoxidase activity in the damaged tissue (86%) than the commercial formulation (16%). Copyright © 2016 Elsevier B.V. All rights reserved.

  1. [Insulin sensitizer--anti-diabetic drugs, metformin and pioglitazone that can improve insulin resistance].

    PubMed

    Korenaga, Masaaki; Kawaguchi, Koutaro; Korenaga, Keiko; Uchida, Kouichi; Sakaida, Iso

    2006-06-01

    Nonalcoholic steatohepatitis (NASH), which is considered the hepatic manifestation of the metabolic syndrome is an increasingly cause of chronic liver disease in Japan. NASH is finally lead to liver cirrhosis and hepatocellular carcinoma as viral hepatitis, therefore, medical treatment should be considered, when NASH occurs. Treatment of patients with metabolic syndrome has been focused on the management of associated conditions such as obesity, hyperlipidemia, hypertension and hyperinsulinemia. Insulin resistance, that could accelerate liver inflammation and fibrosis by up-regulation of TNFa seems to be most important factor in many cases of NASH. The insulin-sensitizing drugs, which were biguanides (metformin) and thiazolidinediones (pioglitazone) have been shown to correct not only insulin resistance but also steatosis and inflammation in the liver. Metformin and pioglitazone might be useful drugs against NASH, however further investigations were needed.

  2. Structural modifications in polymeric micelles to impart multifunctionality for improved drug delivery.

    PubMed

    Mittal, Anupama; Chitkara, Deepak

    2016-01-01

    Polymeric micelles are macromolecular nanoconstructs which are formed by self-assembly of synthetic amphiphilic block copolymers. These copolymers could be chemically modified to expand their functionality and hence obtain a multifunctional micelle which could serve several functions simultaneously, for example, long circulation time along with active targeting, smart polymeric micelles providing on-demand drug release for example, pH responsive micelles, redox- and light-sensitive micelles, charge-conversion micelles and core/shell cross-linked micelles. Additionally, micelles could be tailored to carry a contrast agent or siRNA/miRNA along with the drug for greater clinical benefit. The focus of the current commentary would be to highlight such chemical modifications which impart multifunctionality to a single carrier and discuss challenges involved in clinical translation of these multifunctional micelles.

  3. Combined dipyridamole and aspirin pellet formulation for improved oral drug delivery. Part 1: Development pharmaceutics.

    PubMed

    Deasy, P B; Murtagh, P W

    1996-01-01

    The dissolution profile of various weight fractions of dipyridamole: hydropropylmethylcellulose acetate succinate (HPMC-AS) and dipyridamole: hydroxypropylmethylcellulose phthalate co-precipitates lead to the choice of 1:2 dipyridamole: HPMC-AS as the controlled-release component. It was deposited to form two-third of the total dose as an inner layer on inert sucrose cores by air suspension coating for release mainly in the small intestine. Further examination of this material by IR spectroscopy, differential scanning calorimetry and X-ray diffraction indicated some free drug, preferentially soluble under gastric pH conditions. One-third of the total dose was applied by pan coating as an outer layer of micronized dipyridamole around the inner enteric co-precipitate layer. Aspirin-loaded cores were prepared also by pan coating for use in the final product, which contained both anti-platelet drugs.

  4. Improving cyclodextrin complexation of a new antihepatitis drug with glacial acetic acid.

    PubMed

    Johnson, Jennifer L H; He, Yan; Jain, Akash; Yalkowsky, Samuel H

    2006-02-24

    The purpose of this study was to develop and evaluate a solid nonaqueous oral dosage form for a new hepatitis C drug, PG301029, which is insoluble and unstable in water. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) and PG301029 were dissolved in glacial acetic acid. The acetic acid was removed by rotoevaporation such that the drug exists primarily in the complexed form. The stability of formulated PG301029 was determined upon dry storage and after reconstitution in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulated PG301029 was found to be stable upon storage and can be reconstituted with water to a concentration 200 times that of the intrinsic solubility. Once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours in SGF, SIF, and water. The unique use of acetic acid and HPbetaCD results in a solid dosage form of PG301029 that is both soluble and stable in water.

  5. Ginseng and Anticancer Drug Combination to Improve Cancer Chemotherapy: A Critical Review

    PubMed Central

    Chen, Shihong; Huang, Ying; O'Barr, Stephen A.; Wong, Rebecca A.; Chow, Moses Sing Sum

    2014-01-01

    Ginseng, a well-known herb, is often used in combination with anticancer drugs to enhance chemotherapy. Its wide usage as well as many documentations are often cited to support its clinical benefit of such combination therapy. However the literature based on objective evidence to make such recommendation is still lacking. The present review critically evaluated relevant studies reported in English and Chinese literature on such combination. Based on our review, we found good evidence from in vitro and in vivo animal studies showing enhanced antitumor effect when ginseng is used in combination with some anticancer drugs. However, there is insufficient clinical evidence of such benefit as very few clinical studies are available. Future research should focus on clinically relevant studies of such combination to validate the utility of ginseng in cancer. PMID:24876866

  6. Improved dissolution rate of poorly soluble drug by incorporation of buffers.

    PubMed

    Preechagoon, D; Udomprateep, A; Manwiwattanagul, G

    2000-08-01

    This study focused on comparing dissolution rates of indomethacin after co-compressing with three different buffers (calcium carbonate, sodium carbonate, and sodium citrate) at pH 2 and 7. Factors affecting the dissolution rate were also examined, such as type and particle size of buffer and weight-to-weight ratio of drug to buffer. It was found that, at pH 7, the release rates of indomethacin with sodium carbonate (< 74 microns, all proportions) and sodium citrate (< 74 microns, 75% loading) at a 20-min test time were about 10-fold and 6-fold greater, respectively, than that of indomethacin alone. When the drug and buffer were compressed into tablets using a tableting machine, the release rates of indomethacin for the control, sodium carbonate incorporated (25% and 75% buffer loading), and sodium citrate incorporated (75% buffer loading) at a 15-min test time were 50%, 90%, 66%, and 67%, respectively.

  7. Antispasmodic drugs in colonoscopy: a review of their pharmacology, safety and efficacy in improving polyp detection and related outcomes.

    PubMed

    Sanagapalli, Santosh; Agnihotri, Kriti; Leong, Rupert; Corte, Crispin John

    2017-01-01

    Antispasmodic drugs are cheap, effective and generally safe. They may improve outcomes in colonoscopy, however their use has not been consistent or widespread. This manuscript reviews the three most commonly used antispasmodics in colonoscopy, namely, hyoscine butylbromide (and related ammonium compounds), glucagon and peppermint oil. The pharmacology, action and safety of the agents, as well as the evidence for them improving colonoscopic outcomes will be discussed. In addition to polyp detection, other colonoscopic outcome endpoints of interest include cecal and ileal intubation, and patient comfort. The drugs studied were all found to be effective gastrointestinal antispasmodics with good safety profiles. There is insufficient evidence to conclude whether antispasmodics improve cecal intubation rate, predominantly because the baseline rates are already high. Antispasmodics probably have efficacy in reducing cecal intubation time especially in those with marked colonic spasm. Antispasmodics do not offer significant benefit in polyp detection or improving patient comfort during colonoscopy. Future studies should focus on inexperienced colonoscopists as well as those with marked colonic spasm, in whom the greatest benefit seems to lie.

  8. Antispasmodic drugs in colonoscopy: a review of their pharmacology, safety and efficacy in improving polyp detection and related outcomes

    PubMed Central

    Sanagapalli, Santosh; Agnihotri, Kriti; Leong, Rupert; Corte, Crispin John

    2016-01-01

    Antispasmodic drugs are cheap, effective and generally safe. They may improve outcomes in colonoscopy, however their use has not been consistent or widespread. This manuscript reviews the three most commonly used antispasmodics in colonoscopy, namely, hyoscine butylbromide (and related ammonium compounds), glucagon and peppermint oil. The pharmacology, action and safety of the agents, as well as the evidence for them improving colonoscopic outcomes will be discussed. In addition to polyp detection, other colonoscopic outcome endpoints of interest include cecal and ileal intubation, and patient comfort. The drugs studied were all found to be effective gastrointestinal antispasmodics with good safety profiles. There is insufficient evidence to conclude whether antispasmodics improve cecal intubation rate, predominantly because the baseline rates are already high. Antispasmodics probably have efficacy in reducing cecal intubation time especially in those with marked colonic spasm. Antispasmodics do not offer significant benefit in polyp detection or improving patient comfort during colonoscopy. Future studies should focus on inexperienced colonoscopists as well as those with marked colonic spasm, in whom the greatest benefit seems to lie. PMID:28286563

  9. Improvement of Transmembrane Transport Mechanism Study of Imperatorin on P-Glycoprotein-Mediated Drug Transport.

    PubMed

    Liao, Zheng-Gen; Tang, Tao; Guan, Xue-Jing; Dong, Wei; Zhang, Jing; Zhao, Guo-Wei; Yang, Ming; Liang, Xin-Li

    2016-11-24

    P-glycoprotein (P-gp) affects the transport of many drugs; including puerarin and vincristine. Our previous study demonstrated that imperatorin increased the intestinal absorption of puerarin and vincristine by inhibiting P-gp-mediated drug efflux. However; the underlying mechanism was not known. The present study investigated the mechanism by which imperatorin promotes P-gp-mediated drug transport. We used molecular docking to predict the binding force between imperatorin and P-gp and the effect of imperatorin on P-gp activity. P-gp efflux activity and P-gp ATPase activity were measured using a rhodamine 123 (Rh-123) accumulation assay and a Pgp-Glo™ assay; respectively. The fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH) was used to assess cellular membrane fluidity in MDCK-MDR1 cells. Western blotting was used to analyze the effect of imperatorin on P-gp expression; and P-gp mRNA levels were assessed by qRT-PCR. Molecular docking results demonstrated that the binding force between imperatorin and P-gp was much weaker than the force between P-gp and verapamil (a P-gp substrate). Imperatorin activated P-gp ATPase activity; which had a role in the inhibition of P-gp activity. Imperatorin promoted Rh-123 accumulation in MDCK-MDR1 cells and decreased cellular membrane fluidity. Western blotting demonstrated that imperatorin inhibited P-gp expression; and qRT-PCR revealed that imperatorin down-regulated P-gp (MDR1) gene expression. Imperatorin decreased P-gp-mediated drug efflux by inhibiting P-gp activity and the expression of P-gp mRNA and protein. Our results suggest that imperatorin could down-regulate P-gp expression to overcome multidrug resistance in tumors.

  10. Using the level of Service Inventory-Revised to improve assessment and treatment in drug court.

    PubMed

    Guastaferro, Wendy P

    2012-08-01

    More than 2,000 drug courts in the United States provide supervision and substance-abuse treatment to thousands of offenders. Yet the treatment continuum from assessment to aftercare is underexplored. The effectiveness of the Level of Service Inventory-Revised (LSI-R) as a risk assessment tool is well established. However, fewer studies have considered its use in guiding treatment strategies. In using the LSI-R, the drug court program relied on the structured interview protocol (not the risk classification scores) to identify criminogenic needs that then helped determine placement in a high- or low-needs treatment track. To evaluate the effectiveness of these treatment placement decisions, this research used the LSI-R scores to examine individual and group differences (N = 182). Significant and substantive differences at the individual and group levels were found thus providing empirical support for using the LSI-R as a link between assessment and treatment. Implications for developing standards and practice protocols for drug courts are discussed.

  11. Improving Safe and Effective Use of Drugs in Pregnancy and Lactation: Workshop Summary.

    PubMed

    Riley, Laura E; Cahill, Alison G; Beigi, Richard; Savich, Renate; Saade, George

    2017-07-01

    In February 2015, given high rates of use of medications by pregnant women and the relative lack of data on safety and efficacy of many drugs utilized in pregnancy, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the Society for Maternal-Fetal Medicine (SMFM), the American College of Obstetricians and Gynecologists (ACOG), and the American Academy of Pediatrics (AAP) convened a group of experts to review the "current" state of the clinical care and science regarding medication use during the perinatal period. The expert panel chose select medications to demonstrate what existing safety and efficacy data may be available for clinicians and patients when making decisions about use in pregnancy or lactation. Furthermore, these example medications also provided opportunities to highlight where data are lacking, thus forming a list of research gaps. Last, after reviewing the existing vaccine safety surveillance system as well as the legislative history surrounding the use of drugs for pediatric diseases, the expert panel made specific recommendations concerning policy efforts to stimulate more research and regulatory attention on drugs for pregnant and lactating women. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  12. Designing structural features of novel benznidazole-loaded cationic nanoparticles for inducing slow drug release and improvement of biological efficacy.

    PubMed

    Dos Santos-Silva, Alaine M; de Caland, Lilia B; de S L Oliveira, Ana Luíza C; de Araújo-Júnior, Raimundo F; Fernandes-Pedrosa, Matheus F; Cornélio, Alianda Maira; da Silva-Júnior, Arnóbio A

    2017-09-01

    Several polymers have been investigated for producing cationic nanocarriers due to their ability to cross biological barriers. Polycations such as copolymers of polymethylmethacrylate are highlighted due to their biocompatibility and low toxicity. The purpose of this study was to produce small and narrow-sized cationic nanoparticles able to overcome cell membranes and improve the biological activity of benznidazole (BNZ) in normal and cancer cells. The effect of composition and procedure parameters of the used emulsification-solvent evaporation method were controlled for this purpose. The experimental approach included particle size, polydispersity index, zeta potential, atomic force microscopy (AFM), attenuated total reflectance Fourier transforms infrared spectroscopy (ATR- FTIR), drug loading efficiency, and physical stability assays. Spherical and stable (over six weeks) sub 150nm cationic nanoparticles were optimized, with the encapsulation efficiency >80%. The used drug/copolymer ratio modulated the slow drug release, which was adjusted by the parabolic diffusion mathematical model. In addition, the ability of the cationic nanoparticles improve the BNZ uptake in the normal kidney cells (HEK 293) and the human colorectal cancer cells (HT 29) demonstrate that this novel BNZ-loaded cationic has great potential as a chemotherapeutic application of benznidazole. Copyright © 2017. Published by Elsevier B.V.

  13. Equipment management guide. Improving the drug distribution process--do you need an automated decentralized pharmacy dispensing system?

    PubMed

    1996-12-01

    In this Equipment Management Guide, we provide guidance to help hospitals determine whether implementing an automated decentralized pharmacy dispensing system (ADPDS) will be an effective way to improve their drug distribution process. We describe the ADPDSs themselves and then discuss factors that hospitals should consider before deciding on such a system. Specifically, we identify several areas that many pharmacies target for improvement and discuss whether and how an ADPDS can help the facility make the desired improvements. We also provide guidance for determining the cost-effectiveness of such a system, as well as for selecting a system that will most appropriately meet the hospital's needs. In the Evaluation that follows this Guide, we present our criteria for evaluating ADPDSs and the results of our testing of three such systems.

  14. Selective Reduction of Methylsulfinyl-containing Compounds by mammalian MsrA Suggests a Strategy for Improved Drug Efficacy

    PubMed Central

    Lee, Byung Cheon; Fomenko, Dmitri E.; Gladyshev, Vadim N.

    2011-01-01

    Identification of pathways of drug metabolism provides critical information regarding efficacy and safety of these compounds. Particularly challenging cases involve stereospecific processes. We found that broad classes of compounds containing methylsulfinyl groups are reduced to methylsulfides specifically by methionine sulfoxide reductase A, which acts on the S-stereomers of methionine sulfoxides, whereas the R-stereomers of these compounds could not be efficiently reduced by any methionine sulfoxide reductase in mammals. The findings of efficient reduction of S-methylsulfinyls and deficiency in the reduction of R-methylsulfinyls by methionine sulfoxide reductases suggest strategies for improved efficacy and decreased toxicity of drugs and natural compounds containing methylsulfinyls through targeted use of their enantiomers. PMID:21823615

  15. Improving access to sterile syringes and safe syringe disposal for injection drug users in methadone maintenance treatment.

    PubMed

    McNeely, Jennifer; Arnsten, Julia H; Gourevitch, Marc N

    2006-07-01

    We evaluated a novel intervention designed to improve access to sterile syringes and safe syringe disposal for injection drug users (IDUs) newly enrolled in methadone maintenance, through interviews with two sequential cohorts of 100 recent entrants into a methadone program in the Bronx, NY. A substantial number of participants had injected in the previous 6 months, and most continued injecting during the early weeks of treatment. The intervention was associated with significant behavior changes among IDUs, including increased use of pharmacies as a primary source of syringes (11% vs. 37%, p < .05) and decreases in both purchasing of syringes on the street (51% vs. 27%, p < .05) and needle sharing (40% vs. 7%, p < .01). The intervention had no impact on the prevalence of injection or on syringe disposal practices. Our findings suggest that drug treatment programs can serve an important role in reducing injection-related risk behavior by facilitating access to sterile syringes.

  16. Improved Oral Bioavailability Using a Solid Self-Microemulsifying Drug Delivery System Containing a Multicomponent Mixture Extracted from Salvia miltiorrhiza.

    PubMed

    Bi, Xiaolin; Liu, Xuan; Di, Liuqing; Zu, Qiang

    2016-04-08

    The active ingredients of salvia (dried root of Salvia miltiorrhiza) include both lipophilic (e.g., tanshinone IIA, tanshinone I, cryptotanshinone and dihydrotanshinone I) and hydrophilic (e.g., danshensu and salvianolic acid B) constituents. The low oral bioavailability of these constituents may limit their efficacy. A solid self-microemulsifying drug delivery system (S-SMEDDS) was developed to load the various active constituents of salvia into a single drug delivery system and improve their oral bioavailability. A prototype SMEDDS was designed using solubility studies and phase diagram construction, and characterized by self-emulsification performance, stability, morphology, droplet size, polydispersity index and zeta potential. Furthermore, the S-SMEDDS was prepared by dispersing liquid SMEDDS containing liposoluble extract into a solution containing aqueous extract and hydrophilic polymer, and then freeze-drying. In vitro release of tanshinone IIA, salvianolic acid B, cryptotanshinone and danshensu from the S-SMEDDS was examined, showing approximately 60%-80% of each active component was released from the S-SMEDDS in vitro within 20 min. In vivo bioavailability of these four constituents indicated that the S-SMEDDS showed superior in vivo oral absorption to a drug suspension after oral administration in rats. It can be concluded that the novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of both lipophilic and hydrophilic constituents of salvia. Thus, the S-SMEDDS can be regarded as a promising new method by which to deliver salvia extract, and potentially other multicomponent drugs, by the oral route.

  17. Higher magnitude cash payments improve research follow-up rates without increasing drug use or perceived coercion.

    PubMed

    Festinger, David S; Marlowe, Douglas B; Dugosh, Karen L; Croft, Jason R; Arabia, Patricia L

    2008-07-01

    In a prior study [Festinger, D.S., Marlowe, D.B., Croft, J.R., Dugosh, K.L., Mastro, N.K., Lee, P.A., DeMatteo, D.S., Patapis, N.S., 2005. Do research payments precipitate drug use or coerce participation? Drug Alcohol Depend. 78 (3) 275-281] we found that neither the mode (cash vs. gift card) nor magnitude ($10, $40, or $70) of research follow-up payments increased rates of new drug use or perceptions of coercion. However, higher payments and payments in cash were associated with better follow-up attendance, reduced tracking efforts, and improved participant satisfaction with the study. The present study extended those findings to higher payment magnitudes. Participants from an urban outpatient substance abuse treatment program were randomly assigned to receive $70, $100, $130, or $160 in either cash or a gift card for completing a follow-up assessment at 6 months post-admission (n congruent with 50 per cell). Apart from the payment incentives, all participants received a standardized, minimal platform of follow-up efforts. Findings revealed that neither the magnitude nor mode of payment had a significant effect on new drug use or perceived coercion. Consistent with our previous findings, higher payments and cash payments resulted in significantly higher follow-up rates and fewer tracking calls. In addition participants receiving cash vs. gift cards were more likely to use their payments for essential, non-luxury purchases. Follow-up rates for participants receiving cash payments of $100, $130, and $160 approached or exceeded the FDA required minimum of 70% for studies to be considered in evaluations of new medications. This suggests that the use of higher magnitude payments and cash payments may be effective strategies for obtaining more representative follow-up samples without increasing new drug use or perceptions of coercion.

  18. Pharmaceutical solid dispersion technology: a strategy to improve dissolution of poorly water-soluble drugs.

    PubMed

    Kumar, Shobhit; Gupta, Satish K

    2013-08-01

    Oral bioavailability is the major problem when a poorly water-soluble active agent is delivered via oral route. To overcome such problems, solid dispersion systems have been demonstrated in literature to enhance the dissolution property of poorly water-soluble drugs. In the present review, the important aspects to be considered during preparation of solid dispersion systems viz., properties of polymer and preparation techniques of solid dispersion which affect the dissolution rate are discussed. Formulation and evaluation techniques for solid dispersions have been described. The final section of article highlights the recent patents and studies related to solid dispersion systems.

  19. Rewarding results: Improving the quality of treatment for people with alcohol and drug problems.

    PubMed

    2004-03-01

    Substance use disorders are the nation's number one health problem, and lie at the root of many public safety and workplace issues. Improving quality of treatment is as important as improving access to treatment. Leadership for improvement must come from many sources: Congress, SAMHSA, state legislatures, state and local treatment agencies, criminal justice, welfare and other public agencies, employers and managed care organizations, providers, and community leaders. We hope that our report helps leaders see ways to improve treatment quality. Our recommendations can be summed up in a single phrase: reward results. We recognize that there are many avenues for treatment quality improvement, including training, credentialing, best practice dissemination, work force development, facility licensing standards, improvement and implementation of new models for treatment of dual diagnosis patients. We believe, however, that rewarding results is essential to motivating action for improvement. We also believe that if providers receive rewards for improved results, they will creatively open new avenues for improvement--a focus on results gives greater freedom than more detailed mandates for change. Finally, we believe that rewards for result may lead to a restructured treatment system with greater stability and correspondingly greater capacity to improve. While we have placed central emphasis on the role of institutional buyers and managers of care, we believe that the voices of patients and families must be heard. People who have progressed to the stage of recovery, and their families, often have essential insight into what did and did not work for them--their personal stories are frequently compelling and persuasive. We also believe that providers of treatment for substance use disorders are profoundly committed to serving their patients, and often have great understanding of what works. Wise managers will listen very carefully and systematically to the voices of consumers

  20. Self nanoemulsifying drug delivery system of stabilized ellagic acid-phospholipid complex with improved dissolution and permeability.

    PubMed

    Avachat, Amelia M; Patel, Vijay G

    2015-07-01

    Ellagic acid (EA), a plant polyphenol known for its wide-range of health benefits has limited use due to its low oral bioavailability. In this study, a new self-nanoemulsifying drug delivery system (SNEDDS), based on the phospholipid complex technique, was developed to improve the oral bioavailability of ellagic acid. Ellagic acid-phospholipid complex was prepared by an anti-solvent method and characterized. Enhanced lipophilicity after the formation of ellagic acid-phospholipid complex was verified through solubility studies. Preliminary screening was carried out to select oil, surfactant and co-surfactant. Ternary phase diagrams were constructed to identify the area of nanoemulsification. Formulations were optimized on the basis of globule size, cloud point and robustness to dilution. The optimized SNEDDS of ellagic acid-phospholipid complex showed mean globule size of 106 ± 0.198 nm and cloud point at 83-85 °C. The in vitro drug release from SNEDDS was found to be higher compared to EA suspension and complex, while ex vivo studies showed increased permeation from SNEDDS compared to EA suspension. Moreover, SNEDDS overcome the food effect which was shown by EA suspension. Thus, SNEDDS were found to be influential in improving the release performance of EA, indicating their potential to improve the oral bioavailability of EA.

  1. Self nanoemulsifying drug delivery system of stabilized ellagic acid–phospholipid complex with improved dissolution and permeability

    PubMed Central

    Avachat, Amelia M.; Patel, Vijay G.

    2014-01-01

    Ellagic acid (EA), a plant polyphenol known for its wide-range of health benefits has limited use due to its low oral bioavailability. In this study, a new self-nanoemulsifying drug delivery system (SNEDDS), based on the phospholipid complex technique, was developed to improve the oral bioavailability of ellagic acid. Ellagic acid–phospholipid complex was prepared by an anti-solvent method and characterized. Enhanced lipophilicity after the formation of ellagic acid–phospholipid complex was verified through solubility studies. Preliminary screening was carried out to select oil, surfactant and co-surfactant. Ternary phase diagrams were constructed to identify the area of nanoemulsification. Formulations were optimized on the basis of globule size, cloud point and robustness to dilution. The optimized SNEDDS of ellagic acid–phospholipid complex showed mean globule size of 106 ± 0.198 nm and cloud point at 83–85 °C. The in vitro drug release from SNEDDS was found to be higher compared to EA suspension and complex, while ex vivo studies showed increased permeation from SNEDDS compared to EA suspension. Moreover, SNEDDS overcome the food effect which was shown by EA suspension. Thus, SNEDDS were found to be influential in improving the release performance of EA, indicating their potential to improve the oral bioavailability of EA. PMID:26106276

  2. Structural Basis of Resistance to Anti-Cytochrome bc1 Complex Inhibitors: Implication for Drug Improvement

    PubMed Central

    Esser, Lothar; Yu, Chang-An; Xia, Di

    2016-01-01

    The emergence of drug resistance has devastating economic and social consequences, a testimonial of which is the rise and fall of inhibitors against the respiratory component cytochrome bc1 complex, a time tested and highly effective target for disease control. Unfortunately, the mechanism of resistance is a multivariate problem, including primarily mutations in the gene of the cytochrome b subunit but also activation of alternative pathways of ubiquinol oxidation and pharmacokinetic effects. There is a considerable interest in designing new bc1 inhibitors with novel modes of binding and lower propensity to induce the development of resistance. The accumulation of crystallographic data of bc1 complexes with and without inhibitors bound provides the structural basis for rational drug design. In particular, the cytochrome b subunit offers two distinct active sites that can be targeted for inhibition - the quinol oxidation site and the quinone reduction site. This review brings together available structural information of inhibited bc1 by various quinol oxidation- and reduction-site inhibitors, the inhibitor binding modes, conformational changes upon inhibitor binding of side chains in the active site and large scale domain movements of the iron-sulfur protein subunit. Structural data analysis provides a clear understanding of where and why existing inhibitors fail and points towards promising alternatives. PMID:23688079

  3. Roles of dextrans on improving lymphatic drainage for liposomal drug delivery system.

    PubMed

    Feng, Linglin; Zhang, Lei; Liu, Min; Yan, Zhiqiang; Wang, Chenyu; Gu, Bing; Liu, Yu; Wei, Gang; Zhong, Gaoren; Lu, Weiyue

    2010-04-01

    Our aim was to develop a novel liposomal drug delivery system containing dextrans to reduce undesirable retention of antineoplastic agents and thus alleviate local tissue damage. At the cell level, diethylaminoethyl-dextran (DEAE-Dx) showed the strongest inhibiting effect on liposome uptake by macrophages among tested dextrans. The distribution of radiolabeled liposomes mixed with dextrans in injection site and draining lymph node was investigated in rats after subcutaneous injection. DEAE-Dx substantially reduced the undesired local retention and promoted the draining of liposome into lymphatics, which was further confirmed by confocal microscopy images revealing the substantial prevention of rhodamine B-labelled liposome sequestration by macrophages in normal lymph node in rats. Pharmacokinetic data indicated the accelerated drainage of liposome through lymphatics back to systemic circulation by mixing with DEAE-Dx. In the toxicological study in rabbits, DEAE-Dx alleviated the local tissue damage caused by liposomal doxorubicin. In conclusion, dextrans, particularly DEAE-Dx, could efficiently enhanced liposomes drainage into lymphatics, which proves themselves as promising adjuvants for lymphatic-targeted liposomal drug delivery system.

  4. Ester prodrugs of morphine improve transdermal drug delivery: a mechanistic study.

    PubMed

    Wang, Jhi-Joung; Sung, K C; Huang, Jeng-Fen; Yeh, Chih-Hui; Fang, Jia-You

    2007-07-01

    Two alkyl esters of morphine, morphine propionate (MPR) and morphine enanthate (MEN), were synthesized as potential prodrugs for transdermal delivery. The ester prodrugs could enhance transdermal morphine delivery. The mechanisms of this enhancing effect were elucidated in this study. Both prodrugs were more lipophilic than their parent drug as evaluated by the skin/vehicle partition coefficient (log P) and capacity factor (log K'). The in-vitro skin permeation of morphine and its prodrugs from pH 6 buffer was in the order of MEN > MPR > morphine. MPR and MEN respectively enhanced the transdermal delivery of morphine by 2- and 5-fold. A contrary result was observed when using sesame oil as the vehicle. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were readily hydrolysed to the parent drug when exposed to skin homogenate and esterase. Approximately 98% MPR and approximately 75% MEN were converted to morphine in an in-vitro permeation experiment. The viable epidermis/dermis contributed to a significant resistance to the permeation of ester prodrugs. According to the data of skin permeation across ethanol-, alpha-terpineol-, and oleic acid-pretreated skin, MEN was predominantly transported via lipid bilayer lamellae in the stratum corneum. The intercellular pathway was not important for either morphine or MPR permeation.

  5. Characterization of supersaturatable formulations for improved absorption of poorly soluble drugs.

    PubMed

    Gao, Ping; Shi, Yi

    2012-12-01

    With the increasing number of poorly water-soluble compounds in contemporary drug discovery pipelines, the concept of supersaturation as an effective formulation approach for enhancing bioavailability is gaining momentum. This is intended to design the formulation to yield significantly high intraluminal concentrations of the drug than the thermodynamic equilibrium solubility through achieving supersaturation and thus to enhance the intestinal absorption. The major challenges faced by scientists developing supersaturatable formulations include controlling the rate and degree of supersaturation with the application of polymeric precipitation inhibitor and maintenance of post-administration supersaturation. This review is intended to cover publications on this topic since April 2009. Scientific publications associated with characterization of supersaturatable systems and related preclinical and clinical pharmacokinetics (PK) studies are reviewed. Specifically, this review will address issues related to assessing the performance of supersaturatable systems including: (1) Diversified approaches for developing supersaturatable formulations, (2) meaningful in vitro test methods to evaluate supersaturatable formulations, and (3) in vivo PK study cases which have demonstrated direct relevance between the supersaturation state and the exposure observed in animal models and human subjects.

  6. The pH-sensitive polyampholyte nanogels: inclusion of carbon nanotubes for improved drug loading.

    PubMed

    Sankar, Rajavelu Murali; Seeni Meera, Kamal Mohamed; Samanta, Debasis; Jithendra, Panneerselvam; Mandal, Asit Baran; Jaisankar, Sellamuthu N

    2013-12-01

    We report a simple and facile method to prepare a novel pH sensitive polyampholyte nanogel by copolymerizing vinylimidazole (VIM) with acrylic acid (AA) using functionalized single-walled carbon nanotubes (f-SWCNTs) (as reinforcing material) and cyanuric chloride via an intermolecular quaternization reaction. The polyampholyte nanogels have been characterized by various microscopic and spectroscopic methods. These studies reveal that incorporation of nanotubes in cross-linked copolymer of poly(vinylimidazole-co-acrylic acid) (PVI-co-AA) form polyampholyte nanogel with enhanced physical properties. The thermal experiments show that the introduction of f-SWCNTs into PVI-co-AA has significant impact on the thermal stability of nanogels. The rheological study showed that the nanogel is more viscoelastic than native gel. MTT assay indicates that the prepared polyampholyte gels possess biocompatibility and cell viability. The nanogel is also useful material to load water-soluble drug such as promethazine hydrochloride. The releasing profile of the drug from the nanogel clearly shows the pH-sensitive property of the material.

  7. Mouse Models for Drug Discovery. Can New Tools and Technology Improve Translational Power?

    PubMed

    Zuberi, Aamir; Lutz, Cathleen

    2016-12-01

    The use of mouse models in biomedical research and preclinical drug evaluation is on the rise. The advent of new molecular genome-altering technologies such as CRISPR/Cas9 allows for genetic mutations to be introduced into the germ line of a mouse faster and less expensively than previous methods. In addition, the rapid progress in the development and use of somatic transgenesis using viral vectors, as well as manipulations of gene expression with siRNAs and antisense oligonucleotides, allow for even greater exploration into genomics and systems biology. These technological advances come at a time when cost reductions in genome sequencing have led to the identification of pathogenic mutations in patient populations, providing unprecedented opportunities in the use of mice to model human disease. The ease of genetic engineering in mice also offers a potential paradigm shift in resource sharing and the speed by which models are made available in the public domain. Predictively, the knowledge alone that a model can be quickly remade will provide relief to resources encumbered by licensing and Material Transfer Agreements. For decades, mouse strains have provided an exquisite experimental tool to study the pathophysiology of the disease and assess therapeutic options in a genetically defined system. However, a major limitation of the mouse has been the limited genetic diversity associated with common laboratory mice. This has been overcome with the recent development of the Collaborative Cross and Diversity Outbred mice. These strains provide new tools capable of replicating genetic diversity to that approaching the diversity found in human populations. The Collaborative Cross and Diversity Outbred strains thus provide a means to observe and characterize toxicity or efficacy of new therapeutic drugs for a given population. The combination of traditional and contemporary mouse genome editing tools, along with the addition of genetic diversity in new modeling systems

  8. Solid lipid nanoparticles for oral drug delivery: chitosan coating improves stability, controlled delivery, mucoadhesion and cellular uptake.

    PubMed

    Luo, Yangchao; Teng, Zi; Li, Ying; Wang, Qin

    2015-05-20

    The poor stability of solid lipid nanoparticles (SLN) under acidic condition resulted in large aggregation in gastric environment, limiting their application as oral delivery systems. In this study, a series of SLN was prepared to investigate the effects of surfactant/cosurfactant and chitosan coating on their physicochemical properties as well as cellular uptake. SLN was prepared from Compritol 888 ATO using a low-energy method combining the solvent-diffusion and hot homogenization technique. Poloxamer 188 and polyethylene glycol (PEG) were effective emulsifiers to produce SLN with better physicochemical properties than SLN control. Chitosan-coated SLN exhibited the best stability under acidic condition by forming a thick layer around the lipid core, as clearly observed by transmission electron microscope. The intermolecular interactions in different formulations were monitored by Fourier transform infrared spectroscopy. Chitosan coating also significantly improved the mucoadhesive property of SLN as determined by Quartz Crystal Microbalance. In vitro drug delivery assays, cytotoxicity, and cellular uptake of SLN were studied by incorporating coumarin 6 as a fluorescence probe. Overall, chitosan-coated SLN was superior to other formulations and held promising features for its application as a potential oral drug delivery system for hydrophobic drugs.

  9. Understanding patients' perspective in the use of generic antiepileptic drugs: compelling lessons for physicians to improve physician/patient communication

    PubMed Central

    Liow, Kore

    2009-01-01

    Background Epilepsy is a condition in which consistency of treatment is paramount to successful management and for most patients, effective seizure control can be achieved. Given the severe consequences of even a single breakthrough seizure, patients should be afforded every opportunity to succeed on their given regimens. Discussion Some experts argue that global policy on generic antiepileptic drug substitution in epilepsy should be limited – occurring at the discretion of and with careful monitoring by the physician. While the debate continues, physicians still have daily responsibilities to their patients to help them best manage their epilepsy within the context of the current environment – the reality of which may involve switching to a generic antiepileptic drug or navigating various formulations between generics. Summary To provide context, this paper first reviews the main "hot button" issues fueling the ongoing generic debate, including a broad overview of the current state of the literature. The main goal however is to provide physicians with a patient perspective on generic antiepileptic drug use in epilepsy as a source of clinically useful, everyday advice to improve communication and increase patient self-advocacy, both of which are necessary for optimal patient outcome. PMID:19292903

  10. [Improvement of quality of practices for the preparation of cytotoxic drugs: results of a "before-after" study].

    PubMed

    Gilles, L; Favier, B; Catillon, F; Dussart, C; Peyron, F; Simoens, X; Latour, J-F; Farsi, F; Biron, P

    2009-09-01

    Despite the publication of guidelines for handling antineoplastic agents, measurable amounts of these drugs are still found at various hospital sites. In this context, the French cancer network ONCORA supported the present study to assess the impact of environmental contamination controls on the quality of practices during the preparation of cytotoxic drugs. The first part of the study was conducted at five voluntary hospitals. A total of 65 wipe samples of objects and surfaces were taken in the drug preparation rooms and analyzed for the presence of 5-fluorouracil (5-FU). Measurable amounts of 5-FU were detected in 21 samples (32%). Many surfaces within Biological Safety Cabinets and isolators were found contaminated (36%). The worse results were obtained on gloves and on the outside of infusion bags. The same method was applied during the second part of the study, conducted six months after the end of the first audit. Global contamination was reduced to 17%. This study shows that appropriate handling helps decrease the number of samples contaminated, making it possible to recommend these controls for evaluating and improving the quality of practices. Since 2007, the network's laboratory has extended its activities to all French hospitals interested in this quality assurance programme.

  11. Factors to Improve the Management of Hepatitis C in Drug Users: An Observational Study in an Addiction Centre

    PubMed Central

    Moussalli, Joseph; Delaquaize, Helene; Boubilley, Dominique; Lhomme, Jean Pierre; Merleau Ponty, Jules; Sabot, David; Kerever, Anne; Valleur, Marc; Poynard, Thierry

    2010-01-01

    Barriers to management of HCV in injection drug users are related to patients, health providers, and facilities. In a primary care drug user's addiction centre we studied access to HCV standard of care before and after using an onsite total care concept provided by a multidisciplinary team and noninvasive liver fibrosis evaluation. A total of 586 patients were seen between 2002 and 2004. The majority, 417 patients, were HCV positive and of these patients 337 were tested positive for HCV RNA. In 2002, patients were sent to the hospital. with the Starting of 2003, patients were offered standard of care HCV management in the center by a team of general practitioners, a consultant hepatologist, psychiatrists, nurses, and a health counsellor. Liver fibrosis was assessed by a non invasive method. In 2002, 6 patients had liver fibrosis assessment at hospital facilities, 4 patients were assessed with liver biopsy and 2 patients with Fibrotest-Actitest. 2 patients were treated for HCV at hospital. In 2003 and 2004, 224 patients were assessed with Fibrotest-Actitest on site. Of these, 85 were treated for HCV. SVR was achieved in 43%. We conclude that the combination of an onsite multidisciplinary team with the use of a noninvasive assessment method led to improved management of HCV infection in drug users' primary care facility. PMID:20811482

  12. Noninvasive quantitation of drug concentration in prostate and seminal vesicles: improvement and validation with desipramine and aspirin.

    PubMed

    Cao, Ying-Jun; Caffo, Brian; Choi, Leena; Radebaugh, Christine L; Fuchs, Edward J; Hendrix, Craig W

    2008-02-01

    The accessory glands of the male genital tract are the sites of several major health problems, including benign prostatic hyperplasia, prostate cancer, and human immunodeficiency virus (HIV) transmission. We aimed to validate and improve our noninvasive method for the quantitation of drug concentrations in these physiological subcompartments. Twenty-seven men were dosed with 100 mg desipramine (a weak base) and 975 mg aspirin (a weak acid) and ejaculated their semen in 1 pass across 5 compartments of a collection device 2.5 hours later. A Bayesian latent-variable model previously developed by our group was further advanced for the estimation of drug concentrations in prostate and seminal vesicles based on drug and biomarker concentrations in the split ejaculate. Under normality assumptions, desipramine concentration (with 95% credible intervals) in prostate and seminal vesicles were 27 (8.3-52) ng/mL and 7.6 (4.0-11) ng/mL, respectively; salicylate concentration in prostate and seminal vesicles were 2.0 (0.093-6.5) microg/mL, and 9.9 (8.2-12) microg/mL, respectively. The prostate-to-seminal vesicles concentration ratio was 0.20 (0.0087-0.75) for salicylate and 3.6 (0.91-9.9) for desipramine. We conclude that our quantitative analysis along with the split ejaculate method is sensitive, reproducible, and applicable for the assessment of pharmacokinetics of the accessory glands of the male genital tract.

  13. II. Technological approaches to improve the dissolution behavior of nateglinide, a lipophilic insoluble drug: co-milling.

    PubMed

    Maggi, Lauretta; Bruni, Giovanna; Maietta, Mariarosa; Canobbio, Andrea; Cardini, Andrea; Conte, Ubaldo

    2013-09-15

    Nateglinide is an oral antidiabetic agent that should be administered 10-30 min before the meal, but it shows low and pH-dependent solubility that may reduce its oral bioavailability. To improve nateglinide dissolution rate, the active was co-milled with three different super-disintegrants or with some hydrophilic excipients, in 1:1, 1:2, and 1:4 drug to carrier ratio (w:w). The three super-disintegrants were crosslinked polyvinylpyrrolidone (PVPC), sodium starch glycolate (SSG) and crosslinked carboxymethyl cellulose (CMCC). The three hydrophilic excipient were amorphous silica (AS), mannitol (M) and Poloxamer (PO). A strong enhancement of drug dissolution rate was obtained from the nateglinide:super-disintegrant co-milled systems in 1:4 ratio, which can be explained by a combination of several factors: an increase in wettability, due to the hydrophilic nature of the carriers, a possible reduction of particle size and a more intimate dispersion of the drug onto the carrier, as a result of the mechanical treatment. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Factors to improve the management of hepatitis C in drug users: an observational study in an addiction centre.

    PubMed

    Moussalli, Joseph; Delaquaize, Helene; Boubilley, Dominique; Lhomme, Jean Pierre; Merleau Ponty, Jules; Sabot, David; Kerever, Anne; Valleur, Marc; Poynard, Thierry

    2010-01-01

    Barriers to management of HCV in injection drug users are related to patients, health providers, and facilities. In a primary care drug user's addiction centre we studied access to HCV standard of care before and after using an onsite total care concept provided by a multidisciplinary team and noninvasive liver fibrosis evaluation. A total of 586 patients were seen between 2002 and 2004. The majority, 417 patients, were HCV positive and of these patients 337 were tested positive for HCV RNA. In 2002, patients were sent to the hospital. with the Starting of 2003, patients were offered standard of care HCV management in the center by a team of general practitioners, a consultant hepatologist, psychiatrists, nurses, and a health counsellor. Liver fibrosis was assessed by a non invasive method. In 2002, 6 patients had liver fibrosis assessment at hospital facilities, 4 patients were assessed with liver biopsy and 2 patients with Fibrotest-Actitest. 2 patients were treated for HCV at hospital. In 2003 and 2004, 224 patients were assessed with Fibrotest-Actitest on site. Of these, 85 were treated for HCV. SVR was achieved in 43%. We conclude that the combination of an onsite multidisciplinary team with the use of a noninvasive assessment method led to improved management of HCV infection in drug users' primary care facility.

  15. Delivery of a peptide-drug conjugate targeting the blood brain barrier improved the efficacy of paclitaxel against glioma

    PubMed Central

    Li, Ying; Zheng, Xuemin; Gong, Min; Zhang, Jianning

    2016-01-01

    The challenge of effectively delivering therapeutic agents to the brain has created an entire field of active research devoted to overcoming the blood brain barrier (BBB) and efficiently delivering drugs to the brain. Angiopep-2 can trigger transcytosis and traverse the BBB by recognizing low-density lipoprotein related protein-1 (LRP-1) expressed on the brain capillary endothelial cells. Here, we designed a novel strategy for the delivery of drugs to the brain. The novel drug delivery system was a combination of a receptor-targeting ligand, such as low-density lipoprotein related protein 1, and a cell-penetrating peptide (CPP). It was hypothesized that this conjugate will enhance the delivery of associated therapeutic cargo across the BBB and increase the permeability of a solid tumor. Our findings indicate that the combination of these two agents in a delivery vehicle significantly improved translocation of small molecules (paclitaxel) into the brain compared to the vehicle treatment, which contained only receptor-targeting ligand. The application of this strategy could potentially expand the horizons for the treatment of central nervous system disorders. PMID:27765902

  16. Improved intestinal absorption of water-soluble drugs by acetylation of G2 PAMAM dendrimer nanocomplexes in rat.

    PubMed

    Yan, Chengyun; Gu, Jiwei; Lv, Yuguang; Shi, Weiguo; Jing, Hongying

    2017-03-16

    In search of an effective and less toxic absorption enhancer, we synthesized primary amine acetylation of generation 2 polyamidoamine (G2 PAMAM) dendrimer (Ac-G2) by the reaction of G2 PAMAM dendrimer with acetic anhydride, and evaluated the effects of Ac-G2 on the intestinal absorption of poorly absorbable water-soluble drugs using an in situ closed-loop method in rats. The results indicated that Ac50-G2 had a greatest absorption enhancing effect for 5(6)-carboxyfluorescein (CF) in various acetylation levels of G2 PAMAM dendrimers. Ac50-G2 with various concentrations (0.1-1.0%, w/v) could significantly improve the intestinal absorption of alendronate, CF, and fluorescein isothiocyanate-labeled dextrans (FD4), although they did not enhance the absorption of macromolecular drug of FD10, and the absorption enhancement effect of Ac50-G2 was concentration-dependent. Furthermore, we examined the intestinal membrane damage with or without Ac50-G2. The results displayed Ac50-G2 at lower concentrations (0.1-0.5%, w/v) did not cause any observed toxic effect to the intestinal membranes. These findings suggested Ac50-G2 at lower concentrations (below 0.5%, w/v) might be promising as an effective and safe absorption enhancers to promote the intestinal absorption of poorly absorbable drugs.

  17. Colistin combination therapy improves microbiologic cure in critically ill patients with multi-drug resistant gram-negative pneumonia.

    PubMed

    Parchem, N L; Bauer, K A; Cook, C H; Mangino, J E; Jones, C D; Porter, K; Murphy, C V

    2016-09-01

    Currently, in vitro synergy with colistin has not translated into improved clinical outcomes. This study aimed to compare colistin combination therapy to colistin monotherapy in critically ill patients with multi-drug resistant gram-negative (MDR-GN) pneumonia. This was a retrospective analysis of critically ill adult patients receiving intravenous colistin for MDR-GN pneumonia comparing colistin combination therapy to colistin monotherapy with a primary endpoint of clinical cure. Combination therapy was defined by administration of another antibiotic to which the MDR-GN pathogen was reported as susceptible or intermediate. Ninety patients were included for evaluation (41 combination therapy and 49 monotherapy). Baseline characteristics were similar between groups. No difference in clinical cure was observed between combination therapy and monotherapy in univariate analysis, nor when adjusted for APACHE II score and time to appropriate antibiotic therapy (57.1 vs. 63.4 %, adjusted OR 1.15, p = 0.78). Microbiological cure was significantly higher for combination therapy (87 vs. 35.5 %, p < 0.001). Colistin combination therapy was associated with a significant improvement in microbiological cure, without improvement in clinical cure. Based on the in vitro synergy and improvement in microbiological clearance, colistin combination therapy should be prescribed for MDR-GN pneumonia. Further research is warranted to determine if in vitro synergy with colistin translates into improved clinical outcomes.

  18. Mapping of the WHO-ART terminology on Snomed CT to improve grouping of related adverse drug reactions.

    PubMed

    Alecu, Iulian; Bousquet, Cedric; Mougin, Fleur; Jaulent, Marie-Christine

    2006-01-01

    The WHO-ART and MedDRA terminologies used for coding adverse drug reactions (ADR) do not provide formal definitions of terms. In order to improve groupings, we propose to map ADR terms to equivalent Snomed CT concepts through UMLS Metathesaurus. We performed such mappings on WHO-ART terms and can automatically classify them using a description logic definition expressing their synonymies. Our gold standard was a set of 13 MedDRA special search categories restricted to ADR terms available in WHO-ART. The overlapping of the groupings within the new structure of WHO-ART on the manually built MedDRA search categories showed a 71% success rate. We plan to improve our method in order to retrieve associative relations between WHO-ART terms.

  19. Impaired synthesis of stromal components in response to Minnelide improves vascular function, drug delivery and survival in pancreatic cancer

    PubMed Central

    Banerjee, Sulagna; Modi, Shrey; McGinn, Olivia; Zhao, Xianda; Dudeja, Vikas; Ramakrishnan, Sundaram; Saluja, Ashok K

    2015-01-01

    Purpose Pancreatic cancer stromal microenvironment is considered to be the major reason for failure of conventional and targeted therapy for this disease. The desmoplastic stroma, comprising mainly of collagen and glycosaminoglycans like hyaluronan (HA), is responsible for compression of vasculature in the tumor resulting in impaired drug delivery and poor prognosis. Minnelide, a water-soluble pro-drug of triptolide currently in Phase I clinical trial, has been very effective in multiple animal models of pancreatic cancer. However, whether Minnelide will have efficacious delivery into the tumor in spite of the desmoplastic stroma, has not been evaluated before. Experiment design Patient tumor derived xenografts (PDX) and spontaneous pancreatic cancer mice were treated with 0.42 mg/kg and 0.21 mg/kg body weight for 30 days. Stromal components were determined by IHC and ELISA based assays. Vascular functionality and drug delivery to the tumor were assessed following treatment with Minnelide. Result Our current study shows that treatment with Minnelide resulted in reduction of ECM components like hyaluronan (HA) and collagen in the pancreatic cancer stroma of both the spontaneous KPC mice as well as in patient tumor xenografts. Further, treatment with Minnelide improved functional vasculature in the tumors resulting in 4- times more functional vessels in the treated animals compared to untreated animals. Consistent with this observation, Minnelide also resulted in increased drug delivery into the tumor compared to untreated animals. Along with this, Minnelide also decreased viability of the stromal cells along with the tumor cells in pancreatic adenocarcinoma. Conclusion In conclusion, these results are extremely promising as they indicate that Minnelide, along with having anti-cancer effects is also able to deplete stroma in pancreatic tumors, which makes it an effective therapy for pancreatic cancer. PMID:26405195

  20. Self-microemulsifying drug-delivery system for improved oral bioavailability of pranlukast hemihydrate: preparation and evaluation.

    PubMed

    Baek, Myoung-Ki; Lee, Jong-Hwa; Cho, Young-Ho; Kim, Hak-Hyung; Lee, Gye-Won

    2013-01-01

    The purpose of the present investigation was to develop and evaluate a self-microemulsifying drug delivery system (SMEDDS) for improving the oral absorption of a pranlukast hemihydrate (PLH), a very poorly water-soluble drug. An efficient self-microemulsifying vehicle for PLH was selected and optimized using solubility testing and phase diagram construction. The formulations were characterized by assessing self-emulsification performance, droplet size analysis, in vitro drug release characteristics and formulation stability studies. Optimized formulations for in vitro dissolution and bioavailability assessment were Triethylcitrate (TEC; 10%), Tween 20 (50%), Span 20 (25%), triethanolamine (5%), and benzyl alcohol (10%). The SMEDDS readily released the lipid phase to form a fine oil-in-water microemulsion with a narrow distribution size. Saturated solubilities of PLH from SMEDDS in water, pH 4.0 and 6.8, were over 150 times greater than that of plain PLH. The release of 100% PLH from SMEDDS was considerably greater compared to only 1.12% in simulated intestinal fluid (pH 6.8) from plain PLH after 2 hours. The PLH suspension with 0.5% sodium carboxymethylcellulose or 3% PLH-loaded SMEDDS was administrated at a dose of 40 mg/kg as PLH to fasted rats. The absorption of PLH from SMEDDS resulted in about a threefold increase in bioavailability compared with plain PLH aqueous suspension. Our studies illustrated that the potential use of the new SMEDDS can be used as a possible alternative to oral delivery of a poorly water-soluble drug such as PLH.

  1. Improvement of drug dose calculations by classroom teaching or e-learning: a randomised controlled trial in nurses

    PubMed Central

    Simonsen, Bjoerg O; Daehlin, Gro K; Johansson, Inger; Farup, Per G

    2014-01-01

    Introduction Insufficient skills in drug dose calculations increase the risk for medication errors. Even experienced nurses may struggle with such calculations. Learning flexibility and cost considerations make e-learning interesting as an alternative to classroom teaching. This study compared the learning outcome and risk of error after a course in drug dose calculations for nurses with the two methods. Methods In a randomised controlled open study, nurses from hospitals and primary healthcare were randomised to either e-learning or classroom teaching. Before and after a 2-day course, the nurses underwent a multiple choice test in drug dose calculations: 14 tasks with four alternative answers (score 0–14), and a statement regarding the certainty of each answer (score 0–3). High risk of error was being certain that incorrect answer was correct. The results are given as the mean (SD). Results 16 men and 167 women participated in the study, aged 42.0 (9.5) years with a working experience of 12.3 (9.5) years. The number of correct answers after e-learning was 11.6 (2.0) and after classroom teaching 11.9 (2.0) (p=0.18, NS); improvement were 0.5 (1.6) and 0.9 (2.2), respectively (p=0.07, NS). Classroom learning was significantly superior to e-learning among participants with a pretest score below 9. In support of e-learning was evaluation of specific value for the working situation. There was no difference in risk of error between groups after the course (p=0.77). Conclusions The study showed no differences in learning outcome or risk of error between e-learning and classroom teaching in drug dose calculations. The overall learning outcome was small. Weak precourse knowledge was associated with better outcome after classroom teaching. PMID:25344483

  2. Orthogonal PLS (OPLS) Modeling for Improved Analysis and Interpretation in Drug Design.

    PubMed

    Eriksson, Lennart; Rosén, Josefin; Johansson, Erik; Trygg, Johan

    2012-07-01

    Partial least squares (PLS) regression is a flexible data analytical approach, which can be made even more versatile and useful by various modifications. In this article we describe the extension into orthogonal PLS modeling, in terms of two new methods, called OPLS and O2PLS, with similar prediction capacity but improved model interpretation.

  3. Vendor-to-vendor education to improve malaria treatment by private drug outlets in Bungoma District, Kenya.

    PubMed

    Tavrow, Paula; Shabahang, Jennifer; Makama, Sammy

    2003-05-07

    Private outlets are the main suppliers of uncomplicated malaria treatment in Africa. However, they are so numerous that they are difficult for governments to influence and regulate. This study's objective was to evaluate a low-cost outreach education (vendor-to-vendor) programme to improve the private sector's compliance with malaria guidelines in Bungoma district, Kenya. The cornerstone of the programme was the district's training of 73 wholesalers who were equipped with customized job aids for distribution to small retailers. Six months after training the wholesalers, the programme was evaluated using mystery shoppers. The shoppers posed as caretakers of sick children needing medication at 252 drug outlets. Afterwards, supervisors assessed the outlets' knowledge, drug stocks, and prices. The intervention seems to have had a significant impact on stocking patterns, malaria knowledge and prescribing practices of shops/kiosks, but not consistently on other types of outlets. About 32% of shops receiving job aids prescribed to mystery shoppers the approved first-line drug, sulfadoxine-pyremethamine, as compared to only 3% of the control shops. In the first six months, it is estimated that 500 outlets were reached, at a cost of about $8000. Changing private sector knowledge and practices is widely acknowledged to be slow and difficult. The vendor-to-vendor programme seems a feasible district-level strategy for achieving significant improvements in knowledge and practices of shops/kiosks. However, alternate strategies will be needed to influence pharmacies and clinics. Overall, the impact will be only moderate unless national policies and programmes are also introduced.

  4. Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue

    PubMed Central

    Incecayir, Tuba; Sun, Jing; Tsume, Yasuhiro; Xu, Hao; Gose, Tomoka; Nakanishi, Takeo; Tamai, Ikumi; Hilfinger, John; Lipka, Elke; Amidon, Gordon L.

    2016-01-01

    The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carrier mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylenedioxy linker (GOC-ISP-Val) was evaluated as the potential substrate for intestinal oligopeptide transporter, hPEPT1 in Xenopus laevis oocytes heterologously expressing hPEPT1 and an intestinal mouse perfusion system. The diastereomers of GOC-ISP-Val were assessed for chemical and metabolic stability. Permeability of GOC-ISP-Val was determined in Caco-2 cells and mice. Diastereomer 2 was about two times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a nine times enhanced apparent permeability (Papp) in Caco-2 cells compared to the parent drug. Both diastereomer exhibited high effective permeability (Peff ) in mice, 6.32±3.12 and 5.20±2.81 x10−5 cm/s for diastereomer 1 and 2, respectively. GOC-ISP-Val was found to be a substrate of hPEPT1. Overall, this study indicates that the prodrug, GOC-ISP-Val seems to be a promising oral anti-influenza agent that has sufficient stability at physiologically relevant pHs prior to absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells. PMID:26869437

  5. Hot Melt Extruded Amorphous Solid Dispersion of Posaconazole with Improved Bioavailability: Investigating Drug-Polymer Miscibility with Advanced Characterisation

    PubMed Central

    Amin, Purnima

    2014-01-01

    Invasive antifungal infections are reasons for morbidity and mortality in immunogenic patients worldwide. Posaconazole is a most promising antifungal agent against all types of invasive infections with high % of cure rate. The marketed suspension formulation has low bioavailability and is needed to be taken with food. In this paper, PCZ hot melt extruded amorphous solid dispersion (SD) with immediate release and improved bioavailability was prepared using Soluplus (Sol) as primary carrier for solubilization. Surfactants such as PEG 400, Lutrol F27, Lutrol F68, and TPGS are also used in combination with Soluplus to improve the physicochemical performance of the formulation when it comes in contact with GI (gastrointestinal) fluid. Drug-polymer miscibility of SD was investigated using advanced techniques. In the in vivo study, the AUC(0–72) and Cmax of PCZ/Soluplus were 11.5 and 11.74 time higher than those of pure PCZ. The formulation of the extrudate SD had an AUC(0–72) and Cmax higher than those with the commercial capsule (Noxafil). Molecular dynamic (MD) simulation studies were carried out using in silico molecular modelling to understand the drug-polymer intermolecular behaviour. The results of this research ensure enhanced dissolution and bioavailability of the solid dispersion of PCZ prepared by HME compared with the PCZ suspension. PMID:25143935

  6. Hot melt extruded amorphous solid dispersion of posaconazole with improved bioavailability: investigating drug-polymer miscibility with advanced characterisation.

    PubMed

    Fule, Ritesh; Amin, Purnima

    2014-01-01

    Invasive antifungal infections are reasons for morbidity and mortality in immunogenic patients worldwide. Posaconazole is a most promising antifungal agent against all types of invasive infections with high % of cure rate. The marketed suspension formulation has low bioavailability and is needed to be taken with food. In this paper, PCZ hot melt extruded amorphous solid dispersion (SD) with immediate release and improved bioavailability was prepared using Soluplus (Sol) as primary carrier for solubilization. Surfactants such as PEG 400, Lutrol F27, Lutrol F68, and TPGS are also used in combination with Soluplus to improve the physicochemical performance of the formulation when it comes in contact with GI (gastrointestinal) fluid. Drug-polymer miscibility of SD was investigated using advanced techniques. In the in vivo study, the AUC(0-72) and C(max) of PCZ/Soluplus were 11.5 and 11.74 time higher than those of pure PCZ. The formulation of the extrudate SD had an AUC(0-72) and C(max) higher than those with the commercial capsule (Noxafil). Molecular dynamic (MD) simulation studies were carried out using in silico molecular modelling to understand the drug-polymer intermolecular behaviour. The results of this research ensure enhanced dissolution and bioavailability of the solid dispersion of PCZ prepared by HME compared with the PCZ suspension.

  7. An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells

    SciTech Connect

    Noor, Fozia Niklas, Jens Mueller-Vieira, Ursula Heinzle, Elmar

    2009-06-01

    Efficient and accurate safety assessment of compounds is extremely important in the preclinical development of drugs especially when hepatotoxicty is in question. Multiparameter and time resolved assays are expected to greatly improve the prediction of toxicity by assessing complex mechanisms of toxicity. An integrated approach is presented in which Hep G2 cells and primary rat hepatocytes are compared in frequently used cytotoxicity assays for parent compound toxicity. The interassay variability was determined. The cytotoxicity assays were also compared with a reliable alternative time resolved respirometric assay. The set of training compounds consisted of well known hepatotoxins; amiodarone, carbamazepine, clozapine, diclofenac, tacrine, troglitazone and verapamil. The sensitivity of both cell systems in each tested assay was determined. Results show that careful selection of assay parameters and inclusion of a kinetic time resolved assay improves prediction for non-metabolism mediated toxicity using Hep G2 cells as indicated by a sensitivity ratio of 1. The drugs with EC{sub 50} values 100 {mu}M or lower were considered toxic. The difference in the sensitivity of the two cell systems to carbamazepine which causes toxicity via reactive metabolites emphasizes the importance of human cell based in-vitro assays. Using the described system, primary rat hepatocytes do not offer advantage over the Hep G2 cells in parent compound toxicity evaluation. Moreover, respiration method is non invasive, highly sensitive and allows following the time course of toxicity. Respiration assay could serve as early indicator of changes that subsequently lead to toxicity.

  8. Clobazam Therapeutic Drug Monitoring: A Comprehensive Review of the Literature with Proposals to Improve Future Studies

    PubMed Central

    de Leon, Jose; Spina, Edoardo; Diaz, Francisco J.

    2012-01-01

    Background Clobazam was recently approved for Lennox-Gastaut syndrome in the US. There is no published review article focused on clobazam therapeutic drug monitoring (TDM) in English. Methods More than two hundred clobazam articles identified by a PubMed search were carefully reviewed for information on clobazam pharmacokinetics. Clobazam is mainly metabolized by a cytochrome P450 (CYP) isoenzyme, CYP3A4, to its active metabolite, N-desmethylclobazam. Then, N-desmethylclobazam is mainly metabolized by CYP2C19 unless the individual has no CYP2C19 activity (poor metabolizer, PM). Results Using a mechanistic approach to reinterpret the published findings of steady-state TDM and single-dosing pharmacokinetic studies, four different serum clobazam concentration ratios were studied. The available limited steady-state TDM data suggest that the serum N-desmethylclobazam/clobazam ratio can be useful for clinicians, including identifying CYP2C19 PMs (ratio >25 in the absence of inhibitors). There are three possible concentration/dose (C/D) ratios. The clobazam C/D ratio has the potential to measure the contribution of CYP3A4 activity to the clearance of clobazam from the body. The N-desmethylclobazam C/D ratio does not appear to be a good measure of clobazam clearance and should be substituted with the total (clobazam+N-desmethylclobazam) C/D ratio. Conclusions Future clobazam TDM studies need to use trough concentrations after steady-state has been reached (>3 weeks in normal individuals and several months in CYP2C19 PMs). These future studies need to explore the potential of clobazam and total C/D ratios. Better studies on the relative potency of N-desmethylclobazam compared to the parent compound are needed to provide weighted total serum concentrations that correct for the possible lower N-desmethylclobazam pharmacodynamic activity. Standardization and more studies of C/D ratios from clobazam and other drugs can be helpful to move TDM forward. PMID:23318278

  9. Preoperative Drug Induced Sleep Endoscopy Improves the Surgical Approach to Treatment of Obstructive Sleep Apnea.

    PubMed

    Huntley, Colin; Chou, David; Doghramji, Karl; Boon, Maurits

    2017-06-01

    Drug induced sleep endoscopy (DISE) allows for preoperative evaluation of the specific site and character of upper airway obstruction in obstructive sleep apnea (OSA). We aim to assess the impact DISE has on customizing the surgical plan and evaluate its role in surgical success. We retrospectively reviewed patients undergoing surgery for OSA. We compared those patients undergoing preoperative DISE to those that did not to assess procedures performed and surgical outcomes. We found 87 patients undergoing surgery for OSA who had postoperative polysomnogram results. Of the group undergoing preoperative DISE, 8% had multilevel surgery. This compared to 59.5% in those not undergoing DISE ( p = .0004). The success rate of patients who had preoperative DISE was 86% compared to 51.4% in those who did not have preoperative DISE ( p < .001). We found no difference in age, gender, preoperative apnea-hypopnea index (AHI), oxygen nadir, Epworth sleepiness scale score (ESS), body mass index (BMI) and postoperative oxygen nadir, ESS, or BMI in the DISE and no DISE cohorts. The addition of DISE to our preoperative workup has contributed to a decreased rate of multilevel surgery and increased rate of surgical success through identification of the individual patient's OSA architecture and customization of the surgical plan.

  10. In silico design and analysis of a new hyperglycosylated analog of erythropoietin to improve drug efficacy

    PubMed Central

    Kianmehr, Anvarsadat; Mohammadi, Hamid Shahbaz; Shokrgozar, Mohammad Ali; Omidinia, Eskandar

    2015-01-01

    Background: The enhancement of glycosylation by applying glycoengineering approaches has become widely used to boost properties for protein therapeutics. The objective of this work was to engineer a new hyperglycosylated analog of erythropoietin (EPO) with appropriately targeted N-linked carbohydrates through bioinformatics tools. Materials and Methods: The EPO protein sequence was retrieved from NCBI protein sequence database. Prediction of N-glycosylation sites for the target protein was done using the prediction server, NetNGlyc. The three-dimensional model of glycoengineered EPO (named as kypoetin) was constructed using the homology modeling program. Ramchandran plot obtained from PROCHECK server was used to check stereochemical property. Meanwhile, 3D model of kypoetin with attached N-carbohydrates was built up using the GlyProt server. Results: In the new modified analog, three additional N-glycosylation sites at amino-acid positions 30, 34 and 86 were inserted. Ramchandran plot analysis showed 81.6% of the residues in the most favored region, 15.6% in the additional allowed, 1.4% in the generously allowed regions and 1.4% in the disallowed region. 3D structural modeling showed that attached carbohydrates were on the proper spatial position. The whole solvent accessible surface areas of kypoetin (15132.69) were higher than EPO (9938.62). Conclusions: Totally, various model evaluation methods indicated that the glycoengineered version of EPO had considerably good geometry and acceptable profiles for clinical studies and could be considered as the effective drug. PMID:26322290

  11. New anthracenedione derivatives with improved biological activity by virtue of stable drug-DNA adduct formation.

    PubMed

    Mansour, Oula C; Evison, Benny J; Sleebs, Brad E; Watson, Keith G; Nudelman, Abraham; Rephaeli, Ada; Buck, Damian P; Collins, J Grant; Bilardi, Rebecca A; Phillips, Don R; Cutts, Suzanne M

    2010-10-14

    Mitoxantrone is an anticancer agent that acts as a topoisomerase II poison, however, it can also be activated by formaldehyde to form DNA adducts. Pixantrone, a 2-aza-anthracenedione with terminal primary amino groups in its side chains, forms formaldehyde-mediated adducts with DNA more efficiently than mitoxantrone. Molecular modeling studies indicated that extension of the "linker" region of anthracenedione side arms would allow the terminal primary amino greater flexibility and thus access to the guanine residues on the opposite DNA strand. New derivatives based on the pixantrone and mitoxantrone backbones were synthesized, and these incorporated primary amino groups as well as extended side chains. The stability of DNA adducts increased with increasing side chain length of the derivatives. A mitoxantrone derivative bearing extended side chains (7) formed the most stable adducts with ∼100-fold enhanced stability compared to mitoxantrone. This finding is of great interest because long-lived drug-DNA adducts are expected to perturb DNA-dependent functions at all stages of the cell cycle.

  12. Inhaler technique: facts and fantasies. A view from the Aerosol Drug Management Improvement Team (ADMIT).

    PubMed

    Levy, Mark L; Dekhuijzen, P N R; Barnes, P J; Broeders, M; Corrigan, C J; Chawes, B L; Corbetta, L; Dubus, J C; Hausen, Th; Lavorini, F; Roche, N; Sanchis, J; Usmani, Omar S; Viejo, J; Vincken, W; Voshaar, Th; Crompton, G K; Pedersen, Soren

    2016-04-21

    Health professionals tasked with advising patients with asthma and chronic obstructive pulmonary disease (COPD) how to use inhaler devices properly and what to do about unwanted effects will be aware of a variety of commonly held precepts. The evidence for many of these is, however, lacking or old and therefore in need of re-examination. Few would disagree that facilitating and encouraging regular and proper use of inhaler devices for the treatment of asthma and COPD is critical for successful outcomes. It seems logical that the abandonment of unnecessary or ill-founded practices forms an integral part of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages. We review the evidence, or lack thereof, underlying ten items of inhaler 'lore' commonly passed on by health professionals to each other and thence to patients. The exercise is intended as a pragmatic, evidence-informed review by a group of clinicians with appropriate experience. It is not intended to be an exhaustive review of the literature; rather, we aim to stimulate debate, and to encourage researchers to challenge some of these ideas and to provide new, updated evidence on which to base relevant, meaningful advice in the future. The discussion on each item is followed by a formal, expert opinion by members of the ADMIT Working Group.

  13. Gastroretentive inorganic-organic hybrids to improve class IV drug absorption.

    PubMed

    Perioli, Luana; Pagano, Cinzia

    2014-12-30

    Therapeutic efficacy of some orally administered molecules is often conditioned by their solubility in physiological fluids as well as their absorption. The last aspect becomes more limitative and conditioning drug plasmatic profiles when the active ingredient is preferentially absorbed in a specific region of the gastrointestinal tract. A case is represented by furosemide (FURO) preferentially absorbed in the stomach, site in which, because of its acidic nature, is poorly soluble. To solve this problem new oral solid formulations have been developed. The inorganic-organic hybrid MgAl-HTlc-FURO has been formulated in tablet in which floating and mucoadhesion properties have been combined. Swellable (Methocel K4, Methocel K15, Methocel K100 M, hydroxypropyl methyl cellulose) or swellable/erodible polymers (Methocel E50 LV, Methocel K100 LV), used to obtain the floating, were combined to Carbopol(®) (971P or 974P) to confer mucoadhesion capacity. Prepared tablets were deeply characterized in terms of hydration capacity, erosion %, buoyancy lag time/floating time and mucoadhesion. The most suitable tablets selected from these preliminary tests, submitted to in vitro release studies, showed a sustained release of FURO. This is useful to maintain the therapeutic concentrations for a long time, in comparison to conventional dosage forms, thanking to the enhancement of formulation residence time in the stomach.

  14. Novel designed polyoxyethylene nonionic surfactant with improved safety and efficiency for anticancer drug delivery.

    PubMed

    Li, Chang; Sun, Chunmeng; Li, Shasha; Han, Peng; Sun, Huimin; Ouahab, Ammar; Shen, Yan; Xu, Yourui; Xiong, Yerong; Tu, Jiasheng

    2014-01-01

    In order to limit the adverse reactions caused by polysorbate 80 in Taxotere(®), a widely used formulation of docetaxel, a safe and effective nanocarrier for this drug has been developed based on micelles formed by a new class of well-defined polyoxyethylene sorbitol oleate (PSO) with sorbitol as the matrix in aqueous solution. The physicochemical properties of the amphiphilic surfactant and the resulting micelles can be easily fine-tuned by the homogeneous sorbitol matrix and pure oleic acid. Composition, critical micelle concentration, and entrapment efficiency were investigated by ultraviolet visible spectroscopy, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorospectrophotometry, and high-performance liquid chromatography. In vitro and in vivo evaluation revealed that PSO had exceptionally low hemolysis and histamine release rates compared with commercial polysorbate 80. Moreover, the tumor targeting delivery of PSO was investigated by in vivo imaging in S180 tumor-bearing mice. The results suggest that this novel delivery system, PSO, provides an acceptable alternative to polysorbate 80 for delivery of docetaxel. Further, due to the hypoallergenic nature of PSO, the mechanism of pseudoallergy caused by the polyoxyethylene nonionic surfactant was investigated. Based on in vitro cell analysis, it was assumed that the initial contact of polyoxyethylene nonionic surfactant with mast cells provoked pseudoallergy via polyamine receptor-mediated endocytosis.

  15. Novel designed polyoxyethylene nonionic surfactant with improved safety and efficiency for anticancer drug delivery

    PubMed Central

    Li, Chang; Sun, Chunmeng; Li, Shasha; Han, Peng; Sun, Huimin; Ouahab, Ammar; Shen, Yan; Xu, Yourui; Xiong, Yerong; Tu, Jiasheng

    2014-01-01

    In order to limit the adverse reactions caused by polysorbate 80 in Taxotere®, a widely used formulation of docetaxel, a safe and effective nanocarrier for this drug has been developed based on micelles formed by a new class of well-defined polyoxyethylene sorbitol oleate (PSO) with sorbitol as the matrix in aqueous solution. The physicochemical properties of the amphiphilic surfactant and the resulting micelles can be easily fine-tuned by the homogeneous sorbitol matrix and pure oleic acid. Composition, critical micelle concentration, and entrapment efficiency were investigated by ultraviolet visible spectroscopy, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorospectrophotometry, and high-performance liquid chromatography. In vitro and in vivo evaluation revealed that PSO had exceptionally low hemolysis and histamine release rates compared with commercial polysorbate 80. Moreover, the tumor targeting delivery of PSO was investigated by in vivo imaging in S180 tumor-bearing mice. The results suggest that this novel delivery system, PSO, provides an acceptable alternative to polysorbate 80 for delivery of docetaxel. Further, due to the hypoallergenic nature of PSO, the mechanism of pseudoallergy caused by the polyoxyethylene nonionic surfactant was investigated. Based on in vitro cell analysis, it was assumed that the initial contact of polyoxyethylene nonionic surfactant with mast cells provoked pseudoallergy via polyamine receptor-mediated endocytosis. PMID:24812509

  16. In silico design and analysis of a new hyperglycosylated analog of erythropoietin to improve drug efficacy.

    PubMed

    Kianmehr, Anvarsadat; Mohammadi, Hamid Shahbaz; Shokrgozar, Mohammad Ali; Omidinia, Eskandar

    2015-01-01

    The enhancement of glycosylation by applying glycoengineering approaches has become widely used to boost properties for protein therapeutics. The objective of this work was to engineer a new hyperglycosylated analog of erythropoietin (EPO) with appropriately targeted N-linked carbohydrates through bioinformatics tools. The EPO protein sequence was retrieved from NCBI protein sequence database. Prediction of N-glycosylation sites for the target protein was done using the prediction server, NetNGlyc. The three-dimensional model of glycoengineered EPO (named as kypoetin) was constructed using the homology modeling program. Ramchandran plot obtained from PROCHECK server was used to check stereochemical property. Meanwhile, 3D model of kypoetin with attached N-carbohydrates was built up using the GlyProt server. In the new modified analog, three additional N-glycosylation sites at amino-acid positions 30, 34 and 86 were inserted. Ramchandran plot analysis showed 81.6% of the residues in the most favored region, 15.6% in the additional allowed, 1.4% in the generously allowed regions and 1.4% in the disallowed region. 3D structural modeling showed that attached carbohydrates were on the proper spatial position. The whole solvent accessible surface areas of kypoetin (15132.69) were higher than EPO (9938.62). Totally, various model evaluation methods indicated that the glycoengineered version of EPO had considerably good geometry and acceptable profiles for clinical studies and could be considered as the effective drug.

  17. Inhaler technique: facts and fantasies. A view from the Aerosol Drug Management Improvement Team (ADMIT)

    PubMed Central

    Levy, Mark L; Dekhuijzen, P N R; Barnes, P J; Broeders, M; Corrigan, C J; Chawes, B L; Corbetta, L; Dubus, J C; Hausen, Th; Lavorini, F; Roche, N; Sanchis, J; Usmani, Omar S; Viejo, J; Vincken, W; Voshaar, Th; Crompton, G K; Pedersen, Soren

    2016-01-01

    Health professionals tasked with advising patients with asthma and chronic obstructive pulmonary disease (COPD) how to use inhaler devices properly and what to do about unwanted effects will be aware of a variety of commonly held precepts. The evidence for many of these is, however, lacking or old and therefore in need of re-examination. Few would disagree that facilitating and encouraging regular and proper use of inhaler devices for the treatment of asthma and COPD is critical for successful outcomes. It seems logical that the abandonment of unnecessary or ill-founded practices forms an integral part of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages. We review the evidence, or lack thereof, underlying ten items of inhaler ‘lore’ commonly passed on by health professionals to each other and thence to patients. The exercise is intended as a pragmatic, evidence-informed review by a group of clinicians with appropriate experience. It is not intended to be an exhaustive review of the literature; rather, we aim to stimulate debate, and to encourage researchers to challenge some of these ideas and to provide new, updated evidence on which to base relevant, meaningful advice in the future. The discussion on each item is followed by a formal, expert opinion by members of the ADMIT Working Group. PMID:27098045

  18. Lessons from history of socioeconomic improvements: a new approach to treating multi-drug-resistant tuberculosis.

    PubMed

    Holloway, K L; Staub, K; Rühli, F; Henneberg, M

    2014-09-01

    This study investigated the trends in tuberculosis mortality through time in Switzerland. Information on the decline in mortality before chemotherapies were introduced may be useful in developing countries where drug-resistant tuberculosis is now becoming a major problem. Swiss data were collected from historical records and comparative data were obtained from the literature for England and Wales, New York, Japan, Brazil and Sierra Leone. Logistic curves were fitted to examine the rate of decline before introduction of pharmacotherapies and these show that the decline would have continued without the introduction of chemical therapies, including antibiotics. In Switzerland, England and Wales and New York, the decline had occurred long before the introduction of specific anti-tuberculosis agents. In Brazil and Japan, chemical therapy was co-incident with the decline in tuberculosis mortality rates. Overall, it is suggested that the effective control of tuberculosis can be achieved through a combination of chemical interventions, conservative therapy (rest, good nutrition, ventilation, etc.) as well as public health interventions addressing hygiene, nutrition, reducing exposure to infections and educating the population about tuberculosis.

  19. Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery.

    PubMed

    Mao, Fei; Kong, Qingya; Ni, Wei; Xu, Xiang; Ling, Dazheng; Lu, Zhengyu; Li, Jian

    2016-08-01

    The melting point (MP), an easily accessible physical parameter, has considerable potential for the judgment of drug-like properties. However, to the best of our knowledge, there are no useful guidelines for understanding the relationship between the MP and drug-like properties. To this end, we have constructed the largest MP database (experimental value) of globally approved drugs (3164 organic small-molecule drugs) and discontinued drugs (417 organic small-molecule drugs) and subsequently extracted six subdatabases from the whole approved database and two subdatabases from the discontinued database. The MP distribution statistics and analysis of approved drugs reveal five noteworthy observations; moreover, the MP distribution statistics and analysis of discontinued drugs further supplement these criteria. In addition, the comparison of molecular weight (MW) versus MP and Clog P versus MP distributions of different classes of approved drugs indicated that the MWs and Clog P values of most drugs in the optimal MP range were not more than 500 and 5, respectively, implying the MP distribution criterion was in accordance with Lipinski's rule of five.

  20. Improvements in analytical methodology for the determination of frequently consumed illicit drugs in urban wastewater.

    PubMed

    Bijlsma, Lubertus; Beltrán, Eduardo; Boix, Clara; Sancho, Juan V; Hernández, Félix

    2014-07-01

    Rapid and sensitive analytical methodology based on ultra high-performance liquid chromatography-tandem mass spectrometry has been developed for the determination of widely consumed drugs of abuse (amphetamines, MDMA, cocaine, opioids, cannabis and ketamine) and their major metabolites in urban wastewaters. Sample clean-up and pre-concentration was performed by a generic off-line SPE procedure using Oasis HLB. Special effort was made to incorporate amphetamine, which was found highly problematic in the wastewater samples tested, including an additional clean-up with Oasis MCX SPE and dispersive primary secondary amine. Correction for possible SPE losses or degradation during storage was made by the use of isotope-labelled internal standards (ILIS), available for all compounds, which were added to the samples as surrogates. Although ILIS were also efficient for matrix effects correction, the strong ionization suppression observed was not eliminated; therefore, a four-fold dilution prior to SPE was applied to influent wastewaters and a low injection volume was selected (3 μL), in order to reach a compromise between matrix effects, chromatographic performance and sensitivity. The method was validated at 25 and 200 ng L(-1) (effluent), and 100 and 800 ng L(-1) (influent), obtaining limits of quantification (i.e. the lowest level that the compound can be quantified and also confirmed with at least two MS/MS transitions) between 0.4-25 ng L(-1) (effluent) and 2-100 ng L(-1) (influent). The applicability of the method was demonstrated by analysis of 14 influent and 14 effluent wastewater samples collected over 2 weeks in Castellón (Spain) within a European collaborative study.

  1. An improved leaping detector for flow analysis applied to iron speciation in drugs

    PubMed Central

    Santos, Sérgio R. B.; Araújo, Mário C. U.; Honorato, Ricardo S.; Zagatto, Elias A. G.; Lima, José F. C.; Lapa, Rui A. S.

    2000-01-01

    A low inner volume (ca. 64 ml) probe was built up in an injector-commutator in order to behave as a photometric leaping detector in flow analysis. It comprises a bicolour light-emitting diode (BLED), as a source of pulsed radiation in the red and green visible region, and two phototransistors as transducers. Sample injection, detector relocation, analytical signal recording, data treatment and definition of the spectral working range were computer-controlled. The feasibility of the system was initially demonstrated in the flow-injection speciation of iron, and the overall standard deviation of results was estimated as ± 1.6 and ± 1.4% for 1.6–4.0 mg l−1 Fe(II) or total iron after eightfold processing of synthetic samples. The system was further applied to drug analysis: the mean deviations of results for typical samples were estimated as ± 5.2 and ± 3.3%, and the relative standard deviation as ± 1.6 and ± 1.3% for Fe(II) and total iron, respectively. Results were compared with those obtained by a conventional spectrophotometric procedure and no statistic differences at the 95% confidence level were found. In relation to an earlier system with multi-site detection, the proposed system is more stable, presenting low drift with a relative standard deviation of 0.026% and 0.039% for measurements (n=120 during 4 h of observation) with green and red emission. It is also faster with a sampling rate of 133 h−1 and carryover problems are not found. The possibility of compensating the Schlieren noise by dual-wavelength spectrophotometry is discussed. PMID:18924860

  2. Molecular Farming in Artemisia annua, a Promising Approach to Improve Anti-malarial Drug Production

    PubMed Central

    Pulice, Giuseppe; Pelaz, Soraya; Matías-Hernández, Luis

    2016-01-01

    Malaria is a parasite infection affecting millions of people worldwide. Even though progress has been made in prevention and treatment of the disease; an estimated 214 million cases of malaria occurred in 2015, resulting in 438,000 estimated deaths; most of them occurring in Africa among children under the age of five. This article aims to review the epidemiology, future risk factors and current treatments of malaria, with particular focus on the promising potential of molecular farming that uses metabolic engineering in plants as an effective anti-malarial solution. Malaria represents an example of how a health problem may, on one hand, influence the proper development of a country, due to its burden of the disease. On the other hand, it constitutes an opportunity for lucrative business of diverse stakeholders. In contrast, plant biofarming is proposed here as a sustainable, promising, alternative for the production, not only of natural herbal repellents for malaria prevention but also for the production of sustainable anti-malarial drugs, like artemisinin (AN), used for primary parasite infection treatments. AN, a sesquiterpene lactone, is a natural anti-malarial compound that can be found in Artemisia annua. However, the low concentration of AN in the plant makes this molecule relatively expensive and difficult to produce in order to meet the current worldwide demand of Artemisinin Combination Therapies (ACTs), especially for economically disadvantaged people in developing countries. The biosynthetic pathway of AN, a process that takes place only in glandular secretory trichomes of A. annua, is relatively well elucidated. Significant efforts have been made using plant genetic engineering to increase production of this compound. These include diverse genetic manipulation approaches, such as studies on diverse transcription factors which have been shown to regulate the AN genetic pathway and other biological processes. Results look promising; however, further

  3. Adolescent Athletes and the Demand and Supply of Drugs to Improve Their Performance

    PubMed Central

    Laure, Patrick; Binsinger, Caroline

    2005-01-01

    The aim of this study was to gather information into the principal methods and means employed to supply adolescents with doping agents and others substances used to improve their sporting performance. We conducted a nation wide study in France among adolescent athletes, using a self-completed questionnaire. Exploitable questionnaires (n = 6402) were returned, corresponding to 48.9% for the girls and 51.1% for the boys, both aged on average from 16.1 ± 2.2 years. These adolescents practise on average 10.0 ± 5.2 hours of sport per week. 21.9% participate on a national or international competition level. Of our respondents, 4.0% (95% confidence interval: 3.5% - 4.5%) say they have been enticed into using products which are prohibited for athletes. 10.3% of the adolescents say that they have received substances to improve their performance at least once from an average of two different people. It was mostly a friend, their parents and the family doctor. On average, in 33.2% of the cases, the adolescent received the product without asking for it, and in nearly half the cases (46.6%), the adolescent paid for the product. We feel that it is necessary to better understand the ways in which this black market functions: for example; the initial sources of the products sold, the number and the ‘profiles’ of the dealers, the general organisation of the market and the sums of money involved. Key Points This study confirms the existence of a ‘black market’ for products to improve performance, which is directed at adolescent athletes engaged in high-level competitions. This market is characterized by its ease of accessibility and also the diversity of its ‘suppliers’, the two main sources being friends and parents. PMID:24453531

  4. Adolescent athletes and the demand and supply of drugs to improve their performance.

    PubMed

    Laure, Patrick; Binsinger, Caroline

    2005-09-01

    The aim of this study was to gather information into the principal methods and means employed to supply adolescents with doping agents and others substances used to improve their sporting performance. We conducted a nation wide study in France among adolescent athletes, using a self-completed questionnaire. Exploitable questionnaires (n = 6402) were returned, corresponding to 48.9% for the girls and 51.1% for the boys, both aged on average from 16.1 ± 2.2 years. These adolescents practise on average 10.0 ± 5.2 hours of sport per week. 21.9% participate on a national or international competition level. Of our respondents, 4.0% (95% confidence interval: 3.5% - 4.5%) say they have been enticed into using products which are prohibited for athletes. 10.3% of the adolescents say that they have received substances to improve their performance at least once from an average of two different people. It was mostly a friend, their parents and the family doctor. On average, in 33.2% of the cases, the adolescent received the product without asking for it, and in nearly half the cases (46.6%), the adolescent paid for the product. We feel that it is necessary to better understand the ways in which this black market functions: for example; the initial sources of the products sold, the number and the 'profiles' of the dealers, the general organisation of the market and the sums of money involved. Key PointsThis study confirms the existence of a 'black market' for products to improve performance, which is directed at adolescent athletes engaged in high-level competitions.This market is characterized by its ease of accessibility and also the diversity of its 'suppliers', the two main sources being friends and parents.

  5. An intervention to improve spontaneous adverse drug reaction reporting by hospital physicians: a time series analysis in Spain.

    PubMed

    Pedrós, Consuelo; Vallano, Antoni; Cereza, Gloria; Mendoza-Aran, Gemma; Agustí, Antònia; Aguilera, Cristina; Danés, Immaculada; Vidal, Xavier; Arnau, Josep M

    2009-01-01

    Spontaneous reporting of adverse drug reactions (ADRs) in hospitals is scarce and several obstacles to such reporting have been identified previously. To assess the effectiveness of a multifaceted intervention based on healthcare management agreements for improving spontaneous reporting of ADRs by physicians in a hospital setting. In 2003, the spontaneous reporting of ADRs was included as one of the objectives of hospital physicians at the Vall d'Hebron Hospital, Barcelona, Spain, within the context of management agreements between clinical services and hospital managers. A continuous intervention related to these management agreements, including periodic educational meetings and economic incentives, was then initiated. We carried out an ecological time series analysis and assessed the change in the total number of spontaneous reports of ADRs, and the number of serious ADRs, unexpected ADRs, and ADRs associated with new drugs between a period previous to the intervention (from 1998 to 2002) and the period during the intervention (from 2003 to 2005). A time series analysis with ARIMA (Auto-Regressive Integrated Moving Average) models was performed. The median number of reported ADRs per year increased from 40 (range 23-55) in the first period to 224 (range 98-248) in the second period. In the first period, the monthly number of reported ADRs was stable (3.47 per month; 95% CI 1.90, 5.03), but in the second period the number increased progressively (increase of 0.74 per month; 95% CI 0.62, 0.86). In the second period, the proportion of reported serious ADRs increased nearly 2-fold (63.1% vs 32.5% in the first period). The absolute number of previously unknown or poorly known ADRs increased 4-fold in the second period (54 vs 13 in the first period). There was also an increase in the absolute number of suspected pharmacological exposures to new drugs (97 vs 28) and in the number of different new drugs suspected of causing ADRs (50 vs 19). A continuous intervention

  6. Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system

    PubMed Central

    Chen, Zhi-Qiang; Liu, Ying; Zhao, Ji-Hui; Wang, Lan; Feng, Nian-Ping

    2012-01-01

    Background Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed to improve the oral bioavailability of indirubin. Methods A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats. Results The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor® EL:Transcutol® P (15:40:45, w/w/w). Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS. Conclusion The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin. PMID:22403491

  7. Nanomedicine-nanoemulsion formulation improves safety and efficacy of the anti-cancer drug paclitaxel according to preclinical assessment.

    PubMed

    Lee, King C; Maturo, Claudia; Rodriguez, Robert; Nguyen, Hoang-Lan; Shorr, Robert

    2011-08-01

    Paclitaxel is an important anticancer drug and is currently used to treat a variety of cancers, including ovarian carcinomas, breast cancer, non-small cell lung cancer, and AIDS-related Kaposi's sarcoma. The objectives of the studies were to assess and compare the safety and efficacy of EmPAC (a newly developed nanoemulsion formulation of paclitaxel) versus Taxol (the injectable formulation of paclitaxel involving the use of polyethylated or polyoxyl castor oil currently used in the clinic). The objectives were also to investigate the mechanism for the improved safety and efficacy of EmPAC over Taxol. These results showed that EmPAC had better anti-tumor efficacy than Taxol, according to in vitro cell culture studies and studies in animal tumor models. EmPAC had improved anti-tumor efficacy even in tumor cell lines that are known to be multi-drug resistant. Part of the mechanism of action for the improved efficacy may be related to EmPAC inducing greater cellular uptake of paclitaxel into tumor cells than Taxol did, according to the in vitro cell culture radioactive-labeled studies and in vitro cell culture antibody studies. It may also partly be because EmPAC delivered more paclitaxel to the tumor mass than Taxol, while the delivery of paclitaxel to other tissues (e.g., blood, muscle, liver, spleen, kidney and lung) were similar between the two formulations of paclitaxel, according to studies in animals with tumor xenograft. EmPAC also had better safety than Taxol according to toxicology studies in rabbits. This may be because EmPAC does not contain the toxic ingredients used in formulating Taxol (such as polyethylated or polyoxyl castor oil). These results support the clinical development of the nanoemulsion formulation of paclitaxel.

  8. An improved approach to the analysis of drug-protein binding by distance geometry

    NASA Technical Reports Server (NTRS)

    Goldblum, A.; Kieber-Emmons, T.; Rein, R.

    1986-01-01

    The calculation of side chain centers of coordinates and the subsequent generation of side chain-side chain and side chain-backbone distance matrices is suggested as an improved method for viewing interactions inside proteins and for the comparison of protein structures. The use of side chain distance matrices is demonstrated with free PTI, and the use of difference distance matrices for side chains is shown for free and trypsin-bound PTI as well as for the X-ray structures of trypsin complexes with PTI and with benzamidine. It is found that conformational variations are reflected in the side chain distance matrices much more than in the standard C-C distance representations.

  9. An improved approach to the analysis of drug-protein binding by distance geometry

    NASA Technical Reports Server (NTRS)

    Goldblum, A.; Kieber-Emmons, T.; Rein, R.

    1986-01-01

    The calculation of side chain centers of coordinates and the subsequent generation of side chain-side chain and side chain-backbone distance matrices is suggested as an improved method for viewing interactions inside proteins and for the comparison of protein structures. The use of side chain distance matrices is demonstrated with free PTI, and the use of difference distance matrices for side chains is shown for free and trypsin-bound PTI as well as for the X-ray structures of trypsin complexes with PTI and with benzamidine. It is found that conformational variations are reflected in the side chain distance matrices much more than in the standard C-C distance representations.

  10. Improvement in the antifilarial efficacy of doxycycline and rifampicin by combination therapy and drug delivery approach.

    PubMed

    Dangi, Anil; Dwivedi, Varun; Vedi, Satish; Owais, Mohammad; Misra-Bhattacharya, Shailja

    2010-06-01

    The present investigation deals with the evaluation of antifilarial efficacy of liposome entrapped antiwolbachial antibiotics doxycycline and rifampicin (5 doses at 10 mg/kg, subcutaneously for 15 days) alone and/or in combination with standard filaricide diethylcarbamazine (DEC) against human lymphatic filariid Brugia malayi in rodent host Mastomys coucha. The delivery system maintained the sustained release of antibiotics up to 48 h and significantly (P < 0.05) augmented the antifilarial potential of these antibiotics over their free administration. A combination of DEC with each entrapped antibiotics significantly (P<0.05) improved microfilaricidal efficacy, while marginal enhancement was noticed in adulticidal activity. Combination of both antibiotics formulation with DEC demonstrated marginal increase in macrofilaricidal efficacy; however, it was highest ( approximately 75%).

  11. The role of drug vendors in improving basic health-care services in Nigeria.

    PubMed

    Liu, Jenny; Prach, Lisa M; Treleaven, Emily; Hansen, Mara; Anyanti, Jennifer; Jagha, Temple; Seaman, Vince; Ajumobi, Olufemi; Isiguzo, Chinwoke

    2016-04-01

    To characterize patent and proprietary medicine vendors and shops in Nigeria and to assess their ability to help improve access to high-quality, primary health-care services. In 2013 and 2014, a census of patent and proprietary medicine shops in 16 states of Nigeria was carried out to determine: (i) the size and coverage of the sector; (ii) the basic characteristics of shops and their staff; and (iii) the range of products stocked for priority health services, particularly for malaria, diarrhoea and family planning. The influence of the medical training of people in charge of the shops on the health-care products stocked and registration with official bodies was assessed by regression analysis. The number of shops per 100,000 population was higher in southern than in northern states, but the average percentage of people in charge with medical training across local government areas was higher in northern states: 52.6% versus 29.7% in southern states. Shops headed by a person with medical training were significantly more likely to stock artemisinin-based combination therapy, oral rehydration salts, zinc, injectable contraceptives and intrauterine contraceptive devices. However, these shops were less likely to be registered with the National Association of Patent and Proprietary Medicine Dealers and more likely to be registered with the regulatory body, the Pharmacist Council of Nigeria. Many patent and proprietary medicine vendors in Nigeria were medically trained. With additional training and oversight, they could help improve access to basic health-care services. Specifically, vendors with medical training could participate in task-shifting interventions.

  12. A novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for improved stability and oral bioavailability of an oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol.

    PubMed

    Kim, Kyeong Soo; Yang, Eun Su; Kim, Dong Shik; Kim, Dong Wuk; Yoo, Hye Hyun; Yong, Chul Soon; Youn, Yu Seok; Oh, Kyung Taek; Jee, Jun-Pil; Kim, Jong Oh; Jin, Sung Giu; Choi, Han Gon

    2017-11-01

    To develop a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for a water-insoluble oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) with improved stability and oral bioavailability, numerous S-SNEDDS were prepared with surfactant, hydrophilic polymer, antioxidant, and calcium silicate (porous carrier) using the spray-drying method. Their physicochemical properties were evaluated using emulsion droplet size analysis, SEM and PXRD. Moreover, the solubility, dissolution, stability, and pharmacokinetics of the selected S-SNEDDS were assessed compared with the drug and a commercial soft capsule. Sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) with the highest drug solubility were selected as surfactant and hydrophilic polymer, respectively. Among the antioxidants tested, only butylated hydroxyanisole (BHA) could completely protect the drug from oxidative degradation. The S-SNEDDS composed of PLAG/SLS/HPMC/BHA/calcium silicate at a weight ratio of 1: 0.25: 0.1: 0.0002: 0.5 provided an emulsion droplet size of less than 300 nm. In this S-SNEDDS, the drug and other ingredients might exist in the pores of carrier and attach onto its surface. It considerably improved the drug stability (about 100 vs. 70%, 60 °C for 5 d) and dissolution (about 80 vs. 20% in 60 min) compared to the commercial soft capsule. Moreover, the S-SNEDDS gave higher AUC, Cmax, and Tmax values than the commercial soft capsule; in particular, the former improved the oral bioavailability of PLAG by about 3-fold. Our results suggested that this S-SNEDDS provided excellent stability and oral bioavailability of PLAG. Thus, this S-SNEDDS would be recommended as a powerful oral drug delivery system for an oily drug, PLAG.

  13. Higher Magnitude Cash Payments Improve Research Follow-up Rates Without Increasing Drug Use or Perceived Coercion

    PubMed Central

    Festinger, David S.; Marlowe, Douglas B.; Dugosh, Karen L.; Croft, Jason R.; Arabia, Patricia L.

    2008-01-01

    In a prior study (Festinger et al., 2005) we found that neither the mode (cash vs. gift card) nor magnitude ($10, $40, or $70) of research follow-up payments increased rates of new drug use or perceptions of coercion. However, higher payments and payments in cash were associated with better follow-up attendance, reduced tracking efforts, and improved participant satisfaction with the study. The present study extended those findings to higher payment magnitudes. Participants from an urban outpatient substance abuse treatment program were randomly assigned to receive $70, $100, $130, or $160 in either cash or a gift card for completing a follow-up assessment at 6 months post-admission (n ≅ 50 per cell). Apart from the payment incentives, all participants received a standardized, minimal platform of follow-up efforts. Findings revealed that neither the magnitude nor mode of payment had a significant effect on new drug use or perceived coercion. Consistent with our previous findings, higher payments and cash payments resulted in significantly higher follow-up rates and fewer tracking calls. In addition participants receiving cash vs. gift cards were more likely to use their payments for essential, non-luxury purchases. Follow-up rates for participants receiving cash payments of $100, $130, and $160 approached or exceeded the FDA required minimum of 70% for studies to be considered in evaluations of new medications. This suggests that the use of higher magnitude payments and cash payments may be effective strategies for obtaining more representative follow-up samples without increasing new drug use or perceptions of coercion. PMID:18395365

  14. Melting Point Distribution Analysis of Globally Approved and Discontinued Drugs: A Research for Improving the Chance of Success of Drug Design and Discovery

    PubMed Central

    Mao, Fei; Kong, Qingya; Ni, Wei; Xu, Xiang; Ling, Dazheng; Lu, Zhengyu

    2016-01-01

    Abstract The melting point (MP), an easily accessible physical parameter, has considerable potential for the judgment of drug‐like properties. However, to the best of our knowledge, there are no useful guidelines for understanding the relationship between the MP and drug‐like properties. To this end, we have constructed the largest MP database (experimental value) of globally approved drugs (3164 organic small‐molecule drugs) and discontinued drugs (417 organic small‐molecule drugs) and subsequently extracted six subdatabases from the whole approved database and two subdatabases from the discontinued database. The MP distribution statistics and analysis of approved drugs reveal five noteworthy observations; moreover, the MP distribution statistics and analysis of discontinued drugs further supplement these criteria. In addition, the comparison of molecular weight (MW) versus MP and Clog P versus MP distributions of different classes of approved drugs indicated that the MWs and Clog P values of most drugs in the optimal MP range were not more than 500 and 5, respectively, implying the MP distribution criterion was in accordance with Lipinski's rule of five. PMID:27547646

  15. Stepwise optimization approach for improving LC-MS/MS analysis of zwitterionic antiepileptic drugs with implementation of experimental design.

    PubMed

    Kostić, Nađa; Dotsikas, Yannis; Malenović, Anđelija; Jančić Stojanović, Biljana; Rakić, Tijana; Ivanović, Darko; Medenica, Mirjana

    2013-07-01

    In this article, a step-by-step optimization procedure for improving analyte response with implementation of experimental design is described. Zwitterionic antiepileptics, namely vigabatrin, pregabalin and gabapentin, were chosen as model compounds to undergo chloroformate-mediated derivatization followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis. Application of a planned stepwise optimization procedure allowed responses of analytes, expressed as areas and signal-to-noise ratios, to be improved, enabling achievement of lower limit of detection values. Results from the current study demonstrate that optimization of parameters such as scan time, geometry of ion source, sheath and auxiliary gas pressure, capillary temperature, collision pressure and mobile phase composition can have a positive impact on sensitivity of LC-MS/MS methods. Optimization of LC and MS parameters led to a total increment of 53.9%, 83.3% and 95.7% in areas of derivatized vigabatrin, pregabalin and gabapentin, respectively, while for signal-to-noise values, an improvement of 140.0%, 93.6% and 124.0% was achieved, compared to autotune settings. After defining the final optimal conditions, a time-segmented method was validated for the determination of mentioned drugs in plasma. The method proved to be accurate and precise with excellent linearity for the tested concentration range (40.0 ng ml(-1)-10.0 × 10(3)  ng ml(-1)).

  16. Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery.

    PubMed

    Tian, Xi; Lara, Haydee; Wagner, Kyle T; Saripalli, Srinivas; Hyder, Syed Nabeel; Foote, Michael; Sethi, Manish; Wang, Edina; Caster, Joseph M; Zhang, Longzhen; Wang, Andrew Z

    2015-12-21

    Radiotherapy is a key component of cancer treatment. Because of its importance, there has been high interest in developing agents and strategies to further improve the therapeutic index of radiotherapy. DNA double-strand repair inhibitors (DSBRIs) are among the most promising agents to improve radiotherapy. However, their clinical translation has been limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this limitation. In this study, we aim to demonstrate the proof of principle by developing and evaluating nanoparticle (NP) formulations of KU55933, a DSBRI. We engineered a NP formulation of KU55933 using nanoprecipitation method with different lipid polymer nanoparticle formulation. NP KU55933 using PLGA formulation has the best loading efficacy as well as prolonged drug release profile. We demonstrated that NP KU55933 is a potent radiosensitizer in vitro using clonogenic assay and is more effective as a radiosensitizer than free KU55933 in vivo using mouse xenograft models of non-small cell lung cancer (NSCLC). Western blots and immunofluorescence showed NP KU55933 exhibited more prolonged inhibition of DNA repair pathway. In addition, NP KU55933 leads to lower skin toxicity than KU55933. Our study supports further investigations using NP to deliver DSBRIs to improve cancer radiotherapy treatment.

  17. Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery

    NASA Astrophysics Data System (ADS)

    Tian, Xi; Lara, Haydee; Wagner, Kyle T.; Saripalli, Srinivas; Hyder, Syed Nabeel; Foote, Michael; Sethi, Manish; Wang, Edina; Caster, Joseph M.; Zhang, Longzhen; Wang, Andrew Z.

    2015-11-01

    Radiotherapy is a key component of cancer treatment. Because of its importance, there has been high interest in developing agents and strategies to further improve the therapeutic index of radiotherapy. DNA double-strand repair inhibitors (DSBRIs) are among the most promising agents to improve radiotherapy. However, their clinical translation has been limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this limitation. In this study, we aim to demonstrate the proof of principle by developing and evaluating nanoparticle (NP) formulations of KU55933, a DSBRI. We engineered a NP formulation of KU55933 using nanoprecipitation method with different lipid polymer nanoparticle formulation. NP KU55933 using PLGA formulation has the best loading efficacy as well as prolonged drug release profile. We demonstrated that NP KU55933 is a potent radiosensitizer in vitro using clonogenic assay and is more effective as a radiosensitizer than free KU55933 in vivo using mouse xenograft models of non-small cell lung cancer (NSCLC). Western blots and immunofluorescence showed NP KU55933 exhibited more prolonged inhibition of DNA repair pathway. In addition, NP KU55933 leads to lower skin toxicity than KU55933. Our study supports further investigations using NP to deliver DSBRIs to improve cancer radiotherapy treatment.

  18. Applying human factors to develop an improved package design for (Rx) medication drug labels in a pharmacy setting.

    PubMed

    Gerhart, Julie M; Spriggs, Holly; Hampton, Tonja W; Hoy, Rose Mary B; Strochlic, Allison Y; Proulx, Susan; Goetchius, Debra B

    2015-12-01

    As many as 98,000 people die every year from preventable medical errors. Among pharmacists, the most common error reported is the selection of the wrong drug. Merck met with the U.S. Food and Drug Administration (FDA) to discuss the optimization of the U.S. label for solid oral dosage forms of Merck medications. These discussions led to the development of revised label designs for six products that were then evaluated using failure modes and effects analysis and an expert review by human factors specialists. There were no errors among 425 filled prescriptions in the validation test of the final label. Key changes to the original labels include the use of a non-branded logo, high-contrast color bands for dosage strength, and an enhanced three-dimensional tablet image. The redesigned labels were approved by the US FDA in June 2011. The redesigned label should improve the accurate selection of medications from pharmacy shelves. Copyright © 2015 Elsevier Ltd and National Safety Council. All rights reserved.

  19. Conditionally replicating luciferase reporter phages: improved sensitivity for rapid detection and assessment of drug susceptibility of Mycobacterium tuberculosis.

    PubMed Central

    Carrière, C; Riska, P F; Zimhony, O; Kriakov, J; Bardarov, S; Burns, J; Chan, J; Jacobs, W R

    1997-01-01

    TM4 is a lytic mycobacteriophage which infects mycobacteria of clinical importance. A luciferase reporter phage, phAE40, has been constructed from TM4 and was previously shown to be useful for the rapid detection and drug susceptibility testing of Mycobacterium tuberculosis. However, the lytic nature of the phage results in a loss of detectable light output and limits the sensitivity of detection. We describe several strategies aimed at improving the luciferase activity generated by TM4 luciferase phages, including (i) varying the position of the luciferase gene in the phage genome, (ii) isolating host-range mutants of the phage, and (iii) introducing temperature-sensitive mutations in the phage such that it will not replicate at the infecting temperature. Several new phages generated by these methods show increased intensity of luciferase production compared to the first-generation reporter phage phAE40, and one phage, phAE88, also demonstrates an enhanced duration of luciferase activity. This has allowed the detection of as few as 120 BCG cells and the determination of drug susceptibilities of M. tuberculosis in as little as 1 day. PMID:9399525

  20. Investigating the Use of Polymeric Binders in Twin Screw Melt Granulation Process for Improving Compactibility of Drugs.

    PubMed

    Batra, Amol; Desai, Dipen; Serajuddin, Abu T M

    2017-01-01

    Traditionally, the melt granulation for pharmaceutical products was performed at low temperature (<90°C) with high-shear granulators using low-melting waxy binders, and tablets produced using such granules were not amenable to large-scale manufacturing. The situation has changed in recent years by the use of twin screw extruder where the processing temperature could be increased to as high as 180°C and polymers with high Tg could be used as binders. In this study, different polymeric binders were screened for their suitability in improving compactibility of 2 drugs, metformin hydrochloride and acetaminophen, by twin screw melt granulation. Processing temperatures for the 2 drugs were set at 180°C and 130°C, respectively. Screw configuration, screw speed, and feed rate were optimized such that all polymeric binders used produced granules. Several hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and methacrylate-based polymers, including Klucel(®) EXF, Eudragit(®) EPO, and Soluplus(®), demonstrated good tablet tensile strength (>2 MPa) when granules were produced using only 10% wt/wt polymer concentration. Certain polymers provided acceptable compactibility even at 5% wt/wt. Thus, twin screw melt granulation process may be used with different polymers at a wide range of temperature. Due to low excipient concentration, this granulation method is especially suitable for high-dose tablets.

  1. Application of the optimal design approach to improve a pretransplant drug dose finding design for ciclosporin.

    PubMed

    Hennig, Stefanie; Nyberg, Joakim; Fanta, Samuel; Backman, Janne T; Hoppu, Kalle; Hooker, Andrew C; Karlsson, Mats O

    2012-03-01

    A time and sampling intensive pretransplant test dose design was to be reduced, but at the same time optimized so that there was no loss in the precision of predicting the individual pharmacokinetic (PK) estimates of posttransplant dosing. The following variables were optimized simultaneously: sampling times, ciclosporin dose, time of second dose, infusion duration, and administration order, using a published ciclosporin population PK model as prior information. The original design was reduced from 22 samples to 6 samples/patient and both doses (intravenous oral) were administered within 8 hours. Compared with the prior information given by the published ciclosporin population PK model, the expected standard deviations (SDs) of the individual parameters for clearance and bioavailability could be reduced by, on average, 40% under the optimized sparse designs. The gain of performing the original rich design compared with the optimal reduced design, considering the standard errors of the parameter estimates, was found to be minimal. This application demonstrates, in a practical clinical scenario, how optimal design techniques may be used to improve diagnostic procedures given available software and methods.

  2. Improved mucoadhesive properties of self-nanoemulsifying drug delivery systems (SNEDDS) by introducing acyl chitosan.

    PubMed

    Efiana, Nuri Ari; Mahmood, Arshad; Lam, Hung Thanh; Zupančič, Ožbej; Leonaviciute, Gintare; Bernkop-Schnürch, Andreas

    2017-03-15

    This study was aimed to improve the mucoadhesive properties of SNEDDS by the incorporation of acyl chitosan including octanoyl chitosan (OC), lauroyl chitosan (LC) and palmitoyl chitosan (PC). SNEDDS and acyl chitosan SNEDDS were characterized regarding droplet size and zeta potential. Their mucoadhesivity on porcine intestinal mucosa was evaluated by falling liquid film technique using Sudan Red G as marker. Degree of substitution of chitosan was determined to be 52.8%, 64.8 and 48.5% for OC, LC and PC, respectively. SNEDDS and acyl chitosan SNEDDS displayed a droplet size less than 50nm and 80-300nm as well as a zeta potential of -0.2 to -1.6 and 0.05 to 0.99mV, respectively. Introducing 2% acyl chitosan into SNEDDS increased the residence time of SNEDDS on intestinal mucosa 2-fold. It is concluded that due to the incorporation of acyl chitosan into SNEDDS, their mucoadhesive properties can be increased. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole.

    PubMed

    Vialpando, Monica; Smulders, Stefanie; Bone, Scott; Jager, Casey; Vodak, David; Van Speybroeck, Michiel; Verheyen, Loes; Backx, Katrien; Boeykens, Peter; Brewster, Marcus E; Ceulemans, Jens; Novoa de Armas, Hector; Van Geel, Katrien; Kesselaers, Emma; Hillewaert, Vera; Lachau-Durand, Sophie; Meurs, Greet; Psathas, Petros; Van Hove, Ben; Verreck, Geert; Voets, Marieke; Weuts, Ilse; Mackie, Claire

    2016-09-01

    This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.

  4. Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma

    PubMed Central

    Friesen, Claudia; Hormann, Inis; Roscher, Mareike; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf; Debatin, Klaus-Michael; Miltner, Erich

    2014-01-01

    Glioblastoma are the most frequent and malignant human brain tumors, having a very poor prognosis. The enhanced radio- and chemoresistance of glioblastoma and the glioblastoma stem cells might be the main reason why conventional therapies fail. The second messenger cyclic AMP (cAMP) controls cell proliferation, differentiation, and apoptosis. Downregulation of cAMP sensitizes tumor cells for anti-cancer treatment. Opioid receptor agonists triggering opioid receptors can activate inhibitory Gi proteins, which, in turn, block adenylyl cyclase activity reducing cAMP. In this study, we show that downregulation of cAMP by opioid receptor activation improves the effectiveness of anti-cancer drugs in treatment of glioblastoma. The µ-opioid receptor agonist D,L-methadone sensitizes glioblastoma as well as the untreatable glioblastoma stem cells for doxorubicin-induced apoptosis and activation of apoptosis pathways by reversing deficient caspase activation and deficient downregulation of XIAP and Bcl-xL, playing critical roles in glioblastomas’ resistance. Blocking opioid receptors using the opioid receptor antagonist naloxone or increasing intracellular cAMP by 3-isobutyl-1-methylxanthine (IBMX) strongly reduced opioid receptor agonist-induced sensitization for doxorubicin. In addition, the opioid receptor agonist D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux, whereas doxorubicin increased opioid receptor expression in glioblastomas. Furthermore, opioid receptor activation using D,L-methadone inhibited tumor growth significantly in vivo. Our findings suggest that opioid receptor activation triggering downregulation of cAMP is a promising strategy to inhibit tumor growth and to improve the effectiveness of anti-cancer drugs in treatment of glioblastoma and in killing glioblastoma stem cells. PMID:24626197

  5. Effectiveness of involving pharmacists in the process of ambulatory health care to improve drug treatment adherence and disease control.

    PubMed

    Mino-León, Dolores; Reyes-Morales, Hortensia; Flores-Hernández, Sergio

    2015-02-01

    To evaluate the effectiveness of incorporating the pharmacist into the ambulatory health care team to increase the proportion of patients with type 2 diabetes mellitus (T2DM) and/or hypertension who adhere to their drug regimen and to improve disease control. A non-randomized clinical trial was carried out in patients with T2DM and/or hypertension from two primary care clinics. Patients from one of the clinics comprised the intervention group (IG) who received 'counselling' from the pharmacist. The control group (CG) was comprised of patients who attended another clinic and received the usual care. Adherence was measured by counting pills; hypertension control was evaluated by blood pressure and diabetes control by blood glucose. Statistical analysis was carried out by intention to treat using generalized linear models. There were 440 patients included. There was no difference in the proportion of IG and CG patients who adhered to treatment according to baseline measurements. An increase in the proportion of adherence at baseline and final determination was observed in both groups (IG 71-80%, P=0.006 and CG 72-87%, P=0.000). Generalized linear models showed a 55% or higher probability of IG patients achieving control of hypertension in comparison with the CG. Patients from the IG with T2DM have 13% more possibility of achieving glycaemic control than those of the CG. Counselling offered by the pharmacist proved to be effective for improving drug adherence of diabetic and hypertensive patients in ambulatory health care. © 2014 John Wiley & Sons, Ltd.

  6. Proceedings of the 2013 CINP summit: innovative partnerships to accelerate CNS drug discovery for improved patient care.

    PubMed

    Phillips, Anthony George; Hongaard-Andersen, Peter; Moscicki, Richard A; Sahakian, Barbara; Quirion, Rémi; Krishnan, K Ranga Rama; Race, Tim

    2014-12-25

    Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21(st) century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders. Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain: Code of conduct dealing with conflict of interest issues, Prevention, early diagnosis, and treatment, Linking science and regulation, Patient involvement in trial design, definition of endpoints, etc., Novel trial design, Reproduction and confirmation of data, Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority), Large-scale, global patient registries, Editorials on nomenclature, biomarkers, and diagnostic tools, and Public awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in

  7. Improvement of drug dose calculations by classroom teaching or e-learning: a randomised controlled trial in nurses.

    PubMed

    Simonsen, Bjoerg O; Daehlin, Gro K; Johansson, Inger; Farup, Per G

    2014-10-24

    Insufficient skills in drug dose calculations increase the risk for medication errors. Even experienced nurses may struggle with such calculations. Learning flexibility and cost considerations make e-learning interesting as an alternative to classroom teaching. This study compared the learning outcome and risk of error after a course in drug dose calculations for nurses with the two methods. In a randomised controlled open study, nurses from hospitals and primary healthcare were randomised to either e-learning or classroom teaching. Before and after a 2-day course, the nurses underwent a multiple choice test in drug dose calculations: 14 tasks with four alternative answers (score 0-14), and a statement regarding the certainty of each answer (score 0-3). High risk of error was being certain that incorrect answer was correct. The results are given as the mean (SD). 16 men and 167 women participated in the study, aged 42.0 (9.5) years with a working experience of 12.3 (9.5) years. The number of correct answers after e-learning was 11.6 (2.0) and after classroom teaching 11.9 (2.0) (p=0.18, NS); improvement were 0.5 (1.6) and 0.9 (2.2), respectively (p=0.07, NS). Classroom learning was significantly superior to e-learning among participants with a pretest score below 9. In support of e-learning was evaluation of specific value for the working situation. There was no difference in risk of error between groups after the course (p=0.77). The study showed no differences in learning outcome or risk of error between e-learning and classroom teaching in drug dose calculations. The overall learning outcome was small. Weak precourse knowledge was associated with better outcome after classroom teaching. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  8. Proceedings of the 2013 CINP Summit: Innovative Partnerships to Accelerate CNS Drug Discovery for Improved Patient Care

    PubMed Central

    Hongaard-Andersen, Peter; Moscicki, Richard A.; Sahakian, Barbara; Quirion, Rémi; Krishnan, K. Ranga Rama; Race, Tim

    2015-01-01

    Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21st century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders. Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain: Code of conduct dealing with conflict of interest issues,Prevention, early diagnosis, and treatment,Linking science and regulation,Patient involvement in trial design, definition of endpoints, etc.,Novel trial design,Reproduction and confirmation of data,Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority),Large-scale, global patient registries,Editorials on nomenclature, biomarkers, and diagnostic tools, andPublic awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in Davos

  9. Shenmai injection enhances the cytotoxicity of chemotherapeutic drugs against colorectal cancers via improving their subcellular distribution.

    PubMed

    Liu, Wen-Yue; Zhang, Jing-Wei; Yao, Xue-Quan; Jiang, Chao; He, Ji-Chao; Ni, Pin; Liu, Jia-Li; Chen, Qian-Ying; Li, Qing-Ran; Zang, Xiao-Jie; Yao, Lan; Liu, Ya-Zhong; Wang, Mu-Lan; Shen, Pei-Qiang; Wang, Guang-Ji; Zhou, Fang

    2017-02-01

    Shenmai injection (SMI) is a Chinese patent-protected injection, which was mainly made of Red Ginseng and Radix Ophiopogonis and widely used for treating coronary heart disease and tumors by boosting Qi and nourishing Yin. In this study we examined whether SMI could produce direct synergetic effects on the cytoxicity of adriamycin (ADR) and paclitaxel (PTX) in colorectal cancers in vivo and in vitro, and explored the underlying pharmacokinetic mechanisms. BALB/c nude mice with LoVo colon cancer xenografts were intraperitoneally injected with ADR (2 mg·kg(-1)·3d(-1)) or PTX (7.5 mg·kg(-1)·3d(-1)) with or without SMI (0.01 mL·g(-1)·d(-1)) for 13 d. Co-administration of SMI significantly enhanced the chemotherapeutic efficacy of ADR and PTX, whereas administration of SMI alone at the given dosage did not produce visible anti-cancer effects, The chemosensitizing action of SMI was associated with increased concentrations of ADR and PTX in the plasma and tumors. In Caco-2 and LoVo cells in vitro, co-treatment with SMI (2 μL/mL) significantly enhanced the cytotoxicity of ADR and PTX, and resulted in some favorable pharmacokinetic changes in the subcellular distribution of ADR and PTX. In addition, SMI-induced intracellular accumulation of ADR was closely correlated with the increased expression levels of P-glycoprotein in 4 colon cancer cell lines (r(2)=+0.8558). SMI enhances the anti-cancer effects of ADR and PTX in colon cancers in vivo and in vitro by improving the subcellular distributions of ADR and PTX.

  10. Shenmai injection enhances the cytotoxicity of chemotherapeutic drugs against colorectal cancers via improving their subcellular distribution

    PubMed Central

    Liu, Wen-yue; Zhang, Jing-wei; Yao, Xue-quan; Jiang, Chao; He, Ji-chao; Ni, Pin; Liu, Jia-li; Chen, Qian-ying; Li, Qing-ran; Zang, Xiao-jie; Yao, Lan; Liu, Ya-zhong; Wang, Mu-lan; Shen, Pei-qiang; Wang, Guang-ji; Zhou, Fang

    2017-01-01

    Shenmai injection (SMI) is a Chinese patent-protected injection, which was mainly made of Red Ginseng and Radix Ophiopogonis and widely used for treating coronary heart disease and tumors by boosting Qi and nourishing Yin. In this study we examined whether SMI could produce direct synergetic effects on the cytoxicity of adriamycin (ADR) and paclitaxel (PTX) in colorectal cancers in vivo and in vitro, and explored the underlying pharmacokinetic mechanisms. BALB/c nude mice with LoVo colon cancer xenografts were intraperitoneally injected with ADR (2 mg·kg−1·3d−1) or PTX (7.5 mg·kg−1·3d−1) with or without SMI (0.01 mL·g−1·d−1) for 13 d. Co-administration of SMI significantly enhanced the chemotherapeutic efficacy of ADR and PTX, whereas administration of SMI alone at the given dosage did not produce visible anti-cancer effects, The chemosensitizing action of SMI was associated with increased concentrations of ADR and PTX in the plasma and tumors. In Caco-2 and LoVo cells in vitro, co-treatment with SMI (2 μL/mL) significantly enhanced the cytotoxicity of ADR and PTX, and resulted in some favorable pharmacokinetic changes in the subcellular distribution of ADR and PTX. In addition, SMI-induced intracellular accumulation of ADR was closely correlated with the increased expression levels of P-glycoprotein in 4 colon cancer cell lines (r2=+0.8558). SMI enhances the anti-cancer effects of ADR and PTX in colon cancers in vivo and in vitro by improving the subcellular distributions of ADR and PTX. PMID:27867186

  11. Albendazole failure to control resistant nematodes in lambs: lack of effect of fasting-induced improvement on drug absorption.

    PubMed

    Alvarez, L; Entrocasso, C; Lifschitz, A; Manazza, J; Ceballos, L; Borda, B; Lanusse, C

    2010-12-01

    Enhanced plasma availability of albendazole sulphoxide (ABZSO), the active metabolite of albendazole (ABZ), has been described in feed-restricted sheep. The aim of the present work was to determine if the absorption-related pharmacokinetic changes derived from fasting animals prior to drug treatment would modify the clinical efficacy of ABZ against resistant gastrointestinal nematodes in lambs. Forty Corriedale lambs, naturally infected with resistant gastrointestinal nematodes, were divided into 4 groups. Controls were fed ad libitum and did not receive any drug treatment. Treated animals were fed ad libitum up to 30 min prior to treatment with ABZ (3.8 mg/kg) by the intraruminal route. The control (fasted) animals were not fed during the 24-hr period prior to the start of the experiment and did not receive any drug treatment. A second treated group of animals were fasted 24 hr prior to the treatment with ABZ, as previously described for the fed-treated group. Blood samples were collected over a period of 72 hr post-treatment from 6 animals in each treated group. Plasma samples were analyzed by high performance liquid chromatography. The pharmacokinetic parameters were statistically compared using parametric statistical tests. The estimation of the efficacy of the different treatments was performed by the fecal egg count reduction test (FECRT). Additionally, 4 animals randomly chosen from the control-fed and treated groups were killed 13 days post-treatment to evaluate the efficacy against different adult nematode parasites. The results were statistically compared by parametric and non-parametric tests. Significantly (P < 0.05) higher Cmax and AUC values were observed for both the ABZSO and ABZ-sulphone (ABZSO(2)) metabolites in the fasted compared to the fed animals. These kinetic results may be due to a fasting-induced delay in the GI transit time which increases ABZ dissolution and GI absorption. However, a poor ABZ efficacy (measured as FECRT), compatible with

  12. The use of external data sources and ratio estimation to improve estimates of hardcore drug use from the NHSDA.

    PubMed

    Wright, D; Gfroerer, J; Epstein, J

    1997-01-01

    Levels of hardcore drug use have been especially difficult to estimate because of the relative rarity of the behavior, the difficulty of locating hardcore drug users, and the tendency to underreport stigmatized behavior. This chapter presents a new application of ratio estimation, combining sample data from the National Household Survey on Drug Abuse (NHSDA) together with population counts of the number of persons arrested in the past year from the Uniform Crime Report (UCR) and the number of persons in drug treatment programs in the past year from the National Drug and Alcoholism Treatment Unit Survey (NDATUS). The population counts serve as a benchmark accounting for undercoverage and underreporting of hard drug users.

  13. Risk Evaluation and Mitigation Strategies (REMSs): Are They Improving Drug Safety? A Critical Review of REMSs Requiring Elements to Assure Safe Use (ETASU).

    PubMed

    Boudes, Pol F

    2017-06-01

    Risk Evaluation and Mitigation Strategies (REMSs) with Elements to Assure Safe Use (ETASU) are requested for drugs with significant safety risks. We reviewed REMS programs issued since 2011 to evaluate their rationales, characteristics, and consistencies, and evaluated their impact on improving drug safety. We conducted a literature search and a survey of relevant websites (FDA, manufacturers, and REMSs). ETASU characteristics were summarized. REMS risks were compared with labeled risks, including black box warnings. Forty-two programs were analyzed. Seven incorporated drugs of the same class. Most drugs (57%) were indicated for an orphan disease. A single risk was mentioned in 24 REMSs, and multiple risks in 18. Embryo-fetal toxicity and abuse or misuse were the most frequent risks. All risks were identified during clinical development but some were hypothetical. Thirty-six drugs had a black box warning. REMS risks and black box risks differed for 11 drugs. A drug with multiple indications could have a REMS for one of them but not for another. Most REMSs required prescriber training and certification, half required dispenser certification and patient enrolment. REMSs were revised multiple times and only three (7%) were discontinued. No data were available to establish whether REMSs were effective in improving drug safety. Some REMSs were deemed inefficient. REMSs with ETASU continue to be implemented but their impact on improving drug safety is still not documented. Hence, one of the main requirements of the FDA Amendments Act of 2007 is not being addressed. In addition, REMSs are complex and their logic is inconsistent; we recommend a thorough re-evaluation of the REMS program.

  14. A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria.

    PubMed

    Phillips, Margaret A; White, Karen L; Kokkonda, Sreekanth; Deng, Xiaoyi; White, John; El Mazouni, Farah; Marsh, Kennan; Tomchick, Diana R; Manjalanagara, Krishne; Rudra, Kakali Rani; Wirjanata, Grennady; Noviyanti, Rintis; Price, Ric N; Marfurt, Jutta; Shackleford, David M; Chiu, Francis C K; Campbell, Michael; Jimenez-Diaz, Maria Belen; Bazaga, Santiago Ferrer; Angulo-Barturen, Iñigo; Martinez, Maria Santos; Lafuente-Monasterio, Maria; Kaminsky, Werner; Silue, Kigbafori; Zeeman, Anne-Marie; Kocken, Clemens; Leroy, Didier; Blasco, Benjamin; Rossignol, Emilie; Rueckle, Thomas; Matthews, Dave; Burrows, Jeremy N; Waterson, David; Palmer, Michael J; Rathod, Pradipsinh K; Charman, Susan A

    2016-12-09

    The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.

  15. [Rising attention to the market to ratio meet demand of improving efficiency of pharmaceutical circulation--based on complicated variety and specification of drugs].

    PubMed

    Chen, Zhaoxing; Sun, Lihua

    2010-05-01

    Analyzing the complicated variety and specification of drugs and the objective demand of pharmaceutical circulation, to seek out the key factors in improving the efficiency of pharmaceutical circulation, for putting forward suggestions to promote the development of pharmaceutical circulation in China. The conclusion is drawed from industrial organization theory and successful experience of foreign countries, high market attention met with the demand of complicated variety and specification of drugs in pharmaceutical circulation.

  16. Preparation of a novel starch-derived three-dimensional ordered macroporous carbon for improving the dissolution rate and oral bioavailability of water-insoluble drugs.

    PubMed

    Liu, Ying; Wu, Chao; Hao, Yanna; Xu, Jie; Zhao, Ying; Qiu, Yang; Jiang, Jie; Yu, Tong; Ji, Peng

    2016-01-25

    In our study, soluble starch was applied as a novel carbon source for preparing three-dimensional ordered macroporous carbon (3DOMC) using monodisperse silica nanospheres as the hard template. The 3DOMC was used as an insoluble drug carrier when it was found that it could markedly improve the water solubility of felodipine (FDP). The structural features of 3DOMC were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The 3DOMC structure was found to have a higher drug loading than microporous and mesoporous structures, and the interconnected nanostructure effectively inhibited the formation of drug crystals. FDP, belonging to the Biopharmaceutics Classification System II (BCSII), was chosen as the model drug and was loaded into the 3DOMC structure by solvent evaporation. The state of FDP in the 3DOMC structure was characterized by powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). The results obtained showed that FDP was present in the pores in an amorphous or microcrystalline state. In vivo and in vitro experiments indicated that 3DOMC could significantly improve the drug dissolution rate, but the FDP-3DOMC self-made common tablets had the disadvantage of a burst effect. For this reason, osmotic pump technology was used to control the drug release rate. We developed a potentially useful insoluble drug carrier for pharmaceutical applications.

  17. Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process.

    PubMed

    Shah, Navnit; Iyer, Raman M; Mair, Hans-Juergen; Choi, Duk Soon; Tian, Hung; Diodone, Ralph; Fähnrich, Karsten; Pabst-Ravot, Anni; Tang, Kin; Scheubel, Emmanuel; Grippo, Joseph F; Moreira, Sebastian A; Go, Zenaida; Mouskountakis, James; Louie, Theresa; Ibrahim, Prabha N; Sandhu, Harpreet; Rubia, Linda; Chokshi, Hitesh; Singhal, Dharmendra; Malick, Waseem

    2013-03-01

    The present work deals with improving the solubility of vemurafenib, a practically insoluble drug, by converting it into an amorphous-solid dispersion using a solvent-controlled precipitation process. The dispersion containing vemurafenib and hypromellose acetate succinate (HPMCAS), an enteric polymer, is termed microprecipitated bulk powder (MBP), in which the drug is uniformly dispersed within the polymeric substrate. HPMCAS was found to be the most suitable polymer for vemurafenib MBP, among a series of enteric polymers based on superior physical stability and drug-release characteristics of the MBP. The MBP provided a greater rate and extent of dissolution than crystalline drug, reaching an apparent drug concentration of 28-35 µg/mL, almost 30-fold higher than solubility of crystalline drug at 1 µg/mL. The supersaturation was also maintained for more than 4 h. Upon exposure to high temperature and humidity, the MBP was destabilized, resulting in crystallization and lower dissolution rate. The control of moisture and temperature is essential to maintain the stability of the MBP. In a relative human bioavailability study, vemurafenib MBP provided a four- to fivefold increase in exposure compared with crystalline drug. Improving solubility with an amorphous-solid dispersion is a viable strategy for the development of practically insoluble compounds.

  18. Controlled Substance Reconciliation Accuracy Improvement Using Near Real-Time Drug Transaction Capture from Automated Dispensing Cabinets.

    PubMed

    Epstein, Richard H; Dexter, Franklin; Gratch, David M; Perino, Michael; Magrann, Jerry

    2016-06-01

    Accurate accounting of controlled drug transactions by inpatient hospital pharmacies is a requirement in the United States under the Controlled Substances Act. At many hospitals, manual distribution of controlled substances from pharmacies is being replaced by automated dispensing cabinets (ADCs) at the point of care. Despite the promise of improved accountability, a high prevalence (15%) of controlled substance discrepancies between ADC records and anesthesia information management systems (AIMS) has been published, with a similar incidence (15.8%; 95% confidence interval [CI], 15.3% to 16.2%) noted at our institution. Most reconciliation errors are clerical. In this study, we describe a method to capture drug transactions in near real-time from our ADCs, compare them with documentation in our AIMS, and evaluate subsequent improvement in reconciliation accuracy. ADC-controlled substance transactions are transmitted to a hospital interface server, parsed, reformatted, and sent to a software script written in Perl. The script extracts the data and writes them to a SQL Server database. Concurrently, controlled drug totals for each patient having care are documented in the AIMS and compared with the balance of the ADC transactions (i.e., vending, transferring, wasting, and returning drug). Every minute, a reconciliation report is available to anesthesia providers over the hospital Intranet from AIMS workstations. The report lists all patients, the current provider, the balance of ADC transactions, the totals from the AIMS, the difference, and whether the case is still ongoing or had concluded. Accuracy and latency of the ADC transaction capture process were assessed via simulation and by comparison with pharmacy database records, maintained by the vendor on a central server located remotely from the hospital network. For assessment of reconciliation accuracy over time, data were collected from our AIMS from January 2012 to June 2013 (Baseline), July 2013 to April 2014

  19. Disulfide-crosslinked nanomicelles confer cancer-specific drug delivery and improve efficacy of paclitaxel in bladder cancer

    NASA Astrophysics Data System (ADS)

    Pan, Amy; Zhang, Hongyong; Li, Yuanpei; Lin, Tzu-yin; Wang, Fuli; Lee, Joyce; Cheng, Mingshan; Dall'Era, Marc; Li, Tianhong; deVere White, Ralph; Pan, Chong-Xian; Lam, Kit S.

    2016-10-01

    Chemotherapy commonly used in the treatment of advanced bladder cancer is only moderately effective and associated with significant toxicity. There has been no appreciable improvement in overall survival over the last three decades. The goal of this project is to develop and characterize bladder cancer-specific nanometer-scale micelles loaded with the chemotherapeutic drug paclitaxel (PTX) and determine the anti-tumor activity and toxicity. Micelle-building-material telodendrimers were synthesized through the stepwise conjugation of eight cholic acid units at one terminus of polyethylene glycol (PEG) and a bladder cancer-specific targeting peptide named PLZ4 at the other terminus. To synthesize disulfide-crosslinked PLZ4 nanomicelles (DC-PNM), cysteine was introduced between the cholic acid and PEG. DC-PNM-PTX was synthesized through the evaporation method by loading PTX in the core. The loading capacity of PTX in DC-PNM was 25% (W/W). The loading efficiency was over 99%. DC-PNM-PTX was spherical with the median size of 25 nm. The stability of DC-PNM-PTX was determined in a solution containing sodium docecyl sulfate (SDS). It was stable in a SDS solution, but dissolved within 5 min after the addition of glutathione at the physiological intracellular concentration of 10 mM. In vivo targeting and anti-tumor activity were determined in immunodeficient mice carrying patient-derived bladder cancer xenografts (PDXs). After intravenous administration, DC-PNM specifically targeted the bladder cancer PDXs, but very little to the lung cancer xenografts in the same mice (p < 0.001). DC-PNM loaded with PTX overcame cisplatin resistance, and improved the median survival from 55 d with free PTX to 69.5 d (p = 0.03) of mice carrying PDXs. In conclusion, DC-PNM remained stable in the SDS solution, specifically targeted the bladder cancer xenografts in vivo, and improved the anti-cancer efficacy of PTX.

  20. No country for old stents? Improving long-term patient outcomes with biodegradable polymer drug-eluting stents.

    PubMed

    Byrne, Robert A; Kastrati, Adnan

    2012-04-01

    Biodegradable polymer-coated drug-eluting stents (DESs) represent an attractive approach to improve vascular healing after coronary intervention. The proof-of-concept chain of investigation includes preclinical safety assessment, surrogate end point clinical efficacy studies and large-scale clinical outcome studies, in which noninferiority against benchmark devices is assessed at 12 months, with adjudication of hypothesized clinical advantage at long-term follow-up. The 4-year outcome data from large-scale trials such as the LEADERS study repres