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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 receptor phosphorylation and desensitization induced by transforming growth factor-beta.

    PubMed Central

    Romero-Avila, M Teresa; Flores-Jasso, C Fabián; García-Sáinz, J Adolfo

    2002-01-01

    Transforming growth factor-beta (TGF-beta) induced alpha(1B)-adrenergic receptor phosphorylation in Rat-1 fibroblasts stably expressing these adrenoceptors. This effect of TGF-beta was rapid, reaching a maximum within 30 min and decreasing thereafter, and concentration-dependent (EC(50) 0.3 pM). The phosphoinositide 3-kinase inhibitors wortmannin and LY294002, and the protein kinase C inhibitors staurosporine, Ro 318220 and bisindolylmaleimide, blocked the effect of this growth factor. alpha(1B)-Adrenergic receptor phosphorylation was associated with desensitization, as indicated by a reduction in the adrenergic-mediated production of [(3)H]inositol phosphates. Phosphorylation of alpha(1B)-adrenergic receptors by TGF-beta was also observed in Cos-1 cells transfected with the receptor. Co-transfection of the dominant-negative mutant of the regulatory subunit of phosphoinositide 3-kinase (Deltap85) inhibited the phosphorylation of alpha(1B)-adrenergic receptors induced by TGF-beta. Our results indicate that activation of TGF-beta receptors induces alpha(1B)-adrenergic receptor phosphorylation and desensitization. The data suggest that phosphoinositide 3-kinase and protein kinase C play key roles in this effect of TGF-beta. PMID:12234252

  3. alpha1B-Adrenergic receptor phosphorylation and desensitization induced by transforming growth factor-beta.

    PubMed

    Romero-Avila, M Teresa; Flores-Jasso, C Fabián; García-Sáinz, J Adolfo

    2002-12-01

    Transforming growth factor-beta (TGF-beta) induced alpha(1B)-adrenergic receptor phosphorylation in Rat-1 fibroblasts stably expressing these adrenoceptors. This effect of TGF-beta was rapid, reaching a maximum within 30 min and decreasing thereafter, and concentration-dependent (EC(50) 0.3 pM). The phosphoinositide 3-kinase inhibitors wortmannin and LY294002, and the protein kinase C inhibitors staurosporine, Ro 318220 and bisindolylmaleimide, blocked the effect of this growth factor. alpha(1B)-Adrenergic receptor phosphorylation was associated with desensitization, as indicated by a reduction in the adrenergic-mediated production of [(3)H]inositol phosphates. Phosphorylation of alpha(1B)-adrenergic receptors by TGF-beta was also observed in Cos-1 cells transfected with the receptor. Co-transfection of the dominant-negative mutant of the regulatory subunit of phosphoinositide 3-kinase (Deltap85) inhibited the phosphorylation of alpha(1B)-adrenergic receptors induced by TGF-beta. Our results indicate that activation of TGF-beta receptors induces alpha(1B)-adrenergic receptor phosphorylation and desensitization. The data suggest that phosphoinositide 3-kinase and protein kinase C play key roles in this effect of TGF-beta. PMID:12234252

  4. Molecular characterization of a rat alpha 2B-adrenergic receptor.

    PubMed Central

    Zeng, D W; Harrison, J K; D'Angelo, D D; Barber, C M; Tucker, A L; Lu, Z H; Lynch, K R

    1990-01-01

    Alpha 2-adrenergic receptors comprise a heterogeneous population based on pharmacologic and molecular evidence. We have isolated a cDNA clone (pRNG alpha 2) encoding a rat alpha 2-adrenergic receptor. A rat kidney cDNA library was screened with an oligonucleotide complementary to a highly conserved region found in all biogenic amine receptors described to date. The deduced amino acid sequence displays many features of guanyl nucleotide-binding protein-coupled receptors except it does not have a consensus N-linked glycosylation site near the amino terminus. Membranes prepared from COS cells transfected with pRNG alpha 2 DNA display high affinity and saturable binding to [3H]rauwolscine (Kd = 2 nM). Competition curve data analysis shows that RNG alpha 2 protein binds to a variety of adrenergic drugs with the following rank order of potency: yohimbine greater than or equal to chlorpromazine greater than or equal to prazosin greater than or equal to clonidine greater than norepinephrine greater than or equal to oxymetazoline. RNG alpha 2 RNA accumulates in both rat kidney and neonatal rat lung (predominant species is 4000 nucleotides). When a cysteine residue (Cys-169) that is conserved among all members of the seven-transmembrane-region superfamily is changed to phenylalanine, the RNG alpha 2 protein fails to bind [3H]rauwolscine after expression in COS cells. We conclude that pRNG alpha 2 likely represents a cDNA for a rat alpha 2B-adrenergic receptor. Images PMID:2158103

  5. α1B-adrenergic receptors differentially associate with Rab proteins during homologous and heterologous desensitization.

    PubMed

    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

  6. 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

  7. Cloning and expression of a rat brain. alpha. sub 2B -adrenergic receptor

    SciTech Connect

    Flordellis, C.S.; Handy, D.E.; Bresnahan, M.R.; Zannis, V.I.; Gavras, H. )

    1991-02-01

    The authors isolated a cDNA clone (RB{alpha}{sub 2B}) and its homologous gene (GR{alpha}{sub 2B}) encoding an {alpha}{sub 2B}-adrenergic receptor subtype by screening a rat brain cDNA and a rat genomic library. Nucleotide sequence analysis showed that both clones code for a protein of 458 amino acids, which is 87% homologous to the human kidney glycosylated adrenergic receptor ({alpha}{sub 2}-C4) and divergent from the rat kidney nonglycosylated {alpha}{sub 2B} subtype (RNG{alpha}{sub 2}). Transient expression of RB{alpha}{sub 2B} in COS-7 cells resulted in high-affinity saturable binding for ({sup 3}H)rauwolscine and a high receptor number in the membranes of transfected COS-7 cells. Pharmacological analysis demonstrated that the expressed receptor bound adrenergic ligands with the following order of potency: rauwolscine {gt} yohimbine {gt} prazosin {gt} oxymetazoline, with a prazosin-to-oxymetazoline K{sub i} ratio of 0.34. This profile is characteristic of the {alpha}{sub 2B}-adrenergic receptor subtype. Blotting analysis of rat brain mRNA gave one major and two minor mRNA species, and hybridization with strand-specific probes showed that both DNA strands of GR{alpha}{sub 2B} may be transcriptionally active. These findings show that rat brain expresses an {alpha}{sub 2B}-adrenergic receptor subtype that is structurally different from the rat kidney nonglycosylated {alpha}{sub 2B} subtype. Thus the rat expresses at least two divergent {alpha}{sub 2B}-adrenergic receptors.

  8. 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

  9. 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. PMID:26968030

  10. 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

  11. Alpha2B-adrenergic receptor interaction with tubulin controls its transport from the endoplasmic reticulum to the cell surface.

    PubMed

    Duvernay, Matthew T; Wang, Hong; Dong, Chunmin; Guidry, Jesse J; Sackett, Dan L; Wu, Guangyu

    2011-04-22

    It is well recognized that the C terminus (CT) plays a crucial role in modulating G protein-coupled receptor (GPCR) transport from the endoplasmic reticulum (ER) to the cell surface. However the molecular mechanisms that govern CT-dependent ER export remain elusive. To address this issue, we used α(2B)-adrenergic receptor (α(2B)-AR) as a model GPCR to search for proteins interacting with the CT. By using peptide-conjugated affinity matrix combined with proteomics and glutathione S-transferase fusion protein pull-down assays, we identified tubulin directly interacting with the α(2B)-AR CT. The interaction domains were mapped to the acidic CT of tubulin and the basic Arg residues in the α(2B)-AR CT, particularly Arg-437, Arg-441, and Arg-446. More importantly, mutation of these Arg residues to disrupt tubulin interaction markedly inhibited α(2B)-AR transport to the cell surface and strongly arrested the receptor in the ER. These data provide the first evidence indicating that the α(2B)-AR C-terminal Arg cluster mediates its association with tubulin to coordinate its ER-to-cell surface traffic and suggest a novel mechanism of GPCR export through physical contact with microtubules. PMID:21357695

  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. PMID:27173823

  13. Using an alarm to improve drug trolley safety.

    PubMed

    Hodges, Emily; Pearson, Darcy; Moondi, Parvez; Gibson, John; Blunt, Mark; Young, Peter; Mariyaselvam, Maryanne

    Leaving drug trolleys unlocked and unattended during drug rounds creates opportunities for drug theft and tampering. A new device was developed by our trust to detect when an open drug trolley is left unattended; it then sounds an alarm to remind staff to return to the trolley. This article describes use of the alarm on general hospital wards in one trust in the east of England. When the alarm was installed into drug trolleys on ahospital ward, it reduced the number of times unlocked trolleys were left unattended. The drug trolley alarm successfully changed the behaviour of staff on drug rounds and, in so doing, improved patient safety. PMID:26625697

  14. Improving the tuberculosis drug development pipeline.

    PubMed

    Evangelopoulos, Dimitrios; McHugh, Timothy D

    2015-11-01

    Mycobacterium tuberculosis is considered one of the most successful pathogens and multidrug-resistant tuberculosis, a disease that urgently requires new chemical entities to be developed for treatment. There are currently several new molecules under clinical investigation in the tuberculosis (TB) drug development pipeline. However, the complex lifestyle of M. tuberculosis within the host presents a barrier to the development of new drugs. In this review, we highlight the reasons that make TB drug discovery and development challenging as well as providing solutions, future directions and alternative approaches to new therapeutics for TB. PMID:25772393

  15. Can pharmacogenomics improve malaria drug policy?

    PubMed Central

    McLeod, Howard; Juliano, Jonathan J

    2011-01-01

    Abstract Coordinated global efforts to prevent and control malaria have been a tour-de-force for public health, but success appears to have reached a plateau in many parts of the world. While this is a multifaceted problem, policy strategies have largely ignored genetic variations in humans as a factor that influences both selection and dosing of antimalarial drugs. This includes attempts to decrease toxicity, increase effectiveness and reduce the development of drug resistance, thereby lowering health care costs. We review the potential hurdles to developing and implementing pharmacogenetic-guided policies at a national or regional scale for the treatment of uncomplicated falciparum malaria. We also consider current knowledge on some component drugs of artemisinin combination therapies and ways to increase our understanding of host genetics, with the goal of guiding policy decisions for drug selection. PMID:22084530

  16. Augmenting drug-carrier compatibility improves tumour nanotherapy efficacy.

    PubMed

    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

    2016-01-01

    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. PMID:27071376

  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. [Metabolomics has the potential to improve drug therapy.

    PubMed

    Stage, Claus; Jürgens, Gesche; Dalhoff, Kim Peder; Rasmussen, Henrik Berg

    2014-03-17

    Until now drug therapy has primarily been controlled by dose titration on the basis of effects and side effects. However, a lot of people being treated with a drug experience too little effect or too many side effects. Therefore it will be advantageous to improve drug therapy and make it even more "individualized". In this chase metabolomics is a hot topic. The aim of this paper is to review the concepts of metabolomics and the possible applications in regard to drug development, drug therapy and diagnosis, prognosis and monitoring of diseases. PMID:25096206

  19. Drug utilisation study in a tertiary care center: recommendations for improving hospital drug dispensing policies.

    PubMed

    Mittal, Niti; Mittal, R; Singh, I; Shafiq, Nusrat; Malhotra, S

    2014-07-01

    Drug therapy accounts for a major portion of health expenditure. A useful strategy for achieving cost efficient healthcare is drug utilisation research as it forms the basis for making amendments in drug policies and helps in rational drug use. The present observational study was conducted to generate data on drug utilization in inpatients of our tertiary care hospital to identify potential targets for improving drug prescribing patterns. Data was collected retrospectively from randomly selected 231 medical records of patients admitted in various wards of the hospital. WHO Anatomical Therapeutic Chemical/Defined Daily Dose methodology was used to assess drug utilisation data and drug prescriptions were analysed by WHO core drug indicators. Antibiotics were prescribed most frequently and also accounted for majority of drug costs. The prescribed daily dose for most of the antibiotics corresponded to defined daily dose reflecting adherence to international recommendations. Brand name prescribing and polypharmacy was very common.78% of the total drugs prescribed were from the National List of Essential Medicines 2003. Restricting the use of newer and costlier antibiotics, branded drugs and number of drugs per prescription could be considered as targets to cut down the cost of drug therapysignificantly. PMID:25284928

  20. Improving the drug quality and safety net.

    PubMed

    Carter, Alan

    2014-07-01

    When large quantities of contaminated, subpotent, or superpotent drugs are introduced into the medical supply pipeline, injury or death of hundreds or thousands of patients can occur. Tracing the origin of substandard and dangerous products and tracking across regions and countries where shipped is quite costly in both money and time. From patients' perspective, timely access to quality product is paramount. Receiving deficient product threatens their survival and creates huge sums of financial cost to both them and the medical system. With the passage of HR 3204 the FDA must now find a way to be proactive in policing the global medical product supply line without restricting market availability. Without a comprehensive, world-focused implementation plan these new regulations will fail to protect the public. PMID:24876419

  1. Improving interorganizational data interchange for drug development.

    PubMed

    Canfield, K

    1999-01-01

    This paper presents a reengineered process that uses a markup language to do interorganizational data interchange between the participants in the US drug development process. The two major goals of this paper are to present (1) a detailed enough description of the reengineered version of this process that a practitioner will be able to use it and (2) a case-study of the reengineering of an interorganizational data interchange system that is applicable to other areas in health care. The detailed description is augmented with a companion web-site that shows all programs in a working prototype. The case-study uses an IDEF0 model to show the structure of benefits from markup standards for interorganizational data interchange. PMID:10207657

  2. 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

  3. 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. PMID:25526702

  4. 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

  5. Pharmacological Drug Delivery Strategies for Improved Therapeutic Effects: Recent Advances.

    PubMed

    Savaliya, Reema; Singh, Poornima; Singh, Sanjay

    2016-01-01

    The latest pharmacologic research has resulted number of new molecules with the potential to modernize the prevention or treatment of different complex diseases, including cancer. The therapeutics generally include moieties such as proteins, drugs and genes, etc. Current activities in the pharmacological field include the development of novel drug-delivery systems to overcome pharmacokinetic glitches such as limited bioavailability, unwanted distribution, drug resistant, and stability, etc. Therefore, to address these issues various biotechnological and pharmacological techniques has been introduced. However, effective drug delivery with improved efficacy remains challenging. This review is focused towards different strategies such as physical and biological methods for efficacious delivery at desired tissues and even sub-cellular targeting. Emphasis is also given about nanotechnology based drug or gene delivery strategies and co-delivery of drug-drug; gene-gene or combinations of drug-gene, etc. are the current cuttingedge methods, which are under clinical or pre-clinical stage of research. Uses of biodegradable materials, such as liposomes and polymeric particles are another class of drug delivery vehicles, which have shown tremendous success, are also discussed. Towards the end, future directions of pharmacological drug delivery methods have also been summarized. PMID:26654439

  6. Modifications of Antiepileptic Drugs for Improved Tolerability and Efficacy

    PubMed Central

    Landmark, Cecilie Johannessen; Johannessen, Svein I.

    2008-01-01

    Introduction A large number of antiepileptic drugs (AEDs) are available today, but they may not be satisfactory regarding clinical efficacy, tolerance, toxicity or pharmacokinetic properties. The purpose of this review is to focus upon the rationale behind the chemical modifications of several recently marketed AEDs or drugs in development and to categorize them according to the main purposes for the improvements: better efficacy or tolerability accompanied by improved pharmacokinetic properties. Material and Method AEDs that have been chemically modified to new derivatives during the last years are reviewed based on recent publications and PubMed-searches. Results and Discussion Improvement in pharmacokinetic parameters may affect both tolerability and efficacy. Modifications to improve tolerability include various valproate analogues, divided into aliphatic amides, cyclic derivatives or amino acid conjugates. Furthermore, there are the carbamazepine analogues oxcarbazepine and eslicarbazepine, the felbamate analogues fluorofelbamate and carisbamate (RWJ 33369), and the lamotrigine analogue JZP-4. The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds. Other new drugs have new mechanisms of action related to GABA and glutamate receptors; the glutamate antagonists like topiramate (talampanel and NS-1209), and GABAA receptor agonists, benzodiazepine or progesterone analogues (ELB-139 and ganaxolone). Conclusion Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity. These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders. PMID:19787095

  7. Improving Viral Protease Inhibitors to Counter Drug Resistance.

    PubMed

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

    2016-07-01

    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

  8. The Drug Facts Box: Improving the communication of prescription drug information

    PubMed Central

    Schwartz, Lisa M.; Woloshin, Steven

    2013-01-01

    Communication about prescription drugs ought to be a paragon of public science communication. Unfortunately, it is not. Consumers see $4 billion of direct-to-consumer advertising annually, which typically fails to present data about how well drugs work. The professional label—the Food and Drug Administration's (FDA) mechanism to get physicians information needed for appropriate prescribing—may also fail to present benefit data. FDA labeling guidance, in fact, suggests that industry omit benefit data for new drugs in an existing class and for drugs approved on the basis of unfamiliar outcomes (such as depression rating scales). The medical literature is also problematic: there is selective reporting of favorable trials, favorable outcomes within trials, and “spinning” unfavorable results to maximize benefit and minimize harm. In contrast, publicly available FDA reviews always include the phase 3 trial data on benefit and harm, which are the basis of drug approval. However, these reviews are practically inaccessible: lengthy, poorly organized, and weakly summarized. To improve accessibility, we developed the Drug Facts Box: a one-page summary of benefit and harm data for each indication of a drug. A series of studies—including national randomized trials—demonstrates that most consumers understand the Drug Facts Box and that it improves decision-making. Despite calls from their own Risk Communication Advisory Committee and Congress (in the Affordable Care Act) to consider implementing boxes, the FDA announced it needs at least 3–5 y more to make a decision. Given its potential public health impact, physicians and the public should not have to wait that long for better drug information. PMID:23942130

  9. 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. PMID:23942130

  10. 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

  11. 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

  12. Improved delivery of the natural anticancer drug tetrandrine.

    PubMed

    Shi, Chen; Ahmad Khan, Saeed; Wang, Kaiping; Schneider, Marc

    2015-02-01

    The study aims at designing a nanoparticle-based delivery system to improve the efficacy of the natural compound tetrandrine against lung cancer. Nanoparticles from poly(lactic-co-glycolic acid) (PLGA) were prepared by the emulsion solvent diffusion method and characterized for their physicochemical properties and drug-loading efficiency. Furthermore, the cellular uptake and the anti-cancerous activity was studied on A549 cell line. To investigate the surface properties and uptake, three different stabilizers were used to analyze the effect on size and zeta potential of nanoparticles as well as the effect on the cellular uptake. Nanoparticles in the size range of 180-200 nm with spherical shape were obtained with polyvinyl alcohol (PVA), Pluronic-F127 (PF127) and didodecyldimethylammonium bromide (DMAB), 2%, 1% and 0.1%, respectively. An entrapment efficiency of 50-60% with a loading of 1.5-2% was observed. In vitro release profile at pH 7.4 PBS solution showed a consistent release over 168 h. All particle systems showed an improved performance over the pure drug at the same drug concentration. DMAB stabilized particles demonstrated the most pronounced effect against A549 cells compared to pure drug while PVA stabilized particles were least effective in terms of antitumor activity. PMID:25510598

  13. [Adult GM2 gangliosidosis: improvement of ataxia with GABAergic drugs].

    PubMed

    Gazulla Abío, J; Benavente Aguilar, I

    2002-03-01

    The authors present a case of adult GM2 gangliosidosis, B1 enzymatic type. The main clinical features found were cerebellar ataxia, proximal lower limb weakness and myokymia. The neurological examination, and the biochemical, electrophysiologic and imaging studies are all described. Decreased activity of the enzyme beta-hexosaminidase A in the metabolism of the sulfate substrate 4-MU-NAGS was found in serum. Global cerebellar atrophy was observed in a cranial nuclear magnetic resonance. The electrophysiologic study showed continuous spontaneous activity integrated by myokymia and neuromyotonic discharges in addition to signs of acute and chronic denervation. Disappearance of the myokymia and improvement in the ataxia were attained with the use of the GABAergic drugs gabapentin and tiagabine. The authors try to explain the clinical improvement obtained with the drugs by relating their mechanisms of action to the central nervous system neurotransmitter alterations proposed for this disease. PMID:11927106

  14. 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.

  15. High-throughput screening of drug-binding dynamics to HERG improves early drug safety assessment.

    PubMed

    Di Veroli, Giovanni Y; Davies, Mark R; Zhang, Henggui; Abi-Gerges, Najah; Boyett, Mark R

    2013-01-01

    The use of computational models to predict drug-induced changes in the action potential (AP) is a promising approach to reduce drug safety attrition but requires a better representation of more complex drug-target interactions to improve the quantitative prediction. The blockade of the human ether-a-go-go-related gene (HERG) channel is a major concern for QT prolongation and Torsade de Pointes risk. We aim to develop quantitative in-silico AP predictions based on a new electrophysiological protocol (suitable for high-throughput HERG screening) and mathematical modeling of ionic currents. Electrophysiological recordings using the IonWorks device were made from HERG channels stably expressed in Chinese hamster ovary cells. A new protocol that delineates inhibition over time was applied to assess dofetilide, cisapride, and almokalant effects. Dynamic effects displayed distinct profiles for these drugs compared with concentration-effects curves. Binding kinetics to specific states were identified using a new HERG Markov model. The model was then modified to represent the canine rapid delayed rectifier K(+) current at 37°C and carry out AP predictions. Predictions were compared with a simpler model based on conductance reduction and were found to be much closer to experimental data. Improved sensitivity to concentration and pacing frequency variables was obtained when including binding kinetics. Our new electrophysiological protocol is suitable for high-throughput screening and is able to distinguish drug-binding kinetics. The association of this protocol with our modeling approach indicates that quantitative predictions of AP modulation can be obtained, which is a significant improvement compared with traditional conductance reduction methods. PMID:23103500

  16. 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

  17. 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

  18. Novel drug delivery strategies for improving econazole antifungal action.

    PubMed

    Firooz, Alireza; Nafisi, Shohreh; Maibach, Howard I

    2015-11-10

    Econazole is a commonly used azole antifungal in clinical treatment of superficial fungal infections. It is generally used as conventional cream and gel preparations under the brand names of Spectazole (United States), Ecostatin (Canada), Pevaryl (Western Europe). Treatment efficiency of antifungal drugs depends on their penetration through target layers of skin at effective concentrations. Econazole's poor water solubility limits its bioavailability and antifungal effects. Therefore, formulation strategies have been examined for delivering econazole through targeted skin sites. The present overview focuses on novel nano-based formulation approaches used to improve econazole penetration through skin for treatment of superficial fungal infections. PMID:26383840

  19. Using improved serial blood sampling method of mice to study pharmacokinetics and drug-drug interaction.

    PubMed

    Watanabe, Ayahisa; Watari, Ryosuke; Ogawa, Keiko; Shimizu, Ryosuke; Tanaka, Yukari; Takai, Nozomi; Nezasa, Ken-ichi; Yamaguchi, Yoshitaka

    2015-03-01

    In pharmacokinetic evaluation of mice, using serial sampling methods rather than a terminal blood sampling method could reduce the number of animals needed and lead to more reliable data by excluding individual differences. In addition, using serial sampling methods can be valuable for evaluation of the drug-drug interaction (DDI) potential of drug candidates. In this study, we established an improved method for serially sampling the blood from one mouse by only one incision of the lateral tail vein, and investigated whether our method could be adapted to pharmacokinetic and DDI studies. After intravenous and oral administration of ibuprofen and fexofenadine (BCS class II and III), the plasma concentration and pharmacokinetic parameters were evaluated by our method and a terminal blood sampling method, with the result that both methods gave comparable results (ibuprofen: 63.8 ± 4.0% and 64.4%, fexofenadine: 6.5 ± 0.7% and 7.9%, respectively, in bioavailability). In addition, our method could be adapted to DDI study for cytochrome P450 and organic anion transporting polypeptide inhibition. These results demonstrate that our method can be useful for pharmacokinetic evaluation from the perspective of reliable data acquisition as well as easy handling and low stress to mice and improve the quality of pharmacokinetic and DDI studies. PMID:25452230

  20. 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

  1. 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. PMID

  2. New improved drug delivery technologies for pentacyclic triterpenes: a review.

    PubMed

    Soica, Codruta; Trandafirescu, Cristina; Danciu, Corina; Muntean, Danina; Dehelean, Cristina; Simu, Georgeta

    2014-01-01

    Phytochemicals are becoming more and more interesting in the field of therapeutic research, mainly in the treatment of chronic illnesses, due to the fact that many synthetic drugs cause important side effects that impact on pa- tient's life quality. Pentacyclic triterpenes are a class of compounds with several therapeutic effects and increasing impor- tance in cancer therapy; however, a major disadvantage is their low water solubility and bioavailability which leads to rather poor therapeutic results in vivo.Technological attempts to improve the pharmacokinetic profile of the main repre- sentatives of this class include the use of cyclodextrins, micro- and nanoemulsions, liposomes, polymeric nanoparticles, and nanocapsules. This paper is aimed to briefly summarize the most significant achievements in this field. PMID:25106907

  3. Improving Outcomes in State AIDS Drug Assistance Programs

    PubMed Central

    Linas, Benjamin P.; Losina, Elena; Rockwell, Annette; Walensky, Rochelle P.; Cranston, Kevin; Freedberg, Kenneth A.

    2009-01-01

    Background State AIDS Drug Assistance Programs (ADAPs) provide antiretroviral medications to patients with no access to medications. Resource constraints limit many ADAPs' ability to meet demand for services. Objective To determine ADAP eligibility criteria that minimize morbidity and mortality and contain costs. Methods We used Discrete Event Simulation to model the progression of HIV-infected patients and track utilization of an ADAP. Outcomes included five-year mortality and incidence of first opportunistic infection or death, and time to starting ART. We compared expected outcomes for two policies: 1) first-come, first-served (FCFS) eligibility for all with CD4 count ≤350/μl (current standard), and 2) CD4 count prioritized eligibility for those with CD4 counts below a defined threshold. Results In the base case, prioritizing patients with CD4 counts ≤250/μl led to lower five-year mortality than FCFS eligibility [2.77 vs. 3.27 deaths/1,000 person months], and to a lower incidence of first opportunistic infection or death [5.55 vs. 6.98 events/1,000 person months]. CD4-based eligibility reduced the time to starting ART for patients with CD4 counts ≤200/μl. In sensitivity analyses, CD4-based eligibility consistently led to lower morbidity and mortality than FCFS eligibility. Conclusions When resources are limited, programs that provide ART can improve outcomes by prioritizing patients with low CD4 counts. PMID:19561518

  4. 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

    ... content and format requirements for labeling to make it easier to access, read, and use (71 FR 3922... HUMAN SERVICES Food and Drug Administration 21 CFR Parts 201, 314, and 601 Center for Drug Evaluation... . Submit written comments to the Division of Dockets Management (HFA- 301), Food and Drug...

  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 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. PMID:26068584

  7. Drugs and diagnostic innovations to improve global health.

    PubMed

    Peeling, Rosanna W; Nwaka, Solomon

    2011-09-01

    Infectious diseases remain the major cause of morbidity and mortality in the developing world. Affordable effective drugs and diagnostics are critical for patient management and disease control but the development of new drugs and diagnostics is too slow to keep up with the emergence and spread of infectious diseases around the world. Innovative collaborative research and development involving disease endemic countries and developed countries are urgently needed to accelerate progress along the path from discovery to product adoption. These emerging approaches and the need for increased investment in human and financial resources to support them are discussed. PMID:21896368

  8. [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. PMID:22260037

  9. [New pediatric drug dosage aids : Improving patient safety].

    PubMed

    Strauß, J M

    2016-03-01

    Dosing errors when administering medicine to children occur often and are due, e.g., to the commonly required dilution of the drugs, misjudgment of the patient's weight, confusion between drugs with similar names, and inadequate communication. Various aids (e.g., measuring tapes and dilution tables) have been designed to avoid mistakes to the greatest extent possible. In daily clinical practice, books and pocket cards are still used for rapid orientation. Use of smartphone-based apps continues to increase, whereby the user is ultimately responsible for their validity. In clinical practice, the simplest possible strategies should be used. A culture that encourages disclosure of errors is useful in order to optimize processes and avoid future errors. PMID:26459455

  10. 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. PMID:26983887

  11. 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

  12. 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. PMID:16876919

  13. Improving drug retention in liposomes by aging with the aid of glucose.

    PubMed

    Zhang, Wenli; Falconer, James R; Baguley, Bruce C; Shaw, John P; Kanamala, Manju; Xu, Hongtao; Wang, Guangji; Liu, Jianping; Wu, Zimei

    2016-05-30

    This paper describes a novel method to improve drug retention in liposomes for the poorly water-soluble (lipophilic) model drug asulacrine (ASL). ASL was loaded in the aqueous phase of liposomes and the effects of aging conditions and drug loading levels on drug retention were investigated using an in vitro bio-relevant drug release test established in this study. The status of intra-liposomal drug was investigated using differential scanning calorimetry (DSC) and cryo-transmission electron microscopy (cryo-TEM). Pharmacokinetics and venous tolerance of the formulations were simultaneously studied in rabbits following one-hour intravenous infusion via the ear vein. The presence of glucose during aging was found to be crucial to accelerate drug precipitation and to stabilize the liposomal membrane with high drug loading (8.9% over 4.5% w/w) as a prerequisite. Although no drug crystals were detected, DSC showed a lower phase-transition peak in the glucose-assisted aged ASL-liposomes, indicating interaction of phospholipids with the sugar. Cryo-TEM revealed more 'coffee bean' like drug precipitate in the ASL-liposomes aged in the glucose solution. In rabbits, these liposomes gave rise to a 1.9 times longer half-life than the fresh liposomes, with no venous irritation observed. Inducing and stabilizing drug precipitation in the liposome cores by aging in the presence of sugar provided an easy approach to improve drug retention in liposomes. The study also highlighted the importance of bio-relevance of in vitro release methods to predict in vivo drug release. PMID:27021465

  14. [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. PMID:26911033

  15. 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. PMID:17339677

  16. Improving malaria home treatment by training drug retailers in rural Kenya.

    PubMed

    Marsh, V M; Mutemi, W M; Willetts, A; Bayah, K; Were, S; Ross, A; Marsh, K

    2004-04-01

    Recent global malaria control initiatives highlight the potential role of drug retailers to improve access to early effective malaria treatment. We report on the findings and discuss the implications of an educational programme for rural drug retailers and communities in Kenya between 1998 and 2001 in a study population of 70,000. Impact was evaluated through annual household surveys of over-the-counter (OTC) drug use and simulated retail client surveys in an early (1999) and a late (2000) implementation area. The programme achieved major improvements in drug selling practices. The proportion of OTC anti-malarial drug users receiving an adequate dose rose from 8% (n = 98) to 33% (n = 121) between 1998 and 1999 in the early implementation area. By 2001, and with the introduction of sulphadoxine pyrimethamine group drugs in accordance with national policy, this proportion rose to 64% (n = 441) across the early and late implementation areas. Overall, the proportion of shop-treated childhood fevers receiving an adequate dose of a recommended anti-malarial drug within 24 h rose from 1% (n = 681) to 28% (n = 919) by 2001. These findings strongly support the inclusion of private drug retailers in control strategies aiming to improve prompt effective treatment of malaria. PMID:15078263

  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. Investigation on fabrication process of dissolving microneedle arrays to improve effective needle drug distribution.

    PubMed

    Wang, Qingqing; Yao, Gangtao; Dong, Pin; Gong, Zihua; Li, Ge; Zhang, Kejian; Wu, Chuanbin

    2015-01-23

    The dissolving microneedle array (DMNA) offers a novel potential approach for transdermal delivery of biological macromolecular drugs and vaccines, because it can be as efficient as hypodermic injection and as safe and patient compliant as conventional transdermal delivery. However, effective needle drug distribution is the main challenge for clinical application of DMNA. This study focused on the mechanism and control of drug diffusion inside DMNA during the fabrication process in order to improve the drug delivery efficiency. The needle drug loading proportion (NDP) in DMNAs was measured to determine the influences of drug concentration gradient, needle drying step, excipients, and solvent of the base solution on drug diffusion and distribution. The results showed that the evaporation of base solvent was the key factor determining NDP. Slow evaporation of water from the base led to gradual increase of viscosity, and an approximate drug concentration equilibrium was built between the needle and base portions, resulting in NDP as low as about 6%. When highly volatile ethanol was used as the base solvent, the viscosity in the base rose quickly, resulting in NDP more than 90%. Ethanol as base solvent did not impact the insertion capability of DMNAs, but greatly increased the in vitro drug release and transdermal delivery from DMNAs. Furthermore, the drug diffusion process during DMNA fabrication was thoroughly investigated for the first time, and the outcomes can be applied to most two-step molding processes and optimization of the DMNA fabrication. PMID:25446513

  19. 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

  20. Development and characterization of naproxen-chitosan solid systems with improved drug dissolution properties.

    PubMed

    Mura, Paola; Zerrouk, Naima; Mennini, Natascia; Maestrelli, Francesca; Chemtob, Chantal

    2003-05-01

    The solubilizing and amorphizing properties toward naproxen (a poorly water-soluble antiinflammatory drug) of chitosan, an emerging pharmaceutical biopolymer, have been investigated. Solid binary systems at different drug/polymer ratios have been prepared according to different techniques (mixing, cogrinding, kneading, coevaporation) using chitosan at low (CS-L(w)) and medium (CS-M(w)) molecular weight, and tested for dissolution properties. Drug-carrier interactions were investigated in both the liquid and solid state, by phase solubility analysis, differential scanning calorimetry, X-ray powder diffractometry, FT-IR spectroscopy, and scanning electron microscopy. Drug dissolution parameters improved with increasing the polymer amount in the mixture, reaching the highest values at the 1:9 (w/w) drug/polymer ratio, and CS-L(w) was more efficacious than CS-M(w). Cogrinding was the most effective technique, showing the strongest amorphizing effect toward the drug and enabling an increase of more than ten times its relative dissolution rate. Coground mixtures at 3:7 (w/w) drug/polymer ratio were able to give directly compressed tablets which maintained unchanged the improved drug dissolution properties. Enhancer dissolution properties combined with its direct compression feasibility and antiulcerogenic action make CS-L(w) an optimal carrier for developing fast-release oral solid dosage forms of naproxen. PMID:12729863

  1. 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.

  2. Biocompatible polymer coating of titania nanotube arrays for improved drug elution and osteoblast adhesion.

    PubMed

    Gulati, Karan; Ramakrishnan, Saminathan; Aw, Moom Sinn; Atkins, Gerald J; Findlay, David M; Losic, Dusan

    2012-01-01

    Bacterial infection, extensive inflammation and poor osseointegration have been identified as the major reasons for [early] orthopaedic implant failures based on titanium. Creating implants with drug-eluting properties to locally deliver drugs is an appealing way to address some of these problems. To improve properties of titanium for orthopaedic applications, this study explored the modification of titanium surfaces with titaniananotube (TNT) arrays, and approach that combines drug delivery into bone and potentially improved bone integration. A titania layer with an array of nanotube structures (∼120 nm in diameter and 50 μm in length) was synthesized on titanium surfaces by electrochemical anodization and loaded with the water-insoluble anti-inflammatory drug indomethacin. A simple dip-coating process of polymer modification formed thin biocompatible polymer films over the drug-loaded TNTs to create TNTs with predictable drug release characteristics. Two biodegradable and antibacterial polymers, chitosan and poly(lactic-co-glycolic acid), were tested for their ability to extend the drug release time of TNTs and produce favourable bone cell adhesion properties. Dependent on polymer thickness, a significant improvement in the drug release characteristics was demonstrated, with reduced burst release (from 77% to >20%) and extended overall release from 4 days to more than 30 days. Excellent osteoblast adhesion and cell proliferation on polymer-coated TNTs compared with uncoated TNTs were also observed. These results suggest that polymer-modified implants with a TNT layer are capable of delivering a drug to a bone site over an extended period and with predictable kinetics. In addition, favourable bone cell adhesion suggests that such an implant would have good biocompatibility. The described approach is broadly applicable to a wide range of drugs and implants currently used in orthopaedic practice. PMID:21930254

  3. Improved dissolution of an insoluble drug using a 4-fluid nozzle spray-drying technique.

    PubMed

    Chen, Richer; Tagawa, Maya; Hoshi, Noboru; Ogura, Toshihiro; Okamoto, Hirokazu; Danjo, Kazumi

    2004-09-01

    A solid dispersion of the drug can be made using a polymer carrier to improve solubility. Generally, drugs become amorphized when solid dispersion is formed using a polymer carrier. In such high energy conditions, the solubility of the drug molecule is increased. We previously prepared solid dispersion using a spray-drying technique and reported its solubility and crystallinity. In this study, hydroxypropylmethylcellulose (HPMC) was used as the carrier, and tolubutamide was the model drug, which is water-insoluble. Solubility was evaluated by preparing a solid dispersion using a newly developed 4-fluid nozzle spray dryer. Observation of particle morphology by scanning electron microscopy (SEM) revealed that the particles from the spray drying were atomized to several microns, and they had also become spherical. Assessment of the crystallinity of the spray-dried particles by powder X-ray diffraction and differential scanning calorimetry demonstrated that the tolbutamide had been amorphized, forming a solid dispersion. The apparent release rate constant K of the drug from the spray-dried particles was 4 to 6 times faster than the original drug in pH 1.2, and it was also 1.5 to 1.9 times faster than the original drug in pH 6.8. The 70% release time (T(70)) of the drug from the spray-dried particles was 20 to 30 times faster than the original drug in pH 1.2 solution as well as 2 to 3 times faster than the original drug in pH 6.8 solution. Pharmaceutical preparations prepared in this way using the 4-fluid nozzle system spray dryer formed composite particles, resulting in a remarkably improved dissolution rates of the drug. PMID:15340191

  4. 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. PMID:25514636

  5. Improved bioavailability of a water-insoluble drug by inhalation of drug-containing maltosyl-β-cyclodextrin microspheres using a four-fluid nozzle spray drier.

    PubMed

    Ozeki, Tetsuya; Kano, Yoshihito; Takahashi, Norimitsu; Tagami, Tatsuaki; Okada, Hiroaki

    2012-12-01

    We previously developed a unique four-fluid nozzle spray drier that can produce water-soluble microspheres containing water-insoluble drug nanoparticles in one step without any common solvent between the water-insoluble drug and water-soluble carrier. In the present study, we focused on maltosyl-β-cyclodextrin (malt-β-CD) as a new water-soluble carrier and it was investigated whether drug/malt-β-CD microspheres could improve the bioavailability compared with our previously reported drug/mannitol (MAN) microspheres. The physicochemical properties of bare drug microparticles (ONO-2921, a model water-insoluble drug), drug/MAN microspheres, and drug/malt-β-CD microspheres were evaluated. In vitro aerosol performance, in vitro dissolution rate, and the blood concentration profiles after intratracheal administration were compared between these formulations. The mean diameter of both drug/MAN and drug/malt-β-CD microspheres was approximately 3-5 μm and both exhibited high aerosol performance (>20% in stages 2-7), but drug/malt-β-CD microspheres had superior release properties. Drug/malt-β-CD microspheres dissolved in an aqueous phase within 2 min, while drug/MAN microspheres failed to dissolve in 30 min. Inhalation of drug/malt-β-CD microspheres enhanced the area under the curve of the blood concentration curve by 15.9-fold than that of bare drug microparticles and by 6.1-fold than that of drug/MAN microspheres. Absolute bioavailability (pulmonary/intravenous route) of drug/malt-β-CD microspheres was also much higher (42%) than that of drug/MAN microspheres (6.9%). These results indicate that drug/malt-β-CD microspheres prepared by our four-fluid nozzle spray drier can improve drug solubility and pulmonary delivery. PMID:22945234

  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. PMID:26306524

  7. Delivering therapy to target: improving the odds for successful drug development.

    PubMed

    Raghavan, Raghu; Brady, Martin L; Sampson, John H

    2016-07-01

    The direct delivery of drugs and other agents into tissue (in contrast to systemic administration) has been used in clinical trials for brain cancer, neurodegenerative diseases and peripheral tumors. However, continuing evidence suggests that clinical efficacy depends on adequate delivery to a target. Inadequate delivery may have doomed otherwise effective drugs, through failure to distinguish drug inefficacy from poor distribution at the target. Conventional pretreatment clinical images of the patient fail to reveal the complexity and diversity of drug transport pathways in tissue. We discuss the richness of these pathways and argue that development and patient treatment can be sped up and improved by: using quantitative as well as 'real-time' imaging; customized simulations using data from that imaging; and device designs that optimize the drug-device combination. PMID:27403630

  8. 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.

  9. 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. PMID:27188644

  10. 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

  11. 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

  12. 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

  13. Development of a core drug list towards improving prescribing education and reducing errors in the UK

    PubMed Central

    Baker, Emma; Pryce Roberts, Adele; Wilde, Kirsty; Walton, Hannah; Suri, Sati; Rull, Gurvinder; Webb, Andrew

    2011-01-01

    AIM To develop a core list of 100 commonly prescribed drugs to support prescribing education. METHODS A retrospective analysis of prescribing data from primary care in England (2006 and 2008) and from two London Teaching Hospitals (2007 and 2009) was performed. A survey of prescribing by foundation year 1 (FY1) doctors in 39 NHS Trusts across London was carried out. RESULTS A core list of 100 commonly prescribed drugs comprising ≥0.1% prescriptions in primary and/or secondary care was developed in 2006/7. The core list remained stable over 2 years. FY1 doctors prescribed 65% drugs on the list at least monthly. Seventy-six% of FY1 doctors did not regularly prescribe any drugs not on the core list. There was a strong correlation between prescribing frequency (prescriptions for each drug class expressed as percentage of all prescriptions written) and error rate described in the EQUIP study (errors made when prescribing each drug class expressed as a percentage of all errors made), n= 39, r= 0.861, P= 0.000. CONCLUSIONS Our core drug list identifies drugs that are commonly used and associated with error and is stable over at least 2 years. This list can now be used to develop learning resources and training programmes to improve prescribing of drugs in regular use. Complementary skills required for prescribing less familiar drugs must be developed in parallel. Ongoing research is required to monitor the effect of new training initiatives on prescribing error and patient safety. PMID:21219399

  14. 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

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

    PubMed

    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

  16. 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.

  17. Role of Solvents in Improvement of Dissolution Rate of Drugs: Crystal Habit and Crystal Agglomeration

    PubMed Central

    Maghsoodi, Maryam

    2015-01-01

    Crystallization is often used for manufacturing drug substances. Advances of crystallization have achieved control over drug identity and purity, but control over the physical form remains poor. This review discusses the influence of solvents used in crystallization process on crystal habit and agglomeration of crystals with potential implication for dissolution. According to literature it has been known that habit modification of crystals by use of proper solvents may enhance the dissolution properties by changing the size, number and the nature of crystal faces exposed to the dissolution medium. Also, the faster dissolution rate of drug from the agglomerates of crystals compared with the single crystals may be related to porous structure of the agglomerates and consequently their better wettability. It is concluded from this review that in-depth understanding of role of the solvents in crystallization process can be applied to engineering of crystal habit or crystal agglomeration, and predictably dissolution improvement in poorly soluble drugs. PMID:25789214

  18. An Interactive User Interface for Drug Labeling to Improve Readability and Decision-Making

    PubMed Central

    Abedtash, Hamed; Duke, Jon D.

    2015-01-01

    FDA-approved prescribing information (also known as product labeling or labels) contain critical safety information for health care professionals. Drug labels have often been criticized, however, for being overly complex, difficult to read, and rife with overwarning, leading to high cognitive load. In this project, we aimed to improve the usability of drug labels by increasing the ‘signal-to-noise ratio’ and providing meaningful information to care providers based on patient-specific comorbidities and concomitant medications. In the current paper, we describe the design process and resulting web application, known as myDrugLabel. Using the Structured Product Label documents as a base, we describe the process of label personalization, readability improvements, and integration of diverse evidence sources, including the medical literature from PubMed, pharmacovigilance reports from FDA adverse event reporting system (FAERS), and social media signals directly into the label. PMID:26958158

  19. An Interactive User Interface for Drug Labeling to Improve Readability and Decision-Making.

    PubMed

    Abedtash, Hamed; Duke, Jon D

    2015-01-01

    FDA-approved prescribing information (also known as product labeling or labels) contain critical safety information for health care professionals. Drug labels have often been criticized, however, for being overly complex, difficult to read, and rife with overwarning, leading to high cognitive load. In this project, we aimed to improve the usability of drug labels by increasing the 'signal-to-noise ratio' and providing meaningful information to care providers based on patient-specific comorbidities and concomitant medications. In the current paper, we describe the design process and resulting web application, known as myDrugLabel. Using the Structured Product Label documents as a base, we describe the process of label personalization, readability improvements, and integration of diverse evidence sources, including the medical literature from PubMed, pharmacovigilance reports from FDA adverse event reporting system (FAERS), and social media signals directly into the label. PMID:26958158

  20. 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

  1. 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. PMID:27498233

  2. 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. PMID:24243526

  3. 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

  4. Improving protocol design feasibility to drive drug development economics and performance.

    PubMed

    Getz, Kenneth

    2014-05-01

    Protocol design complexity has increased substantially during the past decade and this in turn has adversely impacted drug development economics and performance. This article reviews the results of two major Tufts Center for the Study of Drug Development studies quantifying the direct cost of conducting less essential and unnecessary protocol procedures and of implementing amendments to protocol designs. Indirect costs including personnel time, work load and cycle time delays associated with complex protocol designs are also discussed. The author concludes with an overview of steps that research sponsors are taking to improve protocol design feasibility. PMID:24823665

  5. Improving Protocol Design Feasibility to Drive Drug Development Economics and Performance

    PubMed Central

    Getz, Kenneth

    2014-01-01

    Protocol design complexity has increased substantially during the past decade and this in turn has adversely impacted drug development economics and performance. This article reviews the results of two major Tufts Center for the Study of Drug Development studies quantifying the direct cost of conducting less essential and unnecessary protocol procedures and of implementing amendments to protocol designs. Indirect costs including personnel time, work load and cycle time delays associated with complex protocol designs are also discussed. The author concludes with an overview of steps that research sponsors are taking to improve protocol design feasibility. PMID:24823665

  6. 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. PMID:25450741

  7. Cross-linked sodium carboxymethylcellulose as a carrier for dissolution rate improvement of drugs.

    PubMed

    Sangalli, M E; Giunchedi, P; Colombo, P; Conte, U; Gazzaniga, A; La Manna, A

    1989-01-01

    The dissolution rate is often the limiting step in gastrointestinal absorption of water insoluble drugs from solid oral dosage forms. The aim of this work was to use a swellable polymer chosen among superdisintegrants, for improving the dissolution rate of a sparingly soluble drug, loaded on its surface. Nifedipine, which has a very low water solubility, was chosen as a model drug, while cross-linked sodium carboxymethylcellulose (Ac-Di-Sol) was chosen as the swellable polymer. The Nifedipine/Ac-Di-Sol systems were prepared using two different techniques: evaporation and spraying; in some preparations polyethylene glycol (PEG 1500), or sucrose palmitate (Sucrodet), or dioctyl sodium sulfosuccinate (Aerosol OT) were added. The results of the dissolution tests showed that the dissolution rate of Nifedipine from the systems prepared increases, particularly in the case of the preparation composed of Ac-Di-Sol plus surfactant agents. PMID:2611009

  8. Improvement in solubility of poor water-soluble drugs by solid dispersion

    PubMed Central

    Sareen, Swati; Mathew, George; Joseph, Lincy

    2012-01-01

    This article is intended to combine recent literature on solid dispersion technology for solubility enhancement with special emphasis on mechanism responsible for the same by solid dispersion, various preparation methods, and evaluation parameters. Solubility behavior is the most challenging aspect for various new chemical entities as 60% of the new potential products possess solubility problems. This is the biggest reason for new drug molecules not reaching to the market or not reaches to full potential. There are various techniques to enhance the drug solubility such as particle size reduction, nanosuspension, use of surfactants, salt formation, solid dispersion, etc. From this article it may be concluded that solid dispersion is an important approach for improvement of bioavailability of poor water-soluble drugs. PMID:23071955

  9. Improving understanding of chromatin regulatory proteins and potential implications for drug discovery.

    PubMed

    Rafehi, Haloom; Khan, Abdul Waheed; El-Osta, Assam

    2016-04-01

    Many epigenetic-based therapeutics, including drugs such as histone deacetylase inhibitors, are now used in the clinic or are undergoing advanced clinical trials. The study of chromatin-modifying proteins has benefited from the rapid advances in high-throughput sequencing methods, the organized efforts of major consortiums and by individual groups to profile human epigenomes in diverse tissues and cell types. However, while such initiatives have carefully characterized healthy human tissue, disease epigenomes and drug-epigenome interactions remain very poorly understood. Reviewed here is how high-throughput sequencing improves our understanding of chromatin regulator proteins and the potential implications for the study of human disease and drug development and discovery. PMID:26923902

  10. An improved approach for predicting drug-target interaction: proteochemometrics to molecular docking.

    PubMed

    Shaikh, Naeem; Sharma, Mahesh; Garg, Prabha

    2016-02-23

    Proteochemometric (PCM) methods, which use descriptors of both the interacting species, i.e. drug and the target, are being successfully employed for the prediction of drug-target interactions (DTI). However, unavailability of non-interacting dataset and determining the applicability domain (AD) of model are a main concern in PCM modeling. In the present study, traditional PCM modeling was improved by devising novel methodologies for reliable negative dataset generation and fingerprint based AD analysis. In addition, various types of descriptors and classifiers were evaluated for their performance. The Random Forest and Support Vector Machine models outperformed the other classifiers (accuracies >98% and >89% for 10-fold cross validation and external validation, respectively). The type of protein descriptors had negligible effect on the developed models, encouraging the use of sequence-based descriptors over the structure-based descriptors. To establish the practical utility of built models, targets were predicted for approved anticancer drugs of natural origin. The molecular recognition interactions between the predicted drug-target pair were quantified with the help of a reverse molecular docking approach. The majority of predicted targets are known for anticancer therapy. These results thus correlate well with anticancer potential of the selected drugs. Interestingly, out of all predicted DTIs, thirty were found to be reported in the ChEMBL database, further validating the adopted methodology. The outcome of this study suggests that the proposed approach, involving use of the improved PCM methodology and molecular docking, can be successfully employed to elucidate the intricate mode of action for drug molecules as well as repositioning them for new therapeutic applications. PMID:26822863

  11. 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

  12. 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

  13. Pharmacokinetic Evaluation of Improved Oral Bioavailability of Valsartan: Proliposomes Versus Self-Nanoemulsifying Drug Delivery System.

    PubMed

    Nekkanti, Vijaykumar; Wang, Zhijun; Betageri, Guru V

    2016-08-01

    The objective of this study was to develop proliposomes and self-nanoemulsifying drug delivery system (SNEDDS) for a poorly bioavailable drug, valsartan, and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin-film hydration method using different lipids such as soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoyl phosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. SNEDDS formulations were prepared using varying concentrations of capmul MCM, labrafil M 2125, and Tween 80. Both proliposomes and SNEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water and 0.1 N HCl using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal permeation techniques. Among the formulations, the proliposomes with drug/DMPG/cholesterol in the ratio of 1:1:0.5 and SNEDDS with capmul MCM (16.0% w/w), labrafil M 2125 (64.0% w/w), and Tween 80 (18.0% w/w) showed the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SNEDDS as compared to pure valsartan. Valsartan permeability across PAMPA and everted rat intestinal permeation models was significantly higher with proliposomes and SNEDDS. Following single oral administration of proliposomes and SNEDDS, a relative bioavailability of 202.36 and 196.87%, respectively, was achieved compared to pure valsartan suspension. The study results indicated that both proliposomes and SNEDDS formulations are comparable in improving the oral bioavailability of valsartan. PMID:26381913

  14. Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery

    PubMed Central

    Brunstein, F; Rens, J; van Tiel, S T; Eggermont, A M M; ten Hagen, T L M

    2006-01-01

    Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents. PMID:17106443

  15. 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. PMID:27329201

  16. 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. PMID:26851083

  17. 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

  18. 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

  19. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery.

    PubMed

    Suk, Jung Soo; Xu, Qingguo; Kim, Namho; Hanes, Justin; Ensign, Laura M

    2016-04-01

    Coating the surface of nanoparticles with polyethylene glycol (PEG), or "PEGylation", is a commonly used approach for improving the efficiency of drug and gene delivery to target cells and tissues. Building from the success of PEGylating proteins to improve systemic circulation time and decrease immunogenicity, the impact of PEG coatings on the fate of systemically administered nanoparticle formulations has, and continues to be, widely studied. PEG coatings on nanoparticles shield the surface from aggregation, opsonization, and phagocytosis, prolonging systemic circulation time. Here, we briefly describe the history of the development of PEGylated nanoparticle formulations for systemic administration, including how factors such as PEG molecular weight, PEG surface density, nanoparticle core properties, and repeated administration impact circulation time. A less frequently discussed topic, we then describe how PEG coatings on nanoparticles have also been utilized for overcoming various biological barriers to efficient drug and gene delivery associated with other modes of administration, ranging from gastrointestinal to ocular. Finally, we describe both methods for PEGylating nanoparticles and methods for characterizing PEG surface density, a key factor in the effectiveness of the PEG surface coating for improving drug and gene delivery. PMID:26456916

  20. Improved drug-like properties of therapeutic proteins by directed evolution.

    PubMed

    Buchanan, Andrew; Ferraro, Franco; Rust, Steven; Sridharan, Sudharsan; Franks, Ruth; Dean, Greg; McCourt, Matthew; Jermutus, Lutz; Minter, Ralph

    2012-10-01

    Many natural human proteins have functional properties that make them useful as therapeutic drugs. However, not all these proteins are compatible with large-scale manufacturing processes or sufficiently stable to be stored for long periods prior to use. In this study, we focus on small four-helix bundle proteins and employ ribosome display in conjunction with three parallel selection pressures to favour the isolation of variant proteins with improved expression, solubility and stability. This in vitro evolution strategy was applied to two human proteins with known drug development issues, granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO). In the case of G-CSF, the soluble expression levels in Escherichia coli were improved 1000-fold, while for EPO the level of aggregation in an accelerated shelf-life study was reduced from over 80% to undetectable levels. These results exemplify the general utility of our in vitro evolution strategy for improving the drug-like properties of therapeutic proteins. PMID:22942395

  1. Twelve cases of drug-induced blepharospasm improved within 2 months of psychotropic cessation

    PubMed Central

    Emoto, Yuko; Emoto, Hirofumi; Oishi, Eriko; Hikita, Syunichi; Wakakura, Masato

    2011-01-01

    Background: To determine whether psychotropic cessation in patients with drug-induced blepharospasm improves motor symptoms. Methods: In patients with drug-induced blepharospasm, we withdrew part or all of their psychotropic medication and assessed motor symptoms using the Jankovic rating scale (0 = none, 1 = noticeable, 2 = mild, 3 = moderate, 4 = severe) at first presentation and after cessation. Results: Twelve patients (eleven women and one man, mean age 60.4 years) were enrolled. Psychotropics were administered before the onset of blepharospasm in all patients. The mean duration of treatment with psychotropic medication was 47.3 (range 3–120) months. Jankovic rating scale at initial presentation was 3 in eleven patients and 2 in one patient. After cessation, blepharospasm started to improve in all cases within 2 months (average 3.9 weeks). While the effect of psychotropic cessation was variable, the symptoms eventually improved to more than 2 on the rating scale. Three of the twelve patients underwent a single botulinum neurotoxin injection and were withdrawn from therapy after cessation. Conclusion: Psychotropic drugs can cause blepharospasm in some cases. Clinicians should consider reducing psychotropic medication as far as possible in patients with blepharospasm taking these agents. PMID:21753898

  2. 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. PMID:25915176

  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. PMID:25454662

  4. 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

  5. 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. PMID:26997426

  6. The evolution of drugs on schistosoma treatment: looking to the past to improve the future.

    PubMed

    da Rocha Pitta, Maira Galdino; da Rocha Pitta, Marina Galdino; de Melo Rêgo, Moacyr Jesus Barreto; Galdino, Suely Lins

    2013-04-01

    Schistosomiasis is a devastating worldwide widespread tropical disease that currently affects more than 230 million people, making it an issue of great socioeconomic and public health importance. Unfortunatelly there is a single drug for the treatment of all forms of schistosomiasis, praziquantel, which was introduced in therapy in 1980. The article goes by antimony compounds, emetine, hydantoin, nitrofurans, lucanthone, hycanthone, oxamniquine derivatives and organophosphates until it finally gets to praziquantel derivatives. The intent of this review is to provide a panorama of drugs that were and are being used in human chemotherapy looking to the past to improve rational design drugs in the future. Not only clinical used compounds will be shown but also synthesized and tested compounds in vitro and in vivo in animal models which haven't yet to be used in humans. Prospects for drug discovery and vaccines to be used in the treatment and prevention of schistosomiasis, clinical trials, concerns about the resistance/decreased effectiveness of the treatment, and patent database will also be discussed. At the end of the review the reader will notice that much has been done but much still needs to be done yet. PMID:23373654

  7. 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. PMID:21968337

  8. 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. PMID:25646113

  9. A novel integrated framework and improved methodology of computer-aided drug design.

    PubMed

    Chen, Calvin Yu-Chian

    2013-01-01

    Computer-aided drug design (CADD) is a critical initiating step of drug development, but a single model capable of covering all designing aspects remains to be elucidated. Hence, we developed a drug design modeling framework that integrates multiple approaches, including machine learning based quantitative structure-activity relationship (QSAR) analysis, 3D-QSAR, Bayesian network, pharmacophore modeling, and structure-based docking algorithm. Restrictions for each model were defined for improved individual and overall accuracy. An integration method was applied to join the results from each model to minimize bias and errors. In addition, the integrated model adopts both static and dynamic analysis to validate the intermolecular stabilities of the receptor-ligand conformation. The proposed protocol was applied to identifying HER2 inhibitors from traditional Chinese medicine (TCM) as an example for validating our new protocol. Eight potent leads were identified from six TCM sources. A joint validation system comprised of comparative molecular field analysis, comparative molecular similarity indices analysis, and molecular dynamics simulation further characterized the candidates into three potential binding conformations and validated the binding stability of each protein-ligand complex. The ligand pathway was also performed to predict the ligand "in" and "exit" from the binding site. In summary, we propose a novel systematic CADD methodology for the identification, analysis, and characterization of drug-like candidates. PMID:23651478

  10. Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.

    PubMed

    Liu, Rong; Colby, Aaron H; Gilmore, Denis; Schulz, Morgan; Zeng, Jialiu; Padera, Robert F; Shirihai, Orian; Grinstaff, Mark W; Colson, Yolonda L

    2016-09-01

    The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 h of injection and persistent intratumoral retention for >14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles. PMID:27343465

  11. A prototype home robot with an ambient facial interface to improve drug compliance.

    PubMed

    Takacs, Barnabas; Hanak, David

    2008-01-01

    We have developed a prototype home robot to improve drug compliance. The robot is a small mobile device, capable of autonomous behaviour, as well as remotely controlled operation via a wireless datalink. The robot is capable of face detection and also has a display screen to provide facial feedback to help motivate patients and thus increase their level of compliance. An RFID reader can identify tags attached to different objects, such as bottles, for fluid intake monitoring. A tablet dispenser allows drug compliance monitoring. Despite some limitations, experience with the prototype suggests that simple and low-cost robots may soon become feasible for care of people living alone or in isolation. PMID:18852325

  12. 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

  13. 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

  14. A Novel Combined Approach of Short-Chain Sphingolipids and Thermosensitive Liposomes for Improved Drug Delivery to Tumor Cells.

    PubMed

    Haeri, Azadeh; Pedrosa, Lilia R C; Ten Hagen, Timo L M; Dadashzadeh, Simin; Koning, Gerben A

    2016-04-01

    Despite the advantages of liposomal drug delivery, the bioavailability of the chemotherapeutic drugs to tumor cells is limited by their slow release from nanocarriers and low drug permeability across cell membranes. Drug encapsulation into stealth thermosensitive liposomes can improve drug delivery to tumors by combining efficient accumulation at tumors and the active release of the payload following remote heat triggering. Short-chain sphingolipids are known to enhance cellular uptake of amphiphilic drugs. We hypothesized that short-chain sphingolipids could be utilized to further improve intracellular drug delivery from a thermoresponsive formulation by enhancing the cell membrane passage of released drug. The following two strategies were investigated: (1) co-delivery of C8-glucosylceramide and doxorubicin within the thermosensitive liposomes and (2) pretreatment with glucosylceramide-enriched drug-free liposomes and subsequent treatment with doxorubicin loaded thermosensitive liposomes. Liposomes were prepared and extensively characterized. Drug uptake, cell cytotoxicity and live cell imaging were performed under normothermic and hyperthermic conditions in melanoma cells. In these studies, hyperthermia improved drug delivery from doxorubicin loaded thermosensitive formulations. However, the results from cell experiments indicated that there was no additional benefit in the co-delivery strategy using doxorubicin loaded glucosylceramide-enriched thermosensitive liposomes. In contrast, cellular studies showed significantly higher doxorubicin internalization in the pretreatment strategy. One-hour exposure of the cells to C8-glucosylceramide before applying hyperthermia caused improved doxorubicin uptake and cytotoxicity as well as an almost instantaneous cellular entry of the doxorubicin released from thermosensitive liposomes. This novel, two-step drug delivery approach can be potentially beneficial for the intracellular delivery of cell impermeable

  15. Improving access to drugs by poor households through a cost sharing drug scheme: a wealth ranking approach.

    PubMed

    Karkee, Shiba Bahadur; Tamang, Asha Lal; Gurung, Yam Bahadur; Mishra, Gokul; Banez-Ockelford, Jane; Saunders, Philippa; Rai, Chanda

    2005-06-01

    In Nepal lack of drugs in government health institutions has markedly reduced access to essential drugs by poor patients. Despite the implementation of a drug scheme with adequate availability of drugs and with provision of fee exemption for the poor, the poorest people still had no access to drugs. We carried out a wealth ranking process to identify poorest of the poor households in a village. Each of the poorest household was provided with a free treatment card and information about the availability of free service at the local health post. Baseline and post intervention data on service utilisation and prescribing practices were collected using carbon copies of prescriptions. Data were also collected about the attitude of patients, using qualitative interviews. About 1.8% of the total annual patient visits to the Health Post were from cardholder households. The annual health post utilization rate for the poor patients was about 1.2, whereas among other patients it was 0.7. On average, about 2.4 drugs were prescribed to any of the cardholder patients, and 50.8% of prescriptions included at least one antibiotic drug. No injection was prescribed. Within 18 months, the total fee exemption provided to a poorest household was equivalent to about US dollars 1.6. Since the method is valued by local people, and is also feasible to implement through the communities' efforts, it is recommended to initiate it in other drug scheme areas as well. PMID:16295717

  16. 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

  17. Nanoparticle-Loaded Protein-Polymer Nanodroplets for Improved Stability and Conversion Efficiency in Ultrasound Imaging and Drug Delivery.

    PubMed

    Lee, Jeong Yu; Carugo, Dario; Crake, Calum; Owen, Joshua; de Saint Victor, Marie; Seth, Anjali; Coussios, Constantin; Stride, Eleanor

    2015-10-01

    A new formulation of volatile nanodroplets stabilized by a protein and polymer coating and loaded with magnetic nanoparticles is developed. The droplets show enhanced stability and phase conversion efficiency upon ultrasound exposure compared with existing formulations. Magnetic targeting, encapsulation, and release of an anticancer drug are demonstrated in vitro with a 40% improvement in cytotoxicity compared with free drug. PMID:26265592

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

    PubMed

    Meador, Kimford J; Loring, David W

    2016-01-19

    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

  19. 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

  20. 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.

  1. The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect.

    PubMed

    Chu, Shifeng; Liu, Shaolin; Duan, Wenzhen; Cheng, Yong; Jiang, Xueying; Zhu, Chuanjiang; Tang, Kang; Wang, Runsheng; Xu, Lin; Wang, Xiaoying; Yu, Xiaoming; Wu, Kemei; Wang, Yan; Wang, Muzou; Huang, Huiyong; Zhang, Juntian

    2016-06-01

    Multi-target drugs, such as the cocktail therapy used for treating AIDS, often show stronger efficacy than single-target drugs in treating complicated diseases. This review will focus on clausenamide (clau), a small molecule compound originally isolated from the traditional Chinese herbal medicine, Clausenalansium. The finding of four chiral centers in clau molecules predicted the presence of 16 clau enantiomers, including (-)-clau and (+)-clau. All of the predicted enantiomers have been successfully synthesized via innovative chemical approaches, and pharmacological studies have demonstrated (-)-clau as a eutomer and (+)-clau as a distomer in improving cognitive function in both normal physiological and pathological conditions. Mechanistically, the nootropic effect of (-)-clau is mediated by its multi-target actions, which include mild elevation of intracellular Ca(2+) concentrations, modulation of the cholinergic system, regulation of synaptic plasticity, and activation of cellular and molecular signaling pathways involved in learning and memory. Furthermore, (-)-clau suppresses the pathogenesis of Alzheimer's disease by inhibiting multiple etiological processes: (1) beta amyloid protein-induced intracellular Ca(2+) overload and apoptosis and (2) tau hyperphosphorylation and neurodegeneration. In conclusion, the nature of the multi-target actions of (-)-clau substantiates it as a promising chiral drug candidate for enhancing human cognition in normal conditions and treating memory impairment in neurodegenerative diseases. PMID:26812265

  2. Improved drug targeting of cancer cells by utilizing actively targetable folic acid-conjugated albumin nanospheres.

    PubMed

    Shen, Zheyu; Li, Yan; Kohama, Kazuhiro; Oneill, Brian; Bi, Jingxiu

    2011-01-01

    Folic acid-conjugated albumin nanospheres (FA-AN) have been developed to provide an actively targetable drug delivery system for improved drug targeting of cancer cells with reduced side effects. The nanospheres were prepared by conjugating folic acid onto the surface of albumin nanospheres using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) as a catalyst. To test the efficacy of these nanospheres as a potential delivery platform, doxorubicin-loaded albumin nanospheres (DOX-AN) and doxorubicin-loaded FA-AN (FA-DOX-AN) were prepared by entrapping DOX (an anthracycline, antibiotic drug widely used in cancer chemotherapy that works by intercalating DNA) into AN and FA-AN nanoparticles. Cell uptake of the DOX was then measured. The results show that FA-AN was incorporated into HeLa cells (tumor cells) only after 2.0h incubation, whereas HeLa cells failed to incorporate albumin nanospheres without conjugated folic acid after 4.0h incubation. When HeLa cells were treated with the DOX-AN, FA-DOX-AN nanoparticles or free DOX, cell viability decreased with increasing culture time (i.e. cell death increases with time) over a 70h period. Cell viability was always the lowest for free DOX followed by FA-DOX-AN4 and then DOX-AN. In a second set of experiments, HeLa cells washed to remove excess DOX after an initial incubation for 2h were incubated for 70h. The corresponding cell viability was slightly higher when the cells were treated with FA-DOX-AN or free DOX whilst cells treated with DOX-AN nanoparticles remained viable. The above experiments were repeated for non-cancerous, aortic smooth muscle cells (AoSMC). As expected, cell viability of the HeLa cells (with FA receptor alpha, FRα) and AoSMC cells (without FRα) decreased rapidly with time in the presence of free DOX, but treatment with FA-DOX-AN resulted in selective killing of the tumor cells. These results indicated that FA-AN may be used as a promising actively targetable drug delivery system to improve drug

  3. Design and evaluation of a PEGylated lipopeptide equipped with drug-interactive motifs as an improved drug carrier.

    PubMed

    Zhang, Peng; Lu, Jianqin; Huang, Yixian; Zhao, Wenchen; Zhang, Yifei; Zhang, Xiaolan; Li, Jiang; Venkataramanan, Raman; Gao, Xiang; Li, Song

    2014-01-01

    Micelles are attractive delivery systems for hydrophobic drugs due to their small size and the ease of application. However, the limited drug loading capacity and the intrinsic poor stability of drug-loaded formulations represent two major issues for some micellar systems. In this study, we designed and synthesized a micelle-forming PEG-lipopeptide conjugate with two Fmoc groups located at the interfacial region, and two oleoyl chains as the hydrophobic core. The significance of Fmoc groups as a broadly applicable drug-interactive motif that enhances the carrier-drug interaction was examined using eight model drugs of diverse structures. Compared with an analogue without carrying a Fmoc motif, PEG5000-(Fmoc-OA)₂ demonstrated a lower value of critical micelle concentration and three-fold increases of loading capacity for paclitaxel (PTX). These micelles showed tubular structures and small particle sizes (∼70 nm), which can be lyophilized and readily reconstituted with water without significant changes in particle sizes. Fluorescence quenching study illustrated the Fmoc/PTX π-π stacking contributes to the carrier/PTX interaction, and drug-release study demonstrated a much slower kinetics than Taxol, a clinically used PTX formulation. PTX/PEG5000-(Fmoc-OA)₂ mixed micelles exhibited higher levels of cytotoxicity than Taxol in several cancer cell lines and more potent inhibitory effects on tumor growth than Taxol in a syngeneic murine breast cancer model (4T1.2). We have further shown that seven other drugs can be effectively formulated in PEG5000-(Fmoc-OA)₂ micelles. Our study suggests that micelle-forming PEG-lipopeptide surfactants with interfacial Fmoc motifs may represent a promising formulation platform for a broad range of drugs with diverse structures. PMID:24281690

  4. 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. PMID:20435112

  5. Pharmacokinetic strategies to improve drug penetration and entrapment within solid tumors.

    PubMed

    Al-Abd, Ahmed M; Aljehani, Zekra K; Gazzaz, Rana W; Fakhri, Sarah H; Jabbad, Aisha H; Alahdal, Abdulrahman M; Torchilin, Vladimir P

    2015-12-10

    Despite the discovery of a large number of anticancer agents, cancer still remains among the leading causes of death since the middle of the twentieth century. Solid tumors possess a high degree of genetic instability and emergence of treatment resistance. Tumor resistance has emerged for almost all approved anticancer drugs and will most probably emerge for newly discovered anticancer agents as well. The use of pharmacokinetic approaches to increase anticancer drug concentrations within the solid tumor compartment and prolong its entrapment might diminish the possibility of resistance emergence at the molecular pharmacodynamic level and might even reverse tumor resistance. Several novel treatment modalities such as metronomic therapy, angiogenesis inhibitors, vascular disrupting agents and tumor priming have been introduced to improve solid tumor treatment outcomes. In the current review we will discuss the pharmacokinetic aspect of these treatment modalities in addition to other older treatment modalities, such as extracellular matrix dissolving agents, extracellular matrix synthesis inhibitors, chemoembolization and cellular efflux pump inhibition. Many of these strategies showed variable degrees of success/failure; however, reallocating these modalities based on their influence on the intratumoral pharmacokinetics might improve their understanding and treatment outcomes. PMID:26342660

  6. 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. PMID

  7. 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. PMID:22254527

  8. Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

    PubMed

    Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

    2016-05-01

    The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. PMID:26939698

  9. 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. PMID:24796274

  10. 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

  11. Improving the outcome of patients with castration-resistant prostate cancer through rational drug development

    PubMed Central

    Attard, G; Sarker, D; Reid, A; Molife, R; Parker, C; de Bono, J S

    2006-01-01

    Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development. Therapeutic targets include the adrenal steroid synthesis pathway, androgen receptor signalling, the epidermal growth factor receptor family, insulin growth factor-1 receptor, histone deacetylase, heat shock protein 90 and the tumour vasculature. Drugs against these targets are giving an insight into the molecular pathogenesis of this disease and promise to improve patient quality of life and survival. Finally, the recent discovery of chromosomal translocations resulting in the upregulation of one of at least 3 ETS genes (ERG, ETV1, ETV4) may lead to novel agents for the treatment of this disease. PMID:16983403

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

    PubMed

    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

  13. 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. PMID:26276694

  14. 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

  15. 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

  16. Small group intervention vs formal seminar for improving appropriate drug use.

    PubMed

    Santoso, B; Suryawati, S; Prawaitasari, J E

    1996-04-01

    In an attempt to evaluate the efficacy of different methods of interventions to improve the appropriate use of drugs for acute diarrhoea, a controlled study has been carried out in 6 districts in Yogyakarta and Central Java provinces, Indonesia. This study was designed to investigate the impacts of two different methods of educational intervention, i.e. a small group face-to-face intervention and a formal seminar for prescribers, on prescribing practice in acute diarrhoea. The districts were randomly assigned into 3 groups and 15 health centers were selected from each district. Prescribers in Group 1 underwent a small group face-to-face intervention conducted in the respective health center. Those in Group 2 attended a formal seminar conducted at the district level. Prescribers in Group 3 served as the control group. Both interventions were given on a single occasion without follow-up supervision or monitoring. Written information materials on the appropriate management of acute diarrhoea were developed and were provided to all prescribers in the intervention groups. Focus group discussions (FGDs) involving prescribers and consumers in the 6 districts were carried out to identify various underlying motivations of drug use in acute diarrhoea. The findings of the FGDs were used as part of the intervention materials. To evaluate the impacts of these interventions on prescribing practice, a prescribing survey for patients under five years old with acute diarrhoea was carried out in health centers covering 3-month periods before and after the intervention. The results showed that both interventions were equally effective in improving the levels of knowledge of prescribers about the appropriate management of acute diarrhoea. They were also partially effective in improving the appropriate use of drugs, reducing the use of non-rehydration medications. There was a highly significant reduction of antimicrobial usage either after small-group face-to-face intervention (77

  17. Hetero-modification of TRAIL trimer for improved drug delivery and in vivo antitumor activities

    PubMed Central

    Pan, Li-Qiang; Zhao, Wen-Bin; Lai, Jun; Ding, Ding; Wei, Xiao-Yue; Li, Yang-Yang; Liu, Wen-Hui; Yang, Xiao-Yue; Xu, Ying-Chun; Chen, Shu-Qing

    2015-01-01

    Poor pharmacokinetics and resistance within some tumor cell lines have been the major obstacles during the preclinical or clinical application of TRAIL (tumor-necrosis-factor (TNF)-related apoptosis-inducing ligand). The half-life of TRAIL114-281 (114 to 281 amino acids) was revealed to be no more than 30 minutes across species. Therefore maleimido activated PEG (polyethylene glycol) and MMAE (Monomethyl Auristatin E) were applied to site-specifically conjugate with the mutated cysteines from different monomers of TRAIL successively, taking advantage of steric effects involved within TRAIL mutant conjugations. As a result, TRAIL trimer was hetero-modified for different purposes. And the resulting PEG-TRAIL-vcMMAE conjugate exhibited dramatically improved half-life (11.54 h), favourable in vivo targeting capability and antitumor activities while no sign of toxicity in xenograft models, suggesting it’s a viable therapeutic and drug delivery strategy. PMID:26445897

  18. Improved intestinal absorption of a poorly water-soluble oral drug using mannitol microparticles containing a nanosolid drug dispersion.

    PubMed

    Nishino, Yukiko; Kubota, Aya; Kanazawa, Takanori; Takashima, Yuuki; Ozeki, Tetsuya; Okada, Hiroaki

    2012-11-01

    A nozzle for a spray dryer that can prepare microparticles of water-soluble carriers containing various nanoparticles in a single step was previously developed in our laboratory. To enhance the solubility and intestinal absorption of poorly water-soluble drugs, we used probucol (PBL) as a poorly water-soluble drug, mannitol (MAN) as a water-soluble carrier for the microparticles, and EUDRAGIT (EUD) as a polymer vehicle for the solid dispersion. PBL-EUD-acetone-methanol and aqueous MAN solutions were simultaneously supplied through different liquid passages of the spray nozzle and dried together. PBL-EUD solid dispersion was nanoprecipitated in the MAN solution using an antisolvent mechanism and rapidly dried by surrounding it with MAN. PBL in the dispersion vehicle was amorphous and had higher physical stability according to powder X-ray diffraction and differential scanning calorimetry analysis. The bioavailability of PBL in PBL-EUD S-100-MAN microparticles after oral administration in rats was markedly higher (14- and 6.2-fold, respectively) than that of the original PBL powder and PBL-MAN microparticles. These results demonstrate that the composite microparticles containing a nanosized solid dispersion of a poorly water-soluble drug prepared using the spray nozzle developed by us should be useful to increase the solubility and bioavailability of drugs after oral administration. PMID:22864998

  19. Drug-eluting stent with improved durability and controllability properties, obtained via electrocoated adhesive promotion layer.

    PubMed

    Levy, Yair; Tal, Noam; Tzemach, Gilad; Weinberger, Judah; Domb, Abraham J; Mandler, Daniel

    2009-11-01

    Drug-eluting stents (DES) have become an accepted technology in intravascular intervention. Manufacturing methodologies of DES are based mainly on mechanical processes, which tend to generate coatings that have poor stability properties; these were recently related as a potential hazard. A novel approach for significantly increasing the adhesion of polymer coatings onto DES is presented. The method is based on the electrochemistry of diazonium salts. These substances are organic compounds with the characteristic structure of R-N(2) (+) X(-), where R is an organic residue and X(-) is an anion. The objective of this article is to study the properties of a selected diazonium salt 4-(1-dodecyloxy)-phenyldiazonium tetrafluoroborate, referred as C(12)-phenyldiazonium. This material was found to be a superior adhesive promoter for polymeric coatings applied onto metallic stents. C(12)-phenyldiazonium was synthesized and electrocoated on metallic stents and plates. The multilayer films of C(12)-phenyldiazonium were further characterized through electrochemical (cyclic voltammetry, impedance spectroscopy), physical (light and scanning electron microscopy, X-ray photoelectron spectroscopy, peeling tests), and chemical methodology (high pressure liquid chromatography). Further biocompatibility properties of the electrocoated basecoat were evaluated using in vitro and in vivo models. Synthesized C(12)-phenyldiazonium was successfully electrocoated onto metallic surfaces. Electrochemical tests demonstrated its efficient and controllable electrocoating. C(12)-phenyldiazonium was found to increase polymeric coating stability as was reflected by a standard adhesion test. Electrocoated metallic stents spray-coated with a second polymeric film showed improved durability following incubation in physiological buffer. Furthermore, this improvement in durability exhibits stabilized drug release. In addition, biocompatibility evaluations have demonstrated basecoat's inert properties

  20. 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

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

    PubMed

    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

  2. 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

  3. Disease-modifying anti-rheumatic drugs improve autonomic neuropathy in arthritis: DIANA study.

    PubMed

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

    2015-07-01

    Autonomic neuropathy (AN) is a risk predictor for sudden cardiac death in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, the impact of most commonly employed disease-modifying anti-rheumatic drug (DMARD) therapy on autonomic neuropathy in rheumatic diseases is not known. Hence, we investigated the efficacy of DMARDs on autonomic neuropathy in RA and AS. We performed autonomic function assessment in 60 patients in this open-label, 12-week pilot study including 42 patients with RA, 18 with AS, and 30 aged-matched healthy subjects. The methodology included assessment of cardiovascular autonomic 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. Sudomotor function was assessed by Sudoscan. Cardiovascular reflex tests were impaired significantly among the patients as compared to healthy subjects (p < 0.05). Autonomic neuropathy was more pronounced in biologic-naive RA and AS patients. After treatment with combination synthetic DMARDs, parasympathetic, and sudomotor dysfunction significantly (p < 0.05) improved in RA and AS. Biologic DMARDs significantly improved parasympathetic, sympathetic and peripheral sympathetic autonomic neuropathy (p < 0.05) in biologic-naive RA and AS patients. In conclusion, synthetic DMARDs improved parasympathetic and sudomotor dysfunction in both DMARD-naive RA and AS patients. However, biologic DMARDs improved parasympathetic, sympathetic and sudomotor dysfunction to a greater extent than synthetic DMARDs in both RA and AS patients. PMID:24928343

  4. 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

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

    PubMed Central

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

    2014-01-01

    Background: The reporting of adverse drug reactions (ADRs) by nurses in hospitals is very important. Aims: 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. Materials and Methods: 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. Results: 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. Conclusion: Continuous ADR educational program, training, and integration of ADRs’ reporting into the activities of the nurses would likely improve ADR reporting. PMID:24554968

  6. 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. PMID:22588676

  7. 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 (Mage = 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. PMID:26693964

  8. 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

  9. 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

  10. 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

  11. 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

  12. An experimental study on drugs for improving blood circulation and removing blood stasis in treating mild chronic hepatic damage.

    PubMed

    Xie, F; Li, X; Sun, K; Chu, Y; Cao, H; Chen, N; Wang, W; Liu, M; Liu, W; Mao, D

    2001-09-01

    Large and small doses of drugs for improving blood circulation and removing blood stasis were used in model rats to treat mild chronic hepatic damage induced by carbon tetrachloride (CCl4). The results show that large dose of Dang Gui ([symbol: see text] Radix Angelicae Sinensis) and Dan Shen ([symbol: see text] Radix Salviae Miltiorrhizae) (drugs for regulating blood flow) and small dose of Yu Jin ([symbol: see text] Radix Curcumae) and Niu Xi ([symbol: see text] Radix Achyranthis Bidentatae) (drugs for activating blood flow) can significantly elevate the activity of SOD (P < 0.05) and/or lower the T/K ratio, markedly reduce the MDA content (P < 0.05 or P < 0.01) and significantly decrease the activities of ALT and AST (P < 0.05 or P < 0.01), demonstrating that these drugs are effective in combating oxygen free radicals (OFR) in chronic liver damage. On the contrary, large dose of Tu Bie Chong ([symbol: see text] Eupolyphaga seu Steleophaga) and E Zhu ([symbol: see text] Rhizoma Curcumae) (drugs for removing blood stasis) tend to increase the ALT and AST (P < 0.05) activities. The results suggest that the synergism of elevation of the SOD activity and reduction of T/K ratio contributes to the action of drugs for improving blood circulation and removing blood stasis in combating the liver damage induced by CCl4. PMID:11789334

  13. 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

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

    PubMed

    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

  15. 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. PMID:14596759

  16. 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. PMID:24464737

  17. 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

  18. Green design "bioinspired disassembly-reassembly strategy" applied for improved tumor-targeted anticancer drug delivery.

    PubMed

    Wang, Ruoning; Gu, Xiaochen; Zhou, Jianping; Shen, Lingjia; Yin, Lifang; Hua, Peiying; Ding, Yang

    2016-08-10

    In this study, a simple and green approach 'bioinspired disassembly-reassembly strategy' was employed to reconstitute lipoprotein nanoparticles (RLNs) using whole-components of endogenous ones (contained dehydrated human lipids and native apolipoproteins). These RLNs were engineered to mimic the configuration and properties of natural lipoproteins for efficient drug delivery. In testing therapeutic targeting to microtubules, paclitaxel (PTX) was reassembled into RLNs to achieve improved targeted anti-carcinoma treatment and minimize adverse effects, demonstrating ultimately more applicable than HDL-like particles which are based on exogenous lipid sources. We have characterized that apolipoprotein-decoration of PTX-loaded RLNs (RLNs-PTX) led to favoring uniformly dispersed distribution, increasing PTX-encapsulation with a sustained-release pattern, while enhancing biostability during blood circulation. The innate biological RLNs induced efficient intracellular trafficking of cargos in situ via multi-targeting mechanisms, including scavenger receptor class B type I (SR-BI)-mediated direct transmembrane delivery, as well as other lipoprotein-receptors associated endocytic pathways. The resulting anticancer treatment from RLNs-PTX was demonstrated a half-maximal inhibitory concentration of 0.20μg/mL, cell apoptosis of 18.04% 24h post-incubation mainly arresting G2/M cell cycle in vitro, and tumor weight inhibition of 70.51% in vivo. Collectively, green-step assembly-based RLNs provided an efficient strategy for mediating tumor-targeted accumulation of PTX and enhanced anticancer efficacy. PMID:27238442

  19. 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

  20. A computer-based intervention for improving the appropriateness of antiepileptic drug level monitoring.

    PubMed

    Chen, Philip; Tanasijevic, Milenko J; Schoenenberger, Ronald A; Fiskio, Julie; Kuperman, Gilad J; Bates, David W

    2003-03-01

    We designed and implemented 2 automated, computerized screens for use at the time of antiepileptic drug (AED) test order entry to improve appropriateness by reminding physicians when a potentially redundant test was ordered and providing common indications for monitoring and pharmacokinetics of the specific AED. All computerized orders for inpatient serum AED levels during two 3-month periods were included in the study. During the 3-month period after implementation of the automated intervention, 13% of all AED tests ordered were canceled following computerized reminders. For orders appearing redundant, the cancellation rate was 27%. For nonredundant orders, 4% were canceled when information on specific AED monitoring and pharmacokinetics was provided. The cancellation rate was sustained after 4 years. There has been a 19.5% decrease in total AED testing volume since implementation of this intervention, despite a 19.3% increase in overall chemistry test volume. Inappropriateness owing to repeated testing before pharmacologic steady state was reached decreased from 54% of all AED orders to 14.6%. A simple, automated, activity-based intervention targeting a specific test-ordering behavior effectively reduced inappropriate laboratory testing. The sustained benefit supports the idea that computerized interventions may durably affect physician behavior. Computerized delivery of such evidence-based boundary guidelines can help narrow the gap between evidence and practice. PMID:12645347

  1. Improving psychotropic drug prescription in nursing home patients with dementia: design of a cluster randomized controlled trial

    PubMed Central

    2013-01-01

    Background Neuropsychiatric symptoms are highly prevalent in nursing home patients with dementia. Despite modest effectiveness and considerable side effects, psychotropic drugs are frequently prescribed for these neuropsychiatric symptoms. This raises questions whether psychotropic drugs are appropriately prescribed. The aim of the PROPER (PRescription Optimization of Psychotropic drugs in Elderly nuRsing home patients with dementia) II study is to investigate the efficacy of an intervention for improving the appropriateness of psychotropic drug prescription in nursing home patients with dementia. Methods/design The PROPER II study is a multi-center cluster randomized controlled, pragmatic trial using parallel groups. It has a duration of eighteen months and four six-monthly assessments. Six nursing homes will participate in the intervention and six will continue care as usual. The nursing homes will be located throughout the Netherlands, each participating with two dementia special care units with an average of fifteen patients per unit, resulting in 360 patients. The intervention consists of a structured and repeated multidisciplinary medication review supported by education and continuous evaluation. It is conducted by pharmacists, physicians, and nurses and consists of three components: 1) preparation and education, 2) conduct, and 3) evaluation/guidance. The primary outcome is the proportion of patients with appropriate psychotropic drug use. Secondary outcomes are the overall frequency of psychotropic drug use, neuropsychiatric symptoms, quality of life, activities of daily living, psychotropic drug side effects and adverse events (including cognition, comorbidity, and mortality). Besides, a process analysis on the intervention will be carried out. Discussion This study is expected to improve the appropriateness of psychotropic drug prescription for neuropsychiatric symptoms in nursing home patients with dementia by introducing a structured and repeated

  2. 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. PMID:26117764

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

    PubMed

    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

  4. Designing micellar nanocarriers with improved drug loading and stability based on solubility parameter.

    PubMed

    Tian, Ye; Shi, Chenjun; Sun, Yujiao; Zhu, Chengyun; Sun, Changquan Calvin; Mao, Shirui

    2015-03-01

    The objective of this study is to demonstrate the feasibility of using solubility parameter as guidance for the design and identification of a stable micellar system with a high drug loading capacity for oral drug delivery. Using hydroxycamptothecin (HCPT) as a model drug, the effect of three hydrophobic blocks (fatty glycerides) grafted onto chitosan on the drug loading and stability of HCPT-loaded micellar nanoparticles formed by pH precipitation method were studied systematically. The Flory-Huggins interaction parameter (χFH) calculated by the group contribution method (GCM) and molecular dynamics simulation (MDS) was used to assess the compatibility between HCPT and the copolymers. The predicted order of compatibility between three chitosan derivatives and HCPT was verified experimentally. A high drug loading and remarkably stable micellar system for oral administration based on succinylated glycerol monooleate-chitosan was discovered in this study. Our study suggests that the miscibility between drug and copolymer is crucial to drug loading and stability of the micellar system. Thus, the calculation of χFH using GCM and MDS methods is useful for guiding the design or screening of a suitable copolymer for preparing drug-loaded micellar nanocarrier systems. PMID:25587749

  5. Improving community health and safety in Canada through evidence-based policies on illegal drugs

    PubMed Central

    Wood, Evan; McKinnon, Moira; Strang, Robert; Kendall, Perry R

    2012-01-01

    Illegal drug use remains a serious threat to community health in Canada, yet there has been a remarkable discordance between scientific evidence and policy in this area, with most resources going to drug use prevention and drug law enforcement activities that have proven ineffective. Conversely, evidence-based drug treatment programs have been chronically underfunded, despite their cost-effectiveness. Similarly, various harm reduction strategies, such as needle exchange, supervised injecting programs and opioid substitution therapy, have also proven effective at reducing drug-related harm but receive limited government support. Accordingly, Canadian society would greatly benefit from reorienting its drug policies on addiction, with consideration of addiction as a health issue, rather than primarily a criminal justice issue. In this context, and in light of the simple reality that drug prohibition has not effectively reduced the availability of most illegal drugs and has instead contributed to a vast criminal enterprise and related violence, among other harms, alternatives should be prioritized for evaluation. PMID:22567081

  6. 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.

  7. 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. PMID:17107929

  8. 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

  9. Anabolic and antiresorptive drugs improve trabecular microarchitecture and reduce fracture risk following radiation therapy.

    PubMed

    Arrington, Sarah A; Fisher, Erica R; Willick, Gordon E; Mann, Kenneth A; Allen, Matthew J

    2010-09-01

    Many patients with symptomatic bone metastases receive radiation therapy, even though radiation is known to have potential adverse effects on bone. We hypothesized that the concurrent use of a bisphosphonate drug (zoledronic acid, ZA) or a combination of ZA plus an anabolic agent (parathyroid hormone, PTH) would lead to improvements in the microarchitecture and mechanical properties of irradiated bone. Human breast cancer cells were injected into the distal femur of 56 female nude mice, which were then divided into four groups: no treatment (0 Gy), radiation administered 4 weeks postinjection (20 Gy), radiation plus ZA (12.5 microg/kg weekly from weeks 4 to 12) (20 Gy + ZA), and radiation followed by ZA (25 microg/kg weekly from weeks 4 to 8) and PTH(1-34) (100 microg microg/kg daily from weeks 8 to 12) (20 Gy + ZA + PTH). Left limbs served as normal control bones. Bone loss over the 12-week study was tracked with serial radiography and bone densitometry. At the end of the study, micro-computed tomography and mechanical testing were used to quantify bone microarchitecture and bone strength. Radiation alone failed to prevent tumor-induced decreases in bone mineral density (BMD), trabecular bone volume, and bone strength. Treatment with 20 Gy + ZA or 20 Gy + ZA + PTH as adjuncts to radiation was effective at preserving trabecular bone architecture and bone strength at normal levels. ZA reduced the risk of mechanical fragility following irradiation of a lytic bone lesion. Supplemental use of PTH did not result in further increases in bone strength but was associated with significant increases in BMD and bone mass, suggesting that it may be beneficial in enhancing bone architecture following radiation therapy. PMID:20563797

  10. 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)

  11. Biological evaluation of endophytic fungus, Chaetomium globosum JN711454, as potential candidate for improving drug discovery.

    PubMed

    Selim, Khaled A; El-Beih, Ahmed A; Abdel-Rahman, Tahany M; El-Diwany, Ahmed I

    2014-01-01

    The main objective of this research work focused on investigating the biological and chemical aspects of endophytic fungus Chaetomium globosum, for pharmaceutical purposes to improve the drug discovery process. The endophytic C. globosum was isolated from healthy leaves of Egyptian medicinal plant Adiantum capillus-veneris collected from Saint Katherine Protectorate, Sinai, Egypt. The identification of C. globosum was on the basis of classical and molecular taxonomy. Gene encoding for 18S rRNA was partially sequenced, submitted to the GenBank and got the accession number JN711454, to resolve the phylogenetic relations with fungal ancestor using phylogenetic tree. To explore the biosynthetic power of endophytic C. globosum JN711454, the fungus was cultivated over five different media, oatmeal, rice, yeast malt glucose, potato dextrose agar (PDA) and Czapek's dox media, for 3 weeks at 30 °C, followed by extraction with different solvents, ethyl acetate (EA), and methanol. The ethyl acetate extract of C. globosum cultivated on PDA medium was the most potent extract. It showed strong antioxidant activity with EC50 11.5 μg/ml, potent anticancer activity with 55 % toxicity toward HepG-2 cells at 100 μg/ml and 66 % cytotoxicity to FGC4 cells at 250 μg/ml, promising butyrylcholinesterase inhibitory activities (>85 %), and moderate antimicrobial and stopped the attachment of HSV-2 virus to VERO cells. The metabolomic profiling of PDA-EA extract using LC-MS revealed the presence of several metabolites to which the observed bioactivities could be attributed. Here we report for the first time inhibitory activity of endophytic C. globosum JN711454 secondary metabolites to butyrylcholinesterase, one of neuro hydrolase enzymes that play a major role in development of Alzheimer's disease. PMID:23775636

  12. 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

  13. 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

  14. [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. PMID:25466971

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

    PubMed

    Kang, Jungseog; Hsu, Chien-Hsiang; Wu, Qi; Liu, Shanshan; Coster, Adam D; Posner, Bruce A; Altschuler, Steven J; Wu, Lani F

    2016-01-01

    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 by means of orthogonal, secondary validation assays. Our approach will increase the efficiency, scale and accuracy of phenotypic screens by maximizing their discriminatory power. PMID:26655497

  16. 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. PMID:22721816

  17. Repurposing an Old Drug to Improve the Use and Safety of Tissue Plasminogen Activator for Acute Ischemic Stroke: Minocycline

    PubMed Central

    Hess, David C.; Fagan, Susan C.

    2015-01-01

    There is only 1 US Food and Drug Administration–approved drug for acute ischemic stroke: tissue plasminogen activator (tPA). Due to a short time window and fear of intracerebral hemorrhage (ICH), tPA remains underutilized. There is great interest in developing combination drugs to use with tPA to improve the odds of a favorable recovery and to reduce the risk of ICH. Minocycline is a broad-spectrum antibiotic that has been found to be a neuroprotective agent in preclinical ischemic stroke models. Minocycline inhibits matrix metalloproteinase-9, a biomarker for ICH associated with tPA use. Minocycline is also an anti-inflammatory agent and inhibits poly (ADP-ribose) polymerase-1. Minocycline has been safe and well tolerated in the clinical trials conducted to date. PMID:20410869

  18. Repurposing an old drug to improve the safety and use of tissue plasminogen activator for acute ischemic stroke: Minocycline

    PubMed Central

    Hess, David C; Fagan, Susan

    2014-01-01

    There is only 1 US Food and Drug Administration-approved drug for acute ischemic stroke: tissue plasminogen activator (tPA). Due to a short time window and fear of intracerebral hemorrhage (ICH), tPA remains underutilized. There is great interest in developing combination drugs to use with tPA to improve the odds of a favorable recovery and to reduce the risk of ICH. Minocycline is a broad spectrum antibiotic that has been found to be a neuroprotective agent in preclinical ischemic stroke models. Minocycline inhibits matrix metalloproteinase-9, a biomarker for ICH associated with tPA use. Minocycline is also an anti-inflammatory agent and inhibits poly (ADP-ribose) polymerase- 1. Minocycline has been safe and well tolerated in the clinical trials conducted to date. PMID:20575623

  19. 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

  20. IMPROVING THE PREDICTION OF PHARMACOGENES USING TEXT-DERIVED DRUG-GENE RELATIONSHIPS

    PubMed Central

    GARTEN, YAEL; TATONETTI, NICHOLAS P; ALTMAN, RUSS B

    2011-01-01

    A critical goal of pharmacogenomics research is to identify genes that can explain variation in drug response. We have previously reported a method that creates a genome-scale ranking of genes likely to interact with a drug. The algorithm uses information about drug structure and indications of use to rank the genes. Although the algorithm has good performance, its performance depends on a curated set of drug-gene relationships that is expensive to create and difficult to maintain. In this work, we assess the utility of text mining in extracting a network of drug-gene relationships automatically. This provides a valuable aggregate source of knowledge, subsequently used as input into the algorithm that ranks potential pharmacogenes. Using a drug-gene network created from sentence-level co-occurrence in the full text of scientific articles, we compared the performance to that of a network created by manual curation of those articles. Under a wide range of conditions, we show that a knowledge base derived from text-mining the literature performs as well as, and sometimes better than, a high-quality, manually curated knowledge base. We conclude that we can use relationships mined automatically from the literature as a knowledgebase for pharmacogenomics relationships. Additionally, when relationships are missed by text mining, our system can accurately extrapolate new relationships with 77.4% precision. PMID:19908383

  1. Co-administration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs

    PubMed Central

    Beyer, Ines; Cao, Hua; Persson, Jonas; Song, Hui; Richter, Maximilian; Feng, Qinghua; Yumul, Roma; van Rensburg, Ruan; Li, Zongyi; Berenson, Ronald; Carter, Darrick; Roffler, Steve; Drescher, Charles; Lieber, André

    2013-01-01

    Purpose Epithelial junctions between tumor cells inhibit the penetration of anti-cancer drugs into tumors. We previously reported on recombinant adenovirus serotype 3 derived protein (JO-1), which triggers transient opening of intercellular junctions in epithelial tumors through binding to desmoglein 2 (DSG2), and enhances the anti-tumor effects of several therapeutic monoclonal antibodies. The goal of this study was to evaluate whether JO-1 co-therapy can also improve the efficacy of chemotherapeutic drugs. Experimental Design The effect of intravenous application of JO-1 in combination with several chemotherapy drugs including paclitaxel/Taxol™, nanoparticle albumin bound paclitaxel/Abraxane™, liposomal doxorubicin/Doxil™ and irinotecan/Camptosar™, was tested in xenograft models for breast, colon, ovarian, gastric and lung cancer. Because JO-1 does not bind to mouse cells, for safety studies with JO-1, we also used human DSG2 (hDSG2) transgenic mice with tumors that overexpressed human DSG2. Results JO-1 increased the efficacy of chemotherapeutic drugs, and in several models overcame drug resistance. JO-1 treatment also allowed for the reduction of drug doses required to achieve anti-tumor effects. Importantly, JO-1 co-admininstration protected normal tissues, including bone marrow and intestinal epithelium, against toxic effects that are normally associated with chemotherapeutic agents. Using the hDSG2 transgenic mouse model, we demonstrated that JO-1 predominantly accumulates in tumors. Except for a mild, transient diarrhea, intravenous injection of JO-1 (2mg/kg) had no critical side effects on other tissues or hematological parameters in hDSG2-transgenic mice. Conclusions Our preliminary data suggest that JO-1 co-therapy has the potential to improve the therapeutic outcome of cancer chemotherapy. PMID:22535153

  2. 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. PMID:25437113

  3. 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. PMID:25637067

  4. 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

    2012-08-01

    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. PMID:22738427

  5. Improving access to computer-based library and drug information services in patient-care areas.

    PubMed

    Tobia, R C; Bierschenk, N F; Knodel, L C; Bowden, V M

    1990-01-01

    A project to increase access to drug and biomedical information through electronic linkage of drug information and library services to three patient-care areas is described. In February 1987, microcomputer work stations were installed in the Bexar County Hospital District's hospital emergency department, medical residents' office, and ambulatory-care clinic, as well as in The University of Texas Health Science Center's library reference area and drug information service office. Drug information was available on compact disk through the Micromedex Computerized Clinical Information System (CCIS) database, which includes DRUGDEX, POISINDEX, EMERGINDEX, and IDENTIDEX. Each work station was also connected to the library's computer via modem, allowing access to the Library Information System, books, journals, audiovisual materials, miniMEDLINE, and an electronic mail system. During the six-month project, the system was used 5487 times by 702 people. The system was successful in providing drug and other information in clinical settings and in introducing clinical staff members to new information technology. To increase access to the system after the project ended, the CD-ROM version was discontinued, and the distributed tape version of CCIS for VAX computers was added to the library's online information system, making drug information more available throughout the campus and teaching hospitals. In 1988-89 an average of 200 people accessed the tape version of CCIS each month. Although it is difficult to replace the convenience of an onsite library, at least some drug and biomedical information needs in the clinical setting can be met through computer networking. PMID:2405657

  6. 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. PMID:25925113

  7. Novel application of hydrophobin in medical science: a drug carrier for improving serum stability.

    PubMed

    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

  8. 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

  9. Dual Drug Loaded Biodegradable Nanofibrous Microsphere for Improving Anti-Colon Cancer Activity.

    PubMed

    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

  10. 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

  11. 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.

  12. 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. PMID:24440403

  13. 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

  14. 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

  15. 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

  16. Cancer therapy improvement with mesoporous silica nanoparticles combining targeting, drug delivery and PDT.

    PubMed

    Gary-Bobo, Magali; Hocine, Ouahiba; Brevet, David; Maynadier, Marie; Raehm, Laurence; Richeter, Sébastien; Charasson, Virginie; Loock, Bernard; Morère, Alain; Maillard, Philippe; Garcia, Marcel; Durand, Jean-Olivier

    2012-02-28

    The synthesis of mesoporous silica nanoparticles (MSN) covalently encapsulating fluoresceine or a photosensitizer, functionalized with galactose on the surface is described. Confocal microscopy experiments demonstrated that the uptake of galactose-functionalized MSN by colorectal cancer cells was mediated by galactose receptors leading to the accumulation of the nanoparticles in the endosomal and lysosomal compartments. The MSN functionalized with a photosensitizer and galactose were loaded with the anti-cancer drug camptothecin. Those MSN combining drug delivery and photodynamic therapy were tested on three cancer cell lines and showed a dramatic enhancement of cancer cell death compared to separate treatments. PMID:22178618

  17. Self-microemulsifying Drug Delivery System Improved Oral Bioavailability of 20(S)-Protopanaxadiol: From Preparation to Evaluation.

    PubMed

    Wang, Bing; Pu, Yiqiong; Xu, Benliang; Tao, Jiansheng; Wang, Yuqin; Zhang, Tong; Wu, Peiying

    2015-01-01

    20(S)-Protopanaxadiol (20(S)-PPD) is one type of sapogenin of protopanaxadiols and has a variety of pharmacological activities. In order to improve the dissolution of 20(S)-PPD as well as its oral bioavailability, a self-microemulsifying drug delivery system (SMEDDS) was utilized for 20(S)-PPD preparation. Following the preparation of the 20(S)-PPD SMEDDS, its dissolution, stability, and intestinal absorption in rats were studied, and the pharmacokinetics and optimal dosage after oral administration were evaluated. The dissolution tendency of the SMEDDS in phosphate buffered saline (PBS), 0.1 M HCl and distilled water was consistent. SMEDDS was stable under a condition of high temperature (40°C), high humidity or with strong light irradiation, or within 6 h in artificial digestive tracts. 20(S)-PPD SMEDDS was well-absorbed in all intestinal segments in rats. When the drug concentration was higher than 200 µg/mL or the perfusion flow was faster than 0.5 mL/min, passive diffusion of drug in the duodenum reached a saturated level. In addition, P-glycoprotein inhibitor did not affect the intestinal absorption of 20(S)-PPD SMEDDS. Pharmacokinetic study showed that Tmax in male rats was shortened significantly, while Cmax and area under the curve (AUC(0-t)) were remarkably increased. The relative oral bioavailability of 20(S)-PPD SMEDDS was increased approximately three fold compared with the 20(S)-PPD carboxy methyl cellulose (CMC). 20(S)-PPD SMEDDS (100 mg/mL) was administered by gastric infusion to both mice and rats for 14 d. SMEDDS improved the oral bioavailability of 20(S)-PPD and reduced the necessary drug dosage. 20(S)-PPD SMEDDS could become a promising clinical alternative as an anti-tumor or antidepressant drug. PMID:26084568

  18. 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. PMID:26573643

  19. 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. PMID:22434495

  20. 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…

  1. Winning the arms race by improving drug discovery against mutating targets.

    PubMed

    Anderson, Amy C

    2012-02-17

    Enzymes are often excellent drug targets. Yet drug pressure on an enzyme target often fosters the rise of cells with resistance-conferring mutations, some of which may compromise fitness and others that compensate to restore fitness. This review presents, first, a structural analysis of a diverse group of wild-type and mutant enzyme targets and, second, an in-depth analysis of five diverse targets to elucidate a broader perspective of the effects of resistance-conferring mutations on protein or organismal fitness. The structural analysis reveals that resistance-conferring mutations may introduce steric hindrance or eliminate critical interactions, as expected, but that they may also have indirect effects such as altering protein dynamics and enzyme kinetics. The structure-based development of the latest generation of inhibitors targeting HIV reverse transcriptase, P. falciparum and S. aureus dihydrofolate reductase, neuraminidase, and epithelial growth factor receptor (EGFR) tyrosine kinase, is highlighted to emphasize lessons that may be applied to future drug discovery to overcome mutation-induced resistance. Successful next-generation drugs tend to be more flexible and exploit a greater number of interactions mimicking those of the substrate with conserved residues. PMID:22050347

  2. 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

  3. Biomimickry of UPEC Cytoinvasion: A Novel Concept for Improved Drug Delivery in UTI

    PubMed Central

    Pichl, Clara Maria; Dunkl, Bernhard; Brauner, Bernhard; Gabor, Franz; Wirth, Michael; Neutsch, Lukas

    2016-01-01

    Urinary tract infections (UTIs) are among the most common bacterial infections. In an increasing number of cases, pathogen (multi-)resistance hampers durable treatment success via the standard therapies. On the functional level, the activity of urinary excreted antibiotics is compromized by the efficient tissue colonization mechanism of uropathogenic Escherichia coli (UPEC). Advanced drug delivery systems aim at exploiting a glycan-mediated targeting mechanism, similar to the UPEC invasion pathway, to increase bioavailability. This may be realized by conjugation of intravesically applied drugs or drug carriers to chosen plant lectins. Higher local drug concentrations in or nearby bacterial reservoirs may be gained, with higher chances for complete eradication. In this study, preliminary parameters to clarify the potential of this biorecognitive approach were evaluated. Glycan-triggered interaction cascades and uptake processes of several plant lectins with distinct carbohydrate specificities were characterized, and wheat germ agglutinin (WGA) could be identified as the most promising targeter for crossing the urothelial membrane barrier. In partially differentiated primary cells, intracellular accumulation sites were largely identical for GlcNAc- and Mannose-specific lectins. This indicates that WGA-mediated delivery may also enter host cells via the FimH-dependent uptake pathway. PMID:26861401

  4. Biomimickry of UPEC Cytoinvasion: A Novel Concept for Improved Drug Delivery in UTI.

    PubMed

    Pichl, Clara Maria; Dunkl, Bernhard; Brauner, Bernhard; Gabor, Franz; Wirth, Michael; Neutsch, Lukas

    2016-01-01

    Urinary tract infections (UTIs) are among the most common bacterial infections. In an increasing number of cases, pathogen (multi-)resistance hampers durable treatment success via the standard therapies. On the functional level, the activity of urinary excreted antibiotics is compromized by the efficient tissue colonization mechanism of uropathogenic Escherichia coli (UPEC). Advanced drug delivery systems aim at exploiting a glycan-mediated targeting mechanism, similar to the UPEC invasion pathway, to increase bioavailability. This may be realized by conjugation of intravesically applied drugs or drug carriers to chosen plant lectins. Higher local drug concentrations in or nearby bacterial reservoirs may be gained, with higher chances for complete eradication. In this study, preliminary parameters to clarify the potential of this biorecognitive approach were evaluated. Glycan-triggered interaction cascades and uptake processes of several plant lectins with distinct carbohydrate specificities were characterized, and wheat germ agglutinin (WGA) could be identified as the most promising targeter for crossing the urothelial membrane barrier. In partially differentiated primary cells, intracellular accumulation sites were largely identical for GlcNAc- and Mannose-specific lectins. This indicates that WGA-mediated delivery may also enter host cells via the FimH-dependent uptake pathway. PMID:26861401

  5. A Patient Education Program to Improve Adherence Rates with Antituberculosis Drug Regimens.

    ERIC Educational Resources Information Center

    Morisky, Donald E.; And Others

    1990-01-01

    An incentive scheme to reward positive health behaviors (adherence to antituberculosis drug regimens) was tested with 88 active and 117 preventive patients randomly assigned to intervention and control groups. Preventive patients who received incentives were significantly more likely to continue care and had higher adherence levels. Actives showed…

  6. 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. PMID:22671304

  7. Improved Release of Celecoxib from High Drug Loading Amorphous Solid Dispersions Formulated with Polyacrylic Acid and Cellulose Derivatives.

    PubMed

    Xie, Tian; Taylor, Lynne S

    2016-03-01

    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. PMID:26791934

  8. 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%). PMID:26998867

  9. Low density lipoprotein for cytotoxic drug targeting: improved activity of elliptinium derivative against B16 melanoma in mice.

    PubMed Central

    Samadi-Baboli, M.; Favre, G.; Canal, P.; Soula, G.

    1993-01-01

    Significant low density lipoprotein (LDL) uptake by tumour cells led to the use of LDL as a discriminatory vehicle for the delivery of cytotoxic drugs. In the current study, the lipophilic elliptinium derivative, elliptinium-oleate (OL-NME), was incorporated into LDL to reach an incorporation level of 400 molecules per LDL particle. The OL-NME-LDL complex showed cytotoxic effects on normal human fibroblasts while the cytotoxicity was not observed on receptor-defective human fibroblasts, indicating the ability of the complex to be preferentially metabolised by the LDL receptor. In vivo metabolism of the complex was related to the LDL receptor pathway. The metabolic clearance was the same for native LDL (17.1 ml h-1) and OL-NME-LDL complex (16.2 ml h-1). LDL incorporated OL-NME enhanced the anti-tumour activity against murine B16 melanoma model; this resulted from increased efficacy for OL-NME-LDL at doses equal to free 9-OH-NME (157 vs 76 of Increase Life Span (ILS) (%) values after intraperitoneal (i.p.) drug injection on i.p. implanted tumour model and 45 vs -2 ILS (%) values after intravenous drug injection on subcutaneous implanted tumour model). These data suggest that LDL improves the potency of lipophilic cytotoxic drugs against tumours that express LDL receptor activity. PMID:8347487

  10. Immune regulation of therapy-resistant niches: emerging targets for improving anticancer drug responses.

    PubMed

    Jinushi, Masahisa

    2014-09-01

    Emerging evidence has unveiled a critical role for immunological parameters in predicting tumor prognosis and clinical responses to anticancer therapeutics. On the other hand, responsiveness to anticancer drugs greatly modifies the repertoires, phenotypes, and immunogenicity of tumor-infiltrating immune cells, serving as a critical factor to regulate tumorigenic activities and the emergence of therapy-resistant phenotypes. Tumor-associated immune functions are influenced by distinct or overlapping sets of therapeutic modalities, such as cytotoxic chemotherapy, radiotherapy, or molecular-targeted therapy, and various anticancer modalities have unique properties to influence the mode of cross-talk between tumor cells and immune cells in tumor microenvironments. Thus, it is critical to understand precise molecular machineries whereby each anticancer strategy has a distinct or overlapping role in regulating the dynamism of reciprocal communication between tumor and immune cells in tumor microenvironments. Such an understanding will open new therapeutic opportunities by harnessing the immune system to overcome resistance to conventional anticancer drugs. PMID:24756203

  11. 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

  12. 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. PMID:26769002

  13. Self-microemulsifying drug delivery system for improved oral bioavailability of oleanolic acid: design and evaluation

    PubMed Central

    Yang, Rui; Huang, Xin; Dou, Jinfeng; Zhai, Guangxi; Su, Lequn

    2013-01-01

    Oleanolic acid is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS) has been developed to enhance the solubility and oral bioavailability of oleanolic acid. The formulation design was optimized by solubility assay, compatibility tests, and pseudoternary phase diagrams. The morphology, droplet size distribution, zeta potential, viscosity, electrical conductivity, and refractive index of a SMEDDS loaded with oleanolic acid were studied in detail. Compared with oleanolic acid solution, the in vitro release of oleanolic acid from SMEDDS showed that the drug could be released in a sustained manner. A highly selective and sensitive high-performance liquid chromatographymass spectrometry method was developed for determination of oleanolic acid in rat plasma. This method was used for a pharmacokinetic study of an oleanolic acid-loaded SMEDDS compared with the conventional tablet in rats. Promisingly, a 5.07-fold increase in oral bioavailability of oleanolic acid was achieved for the SMEDDS compared with the marketed product in tablet form. Our studies illustrate the potential use of a SMEDDS for delivery of oleanolic acid via the oral route. PMID:23966781

  14. Alendronate-Loaded Modified Drug Delivery Lipid Particles Intended for Improved Oral and Topical Administration.

    PubMed

    Ochiuz, Lacramioara; Grigoras, Cristian; Popa, Marcel; Stoleriu, Iulian; Munteanu, Corneliu; Timofte, Daniel; Profire, Lenuta; Grigoras, Anca Giorgiana

    2016-01-01

    The present paper focuses on solid lipid particles (SLPs), described in the literature as the most effective lipid drug delivery systems that have been introduced in the last decades, as they actually combine the advantages of polymeric particles, hydrophilic/lipophilic emulsions and liposomes. In the current study, we present our most recent advances in the preparation of alendronate (AL)-loaded SLPs prepared by hot homogenization and ultrasonication using various ratios of a self-emulsifying lipidic mixture of Compritol 888, Gelucire 44/14, and Cremophor A 25. The prepared AL-loaded SLPs were investigated for their physicochemical, morphological and structural characteristics by dynamic light scattering, differential scanning calorimetry, thermogravimetric and powder X-ray diffraction analysis, infrared spectroscopy, optical and scanning electron microscopy. Entrapment efficacy and actual drug content were assessed by a validated HPLC method. In vitro dissolution tests performed in simulated gastro-intestinal fluids and phosphate buffer solution pH 7.4 revealed a prolonged release of AL of 70 h. Additionally, release kinetics analysis showed that both in simulated gastrointestinal fluids and in phosphate buffer solution, AL is released from SLPs based on equal ratios of lipid excipients following zero-order kinetics, which characterizes prolonged-release drug systems. PMID:27367664

  15. Multifunctional SMA-based smart inhaler system for improved aerosol drug delivery: design and fabrication

    NASA Astrophysics Data System (ADS)

    Pausley, Matthew E.; Seelecke, Stefan

    2008-03-01

    This paper documents the development of a prototype smart aerosol drug inhaler system using shape memory alloy (SMA) actuators. Unlike conventional dispersed-release inhalers, the smart inhaler system releases the aerosol drug in a very small area within the mouth inlet. Kleinstreuer and Zhang [1] have found that controlled release in the mouth inlet increases drug efficiency and allows targeting of specific sites within the lung. The methodology has been validated numerically and experimentally using fixed-exit position inhalers. The design presented in this work, however, allows for variation of nozzle exit position using SMA wire actuators in a combined actuator/sensor role. In contrast to other possible mechanisms, SMA wires are lightweight, require low power, and are the least obstructive to the flow of air through the inhaler. The dual actuator/sensor nature of the SMA wires (via resistance measurement) further simplifies the design. Solutions and insights into several SMA actuator design challenges are presented. SMA wire actuator characteristics such as achievable stroke and their effect on the design are highlighted. Consideration of actuator force requirements and the capabilities of SMA wires and studied. The problems posed by the thermal characteristics of SMA wires and innovative solutions are reported.

  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

    2016-01-01

    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. PMID:27070565

  17. 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

  18. Hollow crystal anti-solvent preparation process as a promising technique to improve dissolution of poorly soluble drugs

    NASA Astrophysics Data System (ADS)

    Paulino, A. S.; Rauber, G. S.; Campos, C. E. M.; Maurício, M. H. P.; de Avillez, R. R.; Cuffini, S. L.; Cardoso, S. G.

    2013-03-01

    Innovative results using the anti-solvent preparation process to obtain hollow crystals of Deflazacort (DFZ) and Carbamazepine (CBZ) with improved dissolution characteristics are presented. DFZ is a methyloxazoline which is prefered over other corticosteroids due to its major advantages and performance. CBZ is a well-established drug for epilepsy treatment and exhibits at least four polymorphic forms and hydrate or solvate forms. Both drugs are poorly soluble in water and several strategies have been developed in order to find preparation methods to improve their dissolution rates. Moreover, reports have shown high dissolution variability in the tablets of DFZ and CBZ currently on the market. In this work, the hollow crystals of DFZ and CBZ were crystallized and characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRD), thermal analysis (DSC) and diffuse reflectance infrared Fourier (DRIFT) spectroscopy. DFZ showed prismatic hollow crystals with the same crystal structure of the raw material. The morphology of crystallized samples of CBZ showed the same shape; however, the raw material was a monoclinic form (polymorph III) while hollow crystals presented triclinic crystal structure (polymorph I). Finally, in both cases, the hollow crystals of CBZ and DFZ significantly improved the dissolution properties in comparison with the initial raw materials.

  19. Assessing cognitive improvement in people with Down syndrome: important considerations for drug-efficacy trials.

    PubMed

    Fernandez, Fabian; Reeves, Roger H

    2015-01-01

    Experimental research over just the past decade has raised the possibility that learning deficits connected to Down syndrome (DS) might be effectively managed by medication. In the current chapter, we touch on some of the work that paved the way for these advances and discuss the challenges associated with translating them. In particular, we highlight sources of phenotypic variability in the DS population that are likely to impact performance assessments. Throughout, suggestions are made on how to detect meaningful changes in cognitive-adaptive function in people with DS during drug treatment. The importance of within-subjects evaluation is emphasized. PMID:25977089

  20. Novel oral formulation safely improving intestinal absorption of poorly absorbable drugs: utilization of polyamines and bile acids.

    PubMed

    Miyake, Masateru; Minami, Takanori; Hirota, Masao; Toguchi, Hajime; Odomi, Masaaki; Ogawara, Ken-ichi; Higaki, Kazutaka; Kimura, Toshikiro

    2006-03-10

    In order to develop a novel oral formulation that can safely improve the intestinal absorption of poorly absorbable drugs, polyamines such as spermine (SPM) and spermidine (SPD) was examined as an absorption enhancing adjuvant in rats. The absorption of rebamipide, classified into BCS Class IV, from colon was significantly improved by SPM or SPD, and the enhancing ability of SPM was larger than that of SPD. As a possible mixing and/or interaction of polyamines with bile acids were expected, the combinatorial use of sodium taurocholate (STC) with polyamines was also examined. The absorption of rebamipide was drastically improved by the combinatorial use of SPM or SPD with STC. As STC itself did not enhance the absorption of rebamipide so much, it was considered that polyamines and STC had a synergistic enhancing effect. In-vivo oral absorption study was also performed to investigate the effectiveness and safety of polyamines and their combinatorial use with STC in rats. Although the enhancing effect slightly attenuated comparing with the in-situ loop study, the absorption of rebamipide was significantly improved and the combinatorial use of 10 mM SPM with 25 mM STC showed the largest enhancing effect. Histopathological studies clearly showed that any significant change in stomach and duodenum was not caused by SPM (10 mM), SPD (10 mM) or their combinatorial use with STC (25 mM) at 1.5 or 8.0 h after oral administration. Taken all together, polyamines, especially SPM, and its combinatorial use with STC could improve the absorption of poorly absorbable drugs without any significant changes in gastrointestinal tract after oral administration in rats. PMID:16410031

  1. Radiation-guided drug delivery to tumor blood vessels results in improved tumor growth delay.

    PubMed

    Geng, Ling; Osusky, Katherine; Konjeti, Sekhar; Fu, Allie; Hallahan, Dennis

    2004-10-19

    Tumor blood vessels are biological targets for cancer therapy. In this study, a tumor vasculature targeting system that consisted of liposomes and lectin (WGA) was built. Liposomes were used to carry a number of liposome-friendly anti-tumoral agents along with WGA, a lectin which posseses a specific affinity for binding to inflamed endothelial cells. In order to target tumor vasculature, inflammation of endothelial cells was induced by radiation. Because ionizing radiation induces an inflammatory response in tumor vasculature, lectin-conjugates were utilized to determine whether radiation can be used to target drug delivery to tumor vessels. Wheat germ agglutinin (WGA) is one such lectin that binds to inflamed microvasculature. WGA was conjugated to liposomes containing cisplatin and administered to tumor bearing mice. Tumor growth delay was used to analyze the efficacy of cytotoxicity. FITC-conjugated WGA accumulated within irradiated tumor microvasculature. WGA was conjugated to liposomes and labeled with 111In. This demonstrated radiation-inducible tumor-selective binding. WGA-liposome-conjugates were loaded with Cisplatin and administered to mice bearing irradiated tumors. Tumors treated with a combination of liposome encapsulated cisplatin together with radiation showed a significant increase in tumor growth delay as compared to radiation alone. These findings demonstrate that ionizing radiation can be used to guide drug delivery to tumor microvasculature. PMID:15451595

  2. Improved visualization and quantitative analysis of drug effects using micropatterned cells.

    PubMed

    Degot, Sébastien; Auzan, Muriel; Chapuis, Violaine; Béghin, Anne; Chadeyras, Amélie; Nelep, Constantin; Calvo-Muñoz, Maria Luisa; Young, Joanne; Chatelain, François; Fuchs, Alexandra

    2010-01-01

    To date, most HCA (High Content Analysis) studies are carried out with adherent cell lines grown on a homogenous substrate in tissue-culture treated micro-plates. Under these conditions, cells spread and divide in all directions resulting in an inherent variability in cell shape, morphology and behavior. The high cell-to-cell variance of the overall population impedes the success of HCA, especially for drug development. The ability of micropatterns to normalize the shape and internal polarity of every individual cell provides a tremendous opportunity for solving this critical bottleneck (1-2). To facilitate access and use of the micropatterning technology, CYTOO has developed a range of ready to use micropatterns, available in coverslip and microwell formats. In this video article, we provide detailed protocols of all the procedures from cell seeding on CYTOOchip micropatterns, drug treatment, fixation and staining to automated acquisition, automated image processing and final data analysis. With this example, we illustrate how micropatterns can facilitate cell-based assays. Alterations of the cell cytoskeleton are difficult to quantify in cells cultured on homogenous substrates, but culturing cells on micropatterns results in a reproducible organization of the actin meshwork due to systematic positioning of the cell adhesion contacts in every cell. Such normalization of the intracellular architecture allows quantification of even small effects on the actin cytoskeleton as demonstrated in these set of protocols using blebbistatin, an inhibitor of the actin-myosin interaction. PMID:21189468

  3. 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

  4. 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. PMID:27230510

  5. Further characterization of theobroma oil-beeswax admixtures as lipid matrices for improved drug delivery systems.

    PubMed

    Attama, A A; Schicke, B C; Müller-Goymann, C C

    2006-11-01

    There is an increasing interest in lipid based drug delivery systems due to factors such as better characterization of lipidic excipients and formulation versatility and the choice of different drug delivery systems. It is important to know the thermal characteristics, crystal habit, texture, and appearance of a new lipid matrix when determining its suitability for use in certain pharmaceutical application. It is line with this that this research was embarked upon to characterize mixtures of beeswax and theobroma oil with a view to applying their admixtures in drug delivery systems such as solid lipid nanoparticles and nanostructured lipid carriers. Admixtures of theobroma oil and beeswax were prepared to contain 25% w/w, 50% w/w, and 75% w/w of theobroma oil. The admixtures were analyzed by differential scanning calorimetry (DSC), small angle X-ray diffraction (SAXD), wide angle X-ray diffraction (WAXD), and isothermal heat conduction microcalorimetry (IMC). The melting behavior and microstructures of the lipid admixtures were monitored by polarized light microscopy (PLM). Transmission electron microscopy (TEM) was used to study the internal structures of the lipid bases. DSC traces indicated that the higher melting peaks were roughly constant for the different admixtures, but lower melting peaks significantly increased (p < 0.05). The admixture containing 25% w/w of theobroma oil possessed highest crystallinity index of 95.6%. WAXD studies indicated different reflections for the different lipid matrices. However, new interferences were detected for all the lipid matrix admixtures between 2theta = 22.0 degrees and 2theta = 25.0 degrees. The lipid matrices containing 50% w/w and 25% w/w of theobroma oil showed absence of the weak reflection characteristic of pure theobroma oil, while there was disappearance of the strong intensity reflection of beeswax in all the lipid matrix admixtures at all stages of the study. PLM micrographs revealed differences with regard to

  6. Application of vasoactive and matrix-modifying drugs can improve polyplex delivery to tumors upon intravenous administration.

    PubMed

    Durymanov, Mikhail O; Yarutkin, Alexey V; Bagrov, Dmitry V; Klinov, Dmitry V; Kedrov, Alexander V; Chemeris, Nikolay K; Rosenkranz, Andrey A; Sobolev, Alexander S

    2016-06-28

    Low efficacy of cationic polymer-based formulations (polyplexes) for systemic gene delivery to tumors remains the crucial concern for their clinical translation. Here we show that modulating the physiological state of a tumor using clinically approved pharmaceuticals can improve delivery of intravenously injected polyplexes to murine melanoma tumors with different characteristics. Direct comparison of drugs with different mechanisms of action has shown that application of nitroglycerin or losartan improved extravasation and tumor uptake of polyplex nanoparticles, whereas angiotensin II had almost no effect on polyplex accumulation and microdistribution in the tumor tissue. Application of nitroglycerin and losartan caused from 2- to 6-fold enhanced efficacy of polyplex-mediated gene delivery depending on the tumor model. The results obtained on polyplex behavior in tumor tissues depending on physiological state of the tumor can be relevant to optimize delivery of polyplexes and other nanomedicines with similar physicochemical properties. PMID:27072027

  7. 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

  8. Strategies for improved modeling of GPCR-drug complexes: blind predictions of serotonin receptors bound to ergotamine.

    PubMed

    Rodríguez, David; Ranganathan, Anirudh; Carlsson, Jens

    2014-07-28

    The recent increase in the number of atomic-resolution structures of G protein-coupled receptors (GPCRs) has contributed to a deeper understanding of ligand binding to several important drug targets. However, reliable modeling of GPCR-ligand complexes for the vast majority of receptors with unknown structure remains to be one of the most challenging goals for computer-aided drug design. The GPCR Dock 2013 assessment, in which researchers were challenged to predict the crystallographic structures of serotonin 5-HT(1B) and 5-HT(2B) receptors bound to ergotamine, provided an excellent opportunity to benchmark the current state of this field. Our contributions to GPCR Dock 2013 accurately predicted the binding mode of ergotamine with RMSDs below 1.8 Å for both receptors, which included the best submissions for the 5-HT(1B) complex. Our models also had the most accurate description of the binding sites and receptor-ligand contacts. These results were obtained using a ligand-guided homology modeling approach, which combines extensive molecular docking screening with incorporation of information from multiple crystal structures and experimentally derived restraints. In this work, we retrospectively analyzed thousands of structures that were generated during the assessment to evaluate our modeling strategies. Major contributors to accuracy were found to be improved modeling of extracellular loop two in combination with the use of molecular docking to optimize the binding site for ligand recognition. Our results suggest that modeling of GPCR-drug complexes has reached a level of accuracy at which structure-based drug design could be applied to a large number of pharmaceutically relevant targets. PMID:25030302

  9. Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme.

    PubMed

    Tivnan, Amanda; Zakaria, Zaitun; O'Leary, Caitrín; Kögel, Donat; Pokorny, Jenny L; Sarkaria, Jann N; Prehn, Jochen H M

    2015-01-01

    Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30-40% response rate, many fall into the range of 10-20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it's role in BBB active transport, highlights this member of the ABC transporter family as a target for improving drug responses in GBM. In this study we show that small molecule inhibitors and gene silencing of MRP1 had a significant effect on GBM cell response to temozolomide (150 μM), vincristine (100 nM), and etoposide (2 μM). Pre-treatment with Reversan (inhibitor of MRP1 and P-glycoprotein) led to a significantly improved response to cell death in the presence of all three chemotherapeutics, in both primary and recurrent GBM cells. The presence of MK571 (inhibitor of MRP1 and multidrug resistance protein 4 (MRP4) led to an enhanced effect of vincristine and etoposide in reducing cell viability over a 72 h period. Specific MRP1 inhibition led to a significant increase in vincristine and etoposide-induced cell death in all three cell lines assessed. Treatment with MK571, or specific MRP1 knockdown, did not have any effect on temozolomide drug response in these cells. These findings have significant implications in providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients. PMID:26136652

  10. Vendor-to-vendor education to improve malaria treatment by private drug outlets in Bungoma District, Kenya

    PubMed Central

    Tavrow, Paula; Shabahang, Jennifer; Makama, Sammy

    2003-01-01

    Background 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. Methods 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. Results 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. Conclusions 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. PMID:12812525

  11. 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

  12. An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells.

    PubMed

    Noor, Fozia; Niklas, Jens; Müller-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 hepatotoxicity 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(50) values 100 microM 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. PMID:19332084

  13. Improving dosing of gentamicin in the obese patient: a 3-cycle drug chart and case note audit

    PubMed Central

    Manjaly, Joseph G; Reece-Smith, Alexander M; Sivaloganathan, Sivan S; Thuraisamy, Christina; Smallwood, Katie LM; Jonas, Elizabeth; Longman, Robert J

    2012-01-01

    Objectives To assess the use of an electronic dose calculator to improve accuracy in the use of a complex Gentamicin prescription policy and assess turnaround time of blood sampling to dose delivery in an NHS hospital. Design Retrospective review of drug chart, case notes and hospital antibiotic database. Setting University Hospitals Bristol, UK Participants Patients receiving once daily intravenous gentamicin using the trust protocol, during the same time window for 3 consecutive years. Main outcome measures i) Accuracy of dose and frequency prescription of Gentamicin. ii) Time frame for measurement of serum Gentamicin levels. Results Following the introduction of the online calculator, prescribing errors in obese patients dropped from 43% to 20%, a similar level as in non-obese patients. Errors in frequency calculations dropped from 12.8% to 4%. On average, drug doses could be administered within 2.5 hours of a blood sample being taken. Conclusions Online tools can be used to improve prescribing for the complex dosing policies that will increasingly been required to tailor prescribing in obese patients. Serum gentamicin levels can be measured within a 2.5 hour time frame in the environment of an NHS hospital. PMID:22715426

  14. 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.

  15. 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. PMID:27547646

  16. 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

  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. Improved conversion rates in drug screening applications using miniaturized electrochemical cells with frit channels.

    PubMed

    Odijk, Mathieu; Olthuis, Wouter; van den Berg, A; Qiao, Liang; Girault, Hubert

    2012-11-01

    This paper reports a novel design of a miniaturized three-electrode electrochemical cell, the purpose of which is aimed at generating drug metabolites with a high conversion efficiency. The working electrode and the counter electrode are placed in two separate channels to isolate the reaction products generated at both electrodes. The novel design includes connecting channels between these two electrode channels to provide a uniform distribution of the current density over the entire working electrode. In addition, the effect of ohmic drop is decreased. Moreover, two flow resistors are included to ensure an equal flow of analyte through both electrode channels. Total conversion of fast reacting ions is achieved at flow rates up to at least 8 μL/min, while the internal chip volume is only 175 nL. Using this electrochemical chip, the metabolism of mitoxantrone is studied by microchip electrospray ionization-mass spectrometry. At an oxidation potential of 700 mV, all known metabolites from direct oxidation are observed. The electrochemical chip performs equally well, compared to a commercially available cell, but at a 30-fold lower flow of reagents. PMID:23020795

  19. Nonsteroidal anti-inflammatory drug reduces neutrophil and macrophage accumulation but does not improve tendon regeneration.

    PubMed

    Marsolais, David; Côté, Claude H; Frenette, Jérôme

    2003-07-01

    Whether nonsteroidal anti-inflammatory drugs have a beneficial effect on tendon regeneration is still a matter of debate. Given that inflammatory cells are thought to induce nonspecific damage following an injury, we tested the hypothesis that a 3-day treatment with diclofenac would protect tendons from inflammatory cell injury and would promote healing. Neutrophil and ED1(+) macrophage concentrations were determined in the paratenon and the core of the rat Achilles tendon following collagenase-induced injury. Hydroxyproline content, edema, and mechanical properties were also evaluated at 1, 3, 7, 14, and 28 days post-trauma. Collagenase injections induced a 70% decrease in the ultimate rupture point at Day 3. Diclofenac treatments (1 mg/kg bid) selectively decreased the accumulation of neutrophils and ED1(+) macrophages by 59% and 35%, respectively, in the paratenon, where blood vessels are numerous, but did not reduce the accumulation of neutrophils and ED1(+) macrophages in the core of the tendon. Edema was significantly reduced on Day 3 but persisted during the remodeling phase in the diclofenac-treated group only. The inhibition of leukocyte accumulation by diclofenac did not translate into a reduction of tissue damage or a promotion of tissue healing, because the mechanical properties of injured Achilles tendons were identical in placebo and diclofenac-treated groups. These results indicate that diclofenac reduced both edema and the accumulation of inflammatory cells within the paratenon but provided no biochemical or functional benefits for the Achilles tendon. PMID:12861039

  20. Improved Antioxidant Capacity of Optimization of a Self-Microemulsifying Drug Delivery System for Resveratrol.

    PubMed

    Chen, Ying; Zhang, Huiyong; Yang, Jing; Sun, Haiyan

    2015-01-01

    The use of nano-encapsulated resveratrol (RSV) in self-micro-emulsified drug delivery systems (SMEDDS) formulations was investigated. Self-emulsifying grading tests were used to establish the optimal ratio of oil, surfactant, and co-surfactant. The optimized system was further investigated for the droplet size and zeta potential at the different medium pH values by a Malvern Zetasizer and transmission electron microscopy (TEM). The antioxidant capacity and cytotoxicity of the formulation were detected by DCFH-DA and a CCK-8 assays. The results showed that the nano-emulsion based on ethyl oleate, Tween-80, and PEG-400 (35:40:25, w/w/w) was the most stable formulation due to the small droplet size (approximately 50 nm) and high zeta potential in a neutral environment. Furthermore, this formulation also exhibited a greater antioxidant capacity with less toxicity than free RSV. Taken together, considering these results and the simple fabrication process, this formulation could be used to deliver nutritional food supplements in a stable, efficient, and safe manner. PMID:26633319

  1. 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

  2. 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

    2016-01-01

    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

  3. Novel method to improve transdermal drug delivery by atmospheric microplasma irradiation.

    PubMed

    Shimizu, Kazuo; Hayashida, Kentaro; Blajan, Marius

    2015-01-01

    Application of atmospheric plasma could be used for wound healing, skin rejuvenation, and wrinkle treatment. The authors explored the feasibility of atmospheric microplasma irradiation (AMI) for enhancement of percutaneous absorption of drugs as an alternative to hypodermic needles. Pig skin was used as a biological sample exposed to AMI and analyzed by attenuated total reflection-Fourier transform infrared spectroscopy. A tape-stripping test (an evaluation method for skin-barrier performance) was also conducted to compare with AMI. Transepidermal water loss was also measured and compared with and without AMI. Results showed that surface modification of the stratum corneum (outermost skin layer) was observed upon AMI. Small pores on sample skin were observed with plasma jet irradiation due to the collision of charged particles. Percutaneous absorption was confirmed without damage upon microplasma irradiation. Our data suggested that dye pathways through skin samples could be related to the dynamic behavior of intercellular lipid bilayers, suggesting that AMI could enhance percutaneous absorption. PMID:25947391

  4. 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. PMID:24812509

  5. Mixed PEG-PE/Vitamin E Tumor-Targeted Immunomicelles as Carriers for Poorly Soluble Anti-Cancer Drugs: Improved Drug Solubilization and Enhanced In Vitro Cytotoxicity

    PubMed Central

    Sawant, Rupa R.; Sawant, Rishikesh M.; Torchilin, Vladimir P.

    2008-01-01

    Two poorly soluble, potent anticancer drugs, paclitaxel and camptothecin, were successfully solubilized by mixed micelles of polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) and vitamin E. Drug containing micelles were additionally modified with anti-nucleosome monoclonal antibody 2C5 (mAb 2C5), which can specifically bring micelles to tumor cells in vitro. The optimized micelles had an average size of about 13-to-22 nm and the immuno-modification of micelles did not significantly change it. The solubilization of both drugs by the mixed micelles was more efficient than by micelles made of PEG-PE alone. Solubilization of camptothecin in micelles prevented also the hydrolysis of active lactone form of the drug to inactive carboxylate form. Drug loaded mixed micelles and mAb 2C5-immunomicelles demonstrated significantly higher in vitro cytotoxicity than free drug against various cancer cell lines. PMID:18583114

  6. 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. PMID:24752696

  7. 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

  8. 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

  9. Improving the translation of analgesic drugs to the clinic: animal models of neuropathic pain

    PubMed Central

    Percie du Sert, N; Rice, A S C

    2014-01-01

    Neuropathic pain remains an area of considerable unmet clinical need. Research based on preclinical animal models has failed to deliver truly novel treatment options, questioning the predictive value of these models. This review addresses the shortcomings of rodent in vivo models commonly used in the field and highlights approaches which could increase their predictivity, including more clinically relevant assays, outcome measures and animal characteristics. The methodological quality of animal studies also needs to be improved. Low internal validity and incomplete reporting lead to a waste of valuable research resources and animal lives, and ultimately prevent an objective assessment of the true predictivity of in vivo models. PMID:24527763

  10. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain

    PubMed Central

    Cannon, Ronald E.; Peart, John C.; Hawkins, Brian T.; Campos, Christopher R.; Miller, David S.

    2012-01-01

    P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to the delivery of small-molecule drugs across the blood-brain barrier and into the CNS. Here we test a unique signaling-based strategy to overcome this obstacle. We used a confocal microscopy-based assay with isolated rat brain capillaries to map a signaling pathway that within minutes abolishes P-glycoprotein transport activity without altering transporter protein expression or tight junction permeability. This pathway encompasses elements of proinflammatory- (TNF-α) and sphingolipid-based signaling. Critical to this pathway was signaling through sphingosine-1-phosphate receptor 1 (S1PR1). In brain capillaries, S1P acted through S1PR1 to rapidly and reversibly reduce P-glycoprotein transport activity. Sphingosine reduced transport by a sphingosine kinase-dependent mechanism. Importantly, fingolimod (FTY720), a S1P analog recently approved for treatment of multiple sclerosis, also rapidly reduced P-glycoprotein activity; similar effects were found with the active, phosphorylated metabolite (FTY720P). We validated these findings in vivo using in situ brain perfusion in rats. Administration of S1P, FTY720, or FTY729P increased brain uptake of three radiolabeled P-glycoprotein substrates, 3H-verapamil (threefold increase), 3H-loperamide (fivefold increase), and 3H-paclitaxel (fivefold increase); blocking S1PR1 abolished this effect. Tight junctional permeability, measured as brain 14C-sucrose accumulation, was not altered. Therefore, targeting signaling through S1PR1 at the blood-brain barrier with the sphingolipid-based drugs, FTY720 or FTY720P, can rapidly and reversibly reduce basal P-glycoprotein activity and thus improve delivery of small-molecule therapeutics to the brain. PMID:22949658

  11. 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

  12. 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.

  13. Erodible time-dependent colon delivery systems with improved efficiency in delaying the onset of drug release.

    PubMed

    Del Curto, Maria Dorly; Palugan, Luca; Foppoli, Anastasia; Zema, Lucia; Gazzaniga, Andrea; Maroni, Alessandra

    2014-11-01

    To prepare swellable/erodible time-dependent colon delivery systems with improved efficiency in delaying drug release, the application of an outer Eudragit® NE film, which contained the superdisintegrant Explotab® V17 as a pore former, was attempted. Tablet cores were successively spray-coated with a hydroxypropyl methylcellulose (HPMC) solution and diluted Eudragit® NE 30 D, wherein fixed amounts of Explotab® V17 were present. The resulting two-layer systems yielded lag phases of extended duration as compared with formulations provided with the HPMC layer only. By raising the thickness of the outer film, longer lag times were generally observed, whereas the effectiveness in deferring the drug liberation was reduced by increasing the pore former content, which, however, also resulted in a lower data variability. The films containing 20% of Explotab® V17 effectively and consistently prolonged the in vitro lag phase imparted by HPMC as a function of their thickness. Stored for 3 years under ambient conditions, a two-layer system with this outer film composition pointed out unmodified release patterns. The same system proved to meet gastroresistance criteria when enteric coated. The results obtained indicated that the proposed strategy would enable the preparation of erodible delivery systems with reduced size, possibly suitable as multiple-unit dosage forms. PMID:25213173

  14. The role of drug vendors in improving basic health-care services in Nigeria

    PubMed Central

    Prach, Lisa M; Treleaven, Emily; Hansen, Mara; Anyanti, Jennifer; Jagha, Temple; Seaman, Vince; Ajumobi, Olufemi; Isiguzo, Chinwoke

    2016-01-01

    Abstract Objective 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. Methods 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. Findings 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. Conclusion 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. PMID:27034520

  15. 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.

  16. 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

  17. Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.

    PubMed

    Incecayir, Tuba; Sun, Jing; Tsume, Yasuhiro; Xu, Hao; Gose, Tomoka; Nakanishi, Takeo; Tamai, Ikumi; Hilfinger, John; Lipka, Elke; Amidon, Gordon L

    2016-02-01

    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-methylene-dioxy 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 2 times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a 9 times-enhanced apparent permeability (P(app)) in Caco-2 cells compared with the parent drug. Both diastereomer exhibited high effective permeability (P(eff)) in mice, 6.32 ± 3.12 and 5.20 ± 2.81 × 10(-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 before absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells. PMID:26869437

  18. 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

    2015-02-01

    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

  19. 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

  20. Improvements in HIV treatment outcomes among indigenous and non-indigenous people who use illicit drugs in a Canadian setting

    PubMed Central

    Milloy, M-J; King, Alexandra; Kerr, Thomas; Adams, Evan; Samji, Hasina; Guillemi, Silvia; Wood, Evan; Montaner, Julio

    2016-01-01

    Introduction In many settings worldwide, members of indigenous groups experience a disproportionate burden of HIV. In Canada, there is an urgent need to improve HIV treatment outcomes for indigenous people living with HIV (IPLWH), to not only reduce HIV/AIDS-associated morbidity and mortality but also curb elevated rates of viral transmission. Thus, by comparing indigenous and non-indigenous participants in an ongoing longitudinal cohort of HIV-positive people who use illicit drugs, we sought to investigate longitudinal changes in three HIV treatment indicators for IPLWH who use illicit drugs during a community-wide treatment-as-prevention (TasP) initiative in British Columbia, Canada. Methods We used data from the ACCESS study, an ongoing observational prospective cohort of HIV-positive illicit drug users recruited from community settings in Vancouver, British Columbia. Cohort data are linked to comprehensive retrospective and prospective clinical records in a setting of no-cost HIV/AIDS treatment and care. We used multivariable generalized estimating equations (GEE) to evaluate longitudinal changes in the proportion of participants with exposure to antiretroviral therapy (ART) in the previous 180 days, optimal adherence to ART (i.e. ≥95% vs. <95%) and non-detectable HIV-1 RNA viral load (VL <50 copies/mL plasma). Results Between 2005 and 2014, 845 individuals were recruited, including 326 (39%) self-reporting any indigenous ancestry, and contributed 6732 interviews and 13,495 VL measurements. Among indigenous participants, the proportion with recent ART increased from 51 to 94% and non-detectable VL from 23 to 65%. In multivariable models, later interview period was positively associated with recent ART (adjusted odds ratio (AOR)=1.16 per interview period, 95% confidence interval (CI): 1.11 to 1.20) and non-detectable VL (AOR=1.07, 95% CI: 1.04 to 1.10). In adjusted models comparing indigenous and non-indigenous participants, we did not observe differences

  1. 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. PMID:27113473

  2. Deoxyadenosine family: improved synthesis, DNA damage and repair, analogs as drugs.

    PubMed

    Biswas, Himadri; Kar, Indrani; Chattopadhyaya, Rajagopal

    2013-08-01

    Improved synthesis of 2'-deoxyadenosine using Escherichia coli overexpressing some enzymes and gram-scale chemical synthesis of 2'-deoxynucleoside 5'-triphosphates reported recently are described in this review. Other topics include DNA damage induced by chromium(VI), Fenton chemistry, photoinduction with lumazine, or by ultrasound in neutral solution; 8,5'-cyclo-2'-deoxyadenosine isomers as potential biomarkers; and a recapitulation of purine 5',8-cyclonucleoside studies. The mutagenicities of some products generated by oxidizing 2'-deoxyadenosine 5'-triphosphate, nucleotide pool sanitization, and translesion synthesis are also reviewed. Characterizing cross-linking between nucleosides in opposite strands of DNA and endonuclease V-mediated deoxyinosine excision repair are discussed. The use of purine nucleoside analogs in the treatment of rarer chronic lymphoid leukemias is reviewed. Some analogs at the C8 position induced delayed polymerization arrest during HIV-1 reverse transcription. The susceptibility of clinically metronidazole-resistant Trichomonas vaginalis to two analogs, toyocamycin and 2-fluoro-2'-deoxyadenosine, were tested in vitro. GS-9148, a dAMP analog, was translocated to the priming site in a complex with reverse transcriptase and double-stranded DNA to gain insight into the mechanism of reverse transcriptase inhibition. PMID:25436589

  3. Designing Paclitaxel Drug Delivery Systems Aimed at Improved Patient Outcomes: Current Status and Challenges

    PubMed Central

    Surapaneni, Madhu S.; Das, Sudip K.; Das, Nandita G.

    2012-01-01

    Paclitaxel is one of the most widely used and effective antineoplastic agents derived from natural sources. It has a wide spectrum of antitumor activity, particularly against ovarian cancer, breast cancer, nonsmall cell lung cancer, head and neck tumors, Kaposi's sarcoma, and urologic malignancies. It is a highly lipophilic compound with a log P value of 3.96 and very poor aqueous solubility of less than 0.01 mg/mL. In addition, the compound lacks functional groups that are ionizable which could potentially lead to an increase in its solubility with the alteration in pH. Therefore, the delivery of paclitaxel is associated with substantial challenges. Until the introduction of Abraxane, only commercial formulation was solution of paclitaxel in cremophor, which caused severe side effects. However, in recent years, a number of approaches have been reported to solubilize paclitaxel using cosolvents and inclusion complexes. In addition, innovative approaches have been reported for passive targeting of tumors using nanoparticles, nanosuspensions, liposomes, emulsions, micelles, implants, pastes and gels. All approaches for delivery of improved therapeutic outcome have been discussed in this paper. PMID:22934190

  4. Criticisms of drugs in early development for the treatment of depression: what can be improved?

    PubMed

    Wang, Sheng-Min; Han, Changsu; Pae, Chi-Un

    2015-04-01

    Major depressive disorder (MDD) is a common and debilitating mental illness, which leads to serious functional impairment in patients, and treatment-wise, there are currently a number of different classes of antidepressants already on the market. However, emerging evidence from numerous clinical trials has confirmed that there is still an unmet need for antidepressant efficacy in terms of response and remission. Approximately only 30% of patients with MDD may remit after adequate treatment with antidepressants in clinical practice. The drawbacks of the currently available antidepressants also include inadequate overall efficacy, safety issues and the lag prior to onset of clinical improvement. The need for new agents with novel mechanisms of action has led to the development of several newer antidepressants including vilazodone, edivoxetine, ketamine, atomoxetine and vortioxetine, which have been approved for the treatment of MDD. However, the efficacy and safety of these next-generation antidepressants, in clinical trials, are still unsatisfactory. This paper provides a brief updated overview of the progress and critical limitations in the development of novel antidepressants. PMID:25529224

  5. Does the Addition of a Second Antipsychotic Drug Improve Clozapine Treatment?

    PubMed Central

    Barbui, Corrado; Signoretti, Alessandra; Mulè, Serena; Boso, Marianna; Cipriani, Andrea

    2009-01-01

    In patients with schizophrenia who do not have an optimal response to clozapine, it remains unclear if there is an evidence base to support a second antipsychotic in combination with clozapine. The present systematic review was therefore carried out to determine the efficacy of various clozapine combination strategies with antipsychotics. Relevant studies were located by searching the Cochrane Schizophrenia Group Trials Register, Medline, and Embase (up to November 2007). Only studies randomly allocating patients to clozapine plus another antipsychotic vs clozapine monotherapy were included. The search yielded 21 studies suitable for reanalysis. In 3 trials, clozapine was combined with a phenothiazine, in 8 trials with a benzamide, and in the remaining trials with risperidone. While the majority of randomized trials were not double blind, 6 studies were double-blind placebo-controlled trials. A total of 14 randomized open studies significantly favored clozapine combination strategy in terms of mean difference (random effect standardized mean difference [SMD] = −0.80, 95% confidence interval [CI] = −1.14 to −0.46); however, data extracted from 6 randomized double-blind studies did not show a statistically significant positive effect of this combination strategy in terms of mean difference (SMD = −0.12, 95% CI = −0.57 to 0.32). In terms of percentage of patients failing to show an improvement, a total of 10 randomized open studies significantly favored clozapine combination strategy (random effect relative risk [RR] = 0.64, 95% CI = 0.42 to 0.97), but data extracted from 6 randomized double-blind studies did not show a statistically significant positive effect of this combination strategy (RR = 0.91, 95% CI = 0.75 to 1.11). We conclude that the evidence base supporting a second antipsychotic in addition to clozapine in partially responsive patients with schizophrenia is weak. This weak evidence indicates modest to absent benefit. PMID:18436527

  6. 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. PMID:26580824

  7. Large-scale combining signals from both biomedical literature and the FDA Adverse Event Reporting System (FAERS) to improve post-marketing drug safety signal detection

    PubMed Central

    2014-01-01

    Background Independent data sources can be used to augment post-marketing drug safety signal detection. The vast amount of publicly available biomedical literature contains rich side effect information for drugs at all clinical stages. In this study, we present a large-scale signal boosting approach that combines over 4 million records in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) and over 21 million biomedical articles. Results The datasets are comprised of 4,285,097 records from FAERS and 21,354,075 MEDLINE articles. We first extracted all drug-side effect (SE) pairs from FAERS. Our study implemented a total of seven signal ranking algorithms. We then compared these different ranking algorithms before and after they were boosted with signals from MEDLINE sentences or abstracts. Finally, we manually curated all drug-cardiovascular (CV) pairs that appeared in both data sources and investigated whether our approach can detect many true signals that have not been included in FDA drug labels. We extracted a total of 2,787,797 drug-SE pairs from FAERS with a low initial precision of 0.025. The ranking algorithm combined signals from both FAERS and MEDLINE, significantly improving the precision from 0.025 to 0.371 for top-ranked pairs, representing a 13.8 fold elevation in precision. We showed by manual curation that drug-SE pairs that appeared in both data sources were highly enriched with true signals, many of which have not yet been included in FDA drug labels. Conclusions We have developed an efficient and effective drug safety signal ranking and strengthening approach We demonstrate that large-scale combining information from FAERS and biomedical literature can significantly contribute to drug safety surveillance. PMID:24428898

  8. Anti-infective Activity of 2-Cyano-3-Acrylamide Inhibitors with Improved Drug-Like Properties against Two Intracellular Pathogens.

    PubMed

    Passalacqua, Karla D; Charbonneau, Marie-Eve; Donato, Nicholas J; Showalter, Hollis D; Sun, Duxin; Wen, Bo; He, Miao; Sun, Hanshi; O'Riordan, Mary X D; Wobus, Christiane E

    2016-07-01

    Due to the rise of antibiotic resistance and the small number of effective antiviral drugs, new approaches for treating infectious diseases are urgently needed. Identifying targets for host-based therapies represents an emerging strategy for drug discovery. The ubiquitin-proteasome system is a central mode of signaling in the eukaryotic cell and may be a promising target for therapies that bolster the host's ability to control infection. Deubiquitinase (DUB) enzymes are key regulators of the host inflammatory response, and we previously demonstrated that a selective DUB inhibitor and its derivative promote anti-infective activities in host cells. To find compounds with anti-infective efficacy but improved toxicity profiles, we tested a library of predominantly 2-cyano-3-acrylamide small-molecule DUB inhibitors for anti-infective activity in macrophages against two intracellular pathogens: murine norovirus (MNV) and Listeria monocytogenes We identified compound C6, which inhibited DUB activity in human and murine cells and reduced intracellular replication of both pathogens with minimal toxicity in cell culture. Treatment with C6 did not significantly affect the ability of macrophages to internalize virus, suggesting that the anti-infective activity interferes with postentry stages of the MNV life cycle. Metabolic stability and pharmacokinetic assays showed that C6 has a half-life in mouse liver microsomes of ∼20 min and has a half-life of approximately 4 h in mice when administered intravenously. Our results provide a framework for targeting the host ubiquitin system in the development of host-based therapies for infectious disease. Compound C6 represents a promising tool with which to elucidate the role of DUBs in the macrophage response to infection. PMID:27139470

  9. Improved Completion Rates and Characterization of Drug Reactions with an Intensive Chagas Disease Treatment Program in Rural Bolivia

    PubMed Central

    Tornheim, Jeffrey A.; Lozano Beltran, Daniel F.; Gilman, Robert H.; Castellon, Mario; Solano Mercado, Marco A.; Sullca, Walter; Torrico, Faustino; Bern, Caryn

    2013-01-01

    Background Chagas disease treatment is limited by drug availability, adverse side effect profiles of available medications, and poor adherence. Methods Adult Chagas disease patients initiating 60-days of benznidazole were randomized to weekly or twice-weekly evaluations of medication adherence and screening for adverse drug events (ADEs). Mid-week evaluations employed phone-based evaluations. Adherence was measured by self-report, pill counts with intentional over-distribution, and Medication Event Monitoring Systems (MEMS). Prospective data were compared to historical controls treated with benznidazole at the same hospital. Results 162 prospective patients were compared to 172 historical patients. Pill counts correlated well with MEMS data (R = 0.498 for 7-day intervals, R = 0.872 for intervals >7 days). Treatment completion rates were higher among prospective than historical patients (82.1% vs. 65.1%), primarily due to lower abandonment rates. Rates of ADEs were lower among prospective than historical patients (56.8% vs. 66.9%). Twice-weekly evaluations increased identification of mild ADEs, prompting higher suspension rates than weekly evaluations. While twice-weekly evaluations identified ADEs earlier, they did not reduce incidence of moderate or severe ADEs. Many dermatologic ADEs were moderately severe upon presentation (35.6%), were not reduced by use of antihistamines, occurred among adult patients of all ages, and occurred throughout treatment, rather than the first few weeks alone. Conclusions Intensive management improved completion and identified more ADEs, but did not reduce moderate or severe ADEs. Risk of dermatologic ADEs cannot be reduced by selecting younger adults or monitoring only during the first few weeks of treatment. Pill counts and phone-based encounters are reliable tools for treatment programming in rural Bolivia. PMID:24069472

  10. Endothelial differentiation of adipose-derived mesenchymal stem cells is improved by epigenetic modifying drug BIX-01294.

    PubMed

    Culmes, Mihaela; Eckstein, Hans-Henning; Burgkart, Rainer; Nüssler, Andreas K; Guenther, Michael; Wagner, Ernst; Pelisek, Jaroslav

    2013-02-01

    Chromatin remodeling plays an essential role in regulation of gene transcription. Consequently, targeted changes in chromatin may also augment pluripotency of somatic cells. The aim of the present study was to evaluate the effect of epigenetic drug BIX-01294 (BIX), a histone G9a inhibitor, on DNA methylation, expression of pluripotency genes POU5F1 (isoform a), NANOG, KLF4, and CMYC in mesenchymal stem cells, and the ability to increase their differentiation potential into endothelial cells (ECs). Human adipose-derived mesenchymal stem cells (AdMSCs) were isolated from abdominal adipose tissue. Cells were pre-treated with BIX for 48h and further differentiated in endothelial medium for 7 and 14 days. Global DNA methylation was determined by MethyLight application, expression of genes for pluripotency, endothelial and angiogenic markers by SYBRGreen-based real-time PCR, immunocytochemistry, and immunobloting. Following treatment with BIX, DNA methylation status of AdMSCs was significantly reduced by 53% (p=0.008), the expression of POU5F1 and NANOG was increased by 2.2-fold (p=0.016) and 1.5-fold (p<0.001), respectively. Furthermore, BIX pre-treatment improved the differentiation capacity of AdMSCs into ECs and significantly increased expression of several endothelial markers and factors involved in blood vessel formation: VCAM-1, PECAM-1, von Willebrand factor, VEGFR-2, PDGF, and ANG-1 in comparison with AdMSCs without BIX pre-treatment. In the present study we demonstrate that epigenetic modifying drug BIX-01294 is able to increase the ability of AdMSCs to differentiate into ECs engaging DNA and histone methylation. Hence, BIX-01294 might serve as a simple tool to increase the differentiation potential of AdMSCs. PMID:23246144

  11. Submicron-Bubble-Enhanced Focused Ultrasound for Blood–Brain Barrier Disruption and Improved CNS Drug Delivery

    PubMed Central

    Ting, Chien-Yu; Lee, Ya-Hsuan; Huang, Chih-Ying; Ma, Yan-Jung; Wei, Kuo-Chen; Yen, Tzu-Chen; Yeh, Chih-Kuang

    2014-01-01

    The use of focused ultrasound (FUS) with microbubbles has been proven to induce transient blood–brain barrier opening (BBB-opening). However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1–4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz) can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg) by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use. PMID:24788566

  12. Patterned, but not tonic, optogenetic stimulation in motor thalamus improves reaching in acute drug-induced Parkinsonian rats.

    PubMed

    Seeger-Armbruster, Sonja; Bosch-Bouju, Clémentine; Little, Shane T C; Smither, Roseanna A; Hughes, Stephanie M; Hyland, Brian I; Parr-Brownlie, Louise C

    2015-01-21

    High-frequency deep brain stimulation (DBS) in motor thalamus (Mthal) ameliorates tremor but not akinesia in Parkinson's disease. The aim of this study was to investigate whether there are effective methods of Mthal stimulation to treat akinesia. Glutamatergic Mthal neurons, transduced with channelrhodopsin-2 by injection of lentiviral vector (Lenti.CaMKII.hChR2(H134R).mCherry), were selectively stimulated with blue light (473 nm) via a chronically implanted fiber-optic probe. Rats performed a reach-to-grasp task in either acute drug-induced parkinsonian akinesia (0.03-0.07 mg/kg haloperidol, s.c.) or control (vehicle injection) conditions, and the number of reaches was recorded for 5 min before, during, and after stimulation. We compared the effect of DBS using complex physiological patterns previously recorded in the Mthal of a control rat during reaching or exploring behavior, with tonic DBS delivering the same number of stimuli per second (rate-control 6.2 or 1.8 Hz, respectively) and with stimulation patterns commonly used in other brain regions to treat neurological conditions (tonic 130 Hz, theta burst (TBS), and tonic 15 Hz rate-control for TBS). Control rats typically executed >150 reaches per 5 min, which was unaffected by any of the stimulation patterns. Acute parkinsonian rats executed <20 reaches, displaying marked akinesia, which was significantly improved by stimulating with the physiological reaching pattern or TBS (both p < 0.05), whereas the exploring and all tonic patterns failed to improve reaching. Data indicate that the Mthal may be an effective site to treat akinesia, but the pattern of stimulation is critical for improving reaching in parkinsonian rats. PMID:25609635

  13. Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space.

    PubMed

    Meanwell, Nicholas A

    2016-04-18

    Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The physical, biological, and toxicological properties of a drug candidate are inextricably linked to its structure, and once a molecule has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biological properties of a molecule from an analysis of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a molecule is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clinical trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective analysis of drug design practices over the past decade has focused attention on the perception that contemporary molecules are unnecessarily obese, burdened by high molecular weight and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chemistry community with practical guideposts to enhancing compound quality in the drug design phase and which can readily be applied, a series of efficiency indices have been proposed that attempt to define aspects of compound quality in the context of a series of physicochemical parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a molecule on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad

  14. Detection of low-affinity anti-drug antibodies and improved drug tolerance in immunogenicity testing by Octet(®) biolayer interferometry.

    PubMed

    Li, Jian; Schantz, Allen; Schwegler, Maureen; Shankar, Gopi

    2011-01-25

    We assessed the utility of the FortéBio Octet(®) system for detection of anti-drug antibodies (ADAs) against an investigational therapeutic human IgG1 monoclonal antibody (mAb), CNTO X. To understand the relative merits of this technology, key performance requirements were compared with two popularly accepted ADA detection methods, a step-wise bridging ELISA and a Meso Scale Discovery (MSD) homogeneous (single step binding) bridging ECLIA. When used to detect 13 monoclonal ADAs of varying affinities and one polyclonal ADA, all three methods demonstrated their greatest apparent sensitivity to the polyclonal sample (1, 6, and 130 ng/mL, respectively for ECLIA, ELISA, and Octet). Sensitivity to monoclonal ADAs tended to vary in accordance with their affinities, however, the sensitivity of the Octet method varied much less between ADAs. As a result, the above ranking became reversed such that Octet was the most and ELISA least sensitive for detection of low-affinity ADAs. With regard to drug tolerance, the presence of CNTO X could lead to false-negative assay results, although each method was affected to a different degree, with the Octet method tolerating up to 10 times more drug than the ECLIA method, which in turn tolerated up to 10 times more than the ELISA. Finally, the ECLIA and Octet methods were applied to the bioanalysis of cynomolgus monkey sera from a pre-clinical multiple dose study of CNTO X. Octet indicated 3 positive animals developed ADA as early as day 15 of the dosing phase while drug was present at nearly 1mg/mL. ECLIA detected only one of these, and only in a day 57 recovery sample after drug had cleared from circulation. We conclude that the Octet is a promising platform for detection of lower affinity ADAs and is particularly suitable for ADA detection when drug persists at levels that negatively impact bridging immunoassays. PMID:20869832

  15. Modified Release and Improved Stability of Unstable BCS II Drug by Using Cyclodextrin Complex as Carrier To Remotely Load Drug into Niosomes.

    PubMed

    Chi, Liandi; Wu, Delin; Li, Zhuo; Zhang, Minmin; Liu, Hongchun; Wang, Caifen; Gui, Shuangying; Geng, Meiyu; Li, Haiyan; Zhang, Jiwen

    2016-01-01

    In answering to the challenge of enzymatic unstability of Biopharmaceutics Classification System (BCS) class II drugs, an effective remote loading strategy was developed to successfully incorporate the drug-cyclodextrin (CD) complex into niosomes to modify the release and stability of a drug candidate, pseudolaric acid B (PAB). Judged by binding constants, and combined solubilization effects of pH and CD complexation on PAB at different pH, the complex internalization driven by a transmembrane pH gradient (from 2.0 to 7.4) and the dynamic shifting of PAB-CD complexation equilibrium at this gradient were introduced. The transfer of PAB-CD complex into the internal aqueous phase of niosomes at 60 °C was primarily verified by synchrotron radiation Fourier transform infrared spectroscopy. The remote loading samples behaved as retarded release at pH 5.8, 6.8, and 7.4, for which the stability of PAB in rat plasma was significantly enhanced (about 8.1-fold), in comparison with niosomes prepared by the passive and lipid bilayer loading of PAB. The drug-carrier interaction based release modeling was further fitted, and the convection rate constant (ks) and free energy difference between free and bound states (ΔG) indicated the strongest PAB-carrier interactions in remote loading niosomes. The remote loading strategy also reduced the CD-cholesterol interaction and provided better physical stability of the system. In conclusion, the remote loading of drug-CD complex into niosomes provides advantages to modify the release and enhance the stability of unstable BCS class II drug. PMID:26569615

  16. Global initiative for interdisciplinary approach to improve innovative clinical research and treatment outcomes in geriatrics: biological cell-based targeted drug delivery systems for geriatrics.

    PubMed

    Zhumadilov, Zhaxybay

    2013-06-01

    At the intersection of the late 20(th) century and early 21(st) century, a worldwide challenge began to emerge--how can the quality of life be improved for a steadily increasing elderly population. It is well known that elderly patients show increased susceptibility to infections and a higher incidence of co-morbidity rates. Older adults frequently demonstrate pharmacokinetic and pharmacodynamic changes promoting adverse drug reactions and complications. Analysis of world literature and practical observations indicate that new approaches are required in gerontology and geriatric medicine due to recent significant advances in biomedical science. Global interdisciplinary approaches to improve medical science and medical care services for growing elderly population are indicated. This global, interdisciplinary initiative should integrate select, tangible clinical results achieved in leading research centers and universities that are applicable in the field of geriatrics and helpful to geriatricians. Among past scientific and clinically significant study results in the field of biomedicine, one must consider targeted drug delivery systems (DDS), which are designed to minimize drug side effects, increase the efficacy of drugs, and prolong and target drug interactions with particular pathological foci in sick patients. Many review articles focus on various methods of drug encapsulation and pharmacokinetics, but not on developing clinical modalities. This article attempts to further the discussion with researchers and clinicians from various fields, as well as to encourage comprehensive and elderly patient-oriented research focused on clinical implementation of DDS, especially erythrocyte-based DDS. PMID:23496161

  17. A Eu3+/Gd3+-EDTA-doped structurally controllable hollow mesoporous carbon for improving the oral bioavailability of insoluble drugs and in vivo tracing

    NASA Astrophysics Data System (ADS)

    Liu, Jia; Zhao, Yating; Cui, Yu; Yue, Yang; Gao, Yikun; Zhao, Qinfu; Liu, Jie; Wang, Siling

    2016-08-01

    A structurally controllable fluorescence-labeled hollow mesoporous carbon (HMC) was simply prepared to improve the oral bioavailability of insoluble drugs and further trace their delivery process in vivo. The hollow structure was derived from an inverse replica process using mesoporous silica as a template and the fluorescent label was prepared by doping the carboxylated HMC with a confinement of Eu3+/Gd3+-EDTA. The physicochemical properties of the composites were systematically characterized by transmission electron microscopy, Fourier transform infrared spectroscopy and photoluminescence spectra tests prior to studying their effects on drug-release behavior and biodistribution. As a result, the thickness of the carrier’s shell was adjusted from 70 nm to 130 nm and the maximum drug loading was up to 73.6%. The model drug carvedilol (CAR) showed sustained release behavior compared to CAR commercial capsules, and the dissolution rate slowed down as the shells got thicker. AUC0-48h and Tmax were enlarged 2.2 and 6.5 fold, respectively, which demonstrated that oral bioavailability was successfully improved. Bioimaging tests showed that the novel carbon vehicle had a long residence time in the gastrointestinal tract. In short, the newly designed HMC is a promising drug carrier for both oral bioavailability improvement and in vivo tracing.

  18. A Eu(3+)/Gd(3+)-EDTA-doped structurally controllable hollow mesoporous carbon for improving the oral bioavailability of insoluble drugs and in vivo tracing.

    PubMed

    Liu, Jia; Zhao, Yating; Cui, Yu; Yue, Yang; Gao, Yikun; Zhao, Qinfu; Liu, Jie; Wang, Siling

    2016-08-01

    A structurally controllable fluorescence-labeled hollow mesoporous carbon (HMC) was simply prepared to improve the oral bioavailability of insoluble drugs and further trace their delivery process in vivo. The hollow structure was derived from an inverse replica process using mesoporous silica as a template and the fluorescent label was prepared by doping the carboxylated HMC with a confinement of Eu(3+)/Gd(3+)-EDTA. The physicochemical properties of the composites were systematically characterized by transmission electron microscopy, Fourier transform infrared spectroscopy and photoluminescence spectra tests prior to studying their effects on drug-release behavior and biodistribution. As a result, the thickness of the carrier's shell was adjusted from 70 nm to 130 nm and the maximum drug loading was up to 73.6%. The model drug carvedilol (CAR) showed sustained release behavior compared to CAR commercial capsules, and the dissolution rate slowed down as the shells got thicker. AUC0-48h and Tmax were enlarged 2.2 and 6.5 fold, respectively, which demonstrated that oral bioavailability was successfully improved. Bioimaging tests showed that the novel carbon vehicle had a long residence time in the gastrointestinal tract. In short, the newly designed HMC is a promising drug carrier for both oral bioavailability improvement and in vivo tracing. PMID:27334550

  19. Nanoparticle Mediated P-Glycoprotein Silencing for Improved Drug Delivery across the Blood-Brain Barrier: A siRNA-Chitosan Approach

    PubMed Central

    Malmo, Jostein; Sandvig, Axel; Vårum, Kjell M.; Strand, Sabina P.

    2013-01-01

    The blood-brain barrier (BBB), composed of tightly organized endothelial cells, limits the availability of drugs to therapeutic targets in the central nervous system. The barrier is maintained by membrane bound efflux pumps efficiently transporting specific xenobiotics back into the blood. The efflux pump P-glycoprotein (P-gp), expressed at high levels in brain endothelial cells, has several drug substrates. Consequently, siRNA mediated silencing of the P-gp gene is one possible strategy how to improve the delivery of drugs to the brain. Herein, we investigated the potential of siRNA-chitosan nanoparticles in silencing P-gp in a BBB model. We show that the transfection of rat brain endothelial cells mediated effective knockdown of P-gp with subsequent decrease in P-gp substrate efflux. This resulted in increased cellular delivery and efficacy of the model drug doxorubicin. PMID:23372682

  20. A New Triglycyl Peptide Linker for Antibody-Drug Conjugates (ADCs) with Improved Targeted Killing of Cancer Cells.

    PubMed

    Singh, Rajeeva; Setiady, Yulius Y; Ponte, Jose; Kovtun, Yelena V; Lai, Katharine C; Hong, E Erica; Fishkin, Nathan; Dong, Ling; Jones, Gregory E; Coccia, Jennifer A; Lanieri, Leanne; Veale, Karen; Costoplus, Juliet A; Skaletskaya, Anna; Gabriel, Rabih; Salomon, Paulin; Wu, Rui; Qiu, Qifeng; Erickson, Hans K; Lambert, John M; Chari, Ravi V J; Widdison, Wayne C

    2016-06-01

    A triglycyl peptide linker (CX) was designed for use in antibody -: drug conjugates (ADC), aiming to provide efficient release and lysosomal efflux of cytotoxic catabolites within targeted cancer cells. ADCs comprising anti-epithelial cell adhesion molecule (anti-EpCAM) and anti-EGFR antibodies with maytansinoid payloads were prepared using CX or a noncleavable SMCC linker (CX and SMCC ADCs). The in vitro cytotoxic activities of CX and SMCC ADCs were similar for several cancer cell lines; however, the CX ADC was more active (5-100-fold lower IC50) than the SMCC ADC in other cell lines, including a multidrug-resistant line. Both CX and SMCC ADCs showed comparable MTDs and pharmacokinetics in CD-1 mice. In Calu-3 tumor xenografts, antitumor efficacy was observed with the anti-EpCAM CX ADC at a 5-fold lower dose than the corresponding SMCC ADC in vivo Similarly, the anti-EGFR CX ADC showed improved antitumor activity over the respective SMCC conjugate in HSC-2 and H1975 tumor models; however, both exhibited similar activity against FaDu xenografts. Mechanistically, in contrast with the charged lysine-linked catabolite of SMCC ADC, a significant fraction of the carboxylic acid catabolite of CX ADC could be uncharged in the acidic lysosomes, and thus diffuse out readily into the cytosol. Upon release from tumor cells, CX catabolites are charged at extracellular pH and do not penetrate and kill neighboring cells, similar to the SMCC catabolite. Overall, these data suggest that CX represents a promising linker option for the development of ADCs with improved therapeutic properties. Mol Cancer Ther; 15(6); 1311-20. ©2016 AACR. PMID:27197308

  1. Can mobile phone messages to drug sellers improve treatment of childhood diarrhoea?--A randomized controlled trial in Ghana.

    PubMed

    Friedman, Willa; Woodman, Benjamin; Chatterji, Minki

    2015-03-01

    Oral rehydration solution (ORS) and zinc are the recommended treatment in developing countries for the management of uncomplicated diarrhoea in children under five (World Health Organization and UNICEF 2004). However, drug sellers often recommend costly and unnecessary treatments instead. This article reports findings from an experiment to encourage licensed chemical sellers (LCS) in Ghana to recommend ORS and zinc for the management of childhood diarrhoea. The intervention consisted of mobile phone text messages (Short Message Service or SMS) sent to a randomly assigned group of LCS who had been trained on the diarrhoea management protocols recommended by the World Health Organization (WHO). The SMS campaign comprised informational messages and interactive quizzes sent over an 8-week period. The study measured the impact of the SMS messages on both reported and actual practices. Analysis of data from both face-to-face interviews and mystery client visits shows that the SMS intervention improved providers' self-reported practices but not their actual practices. The study also finds that actual practices deviate substantially from reported practices. PMID:25759456

  2. Improved oral bioavailability of capsaicin via liposomal nanoformulation: preparation, in vitro drug release and pharmacokinetics in rats.

    PubMed

    Zhu, Yuan; Wang, Miaomiao; Zhang, Jiajia; Peng, Wei; Firempong, Caleb Kesse; Deng, Wenwen; Wang, Qilong; Wang, Shicheng; Shi, Feng; Yu, Jiangnan; Xu, Ximing; Zhang, Weiming

    2015-04-01

    This study innovatively prepared an effective capsaicin-loaded liposome, a nanoformulation with fewer irritants, for oral administration. The in vitro and in vivo properties of the liposomal encapsulation were investigated and the potential possibility of oral administration evaluated. The liposomal agent composed of phospholipid, cholesterol, sodium cholate and isopropyl myristate was prepared using film-dispersion method. A level A in vitro-in vivo correlation (IVIVC) was established for the first time, which demonstrated an excellent IVIVC of both formulated and free capsaicin in oral administration. Physicochemical characterizations including mean particle size, zeta (ζ) potential and average encapsulation efficiency of capsaicin-loaded liposome were found to be 52.2 ± 1.3 nm, -41.5 ± 2.71 mv and 81.9 ± 2.43 %, respectively. In vivo, liposomal encapsulation allowed a 3.34-fold increase in relative bioavailability compared to free capsaicin. The gastric mucosa irritation studies indicated that the liposomal system was a safe carrier for oral administration. These results support the fact that capsaicin, an effective drug for the treatment of neuropathic pain, could be encapsulated in liposome for improved oral bioavailability. The excellent IVIVC of capsaicin-loaded liposome could also be a promising tool in liposomal formulation development with an added advantage of reduced animal testing. PMID:25231341

  3. Physical characterizations and sustained release profiling of gastroretentive drug delivery systems with improved floating and swelling capabilities.

    PubMed

    Chen, Ying-Chen; Ho, Hsiu-O; Lee, Tzu-Yu; Sheu, Ming-Thau

    2013-01-30

    The aim was to develop gastroretentive drug delivery systems (GRDDSs) by combining floating and swelling. GRDDS tablets formulated with hydroxyethylcellulose (HEC), chitosan (CS) and sodium bicarbonate (SB) for evaluating floating capacity (floating lag time and duration) and swelling characteristics. CS was used because it was swellable in acidic media and biocompatible. Losartan was incorporated into the optimized formulations for sustained release profiling. Results demonstrated that for those formulations at HEC:CS ratio of 5:5 containing CS, both the floating lag time and floating duration were optimal and reached the preferred swelling effect and sustain for 24h. Adding SB improved the floating capabilities for all ratios of HEC:CS, but reduced the swelling ability for those formulations containing a higher portion of low viscosity grade CS. Sustained release profiles for losartan in those formulations were achievable, using all viscosity grades of CS at all examined HEC:CS ratios; however, it is more adjustable at different HEC:CS ratios when using a lower viscosity grade of CS. Optimized GRDDS formulations for losartan composed of an equivalent ratio of HEC to CS with 20mg SB resulted in the tablets floating for more than 16 h and an adjustable sustained release profile. PMID:23237874

  4. Improved drug delivery properties of PVDF membranes functionalized with beta-cyclodextrin--application to guided tissue regeneration in periodontology.

    PubMed

    Boschin, F; Blanchemain, N; Bria, M; Delcourt-Debruyne, E; Morcellet, M; Hildebrand, H F; Martel, B

    2006-10-01

    The purpose of this study was to develop a membrane for guided tissue regeneration applicable in periodontology that could release antimicrobial agent during the healing period. Our strategy consisted to graft beta-cyclodextrin (beta-CD), a molecule that is known to form inclusion complexes with a large variety of drugs, onto PVDF membranes. Grafting occurred by using citric acid that provoked a crosslinking reaction of beta-CD, and the resulting polymer was imprisoned into the porous structure of the PVDF membrane. The reaction produced a weight increase of the membrane, the range of which depended on the temperature and on the time of curing applied in the process. The biological behavior of the membranes evaluated by proliferation and vitality tests showed good proliferation and improved activity of L132 epithelial cells on the raw and on the grafted membranes. Doxycyclin (DOX) and chlorhexidine (CHX) were used as antimicrobial agents. Their inclusion into the beta-CD cavity in aqueous solutions was confirmed by NMR spectroscopy. After the impregnation of the membranes with DOX and CHX, their release was studied in vitro in batch type experiments and measured by UV spectrophotometry. Low amounts of DOX and CHX were delivered from the raw membranes within the first few hours of tests. Grafted membranes, however, delivered DOX and CHX in larger quantities within 24 h and 10 days respectively. PMID:16758457

  5. Experience with the use of the Codonics Safe Label System(™) to improve labelling compliance of anaesthesia drugs.

    PubMed

    Ang, S B L; Hing, W C; Tung, S Y; Park, T

    2014-07-01

    The Codonics Safe Labeling System(™) (http://www.codonics.com/Products/SLS/flash/) is a piece of equipment that is able to barcode scan medications, read aloud the medication and the concentration and print a label of the appropriate concentration in the appropriate colour code. We decided to test this system in our facility to identify risks, benefits and usability. Our project comprised a baseline survey (25 anaesthesia cases during which 212 syringes were prepared from 223 drugs), an observational study (47 cases with 330 syringes prepared) and a user acceptability survey. The baseline compliance with all labelling requirements was 58%. In the observational study the compliance using the Codonics system was 98.6% versus 63.8% with conventional labelling. In the user acceptability survey the majority agreed the Codonics machine was easy to use, more legible and adhered with better security than the conventional preprinted label. However, most were neutral when asked about the likelihood of flexibility and customisation and were dissatisfied with the increased workload. Our findings suggest that the Codonics labelling machine is user-friendly and it improved syringe labelling compliance in our study. However, staff need to be willing to follow proper labelling workflow rather than batch label during preparation. Future syringe labelling equipment developers need to concentrate on user interface issues to reduce human factor and workflow problems. Support logistics are also an important consideration prior to implementation of any new labelling system. PMID:24967766

  6. Project Self-Esteem: A Parent Involvement Program for Improving Self-Esteem and Preventing Drug and Alcohol Abuse, K-6. Revised.

    ERIC Educational Resources Information Center

    McDaniel, Sandy; Bielen, Peggy

    This guide presents Project Self-Esteem, a program for improving self-esteem and preventing drug and alcohol abuse in kindergarten through grade 6. Chapter I presents the team leader's guide and discusses introducing the program to the principal, school staff, and parents. Chapter II focuses on kindergarten and includes lessons on being a friend…

  7. Ionotropic Cross-linked Carbo-protein Micro Matrix System: An Approach for Improvement of Drug Release, Compaction and Tableting behavior of Losartan Potassium.

    PubMed

    Khandai, Madhusmruti; Chakraborty, Santanu; Ghosh, Ashoke Kumar

    2015-01-01

    The aim of the present research work is to develop carbo-protein polymeric complex based sustain release microspheres of losartan potassium and investigate the ability of this dosage form to improve the flowability, compressibility and tableting properties of losartan potassium. The influence of silk sericin, alginate and its blend on various physicochemical parameters and in vitro drug release pattern were studied to optimize the concentration of polymeric blend required for 12 h. sustain release. Optimized batch was subjected to different flowability, compressibility and tableting properties studies to observe the effects of carbo-protein microspheres on flow properties. Results indicated that the concentration of sericin was found to be the main influential factor for prolonged drug release. Different micromeritic studies revealed that the poor flowability and compressibility properties of pure losartan potassium were significantly improved by this algino-sericin microspheric dosage form. Research findings also revealed that plasticity, die filling behavior and tableting properties of the pure drug were significantly improved by this microsphere formulation. So these prospective results concluded that carbo-protein polymeric microspheres helps to sustain the drug release for prolong hours as well as improve the flowability, compressibility and tableting properties of losartan potassium. PMID:25760869

  8. Roles of nonpolar and polar intermolecular interactions in the improvement of the drug loading capacity of PEO-b-PCL with increasing PCL content for two hydrophobic Cucurbitacin drugs.

    PubMed

    Patel, Sarthak K; Lavasanifar, Afsaneh; Choi, Phillip

    2009-09-14

    Molecular dynamics (MD) simulation was used to study the roles of nonpolar and polar intermolecular interactions in the improvement of the drug loading capacity of poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) with increasing PCL content for two water insoluble anticancer drugs: Cucurbitacin B (CuB) and Cucurbitacin I (CuI). In particular, random binary mixture models containing 10-12 wt % drug and remaining PEO-b-PCL with three different PCL/PEO (w/w) ratios (0.5, 1, and 2) were used to calculate their Flory-Huggins interaction parameters (chi). The MD simulation results show that, for both CuB and CuI, the computed chi decreases (i.e., affinity increases) with increasing PCL/PEO ratio. Such results are consistent with our experimental observation that increasing the PCL/PEO (w/w) ratio from 1 to 4.8 significantly increases the drug loading capacity of micelles formed by PEO-b-PCL for both drugs. Analysis of the energy data shows that increasing affinity (loading) at higher PCL/PEO ratio is attributed to the increase in favorable polar interactions and to the formation of additional hydrogen bonds (H-bonds) between the drugs and the PCL block rather than to the increase in the hydrophobic characteristics of the diblock copolymer as one would normally expect. In fact, the nonpolar intermolecular interactions became more unfavorable at higher PCL/PEO ratio. Analysis of the radial distribution functions of the model mixtures indicates that at high PCL/PEO ratio, multiple H-bond sites on the PCL block interacted with single H-bond sites on the drug molecules. However, at low PCL/PEO ratio, only single H-bonds formed between various H-bond sites on the drug molecules and those of the PCL and PEO blocks. It seems that formation of H-bonds between multiple H-bond sites on the PCL block and single H-bond sites on the drug molecules is responsible for inducing drug/PEO-b-PCL affinity. The finding also explains the experimental observation that release rates

  9. Understanding the Assessment of Psychotropic Drug Harms in Clinical Trials to Improve Social Workers' Role in Medication Monitoring

    ERIC Educational Resources Information Center

    Hughes, Shannon; Cohen, David

    2010-01-01

    The purpose of this integrative review is to facilitate social work practitioners' understanding of how psychotropic drug harms are assessed in clinical trials and to make specific suggestions for social workers' increased involvement in detecting drug harms in their clients. The authors undertook a comprehensive review of interdisciplinary…

  10. Inhibition of Lysyl Oxidases Improves Drug Diffusion and Increases Efficacy of Cytotoxic Treatment in 3D Tumor Models

    PubMed Central

    Schütze, Friedrich; Röhrig, Florian; Vorlová, Sandra; Gätzner, Sabine; Kuhn, Anja; Ergün, Süleyman; Henke, Erik

    2015-01-01

    Tumors are characterized by a rigid, highly cross-linked extracellular matrix (ECM), which impedes homogeneous drug distribution and potentially protects malignant cells from exposure to therapeutics. Lysyl oxidases are major contributors to tissue stiffness and the elevated expression of these enzymes observed in most cancers might influence drug distribution and efficacy. We examined the effect of lysyl oxidases on drug distribution and efficacy in 3D in vitro assay systems. In our experiments elevated lysyl oxidase activity was responsible for reduced drug diffusion under hypoxic conditions and consequently impaired cytotoxicity of various chemotherapeutics. This effect was only observed in 3D settings but not in 2D-cell culture, confirming that lysyl oxidases affect drug efficacy by modification of the ECM and do not confer a direct desensitizing effect. Both drug diffusion and efficacy were strongly enhanced by inhibition of lysyl oxidases. The results from the in vitro experiments correlated with tumor drug distribution in vivo, and predicted response to therapeutics in murine tumor models. Our results demonstrate that lysyl oxidase activity modulates the physical barrier function of ECM for small molecule drugs influencing their therapeutic efficacy. Targeting this process has the potential to significantly enhance therapeutic efficacy in the treatment of malignant diseases. PMID:26620400

  11. ESI-Q-TOF structural characterization of prominent MS/MS product ions of veterinary drugs for improved regulatory monitoring

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction The misuse of veterinary drugs in animal production could result in a negative impact on food safety, drug resistance, and in the environment. Consequently, countries around the world have regulated their use, which requires effective methods for the qualitative and quantitative residu...

  12. The Anti-Fasciolasis Properties of Silver Nanoparticles Produced by Trichoderma harzianum and Their Improvement of the Anti-Fasciolasis Drug Triclabendazole

    PubMed Central

    Gherbawy, Youssuf A.; Shalaby, Ismail M.; Abd El-sadek, Mahmoud Syed; Elhariry, Hesham M.; Banaja, AbdelElah A.

    2013-01-01

    Recently, new strains of Fasciola demonstrated drug resistance, which increased the need for new drugs or improvement of the present drugs. Nanotechnology is expected to open some new opportunities to fight and prevent diseases using an atomic scale tailoring of materials. The ability to uncover the structure and function of biosystems at the nanoscale, stimulates research leading to improvement in biology, biotechnology, medicine and healthcare. The size of nanomaterials is similar to that of most biological molecules and structures; therefore, nanomaterials can be useful for both in vivo and in vitro biomedical research and applications. Therefore, this work aimed to isolate fungal strains from Taif soil samples, which have the ability to synthesize silver nanoparticles. The fungus Trichoderma harzianum, when challenged with silver nitrate solution, accumulated silver nanoparticles (AgNBs) on the surface of its cell wall in 72 h. These nanoparticles, dislodged by ultrasonication, showed an absorption peak at 420 nm in a UV-visible spectrum, corresponding to the plasmon resonance of silver nanoparticles. The transmission electron micrographs of dislodged nanoparticles in aqueous solution showed the production of reasonably monodisperse silver nanoparticles (average particle size: 4.66 nm) by the fungus. The percentage of non hatching eggs treated with the Triclabendazole drug was 69.67%, while this percentage increased to 89.67% in combination with drug and AgNPs. PMID:24196355

  13. A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity

    SciTech Connect

    Kostadinova, Radina; Boess, Franziska; Suter, Laura; Weiser, Thomas; Singer, Thomas; Roth, Adrian

    2013-04-01

    observed in vivo. ► 3D liver co-cultures can detect species-specific drug toxicity observed in vivo. ► This in vitro model may improve assessment of human relevance of preclinical findings.

  14. Metal ion-assisted drug-loading model for novel delivery system of cisplatin solid lipid nanoparticles with improving loading efficiency and sustained release.

    PubMed

    Yang, Caiqin; Lv, Jie; Lv, Tao; Pan, Yahui; Han, Yazhu; Zhao, Sha; Wang, Jing

    2016-05-01

    Metal ion-assisted drug loading model, in which metal ion was used to modify the microstructure of lipid layer, has been developed to improve drug loading efficiency of solid lipid nanoparticles (SLNs). The microstructure and properties of metal ion-assisted cisplatin-loading SLNs were investigated by infra-red spectroscopy, fluorescence spectroscopy and zetasizer. The reactions of hydrogenated soybean lecithin with Zn(2+), Cu(2+), Mn(2+ )and Mg(2+ )have been detected; the mechanism for higher drug encapsulation efficiency (EE) has been investigated. In metal ion introduction SLNs, the compact degree of the lipid molecules was increased due to the electrostatic interaction between metal ions and phospholipid acyl and choline polarity groups, which result in increasing of drug EE. Meanwhile, these electrostatic interactions slowed the releasing rate of encapsulated drug. The study of cytotoxic activity in vitro indicated that the cell cytotoxicity of metal ions introduction SLNs depended on both cell uptake of SLNs and drug releasing from SLNs. PMID:27113257

  15. Rat Urinary Osteopontin and Neutrophil Gelatinase-Associated Lipocalin Improve Certainty of Detecting Drug-Induced Kidney Injury.

    PubMed

    Phillips, Jonathan A; Holder, Daniel J; Ennulat, Daniela; Gautier, Jean-Charles; Sauer, John-Michael; Yang, Yi; McDuffie, Eric; Sonee, Manisha; Gu, Yi-Zhong; Troth, Sean P; Lynch, Karen; Hamlin, Diane; Peters, David G; Brees, Dominique; Walker, Elizabeth G

    2016-06-01

    Traditional kidney biomarkers are insensitive indicators of acute kidney injury, with meaningful changes occurring late in the course of injury. The aim of this work was to demonstrate the diagnostic potential of urinary osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) for drug-induced kidney injury (DIKI) in rats using data from a recent regulatory qualification submission of translational DIKI biomarkers and to compare performance of NGAL and OPN to five previously qualified DIKI urinary biomarkers. Data were compiled from 15 studies of 11 different pharmaceuticals contributed by Critical Path Institute's Predictive Safety Testing Consortium (PSTC) Nephrotoxicity Working Group (NWG). Rats were given doses known to cause DIKI or other target organ toxicity, and urinary levels of the candidate biomarkers were assessed relative to kidney histopathology and serum creatinine (sCr) and blood urea nitrogen (BUN).OPN and NGAL outperformed sCr and BUN in identifying DIKI manifested as renal tubular epithelial degeneration or necrosis. In addition, urinary OPN and NGAL, when used with sCr and BUN, increased the ability to detect renal tubular epithelial degeneration or necrosis. NGAL and OPN had comparable or improved performance relative to Kim-1, clusterin, albumin, total protein, and beta-2 microglobulin. Given these data, both urinary OPN and NGAL are appropriate for use with current methods for assessing nephrotoxicity to identify and monitor DIKI in regulatory toxicology studies in rats. These data also support exploratory use of urinary OPN and NGAL in safety monitoring strategies of early clinical trials to aid in the assurance of patient safety. PMID:27026710

  16. Microemulsions containing long-chain oil ethyl oleate improve the oral bioavailability of piroxicam by increasing drug solubility and lymphatic transportation simultaneously.

    PubMed

    Xing, Qiao; Song, Jia; You, Xiuhua; Xu, Dongling; Wang, Kexin; Song, Jiaqi; Guo, Qin; Li, Pengyu; Wu, Chuanbin; Hu, Haiyan

    2016-09-25

    Drug solubility and lymphatic transport enhancements are two main pathways to improve drug oral bioavailability for microemulsions. However, it is not easy to have both achieved simultaneously because excipients used for improving lymphatic transport were usually insufficient in forming microemulsions and solubilizing drugs. Our research is to explore whether ethyl oleate, an oil effective in developing microemulsions with desired solubilizing capability, could increase bioavailability to a higher extent by enhancing lymphatic transport. As a long-chain oil, ethyl oleate won larger microemulsion area than short-chain tributyrin and medium-chain GTCC. In contrast, long-chain soybean oil failed to prepare microemulsions. The solubility of piroxicam in ethyl oleate microemulsions (ME-C) increased by about 30 times than in water. ME-C also won significantly higher AUC0-t compared with tributyrin microemulsions (ME-A) and GTCC microemulsions (ME-B). Oral bioavailability in ME-C decreased by 38% after lymphatic transport was blocked by cycloheximide, severer than those in ME-A and ME-B (8% and 34%). These results suggest that improving lymphatic transport and solubility simultaneously might be a novel strategy to increase drug oral bioavailability to a higher extent than increasing solubility only. Ethyl oleate is a preferred oil candidate due to its integrated advantages of high solubilizing capability, large microemulsion area and effective lymphatic transport. PMID:27473280

  17. Prescription for antibiotics at drug shops and strategies to improve quality of care and patient safety: a cross-sectional survey in the private sector in Uganda

    PubMed Central

    Mbonye, Anthony K; Buregyeya, Esther; Rutebemberwa, Elizeus; Clarke, Siân E; Lal, Sham; Hansen, Kristian S; Magnussen, Pascal; LaRussa, Philip

    2016-01-01

    Objectives The main objective of this study was to assess practices of antibiotic prescription at registered drug shops with a focus on upper respiratory tract infections among children in order to provide data for policy discussions aimed at improving quality of care and patient safety in the private health sector in Uganda. Methods A survey was conducted within 57 parishes from August to October 2014 in Mukono District, Uganda. Data was captured on the following variables: drug shop characteristics, training of staff in management of pneumonia, availability of guidelines and basic equipment, available antibiotics, knowledge on treatment of pneumonia in children aged <5 years. The main study outcome was the proportion of private health facilities prescribing an antibiotic. Results A total of 170 registered drug shops were surveyed between August and October 2014. The majority of drug shops, 93.5% were prescribing antibiotics, especially amoxicillin and trimethoprim-sulfamethoxazole (septrin). The professional qualification of a provider was significantly associated with this practice, p=0.04; where lower cadre staff (nursing assistants and enrolled nurses) overprescribed antibiotics. A third, 29.4% of drug shop providers reported that antibiotics were the first-line treatment for children with diarrhoea; yet the standard guideline is to give oral rehydration salts and zinc tablets. Only few providers, 8.2%, had training on antibiotics, with 10.6% on pneumonia case management. Further to this, 7.1% drug shops had WHO-Integrated Management of Childhood Illness guidelines, and a negligible proportion (<1%) had respiratory timers and baby weighing scales. Although the majority of providers, 82.4%, knew severe signs and symptoms of pneumonia, few, 17.6%, knew that amoxicillin was the first-line drug for treatment of pneumonia in children according to the guidelines. Conclusions There is urgent need to regulate drug shop practices of prescribing and selling

  18. Improving introspection to inform free will regarding the choice by healthy individuals to use or not use cognitive enhancing drugs

    PubMed Central

    Thaler, David S

    2009-01-01

    A commentary in Nature entitled "Towards responsible use of cognitive-enhancing drugs by the healthy" (Greely et al 2008 Nature 456: 702–705) offers an opportunity to move toward a humane societal appreciation of mind-altering drugs. Using cognitive enhancing drugs as an exemplar, this article presents a series of hypotheses concerning how an individual might learn optimal use. The essence of the proposal is that individuals can cultivate sensitivity to the effects of ever-smaller amounts of psychoactive drugs thereby making harm less likely and benign effects more probable. Four interrelated hypotheses are presented and briefly discussed. 1. Humans can learn to discriminate ever-smaller doses of at least some mind-altering drugs; a learning program can be designed or discovered that will have this outcome. 2. The skill to discriminate drugs and dose can be generalized, i.e. if learned with one drug a second one is easier and so on. 3. Cultivating this skill/knack would be beneficial in leading to choices informed by a more accurate sense of mind-body interactions. 4. From a philosophical point of view learning the effects of ever-smaller doses of psychoactive agents offers a novel path into and to transcend the objective/subjective barrier and the mind/body problem. Whatever the fate of these specific hypotheses, discussion of cognitive enhancing drugs for healthy individuals has the potential to inspire innovative educational and public policy initiatives toward all types of mind-altering drugs and the people who use them. PMID:19531231

  19. Comparison of drugs use according to surgical procedures as instrument for budgeting and improvement of prescription efficiency.

    PubMed

    Closon, M C

    1999-08-01

    Making an effort to control health expenditure's escalation, especially in hospital, the Belgian government is planning and experimenting with prospective budgeting. A research financed by the Ministry of Public Health allows us to point out the structure of the pathologies treated as well as other variables included in the medical MBDS like urgency, number of diseased systems, ... and explains a high percentage of the variance (62%) in drugs expenditures of the surgical cases. These variables have to be used in order to calibrate hospital drugs budgets. The Interdisciplinary Centre in Health Economics has developed tools to compare drugs prescriptions by type of surgical procedures in order to help hospitals to evaluate their performance should such drugs budgets be progressively introduced. PMID:10499395

  20. Formulation strategies to improve the bioavailability of poorly absorbed drugs with special emphasis on self-emulsifying systems.

    PubMed

    Gupta, Shweta; Kesarla, Rajesh; Omri, Abdelwahab

    2013-12-26

    Poorly water-soluble drug candidates are becoming more prevalent. It has been estimated that approximately 60-70% of the drug molecules are insufficiently soluble in aqueous media and/or have very low permeability to allow for their adequate and reproducible absorption from the gastrointestinal tract (GIT) following oral administration. Formulation scientists have to adopt various strategies to enhance their absorption. Lipidic formulations are found to be a promising approach to combat the challenges. In this review article, potential advantages and drawbacks of various conventional techniques and the newer approaches specifically the self-emulsifying systems are discussed. Various components of the self-emulsifying systems and their selection criteria are critically reviewed. The attempts of various scientists to transform the liquid self-emulsifying drug delivery systems (SEDDS) to solid-SEDDS by adsorption, spray drying, lyophilization, melt granulation, extrusion, and so forth to formulate various dosage forms like self emulsifying capsules, tablets, controlled release pellets, beads, microspheres, nanoparticles, suppositories, implants, and so forth have also been included. Formulation of SEDDS is a potential strategy to deliver new drug molecules with enhanced bioavailability mostly exhibiting poor aqueous solubility. The self-emulsifying system offers various advantages over other drug delivery systems having potential to solve various problems associated with drugs of all the classes of biopharmaceutical classification system (BCS). PMID:24459591

  1. Formulation Strategies to Improve the Bioavailability of Poorly Absorbed Drugs with Special Emphasis on Self-Emulsifying Systems

    PubMed Central

    Gupta, Shweta; Kesarla, Rajesh

    2013-01-01

    Poorly water-soluble drug candidates are becoming more prevalent. It has been estimated that approximately 60–70% of the drug molecules are insufficiently soluble in aqueous media and/or have very low permeability to allow for their adequate and reproducible absorption from the gastrointestinal tract (GIT) following oral administration. Formulation scientists have to adopt various strategies to enhance their absorption. Lipidic formulations are found to be a promising approach to combat the challenges. In this review article, potential advantages and drawbacks of various conventional techniques and the newer approaches specifically the self-emulsifying systems are discussed. Various components of the self-emulsifying systems and their selection criteria are critically reviewed. The attempts of various scientists to transform the liquid self-emulsifying drug delivery systems (SEDDS) to solid-SEDDS by adsorption, spray drying, lyophilization, melt granulation, extrusion, and so forth to formulate various dosage forms like self emulsifying capsules, tablets, controlled release pellets, beads, microspheres, nanoparticles, suppositories, implants, and so forth have also been included. Formulation of SEDDS is a potential strategy to deliver new drug molecules with enhanced bioavailability mostly exhibiting poor aqueous solubility. The self-emulsifying system offers various advantages over other drug delivery systems having potential to solve various problems associated with drugs of all the classes of biopharmaceutical classification system (BCS). PMID:24459591

  2. An improved method for the characterization of supersaturation and precipitation of poorly soluble drugs using pulsatile microdialysis (PMD).

    PubMed

    Shah, Kosha B; Patel, Piyush G; Khairuzzaman, Akm; Bellantone, Robert A

    2014-07-01

    In current pharmaceutical drug discovery, most candidates are poorly soluble in water, which can result in poor bioavailability. To overcome this problem, formulations that create supersaturation of the drug are a well-studied alternative. Characterizing the dissolution from these systems is challenging because conventional methods, such as sampling with a syringe then filtering with a 0.2-0.45 μm filter before an HPLC assay, can overestimate the concentration of dissolved drug by allowing nuclei or small precipitated particles to pass, which then dissolve in the HPLC mobile phase. Nuclei and small particles can also cause overestimation of the dissolved concentration when using optical methods. Such overestimations can lead to failure of in vivo prediction of drug bioavailability from supersaturated systems. This paper reports a novel method to determine the free dissolved drug concentration in a dissolution medium using pulsatile microdialysis (PMD). Ibuprofen was used as a model drug for determining precipitation and supersaturation. Supersaturation was induced chemically by changing pH, and also by dissolution/release from an in-house formulation. The adaptation of a previously developed PMD model is summarized, and experimental results comparing dissolved concentrations determined using PMD and direct sampling by syringe and filtering are presented. PMID:24709210

  3. Use of FMEA analysis to reduce risk of errors in prescribing and administering drugs in paediatric wards: a quality improvement report

    PubMed Central

    Lago, Paola; Bizzarri, Giancarlo; Scalzotto, Francesca; Parpaiola, Antonella; Amigoni, Angela; Putoto, Giovanni; Perilongo, Giorgio

    2012-01-01

    Objective Administering medication to hospitalised infants and children is a complex process at high risk of error. Failure mode and effect analysis (FMEA) is a proactive tool used to analyse risks, identify failures before they happen and prioritise remedial measures. To examine the hazards associated with the process of drug delivery to children, we performed a proactive risk-assessment analysis. Design and setting Five multidisciplinary teams, representing different divisions of the paediatric department at Padua University Hospital, were trained to analyse the drug-delivery process, to identify possible causes of failures and their potential effects, to calculate a risk priority number (RPN) for each failure and plan changes in practices. Primary outcome To identify higher-priority potential failure modes as defined by RPNs and planning changes in clinical practice to reduce the risk of patients harm and improve safety in the process of medication use in children. Results In all, 37 higher-priority potential failure modes and 71 associated causes and effects were identified. The highest RPNs related (>48) mainly to errors in calculating drug doses and concentrations. Many of these failure modes were found in all the five units, suggesting the presence of common targets for improvement, particularly in enhancing the safety of prescription and preparation of endovenous drugs. The introductions of new activities in the revised process of administering drugs allowed reducing the high-risk failure modes of 60%. Conclusions FMEA is an effective proactive risk-assessment tool useful to aid multidisciplinary groups in understanding a process care and identifying errors that may occur, prioritising remedial interventions and possibly enhancing the safety of drug delivery in children. PMID:23253870

  4. Improvements in access to malaria treatment in Tanzania after switch to artemisinin combination therapy and the introduction of accredited drug dispensing outlets - a provider perspective

    PubMed Central

    2010-01-01

    Background To improve access to treatment in the private retail sector a new class of outlets known as accredited drug dispensing outlets (ADDO) was created in Tanzania. Tanzania changed its first-line treatment for malaria from sulphadoxine-pyrimethamine (SP) to artemether-lumefantrine (ALu) in 2007. Subsidized ALu was made available in both health facilities and ADDOs. The effect of these interventions on access to malaria treatment was studied in rural Tanzania. Methods The study was carried out in the villages of Kilombero and Ulanga Demographic Surveillance System (DSS) and in Ifakara town. Data collection consisted of: 1) yearly censuses of shops selling drugs; 2) collection of monthly data on availability of anti-malarials in public health facilities; and 3) retail audits to measure anti-malarial sales volumes in all public, mission and private outlets. The data were complemented with DSS population data. Results Between 2004 and 2008 access to malaria treatment greatly improved and the number of anti-malarial treatment doses dispensed increased by 78%. Particular improvements were observed in the availability (from 0.24 shops per 1,000 people in 2004 to 0.39 in 2008) and accessibility (from 71% of households within 5 km of a shop in 2004 to 87% in 2008) of drug shops. Despite no improvements in affordability this resulted in an increase of the market share from 49% of anti-malarial sales 2005 to 59% in 2008. The change of treatment policy from SP to ALu led to severe stock-outs of SP in health facilities in the months leading up to the introduction of ALu (only 40% months in stock), but these were compensated by the wide availability of SP in shops. After the introduction of ALu stock levels of the drug were relatively high in public health facilities (over 80% months in stock), but the drug could only be found in 30% of drug shops and in no general shops. This resulted in a low overall utilization of the drug (19% of all anti-malarial sales) Conclusions

  5. Solid self-nanoemulsifying drug delivery system (S-SNEDDS) of darunavir for improved dissolution and oral bioavailability: In vitro and in vivo evaluation.

    PubMed

    Inugala, Spandana; Eedara, Basanth Babu; Sunkavalli, Sharath; Dhurke, Rajeshri; Kandadi, Prabhakar; Jukanti, Raju; Bandari, Suresh

    2015-07-10

    The current study was aimed to investigate the potential of solid self-nanoemulsifying drug delivery system (S-SNEDDS) composed of Capmul MCM C8 (oil), Tween 80 (surfactant) and Transcutol P (co-surfactant) in improving the dissolution and oral bioavailability of darunavir. Liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) were developed by using rational blends of components with good solubilizing ability for darunavir which were selected based on solubility studies, further ternary phase diagram was constructed to determine the self-emulsifying region. The prepared L-SNEDDS formulations were evaluated to determine the effect of composition on physicochemical parameters like rate of emulsification, clarity, phase separation, thermodynamic stability, cloud point temperature, globule size and zeta potential. In vitro drug release studies showed initial rapid release of about 13.3 ± 1.4% within 30 min from L-SNEDDS followed by slow continuous release of entrapped drug and reached a maximum of 62.6 ± 3.5% release at the end of 24h. The globule size analysis revealed the formation of nanoemulsion (144 ± 2.3 nm) from the optimized L-SNEDDS formulation and was physically adsorbed onto neusilin US2. In vitro dissolution studies indicated faster dissolution of darunavir from the developed S-SNEDDS with 3 times greater mean dissolution rate (MDR) compared to pure darunavir. Solid state studies concluded the presence of drug in non-crystalline amorphous state without any significant interaction of drug with the components of S-SNEDDS. Furthermore, in vivo pharmacokinetic studies in Wistar rats resulted in enhanced values of peak drug concentration (Cmax) for L-SNEDDS (2.98 ± 0.19 μg/mL) and S-SNEDDS (3.7 ± 0.28 μg/mL) compared to pure darunavir (1.57 ± 0.17 μg/mL). PMID:25845633

  6. 'Stealth' lipid-based formulations: poly(ethylene glycol)-mediated digestion inhibition improves oral bioavailability of a model poorly water soluble drug.

    PubMed

    Feeney, Orlagh M; Williams, Hywel D; Pouton, Colin W; Porter, Christopher J H

    2014-10-28

    supersaturation in comparison to digestible counterparts. This trend was also reflected in vivo, where the relative bioavailability of drug after administration in two stealth LBFs increased to 120% and 182% in comparison to analogous digestible (non-stealth) formulations. The results of the current study indicate that self-assembled "stealth" LBFs have potential as a novel means of improving LBF performance. PMID:25058571

  7. Dithranol-loaded lipid-core nanocapsules improve the photostability and reduce the in vitro irritation potential of this drug.

    PubMed

    Savian, Ana L; Rodrigues, Daiane; Weber, Julia; Ribeiro, Roseane F; Motta, Mariana H; Schaffazick, Scheila R; Adams, Andréa I H; de Andrade, Diego F; Beck, Ruy C R; da Silva, Cristiane B

    2015-01-01

    Dithranol is a very effective drug for the topical treatment of psoriasis. However, it has some adverse effects such as irritation and stain in the skin that make its application and patient adherence to treatment difficult. The aims of this work were to prepare and characterize dithranol-loaded nanocapsules as well as to evaluate the photostability and the irritation potential of these nanocarriers. Lipid-core nanocapsules containing dithranol (0.5 mg/mL) were prepared by interfacial deposition of preformed polymer. EDTA (0.05%) or ascorbic acid (0.02%) was used as antioxidants. After preparation, dithranol-loaded lipid-core nanocapsules showed satisfactory characteristics: drug content close to the theoretical concentration, encapsulation efficiency of about 100%, nanometric mean size (230-250 nm), polydispersity index below 0.25, negative zeta potential, and pH values from 4.3 to 5.6. In the photodegradation study against UVA light, we observed a higher stability of the dithranol-loaded lipid-core nanocapsules comparing to the solution containing the free drug (half-life times around 4 and 1h for the dithranol-loaded lipid-core nanocapsules and free drug solution containing EDTA, respectively; half-life times around 17 and 7h for the dithranol-loaded lipid-core nanocapsules and free drug solution containing ascorbic acid, respectively). Irritation test by HET-CAM method was conducted to evaluate the safety of the formulations. From the results it was found that the nanoencapsulation of the drug decreased its toxicity compared to the effects observed for the free drug. PMID:25491961

  8. Comparative evaluation of proliposomes and self micro-emulsifying drug delivery system for improved oral bioavailability of nisoldipine.

    PubMed

    Nekkanti, Vijaykumar; Rueda, Javier; Wang, Zhijun; Betageri, Guru V

    2016-05-30

    The objective of this study was to develop proliposomal formulation and self micro-emulsifying drug delivery system (SMEDDS) for a poorly bioavailable drug, nisoldipine and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin film hydration method using different lipids such as Soy phosphatidylcholine (SPC), Hydrogenated Soy phosphatidylcholine (HSPC), Dimyristoylphosphatidylcholine (DMPC) and Dimyristoyl phosphatidylglycerol sodium (DMPG), Distearyl phosphatidylcholine (DSPC), and Cholesterol in various ratios. SMEDDS formulations were prepared using varying concentrations of Capmul MCM, Labrasol, Cremophor EL and Tween 80. Both proliposomes and SMEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug release was carried out in purified water using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague-Dawley rats. Among the different formulations, proliposomes with drug:DMPC:cholesterol in the ratio of 1:2:0.5 and SMEDDS with Capmul MCM (13.04% w/w), Labrasol (36.96% w/w), Cremophor EL (34.78% w/w) and Tween 80 (15.22% w/w) demonstrated the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SMEDDS compared to pure nisoldipine in purified water after 1h. Nisoldipine permeability across PAMPA and everted rat intestinal perfusion models was significantly higher with proliposomes and SMEDDS. Following single oral administration of proliposomes and SMEDDS, a relative bioavailability of 301.11% and 239.87% respectively, was achieved compared to pure nisoldipine suspension. PMID:27041124

  9. Drug compartmentalization as strategy to improve the physico-chemical properties of diclofenac sodium loaded niosomes for topical applications.

    PubMed

    Tavano, Lorena; de Cindio, Bruno; Picci, Nevio; Ioele, Giuseppina; Muzzalupo, Rita

    2014-12-01

    The objective of this research was to study the effect of diclofenac sodium compartmentalization on the physico-chemical properties (such as size, drug entrapment efficiency and percutaneous permeation across rabbit skin) of niosomal vesicles used as carriers. Niosomes were prepared starting from nonionic commercial surfactants belonging to the class of Polysorbates and Pluronics: mixtures of Span 60/F127 and Tween 60/F127 at different ratios were used to obtain vesicles and all formulations were compared in terms of dimensions, morphology, polydispersity index and entrapment efficiency. Moreover, the enhancing effect of niosomes on the ex vivo percutaneous penetration of diclofenac sodium was investigated using Franz-type diffusion chambers and compared to that obtained by using the corresponding drug solution. Results demonstrated that niosomes were spherical and homogeneous in shape. Their size was found to be dependent on the hydrophile-lipophile balance of the surfactant mixture: increasing hydrophobicity resulted in smaller vesicles. Drug incorporation led to a significant variation in vesicle size dependently from the compartment in which the drug was located. The permeation of diclofenac from free solution used as control was found to be lower respect to that obtained for all niosomal formulations, that can be considered as percutaneous permeation enhancers. In particular, the results indicated that the highest cumulative amounts of diclofenac permeated across rabbit skin after 24 h were obtained by formulations in which the drug was located in the aqueous core. PMID:25129111

  10. New avenues for improving pancreatic ductal adenocarcinoma (PDAC) treatment: Selective stroma depletion combined with nano drug delivery.

    PubMed

    Bhaw-Luximon, Archana; Jhurry, Dhanjay

    2015-12-28

    The effectiveness of chemotherapy in PDAC is hampered by the dynamic interaction between stroma and cancer cell. The two opposing schools of thought - non-depletion of the stroma vs its depletion - to better drug efficacy are here discussed. Disrupting stroma-cancer cell interaction to reduce tumor progression and promote apoptosis is identified as the new direction of treatment for PDAC. Clinical data have shown that elimination of fibrosis and blockade of the Hedgehog pathway in stroma effectively promote drug delivery to tumor site and apoptosis. Reduced stiffness of ECM, lower fibrosis, higher permeability and higher blood flow after stroma depletion increase drug delivery. Combination strategies involving selective stroma depletion coupled with chemotherapy is currently proving to be the most efficient at clinical level. Striking the right balance between fibrosis depletion and angiogenesis promotion resulting in enhanced drug delivery and apoptosis is a major challenge. The use of nano drug delivery devices coupled with stroma depletion is emerging as the next phase treatment for PDAC. The breakthrough to combat PDAC will likely be a combination of early diagnosis and the emerging chemotherapy strategies. PMID:26415628

  11. Improve bile duct-targeted drug delivery and therapeutic efficacy for cholangiocarcinoma by cucurbitacin B loaded phospholipid complex modified with berberine hydrochloride.

    PubMed

    Cheng, Ling; Xu, Ping-hua; Shen, Bao-de; Shen, Gang; Li, Juan-juan; Qiu, Ling; Liu, Chao-yong; Yuan, Hai-long; Han, Jin

    2015-07-15

    In present study, a novel phospholipid complex loaded cucurbitacin B modified with berberine hydrochloride (CUB-PLC-BER) was prepared by a simple solvent evaporation method with the aim of improving bile duct-targeted drug delivery and therapeutic efficacy for cholangiocarcinoma (CC). The complex's physicochemical properties were systemically investigated in terms of scanning electron microscopy (SEM), x-ray diffraction (XRD) and infrared absorption spectroscopy (IR). In vivo and in vitro antitumor studies, CUB-PLC-BER and the unmodified cucurbitacin B-phospholipid complex (CUB-PLC) presented stronger antitumor efficacy against human cholangiocarcinoma cells (QBC939 cells) than free cucurbitacin B (CUB), while phospholipids (PL) itself had no significant toxicity. Besides that, CUB-PLC showed the advantage over the free CUB and CUB-PLC-BER with regard to the inhibition of tumor growth in vivo antitumor study. Failure to establish the orthotopic CC model, the study attempted to measure the level of CUB in plasma and in bile to explore bile duct-targeted effect indirectly. In the pharmacokinetics study in rats, the average values of Cmax and AUC0-8h of CUB-PLC-BER group in rat bile were higher than those of CUB-PLC, while an opposite result was found in plasma. Meanwhile, the Cmax, AUC0-8h and AUC0-24h of CUB were the least both in plasma and in bile. The results indicated that the CUB-PLC-BER tended to provide a high and prolonged drug concentration to bile duct, and PL played a central role in internalizing CUB into cells to improve the water insoluble drug's permeability, which was of great benefit to enhance the bioavailability of CUB and improve therapeutic efficacy of CC. These results elucidated the potential of CUB-PLC-BER as drug delivery system for improving bile duct-targeted and therapeutic efficacy for CC. PMID:25882012

  12. Zebrafish assessment of cognitive improvement and anxiolysis: Filling the gap between in vitro and rodent models for drug development

    PubMed Central

    Levin, Edward D.

    2015-01-01

    Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxiolytic drugs. They are economical and can provide a relatively quick indication of possible functional efficacy. In as much as they have a complex nervous system and elaborate behavioral repertoire, zebrafish can provide a good intermediate model between in vitro receptor and cell-based assays and classic mammalian models for drug screening. In addition, the variety of molecular tools available in zebrafish makes them outstanding models for helping to determine the neuromolecular mechanisms for psychoactive drugs. However, to use zebrafish as a translational model we must have validated, sensitive and efficient behavioral tests. In a series of studies, our lab has developed tests of cognitive function and stress response, which are sensitive to drug effects in a similar manner as rodent models and humans for cognitive enhancement and alleviating stress response. In particular, the three-chamber task for learning and memory was shown to be sensitive to the cognitive enhancing effects of nicotine and has been useful in helping to determine neural mechanisms crucial for nicotinic-induced cognitive enhancement. The novel tank diving test was shown to be a valid and efficient test of stress response. It is sensitive to the reduction of stress-related behaviors of the anxiolytic drugs diazepam and buspirone but not chlordiazepoxide. Nicotine also causes stress alleviating effects which can be interpreted as anxiolytic effects. Zebrafish models of behavioral pharmacology can be useful to efficiently screen test compounds for drug development and can be useful for helping to determine the mechanisms crucial for new therapeutic treatments of neurobehavioral impairments. PMID:21615262

  13. Encapsulation of zinc-rifampicin complex into transferrin-conjugated silver quantum-dots improves its antimycobacterial activity and stability and facilitates drug delivery into macrophages

    PubMed Central

    Pati, Rashmirekha; Sahu, Rojalin; Panda, Jagannath; Sonawane, Avinash

    2016-01-01

    In order to improve the chemotherapy of tuberculosis, there is an urgent need to enhance the efficacy of existing agents and also to develop more efficient drug delivery systems. Here, we synthesized a novel anti-TB drug complex consisting of zinc and rifampicin (Zn-RIF), and encapsulated it into transferrin-conjugated silver quantum-dots (Zn-RIF-Tf-QD) to improve delivery in macrophages. Successful synthesis of Zn-RIF and Zn-RIF-Tf-QD was confirmed by UV/Vis-spectroscopy, TEM, FTIR, photoluminescence, XRD, XPS, and NMR. The sizes of silver QDs and transferrin-conjugated QDs were found to be in the range of 5–20 nm. Activity assays showed that Zn-RIF-Tf-QD exhibited 10-fold higher antibacterial activity against Mycobacterium smegmatis and Mycobacterium bovis-BCG as compared to Zn-RIF, RIF and Zn. Immunofluorescence studies showed that Zn-RIF-Tf-QD-conjugates were actively endocytosed by macrophages and dendritic cells, but not by lung epithelial cells. Treatment with Zn-RIF-Tf-QD efficiently killed mycobacteria residing inside macrophages without exhibiting cytotoxicity and genotoxicity. Moreover, the conjugates remained stable for upto 48 h, were taken up into the late endosomal compartment of macrophages, and released the drug in a sustainable manner. Our data demonstrate that Zn-RIF-Tf-QDs have a great potential as anti-TB drugs. In addition, transferrin-conjugated QDs may constitute an effective drug delivery system for tuberculosis therapy. PMID:27113139

  14. Encapsulation of zinc-rifampicin complex into transferrin-conjugated silver quantum-dots improves its antimycobacterial activity and stability and facilitates drug delivery into macrophages.

    PubMed

    Pati, Rashmirekha; Sahu, Rojalin; Panda, Jagannath; Sonawane, Avinash

    2016-01-01

    In order to improve the chemotherapy of tuberculosis, there is an urgent need to enhance the efficacy of existing agents and also to develop more efficient drug delivery systems. Here, we synthesized a novel anti-TB drug complex consisting of zinc and rifampicin (Zn-RIF), and encapsulated it into transferrin-conjugated silver quantum-dots (Zn-RIF-Tf-QD) to improve delivery in macrophages. Successful synthesis of Zn-RIF and Zn-RIF-Tf-QD was confirmed by UV/Vis-spectroscopy, TEM, FTIR, photoluminescence, XRD, XPS, and NMR. The sizes of silver QDs and transferrin-conjugated QDs were found to be in the range of 5-20 nm. Activity assays showed that Zn-RIF-Tf-QD exhibited 10-fold higher antibacterial activity against Mycobacterium smegmatis and Mycobacterium bovis-BCG as compared to Zn-RIF, RIF and Zn. Immunofluorescence studies showed that Zn-RIF-Tf-QD-conjugates were actively endocytosed by macrophages and dendritic cells, but not by lung epithelial cells. Treatment with Zn-RIF-Tf-QD efficiently killed mycobacteria residing inside macrophages without exhibiting cytotoxicity and genotoxicity. Moreover, the conjugates remained stable for upto 48 h, were taken up into the late endosomal compartment of macrophages, and released the drug in a sustainable manner. Our data demonstrate that Zn-RIF-Tf-QDs have a great potential as anti-TB drugs. In addition, transferrin-conjugated QDs may constitute an effective drug delivery system for tuberculosis therapy. PMID:27113139

  15. Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.

    PubMed

    Mook, Robert A; Wang, Jiangbo; Ren, Xiu-Rong; Chen, Minyong; Spasojevic, Ivan; Barak, Larry S; Lyerly, H Kim; Chen, Wei

    2015-09-01

    The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic

  16. Ordered nanoporous silica as carriers for improved delivery of water insoluble drugs: a comparative study between three dimensional and two dimensional macroporous silica

    PubMed Central

    Wang, Ying; Zhao, Qinfu; Hu, Yanchen; Sun, Lizhang; Bai, Ling; Jiang, Tongying; Wang, Siling

    2013-01-01

    The goal of the present study was to compare the drug release properties and stability of the nanoporous silica with different pore architectures as a matrix for improved delivery of poorly soluble drugs. For this purpose, three dimensional ordered macroporous (3DOM) silica with 3D continuous and interconnected macropores of different sizes (200 nm and 500 nm) and classic mesoporous silica (ie, Mobil Composition of Matter [MCM]-41 and Santa Barbara Amorphous [SBA]-15) with well-ordered two dimensional (2D) cylindrical mesopores were successfully fabricated and then loaded with the model drug indomethacin (IMC) via the solvent deposition method. Scanning electron microscopy (SEM), N2 adsorption, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were applied to systematically characterize all IMC-loaded nanoporous silica formulations, evidencing the successful inclusion of IMC into nanopores, the reduced crystallinity, and finally accelerated dissolution of IMC. It was worth mentioning that, in comparison to 2D mesoporous silica, 3DOM silica displayed a more rapid release profile, which may be ascribed to the 3D interconnected pore networks and the highly accessible surface areas. The results obtained from the stability test indicated that the amorphous state of IMC entrapped in the 2D mesoporous silica (SBA-15 and MCM-41) has a better physical stability than in that of 3DOM silica. Moreover, the dissolution rate and stability of IMC loaded in 3DOM silica was closely related to the pore size of macroporous silica. The colorimetric 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Cell Counting Kit (CCK)-8 assays in combination with direct morphology observations demonstrated the good biocompatibility of nanoporous silica, especially for 3DOM silica and SBA-15. The present work encourages further study of the drug release properties and stability of drug entrapped in different pore architecture of silica in order to realize

  17. Setting and Improving Policies for Reducing Alcohol and Other Drug Problems on Campus. A Guide for Administrators

    ERIC Educational Resources Information Center

    DeJong, William; Langenbahn, Stacia

    This guide for administrators provides a step-by-step process for establishing new or revised policies to deal with student misuse of alcohol and other drugs on college campuses. Emphasis is on a new doctrine of environmental management which stresses the school's responsibility to take measures against foreseeable hazards and risks in the school…

  18. Community Impact of Pharmacy-Randomized Intervention to Improve Access to Syringes and Services for Injection Drug Users

    ERIC Educational Resources Information Center

    Crawford, Natalie D.; Amesty, Silvia; Rivera, Alexis V.; Harripersaud, Katherine; Turner, Alezandria; Fuller, Crystal M.

    2014-01-01

    Objectives: In an effort to reduce HIV transmission among injection drug users (IDUs), New York State deregulated pharmacy syringe sales in 2001 through the Expanded Syringe Access Program by removing the requirement of a prescription. With evidence suggesting pharmacists' ability to expand their public health role, a structural,…

  19. Perhaps More Consideration of Pavlovian–Operant Interaction May Improve the Clinical Efficacy of Behaviorally Based Drug Treatment Programs

    PubMed Central

    Troisi, Joseph R.

    2014-01-01

    Drug abuse remains costly. Drug-related cues can evoke cue-reactivity and craving, contributing to relapse. The Pavlovian extinction-based cue-exposure therapy (CET) has not been very successful in treating drug abuse. A functional operant analysis of complex rituals involved in CET is outlined and reinterpreted as an operant heterogeneous chain maintained by observing responses, conditioned reinforcers, and discriminative stimuli. It is further noted that operant functions are not predicated on Pavlovian processes but can be influenced by them in contributing to relapse; several empirical studies from the animal and human literature highlight this view. Cue-reactivity evoked by Pavlovian processes is conceptualized as an operant establishing/motivating operation. CET may be more effective in incorporating an operant-based approach that takes into account the complexity of Pavlovian–operant interaction. Extinction of the operant chain coupled with the shaping of alternative behaviors is proposed as an integrated therapy. It is proposed that operant-based drug abuse treatments (contingency management, voucher programs, and the therapeutic work environment) might consider incorporating cue-reactivity, as establishing/motivating operations, to increase long-term success—a hybrid approach based on Pavlovian–operant interaction. PMID:25346551

  20. Non-Drug Interventions for Improving Classroom Behavior and Social Functioning of Young Children with Attention Deficit Hyperactivity Disorder.

    ERIC Educational Resources Information Center

    Radcliff, David

    This paper explores research on use of medication and non-drug interventions to modify the behavior of preschool children with attention deficit hyperactivity disorder (ADHD). It begins by discussing the symptoms of ADHD, neurological differences between children with ADHD and those without ADHD, and expected adolescent and adult outcomes for…

  1. Aqueous coating dispersion (pseudolatex) of zein improves formulation of sustained-release tablets containing very water-soluble drug.

    PubMed

    Li, X N; Guo, H X; Heinamaki, J

    2010-05-01

    Zein is an alcohol soluble protein of corn origin that exhibits hydrophobic properties. Pseudolatexes are colloidal dispersions containing spherical solid or semisolid particles less than 1 microm in diameter and can be prepared from any existing thermoplastic water-insoluble polymer. The novel plasticized film-coating pseudolatex of zein was studied in formulation of sustained-release tablets containing very water-soluble drug. Film formation of plasticized aqueous dispersion was compared with film forming properties of plasticized organic solvent system (ethanol) of zein. The water vapor permeability (WVP), water uptake and erosion, and moisture sorption were evaluated with free films. The tablets containing metoprolol tartrate as a model drug were used in pan-coating experiments. Aqueous film coatings plasticized with PEG 400 exhibited very low water uptake. No significant difference in WVP, moisture sorption and erosion were found between aqueous films and organic solvent-based films of zein plasticized with PEG 400. The atomic force microscopy (AFM) images on microstructure of films showed that colloidal particle size of zein in the aqueous films was smaller than that observed in the solvent-based films. In addition, the aqueous-based films were more compact and smoother than the respective solvent-based films. The aqueous zein-coated tablets containing very water-soluble drug (metoprolol tartrate) exhibited clear sustained-release dissolution profiles in vitro, while the respective solvent-based film-coated tablets showed much faster drug release. Furthermore, aqueous zein-coated tablets had lower water absorption at high humidity conditions. In conclusion, the plasticized aqueous dispersion (pseudolatex) of zein can be used for moisture resistant film coating of sustained-release tablets containing very water-soluble drug. PMID:20129615

  2. Antibody-Drug Conjugates (ADCs) Derived from Interchain Cysteine Cross-Linking Demonstrate Improved Homogeneity and Other Pharmacological Properties over Conventional Heterogeneous ADCs.

    PubMed

    Behrens, Christopher R; Ha, Edward H; Chinn, Lawrence L; Bowers, Simeon; Probst, Gary; Fitch-Bruhns, Maureen; Monteon, Jorge; Valdiosera, Amanda; Bermudez, Abel; Liao-Chan, Sindy; Wong, Tiffany; Melnick, Jonathan; Theunissen, Jan-Willem; Flory, Mark R; Houser, Derrick; Venstrom, Kristy; Levashova, Zoia; Sauer, Paul; Migone, Thi-Sau; van der Horst, Edward H; Halcomb, Randall L; Jackson, David Y

    2015-11-01

    Conventional antibody-drug conjugates (ADCs) are heterogeneous mixtures of chemically distinct molecules that vary in both drugs/antibody (DAR) and conjugation sites. Suboptimal properties of heterogeneous ADCs have led to new site-specific conjugation methods for improving ADC homogeneity. Most site-specific methods require extensive antibody engineering to identify optimal conjugation sites and introduce unique functional groups for conjugation with appropriately modified linkers. Alternative nonrecombinant methods have emerged in which bifunctional linkers are utilized to cross-link antibody interchain cysteines and afford ADCs containing four drugs/antibody. Although these methods have been shown to improve ADC homogeneity and stability in vitro, their effect on the pharmacological properties of ADCs in vivo is unknown. In order to determine the relative impact of interchain cysteine cross-linking on the therapeutic window and other properties of ADCs in vivo, we synthesized a derivative of the known ADC payload, MC-MMAF, that contains a bifunctional dibromomaleimide (DBM) linker instead of a conventional maleimide (MC) linker. The DBM-MMAF derivative was conjugated to trastuzumab and a novel anti-CD98 antibody to afford ADCs containing predominantly four drugs/antibody. The pharmacological properties of the resulting cross-linked ADCs were compared with analogous heterogeneous ADCs derived from conventional linkers. The results demonstrate that DBM linkers can be applied directly to native antibodies, without antibody engineering, to yield highly homogeneous ADCs via cysteine cross-linking. The resulting ADCs demonstrate improved pharmacokinetics, superior efficacy, and reduced toxicity in vivo compared to analogous conventional heterogeneous ADCs. PMID:26393951

  3. Preparation and characterization of aligned porous PCL/zein scaffolds as drug delivery systems via improved unidirectional freeze-drying method.

    PubMed

    Fereshteh, Zeinab; Fathi, Mohammadhossein; Bagri, Akbar; Boccaccini, Aldo R

    2016-11-01

    A novel type of drug-delivery scaffold based on poly(ε-caprolactone) (PCL) and zein blends was prepared by improved unidirectional freeze-drying. Scaffolds with tube-like pore structure and high porosity, up to 89%, were obtained by adjusting the concentration of the PCL and zein solutions. Characters of the prepared scaffolds, such as microstructural, porosity, and compressive strength, were evaluated. The hydrophilicity and the degradability of the composite films were investigated in contact with phosphate buffer saline (PBS). It was found that the presence of zein accelerates the degradation rate of the scaffolds in the period time of investigation (28days). The results showed an acceptable way for controlling the in vitro degradation behavior of PCL composite scaffolds by adapting the concentration of zein. In vitro protein release and degradation results revealed that the absolute weight loss of the PCL/zein scaffolds exhibited an increasing trend by increasing the amount of zein concentration in the scaffolds. The drug delivery capability of the scaffolds was tested using tetracycline hydrochloride (TCH). Sustained release of the drug was obtained, and it was found that the proportion of zein in the scaffold had a great impact on the drug release kinetics. The results demonstrated the potential of the PCL/zein biocomposite scaffolds as a suitable candidate in tissue engineering strategies for bone defect treatment. PMID:27524061

  4. Adverse drug reactions in veterinary patients associated with drug transporters.

    PubMed

    Mealey, Katrina L

    2013-09-01

    For many drugs used in veterinary practice, plasma and tissue concentrations are highly dependent on the activity of drug transporters. This article describes how functional changes in drug transporters, whether mediated by genetic variability or drug-drug interactions, affect drug disposition and, ultimately, drug safety and efficacy in veterinary patients. A greater understanding of species, breed, and individual (genetic) differences in drug transporter function, as well as drug-drug interactions involving drug transporters, will result in improved strategies for drug design and will enable veterinarians to incorporate individualized medicine in their practices. PMID:23890239

  5. Improvement of biodistribution and therapeutic index via increase of polyethylene glycol on drug-carrying liposomes in an HT-29/luc xenografted mouse model.

    PubMed

    Chow, Tong-Hsien; Lin, Yi-Yu; Hwang, Jeng-Jong; Wang, Hsin-Ell; Tseng, Yun-Long; Wang, Shyh-Jen; Liu, Ren-Shyan; Lin, Wuu-Jyh; Yang, Chung-Shi; Ting, Gann

    2009-06-01

    Liposomes modified with a high concentration of polyethylene glycol (PEG) could significantly prolong the retention time of the carried drug in the circulation, thus improving the drug accumulation in the tumor. In this study, 6 mol% rather than 0.9 mol% PEGylated liposomes (100 nm in diameter) encapsulated with indium-111 were used in a human colorectal carcinoma HT-29/luc tumor-bearing mouse model for comparing the PEGylation effect. Pharmacokinetics, biodistribution, passive-targeted assay, bioluminescence imaging (BLI) and tumor growth measurements were used for the spatial and temporal distribution, tumor localization and therapeutic evaluation of the drug. Pharmacokinetic studies indicated that the terminal half-life (T((1/2))lambdaz) and C(max) of 6 mol% PEG (111)In liposomes were similar to those of 0.9 mol% PEG (111)In liposomes. In the blood, the total body clearance (Cl) of 6 mol% PEG (111)In liposomes was about 1.7-fold lower and the area under the curve (AUC) was 1.7-fold higher than those of 0.9 mol% PEG (111)In liposomes. These results showed that the long-term circulation and localization of 6 mol% PEGylated liposomes was more appropriate for use in the tumor-bearing animal model. In addition, the biodistribution of 6 mol% PEG (111)In liposomes showed significantly lower uptake in the liver, spleen, kidneys, small intestine and bone marrow than those of 0.9 mol% PEG (111)In liposomes. The clearance rate of both drugs from the blood decreased with time, with the maximum at 24 h post intravenous (i.v.) injection. Prominent tumor uptake and the highest tumor/muscle ratios were found at 48 h post injection. Both AUC and relative ratio of the AUCs (RR-AUC) also showed that 6 mol% PEGylated liposomes significantly reduced the uptake of drugs in the reticuloendothelial system (RES), yet enhanced the uptake in the tumor. Gamma scintigraphy at 48 h post injection also demonstrated more distinct tumor uptake with 6 mol% PEG (111)In liposomes as compared to

  6. β-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy.

    PubMed

    Zhang, Ling; Chen, Zhen; Yang, Kuan; Liu, Chun; Gao, Jinming; Qian, Feng

    2015-11-01

    β-Lapachone (LPC) is a novel cytotoxic agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme elevated in a variety of tumors, such as non-small cell lung cancer (NSCLC), pancreatic cancer, liver cancer, and breast cancer. Despite its unique mechanism of action, its clinical evaluation has been largely hindered by low water solubility, short blood half-life, and narrow therapeutic window. Although encapsulation into poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-PLA) micelles could modestly improve its solubility and prolong its half-life, the extremely fast intrinsic crystallization tendency of LPC prevents drug loading higher than ∼2 wt %. The physical stability of the LPC-loaded micelles is also far from satisfactory for further development. In this study, we demonstrate that paclitaxel (PTX), a front-line drug for many cancers, can provide two functions when coencapsulated together with LPC in the PEG-PLA micelles; first, as a strong crystallization inhibitor for LPC, thus to significantly increase the LPC encapsulation efficiency in the micelle from 11.7 ± 2.4% to 100.7 ± 2.2%. The total drug loading efficiency of both PTX and LPC in the combination polymeric micelle reached 100.3 ± 3.0%, and the drug loading density reached 33.2 ± 1.0%. Second, the combination of LPC/PTX demonstrates strong synergistic cytotoxicity effect against the NQO1 overexpressing cancer cells, including A549 NSCLC cells, and several pancreatic cancer cells (combination index <1). In vitro drug release study showed that LPC was released faster than PTX either in phosphate-buffered saline (PH = 7.4) or in 1 M sodium salicylate, which agrees with the desired dosing sequence of the two drugs to exert synergistic pharmacologic effect at different cell checkpoints. The PEG-PLA micelles coloaded with LPC and PTX offer a novel nanotherapeutic, with high drug loading, sufficient physical stability, and biological synergy to increase drug delivery efficiency

  7. Drugs, nutrients, and phytoactive principles improving the health span of rodent models of human age-related diseases.

    PubMed

    Lebel, Michel; Picard, Frédéric; Ferland, Guylaine; Gaudreau, Pierrette

    2012-02-01

    Rodents are often the species of choice to examine the effect of drugs on survival and on the progression of specific diseased tissues. This statement is also true for research laboratories working in the field of nutrition and aging. In addition to diets that can reduce the life expectancy of rodents, such as diabetogenic or high-fat diets, genetically modified rodents exhibiting different accelerated age-associated diseases also provide important biologic tools to decipher the impact of drugs, nutrients, or phytoactive compounds on their health and life span. This review covers some of the chemicals believed to decelerate the appearance of age-related diseases in different rodent models. Such chemicals include antioxidants, anti-inflammatory molecules, modulators of metabolic sensors, calorie restriction mimetics, and vegetal polyphenolic compounds that affect mitochondrial functions, cellular proliferation or differentiation as well as cell functionality. PMID:21393422

  8. Formulation and statistical optimization of self-microemulsifying drug delivery system of eprosartan mesylate for improvement of oral bioavailability.

    PubMed

    Dangre, Pankaj; Gilhotra, Ritu; Dhole, Shashikant

    2016-10-01

    The present investigation is aimed to design a statistically optimized self-microemulsifying drug delivery system (SMEDDS) of eprosartan mesylate (EM). Preliminary screening was carried out to find a suitable combination of various excipients for the formulation. A 3(2) full factorial design was employed to determine the effect of various independent variables on dependent (response) variables. The independent variables studied in the present work were concentration of oil (X 1) and the ratio of S mix (X 2), whereas the dependent variables were emulsification time (s), globule size (nm), polydispersity index (pdi), and zeta potential (mV), and the multiple linear regression analysis (MLRA) was employed to understand the influence of independent variables on dependent variables. Furthermore, a numerical optimization technique using the desirability function was used to develop a new optimized formulation with desired values of dependent variables. The optimized SMEDDS formulation of eprosartan mesylate (EMF-O) by the above method exhibited emulsification time, 118.45 ± 1.64 s; globule size, 196.81 ± 1.29 nm; zeta potential, -9.34 ± 1.2 mV, and polydispersity index, 0.354 ± 0.02. For the in vitro dissolution study, the optimized formulation (EMF-O) and pure drug were separately entrapped in the dialysis bag, and the study indicated higher release of the drug from EMF-O. In vivo pharmacokinetic studies in Wistar rats using PK solver software revealed 2.1-fold increment in oral bioavailability of EM from EMF-O, when compared with plain suspension of pure drug. PMID:27465619

  9. Glycan-mediated uptake in urothelial primary cells: Perspectives for improved intravesical drug delivery in urinary tract infections.

    PubMed

    Pichl, Clara Maria; Feilhauer, Sophie; Schwaigerlehner, Rose-Marie; Gabor, Franz; Wirth, Michael; Neutsch, Lukas

    2015-11-30

    Urinary tract infections (UTIs) are among the most common bacterial infections. Despite a wide range of therapeutic options, treatment success is compromised by multiresistance and the efficient mechanism of tissue colonization of uropathogenic Escherichia coli (UPEC). In advanced drug delivery systems, a similar, glycan-mediated targeting mechanism may be realized by conjugating the drug to a plant lectin. This may lead to the drug being more efficiently accumulated at the desired site of action, the bacterial reservoirs. In this study, we aimed at elucidating the potential of this biorecognitive approach. Glycan-triggered interaction cascades and uptake processes of several plant lectins with distinct carbohydrate specificities were characterized using single cells and monolayer culture. Due to pronounced cytoadhesive and cytoinvasive properties, wheat germ agglutinin (WGA) emerged as a promising targeter in porcine urothelial primary cells. The lectin-cell interaction proved highly stabile in artificial urine, simulating the conditions in actual application. Colocalisation studies with internalized WGA and lens culinaris agglutinin (LCA) revealed that intracellular accumulation sites were largely identical for GlcNAc- and Mannose-specific lectins. This indicates that WGA-mediated delivery may indeed constitute a potent tool to reach bacteria taken up via a FimH-triggered invasion process. Existing pitfalls in intravesical treatment schedules may soon be overcome. PMID:26383837

  10. A poly(ether-ester) copolymer for the preparation of nanocarriers with improved degradation and drug delivery kinetics.

    PubMed

    Gagliardi, M; Bertero, A; Bardi, G; Bifone, A

    2016-02-01

    This paper reports the synthesis and the physicochemical, functional and biological characterisations of nanocarriers made of a novel di-block biodegradable poly(ether-ester) copolymer. This material presents tunable, fast biodegradation rates, but its products are less acidic than those of other biosorbable polymers like PLGA, thus presenting a better biocompatibility profile and the possibility to carry pH-sensitive payloads. A method for the production of monodisperse and spherical nanoparticles is proposed; drug delivery kinetics and blood protein adsorption were measured to evaluate the functional properties of these nanoparticles as drug carriers. The copolymer was labelled with a fluorescent dye for internalisation tests, and rhodamine B was used as a model cargo to study transport and release inside cultured cells. Biological tests demonstrated good cytocompatibility, significant cell internalisation and the possibility to vehiculate non-cell penetrating moieties into endothelial cells. Taken together, these results support the potential use of this nanoparticulate system for systemic administration of drugs. PMID:26652400

  11. Integrating risk minimization planning throughout the clinical development and commercialization lifecycle: an opinion on how drug development could be improved.

    PubMed

    Morrato, Elaine H; Smith, Meredith Y

    2015-01-01

    Pharmaceutical risk minimization programs are now an established requirement in the regulatory landscape. However, pharmaceutical companies have been slow to recognize and embrace the significant potential these programs offer in terms of enhancing trust with health care professionals and patients, and for providing a mechanism for bringing products to the market that might not otherwise have been approved. Pitfalls of the current drug development process include risk minimization programs that are not data driven; missed opportunities to incorporate pragmatic methods and market-based insights, outmoded tools and data sources, lack of rapid evaluative learning to support timely adaption, lack of systematic approaches for patient engagement, and questions on staffing and organizational infrastructure. We propose better integration of risk minimization with clinical drug development and commercialization work streams throughout the product lifecycle. We articulate a vision and propose broad adoption of organizational models for incorporating risk minimization expertise into the drug development process. Three organizational models are discussed and compared: outsource/external vendor, embedded risk management specialist model, and Center of Excellence. PMID:25750537

  12. Integrating risk minimization planning throughout the clinical development and commercialization lifecycle: an opinion on how drug development could be improved

    PubMed Central

    Morrato, Elaine H; Smith, Meredith Y

    2015-01-01

    Pharmaceutical risk minimization programs are now an established requirement in the regulatory landscape. However, pharmaceutical companies have been slow to recognize and embrace the significant potential these programs offer in terms of enhancing trust with health care professionals and patients, and for providing a mechanism for bringing products to the market that might not otherwise have been approved. Pitfalls of the current drug development process include risk minimization programs that are not data driven; missed opportunities to incorporate pragmatic methods and market-based insights, outmoded tools and data sources, lack of rapid evaluative learning to support timely adaption, lack of systematic approaches for patient engagement, and questions on staffing and organizational infrastructure. We propose better integration of risk minimization with clinical drug development and commercialization work streams throughout the product lifecycle. We articulate a vision and propose broad adoption of organizational models for incorporating risk minimization expertise into the drug development process. Three organizational models are discussed and compared: outsource/external vendor, embedded risk management specialist model, and Center of Excellence. PMID:25750537

  13. The reasons for the epilepsy treatment gap in Kilifi, Kenya: Using formative research to identify interventions to improve adherence to antiepileptic drugs

    PubMed Central

    Carter, Julie A.; Molyneux, Catherine S.; Mbuba, Caroline K.; Jenkins, Jo; Newton, Charles R.J.C.; Hartley, Sally D.

    2012-01-01

    Many people with epilepsy (PWE) in resource‐poor countries do not receive appropriate treatment, a phenomenon referred to as the epilepsy treatment gap (ETG). We conducted a qualitative study to explore the reasons for this gap and to identify possible interventions in Kilifi, Kenya. Focus group discussions (FGDs) were carried out of PWE and their caregivers. Individual interviews were conducted of PWE, their caregivers, traditional healers, community health workers and leaders, nurses and doctors. In addition, a series of workshops was conducted, and four factors contributing to the ETG were identified: 1) lack of knowledge about the causes, treatment and prognosis of epilepsy; 2) inaccessibility to antiepileptic drugs; 3) misconceptions about epilepsy derived from superstitions about its origin; 4) and dissatisfaction with the communication skills of health providers. These data indicated possible interventions: 1) education and support for PWE and their caregivers; 2) communication skills training for health providers; 3) and improved drug provision. PMID:23160097

  14. Life Skills Interventions to Improve Social Confidence, Self-Management, and Protection against Drug Use in Rural Elementary School Aged Children.

    PubMed

    Tymes, Deborah D; Outlaw, Kerri L; Hamilton, Bernita K

    2016-01-01

    This pilot project evaluated the effectiveness of a life skills training program for elementary-school-aged children for development of social confidence, self-management, and general social and drug resistance skills. The setting was a rural community after-school program. Children participated in 30-min weekly sessions for 8 weeks. Pre- and posttest scores were analyzed to determine effectiveness of the program. Results showed improvements in antismoking and antidrinking attitudes and use of self-management and general social skills, and social confidence in conflict situations. The life skills training intervention serves as a potential supplement to community programs for the prevention of behaviors such as bullying, smoking and drug use among elementary school aged children. PMID:26813051

  15. Novel in situ self-assembly nanoparticles for formulating a poorly water-soluble drug in oral solid granules, improving stability, palatability, and bioavailability

    PubMed Central

    Guo, Shujie; Pham, Kevin; Li, Diana; Penzak, Scott R; Dong, Xiaowei

    2016-01-01

    Purpose The purpose of this study was to develop a novel lipid-based nanotechnology to formulate poorly water-soluble drugs in oral solid granules to improve stability, palatability, and bioavailability. Materials and methods In one method, we prepared ritonavir (RTV) nanoparticles (NPs) by a microemulsion-precursor method and then converted the RTV NPs to solid granules by wet granulation to produce RTV NP-containing granules. In the other innovative method, we did not use water in the formulation preparation, and discovered novel in situ self-assembly nanoparticles (ISNPs). We prepared RTV ISNP granules that did not initially contain NPs, but spontaneously produced RTV ISNPs when the granules were introduced to water with gentle agitation. We fully characterized these RTV nanoformulations. We also used rats to test the bioavailability of RTV ISNP granules. Finally, an Astree electronic tongue was used to assess the taste of the RTV ISNP granules. Results RTV NP-containing granules only had about 1% drug loading of RTV in the solid granules. In contrast, RTV ISNP granules achieved over 16% drug loading and were stable at room temperature over 24 weeks. RTV ISNPs had particle size between 160 nm and 300 nm with narrow size distribution. RTV ISNPs were stable in simulated gastric fluid for 2 hours and in simulated intestinal fluid for another 6 hours. The data from the electronic tongue showed that the RTV ISNP granules were similar in taste to blank ISNP granules, but were much different from RTV solution. RTV ISNP granules increased RTV bioavailability over 2.5-fold compared to RTV solution. Conclusion We successfully discovered and developed novel ISNPs to manufacture RTV ISNP granules that were reconstitutable, stable, and palatable, and improved RTV bioavailability. The novel ISNP nanotechnology is a platform to manufacture oral solid dosage forms for poorly water-soluble drugs, especially for pediatric formulation development. PMID:27103803

  16. AZ17: a new bispecific drug targeting IL-6 and IL-23 with potential clinical use--improves psoriasis in a human xenograft transplantation model.

    PubMed

    Stenderup, Karin; Rosada, Cecilia; Shanebeck, Kurt; Brady, William; Van Brunt, Michael P; King, Gordon; Marelli, Marcello; Slagle, Paul; Xu, Hengyu; Nairn, Natalie W; Johnson, Jeffrey; Wang, Aijun A; Li, Gary; Thornton, Kenneth C; Dam, Tomas N; Grabstein, Kenneth H

    2015-10-01

    Targeting more than one molecule in multifactorial diseases involving several disease mediators may provide improved therapeutic efficacy. Psoriasis is a multifactorial disease in which interleukin (IL)-6 and IL-23 are important disease mediators because they facilitate development of Th17 cells; widely accepted to be associated with psoriasis. To meet the need for new therapeutics, we aimed to create a clinically relevant bispecific drug, by combining the inhibitory properties of anti-IL-6 and anti-IL-23 antibodies, exhibiting high affinity, high stability and the ability to be produced in high yield. The bispecific molecule AZ17 was created by combining high affinity binding domains originating from monoclonal antibodies targeting human IL-6 and IL-23. To allow for high and efficient production, AZ17 was assembled by site-specific bioconjugation from two individual single chain fragment variables that were synthesized separately in Escherichia coli. To improve stability and extend pharmacokinetics, a flexible poly-ethylene glycol molecule was used as linker. In preclinical psoriasis models, AZ17 reduced IL-23-induced ear inflammation and improved psoriasis in a xenograft transplantation model where psoriasis skin is transplanted onto immune-deficient mice. The data presented here suggest AZ17 to be a promising drug candidate in psoriasis and other inflammatory diseases associated with Th17 cell development. PMID:26271488

  17. Towards improved solubility of poorly water-soluble drugs: cryogenic co-grinding of piroxicam with carrier polymers.

    PubMed

    Penkina, Anna; Semjonov, Kristian; Hakola, Maija; Vuorinen, Sirpa; Repo, Timo; Yliruusi, Jouko; Aruväli, Jaan; Kogermann, Karin; Veski, Peep; Heinämäki, Jyrki

    2016-03-01

    Amorphous solid dispersions (SDs) open up exciting opportunities in formulating poorly water-soluble active pharmaceutical ingredients (APIs). In the present study, novel catalytic pretreated softwood cellulose (CPSC) and polyvinylpyrrolidone (PVP) were investigated as carrier polymers for preparing and stabilizing cryogenic co-ground SDs of poorly water-soluble piroxicam (PRX). CPSC was isolated from pine wood (Pinus sylvestris). Raman and Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used for characterizing the solid-state changes and drug-polymer interactions. High-resolution scanning electron microscope (SEM) was used to analyze the particle size and surface morphology of starting materials and final cryogenic co-ground SDs. In addition, the molecular aspects of drug-polymer interactions and stabilization mechanisms are presented. The results showed that the carrier polymer influenced both the degree of amorphization of PRX and stabilization against crystallization. The cryogenic co-ground SDs prepared from PVP showed an enhanced dissolution rate of PRX, while the corresponding SDs prepared from CPSC exhibited a clear sustained release behavior. In conclusion, cryogenic co-grinding provides a versatile method for preparing amorphous SDs of poorly water-soluble APIs. The solid-state stability and dissolution behavior of such co-ground SDs are to a great extent dependent on the carrier polymer used. PMID:26065533

  18. Improvement of antibacterial activity of some sulfa drugs through linkage to certain phthalazin-1(2H)-one scaffolds.

    PubMed

    Ibrahim, Hany S; Eldehna, Wagdy M; Abdel-Aziz, Hatem A; Elaasser, Mahmoud M; Abdel-Aziz, Marwa M

    2014-10-01

    RAB1 5 is a lead antibacterial agent in which trimethoprim is linked to phthalazine moiety. Similarly, our strategy in this research depends on the interconnection between some sulfa drugs and certain phthalazin-1(2H)-one scaffolds in an attempt to enhance their antibacterial activity. This approach was achieved through the combination of 4-substituted phthalazin-1(2H)-ones 9a, b or 14a, b with sulfanilamide 1a, sulfathiazole 1b or sulfadiazine 1c through amide linkers 6a, b to produce the target compounds 10a-d and 15a-e, respectively. The antibacterial activity of the newly synthesized compounds showed that all tested compounds have antibacterial activity higher than that of their reference sulfa drugs 1a-c. Compound 10c represented the highest antibacterial activity against Gram-positive bacteria Streptococcus pneumonia and Staphylococcus aureus with MIC = 0.39 μmol/mL. Moreover, compound 10d displayed excellent antibacterial activity against Gram-negative bacteria Escherichia coli and Salmonella typhimurium with MIC = 0.39 and 0.78 μmol/mL, respectively. PMID:25113876

  19. Arginine deiminase: recent advances in discovery, crystal structure, and protein engineering for improved properties as an anti-tumor drug.

    PubMed

    Han, Rui-Zhi; Xu, Guo-Chao; Dong, Jin-Jun; Ni, Ye

    2016-06-01

    Arginine deiminase (ADI) is an important arginine-degrading enzyme with wide applications, in particular as an anti-cancer agent for the therapy of arginine-auxotrophic tumors. In recent years, novel ADIs with excellent properties have been identified from various organisms, and crystal structures of ADI were investigated. To satisfy the requirements of potential therapeutic applications, protein engineering has been performed to improve the activity and properties of ADIs. In this mini-review, we systematically summarized the latest progress on identification and crystal structure of ADIs, and protein engineering strategies for improved enzymatic properties, such as pH optimum, K m and k cat values, and thermostability. We also outlined the PEGylation of ADI for improved circulating half-life and immunogenicity, as well as their performance in clinical trials. Finally, perspectives on extracellular secretion and property improvement of ADI were discussed. PMID:27087524

  20. PolySearch2: a significantly improved text-mining system for discovering associations between human diseases, genes, drugs, metabolites, toxins and more

    PubMed Central

    Liu, Yifeng; Liang, Yongjie; Wishart, David

    2015-01-01

    PolySearch2 (http://polysearch.ca) is an online text-mining system for identifying relationships between biomedical entities such as human diseases, genes, SNPs, proteins, drugs, metabolites, toxins, metabolic pathways, organs, tissues, subcellular organelles, positive health effects, negative health effects, drug actions, Gene Ontology terms, MeSH terms, ICD-10 medical codes, biological taxonomies and chemical taxonomies. PolySearch2 supports a generalized ‘Given X, find all associated Ys’ query, where X and Y can be selected from the aforementioned biomedical entities. An example query might be: ‘Find all diseases associated with Bisphenol A’. To find its answers, PolySearch2 searches for associations against comprehensive collections of free-text collections, including local versions of MEDLINE abstracts, PubMed Central full-text articles, Wikipedia full-text articles and US Patent application abstracts. PolySearch2 also searches 14 widely used, text-rich biological databases such as UniProt, DrugBank and Human Metabolome Database to improve its accuracy and coverage. PolySearch2 maintains an extensive thesaurus of biological terms and exploits the latest search engine technology to rapidly retrieve relevant articles and databases records. PolySearch2 also generates, ranks and annotates associative candidates and present results with relevancy statistics and highlighted key sentences to facilitate user interpretation. PMID:25925572

  1. PolySearch2: a significantly improved text-mining system for discovering associations between human diseases, genes, drugs, metabolites, toxins and more.

    PubMed

    Liu, Yifeng; Liang, Yongjie; Wishart, David

    2015-07-01

    PolySearch2 (http://polysearch.ca) is an online text-mining system for identifying relationships between biomedical entities such as human diseases, genes, SNPs, proteins, drugs, metabolites, toxins, metabolic pathways, organs, tissues, subcellular organelles, positive health effects, negative health effects, drug actions, Gene Ontology terms, MeSH terms, ICD-10 medical codes, biological taxonomies and chemical taxonomies. PolySearch2 supports a generalized 'Given X, find all associated Ys' query, where X and Y can be selected from the aforementioned biomedical entities. An example query might be: 'Find all diseases associated with Bisphenol A'. To find its answers, PolySearch2 searches for associations against comprehensive collections of free-text collections, including local versions of MEDLINE abstracts, PubMed Central full-text articles, Wikipedia full-text articles and US Patent application abstracts. PolySearch2 also searches 14 widely used, text-rich biological databases such as UniProt, DrugBank and Human Metabolome Database to improve its accuracy and coverage. PolySearch2 maintains an extensive thesaurus of biological terms and exploits the latest search engine technology to rapidly retrieve relevant articles and databases records. PolySearch2 also generates, ranks and annotates associative candidates and present results with relevancy statistics and highlighted key sentences to facilitate user interpretation. PMID:25925572

  2. Synergistically Enhanced Therapeutic Effect of a Carrier-Free HCPT/DOX Nanodrug on Breast Cancer Cells through Improved Cellular Drug Accumulation.

    PubMed

    Chen, Fei; Zhao, Yuanyuan; Pan, Yuanming; Xue, Xiangdong; Zhang, Xu; Kumar, Anil; Liang, Xing-Jie

    2015-07-01

    We are interested in developing systems for simultaneous delivery of two or more chemotherapeutic agents. Simple physical mixing of drugs may reduce the therapeutic effect and cause unexpected or even dangerous side-effects. For example, when 10-hydroxycamptothecin (HCPT) and doxorubicin (DOX) injection solutions are mixed, the curative effect is actually reduced in clinical practice. In this study we demonstrated that when HCPT and DOX are combined into a single nanoparticle, their toxicity to tumor cells in vitro is synergistically enhanced. We used a simple and "green" reprecipitation method to successfully create a carrier-free dual-drug delivery system by self-nanocrystallization of the drug molecules. When HCPT and DOX were coassembled, they formed small, spherical nanodrug particles with a positive surface charge. Cellular uptake of HCPT was improved and nuclear accumulation increased as much as 1.57-fold in comparison to HCPT alone. The carrier-free HCPT/DOX nanoparticles demonstrated enhanced synergistic cytotoxicity against breast cancer cells in vitro, while an antagonistic effect was observed when HCPT and DOX were directly mixed at high concentration. PMID:25996761

  3. The Drug Education Gap

    ERIC Educational Resources Information Center

    Reynolds, John C., Jr.

    1976-01-01

    Examines the problems of alcoholism, smoking and drug addiction and their influence on students. Suggests that intermediate and secondary schools can assist in alcohol and tobacco (the two legal drugs) programs through improved educational methods. (Author/RK)

  4. Improvement in Plasma Drug Activity during the Early Treatment Interval among Tanzanian Patients with Multidrug-Resistant Tuberculosis

    PubMed Central

    Ndusilo, Norah D.; Heysell, Scott K.; Mpagama, Stellah G.; Gratz, Jean; Segesela, Farida H.; Pazia, Saumu J.; Wang, Xin-Qun; Houpt, Eric R.; Kibiki, Gibson S.

    2015-01-01

    Background Individual pharmacokinetic variability may be common in patients treated for multidrug-resistant tuberculosis (MDR-TB) but data are sparse from resource-limited settings and across the early treatment interval. Methods Plasma drug activity, as measured by the TB Drug Activity (TDA) assay at 2 and 4 weeks of treatment with a standardized MDR-TB regimen was performed in patients with pulmonary MDR-TB from Tanzania. TDA values were correlated with measures of early treatment outcome including every two week collection of sputum for time-to-positivity (TTP) in liquid culture from the MGIT 960 automated system. Patients were evaluated at 24 weeks and those surviving without delayed sputum culture conversion (>8 weeks), culture reversion after previously negative, or weight loss were defined as having a favorable outcome. Results Twenty-five patients were enrolled with a mean age of 37 ±12 years. All were culture positive from the pretreatment sputum sample with a mean TTP in MGIT of 257 ±134 hours, and the median time to culture conversion on treatment was 6 weeks. Twenty patients (80%) had an increase in TDA, with the overall mean TDA at 2 weeks of 2.1 ±0.7 compared to 2.4 ±0.8 at 4 weeks (p = 0.005). At 2 weeks 13 subjects (52%) had a TDA value > 2-log killing against their own M. tuberculosis isolate compared to 17 subjects (68%) at 4 weeks (McNemar’s exact test p = 0.29). An interim treatment outcome was able to be determined in 23 patients (92%), of whom 7 had a poor outcome (30%). An increase in TDA from week 2 to week 4 was associated with favorable outcome, [unadjusted OR = 20.0, 95% CI: 1.61–247.98, exact p = 0.017 and adjusted OR = 19.33, 95% CI: 1.55–241.5, exact p = 0.023]. Conclusions The majority of patients with MDR-TB in Tanzania had an increase in plasma drug activity from week 2 to week 4 of treatment as measured by the TDA assay. Understanding the etiology and full impact of this dynamic may inform therapeutic intervention. PMID

  5. Antimicrobial drug use and risk factors associated with treatment incidence and mortality in Swiss veal calves reared under improved welfare conditions.

    PubMed

    Lava, M; Schüpbach-Regula, G; Steiner, A; Meylan, M

    2016-04-01

    Ninety-one Swiss veal farms producing under a label with improved welfare standards were visited between August and December 2014 to investigate risk factors related to antimicrobial drug use and mortality. All herds consisted of own and purchased calves, with a median of 77.4% of purchased calves. The calves' mean age was 29±15days at purchasing and the fattening period lasted at average 120±28 days. The mean carcass weight was 125±12kg. A mean of 58±33 calves were fattened per farm and year, and purchased calves were bought from a mean of 20±17 farms of origin. Antimicrobial drug treatment incidence was calculated with the defined daily dose methodology. The mean treatment incidence (TIADD) was 21±15 daily doses per calf and year. The mean mortality risk was 4.1%, calves died at a mean age of 94±50 days, and the main causes of death were bovine respiratory disease (BRD, 50%) and gastro-intestinal disease (33%). Two multivariable models were constructed, for antimicrobial drug treatment incidence (53 farms) and mortality (91 farms). No quarantine, shared air space for several groups of calves, and no clinical examination upon arrival at the farm were associated with increased antimicrobial treatment incidence. Maximum group size and weight differences >100kg within a group were associated with increased mortality risk, while vaccination and beef breed were associated with decreased mortality risk. The majority of antimicrobial treatments (84.6%) were given as group treatments with oral powder fed through an automatic milk feeding system. Combination products containing chlortetracycline with tylosin and sulfadimidine or with spiramycin were used for 54.9%, and amoxicillin for 43.7% of the oral group treatments. The main indication for individual treatment was BRD (73%). The mean age at the time of treatment was 51 days, corresponding to an estimated weight of 80-100kg. Individual treatments were mainly applied through injections (88.5%), and included

  6. A long-term fatty fish intervention improved executive function in inpatients with antisocial traits and a history of alcohol and drug abuse.

    PubMed

    Hansen, Anita L; Dahl, Lisbeth; Olson, Gina; Thornton, David; Grung, Bjørn; Thayer, Julian F

    2015-10-01

    The aim of the present study was to investigate the effects of fatty fish consumption on cognitive functioning in a group of inpatients characterized by antisocial behavior. Eighty-three male forensic inpatients participated in this study. Participants were randomly assigned into a Fish or a Control group (e.g., meat, chicken, pork). One decision-making task, the Iowa Gambling Task (IGT), and one planning task, the Tower of Hanoi (ToH), were administered before (pre-test) and at the end of the intervention period (post-test). For the IGT the Fish group showed improved performance from pre- to post- test. Moreover, the Fish group showed significantly better performance than the Control group on the IGT at post-test. The Fish group also demonstrated improved performance from pre- to post-test on the ToH; however, this was limited to participants with a history of substance abuse. Further, the improvement was only significant for tasks with high working memory load (5-7 move problems), and not for tasks with low working memory load (1-4 move problems). The Control group showed no improvement on any of the tasks regardless of alcohol or drug abuse history. The present study suggests that regular fatty fish consumption may improve executive functions in forensic inpatients with antisocial traits and a history of substance abuse. Thus, the current results may have important implications with regard to health care interventions. PMID:26032440

  7. Sonication-based improvement of the physicochemical properties of Guar Gum as a potential substrate for modified drug delivery systems.

    PubMed

    Ansari, Siddique Akber; Matricardi, Pietro; Cencetti, Claudia; Di Meo, Chiara; Carafa, Maria; Mazzuca, Claudia; Palleschi, Antonio; Capitani, Donatella; Alhaique, Franco; Coviello, Tommasina

    2013-01-01

    Guar Gum is a natural polysaccharide that, due to its physicochemical properties, is extensively investigated for biomedical applications as a matrix for modified drug delivery, but it is also used in the food industry as well as in cosmetics. A commercial sample of Guar Gum was sonicated for different periods of time, and the reduction in the average molecular weight was monitored by means of viscometric measurements. At the same time, the rheological behaviour was also followed, in terms of viscoelasticity range, flow curves, and mechanical spectra. Sonicated samples were used for the preparation of gels in the presence of borate ions. The effect of borax on the new samples was investigated by recording mechanical spectra, flow curves, and visible absorption spectra of complexes with Congo Red. The anisotropic elongation, observed in previous studies with tablets of Guar Gum and borax, was remarkably reduced when the sonicated samples were used for the preparation of the gels. PMID:23984426

  8. Cyclization of a cell-penetrating peptide via click-chemistry increases proteolytic resistance and improves drug delivery.

    PubMed

    Reichart, Florian; Horn, Mareike; Neundorf, Ines

    2016-06-01

    In this work we report synthesis and biological evaluation of a cell-penetrating peptide (CPP), that is partly cyclized via a triazole bridge. Recently, beneficious properties have been reported for cyclized peptides concerning their metabolic stability and intracellular uptake. A CPP based on human calcitonin was used in this study, and side chain cyclization was achieved via copper catalyzed alkyne-azide click reaction. Cell viability studies in several cell-lines revealed no cytotoxic effects. Furthermore, efficient uptake in breast cancer MCF-7 cells could be determined. Moreover, preliminary studies using this novel peptide as drug transporter for daunorubicin were performed. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:27197760

  9. Exploring Weak Ligand–Protein Interactions by Long-Lived NMR States: Improved Contrast in Fragment-Based Drug Screening**

    PubMed Central

    Buratto, Roberto; Mammoli, Daniele; Chiarparin, Elisabetta; Williams, Glyn; Bodenhausen, Geoffrey

    2014-01-01

    Ligands that have an affinity for protein targets can be screened very effectively by exploiting favorable properties of long-lived states (LLS) in NMR spectroscopy. In this work, we describe the use of LLS for competitive binding experiments to measure accurate dissociation constants of fragments that bind weakly to the ATP binding site of the N-terminal ATPase domain of heat shock protein 90 (Hsp90), a therapeutic target for cancer treatment. The LLS approach allows one to characterize ligands with an exceptionally wide range of affinities, since it can be used for ligand concentrations [L] that are several orders of magnitude smaller than the dissociation constants KD. This property makes the LLS method particularly attractive for the initial steps of fragment-based drug screening, where small molecular fragments that bind weakly to a target protein must be identified, which is a difficult task for many other biophysical methods. PMID:25196717

  10. Nanoparticles incorporating pH-responsive surfactants as a viable approach to improve the intracellular drug delivery.

    PubMed

    Nogueira, Daniele R; Scheeren, Laís E; Pilar Vinardell, M; Mitjans, Montserrat; Rosa Infante, M; Rolim, Clarice M B

    2015-12-01

    The pH-responsive delivery systems have brought new advances in the field of functional nanodevices and might allow more accurate and controllable delivery of specific cargoes, which is expected to result in promising applications in different clinical therapies. Here we describe a family of chitosan-TPP (tripolyphosphate) nanoparticles (NPs) for intracellular drug delivery, which were designed using two pH-sensitive amino acid-based surfactants from the family N(α),N(ε)-dioctanoyl lysine as bioactive compounds. Low and medium molecular weight chitosan (LMW-CS and MMW-CS, respectively) were used for NP preparation, and it was observed that the size distribution for NPs with LMW-CS were smaller (~168 nm) than that for NPs prepared with MMW-CS (~310 nm). Hemolysis assay demonstrated the pH-dependent biomembrane disruptional capability of the constructed NPs. The nanostructures incorporating the surfactants cause negligible membrane permeabilization at pH7.4. However, at acidic pH, prevailing in endosomes, membrane-destabilizing activity in an erythrocyte lysis assay became evident. When pH decreased to 6.6 and 5.4, hemolytic capability of chitosan NPs increased along with the raise of concentration. Furthermore, studies with cell culture showed that these pH-responsive NPs displayed low cytotoxic effects against 3T3 fibroblasts. The influence of chitosan molecular weight, chitosan to TPP weight ratio, nanoparticle size and nature of the surfactant counterion on the membrane-disruptive properties of nanoparticles was discussed in detail. Altogether, the results achieved here showed that by inserting the lysine-based amphiphiles into chitosan NPs, pH-sensitive membranolytic and potentially endosomolytic nanocarriers were developed, which, therefore, demonstrated ideal feasibility for intracellular drug delivery. PMID:26354244

  11. An international perspective on using opioid substitution treatment to improve hepatitis C prevention and care for people who inject drugs: Structural barriers and public health potential.

    PubMed

    Perlman, David C; Jordan, Ashly E; Uuskula, Anneli; Huong, Duong Thi; Masson, Carmen L; Schackman, Bruce R; Des Jarlais, Don C

    2015-11-01

    People who inject drugs (PWID) are central to the hepatitis C virus (HCV) epidemic. Opioid substitution treatment (OST) of opioid dependence has the potential to play a significant role in the public health response to HCV by serving as an HCV prevention intervention, by treating non-injection opioid dependent people who might otherwise transition to non-sterile drug injection, and by serving as a platform to engage HCV infected PWID in the HCV care continuum and link them to HCV treatment. This paper examines programmatic, structural and policy considerations for using OST as a platform to improve the HCV prevention and care continuum in 3 countries-the United States, Estonia and Viet Nam. In each country a range of interconnected factors affects the use OST as a component of HCV control. These factors include (1) that OST is not yet provided on the scale needed to adequately address illicit opioid dependence, (2) inconsistent use of OST as a platform for HCV services, (3) high costs of HCV treatment and health insurance policies that affect access to both OST and HCV treatment, and (4) the stigmatization of drug use. We see the following as important for controlling HCV transmission among PWID: (1) maintaining current HIV prevention efforts, (2) expanding efforts to reduce the stigmatization of drug use, (3) expanding use of OST as part of a coordinated public health approach to opioid dependence, HIV prevention, and HCV control efforts, (4) reductions in HCV treatment costs and expanded health system coverage to allow population level HCV treatment as prevention and OST as needed. The global expansion of OST and use of OST as a platform for HCV services should be feasible next steps in the public health response to the HCV epidemic, and is likely to be critical to efforts to eliminate or eradicate HCV. PMID:26050614

  12. Development of a solidified self-microemulsifying drug delivery system (S-SMEDDS) for atorvastatin calcium with improved dissolution and bioavailability.

    PubMed

    Yeom, Dong Woo; Son, Ho Yong; Kim, Jin Han; Kim, Sung Rae; Lee, Sang Gon; Song, She Hyon; Chae, Bo Ram; Choi, Young Wook

    2016-06-15

    To improve the dissolution and oral bioavailability (BA) of atorvastatin calcium (ATV), we previously introduced an optimized self-microemulsifying drug delivery system (SMEDDS) using Capmul(®) MCM (oil), Tween(®) 20 (surfactant), and tetraglycol (cosurfactant). In this study, various solid carriers were employed to develop a solidified SMEDDS (S-SMEDDS): mannitol (M) and lactose (L) as water-soluble carriers, and Sylysia(®) 350 (S) and Aerosil(®) 200 (A) as water-insoluble carriers. Maximum solidifying capacities (SCmax) of water-insoluble carriers were significantly greater than those of water-soluble carriers were. The resultant powders were free flowing with an angle of repose <40° and Carr's index 5-20%, regardless of the solid carrier types. S-SMEDDS with mannitol (S(M)-SMEDDS) or lactose (S(L)-SMEDDS) had a smaller droplet size and greater dissolution than S-SMEDDS with Sylysia(®) 350 (S(S)-SMEDDS) or Aerosil(®) 200 (S(A)-SMEDDS). Following oral administration of various formulations to rats at a dose equivalent to 25mg/kg of ATV, plasma drug levels were measured by LC-MS/MS. The relative BAs (RBAs) of SMEDDS, S(M)-SMEDDS, and S(S)-SMEDDS were 345%, 216%, and 160%, respectively, compared to that of ATV suspension. Additionally, at a reduced dose of ATV equivalent to 5mg/kg, the RBAs of S(M)-SMEDDS and S(S)-SMEDDS compared to that of SMEDDS were 101% and 65%, respectively. These results suggest that S(M)-SEMDDS offers great potential for the development of solid dosage forms with improved oral absorption of drugs with poor water solubility. PMID:27125455

  13. Solid microcrystalline dispersion films as a new strategy to improve the dissolution rate of poorly water soluble drugs: A case study using olanzapine.

    PubMed

    Modica de Mohac, Laura; de Fátima Pina, Maria; Raimi-Abraham, Bahijja Tolulope

    2016-07-11

    In this study, we evaluate the dissolution rate enhancement of solid microcrystalline dispersion (SMD) films of olanzapine (OLZ) formulated with four water-soluble polymers namely poly(N-vinylpyrrolidone) (PVP), poloxamer 188 (P188), poloxamer 407 (P407) and Soluplus(®) (SLP). Prepared formulations were characterised to determine particle size, morphology, hydrogen bonding interactions, thermal characteristics as well as in vitro dissolution studies conducted under sink conditions (pH 6.8). Particle size of OLZ in all formulations ranged between 42 and 58μm. Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR), Differential Scanning Calorimetry (DSC) and Hot-Stage Microscopy (HSM) studies confirmed OLZ was well maintained in its crystalline state during the formulation process. In vitro dissolution studies showed immediate drug release from all formulation when compared to the drug alone. The greatest increase in in vitro dissolution rate was observed in formulations containing P188 most likely due to its enhanced hydrophilic and surfactant properties compared to the other agents used. Overall, this study successfully generated OLZ loaded SMD films with improved in vitro dissolution rates which is highly likely to result in improved oral bioavailability in vivo. PMID:27154255

  14. CO-DELIVERY OF NATURAL METABOLIC INHIBITORS IN A SELF-MICROEMULSIFYING DRUG DELIVERY SYSTEM FOR IMPROVED ORAL BIOAVAILABILITY OF CURCUMIN

    PubMed Central

    Grill, Alex E.; Koniar, Brenda; Panyam, Jayanth

    2014-01-01

    In spite of its well-documented anticancer chemopreventive and therapeutic activity, the clinical development of curcumin has been limited by its poor oral bioavailability. Curcumin has low aqueous solubility and undergoes extensive first pass metabolism following oral dosing. We hypothesized that oral bioavailability of curcumin can be enhanced by increasing its absorption and decreasing its metabolic clearance simultaneously. To test this hypothesis, we formulated curcumin with naturally occurring UGT inhibitors (piperine, quercetin, tangeretin, and silibinin) in a self-microemulsifying drug delivery system (SMEDDS). Mouse liver microsome studies showed that silibinin and quercetin inhibited curcumin glucuronidation effectively. When dosed orally in mice, the SMEDDS containing curcumin alone increased curcumin glucuronide concentrations in plasma without significantly affecting parent drug concentration. Of the four inhibitors examined in vivo, silibinin significantly improved the Cmax (0.15 μM vs. 0.03 μM for curcumin SMEDDS) and the overall bioavailability (3.5-fold vs. curcumin SMEDDS) of curcumin. Previous studies have shown that silibinin has anticancer activity as well. Thus, co-delivery of silibinin with curcumin in SMEDDS represents a novel and promising approach to improve curcumin bioavailability. PMID:25422796

  15. A simple green route to obtain poly(vinyl alcohol) electrospun mats with improved water stability for use as potential carriers of drugs.

    PubMed

    López-Córdoba, Alex; Castro, Guillermo R; Goyanes, Silvia

    2016-12-01

    Poly(vinyl alcohol) (PVA) is a hydrophilic, biocompatible and nontoxic polymer. However, because of its low water-resistance, some applications for PVA-based materials are limited (e.g., drug delivery systems and wound dressings). In the current work, PVA mats containing tetracycline hydrochloride (TC) were successfully developed by electrospinning. In order to improve the water stability of the systems, the cross-linking of the PVA matrix was induced by citric acid (CA) addition together with heating treatments (150°C or 190°C for 3min). TC presence led to a strong increase in the electrical conductivity of the blends and as a result, fibers with about 44% lower diameter (270nm) than that of the corresponding unloaded mats (485nm) were obtained. Laser scanning confocal microscopy images indicated that TC was well distributed along the PVA nanofibers. The mats were evaluated by FTIR, which revealed chemical interactions between PVA hydroxyl groups and CA carboxylic ones. The treatment at 150°C for 3min proved to be the more suitable for the preparation of TC-containing mats with improved water resistance, maintaining the TC antimicrobial activity against both Escherichia coli and Staphylococcus aureus almost unaltered. These mats showed a burst release of TC, giving around 95% of the drug within the first hour of immersion in water. PMID:27612766

  16. Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation.

    PubMed

    De Keersmaecker, Brenda; Fostier, Karel; Corthals, Jurgen; Wilgenhof, Sofie; Heirman, Carlo; Aerts, Joeri L; Thielemans, Kris; Schots, Rik

    2014-10-01

    Multiple myeloma (MM) is characterized by a malignant proliferation of plasma cells in the bone marrow with associated organ damage. Although the prognosis of MM has improved recently, the disease remains incurable for the large majority of patients. The eradication of residual disease in the bone marrow is a main target on the road toward cure. Immune cells play a role in the control of cancer and can be tools to attack residual MM cells. However, the myeloma-associated immune deficiency is a major hurdle to immunotherapy. We evaluated ex vivo the effects of low doses of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide on several immune cell types from MM patients after autologous stem cell transplantation and with low tumor burden. We observed that these drugs increased CD4(+) and CD8(+) T-cell proliferation and cytokine production, enhanced the lytic capacity of cytotoxic T lymphocytes and reduced the suppressive effects of regulatory T cells on CD8(+) T-cell responses. In addition, we found that functional dendritic cells (DCs) can be generated from mononuclear cells from MM patients. The presence of IMiDs improved the quality of antigen-specific T cells induced or expanded by these DCs as evidenced by a higher degree of T-cell polyfunctionality. Our results provide a rationale for the design of early phase clinical studies to assess the efficacy of DC-based immunotherapy in combination with posttransplant maintenance treatment with IMiDs in MM. PMID:24947180

  17. Lessons Learned and Potentials for Improvement in CNS Drug Development: ISCTM Section on Designing the Right Series of Experiments

    PubMed Central

    Kinon, Bruce J.; Brannan, Stephen K.; Krystal, Andrew K.; van Gerven, Joop M. A.; Mahableshwarkar, Atul; Sachs, Gary S.

    2015-01-01

    Once a molecule has been characterized as engaging an identified target at the appropriate location (affinity and potency), the next step involves designing experiments that will determine its pharmacodynamic activities both for efficacy (on target) and safety-tolerability (on/off target). Two expert presentations focused on looking back at completed programs and two concentrated on looking forward at ongoing programs. Specific discussions pertain to assessment of pharmacologic agonists (mGluR2/3, k-opiate, peroxisome proliferator-activated receptor gamma) and antagonists (orexin and cannabinoid) in disorders of cognition, mood, and anxiety. Advanced experimental study designs using genetics to guide a treatment trial in Alzheimer’s disease and neural target-based approaches as the primary outcome measure in the National Institute of Mental Health-sponsored Fast-Fail Trials (FAST)-Mood and Anxiety Spectrum Disorders (MAS) initiative for depression showcases novel methodological approaches. Of interest, some of these initiatives were successful, while others were not, and two are currently ongoing. In conclusion, methodologies that were utilized and are currently employed to reach a successful clinical drug trial outcome are appreciated, and in case of failure, approaches to reviewing programs to enable learning that would be helpful to future programs are brought forth. This article is based on proceedings from the “Designing the Right Series of Experiments” session, which was held during the International Society for Clinical Trials Meeting (ISCTM) in Philadelphia, Pennsylvania, September 30 to October 2, 2013. PMID:25977837

  18. An improved cryopreservation method for porcine buccal mucosa in ex vivo drug permeation studies using Franz diffusion cells.

    PubMed

    Amores, Sonia; Domenech, José; Colom, Helena; Calpena, Ana C; Clares, Beatriz; Gimeno, Álvaro; Lauroba, Jacinto

    2014-08-18

    The use of isolated animal models to assess percutaneous absorption of molecules is frequently reported. The porcine buccal mucosa has been proposed as a substitute for the buccal mucosa barrier on ex vivo permeability studies avoiding unnecessary sacrifice of animals. But it is not always easy to obtain fresh buccal mucosa. Consequently, human and porcine buccal mucosa is sometimes frozen and stored in liquid nitrogen, but this procedure is not always feasible. One cheaper and simpler alternative is to freeze the buccal mucosa of freshly slaughtered pigs in a mechanical freezer, using DMSO and albumin as cryoprotective agents. This study compared the ex vivo permeability parameters of propranolol hydrochloride through porcine buccal mucosa using a Franz diffusion cell system and HPLC as detection method. The freezing effects on drug permeability parameters were evaluated. Equally histological studies were performed. Furthermore, the use of the parameter transmucosal water loss (TMWL) as an indicator of the buccal mucosa integrity was evaluated just as transepidermal water loss (TEWL) is utilized for skin integrity. The results showed no difference between fresh and frozen mucosal flux, permeability coefficient or lag time of propranolol. However, statistical significant difference in TMWL between fresh and frozen mucosa was observed. PMID:24813111

  19. Beyond Agar: Gel Substrates with Improved Optical Clarity and Drug Efficiency and Reduced Autofluorescence for Microbial Growth Experiments

    PubMed Central

    Jaeger, Philipp A.; McElfresh, Cameron; Wong, Lily R.

    2015-01-01

    Agar, a seaweed extract, has been the standard support matrix for microbial experiments for over a century. Recent developments in high-throughput genetic screens have created a need to reevaluate the suitability of agar for use as colony support, as modern robotic printing systems now routinely spot thousands of colonies within the area of a single microtiter plate. Identifying optimal biophysical, biochemical, and biological properties of the gel support matrix in these extreme experimental conditions is instrumental to achieving the best possible reproducibility and sensitivity. Here we systematically evaluate a range of gelling agents by using the yeast Saccharomyces cerevisiae as a model microbe. We find that carrageenan and Phytagel have superior optical clarity and reduced autofluorescence, crucial for high-resolution imaging and fluorescent reporter screens. Nutrient choice and use of refined Noble agar or pure agarose reduce the effective dose of numerous selective drugs by >50%, potentially enabling large cost savings in genetic screens. Using thousands of mutant yeast strains to compare colony growth between substrates, we found no evidence of significant growth or nutrient biases between gel substrates, indicating that researchers could freely pick and choose the optimal gel for their respective application and experimental condition. PMID:26070672

  20. Impact of a Quality Improvement Intervention to Increase Brief Alcohol and Drug Interventions on a Level I Trauma Service.

    PubMed

    Thomas, Princess; Seale, J Paul; Johnson, J Aaron; Dhabliwala, Jason; Kitchens, Debra; Okosun, Ike S; Stokes, Nathan A; Ashley, Dennis

    2016-05-01

    Screening and brief intervention (SBI) decreases alcohol use and related consequences among trauma patients. Although SBI is required in Level I and II trauma centers, implementation often is difficult. This study used the Plan-Do-Study-Act approach to identify and implement measures to increase the number of patients receiving SBI at a Level I trauma center. A multidisciplinary Quality Improvement Committee with representation from the Trauma Service and SBI Team met monthly during 2011. Stepwise interventions included identifying a resident "champion" responsible for screening, brief intervention, and referral to treatment, including an SBI report at monthly trauma conferences, and incorporating SBI into the trauma order set. Outcomes measures were number of patients screened, patients screening positive, and the number of patients receiving SBI. At baseline, 170 of 362 patients (47%) were screened, 68/170 (40%) had positive screens, and 30/68 (44% of those with positive screens) received SBI services. Quarter 2 saw increases in patients screened-275/437 (63%), patients screening positive (106/275; 39%) and those receiving SBI (60/106; 57%). Increases culminated in Quarter 4 with screening 401/466 (86%; P < 0.001) patients, 208/401 (52%; P < 0.001) patients screening positive, and 114 patients (55%; P = 0.296) receiving services. Use of similar quality improvement measures nationwide could improve rates of provision of this important service. PMID:27215730

  1. Why a Combination of WP 631 and Epo B is an Improvement on the Drugs Singly - Involvement in the Cell Cycle and Mitotic Slippage.

    PubMed

    Bukowska, Barbara; Rogalska, Aneta; Forma, Ewa; Brys, Magdalena; Marczak, Agnieszka

    2016-01-01

    Our previous studies clearly demonstrated that a combination of WP 631 and Epo B has higher activity against ovarian cancer cells than either of these compounds used separately. In order to fully understand the exact mechanism of action in combination, we assessed effects on the cell cycle of SKOV-3 cells. We evaluated three control points essential for WP 631 and Epo B action to determine which cell cycle-regulating proteins (CDK1/cyclin B complex, EpCAM or HMGB1) mediate activity. The effects of the drug on the cell cycle were measured based on the nuclear DNA content using flow cytometry. Expression of cell cycle-regulating genes was analyzed using real-time PCR. It was discovered that WP 631, at the tested concentration, did not affect the SKOV-3 cell cycle. Epo B caused significant G2/M arrest, whereas the drug combination induced stronger apoptosis and lower mitotic arrest than Epo B alone. This is very important information from the point of view of the fight against cancer, as, while mitotic arrest in Epo B-treated cells could be overcame after DNA damage repair, apoptosis which occurs after mitotic slippage in combination-treated cells is irreversible. It clearly explains the higher activity of the drug combination in comparison to Epo B alone. Epo B acts via the CDK1/cyclin B complex and has the ability to inhibit CDK1, which may be a promising strategy for ovarian cancer treatment in the future. The drug combination diminishes EpCAM and HMGB1 expression to a greater degree than either WP 631 and Epo B alone. Owing to the fact that the high expression of these two proteins is a poor prognostic factor for ovarian cancer, a decrease in their expression, observed in our studies, may result in improved efficacy of cancer therapy. The presented findings show that the combination of WP 631 and Epo B is a better therapeutic option than either of these drugs alone. PMID:27039763

  2. [Ureter drugs].

    PubMed

    Raynal, G; Bellan, J; Saint, F; Tillou, X; Petit, J

    2008-03-01

    Many improvements have been made recently in the field of the ureteral smooth muscle pharmacology. After a brief summary on physiological basis, we review what is known about effects on ureter of different drugs class. In a second part, we review clinical applications for renal colic analgesia, calculi expulsive medical therapy, ESWL adjuvant treatment and preoperative treatment before retrograde access. There are now sufficient data on NSAID and alpha-blockers. beta-agonists, especially for beta3 selective ones, and topical drugs before retrograde access are interesting and should be further evaluated. PMID:18472067

  3. Combined citalopram and methylphenidate improved treatment response compared to either drug alone in geriatric depression: a randomized double-blind, placebo-controlled trial

    PubMed Central

    Lavretsky, Helen; Reinlieb, Michelle; Cyr, Natalie St.; Siddarth, Prabha; Ercoli, Linda M.; Senturk, Damla

    2015-01-01

    Objective We evaluated the potential of methylphenidate to improve antidepressant response to citalopram in elderly depressed patients with respect to clinical and cognitive outcomes. Methods We conducted a 16-week randomized double-blind placebo-controlled trial for geriatric depression in 143 older outpatients diagnosed with major depression comparing treatment response in three groups: 1) methylphenidate and placebo (N=48); 2) citalopram and placebo (N=48); 3) methylphenidate and citalopram (N=47). Primary outcome was defined as the change in depression severity. Remission was defined as Hamilton Depression Rating Scale (HDRS-24) score of 6 or below. Secondary outcomes included measures of anxiety, apathy, quality of life, and cognition. Results Citalopram daily doses ranged between 20–60 mg (mean 32 mg); methylphenidate daily doses ranged between 5–40 mg (mean 16 mg). All groups showed significant improvement in the severity of depression. However, the improvement in depression severity and the clinical global impression was more prominent in the methylphenidate and citalopram group compared to methylphenidate and placebo and citalopram and placebo (P<0.05). Additionally, the rate of improvement in the methylphenidate and citalopram group was significantly faster than that in the citalopram and placebo in the first 4 weeks of the trial. The groups did not differ on cognitive improvement or the number of side-effects. Conclusions Combined treatment with citalopram and methylphenidate demonstrated an enhanced clinical response profile in the mood and wellbeing, and the rate of response compared to either drug. All treatments led to an improvement in cognitive functioning, without additional benefit from the use of methylphenidate. PMID:25677354

  4. Improved solubility and bioactivity of theophylline (a bronchodilator drug) through its new nitrate salt analysed by experimental and theoretical approaches

    NASA Astrophysics Data System (ADS)

    Mary Novena, L.; Suresh Kumar, S.; Athimoolam, S.

    2016-07-01

    Synthesis, crystal structure, vibrational spectroscopy, quantum chemical studies and biological activity of the new semi organic compound, Theophyllinium Nitrate [C7H9N4 O2)+. (NO3)-], are reported here. Crystals of Theophyllinium nitrate (TN) were grown by slow solvent evaporation technique. The crystal packing is dominated by N-H···O intermolecular hydrogen bonds. The cations and anions are aggregated almost parallel leading to a lamellar structure. This molecular aggregation features two alternate hydrogen bonded chain C22(8) and C21(6) motifs. Further, a bifurcated ring R12(4) motifs is also seen. This aggregated molecular sheets are parallel to (2 bar 06) and (20 6 bar) planes of the crystal. The solubility test is carried out to enhance the physico-chemical activity of the compound. The atomic charge distribution on different atoms of TN has been calculated by Mulliken charge analysis. A detailed interpretation of FT-IR and FT-Raman spectra of TN show that most of the bands are matching between the experimental and theoretical methods. The strong intensity bands and shifting of bands due to intermolecular hydrogen bonds are also investigated. The NBO analysis is carried out to elucidate the stability of the molecule and charge delocalization within the molecule. The HOMO-LUMO analysis reveals molecular stability and chemical reactivity of the present compound. Also, the compound was examined for its antibacterial activity and found to exhibit notable activity against Pseudomonas aeruginosa. This shows that the present compound is a good candidate for the antimicrobial agent apart from its inherent Bronchodilator drug property. Hence, the new compound (TN) may be a good alternative for patients with Chronic Obstructive Pulmonary Disease (COPD) and bacterial infections.

  5. Improving Drug Penetrability with iRGD Leverages the Therapeutic Response to Sorafenib and Doxorubicin in Hepatocellular Carcinoma.

    PubMed

    Schmithals, Christian; Köberle, Verena; Korkusuz, Hüdayi; Pleli, Thomas; Kakoschky, Bianca; Augusto, Eduardo Alonso; Ibrahim, Ahmed Atef; Arencibia, Jose M; Vafaizadeh, Vida; Groner, Bernd; Korf, Horst-Werner; Kronenberger, Bernd; Zeuzem, Stefan; Vogl, Thomas J; Waidmann, Oliver; Piiper, Albrecht

    2015-08-01

    iRGD is a derivative of the integrin-binding peptide RGD, which selectively increases the penetrability of tumor tissue to various coadministered substances in several preclinical models. In this study, we investigated the ability of iRGD to improve the delivery of sorafenib and doxorubicin therapy in hepatocellular carcinoma (HCC) using established mouse models of the disease. A contrast-enhanced MRI method was developed in parallel to assess the in vivo effects of iRGD in this setting. We found that iRGD improved the delivery of marker substances to the tumors of HCC-bearing mice about three-fold without a parallel increase in normal tissues. Control peptides lacking the critical CendR motif had no effect. Similarly, iRGD also selectively increased the signal intensity from tumors in Gd-DTPA-enhanced MRI. In terms of antitumor efficacy, iRGD coadministration significantly augmented the individual inhibitory effects of sorafenib and doxorubicin without increasing systemic toxicity. Overall, our results offered a preclinical proof of concept for the use of iRGD coadministration as a strategy to widen the therapeutic window for HCC chemotherapy, as monitored by Gd-DTPA-enhanced MRI as a noninvasive, clinically applicable method to identify iRGD-reactive tumors. PMID:26239478

  6. Conjugation of cell-penetrating peptides with poly(lactic-co-glycolic acid)-polyethylene glycol nanoparticles improves ocular drug delivery

    PubMed Central

    Vasconcelos, Aimee; Vega, Estefania; Pérez, Yolanda; Gómara, María J; García, María Luisa; Haro, Isabel

    2015-01-01

    In this work, a peptide for ocular delivery (POD) and human immunodeficiency virus transactivator were conjugated with biodegradable poly(lactic-co-glycolic acid) (PGLA)–polyethylene glycol (PEG)-nanoparticles (NPs) in an attempt to improve ocular drug bioavailability. The NPs were prepared by the solvent displacement method following two different pathways. One involved preparation of PLGA NPs followed by PEG and peptide conjugation (PLGA-NPs-PEG-peptide); the other involved self-assembly of PLGA-PEG and the PLGA-PEG-peptide copolymer followed by NP formulation. The conjugation of the PEG and the peptide was confirmed by a colorimetric test and proton nuclear magnetic resonance spectroscopy. Flurbiprofen was used as an example of an anti-inflammatory drug. The physicochemical properties of the resulting NPs (morphology, in vitro release, cell viability, and ocular tolerance) were studied. In vivo anti-inflammatory efficacy was assessed in rabbit eyes after topical instillation of sodium arachidonate. Of the formulations developed, the PLGA-PEG-POD NPs were the smaller particles and exhibited greater entrapment efficiency and more sustained release. The positive charge on the surface of these NPs, due to the conjugation with the positively charged peptide, facilitated penetration into the corneal epithelium, resulting in more effective prevention of ocular inflammation. The in vitro toxicity of the NPs developed was very low; no ocular irritation in vitro (hen’s egg test–chorioallantoic membrane assay) or in vivo (Draize test) was detected. Taken together, these data demonstrate that PLGA-PEG-POD NPs are promising vehicles for ocular drug delivery. PMID:25670897

  7. Facile and Divergent Synthesis of Lamellarins and Lactam-Containing Derivatives with Improved Drug Likeness and Biological Activities.

    PubMed

    Theppawong, Atiruj; Ploypradith, Poonsakdi; Chuawong, Pitak; Ruchirawat, Somsak; Chittchang, Montakarn

    2015-12-01

    With the goal to improve the aqueous solubility of lamellarins, the lactone ring in their skeleton was replaced with a lactam moiety in azalamellarins. However, the reported synthetic route produced such derivatives in very low yields. Hence, this study focused on developing an efficient simplified total synthetic scheme that could furnish both azalamellarins and the parent lamellarins from the same pyrrole ester intermediates. Subsequent comparative profiling revealed that the introduced lactone-to-lactam replacement rendered these molecules less lipophilic, whereas their cancer cytotoxicity remained equipotent to that of the parent compounds. Interestingly, their inhibitory activity was significantly enhanced towards the multifaceted GSK-3β enzyme. Our results clearly demonstrate the therapeutic potential of this promising class of marine-derived natural products and justify their further development, especially into anticancer agents. PMID:26183429

  8. pH-sensitive micelles based on acid-labile pluronic F68-curcumin conjugates for improved tumor intracellular drug delivery.

    PubMed

    Fang, Xiao-Bin; Zhang, Jin-Ming; Xie, Xi; Liu, Di; He, Cheng-Wei; Wan, Jian-Bo; Chen, Mei-Wan

    2016-04-11

    Curcumin (Cur) is a highly pleiotropic anticancer agent that inhibits cell proliferation and induces apoptosis in cancer cells. A variety of nano-systems constituted by polymer-drug conjugates have been designed to overcome its shortages on water solubility, chemical instability, and poor bioavailability. However, most of them suffer from ineffective release of Cur in cancer cells in vivo. This work developed a novel flexible acid-responsive micelle formulation by covalently conjugating Cur on the hydrophilic terminals of pluronic F68 chains via cis-aconitic anhydride linkers. The synthesized F68-Cis-Cur conjugates can readily precipitate to form homogeneous micelles with average size about 100nm in aqueous solution. In acid environments, F68-Cis-Cur conjugates would break down and subsequently release Cur rapidly, for the reason of pH-sensitive cleavage of cis-aconitic anhydride linkers. In vitro anticancer activity tests demonstrated that F68-Cis-Cur micelles induced higher cytotoxicity against both A2780 and SMMC 7721 cells than free Cur. It provided a larger decrease of mitochondrion membrane potential and induced cellular apoptosis. F68-Cis-Cur micelles remarkably increased cellular uptake of Cur than free Cur through caveolae-mediated endocytosis in an energy-dependent manner. This study demonstrates F68-Cis-Cur conjugation as a promising tool for improving intracellular drug delivery in cancer therapy. PMID:26784981

  9. Improving ex vivo skin permeation of non-steroidal anti-inflammatory drugs: enhancing extemporaneous transformation of liposomes into planar lipid bilayers.

    PubMed

    Vázquez-González, Martha L; Bernad, Rafael; Calpena, Ana C; Domènech, Oscar; Montero, M T; Hernández-Borrell, Jordi

    2014-01-30

    Transdermal delivery of active principles is a versatile method widely used in medicine. The main drawback for the transdermal route, however, is the low efficiency achieved in the absorption of many drugs, mostly due to the complexity of the skin barrier. To improve drug delivery through the skin, we prepared and characterized liposomes loaded with ibuprofen and designed pharmaceutical formulations based on the extemporaneous addition of penetration enhancer (PE) surfactants. Afterwards, permeation and release studies were carried out. According to the permeation studies, the ibuprofen liposomal formulation supplemented with PEs exhibited similar therapeutic effects, but at lower doses (20%) comparing with a commercial formulation used as a reference. Atomic force microscopy (AFM) was used to investigate the effect caused by PEs on the adsorption mechanism of liposomal formulations onto the skin. Non-fused liposomes, bilayers and multilayered lipid structures were observed. The transformation of vesicles into planar structures is proposed as a possible rationale for explaining the lower doses required when a liposome formulation is supplemented with surfactant PEs. PMID:24361268

  10. Club Drugs

    MedlinePlus

    ... Rohypnol, ketamine, as well as MDMA (ecstasy) and methamphetamine ( Drug Facts: Club Drugs , National Institute on Drug ... Club Drugs , National Institute on Drug Abuse, 2010). Methamphetamine is a powerfully addictive stimulant associated with serious ...

  11. Using Electronic Drug Monitor Feedback to Improve Adherence to Antiretroviral Therapy Among HIV-Positive Patients in China

    PubMed Central

    DeSilva, Mary Bachman; Hamer, Davidson H.; Xu, Keyi; Zhang, Jianbo; Li, Tao; Wilson, Ira B.; Gill, Christopher J.

    2009-01-01

    Effective antiretroviral therapy (ART) requires excellent adherence. Little is known about how to improve ART adherence in many HIV/AIDS-affected countries, including China. We therefore assessed an adherence intervention among HIV-positive patients in southwestern China. Eighty subjects were enrolled and monitored for 6 months. Sixty-eight remaining subjects were randomized to intervention/control arms. In months 7–12, intervention subjects were counseled using EDM feedback; controls continued with standard of care. Among randomized subjects, mean adherence and CD4 count were 86.8 vs. 83.8% and 297 vs. 357 cells/μl in intervention vs. control subjects, respectively. At month 12, among 64 subjects who completed the trial, mean adherence had risen significantly among intervention subjects to 96.5% but remained unchanged in controls. Mean CD4 count rose by 90 cells/μl and declined by 9 cells/μl among intervention and control subjects, respectively. EDM feedback as a counseling tool appears promising for management of HIV and other chronic diseases. PMID:19771504

  12. Genetic and Pharmacological Modulation of the Steroid Sulfatase Axis Improves Response Control; Comparison with Drugs Used in ADHD

    PubMed Central

    Davies, William; Humby, Trevor; Trent, Simon; Eddy, Jessica B; Ojarikre, Obah A; Wilkinson, Lawrence S

    2014-01-01

    Maladaptive response control is a feature of many neuropsychiatric conditions, including attention deficit hyperactivity disorder (ADHD). As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase (STS) influences risk for ADHD. We examined whether deletion of the Sts gene in the 39,XY*O mouse model, or pharmacological manipulation of the STS axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analog of the stop-signal reaction time task used to detect inhibitory deficits in individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a prepotent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicates that the STS axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. While the precise neurobiological mechanism(s) underlying the effects remain to be established, there is the potential for exploiting this pathway in the treatment of disorders where failures in behavioral inhibition are prominent. PMID:24842408

  13. Co-overexpression of geraniol-10-hydroxylase and strictosidine synthase improves anti-cancer drug camptothecin accumulation in Ophiorrhiza pumila.

    PubMed

    Cui, Lijie; Ni, Xiaoling; Ji, Qian; Teng, Xiaojuan; Yang, Yanru; Wu, Chao; Zekria, David; Zhang, Dasheng; Kai, Guoyin

    2015-01-01

    Camptothecin (CPT) belongs to a group of monoterpenoidindole alkaloids (TIAs) and its derivatives such as irinothecan and topothecan have been widely used worldwide for the treatment of cancer, giving rise to rapidly increasing market demands. Genes from Catharanthus roseus encoding strictosidine synthase (STR) and geraniol 10-hydroxylase (G10H), were separately and simultaneously introduced into Ophiorrhiza pumila hairy roots. Overexpression of individual G10H (G lines) significantly improved CPT production with respect to non-transgenic hairy root cultures (NC line) and single STR overexpressing lines (S lines), indicating that G10H plays a more important role in stimulating CPT accumulation than STR in O. pumila. Furthermore, co-overexpression of G10H and STR genes (SG Lines) caused a 56% increase on the yields of CPT compared to NC line and single gene transgenic lines, showed that simultaneous introduction of G10H and STR can produce a synergistic effect on CPT biosynthesis in O. pumila. The MTT assay results indicated that CPT extracted from different lines showed similar anti-tumor activity, suggesting that transgenic O. pumila hairy root lines could be an alternative approach to obtain CPT. To our knowledge, this is the first report on the enhancement of CPT production in O. pumila employing a metabolic engineering strategy. PMID:25648209

  14. A Systems-Pharmacology Analysis of Herbal Medicines Used in Health Improvement Treatment: Predicting Potential New Drugs and Targets

    PubMed Central

    Liu, Jianling; Pei, Mengjie; Zheng, Chunli; Li, Yan; Wang, Yonghua; Lu, Aiping; Yang, Ling

    2013-01-01

    For thousands of years, tonic herbs have been successfully used all around the world to improve health, energy, and vitality. However, their underlying mechanisms of action in molecular/systems levels are still a mystery. In this work, two sets of tonic herbs, so called Qi-enriching herbs (QEH) and Blood-tonifying herbs (BTH) in TCM, were selected to elucidate why they can restore proper balance and harmony inside body, organ and energy system. Firstly, a pattern recognition model based on artificial neural network and discriminant analysis for assessing the molecular difference between QEH and BTH was developed. It is indicated that QEH compounds have high lipophilicity while BTH compounds possess high chemical reactivity. Secondly, a systematic investigation integrating ADME (absorption, distribution, metabolism, and excretion) prediction, target fishing and network analysis was performed and validated on these herbs to obtain the compound-target associations for reconstructing the biologically-meaningful networks. The results suggest QEH enhance physical strength, immune system and normal well-being, acting as adjuvant therapy for chronic disorders while BTH stimulate hematopoiesis function in body. As an emerging approach, the systems pharmacology model might facilitate to understand the mechanisms of action of the tonic herbs, which brings about new development for complementary and alternative medicine. PMID:24369484

  15. Herb-drug, food-drug, nutrient-drug, and drug-drug interactions: mechanisms involved and their medical implications.

    PubMed

    Sørensen, Janina Maria

    2002-06-01

    Adverse drug reactions (ADRs) and iatrogenic diseases have been identified as significant factors responsible for patient morbidity and mortality. Significant studies on drug metabolism in humans have been published during the last few years, offering a deeper comprehension of the mechanisms underlying adverse drug reactions and interactions. More understanding of these mechanisms, and of recent advances in laboratory technology, can help to evaluate potential drug interactions when drugs are prescribed concurrently. Increasing knowledge of interindividual variation in drug breakdown capacity and recent findings concerning the influence of environment, diet, nutrients, and herbal products can be used to reduce ADRs and iatrogenic diseases. Reviewed data suggest that drug treatment should be increasingly custom tailored to suit the individual patient and that appropriately co-prescribed diet and herbal remedies, could increase drug efficacy and lessen drug toxicity. This review focuses mainly on recently published research material. The cytochrome p450 enzymes, their role in metabolism, and their mechanisms of action are reviewed, and their role in drug-drug interactions are discussed. Drug-food and drug-herb interactions have garnered attention. Interdisciplinary communication among medical herbalists, medical doctors, and dietetic experts needs to be improved and encouraged. Internet resources for obtaining current information regarding drug-drug, drug-herb, and drug-nutrient interactions are provided. PMID:12165187

  16. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival.

    PubMed

    Powe, Desmond G; Voss, Melanie J; Zänker, Kurt S; Habashy, Hany O; Green, Andrew R; Ellis, Ian O; Entschladen, Frank

    2010-11-01

    Laboratory models show that the beta-blocker, propranolol, can inhibit norepinephrine-induced breast cancer cell migration. We hypothesised that breast cancer patients receiving beta-blockers for hypertension would show reduced metastasis and improved clinical outcome. Three patient subgroups were identified from the medical records of 466 consecutive female patients (median age 57, range 28-71) with operable breast cancer and follow-up (>10 years). Two subgroups comprised 43 and 49 hypertensive patients treated with beta-blockers or other antihypertensives respectively, prior to cancer diagnosis. 374 patients formed a non-hypertensive control group. Metastasis development, disease free interval, tumour recurrence and hazards risk were statistically compared between groups. Kaplan-Meier plots were used to model survival and DM. Beta-blocker treated patients showed a significant reduction in metastasis development (p=0.026), tumour recurrence (p=0.001), and longer disease free interval (p=0.01). In addition, there was a 57% reduced risk of metastasis (Hazards ratio=0.430; 95% CI=0.200-0.926, p=0.031), and a 71% reduction in breast cancer mortality after 10 years (Hazards ratio=0.291; 95% CI=0.119-0.715, p=0.007). This proof-of-principle study showed beta-blocker therapy significantly reduces distant metastases, cancer recurrence, and cancer-specific mortality in breast cancer patients suggesting a novel role for beta-blocker therapy. A larger epidemiological study leading to randomised clinical trials is needed for breast and other cancer types including colon, prostate and ovary. PMID:21317458

  17. Improving Monitoring and Reporting of Adverse Drug Reactions (ADRs) in HIV positive patients on Antiretroviral Therapy (ART) in Nigeria

    PubMed Central

    Agu, Kenneth Anene; Oparah, Azuka Cyriacus; Ochei, Uche M.

    2012-01-01

    Under-reporting of ADR may be associated with poor knowledge, attitudes and practices to pharmacovigilance. This study evaluated knowledge, attitudes and practices of healthcare professionals about ADR monitoring and reporting following interventions. This longitudinal study included 36 healthcare professionals participating in ART program in a tertiary hospital. Interventions included group training on pharmacovigilance (PV) and provision of ADR reporting forms amongst others. Assessments were conducted at months 0 and 6 post-interventions using study-specific Likert-type instruments. Mean attitude scores above midpoint of 3.6 on 5-point scale were regarded as positive and below as negative. P<0.05 used to determine statistical significance. Mean age of participants was 36.6 (95%CI, 34.5–38.7) years; 61.1% males; 44.4% doctors, 13.9% pharmacists, 19.4% nurses, 8.3% laboratory scientists, 8.3% record officers and 5.6% welfare officers. None had received training on PV previously. Mean knowledge test score increased from 53.6% (95%CI, 44.6–63.6) at pre-intervention to 77.1% (95%CI, 72.8–81.4) at post-intervention with a mean change of 146.9% (95%CI, 60.5–233.3; p=0.000). Mean rated attitude scores increased from 3.6 (95%CI, 3.4–3.8) at pre-intervention to 4.2 (95%CI, 4.0–4.4) at post-intervention; the difference was statistically significant (p=0.000). 75.8% reported that ADR reporting forms were not readily available at pre-intervention compared to 18.2% at postintervention; 15.2% had reported ADR previously at pre-intervention compared to 69.7% at post-intervention; 12.1% reported providing information regarding ADRs and its management always at pre-intervention compared to 45.5% at post-intervention; these differences were statistically significant (p<0.05). Lack/inadequate knowledge, unavailability of reporting forms and negative attitudes were barriers identified; and addressing them resulted in significant improvement in this setting. Scaling up

  18. Improving the preclinical models for the study of chemotherapy-induced cardiotoxicity: a Position Paper of the Italian Working Group on Drug Cardiotoxicity and Cardioprotection.

    PubMed

    Madonna, Rosalinda; Cadeddu, Christian; Deidda, Martino; Mele, Donato; Monte, Ines; Novo, Giuseppina; Pagliaro, Pasquale; Pepe, Alessia; Spallarossa, Paolo; Tocchetti, Carlo Gabriele; Zito, Concetta; Mercuro, Giuseppe

    2015-09-01

    Although treatment for heart failure induced by cancer therapy has improved in recent years, the prevalence of cardiomyopathy due to antineoplastic therapy remains significant worldwide. In addition to traditional mediators of myocardial damage, such as reactive oxygen species, new pathways and target cells should be considered responsible for the impairment of cardiac function during anticancer treatment. Accordingly, there is a need to develop novel therapeutic strategies to protect the heart from pharmacologic injury, and improve clinical outcomes in cancer patients. The development of novel protective therapies requires testing putative therapeutic strategies in appropriate animal models of chemotherapy-induced cardiomyopathy. This Position Paper of the Working Group on Drug Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology aims to: (1) define the distinctive etiopatogenetic features of cardiac toxicity induced by cancer therapy in humans, which include new aspects of mitochondrial function and oxidative stress, neuregulin-1 modulation through the ErbB receptor family, angiogenesis inhibition, and cardiac stem cell depletion and/or dysfunction; (2) review the new, more promising therapeutic strategies for cardioprotection, aimed to increase the survival of patients with severe antineoplastic-induced cardiotoxicity; (3) recommend the distinctive pathological features of cardiotoxicity induced by cancer therapy in humans that should be present in animal models used to identify or to test new cardioprotective therapies. PMID:26168714

  19. Critical analysis of India's National Mission on Medicinal Plants (NMMP) in providing access to quality botanical drugs to improve public health

    PubMed Central

    Jain, Rahi; Rao, Bakul

    2015-01-01

    Drugs play an important role in improving health of the population. Medicinal plants help in addressing the health issues of a large section of the population – especially the low and middle-income people. However, there are some concerns about the supply, efficacy and safety in using them. This study reviews India's major initiative toward medicinal plants namely, the National Mission on Medicinal Plants to meet medicinal plants challenges. The study analyzed the mission's probable shortcomings due to its design and operational details. This study used “content analysis” approach for analysis of mission's publicly available documents, viz. “Operational guidelines” and its two amendments. The study identified prevalent 28 shortcomings in the original document related to clarity of the document; accountability, transparency and stakeholders’ representation. These challenges were partially addressed in two amendments, which indicate persistence of shortcomings in design and operational details. The mission can help in improving and strengthening the Ayurveda, Yoga, Unani, Siddha and Homeopathy program by addressing those shortcomings. PMID:26604556

  20. Methadone maintenance treatment programme reduces criminal activity and improves social well-being of drug users in China: a systematic review and meta-analysis

    PubMed Central

    Sun, Hua-Min; Li, Xiao-Yan; Chow, Eric P F; Li, Tong; Xian, Yun; Lu, Yi-Hua; Tian, Tian; Zhuang, Xun; Zhang, Lei

    2015-01-01

    .2%) at 6 months, then to 59.8% (95% CI 52.4% to 66.8%) and 75.0% (95% CI 69.0% to 80.2%) at 12 months after treatment initiation, respectively. Conclusions MMT has significantly reduced criminal activity, and improved employment rate and social well-being, of clients of the MMT programme. MMT is an effective measure to help drug users to resume societal and familial functions in China. PMID:25573521

  1. Novel self-emulsifying formulation of quercetin for improved in vivo antioxidant potential: implications for drug-induced cardiotoxicity and nephrotoxicity.

    PubMed

    Jain, Sanyog; Jain, Amit K; Pohekar, Milind; Thanki, Kaushik

    2013-12-01

    Quercetin (QT) was formulated into a novel self-emulsifying drug delivery system (SEDDS) to improve its oral bioavailability and antioxidant potential compared to free drug. Capmul MCM was selected as the oily phase on the basis of optimum solubility of QT in oil. Tween 20 and ethanol were selected as surfactant and cosurfactant from a large pool of excipients, depending upon their spontaneous self-emulsifying ability with the selected oily phase. Pseudoternary-phase diagrams were constructed to identify the efficient self-emulsification regions in various dilution media, viz., water, pH 1.2, and pH 6.8. The ratio of 40:40:20 w/w, Capmul MCM:QT (19:1)/Tween 20/ethanol was optimized based on its ability to form a spontaneous submicrometer emulsion in simulated gastrointestinal fluids. DPPH scavenging assay showed comparable antioxidant activity of QT-SEDDS to free QT. QT-SEDDS was robust in terms of stability against short-term excursion of freeze/thaw cycles and accelerated stability for 6 months as per International Conference on Harmonisation guidelines. A fluorescent dye-loaded SEDDS formulation showed rapid internalization within 1h of incubation with Caco-2 cells as evident by confocal laser scanning microscopy. QT-SEDDS showed a significant increase in cellular uptake by 23.75-fold in comparison with free QT cultured with Caco-2 cells. The SEDDS demonstrated ~5-fold enhancement in oral bioavailability compared to free QT suspension. The in vitro-in vivo relation between in vitro Caco-2 cell uptake and in vivo pharmacokinetics of QT-SEDDS showed a correlation coefficient of ~0.9961, as evident from a Levy plot. Finally, QT-SEDDS showed a significantly higher in vivo antioxidant potential compared to free QT when evaluated as a function of ability to combat doxorubicin- and cyclosporin A-induced cardiotoxicity and nephrotoxicity, respectively. PMID:23792276

  2. Quality of drug information on the World Wide Web and strategies to improve pages with poor information quality. An intervention study on pages about sildenafil

    PubMed Central

    Martin-Facklam, Meret; Kostrzewa, Michael; Martin, Peter; Haefeli, Walter E

    2004-01-01

    Aims The generally poor quality of health information on the world wide web (WWW) has caused preventable adverse outcomes. Quality management of information on the internet is therefore critical given its widespread use. In order to develop strategies for the safe use of drugs, we scored general and content quality of pages about sildenafil and performed an intervention to improve their quality. Methods The internet was searched with Yahoo and AltaVista for pages about sildenafil and 303 pages were included. For assessment of content quality a score based on accuracy and completeness of essential drug information was assigned. For assessment of general quality, four criteria were evaluated and their association with high content quality was determined by multivariate logistic regression analysis. The pages were randomly allocated to either control or intervention group. Evaluation took place before, as well as 7 and 22 weeks after an intervention which consisted of two letters with individualized feedback information on the respective page which were sent electronically to the address mentioned on the page. Results Providing references to scientific publications or prescribing information was significantly associated with high content quality (odds ratio: 8.2, 95% CI 3.2, 20.5). The intervention had no influence on general or content quality. Conclusions To prevent adverse outcomes caused by misinformation on the WWW individualized feedback to the address mentioned on the page was ineffective. It is currently probably the most straight-forward approach to inform lay persons about indicators of high information quality, i.e. the provision of references. PMID:14678344

  3. Treating mannitol in a saturated solution of mannitol: a novel approach to modify mannitol crystals for improved drug delivery to the lungs.

    PubMed

    Kaialy, Waseem; Nokhodchi, Ali

    2013-05-01

    The aim of this study was to evaluate the influence of treatment of a promising dry powder aerosol carrier (mannitol) on the aerosolization performance of salbutamol sulphate (SS) using a novel approach: treating excess commercial carrier particles in a saturated solution of the same carrier. Commercial mannitol (CM) particles were treated with aqueous mannitol supersaturated solutions (20% and 25% w/v), under stirring, (300 rpm) for either 24h or 48 h. The results showed that particle treatment did not alter the polymorphic form of mannitol (β-mannitol); however, all treated mannitol particles demonstrated smoother surface topography and improved aerosolization performance compared to CM in dry powder inhalations. Unlike the concentration of mannitol solution used during treatment, the time of treatment to collect mannitol crystals was an essential key to modify the physical properties of mannitol and its effect on the aerosolization performance. In comparison to mannitol particles treated for 48 h, mannitol particles treated for 24h demonstrated larger size, more elongated-less regular shape, and smoother surfaces. No apparent relationship was obtained between in vitro aerosolisation behavior of SS with either mannitol particle size or shape descriptors. However, despite their larger size and more irregular-less uniformed shape, treated mannitol particles with smoother surfaces generated drug particles with smaller aerodynamic size and are expected to deliver higher amounts of drug to lower airways. The results demonstrated the potential of treating mannitol particles in aqueous solutions of the same material under controlled conditions to produce mannitol particles promising for dry powder inhaler systems. The results suggested that mannitol particle surface texture properties dominate over both particle size and particle shape of mannitol in terms of determining the aerosolization performance of mannitol. PMID:23500603

  4. Clinically important improvement in the WOMAC and predictor factors for response to non-specific non-steroidal anti-inflammatory drugs in osteoarthritic patients: a prospective study

    PubMed Central

    2012-01-01

    Background The aims of the present study were first to detect MCID for WOMAC in a Moroccan population, and second, to identify the best pre-treatment predictors on the change of health after treatment by non-specific, non-steroidal anti-inflammatory drugs (NSAIDs), and to evaluate whether the predictors were dependent on the choice of the response criterion. Methods The study involved 173 patients with osteoarthritis in whom primary care physicians decided to start treatment with non-selective NSAIDs. Assessments at admission and after 6 weeks were conducted. In order to determine the threshold levels associated with a definition of clinically important improvement, the receiver operating characteristic method was used. Three different measures of response to a 6-week NSAIDs treatment were used: one indirect measure (MCID in the total WOMAC score), one direct measure (transition question) and a combination of both criteria. Results Eighty patients (46.3%) reported "a slightly better" general health status compared to that of 6 weeks before NSAIDs treatment. The MCID proportion is a 16.0% reduction in WOMAC. The most stable pre-treatment predictors on the improvement of health after treatment by NSAIDs were the absence of previous knee injury and a high level of education. Conclusions In our data, a 16.0% reduction of the total WOMAC score from baseline was associated with the highest degree of improvement on the transition scale category. This cut-off point had good accuracy, and should be appropriate for use in the interpretation of clinical studies results, as well as in clinical care. PMID:22269793

  5. Drug allergies

    MedlinePlus

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The ...

  6. Drug allergies

    MedlinePlus

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... Adverse reactions to drugs are common. (adverse means unwanted or unexpected.) Almost any drug can cause an adverse reaction. Reactions range from irritating ...

  7. Drug Safety

    MedlinePlus

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  8. Club Drugs

    MedlinePlus

    ... uses. Other uses of these drugs are abuse. Club drugs are also sometimes used as "date rape" drugs, to make someone unable to say no to or fight back against sexual assault. Abusing these drugs can ...

  9. A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

    PubMed Central

    Kast, Richard E.; Boockvar, John A.; Brüning, Ansgar; Cappello, Francesco; Chang, Wen-Wei; Cvek, Boris; Dou, Q. Ping; Duenas-Gonzalez, Alfonso; Efferth, Thomas; Focosi, Daniele; Ghaffari, Seyed H.; Karpel-Massler, Georg; Ketola, Kirsi; Khoshnevisan, Alireza; Keizman, Daniel; Magné, Nicolas; Marosi, Christine; McDonald, Kerrie; Muñoz, Miguel; Paranjpe, Ameya; Pourgholami, Mohammad H.; Sardi, Iacopo; Sella, Avishay; Srivenugopal, Kalkunte S.; Tuccori, Marco; Wang, Weiguang; Wirtz, Christian R.; Halatsch, Marc-Eric

    2013-01-01

    To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma's compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed. PMID:23594434

  10. Pomegranate seed oil nanoemulsions improve the photostability and in vivo antinociceptive effect of a non-steroidal anti-inflammatory drug.

    PubMed

    Ferreira, Luana Mota; Sari, Marcel Henrique Marcondes; Cervi, Verônica Ferrari; Gehrcke, Mailine; Barbieri, Allanna Valentini; Zborowski, Vanessa Angonesi; Beck, Ruy Carlos Ruver; Nogueira, Cristina Wayne; Cruz, Letícia

    2016-08-01

    The combination of pomegranate seed oil and ketoprofen in nanoemulsions aiming to improve the antinociceptive effect was evaluated according to the writhing test and Complete Freud's Adjuvant induced paw inflammation in mice. The formulations showed adequate characteristics and improved ketoprofen's photostability against UVC radiation exposure. The dialysis bag technique showed that 100% of the drug was released from the nanoemulsions after 3h and the oil amount had no influence on the releasing. Furthermore, time- and dose-response curves were obtained to determine the antinociceptive effect of the formulations. In the post-test, the nanoemulsion containing ketoprofen significantly reduced abdominal constrictions in time-response curve, showing effect up to 12h while the free ketoprofen showed effect up to 3h. In addition, the blank nanoemulsion presented a reduction of abdominal constriction up to 1h of pre-treatment. Regarding the dose-response curve, the free ketoprofen presents effect at 0.5mg/Kg dose and nanoemulsion at 1.0mg/Kg dose. Time- and dose-response curves were performed to determine the antinociceptive effect in inflammatory pain. After the evaluation of mechanical allodynia testing at the Von Frey Hair, the free ketoprofen showed effect up to 6h while nanoemulsions presented effect up to 10h. Moreover, acute toxicity was performed with ALT and AST activity evaluations and urea levels. After 7 days of treatment, no toxic effects for nanoemulsions were found. In conclusion, ketoprofen-loaded pomegranate seed oil nanoemulsions presented adequate characteristics and a high antinociceptive activity in the animal models tested. PMID:27088191

  11. From many deaths to some few cases of drug-resistant tuberculosis: travelling with the systems quality improvement model in Lacs Health District, Togo

    PubMed Central

    Afanvi, Kossivi Agbelenko

    2015-01-01

    The ultimate goal of every tuberculosis (TB) treatment program is a high treatment success rate. Treatment success is extremely important because, when the rate is high, it significantly contributes to declining numbers of new cases by reducing the number and period of infectious cases, TB morbidity and mortality, and prevents the emergence of resistant strains. Our aim was to decrease TB mortality by increasing pulmonary TB patients’ treatment success rate to at least 85 % in Lacs Health District by end of July 2014. A systems and dialogic analysis of the public health system related to TB patients’ treatment revealed that it was not performing well; we found weak coverage and quality of TB services, a poorly-functioning TB health information system, poor-performing health workforce, poor availability of HIV tests and antiretroviral for TB patients, and low degree of patients’ participation in their care. We redesigned the system to correct those weaknesses. The effectiveness of these changes was monitored using plan, do, study, act (PDSA) cycles. We increased TB patient success rate from 80% to 95% between February 2012 and July 2014.The mortality rate dropped from 13% to 3% and the failure to follow-up rate dropped from 3% to 2%. In conclusion, district health systems performance depends on factors such as the closeness of services to population; skilled workforce; the ability to collect and analyze data and use information for action; population empowerment, and good management and improvement capabilities of management team especially the public health director. High TB patients’ success rate depends also on the availability of antiretroviral drugs. It is highly important that every district health management team member develops improvement capabilities. PMID:26734412

  12. Improved drug delivery and therapeutic efficacy of PEgylated liposomal doxorubicin by targeting anti-HER2 peptide in murine breast tumor model.

    PubMed

    Zahmatkeshan, Masoumeh; Gheybi, Fatemeh; Rezayat, Seyed Mahdi; Jaafari, Mahmoud Reza

    2016-04-30

    Targeted cancer therapy is a powerful therapeutic strategy to management of cancer. HER2 as an anticancer target has long been studied. Its overexpression plays an important role in the pathogenesis and progressiveness of breast and other cancers. To establish efficient and reliable drug delivery to HER2-overexpressing cells, the authors of this study have developed anti-HER2 (ErbB2) peptide-liposomal formulations of doxorubicin (DOX) by an engineered breast tumor-targeting peptide ligand, AHNP, Anti-HER2/neu peptide, (FCDGFYACYADV) with three glycine amino acids as spacer before its original sequencing. Towards this goal, PEGylated liposome doxorubicin (PLD) bearing different ligand densities of AHNP was prepared and characterized for their size, zeta potential and peptide conjugation. The AHNP functionalization and density effects on breast tumor cell uptake, selective cytotoxicity, prevention of tumor growth and the tissue biodistribution of encapsulated DOX were studied in mice bearing TUBO breast cancer tumor model. The findings demonstrated that increasing the ligand density of AHNP increases cytotoxicity and cell-uptake in SKBR3 and TUBO cells which overexpress HER2 but not in MDA-MB-231with low HER2 expression profile. The anticancer activity was also superior for targeted liposomal DOX with more AHNP densities. Overall, the results showed that optimum AHNP density functionalization of PLD can significantly improve selectivity and the therapeutic index of liposomal DOX in the treatment of HER2 positive breast cancer and merits further investigation. PMID:26972276

  13. Access to HIV counseling and testing among people who inject drugs in Central Asia: Strategies for improving access and linkages to treatment and care

    PubMed Central

    Terlikbayeva, Assel; Zhussupov, Baurzhan; Primbetova, Sholpan; Gilbert, Louisa; Atabekov, Nurmat; Giyasova, Gusal; Ruziev, Murodali; Soliev, Alijon; Saliev, Daniiar; El-Bassel, Nabila

    2013-01-01

    Introduction As a population profoundly affected by the HIV epidemic and in critical need of linkages to HIV treatment and care, PWID in Central Asia remain largely underserved. This paper provides an overview of the current state of HIV testing and counseling in Central Asia for PWID, identifies main barriers leading to gaps in service delivery, and discusses implications for improving strategies that promote HIV testing for PWID. Methods We reviewed a number of sources for this paper including unpublished government reports, published papers, and Ministries of Health of Kazakhstan, Kyrgyzstan, Tajikistan, and Uzbekistan country progress reports to the UN General Assembly Special Session on HIV/AIDS (UNGASS) for 2012. Results Between 29 to 65% of PLWH in some Central Asian countries have been tested for HIV in the last 12 months. The rates have been increasing in the recent years but still are relatively low. Stigma, discrimination, human rights violations, and repressive legislation are barriers to HTC for people who inject drugs (PWID). Conclusion The use of innovative evidence-based HTC models, such as community mobile-vans, self-testing at home, and rapid HIV testing among PWID in Central Asia are discussed and recommendations given regarding amendments in legislation and scaling up of existing community-based pilot projects to support HIV testing among PWID in CA. PMID:23916319

  14. A case study using a patient satisfaction survey to improve the delivery and effectiveness of drug addiction treatment services: marketing implications and organizational impact.

    PubMed

    Hogan, Beth; Hershey, Lewis; Ritchey, Steven

    2007-01-01

    Drug abuse and addiction continues to negatively impact many lives in this country. The United States health care system has grappled with how to best serve this vulnerable population. Since the personal and societal costs of addiction are high, all recent iterations of the United States strategic health plans (such as Healthy People 2010) have prioritized this area for improvement. At the local level, health care providers who care for those with addictions are challenged with shrinking insurance coverage for services, a difficult patient population, lack of treatment options, growing ranks of indigent patients, as well as a plethora of additional management challenges. It is known that successful treatment is integrally linked with patient satisfaction with services. The most critical factors in successful addiction treatment (from a patient's perspective) are (1) their belief that the counselor cares about them and, (2) their belief that they can recover. This paper reports a case study in the use of a patient satisfaction survey as a quality management/service refinement tool within a methadone treatment setting. Results indicate that the use of the survey itself provides patients with a tangible cue supporting the presence of the critical success factors. Further, the use of a survey provides a baseline for future measurements and trending. The paper concludes with a discussion of the marketing and organizational implications of incorporating the patient satisfaction survey into the ongoing delivery program for addiction services. PMID:19042522

  15. The α2B adrenergic receptor is mutant in cortical myoclonus and epilepsy

    PubMed Central

    De Fusco, Maurizio; Vago, Riccardo; Striano, Pasquale; Di Bonaventura, Carlo; Zara, Federico; Mei, Davide; Kim, Min Seuk; Muallem, Shmuel; Chen, Yunjia; Wang, Qin; Guerrini, Renzo; Casari, Giorgio

    2013-01-01

    Objective Autosomal dominant cortical myoclonus and epilepsy (ADCME) is characterized by distal, fairly rhythmic myoclonus and epilepsy with variable severity. We have previously mapped the disease locus on chromosome 2p11.1-q12.2 by genome-wide linkage analysis. Additional pedigrees affected by similar forms of epilepsy have been associated to chromosome 8q, 5p and 3q, but none of the causing genes has been identified. We aim at identifying the mutant gene responsible for this epileptic form. Methods Genes included in the ADCME critical region were prioritized and directly sequenced. Co-immunoprecipitation, immunofluorescence and electrophysiology approaches on transfected human cells have been utilized for testing the functional significance of the identified mutation. Results Here we show that mutation in the α2-adrenergic receptor subtype B (α2B-AR) associates to ADCME by identifying a novel in-frame insertion/deletion in two Italian families. The mutation alters several conserved residues of the third intracellular (3i) loop, neither hampering the α2B-AR plasma membrane localization nor the arrestin-mediated internalization capacity, but altering the binding with the scaffolding protein spinophilin upon neurotransmitter activation. Spinophilin, in turn, regulates interaction of GPCRs with Regulators of G proteins Signaling proteins. Accordingly, the mutant α2B-AR increases the epinephrine-stimulated calcium signaling. Interpretation The identified mutation is responsible for ADCME, as the loss of α2B-AR/spinophilin interaction causes a gain of function effect. This work implicates for the first time the α-adrenergic system in human epilepsy and opens new ways for understanding the molecular pathway of epileptogenesis, widening the spectrum of possible therapeutic targets. PMID:24114805

  16. Drug discovery in jeopardy

    PubMed Central

    Cuatrecasas, Pedro

    2006-01-01

    Despite striking advances in the biomedical sciences, the flow of new drugs has slowed to a trickle, impairing therapeutic advances as well as the commercial success of drug companies. Reduced productivity in the drug industry is caused mainly by corporate policies that discourage innovation. This is compounded by various consequences of mega-mergers, the obsession for blockbuster drugs, the shift of control of research from scientists to marketers, the need for fast sales growth, and the discontinuation of development compounds for nontechnical reasons. Lessons from the past indicate that these problems can be overcome, and herein, new and improved directions for drug discovery are suggested. PMID:17080187

  17. Guideline on controlled drugs.

    PubMed

    2016-06-01

    The National Institute for Health and Care Excellence has published a guideline for using and managing controlled drugs safely in all NHS settings except care homes. The institute's aims are to improve working practices, make sure they comply with legislation, and ensure robust governance arrangements are in place and reduce the safety risks associated with controlled drugs. The guideline includes recommendations on record keeping, risk assessment, reporting drug-related incidents, prescribing and administering, monitoring drug use, and developing systems for the destruction and disposal of controlled drugs. It is available at www.nice.org.uk/guidance/ng46. PMID:27246424

  18. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014.

    PubMed

    Chau, M M; Kong, D C M; van Hal, S J; Urbancic, K; Trubiano, J A; Cassumbhoy, M; Wilkes, J; Cooper, C M; Roberts, J A; Marriott, D J E; Worth, L J

    2014-12-01

    Antifungal agents may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy. These risks may be minimised by clinical assessment, laboratory monitoring, avoidance of particular drug combinations and dose modification. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. Therapeutic drug monitoring (TDM) of antifungal agents is warranted, especially where non-compliance, non-linear pharmacokinetics, inadequate absorption, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Recommended indications for voriconazole and posaconazole TDM in the clinical management of haematology patients are provided. With emerging knowledge regarding the impact of pharmacogenomics upon metabolism of azole agents (particularly voriconazole), potential applications of pharmacogenomic evaluation to clinical practice are proposed. PMID:25482746

  19. Drugs, drugs--who has the drugs?

    PubMed

    Blair, James

    2012-01-01

    Drug diversion, although on the increase, is not the only problem involving drugs that hospital security officials should be concerned with. Growing drug shortages, offshore production, counterfeiting, and weaknesses in the drug supply chain in case of a world-wide pandemic, are even greater causes for concern, the author claims. PMID:22423518

  20. Improved sensitivity by use of gas chromatography-positive chemical ionization triple quadrupole mass spectrometry for the analysis of drug related substances.

    PubMed

    Van Gansbeke, Wim; Polet, Michael; Hooghe, Fiona; Devos, Christophe; Van Eenoo, Peter

    2015-09-15

    In 2013, the World Anti-Doping Agency (WADA) drastically lowered the minimum required performance levels (MRPLs) of most doping substances, demanding a substantial increase in sensitivity of the existing methods. For a number of compounds, conventional electron impact ionization gas chromatography tandem mass spectrometry (GC-EI-MS/MS) is often no longer sufficient to reach these MRPLs and new strategies are required. In this study, the capabilities of positive ion chemical ionization (PICI) GC-MS/MS are investigated for a wide range of drug related compounds of various classes by injection of silylated reference standards. Ammonia as PICI reagent gas had superior characteristics for GC-MS/MS purposes than methane. Compared to GC-EI-MS/MS, PICI (with ammonia as reagent gas) provided more selective ion transitions and consequently, increased sensitivity by an average factor of 50. The maximum increase (by factor of 500-1000) was observed in the analysis of stimulants, namely chlorprenaline, furfenorex and phentermine. In total, improved sensitivity was obtained for 113 out of 120 compounds. A new GC-PICI-MS/MS method has been developed and evaluated for the detection of a wide variety of exogenous doping substances and the quantification of endogenous steroids in urine in compliance with the required MRPLs established by WADA in 2013. The method consists of a hydrolysis and extraction step, followed by derivatization and subsequent 1μL pulsed splitless injection on GC-PICI-MS/MS (16min run). The increased sensitivity allows the set up of a balanced screening method that meets the requirements for both quantitative and qualitative compounds: sufficient capacity and resolution in combination with high sensitivity and short analysis time. This resulted in calibration curves with a wide linear range (e.g., 48-9600ng/mL for androsterone and etiochanolone; all r(2)>0.99) without compromising the requirements for the qualitative compounds. PMID:26296082

  1. A novel liposomal irinotecan formulation with significant anti-tumour activity: use of the divalent cation ionophore A23187 and copper-containing liposomes to improve drug retention.

    PubMed

    Ramsay, Euan; Alnajim, Jehan; Anantha, Malathi; Zastre, Jason; Yan, Hong; Webb, Murray; Waterhouse, Dawn; Bally, Marcel

    2008-03-01

    We determined whether the method used to encapsulate irinotecan into 1,2-distearoyl-sn-glycero-phosphocholine/cholesterol (DSPC/Chol; 55:45 mol%) liposomes influenced: (i) irinotecan release rate and (ii) therapeutic efficacy. DSPC/Chol (55:45 mol%) liposomes were prepared with: (i) unbuffered CuSO4; (ii) buffered (pH 7.5) CuSO4; (iii) unbuffered MnSO4 and the ionophore A23187 (exchanges internal metal2+ with external 2H+ to establish and maintain a transmembrane pH gradient); and (iv) unbuffered CuSO4 and ionophore A23187. All formulations exhibited >98% irinotecan encapsulation (0.2 drug-to-lipid molar ratio; 10 min incubation at 50 degrees C). Following a single intravenous injection (100mg/kg irinotecan) into Balb/c mice, the unbuffered CuSO4 plus A23187 formulation mediated a half-life of irinotecan release of 44.4h; a >or=4-fold increase compared to the other liposome formulations. This surprising observation demonstrated that the CuSO4 plus A23187 formulation enhanced irinotecan retention compared to the MnSO4 plus A23187 formulation, indicating the importance of the divalent metal. A single dose of the CuSO4 plus A23187 formulation (50mg/kg irinotecan) mediated an 18-fold increase in median T-C (the difference in days for treated and control subcutaneous human LS 180 adenocarcinoma xenografts to increase their initial volume by 400%) when compared to a comparable dose of Camptosar. Improved irinotecan retention was associated with increased therapeutic activity. PMID:17904831

  2. The combination of liquid chromatography/tandem mass spectrometry and chip-based infusion for improved screening and characterization of drug metabolites.

    PubMed

    Staack, Roland F; Varesio, Emmanuel; Hopfgartner, Gérard

    2005-01-01

    An approach has been developed for drug metabolism studies of non-radiolabeled compounds using on-line liquid chromatography/tandem mass spectrometry (LC/MS/MS) combined with chip-based infusion following fraction collection. The potential of this approach, which improves the data quality compared with only LC/MS analysis, has been investigated for the analysis of in vitro metabolites of tolcapone and talinolol, two compounds with well-characterized metabolism. The information-dependent LC/MS/MS analysis enables the characterization of the major metabolites while the chip-based infusion is used to obtain good product ion spectra for lower level metabolites, to generate complementary MS information on potential metabolites detected in the LC/MS trace, or to screen for unexpected metabolites. Fractions from the chromatographic analysis are collected in 20 second steps, into a 96-well plate. The fractions of interest can be re-analyzed with chip-based infusion on a variety of mass spectrometers including triple quadrupole linear ion trap (QqLIT or Q TRAP) and QqTOF systems. Acquiring data for several minutes using multi-channel acquisition (MCA), or signal averaging while infusing the fractions at approximately 200 nL/min, permits about a 50 times gain in sensitivity (signal-to-noise) in MS/MS mode. A 5-10 microL sample fraction can be infused for more than 30 min allowing the time to perform various MS experiments such as MS(n), precursor ion or neutral loss scans and accurate mass measurement, all in either positive or negative mode. Through fraction collection and infusion, a significant gain in data quality is obtained along with a time-saving benefit, because the original sample needs neither to be re-analyzed by re-injection nor to be pre-concentrated. Therefore, a novel hydroxylated talinolol metabolite could be characterized with only one injection. PMID:15685686

  3. Improved drug loading and antibacterial activity of minocycline-loaded PLGA nanoparticles prepared by solid/oil/water ion pairing method

    PubMed Central

    Kashi, Tahereh Sadat Jafarzadeh; Eskandarion, Solmaz; Esfandyari-Manesh, Mehdi; Marashi, Seyyed Mahmoud Amin; Samadi, Nasrin; Fatemi, Seyyed Mostafa; Atyabi, Fatemeh; Eshraghi, Saeed; Dinarvand, Rassoul

    2012-01-01

    Background Low drug entrapment efficiency of hydrophilic drugs into poly(lactic-co-glycolic acid) (PLGA) nanoparticles is a major drawback. The objective of this work was to investigate different methods of producing PLGA nanoparticles containing minocycline, a drug suitable for periodontal infections. Methods Different methods, such as single and double solvent evaporation emulsion, ion pairing, and nanoprecipitation were used to prepare both PLGA and PEGylated PLGA nanoparticles. The resulting nanoparticles were analyzed for their morphology, particle size and size distribution, drug loading and entrapment efficiency, thermal properties, and antibacterial activity. Results The nanoparticles prepared in this study were spherical, with an average particle size of 85–424 nm. The entrapment efficiency of the nanoparticles prepared using different methods was as follows: solid/oil/water ion pairing (29.9%) > oil/oil (5.5%) > water/oil/water (4.7%) > modified oil/water (4.1%) > nano precipitation (0.8%). Addition of dextran sulfate as an ion pairing agent, acting as an ionic spacer between PEGylated PLGA and minocycline, decreased the water solubility of minocycline, hence increasing the drug entrapment efficiency. Entrapment efficiency was also increased when low molecular weight PLGA and high molecular weight dextran sulfate was used. Drug release studies performed in phosphate buffer at pH 7.4 indicated slow release of minocycline from 3 days to several weeks. On antibacterial analysis, the minimum inhibitory concentration and minimum bactericidal concentration of nanoparticles was at least two times lower than that of the free drug. Conclusion Novel minocycline-PEGylated PLGA nanoparticles prepared by the ion pairing method had the best drug loading and entrapment efficiency compared with other prepared nanoparticles. They also showed higher in vitro antibacterial activity than the free drug. PMID:22275837

  4. Ocular drug delivery.

    PubMed

    Gaudana, Ripal; Ananthula, Hari Krishna; Parenky, Ashwin; Mitra, Ashim K

    2010-09-01

    Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiology. Static barriers (different layers of cornea, sclera, and retina including blood aqueous and blood-retinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, especially to the posterior segment. Identification of influx transporters on various ocular tissues and designing a transporter-targeted delivery of a parent drug has gathered momentum in recent years. Parallelly, colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions have been widely explored to overcome various static and dynamic barriers. Novel drug delivery strategies such as bioadhesive gels and fibrin sealant-based approaches were developed to sustain drug levels at the target site. Designing noninvasive sustained drug delivery systems and exploring the feasibility of topical application to deliver drugs to the posterior segment may drastically improve drug delivery in the years to come. Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases. PMID:20437123

  5. Drug Facts

    MedlinePlus Videos and Cool Tools

    ... Weed, Pot) Facts Meth (Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts Other Drugs of Abuse What ... About Drugs Alcohol Cocaine Heroin Marijuana Meth Pain Medicines Tobacco Other Drugs You can call 1-800- ...

  6. Drug Reactions

    MedlinePlus

    ... problem is interactions, which may occur between Two drugs, such as aspirin and blood thinners Drugs and food, such as statins and grapefruit Drugs and supplements, such as gingko and blood thinners ...

  7. Drug Resistance

    MedlinePlus

    HIV Treatment Drug Resistance (Last updated 3/1/2016; last reviewed 3/1/2016) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  8. Hydrophobic ion pairing of a minocycline/Ca(2+)/AOT complex for preparation of drug-loaded PLGA nanoparticles with improved sustained release.

    PubMed

    Holmkvist, Alexander Dontsios; Friberg, Annika; Nilsson, Ulf J; Schouenborg, Jens

    2016-02-29

    Polymeric nanoparticles is an established and efficient means to achieve controlled release of drugs. Incorporation of minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, into biodegradable nanoparticles may therefore provide an efficient means to combat foreign body reactions to implanted electrodes in the brain. However, minocycline is commonly associated with poor encapsulation efficiencies and/or fast release rates due to its high solubility in water. Moreover, minocycline is unstable under conditions of low and high pH, heat and exposure to light, which exacerbate the challenges of encapsulation. In this work drug loaded PLGA nanoparticles were prepared by a modified emulsification-solvent-diffusion technique and characterized for size, drug encapsulation and in vitro drug release. A novel hydrophobic ion pair complex of minocycline, Ca(2+) ions and the anionic surfactant AOT was developed to protect minocycline from degradation and prolong its release. The optimized formulation resulted in particle sizes around 220 nm with an entrapment efficiency of 43% and showed drug release over 30 days in artificial cerebrospinal fluid. The present results constitute a substantial increase in release time compared to what has hitherto been achieved for minocycline and indicate that such particles might provide useful for sustained drug delivery in the CNS. PMID:26773599

  9. Treatment with a nonsteroidal antiinflammatory drug after calving did not improve milk production, health, or reproduction parameters in pasture-grazed dairy cows.

    PubMed

    Meier, S; Priest, N V; Burke, C R; Kay, J K; McDougall, S; Mitchell, M D; Walker, C G; Heiser, A; Loor, J J; Roche, J R

    2014-05-01

    Previous research results have indicated an increase in pregnancy rate in pasture-grazed cows treated with a nonsteroidal antiinflammatory drug (NSAID) 3 to 4 wk postcalving, when a high proportion of nucleated cells from within the uterus were polymorphonucleated; however, no effect on milk production was detected. It was hypothesized that this lack of effect on milk production was because the administration of the NSAID was too late after calving. The aims of the current study were to evaluate the timing of administering a propionic acid-derived NSAID (i.e., carprofen) on milk production, metabolic status, uterine health, and reproductive performance. Six-hundred and thirty-nine cows (134 primiparous and 505 multiparous) calving between July 4 and September 5, 2012, in 2 herds (herd 1: n=228; herd 2: n=411) were enrolled. Using a randomized block design, cows were allocated to 1 of 3 treatment groups as they calved: (1) no treatment (control; n=221), (2) NSAID administered on d 1, 3, and 5 postcalving (early; n=214), and (3) NSAID administered on d 19, 21, and 23 postcalving (late; n=204). Milk production and composition, and body condition were determined weekly. Blood was sampled at 4 time points (1 precalving and 3 postcalving) to determine the effects of treatment on indicators of metabolic health and energy status. Uterine health was determined by measuring the proportion of nucleated cells that were polymorphonucleated following cytobrush sampling of the uterus between d 13 to 24 and d 30 to 49 postcalving. Irrespective of timing of application, NSAID did not affect milk production, body weight, or body condition during early lactation. Treatment with an NSAID 19 to 23 d postcalving increased the proportion of cows submitted for breeding during the first 3 wk of the seasonal breeding program (control: 85%, early: 83%, and late: 92%), but did not affect conception or pregnancy rates. No detectable effect of treatment on uterine health or circulating

  10. Drug Abuse

    MedlinePlus

    ... as drugged driving, violence, stress, and child abuse. Drug abuse can lead to homelessness, crime, and missed work or problems with keeping a job. It harms unborn babies and destroys families. There are different types of treatment for drug abuse. But the best is to prevent drug ...

  11. Controlled drugs.

    PubMed

    2016-05-18

    Essential facts Controlled drugs are defined and governed by the Misuse of Drugs Act 1971 and associated regulations. Examples of controlled drugs include morphine, pethidine and methadone. Since 2012, appropriately qualified nurses and midwives can prescribe controlled drugs for medical conditions within their competence. There are some exceptions when treating addiction. PMID:27191427

  12. Floating lipid beads for the improvement of bioavailability of poorly soluble basic drugs: in-vitro optimization and in-vivo performance in humans.

    PubMed

    Abouelatta, Samar M; Aboelwafa, Ahmed A; Khalil, Rawia M; ElGazayerly, Omaima N

    2015-01-01

    The challenge in developing oral drug delivery systems of poorly soluble basic drugs is primarily due to their pH dependent solubility. Cinnarizine (CNZ), a model for a poorly soluble basic drug, has pH dependent solubility; where it dissolves readily at low pH in the stomach and exhibits a very low solubility at pH values greater than 4. It is also characterized by a short half life of 3-6h, which requires frequent daily administration resulting in poor patient compliance. In an attempt to solve these problems, extended release floating lipid beads were formulated. A 2(4) full factorial design was utilized for optimization of the effects of various independent variables; lipid:drug ratio, % Pluronic F-127, % Sterotex, and Gelucire 43/01:Gelucire 50/13 ratio, on the loading efficiency and release of CNZ from the lipid beads. In-vivo pharmacokinetic study of the optimized CNZ-lipid beads compared to Stugeron® (reference standard) was performed in healthy human volunteers. A promising approach for enhancing the bioavailability of the poorly soluble basic drug, CNZ, utilizing novel and simple floating lipid beads was successfully developed. Zero order release profile of CNZ was achieved for 12h. Mean AUC0-24 and AUC0-∞ of the optimized CNZ-loaded lipid beads were 4.23 and 6.04 times that of Stugeron® tablets respectively. PMID:25448073

  13. Drug diversion

    PubMed Central

    Wood, Danielle

    2015-01-01

    SUMMARY Prescription drug diversion has significant health, legal and social implications. Deaths from misuse of prescription drugs account for a significant proportion of overdose deaths. The drugs most commonly involved are analgesics, particularly opioids, and psychoactive drugs, particularly benzodiazepines. Diverted drugs are most often sourced from a family member or friend, but are also sourced from overseas pharmacies or laboratories, or bought from drug dealers. Drug diversion can be mitigated by good prescribing practices. Systems for monitoring the prescribing and dispensing of medicines are being instituted across Australia. PMID:26648654

  14. Projecting future drug expenditures--1994.

    PubMed

    Santell, J P

    1994-01-15

    The use of information on inflation, generic competition, market introduction of new drug entities, institution-specific drug-use patterns, and federal legislation to project drug expenditures is discussed. Inflation of pharmaceutical prices has been decreasing over the past few years. Increases in the producer price index for drugs and pharmaceuticals diminished from 6.9% in 1991 to 4.3% in the first half of 1993; the specter of government regulation may be one reason. Pharmacy group purchasing organizations (GPOs) predicted that in 1994 expenditures would increase an average of 2.1% for contracted drug items and 8.3% for noncontracted items. Expenditures for biotechnology drugs in January through July 1993 increased 16% over the same period in 1992; such agents are now hospital pharmacies' third most costly drug category, at 10% of total expenditures. Future price competition by generic drug products can be predicted from information on patent or market-exclusivity expiration. To predict the market release of new drug products, new-drug applications filed with FDA can be monitored. The most important component in projecting drug expenditures is a specific institution's pattern of use of high-cost drugs. Mechanisms that can be used to monitor changes in therapeutic strategies and drug-use protocols include drug cost indexes, assessment of drug-use patterns by outside companies, and computerized models for specific high-cost drugs. Drug expenditures can be affected by legislative changes such as the Medicaid rebate provisions of the Omnibus Budget Reconciliation Act of 1990 and the Medicare outpatient drug benefit in the proposed American Health Security Act. The accuracy of projections of drug expenditures can be improved by examining inflation, generic competition, the introduction of new drug entities, institution-specific drug-use patterns, and legislative issues. Pharmacy managers need better methods for estimating institution-specific use of high-cost drugs

  15. Step 7: educates staff in nondrug methods of pain relief and does not promote use of analgesic, anesthetic drugs: the coalition for improving maternity services:.

    PubMed

    Leslie, Mayri Sagady; Romano, Amy; Woolley, Deborah

    2007-01-01

    Step 7 of the Ten Steps of Mother-Friendly Care insures that staff are knowledgeable about nondrug methods of pain relief and that analgesic or anesthetic drugs are not promoted unless required to correct a complication. The rationales for compliance and systematic reviews are presented on massage, hypnosis, hydrotherapy, and the use of opioids, regional analgesia, and anesthesia. PMID:18523667

  16. Comparison of the Effects of Cooperative Learning and Traditional Learning Methods on the Improvement of Drug-Dose Calculation Skills of Nursing Students Undergoing Internships

    ERIC Educational Resources Information Center

    Basak, Tulay; Yildiz, Dilek

    2014-01-01

    Objective: The aim of this study was to compare the effectiveness of cooperative learning and traditional learning methods on the development of drug-calculation skills. Design: Final-year nursing students ("n" = 85) undergoing internships during the 2010-2011 academic year at a nursing school constituted the study group of this…

  17. Environmental Management Approach to Improve College Student and Community Relations to Reduce Binge and High-Risk Alcohol Use and Other Drug Problems. Prevention Update

    ERIC Educational Resources Information Center

    Higher Education Center for Alcohol, Drug Abuse, and Violence Prevention, 2011

    2011-01-01

    A central feature of the U.S. Department of Education's Higher Education Center for Alcohol, Drug Abuse, and Violence Prevention is the promotion of multiple prevention strategies that affect campus and surrounding community environments as a whole and can, thereby, have a large-scale effect on the entire campus community. In outlining the…

  18. Drug companies, UNAIDS make drugs available.

    PubMed

    1998-01-01

    The United Nations AIDS (UNAIDS) initiative is working with several drug companies and four countries on a pilot program to build a health infrastructure that provides affordable drugs to insure that combination therapies are used appropriately. The countries involved in the program are Uganda, Chile, Vietnam and Cote d'Ivoire, and the drug companies are Glaxo Wellcome, Hoffmann-La Roche, and Virco NV. Each country agreed to form national HIV/AIDS drug advisory boards, and non-profit companies will act as clearinghouses. Financing will come from the pharmaceutical companies, local health ministries, and a $1 million grant from UNAIDS. The program will be evaluated in terms of improvements to overall health care delivery, number of people treated, the impact on emergency care, and the rate of illness and death. PMID:11364863

  19. Hybrid dendrimer hydrogel/poly(lactic-co-glycolic acid) nanoparticle platform: an advanced vehicle for topical delivery of antiglaucoma drugs and a likely solution to improving compliance and adherence in glaucoma management.

    PubMed

    Yang, Hu; Leffler, Christopher T

    2013-03-01

    Glaucoma therapy typically begins with topical medications, of which there are 4 major classes in common use in the United States: beta-adrenergic antagonists, alpha-agonists, carbonic anhydrase inhibitors, and prostaglandin analogs. Unfortunately, all 4 classes require at least daily dosing, and 3 of the 4 classes are approved to be administered 2 or 3 times daily. This need for frequent dosing with multiple medications makes compliance difficult. Longer-acting formulations and combinations that require less frequent administration might improve compliance and therefore medication effectiveness. Recently, we developed an ocular drug delivery system, a hybrid dendrimer hydrogel/poly(lactic-co-glycolic acid) nanoparticle platform for delivering glaucoma therapeutics topically. This platform is designed to deliver glaucoma drugs to the eye efficiently and release the drug in a slow fashion. Furthermore, this delivery platform is designed to be compatible with many of the glaucoma drugs that are currently approved for use. In this article, we review this new delivery system with in-depth discussion of its structural features, properties, and preclinical application in glaucoma treatment. In addition, future directions and translational efforts for marketing this technology are elaborated. PMID:23249385

  20. Drugged Driving

    MedlinePlus

    ... Infographics » Drugged Driving Drugged Driving Email Facebook Twitter Text Description of Infographic Top Right Figure : In 2009, ... crash than those who don't smoke. Bottom Text: Develop Social Strategies Offer to be a designated ...

  1. Drug Control

    ERIC Educational Resources Information Center

    Leviton, Harvey S.

    1975-01-01

    This article attempts to assemble pertinent information about the drug problem, particularily marihuana. It also focuses on the need for an educational program for drug control with the public schools as the main arena. (Author/HMV)

  2. Generic Drugs

    MedlinePlus

    ... drugs. There are a few other differences— like color, shape, size, or taste—but they do not ... different . Brand-name drugs are often advertised by color and shape. Remember the ads for the “purple ...

  3. Drug Debacle.

    PubMed

    Sorrel, Amy Lynn

    2016-01-01

    Medicaid's Vendor Drug Program is under examination by the Texas Legislature. TMA's Physicians Medicaid Congress is seizing the opportunity to call for an administrative overhaul of a drug benefit physicians describe as unnecessarily complicated and confusing. PMID:27441421

  4. Improving the ex vivo stability of drug ester compounds in rat and dog serum: inhibition of the specific esterases and implications on their identity.

    PubMed

    Koitka, Matthias; Höchel, Joachim; Gieschen, Hille; Borchert, Hans-Hubert

    2010-02-01

    In drug development, it has been noticed that some drug compounds, especially esters, are unstable in serum samples ex vivo. This can lead to a substantial underestimation of the actual drug concentration. The rat and the dog, representing a rodent and non-rodent species, respectively, are widely used in preclinical studies. We studied the degradation of three structurally different drug esters in rat and dog serum. Moreover, the efficiency of selected enzyme inhibitors to prevent these degradations was investigated. Furthermore, we found indications of the identity of the drug-specific esterases by means of their inhibitor sensitivity as well as by protein purification and identification. The studied drugs were sagopilone, drospirenone, and methylprednisolone aceponate (MPA) all of which are used in (pre-)clinical drug development. The sagopilone-cleaving esterases in rat serum were inhibited by serine hydrolase inhibitors. We partly purified these esterases resulting in an activity yield of 5% and a purification factor of 472. Using matrix-assisted laser desorption ionization (MALDI)-time of flight (TOF)-mass spectrometry (MS), the rat carboxylesterase isoenzyme ES-1 was identified in these fractions, thus pointing to its involvement in sagopilone cleavage. Drospirenone cleavage in rat serum was effected by butyrylcholinesterase (BChE) and paraoxonase 1 (PON1) as we deduced from the high efficacy of certain serine hydrolase and metallohydrolase inhibitors, respectively. Likewise, some inhibition characteristics implied that MPA was cleaved in rat serum by BChE and serine proteases. Partial purification of the MPA-specific esterases resulted in activity yields of 1-2%, exhibiting up to 10,000-fold purification. In dog serum, we found that sagopilone was not degraded which was in contrast to MPA and drospirenone. MPA degradation was mainly prevented by serine hydrolase inhibitors. We used a three-step purification to isolate the esterases cleaving MPA. This

  5. Post-surgical analgesia in rainbow trout: is reduced cardioventilatory activity a sign of improved animal welfare or the adverse effects of an opioid drug?

    PubMed

    Gräns, Albin; Sandblom, Erik; Kiessling, Anders; Axelsson, Michael

    2014-01-01

    The use of fish models in biomedical research is increasing. Since behavioural and physiological consequences of surgical procedures may affect experimental results, these effects should be defined and, if possible, ameliorated. Thus, the use of post-surgical analgesia should be considered after invasive procedures also in fish, but presently, little information exists on the effects of analgesics in fish. This study assessed the effects of an opioid drug, buprenorphine (0.05 mg/kg IM), on resting ventilation and heart rates during 7 days of postsurgical recovery in rainbow trout (Oncorhynchus mykiss) at 10°C by non-invasively recording bioelectric potentials from the fish via electrodes in the water. Baseline ventilation and heart rates were considerably lower compared to previously reported values for rainbow trout at 10°C, possibly due to the non-invasive recording technique. Buprenorphine significantly decreased both ventilation and heart rates further, and the effects were most pronounced at 4-7 days after anaesthesia, surgical procedures and administration of the drug. Somewhat surprisingly, the same effects of buprenorphine were seen in the two control groups that had not been subject to surgery. These results indicate that the reductions in ventilation and heart rates are not caused by an analgesic effect of the drug, but may instead reflect a general sedative effect acting on both behaviour as well as e.g. central control of ventilation in fishes. This resembles what has previously been demonstrated in mammals, although the duration of the drug effect is considerably longer in this ectothermic animal. Thus, before using buprenorphine for postoperative analgesic treatment in fish, these potentially adverse effects need further characterisation. PMID:24736526

  6. Post-Surgical Analgesia in Rainbow Trout: Is Reduced Cardioventilatory Activity a Sign of Improved Animal Welfare or the Adverse Effects of an Opioid Drug?

    PubMed Central

    Gräns, Albin; Sandblom, Erik; Kiessling, Anders; Axelsson, Michael

    2014-01-01

    The use of fish models in biomedical research is increasing. Since behavioural and physiological consequences of surgical procedures may affect experimental results, these effects should be defined and, if possible, ameliorated. Thus, the use of post-surgical analgesia should be considered after invasive procedures also in fish, but presently, little information exists on the effects of analgesics in fish. This study assessed the effects of an opioid drug, buprenorphine (0.05 mg/kg IM), on resting ventilation and heart rates during 7 days of postsurgical recovery in rainbow trout (Oncorhynchus mykiss) at 10°C by non-invasively recording bioelectric potentials from the fish via electrodes in the water. Baseline ventilation and heart rates were considerably lower compared to previously reported values for rainbow trout at 10°C, possibly due to the non-invasive recording technique. Buprenorphine significantly decreased both ventilation and heart rates further, and the effects were most pronounced at 4–7 days after anaesthesia, surgical procedures and administration of the drug. Somewhat surprisingly, the same effects of buprenorphine were seen in the two control groups that had not been subject to surgery. These results indicate that the reductions in ventilation and heart rates are not caused by an analgesic effect of the drug, but may instead reflect a general sedative effect acting on both behaviour as well as e.g. central control of ventilation in fishes. This resembles what has previously been demonstrated in mammals, although the duration of the drug effect is considerably longer in this ectothermic animal. Thus, before using buprenorphine for postoperative analgesic treatment in fish, these potentially adverse effects need further characterisation. PMID:24736526

  7. Drug-induced panniculitides.

    PubMed

    Borroni, G; Torti, S; D'Ospina, R M; Pezzini, C

    2014-04-01

    A substantial number of all panniculitides fails to recognize a specific etiology, and that is true also for a relatively frequent type of panniculitis, such as erythema nodosum (EN). Between the recognized causative factors of panniculitides, infectious, physical agents, autoimmune mechanisms and neoplastic disorders are well known. On the contrary, the role of drugs as inducers of panniculitides is marginally considered, and their report limited to anecdotal observations, often without due histopathological support. Since the clinical and histopathological features of drug-induced panniculitides are indistinguishable from those caused by other agents, the causative relationship may be demonstrated by the history of previous drug intake and by clinical improvement after drug discontinuation. We reviewed the currently reported descriptions of drug-induced panniculitis, including a few exemplificative original observations. EN results as the most frequently reported drug-induced panniculitis. Among the causative drugs of EN a variety of medications, with disparate, or even opposite, mechanisms of action are reported, thus limiting the understanding of the pathogenesis. Common causative drugs include oral contraceptives, nonsteroidal anti-inflammatory drugs, antiobiotics and leukotriene-modifying agents. Unfortunately, in several cases, the diagnosis of drug-induced EN is done on clinical findings alone. In those cases, the lack of histopathological support does not allow to define a precise clinicopathological correlation on etiologic grounds. Drug-induced lobular and mixed panniculitides, including eosinophilic panniculitis, are even more rarely described. Reported causative agents are glatiramer acetate, interferon beta and heparin (at sites of injections), and systemic steroids, tyrosine kinase inhibitors and BRAF with subcutaneous fat involvement at distance. In view of the recent introduction of new classes of drugs, attention should be paid to disclose their

  8. Drug Survey.

    ERIC Educational Resources Information Center

    Gill, Wanda E.; And Others

    Results of a survey of student perceptions of drugs and drug use that was conducted at Bowie State College are presented. Studies that have been conducted on college students' use of alcohol, marijuana, and cocaine in the last five years are reviewed, along with additional studies relating to the general population and the following drugs:…

  9. Computational drug discovery

    PubMed Central

    Ou-Yang, Si-sheng; Lu, Jun-yan; Kong, Xiang-qian; Liang, Zhong-jie; Luo, Cheng; Jiang, Hualiang

    2012-01-01

    Computational drug discovery is an effective strategy for accelerating and economizing drug discovery and development process. Because of the dramatic increase in the availability of biological macromolecule and small molecule information, the applicability of computational drug discovery has been extended and broadly applied to nearly every stage in the drug discovery and development workflow, including target identification and validation, lead discovery and optimization and preclinical tests. Over the past decades, computational drug discovery methods such as molecular docking, pharmacophore modeling and mapping, de novo design, molecular similarity calculation and sequence-based virtual screening have been greatly improved. In this review, we present an overview of these important computational methods, platforms and successful applications in this field. PMID:22922346

  10. Drug Interactions

    PubMed Central

    Tong Logan, Angela; Silverman, Andrew

    2012-01-01

    One of the most clinically significant complications related to the use of pharmacotherapy is the potential for drug-drug or drug-disease interactions. The gastrointestinal system plays a large role in the pharmacokinetic profile of most medications, and many medications utilized in gastroenterology have clinically significant drug interactions. This review will discuss the impact of alterations of intestinal pH, interactions mediated by phase I hepatic metabolism enzymes and P-glycoprotein, the impact of liver disease on drug metabolism, and interactions seen with commonly utilized gastrointestinal medications. PMID:22933873

  11. Drug Interactions and Antiretroviral Drug Monitoring

    PubMed Central

    Foy, Matthew; Sperati, C. John; Lucas, Gregory M.

    2014-01-01

    Due to the improved longevity afforded by combination antiretroviral therapy (cART), HIV-infected individuals are developing several non-AIDS related comorbid conditions. Consequently, medical management of the HIV-infected population is increasingly complex, with a growing list of potential drug-drug interactions (DDIs). This article reviews some of the most relevant and emerging potential interactions between antiretroviral medications and other agents. The most common DDIs are those involving protease inhibitors or non-nucleoside reverse transcriptase inhibitors which alter the cytochrome P450 enzyme system and/or drug transporters such as p-glycoprotein. Of note are the new agents for the treatment of chronic hepatitis C virus infection. These new classes of drugs and others drugs which are increasingly used in this patient population represent a significant challenge with regard to achieving the goals of effective HIV suppression and minimization of drug-related toxicities. Awareness of DDIs and a multidisciplinary approach are imperative in reaching these goals. PMID:24950731

  12. Biosynthesis of Fluorinated Analogs of Drugs Using Human Cytochrome P450 Enzymes Followed by Deoxyfluorination and Quantitative Nuclear Magnetic Resonance Spectroscopy to Improve Metabolic Stability.

    PubMed

    Obach, R Scott; Walker, Gregory S; Brodney, Michael A

    2016-05-01

    Replacement of hydrogen with fluorine is a useful drug design strategy when decreases in cytochrome P450 (P450) metabolic lability are needed. In this paper, a facile two-step method of inserting fluorine into metabolically labile sites of drug molecules is described that utilizes less than 1 mg of starting material and quantitative NMR spectroscopy to ascertain the structures and concentrations of products. In the first step, hydroxyl metabolites are biosynthesized using human P450 enzymes, and in the second step these metabolites are subjected to deoxyfluorination using diethylaminosulfur trifluoride (DAST). The method is demonstrated using midazolam, celecoxib, ramelteon, and risperidone as examples and CYP3A5, 2C9, 1A2, and 2D6 to catalyze the hydroxylations. The drugs and their fluoro analogs were tested for metabolic lability. 9-Fluororisperidone and 4'-fluorocelecoxib were 16 and 4 times more metabolically stable than risperidone and celecoxib, respectively, and 2-fluororamelteon and ramelteon were metabolized at the same rate. 1'-Fluoromidazolam was metabolized at the same rate as midazolam by CYP3A4 but was more stable in CYP3A5 incubations. The P450-catalyzed sites of metabolism of the fluorine-containing analogs were determined. Some of the metabolites arose via metabolism at the fluorine-substituted carbon, wherein the fluorine was lost to yield aldehydes. In summary, this method offers an approach whereby fluorine can be substituted in metabolically labile sites, and the products can be tested to determine whether an enhancement in metabolic stability was obtained. PMID:26921388

  13. Progress in the study of drug nanocrystals.

    PubMed

    Shi, Jing; Guo, Fei; Zheng, Aiping; Zhang, Xiaoyan; Sun, Jianxu

    2015-12-01

    The poor water solubility of many candidate drugs remains a major obstacle to their development and clinical use, especially for oral drug delivery. Nanocrystal technology can improve the solubility and dissolution rates of many poorly water-soluble drugs very effectively, significantly improving their oral bioavailability and decreasing the food effect. For this reason, this technology is becoming a key area of drug delivery research. This review presents much of the recent progress in nanocrystal drug pharmaceuticals, including the characteristics, composition, preparation technology, and clinical applications of these drugs. Finally, the effect of nanocrystal technology on insoluble drugs is quantified and described. PMID:26817271

  14. 4-Aminopyridyl-based CYP51 inhibitors as anti-Trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency.

    PubMed

    Calvet, Claudia M; Vieira, Debora F; Choi, Jun Yong; Kellar, Danielle; Cameron, Michael D; Siqueira-Neto, Jair Lage; Gut, Jiri; Johnston, Jonathan B; Lin, Li; Khan, Susan; McKerrow, James H; Roush, William R; Podust, Larissa M

    2014-08-28

    CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure-activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug-target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection. PMID:25101801

  15. COPD - control drugs

    MedlinePlus

    Chronic obstructive pulmonary disease - control drugs; Bronchodilators - COPD - control drugs; Beta agonist inhaler - COPD - control drugs; Anticholinergic inhaler - COPD - control drugs; Long-acting inhaler - COPD - control drugs; ...

  16. Preparation of biocompatible heat-labile enterotoxin subunit B-bovine serum albumin nanoparticles for improving tumor-targeted drug delivery via heat-labile enterotoxin subunit B mediation

    PubMed Central

    Zhao, Liang; Su, Rongjian; Cui, Wenyu; Shi, Yijie; Liu, Liwei; Su, Chang

    2014-01-01

    Heat-labile enterotoxin subunit B (LTB) is a non-catalytic protein from a pentameric subunit of Escherichia coli. Based on its function of binding specifically to ganglioside GM1 on the surface of cells, a novel nanoparticle (NP) composed of a mixture of bovine serum albumin (BSA) and LTB was designed for targeted delivery of 5-fluorouracil to tumor cells. BSA-LTB NPs were characterized by determination of their particle size, polydispersity, morphology, drug encapsulation efficiency, and drug release behavior in vitro. The internalization of fluorescein isothiocyanate-labeled BSA-LTB NPs into cells was observed using fluorescent imaging. Results showed that BSA-LTB NPs presented a narrow size distribution with an average hydrodynamic diameter of approximately 254±19 nm and a mean zeta potential of approximately −19.95±0.94 mV. In addition, approximately 80.1% of drug was encapsulated in NPs and released in the biphasic pattern. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that BSA-LTB NPs exhibited higher cytotoxic activity than non-targeted NPs (BSA NPs) in SMMC-7721 cells. Fluorescent imaging results proved that, compared with BSA NPs, BSA-LTB NPs could greatly enhance cellular uptake. Hence, the results indicate that BSA-LTB NPs could be a potential nanocarrier to improve targeted delivery of 5-fluorouracil to tumor cells via mediation of LTB. PMID:24851048

  17. Does Computer Survey Technology Improve Reports on Alcohol and Illicit Drug Use in the General Population? A Comparison Between Two Surveys with Different Data Collection Modes In France

    PubMed Central

    Beck, François; Guignard, Romain; Legleye, Stéphane

    2014-01-01

    Background Previous studies have shown that survey methodology can greatly influence prevalence estimates for alcohol and illicit drug use. The aim of this article is to assess the effect of data collection modes on alcohol misuse and drug use reports by comparing national estimates from computer-assisted telephone interviews (CATI) and audio-computer-assisted self interviews (A-CASI). Methods Design: Two national representative surveys conducted in 2005 in France by CATI (n = 24,674) and A-CASI (n = 8,111). Participants: French-speaking individuals aged [18]–[64] years old. Measurements: Alcohol misuse according to the CAGE test, cannabis use (lifetime, last year, 10+ in last month) and experimentation with cocaine, LSD, heroin, amphetamines, ecstasy, were measured with the same questions and wordings in the two surveys. Multivariate logistic regressions controlling for sociodemographic characteristics (age, educational level, marital status and professional status) were performed. Analyses were conducted on the whole sample and stratified by age (18–29 and 30–44 years old) and gender. 45–64 years old data were not analysed due to limited numbers. Results Overall national estimates were similar for 9 out of the 10 examined measures. However, after adjustment, A-CASI provided higher use for most types of illicit drugs among the youngest men (adjusted odds ratio, or OR, of 1.64 [1.08–2.49] for cocaine, 1.62 [1.10–2.38] for ecstasy, 1.99 [1.17–3.37] for LSD, 2.17 [1.07–4.43] for heroin, and 2.48 [1.41–4.35] for amphetamines), whereas use amongst women was similar in CATI and A-CASI, except for LSD in the 30–44 age group (OR = 3.60 [1.64–7.89]). Reported alcohol misuse was higher with A-CASI, for all ages and genders. Conclusions Although differences in the results over the whole population were relatively small between the surveys, the effect of data collection mode seemed to vary according to age and gender. PMID:24465720

  18. A (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer)-dispersed sustained-release tablet for imperialine to simultaneously prolong the drug release and improve the oral bioavailability.

    PubMed

    Lin, Qing; Fu, Yu; Li, Jia; Qu, Mengke; Deng, Li; Gong, Tao; Zhang, Zhirong

    2015-11-15

    Imperialine, extracted from Bulbus Fritillariae Cirrhosae, is an efficient antitussive and expectorant medicine. However, its short half-life and stomach degradation limited imperialine from further clinical use. The current study was conducted to develop a sustained-release tablet for imperialine both to prolong absorption time and to improve the oral bioavailability of the drug. The tablets were prepared by a direct compression method formulated on optimized solid dispersion (SD) for imperialine based on polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus(®)) with imperialine/Soluplus(®) ratio of 1:8 (w/w). In order to obtain the optimized formulation, factors that affected the drug release were investigated by in vitro dissolution studies in the media of pH1.2, 5.8, 7.0 and 7.4. Powder X-ray diffraction and scanning electron microscope confirmed that the imperialine in SD was amorphous instead of crystalline, and still stayed amorphous even after the direct compression. And besides, pharmacokinetic study in Beagle dogs was performed to inspect the in vivo sustained release. Plasma concentration-time curves and pharmacokinetic parameters were gained. As a result, the Cmax of imperialine was one-fold reduced and Tmax was two-fold prolonged, and the mean AUC0-24 was expressed as 89.581±21.243μgh/L, which showed that the oral bioavailability of imperialine was 2.46-fold improved. Moreover, the in vitro-in vivo correlation was recommended to carry out, demonstrating the percentages of drug release in vitro were well-correlated with the absorptive fraction in vivo with the correlation coefficients above 0.9900. By mathematically modeling and moment imaging of the drug release, Peppas equation was selected as the most fitted model for the sustained-release tablets with the diffusional coefficient in the range of 0.59-0.62, indicating the release of imperialine from the sustained-release tablets was an anomalous process involving

  19. Drug Research

    NASA Technical Reports Server (NTRS)

    1989-01-01

    NBOD2, a program developed at Goddard Space Flight Center to solve equations of motion coupled N-body systems is used by E.I. DuPont de Nemours & Co. to model potential drugs as a series of elements. The program analyses the vibrational and static motions of independent components in drugs. Information generated from this process is used to design specific drugs to interact with enzymes in designated ways.

  20. Amides of non-steroidal anti-inflammatory drugs with thiomorpholine can yield hypolipidemic agents with improved anti-inflammatory activity.

    PubMed

    Theodosis-Nobelos, Panagiotis; Kourti, Malamati; Gavalas, Antonios; Rekka, Eleni A

    2016-02-01

    Novel amides of non steroidal anti-inflammatory drugs (NSAIDs), α-lipoic acid and indole-3-acetic acid with thiomorpholine were synthesised by a simple method and at high yields (60-92%). All the NSAID derivatives highly decreased lipidemic indices in the plasma of Triton treated hyperlipidemic rats. The most potent compound was the indomethacin derivative, which decreased total cholesterol, triglycerides and LDL cholesterol by 73%, 80% and 83%, respectively. They reduced acute inflammation equally or more than most parent acids. Hence, it could be concluded that amides of common NSAIDs with thiomorpholine acquire considerable hypolipidemic potency, while they preserve or augment their anti-inflammatory activity, thus addressing significant risk factors for atherogenesis. PMID:26750253

  1. Drug dependence

    MedlinePlus

    ... men References American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Arlington, VA: American Psychiatric Publishing. 2013. Kowalchuk A, Reed BC. Drug abuse. In: ...

  2. Drug abuse

    MedlinePlus

    ... abuse References American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Arlington, VA: American Psychiatric Publishing. 2013. Weiss RD. Drugs of abuse. In: Goldman ...

  3. Characterisation and deposition studies of recrystallised lactose from binary mixtures of ethanol/butanol for improved drug delivery from dry powder inhalers.

    PubMed

    Kaialy, Waseem; Martin, Gary P; Ticehurst, Martyn D; Royall, Paul; Mohammad, Mohammad A; Murphy, John; Nokhodchi, Ali

    2011-03-01

    Dry powder inhaler formulations comprising commercial lactose-drug blends can show restricted detachment of drug from lactose during aerosolisation, which can lead to poor fine particle fractions (FPFs) which are suboptimal. The aim of the present study was to investigate whether the crystallisation of lactose from different ethanol/butanol co-solvent mixtures could be employed as a method of altering the FPF of salbutamol sulphate from powder blends. Lactose particles were prepared by an anti-solvent recrystallisation process using various ratios of the two solvents. Crystallised lactose or commercial lactose was mixed with salbutamol sulphate and in vitro deposition studies were performed using a multistage liquid impinger. Solid-state characterisation results showed that commercial lactose was primarily composed of the α-anomer whilst the crystallised lactose samples comprised a α/β mixture containing a lower number of moles of water per mole of lactose compared to the commercial lactose. The crystallised lactose particles were also less elongated and more irregular in shape with rougher surfaces. Formulation blends containing crystallised lactose showed better aerosolisation performance and dose uniformity when compared to commercial lactose. The highest FPF of salbutamol sulphate (38.0 ± 2.5%) was obtained for the lactose samples that were crystallised from a mixture of ethanol/butanol (20:60) compared to a FPF of 19.7 ± 1.9% obtained for commercial lactose. Engineered lactose carriers with modified anomer content and physicochemical properties, when compared to the commercial grade, produced formulations which generated a high FPF. PMID:21057906

  4. Visits to primary care physicians among persons who inject drugs at high risk of hepatitis C virus infection: room for improvement.

    PubMed

    Artenie, A A; Jutras-Aswad, D; Roy, É; Zang, G; Bamvita, J-M; Lévesque, A; Bruneau, J

    2015-10-01

    The role of primary care physicians (PCP) in hepatitis C virus (HCV) prevention is increasingly emphasized. Yet, little is known about the patterns of contacts with PCP among persons who inject drugs (PWID). We sought to assess the 6-month prevalence of PCP visiting among PWID at risk of HCV infection and to explore the associated factors. Baseline data were collected from HCV-seronegative PWID recruited in HEPCO, an observational Hepatitis Cohort study (2004-2011) in Montreal, Canada. An interviewer-administered questionnaire elicited information on socio-demographic factors, drug use patterns and healthcare services utilization. Blood samples were tested for HCV antibodies. Using the Gelberg-Andersen Behavioral Model, hierarchical logistic regression analyses were conducted to identify predisposing, need and enabling factors associated with PCP visiting. Of the 349 participants (mean age = 34; 80.8% male), 32.1% reported visiting a PCP. In the multivariate model, among predisposing factors, male gender [adjusted odds ratio (AOR) = 0.45 (0.25-0.83)], chronic homelessness [AOR = 0.08 (0.01-0.67)], cocaine injection [AOR = 0.46 (0.28-0.76)] and reporting greater illegal or semi-legal income [AOR = 0.48 (0.27-0.85)] were negatively associated with PCP visits. Markers of need were not associated with the outcome. Among enabling factors, contact with street nurses [AOR = 3.86 (1.49-9.90)] and food banks [AOR = 2.01 (1.20-3.37)] was positively associated with PCP visiting. Only one third of participating PWID reported a recent visit to a PCP. While a host of predisposing factors seems to hamper timely contacts with PCP among high-risk PWID, community-based support services may play an important role in initiating dialogue with primary healthcare services in this population. PMID:25586516

  5. Low Beclin-1 expression predicts improved overall survival in patients treated with immunomodulatory drugs for multiple myeloma and identifies autophagy inhibition as a promising potentially druggable new therapeutic target: an analysis from The Austrian Myeloma Registry (AMR).

    PubMed

    Willenbacher, Wolfgang; Thangavadivel, Shanmugapriya; Greil, Richard; Willenbacher, Ella; Weger, Roman; Manzl, Claudia; Jöhrer, Karin; Brunner, Andrea

    2016-10-01

    Beclin-1 is a key regulator of autophagy and has been suggested to be involved in the development of drug resistance in multiple myeloma (MM). We analyzed the expression of Beclin-1 in a retrospective cohort of 70 MMs. Beclin-1 expression did not influence overall survival (OS) and progression-free survival (PFS) in patients with therapy-naïve MM. In patients treated with immunomodulatory drugs (IMiDs) lack of or low Beclin-1 expression resulted in a significantly improved OS and PFS compared to those treated with bortezomib or nonnovel agents. Beclin-1 expression was more frequently detected in relapsed MM than in therapy-naïve MM probably being a hallmark of tumor progression and therapy resistance. If validated prospectively, Beclin-1 expression might identify patients prone to profit above average from IMiDs and enable a more rational allocation of antimyeloma therapies. Furthermore, the inhibition of autophagy could be a new promising target to improve response to treatment in the relapsed/refractory setting. PMID:26880040

  6. Supramolecular approaches for drug development.

    PubMed

    Kawakami, K; Ebara, M; Izawa, H; Sanchez-Ballester, N M; Hill, J P; Ariga, K

    2012-01-01

    Various supramolecular systems can be used as drug carriers to alter physicochemical and pharmacokinetic characteristics of drugs. Representative supramolecular systems that can be used for this purpose include surfactant/polymer micelles, (micro)emulsions, liposomes, layer-by-layer assemblies, and various molecular conjugates. Notably, liposomes are established supramolecular drug carriers, which have already been marketed in formulations including AmBisome(®) (for treatment of fungal infection), Doxil(®) (for Kaposi's sarcoma), and Visudyne(®) (for age-related macular degeneration and choroidal neovascularization). Microemulsions have been used oral drug delivery of poorly soluble drugs due to improvements in bioavailability and predictable of absorption behavior. Neoral(®), an immunosuppressant used after transplant operations, is one of the most famous microemulsion-based drugs. Polymer micelles are being increasingly investigated as novel drug carriers and some formulations have already been tested in clinical trials. Supramolecular systems can be functionalized by designing the constituent molecules to achieve efficient delivery of drugs to desired sites in the body. In this review, representative supramolecular drug delivery systems, that may improve usability of candidate drugs or add value to existing drugs, are introduced. PMID:22455591

  7. The use of a dual PEDOT and RGD-functionalized alginate hydrogel coating to provide sustained drug delivery and improved cochlear implant function

    PubMed Central

    Chikar, JA; Hendricks, JL; Richardson-Burns, SM; Raphael, Y; Pfingst, BE; Martin, DC

    2011-01-01

    Cochlear implants provide hearing by electrically stimulating the auditory nerve. Implant function can be hindered by device design variables, including electrode size and electrode-to-nerve distance, and cochlear environment variables, including the degeneration of the auditory nerve following hair cell loss. We have developed a dual component cochlear implant coating to improve both the electrical function of the implant and the biological stability of the inner ear, thereby facilitating the long-term perception of sound through a cochlear implant. This coating is a combination of an arginine-glycine-aspartic acid (RGD)-functionalized alginate hydrogel and the conducting polymer poly(3, 4-ethylenedioxythiophene) (PEDOT). Both in vitro and in vivo assays on the effects of these electrode coatings demonstrated improvements in device performance. We found that the coating reduced electrode impedance, improved charge delivery, and locally released significant levels of a trophic factor into cochlear fluids. This coating is non-cytotoxic, clinically relevant, and has the potential to significantly improve the cochlear implant user’s experience. PMID:22182748

  8. [Drug dependence and psychotropic drugs].

    PubMed

    Giraud, M J; Lemonnier, E; Bigot, T

    1994-11-01

    Although the utility of psychotropic drugs has been well demonstrated, caution must still be exercised in their use. Among their potential risks, drug dependency must be kept in mind. This risk is well accepted with regard to benzodiazepines, and it appeared useful to study the potential risk for antidepressants, neuroleptics and thymoregulatory agents. Whatever the drug, the predominant factor appears to be psychological dependency. Prevention of drug dependency is most often achieved by informing the patient, limiting the length of use of the drug, making regular reevaluation of symptoms and of drug indication, and frequently be establishing a "treatment contract". The importance of the patient-physician relationship in the prescription of such treatment must be underlined. PMID:7984941

  9. Mucoadhesive drug delivery systems

    PubMed Central

    Shaikh, Rahamatullah; Raj Singh, Thakur Raghu; Garland, Martin James; Woolfson, A David; Donnelly, Ryan F.

    2011-01-01

    Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Over the past few decades, mucosal drug delivery has received a great deal of attention. Mucoadhesive dosage forms may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The mucoadhesive ability of a dosage form is dependent upon a variety of factors, including the nature of the mucosal tissue and the physicochemical properties of the polymeric formulation. This review article aims to provide an overview of the various aspects of mucoadhesion, mucoadhesive materials, factors affecting mucoadhesion, evaluating methods, and finally various mucoadhesive drug delivery systems (buccal, nasal, ocular, gastro, vaginal, and rectal). PMID:21430958

  10. Antineoplastic Drugs

    NASA Astrophysics Data System (ADS)

    Sadée, Wolfgang; El Sayed, Yousry Mahmoud

    The limited scope of therapeutic drug-level monitoring in cancer chemotherapy results from the often complex biochemical mechanisms that contribute to antineoplastic activity and obscure the relationships among drug serum levels and therapeutic benefits. Moreover, new agents for cancer chemotherapy are being introduced at a more rapid rate than for the treatment of other diseases, although the successful application of therapeutic drug-level monitoring may require several years of intensive study of the significance of serum drug levels. However, drug level monitoring can be of considerable value during phase I clinical trials of new antineoplastic agents in order to assess drug metabolism, bioavailability, and intersubject variability; these are important parameters in the interpretation of clinical studies, but have no immediate benefit to the patient. High performance liquid chromatography (HPLC) probably represents the most versatile and easily adaptable analytical technique for drug metabolite screening (1). HPLC may therefore now be the method of choice during phase I clinical trials of antineoplastic drugs. For example, within a single week we developed an HPLC assay—using a C18 reverse-phase column, UV detection, and direct serum injection after protein precipitation—for the new radiosensitizer, misonidazole (2).

  11. Drug Reactions

    MedlinePlus

    ... using any of these products. Some types of food may also cause adverse drug reactions. For example, grapefruit and grapefruit juice, as well as alcohol and caffeine, may affect how drugs work. Every time your doctor ... interactions with any foods or beverages. What about medicines I've used ...

  12. Drug Education.

    ERIC Educational Resources Information Center

    Sardana, Raj K.

    This autoinstructional lesson deals with the study of such drugs as marijuana and LSD, with emphasis on drug abuse. It is suggested that it can be used in science classes at the middle level of school. No prerequisites are suggested. The teacher's guide lists the behavioral objectives, the equipment needed to complete the experience and suggests…

  13. Finding parasites and finding challenges: improved diagnostic access and trends in reported malaria and anti-malarial drug use in Livingstone district, Zambia

    PubMed Central

    2012-01-01

    Background Understanding the impact of malaria rapid diagnostic test (RDT) use on management of acute febrile disease at a community level, and on the consumption of anti-malarial medicines, is critical to the planning and success of scale-up to universal parasite-based diagnosis by health systems in malaria-endemic countries. Methods A retrospective study of district-wide community-level RDT introduction was conducted in Livingstone District, Zambia, to assess the impact of this programmed on malaria reporting, incidence of mortality and on district anti-malarial consumption. Results Reported malaria declined from 12,186 cases in the quarter prior to RDT introduction in 2007 to an average of 12.25 confirmed and 294 unconfirmed malaria cases per quarter over the year to September 2009. Reported malaria-like fever also declined, with only 4,381 RDTs being consumed per quarter over the same year. Reported malaria mortality declined to zero in the year to September 2009, and all-cause mortality declined. Consumption of artemisinin-based combination therapy (ACT) dropped dramatically, but remained above reported malaria, declining from 12,550 courses dispensed by the district office in the quarter prior to RDT implementation to an average of 822 per quarter over the last year. Quinine consumption in health centres also declined, with the district office ceasing to supply due to low usage, but requests for sulphadoxine-pyrimethamine (SP) rose to well above previous levels, suggesting substitution of ACT with this drug in RDT-negative cases. Conclusions RDT introduction led to a large decline in reported malaria cases and in ACT consumption in Livingstone district. Reported malaria mortality declined to zero, indicating safety of the new diagnostic regime, although adherence and/or use of RDTs was still incomplete. However, a deficiency is apparent in management of non-malarial fever, with inappropriate use of a low-cost single dose drug, SP, replacing ACT. While large

  14. Improving the drug delivery characteristics of graphene oxide based polymer nanocomposites through the "one-pot" synthetic approach of single-electron-transfer living radical polymerization

    NASA Astrophysics Data System (ADS)

    Gao, Peng; Liu, Meiying; Tian, Jianwen; Deng, Fengjie; Wang, Ke; Xu, Dazhuang; Liu, Liangji; Zhang, Xiaoyong; Wei, Yen

    2016-08-01

    Graphene oxide (GO) based polymer nanocomposites have attracted extensive research interest recently for their outstanding physicochemical properties and potential applications. However, surface modification of GO with synthetic polymers has demonstrated to be trouble for most polymerization procedures are occurred under non-aqueous solution, which will in turn lead to the restacking of GO. In this work, a facile and efficient "one-pot" strategy has been developed for surface modification of GO with synthetic polymers through single-electron-transfer living radical polymerization (SET-LRP). The GO based polymer nanocomposites were obtained via SET-LRP in aqueous solution using poly(ethylene glycol) methyl ether methacrylate (PEGMA) as the monomer and 11-bromoundecanoic acid as the initiator, which could be effectively adsorbed on GO through hydrophobic interaction. The successful preparation of GO based polymer nanocomposites was confirmed by a series of characterization techniques such as 1H nuclear magnetic resonance, Fourier transform infrared spectroscopy, thermogravimetric analysis, transmission electron microscopy and X-ray photoelectron spectroscopy. The resultant products exhibit high water disperisibility, excellent biocompatibility and high efficient drug loading capability, making these PEGylated GO nanocomposites promising candidates for biomedical applications.

  15. Design, Synthesis, and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles.

    PubMed

    Kang, Dongwei; Fang, Zengjun; Li, Zhenyu; Huang, Boshi; Zhang, Heng; Lu, Xueyi; Xu, Haoran; Zhou, Zhongxia; Ding, Xiao; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Zhan, Peng; Liu, Xinyong

    2016-09-01

    We designed and synthesized a series of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a piperidine-substituted thiophene[3,2-d]pyrimidine scaffold, employing a strategy of structure-based molecular hybridization and substituent decorating. Most of the synthesized compounds exhibited broad-spectrum activity with low (single-digit) nanomolar EC50 values toward a panel of wild-type (WT), single-mutant, and double-mutant HIV-1 strains. Compound 27 was the most potent; compared with ETV, its antiviral efficacy was 3-fold greater against WT, 5-7-fold greater against Y181C, Y188L, E138K, and F227L+V106A, and nearly equipotent against L100I and K103N, though somewhat weaker against K103N+Y181C. Importantly, 27 has lower cytotoxicity (CC50 > 227 μM) and a huge selectivity index (SI) value (ratio of CC50/EC50) of >159101. 27 also showed favorable, drug-like pharmacokinetic and safety properties in rats in vivo. Molecular docking studies and the structure-activity relationships provide important clues for further molecular elaboration. PMID:27541578

  16. 4-Aminopyridyl-Based CYP51 Inhibitors as Anti-Trypanosoma cruzi Drug Leads with Improved Pharmacokinetic Profile and in Vivo Potency

    PubMed Central

    2015-01-01

    CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure–activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug–target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection. PMID:25101801

  17. Drug carrier systems based on collagen-alginate composite structures for improving the performance of GDNF-secreting HEK293 cells.

    PubMed

    Lee, M; Lo, A C; Cheung, P T; Wong, D; Chan, B P

    2009-02-01

    Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor. Development of drug delivery technologies facilitating controlled release of GDNF is critical to applying GDNF in treating neurodegenerative diseases. We previously developed 3D collagen microspheres and demonstrated enhanced GDNF secretion after encapsulation of HEK293 cells, which were transduced to overexpress GDNF in these microspheres. However, the entrapped HEK293 cells were able to migrate out of the collagen microspheres, making it undesirable for clinical applications. In this report, we investigate two new carrier designs, namely collagen-alginate composite gel and collagen microspheres embedded in alginate gel in preventing cell leakage, maintaining cell growth and controlling GDNF secretion in the HEK293 cells. We demonstrated that inclusion of alginate gel in both designs is efficient in preventing cell leakage to the surrounding yet permitting the GDNF secretion, although the cellular growth rate is reduced in an alginate concentration dependent manner. Differential patterns of GDNF secretion in the two designs were demonstrated. The collagen-alginate composite gel maintains a more or less constant GDNF secretion over time while the collagen microspheres embedded in alginate gel continue to increase the secretion level of GDNF over time. This study contributes towards the development of cell-based GDNF delivery devices for the future therapeutics of neurodegenerative diseases. PMID:19059641

  18. Phenylbutazone, a New Long-Acting Agent that can Improve the Peptide Pharmacokinetic Based on Serum Albumin as a Drug Carrier.

    PubMed

    Zhou, Jie; Li, Xue; Zhu, Xiaoyun; Sun, Jian; Qiu, Qianqian; Huang, Wenlong; Qian, Hai

    2016-06-01

    As a NPY-2 receptor agonist, PYY24-36- Leu31 is reported to suppress appetite and has a potential in obesity treatment, but its short half-life limits the clinical application. The use of chemical modification to improve interactions with human serum albumin (HSA) is an effective strategy for prolonging the half-lives of peptide analogues. So based on the characteristics that phenylbutazone has a good combination with HSA, we selected a proper linker to link with PYY24-36 -Leu31 to create long-acting and highly biologically active PYY24-36 -Leu31 conjugates, and successfully find a novel, long-acting PYY24-36 -Leu31 conjugate 8 that, when dosed every other day in diet induce obese (DIO) mice for 2 weeks, results in a significant reduction in food intake and body weight and improvement in blood parameter and hepatic steatosis. PMID:26808199

  19. Improvement in the drug delivery and anti-tumor efficacy of PEGylated liposomal doxorubicin by targeting RNA aptamers in mice bearing breast tumor model.

    PubMed

    Moosavian, Seyedeh Alia; Abnous, Khalil; Badiee, Ali; Jaafari, Mahmoud Reza

    2016-03-01

    Targeted delivery by ligands such as aptamers, is a promising method to increase the efficiency of PEGylated-liposomal doxorubicin (PL-Dox). In this study, we have successfully conjugated our recently developed anti-breast cancer RNA aptamer (TSA14) to the surface of PL-Dox and characterized for their size, zeta potential, Dox percent encapsulation and release properties in the presence of fetal bovine serum. In vitro experiments showed that aptamer could improve cellular uptake and cytotoxicity of PL-Dox in TUBO breast cell line. In mice bearing TUBO breast tumor, although, the doxorubicin plasma level of liposomal doxorubicin did not significantly change after modification of nanoparticles with aptamer, however, much higher tumor accumulation of Dox as compared with non-targeted liposomes proved the tumor-targeting capability of aptamers. In the same way, aptamer-PL-Dox improved anti-tumor efficiency of liposomes in TUBO breast tumor in mice compared to non-targeted liposomes. Overall, the results showed that aptamer decoration of PL-Dox could significantly improve selectivity and the therapeutic efficacy of liposomal DOX and merits further investigation. PMID:26722819

  20. [Club drugs].

    PubMed

    Guerreiro, Diogo Frasquilho; Carmo, Ana Lisa; da Silva, Joaquim Alves; Navarro, Rita; Góis, Carlos

    2011-01-01

    Club drugs are the following substances: Methylenedioxymethamphetamine (MDMA); Methamphetamine; Lysergic Acid Diethylamide (LSD); Ketamine; Gamma-hydroxybutyrate (GHB) and Flunitrazepam. These substances are mainly used by adolescents and young adults, mostly in recreational settings like dance clubs and rave parties. These drugs have diverse psychotropic effects, are associated with several degrees of toxicity, dependence and long term adverse effects. Some have been used for several decades, while others are relatively recent substances of abuse. They have distinct pharmacodynamic and pharmacokinetic properties, are not easy to detect and, many times, the use of club drugs is under diagnosed. Although the use of these drugs is increasingly common, few health professionals feel comfortable with the diagnosis and treatment. The authors performed a systematic literature review, with the goal of synthesising the existing knowledge about club drugs, namely epidemiology, mechanism of action, detection, adverse reactions and treatment. The purpose of this article is creating in Portuguese language a knowledge data base on club drugs, that health professionals of various specialties can use as a reference when dealing with individual with this kind of drug abuse. PMID:22525626

  1. Non-biologic disease-modifying antirheumatic drugs (DMARDs) improve pain in inflammatory arthritis (IA): a systematic literature review of randomized controlled trials.

    PubMed

    Steiman, Amanda J; Pope, Janet E; Thiessen-Philbrook, Heather; Li, Lihua; Barnabe, Cheryl; Kalache, Fares; Kung, Tabitha; Bessette, Louis; Flanagan, Cathy; Haraoui, Boulos; Hochman, Jacqueline; Leclercq, Sharon; Mosher, Dianne; Thorne, Carter; Bykerk, Vivian

    2013-05-01

    Evidence supports early use of non-biologic DMARDs to prevent irreversible damage in inflammatory arthritides, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and possibly ankylosing spondylitis (AS). However, there is a paucity of data exploring their effects on pain as a primary outcome in these conditions. This systematic literature review investigated the effect of non-biologic DMARDs on pain levels in IA and examined whether disease duration impacted efficacy. We searched Medline, Embase, Cochrane Central, and Cochrane Database of Systematic Reviews, abstracts from the 2008 to 2010 American College of Rheumatology annual congresses, and citation lists of retrieved publications. Only randomized, double-blind controlled trials were analyzed. Quality was assessed with the Risk of Bias tool. Descriptive statistics were used in meta-analysis. 9,860 articles were identified, with 33 eligible for inclusion: 8 in AS, 6 in PsA, 9 in early RA (ERA), and 10 in established RA. In ERA and established RA, all studies of DMARDs (monotherapy and combination therapies) consistently revealed statistically significant reductions in pain except three oral gold studies. In AS, sulfasalazine studies showed significant pain reduction, whereas use of other DMARDs did not. In PsA, 5 of 6 studies reported VAS-pain improvement. From the studies included, we were unable to assess the influence of disease duration on pain outcomes in these rheumatic conditions. DMARDs improve pain in early and established RA. Sulfasalazine may improve pain in AS and PsA. Further study is needed to assess the relationship between disease duration and DMARD efficacy in reducing pain in these conditions. PMID:23292213

  2. Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance.

    PubMed

    Weiss, Maud; Bouchoucha, Soumaya; Aiad, Farouk; Ayme-Dietrich, Estelle; Dali-Youcef, Nassim; Bousquet, Pascal; Greney, Hugues; Niederhoffer, Nathalie

    2015-07-15

    Altered adiponectin signaling and chronic sympathetic hyperactivity have both been proposed as key factors in the pathogenesis of metabolic syndrome. We recently reported that activation of I1 imidazoline receptors (I1R) improves several symptoms of the metabolic syndrome through sympathoinhibition and increases adiponectin plasma levels in a rat model of metabolic syndrome (Fellmann L, Regnault V, Greney H, et al. J Pharmacol Exp Ther 346: 370-380, 2013). The present study was designed to explore the peripheral component of the beneficial actions of I1R ligands (i.e., sympathoinhibitory independent effects). Aged rats displaying insulin resistance and glucose intolerance were treated with LNP509, a peripherally acting I1R agonist. Glucose tolerance, insulin sensitivity, and adiponectin signaling were assessed at the end of the treatment. Direct actions of the ligand on hepatocyte and adipocyte signaling were also studied. LNP509 reduced the area under the curve of the intravenous glucose tolerance test and enhanced insulin hypoglycemic action and intracellular signaling (Akt phosphorylation), indicating improved glucose tolerance and insulin sensitivity. LNP509 stimulated adiponectin secretion acting at I1R on adipocytes, resulting in increased plasma levels of adiponectin; it also enhanced AMPK phosphorylation in hepatic tissues. Additionally, I1R activation on hepatocytes directly enhanced AMPK phosphorylation. To conclude, I1R ligands can improve insulin sensitivity acting peripherally, independently of sympathoinhibition; stimulation of adiponectin and AMPK pathways at insulin target tissues may account for this effect. This may open a promising new way for the treatment of the metabolic syndrome. PMID:26015433

  3. Novel Improved Synthesis of HSP70 Inhibitor, Pifithrin-μ. In Vitro Synergy Quantification of Pifithrin-μ Combined with Pt Drugs in Prostate and Colorectal Cancer Cells.

    PubMed

    McKeon, Aoife M; Egan, Alan; Chandanshive, Jay; McMahon, Helena; Griffith, Darren M

    2016-01-01

    We describe a novel improved approach to the synthesis of the important and well-known heat shock protein 70 inhibitor (HSP70), pifithrin-μ, with corresponding and previously unreported characterisation. The first example of a combination study comprising HSP70 inhibitor pifithrin-μ and cisplatin or oxaliplatin is reported. We have determined, using the Chou-Talalay method, (i) moderate synergistic and synergistic effects in co-treating PC-3 prostate cancer cells with pifithrin-μ and cisplatin and (ii) significant synergistic effects including strong synergism in cotreating HT29 colorectal cancer cells with oxaliplatin and pifithrin-μ. PMID:27455212

  4. Street Drugs and Pregnancy

    MedlinePlus

    ... drugs that are abused How can street drugs harm your pregnancy? Using street drugs can cause problems ... drugs that are abused How can street drugs harm your pregnancy? Using street drugs can cause problems ...

  5. A drug's life: the pathway to drug approval.

    PubMed

    Keng, Michael K; Wenzell, Candice M; Sekeres, Mikkael A

    2013-10-01

    In the United States, drugs and medical devices are regulated by the US Food and Drug Administration (FDA). A drug must undergo rigorous testing prior to marketing to and medical use by the general public. The FDA grants marketing approval for drug products based on a comprehensive review of safety and efficacy data. This review article explains the history behind the establishment of the FDA and examines the historical legislation and approval processes for drugs, specifically in the fields of medical oncology and hematology. The agents imatinib (Gleevec, Novartis) and decitabine (Dacogen, Eisai) are used to illustrate both the current FDA regulatory process-specifically the orphan drug designation and accelerated approval process-and why decitabine failed to gain an indication for acute myeloid leukemia. The purpose and construct of the Oncologic Drugs Advisory Committee are also discussed, along with examples of 2 renal cell cancer drugs-axitinib (Inlyta, Pfizer) and tivozanib-that used progression-free survival as an endpoint. Regulatory approval of oncology drugs is the cornerstone of the development of new treatment agents and modalities, which lead to improvements in the standard of cancer care. The future landscape of drug development and regulatory approval will be influenced by the new breakthrough therapy designation, and choice of drug will be guided by genomic insights. PMID:24518374

  6. Drug-drug plasma protein binding interactions of ivacaftor.

    PubMed

    Schneider, Elena K; Huang, Johnny X; Carbone, Vincenzo; Baker, Mark; Azad, Mohammad A K; Cooper, Matthew A; Li, Jian; Velkov, Tony

    2015-06-01

    Ivacaftor is a novel cystic fibrosis (CF) transmembrane conductance regulator (CFTR) potentiator that improves the pulmonary function for patients with CF bearing a G551D CFTR-protein mutation. Because ivacaftor is highly bound (>97%) to plasma proteins, there is the strong possibility that co-administered CF drugs may compete for the same plasma protein binding sites and impact the free drug concentration. This, in turn, could lead to drastic changes in the in vivo efficacy of ivacaftor and therapeutic outcomes. This biochemical study compares the binding affinity of ivacaftor and co-administered CF drugs for human serum albumin (HSA) and α1 -acid glycoprotein (AGP) using surface plasmon resonance and fluorimetric binding assays that measure the displacement of site-selective probes. Because of their ability to strongly compete for the ivacaftor binding sites on HSA and AGP, drug-drug interactions between ivacaftor are to be expected with ducosate, montelukast, ibuprofen, dicloxacillin, omeprazole, and loratadine. The significance of these plasma protein drug-drug interactions is also interpreted in terms of molecular docking simulations. This in vitro study provides valuable insights into the plasma protein drug-drug interactions of ivacaftor with co-administered CF drugs. The data may prove useful in future clinical trials for a staggered treatment that aims to maximize the effective free drug concentration and clinical efficacy of ivacaftor. PMID:25707701

  7. Drug Control: Observations on Elements of the Federal Drug Control Strategy. Report to Congressional Requesters.

    ERIC Educational Resources Information Center

    General Accounting Office, Washington, DC. General Government Div.

    Although the United States government invests vast sums of money in the war on drugs, the availability of drugs and the number of persons using illegal drugs are still serious problems. Information that Congress can use in improving drug control strategies is provided here. Some of the report's highlights include current research on promising…

  8. Club Drugs

    MedlinePlus

    Skip to main content En español Researchers Medical & Health Professionals Patients & ... Cold Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine Other Drugs ...

  9. Prescription Drugs

    MedlinePlus

    ... body, especially in brain areas involved in the perception of pain and pleasure. Prescription stimulants , such as ... of drug that causes changes in your mood, perceptions, and behavior can affect judgment and willingness to ...

  10. Antiretroviral drugs.

    PubMed

    De Clercq, Erik

    2010-10-01

    In October 2010, it will be exactly 25 years ago that the first antiretroviral drug, AZT (zidovudine, 3'-azido-2',3'-dideoxythymidine), was described. It was the first of 25 antiretroviral drugs that in the past 25 years have been formally licensed for clinical use. These antiretroviral drugs fall into seven categories [nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs). The INIs (i.e. raltegravir) represent the most recent advance in the search for effective and selective anti-HIV agents. Combination of several anti-HIV drugs [often referred to as highly active antiretroviral therapy (HAART)] has drastically altered AIDS from an almost uniformly fatal disease to a chronic manageable one. PMID:20471318

  11. Drug Interactions

    MedlinePlus

    ... not be taken at the same time as antacids. WHAT CAUSES THE MOST INTERACTIONS WITH HIV MEDICATIONS? ... azole” Some antibiotics (names end in “mycin”) The antacid cimetidine (Tagamet) Some drugs that prevent convulsions, including ...

  12. Drugged Driving

    MedlinePlus

    ... Charts Emerging Trends and Alerts Alcohol Club Drugs Cocaine Hallucinogens Heroin Inhalants Marijuana MDMA (Ecstasy/Molly) Methamphetamine ... distance, and decrease coordination. Drivers who have used cocaine or methamphetamine can be aggressive and reckless when ...

  13. Drug-induced pulmonary disease

    MedlinePlus

    ... improve. Some drug-induced lung diseases, such as pulmonary fibrosis, may never go away. ... Complications that may develop include: Diffuse interstitial pulmonary fibrosis Hypoxemia (low blood oxygen) Respiratory failure

  14. Drug abuse in athletes

    PubMed Central

    Reardon, Claudia L; Creado, Shane

    2014-01-01

    Drug abuse occurs in all sports and at most levels of competition. Athletic life may lead to drug abuse for a number of reasons, including for performance enhancement, to self-treat otherwise untreated mental illness, and to deal with stressors, such as pressure to perform, injuries, physical pain, and retirement from sport. This review examines the history of doping in athletes, the effects of different classes of substances used for doping, side effects of doping, the role of anti-doping organizations, and treatment of affected athletes. Doping goes back to ancient times, prior to the development of organized sports. Performance-enhancing drugs have continued to evolve, with “advances” in doping strategies driven by improved drug testing detection methods and advances in scientific research that can lead to the discovery and use of substances that may later be banned. Many sports organizations have come to ban the use of performance-enhancing drugs and have very strict consequences for people caught using them. There is variable evidence for the performance-enhancing effects and side effects of the various substances that are used for doping. Drug abuse in athletes should be addressed with preventive measures, education, motivational interviewing, and, when indicated, pharmacologic interventions. PMID:25187752

  15. Drug abuse in athletes.

    PubMed

    Reardon, Claudia L; Creado, Shane

    2014-01-01

    Drug abuse occurs in all sports and at most levels of competition. Athletic life may lead to drug abuse for a number of reasons, including for performance enhancement, to self-treat otherwise untreated mental illness, and to deal with stressors, such as pressure to perform, injuries, physical pain, and retirement from sport. This review examines the history of doping in athletes, the effects of different classes of substances used for doping, side effects of doping, the role of anti-doping organizations, and treatment of affected athletes. Doping goes back to ancient times, prior to the development of organized sports. Performance-enhancing drugs have continued to evolve, with "advances" in doping strategies driven by improved drug testing detection methods and advances in scientific research that can lead to the discovery and use of substances that may later be banned. Many sports organizations have come to ban the use of performance-enhancing drugs and have very strict consequences for people caught using them. There is variable evidence for the performance-enhancing effects and side effects of the various substances that are used for doping. Drug abuse in athletes should be addressed with preventive measures, education, motivational interviewing, and, when indicated, pharmacologic interventions. PMID:25187752

  16. Does Drug Testing Deter Drug Court Participants from Using Drugs or Alcohol?

    ERIC Educational Resources Information Center

    Kleinpeter, Christine B.; Brocato, Jo; Koob, Jeffrey J.

    2010-01-01

    This study evaluates 3 drug-testing strategies implemented in 5 different jurisdictions with drug courts in Orange County, California. The purpose of the study was to determine whether the sweat patch acts as a deterrent and under what conditions it can be used to improve outcomes. Results indicated that although the use of the sweat patch did not…

  17. Drug allergy

    PubMed Central

    Warrington, Richard

    2012-01-01

    Allergic drug reactions occur when a drug, usually a low molecular weight molecule, has the ability to stimulate an immune response. This can be done in one of two ways. The first is by binding covalently to a self-protein, to produce a haptenated molecule that can be processed and presented to the adaptive immune system to induce an immune response. Sometimes the drug itself cannot do this but a reactive breakdown product of the drug is able to bind covalently to the requisite self-protein or peptide. The second way in which drugs can stimulate an immune response is by binding non-covalently to antigen presenting or antigen recognition molecules such as the major histocompatibility complex (MHC) or the T cell receptor. This is known as the p-I or pharmacological interaction hypothesis. The drug binding in this situation is reversible and stimulation of the response may occur on first exposure, not requiring previous sensitization. There is probably a dependence on the presence of certain MHC alleles and T cell receptor structures for this type of reaction to occur. PMID:22922763