bluuebunny/crossref_metadata_2025 huggingface dataset:
Storage proteins in wheat (Triticum aestivum L.) and the ecological impacts affecting their quality and quantity, with a focus on nitrogen supply
Authors: Horváth Csaba
Published: March 2016

Wheat (Triticum aestivum L.) is the most widely used basic staple for mankind. Wheat is also one of the most important cereals in Hungary with a high economic value. The aim of wheat production is twofold; to provide quantity and quality. Milling and baking quality of wheat is mainly determined by the genetic basis, however it can be influenced by management techniques. Storage proteins account for more than half of the total protein in mature cereal grains and have important impacts on their nutritional quality for humans and livestock and on their functional properties in food processing. Gluten proteins - gliadins and glutenins of wheat determine the quality of the grain for breadmaking and their amount and composition can be influenced by agronomic impacts leading to changes in dough properties and that of baking quality. The present review is dealing with the impact of various agronomic and environmental factors on the performance of storage proteins and within them gluten proteins.
Plant density impact on grain yield of maize (Zea mays L.) hybrids on chernozem soil of the Eastern Hungary
Authors: Pepó Péter , Murányi Eszter
Published: March 2016

The plant density response of 12 maize hybrids was tested in a favourable year (2013) under optimum agrotechnical conditions on chernozem soil by applying plant densities of 50, 70 and 90 thousand plants ha-1. Due to the favourable ecological and agrotechnical conditions yields varied between 11400 and 16300 kg ha-1 depending upon the hybrid and the plant density. From among the hybrids, 5 and 7 produced the maximum yield at 70 and 90 thousand plants ha-1, respectively however the yield increment was not significant between 70 thousand plants ha-1 and 90 thousand plants ha-1. No relationship was found between the season length and the optimum plant density of hybrids. Those hybrids were the most favourable, which gave a stable high yield at different plant densities that is their optimum plant density range was wide (P 9175, P 9494, SY Afinity). Hybrids with a small optimum plant density range (P 9578, DKC 4490, PR 37N01) gave the highest yield at a specific plant density (70 thousand plants ha-1 or 90 thousand plants ha-1). A special complex coordinate system was developed for evaluation for the plant density response of maize genotypes specific ecological and agrotechnical conditions can be evaluated jointly.
Roma fiatalok munkaértékei
Authors: Bocsi Veronika , Csokai Anita
Published: March 2016

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Az új típusú droghasználat szerepe és megjelenése a társadalom perifériáján élő fővárosi roma közösségekben
Authors: Balázs András
Published: March 2016

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Kisiskolások teljesítményszorongásának csökkentése
Authors: Fülöp Ilona
Published: March 2016

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Introduction to Pharmaceutical Calculations - Fourth edition, Judith A. Rees, Ian Smith and Jennie Watson
Authors: Cheng Wilson
Published: March 2016

This book by Rees, Smith and Watson is applicable to pharmacy students, pharmacy technician students, as well as instructors.  The book is divided into 13 chapters and covers topics such as concentrations, dilutions and dosage calculation, that most pharmacy practitioners encounter.  The authors have primarily used the concept of proportions to approach most of the mathematical problems covered in this book.  The use of a consistent approach allows for continuity from one chapter to the next, and teaches students a single approach that enables solving most pharmacy-related mathematical problems.  The drawback, however, is that this one single approach may not suit all readers and learning styles.    The text is well laid out and easy to follow.  Concepts are discussed thoroughly while some areas, e.g., density, specific gravity and significant figures, can benefit from more in depth discussions.  The practice questions are relevant to most situations and are well-used to illustrate the concepts of interest.  The number of examples and practice questions are sufficient. It is evident that the book is primarily intended for students in the UK since the British Pharmacopeia and British National Formulary are its main references.  While readers outside of the UK will not have difficulty understanding the concepts, they will find some of the references not applicable.  The authors included some discussion on infusion rates and concentrations.  However, the book can benefit from inclusion of more in depth discussions and examples relevant to hospital practice (e.g., concentrations and the mixing of intravenous electrolyte solutions).  The inclusion of access to online videos is a welcomed addition and can appeal to students with various learning styles.                  In conclusion, this is a useful text for students and instructors.  The practice questions in this book are relevant to daily practice and can be used as a source of additional practice for students.
The Tape-Stripping Technique as a Method for Drug Quantification in Skin
Authors: Escobar-Chavez Jose Juan , Merino-Sanjuán V. , López-Cervantes M. , Urban-Morlan Z. , Piñón-Segundo E. , Quintanar-Guerrero D. , Ganem-Quintanar A.
Published: March 2016

Quantification of drugs within the skin is essential for topical and transdermal delivery research. Over the last two decades, horizontal sectioning, consisting of tape stripping throughout the stratum corneum, has become one of the traditional investigative techniques.

Tape stripping of human stratum corneum is widely used as a method for studying the kinetics and penetration depth of drugs. This paper shows the applications of the tape stripping technique to quantify drug penetration through the skin, underlining its versatile application in the area of topical and transdermal drugs.
Bicarbonate supplementation as a preventive way in statins-induced muscle damage
Authors: Kobayashi Masaki , Kagawa Toshiki , Narumi Katsuya , Itagaki Shirou , Hirano Takeshi , Iseki Ken
Published: March 2016

ABSTRACT – Purpose. The aim of this study was to evaluate the bicarbonate-induced improvement of statins, cerivastatin, simvastatin acid and lovastatin acid -induced apoptosis using rat myoblast cell line (L6) as a model of in vitro skeletal muscle and of cerivastatin-induced muscle damage in vivo study. Methods. Statin-induced reduction of cell viability and apoptosis was measured by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay and caspase assay. In vivo, we evaluated plasma creatine phosphokinase (CPK) level in cerivastatin-treated rat. Results. Bicarbonate prevented cerivastatin-, simvastatin- acid and lovastatin acid -induced reduction of cell viability, morphological change and caspase activation in L6 cells. Moreover, in the in vivo study, bicarbonate prevented cerivastatin-induced increase in CPK concentrations. Conclusions. These results from in vitro and in vivo studies support that bicarbonate supplementation prevented statin-induced muscle damage.
Co-Encapsulated CpG Oligodeoxynucleotides and Ovalbumin in PLGA Microparticles; An in vitro and in vivo Study
Authors: San Román Beatriz , Gómez Sara , Irache Juan M. , Espuelas Socorro
Published: March 2016

Purpose: The objective of this work was to evaluate the effect in the immune response produced by CpG oligodeoxynucleotides (ODN) co-encapsulated with the antigen ovalbumin (OVA) within poly(lactic-co-glycolic) acid (PLGA) 502 and 752 microparticles (MP). Methods: MP were prepared by blending 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) with PLGA and Total Recirculation One Machine System (TROMS) technology and contained OVA along with CpG sequences associated to DOTAP. After confirming the integrity of both encapsulated molecules, BALB/c mice were immunized with the resulting MP and OVA-specific antibodies and cytokine production were assessed in order to determine the immunological profile induced in mice. Results: One m near non-charged MP co-encapsulated very efficiently both OVA and CpG ODN. The release of both OVA and CpG was slow and incomplete irrespective of polymer. The results of the immune response induced in BALB/c mice indicated that, depending on the PLGA polymer used, co-encapsulation did not improve the immunogenicity of the antigen, compared either with the simply co-administration of both antigen and CpG, or with the microencapsulated antigen. Thus, mice immunized with OVA associated to PLGA 756 displayed an IgG2a characterized response which was biased to an IgG1 profile in case of CpG co-encapsulation. On the contrary, the co-encapsulation of CpG with OVA into PLGA 502 significantly improved the isotype shifting in comparison with the one showed by mice immunized with OVA loaded PLGA 502. Conclusion: This study underlines the importance of MP characteristics to fully exploit simultaneous antigen and CpG ODN particulate delivery as effective vaccine construct.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Metabolism of isorhynchophylline in rats detected by LC-MS
Authors: Wang Wei , Ma Chao-Mei , Hattori Masao
Published: March 2016

PURPOSE This paper investigates the metabolic fate of isorhynchophylline (ISOR) as a main bioactive oxindole alkaloid in the traditional Chinese medicine. METHODS After oral administration of ISOR to rats, plasma, bile, urine and feces were analyzed by LC-MS. Hydroxylation of ISOR and successive glucuronidation proceeded in vitro by incubation with rat liver microsomes. RESULTS ISOR was identified in plasma, 11-hydroxyisorhynchophylline 11-O--D-glucuronide (MI1) and 10-hydroxyisorhynchophylline 10-O--D-glucuronide (MI2) in bile, and free 11-hydroxyisorhynchophylline (MI3) and 10-hydroxyisorhynchophylline (MI4) in urine and feces. Within 24 h, 71.6% of ISOR was excreted into the feces (in 20.0 g) and 13.8% into the urine (in 20.0 ml) of rats after oral administration of 37.5 mg/kg. Monitoring by LC-MS showed that 8.5% of ISOR was metabolized to MI3 and MI4 in a ratio of ca. 1:1. Specific inhibition of CYP isozymes indicated that CYP2D, CYP1A1/2 and CYP2C participate in ISOR hydroxylation. CONCLUSIONS ISOR was involved in the circulatory system after oral administration. Cytochrome P450 (CYP) in rat liver microsomes played a key role in ISOR hydroxylation.
Design and evaluation of a novel floating osmotic pump system
Authors: Zhang Zhihong , Peng Bo , Yang Xinggang , Wang Chao , Sun Guangmei , Pan Weisan
Published: March 2016

PURPOSE. Find a novel delivery system for oral administration of drugs that have absorption window in the upper part of gastrointestinal (GI) track. METHODS. Dipyridamole was chosen as the model drug. A novel system, which combined the osmotic pump controlled release system and the floating system, was designed; matrix tablets (MT) were prepared for compares. The effects of pH, temperature and hydrodynamic conditions on drug release and the floating behavior of floating osmotic pump system (FOP) were investigated. In vivo evaluation was performed by a three-crossover study in six Beagle dogs relative to the conventional tablet (CT). Cumulative percent input in vivo was compared with that of in vitro release profiles. RESULTS. Floating behavior of FOP, drug releases from FOP and MT were sensitive to pH of dissolution media but not sensitive to temperature; the release of dipyridamole from MT was influenced by stirring rate while drug release from FOP was not. AUC of FOP was larger than MT and CT. The linear correlations between fraction absorbed in vivo and fraction dissolved in vitro was established for FOP-a true zero-order release formula, whereas only a nonlinear correlation was obtained for MT. CONCLUTIONS. FOP could be a novel way for the oral administration for drugs like dipyridamole.
Effects of Monoglycerides on Rhodamine 123 Accumulation, Estradiol 17 β-D-Glucuronide Bidirectional Transport and MRP2 Protein Expression within Caco-2 cells
Authors: Jia Jessica X. , Wasan Kishor M
Published: March 2016

Purpose. Oral drug development had been hindered by the bioavailability issue despite vast market popularity. Lipid excipients had shown to enhance bioavailability of a number of reformulated hydrophobic oral drugs, yet the underlying mechanisms of action by lipids are still unclear. One proposed mechanism is that lipid excipients could facilitate drug uptake by altering the activities of apical membrane intestinal efflux transporters. Thus, this study aimed to investigate the effects of 1-monopalmitin, 1-monoolein and 1-monostearin on the efflux activity and protein expression of multidrug resistance-associated protein 2 (MRP2) in vitro. Methods. The 24-hour non-cytotoxic ranges of these monoglycerides were first determined using MTS and LDH assays in Caco-2 cells. Then, both accumulation and bidirectional transport studies were conducted using 10 uM rhodamine 123 (Rh123) and 10 nM estradiol 17 β-D-glucuronide (E217βG), respectively, to assess the functional activities of MRP2. 50 µM MK-571, a specific MRP1 and MRP2 inhibitor, was used as the positive control in both studies. Western blotting was followed to determine the effect of these monoglycerides on MRP2 protein expression. Results. Caco-2 cells were viable when treated with 1-monopalmitin, 1-monostearin and 1-monoolein at concentrations equal or less than 1000 µM, 1000 µM and 500 µM, respectively. Cells treated with 1-monoplamitin, 1-monostearin, 1-monoolein and MK571 resulted in significant increases in Rh123 accumulation and decreases in E217βG efflux ratio compared to the control (medium treated only). MRP2 protein expressions in 1-monopalmitin and 1-monoolein treated cells were decreased by 19% and 35% compared to the control; however, there was no change of MRP2 protein expression in 1-monostearin treated cells. Conclusions. These findings suggested that 1-monoolein, 1-monostearin and 1-monopalmitin could attenuate the activity of MRP2 and possibly other efflux transporters in Caco-2 cells. The reduction of efflux activity of MRP2 by 1-monoolein treatment could be partially accounted by the non-specific down-regulation of MRP2 protein expression.
Influence on Effectiveness of Early Treatment with Anti-TNF Therapy in Rheumatoid Arthritis
Authors: Escudero-Vilaplana Vicente , Ramírez-Herraiz Esther , Trovato-López Nicolás , Alañón-Plaza Estefanía , Bellini María José , Herranz-Alonso Ana , Bellón-Cano José María , Morell-Baladrón Alberto , Sanjurjo-Sáez María
Published: March 2016

Purpose. To evaluate the association between starting early treatment with anti-TNF and effectiveness as well as the possibility of applying therapeutic spacing in daily practice in patients with rheumatoid arthritis (RA). Methods. Observational, retrospective study conducted in two universitary hospitals in Spain. RA patients who received the first anti-TNF (adalimumab: ADA, etanercept: ETN or infliximab: IFX) during the study period (October 2006-2010) were included. Demographic data, time since diagnosis, disease activity (DAS28-ESR) and anti-TNF dosage were analyzed. Therapeutic objective was defined as DAS28
Buoyancy-Generating Agents for Stomach-Specific Drug Delivery: An Overview with Special Emphasis on Floating Behavior
Authors: Ishak Rania A.H.
Published: March 2016

Gastric retentive drug delivery provides a promising technology exhibiting an extended gastric residence and a drug release independent of patient related variables. It is usually useful in improving local gastric treatment as well as overcoming drug-related problems .i.e. drugs having narrow absorption window, short half-life or low intestinal solubility. Buoyancy is considered one of the most promising approaches for gastro-retention of dosage forms. Floating drug delivery systems have a bulk density lower than gastric fluids and thus remain buoyant in the stomach causing an increase in gastric residence time. The buoyancy of these systems is attained by the aid of substances responsible to generate the low density. Various agents with different mechanisms were adopted either gas-generating agents, air entrapping swellable polymers, inherent low density substances, porous excipients, hollow/porous particles inducing preparation techniques or sublimating agents. Therefore, this review gives an exclusive descriptive classification of the different categories of these buoyancy-generating agents while representing the related research works. An overview is also conducted to describe relevant techniques assessing the floating behavior of such dosage forms either in vitro or in vivo. Finally, a collection representing FDA-approved floating pharmaceutical products is adopted with emphasis on the buoyancy-generating agent type used in each product. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Assessing Bioequivalence of Antiepileptic Drugs: Are the Current Requirements too Permissive?
Authors: Rediguieri Camila F , Zeredo Jorge L
Published: March 2016

Purpose: In order to evaluate the permissiveness of current bioequivalence requirements for antiepileptic drugs we investigated how accurate Cmax and AUC0-t of generic antiepileptic drugs approved in Brazil are in comparison to reference products. Methods: Data collected from assessment reports of approved bioequivalence studies archived in the Brazilian regulatory agency in 2007-2012 were: geometric mean ratios and 90% confidence intervals (CI) for Cmax and AUC0-t, intra-subject variability (CV) of Cmax and AUC0-t and number of subjects. Results: The average difference in Cmax and AUC0-t between generic and reference products was 5% and 3%, respectively. Maximum deviation from 1.00 of the CI of Cmax can achieve 15-20% (demonstrated in 27% of studies); for AUC0-t, 25% of studies showed the deviation can be >10%. All studies that used adequate number of subjects for a 90% CI of 0.90-1.11 complied with it for AUC0-t, except one of carbamazepine, but only 33% complied with it for both AUC0-t and Cmax. The CV was strongly correlated to the maximum CI deviation for AUC0-t (CV of approximately 15% corresponding to deviation of 10%). Studies that presented maximum CI deviation ≤ 10 % together with CV ≤ 15% for AUC0-t represented 65% of the total. Weaker correlation was observed for Cmax and no correlation was seen between maximum CI deviation and number of subjects. Conclusions: Modification in legislation for bioequivalence of antiepileptic drugs is suggested, not only with constraint of AUC0-t 90% CI to 0.90-1.11, but also with limitation of the CV to 15%, as to assure similar variance in pharmacokinetics and diminish the risk of critical plasma-level fluctuation when switching between generic and reference formulations. Although most generics presented differences ≤ 10% in AUC0-t compared to their references, some narrow therapeutic index drugs displayed differences that could be clinically significant after product substitution.  This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Brain and Plasma Riluzole Pharmacokinetics: Effect of Minocycline Combination
Authors: Milane Aline , Tortolano Lionel , Fernandez Christine , Bensimon Gilbert , Meininger Vincent , Farinotti Robert
Published: March 2016

PURPOSE: amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the loss of motorneurons. The only drug approved is riluzole. Minocycline is an antibiotic with numerous neuroprotective properties. riluzole and minocycline were given to an animal model of ALS and had beneficial effect on the disease. The combination was then tested in humans in phase II and phase III studies with less beneficial effects and a faster decline of the disease in the group treated with minocycline. In a previous study, we showed that riluzole is transported out of the brain by the P-glycoprotein at the blood-brain barrier level. METHODS: in this work, we studied in CF1 mice, the plasmatic and cerebral pharmacokinetics of riluzole combined or not with minocycline. RESULTS: our results showed that the kinetics of riluzole are not linear with dose, but that cerebral AUC0-∞ increase proportionally with plasmatic AUC0-∞. At the dose of 10 mg/kg, the cerebral AUC0-∞ /plasmatic AUC0-∞ ratio was 4.6 in mdr1a (-/-) mice and 2.4 in mdr1a (+/+) mice. The combination of minocycline (170 mg/kg) and riluzole (10 mg/kg) induced a 2 fold increase in the cerebral AUC0-∞ of riluzole and induced a neuromuscular toxicity in mice. This effect of minocycline was not found at low concentration (10 mg/kg of minocycline). CONCLUSIONS: if our results are confirmed in humans, riluzole cerebral concentrations could be predicted by plasmatic concentrations. Furthermore, the combination of high doses of minocycline with riluzole could induce neurological toxicity that lead to deceiving results in ALS clinical studies.
Selection of Suitable Prodrug Candidates for in vivo Studies via in vitro Studies; The Correlation of Prodrug Stability in Between Cell Culture Homogenates and Human Tissue Homogenates
Authors: Tsume Yasuhiro , Amidon Gordon L
Published: March 2016

Purpose. To determine the correlations/discrepancies of drug stabilities between in the homogenates of human culture cells and of human tissues. Methods. Amino acid/dipeptide monoester prodrugs of floxuridine were chosen as the model drugs. The stabilities (half-lives) of floxuridine prodrugs in human tissues (pancreas, liver, and small intestine) homogenates were obtained and compared with ones in cell culture homogenates (AcPC-1, Capan-2, and Caco-2 cells) as well as human liver microsomes. The correlations of prodrug stability in human small bowel tissue homogenate vs. Caco-2 cell homogenate, human liver tissue homogenate vs. human liver microsomes, and human pancreatic tissue homogenate vs. pancreatic cell, AsPC-1 and Capan-2, homogenates were examined. Results. The stabilities of floxuridine prodrugs in human small bowel homogenate exhibited the great correlation to ones in Caco-2 cell homogenate (slope = 1.0-1.3, r2 = 0.79-0.98). The stability of those prodrugs in human pancreas tissue homogenate also exhibited the good correlations to ones in AsPC-1 and Capan-2 cells homogenates (slope = 0.5-0.8, r2 = 0.58-0.79). However, the correlations of prodrug stabilities between in human liver tissue homogenates and in human liver microsomes were weaker than others (slope = 1.3-1.9, r2 = 0.07-0.24). Conclusions. The correlations of drug stabilities in cultured cell homogenates and in human tissue homogenates were compared. Those results exhibited wide range of correlations between in cell homogenate and in human tissue homogenate (r2 = 0.07 – 0.98). Those in vitro studies in cell homogenates would be good tools to predict drug stabilities in vivo and to select drug candidates for further developments. In the series of experiments, 5′-O-D-valyl-floxuridine and 5′-O-L-phenylalanyl-L-tyrosyl-floxuridine would be selected as candidates of oral drug targeting delivery for cancer chemotherapy due to their relatively good stabilities compared to other tested prodrugs.

This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Effects of Prescription Drug Reduction on Quality of Life in Community-Dwelling Patients with Dementia
Authors: Sakakibara Mikio , Igarashi Ataru , Takase Yoshimasa , Kamei Hiroyuki , Nabeshima Toshitaka
Published: March 2016

Purpose: Due to the use of multiple drugs and prevalence of diminished cognitive function, community-dwelling elderly individuals are more likely to have drug-related issues. We examined changes in quality of life (QOL) and activities of daily living (ADL) 3 months and 6 months after reducing drug use of dementia patients who had newly begun community-dwelling care.  Methods: Prescription drug use was reduced in the intervention group, whereas the non-intervention group continued their regimen or began using additional drugs. QOL and ADL were assessed with the Japanese version of the EQ-5D and the Barthel Index, respectively.  Results: Subjects were 32 individuals aged ≥65 years who had begun community-dwelling between March and July 2014 and had received approval for long-term care insurance. On average, the intervention group (n = 19) stopped using 2.6 prescription drugs. After 6 months, the differences in the QOL and ADL scores in the intervention group were -0.03 ± 0.29 and 6.32 ± 18.6, respectively, while the differences in the QOL and ADL scores in the non-intervention group (n = 13) were -0.13 ± 0.29 and -2.69 ± 23.7, respectively. In the intervention group, ADL scores were significantly increased by 14.0 ± 11.1 6 months after reduced benzodiazepine use.  Conclusions: QOL was maintained with reduced drug use, while ADL score was slightly increased. In addition, the reduction of benzodiazepine use significantly increased ADL. In order to reduce polypharmacy among community-dwelling elderly patients, it is necessary to create an opportunity for pharmacists to re-examine their prescriptions This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Tacrine Sinusoidal Uptake and Biliary Excretion in Sandwich-Cultured Primary Rat Hepatocytes
Authors: Kaddoumi Amal , Mohamed Loqman A.
Published: March 2016

PURPOSE. The knowledge of hepatic disposition kinetics of tacrine, a first cholinesterase inhibitor was approved by FDA for the treatment of Alzheimer’s disease (AD), would help to understand its hepatotoxicity, its therapeutic effect, and improve the management of patients with AD. The current study aims to characterize tacrine hepatic transport kinetics and study the role of organic cation transporters (OCTs), P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP2) in tacrine sinusoidal uptake and biliary excretion. METHODS. Modulation of tacrine hepatic uptake and efflux, biliary excretion index (BEI%), were performed in sandwich-cultured primary rat hepatocytes (SCHs) using transporters inhibitors. Conformation of the integrity of SCHs model was established by capturing images with light-contrast and fluorescence microscopy. RESULTS. Tacrine uptake in SCHs was carrier-mediated process and saturable with apparent Km of 31.5±9.6 µM and Vmax of 908±72 pmol/min/mg protein. Tetraethyl ammonium (TEA), cimetidine and verapamil significantly reduced tacrine uptake with more pronounced effect observed with verapamil which caused 3-fold reduction in tacrine uptake, indicating role for OCTs. Tacrine has a biliary excretion in SCHs with maximum BEI% value of 22.9±1.9% at 10 min of incubation. Addition of MK571 and valspodar decreased the BEI% of tacrine by 40 and 60% suggesting roles for canalicular MRP2 and P-gp, respectively. CONCLUSIONS. Our results show that in addition to metabolism, tacrine hepatic disposition is carrier-mediated process mediated by sinusoidal OCTs, and canalicular MRP2 and P-gp.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
QT Correction: Using an Observed Regression Factor Applicable to a Population Subset
Authors: Oo Charles , Kalbag Suraj S
Published: March 2016

Purpose. A QT interval correction to standardized heart rate (QTc) is essential to compare drug effect or to mitigate cardiac risk in clinical practice. Numerous empirical formulas for QTc have been proposed. However, an effective and readily comprehensible method has been elusive. As QTc is dependent on demographics, concomitant drugs, health status, autonomic and diurnal variation, the applicability of these methods hinge on the characteristics of a population that is assessed. An individual QTc is ideal, but it requires substantial baseline ECG data and is beyond the scope for initial evaluation. As a compromise, an approach for a ‘discontinuous’ population subset is suggested. In this article, we outline the challenges of QTc, and select a power function [QTc = QT/{(RR)a}] in which a regression factor a relevant to a particular population subset is used. The formula is similar to the one used in the Bazett’s (a=1/2) or Fridericia’s (a=1/3) method. The use of this approach is illustrated with two small population subsets separated by age and out- or in-patient status. This QTc approach is relatively simple to implement in drug development or by a busy practitioner within his/her institution. Nevertheless, in view of the limitations of the illustrative sample size and confounding factors of this proposal, additional studies will be necessary for further evaluation of QTc methods.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Enhanced Lactone Stability of CZ48 in Blood Correlates to its Lack of Toxicity in Mice
Authors: Liu Xing , Wang Yang , Cao Zhisong , Zhan Max , Vardeman Dana , Giovanella Beppino
Published: March 2016

Purpose. The aim of this study was to correlate the relationship between the pharmacokinetic behaviors and the toxicity of a new investigational anticancer agent CZ48, a C20-propionate ester of camptothecin (CPT) in mice. Methods. In this study, the safety and pharmacokinetics of oral doses of CZ48 were compared with the oral doses of CPT. Mice were administered orally one of three single doses of CZ48 (50, 200 and 1000 mg/kg) and two single doses of CPT (1.5 mg/kg and 6.0 mg/kg). Blood samples were collected from all mice at the defined time points after drug administration for assessment of plasma CZ48 and CPT concentrations. Results. The study showed that CZ48 was very stable in mouse blood and the majority of this agent stayed intact as the lactone form when in circulation, with only a small fraction of the CZ48 molecules metabolized into CPT. The concentration of the metabolite CPT measured in the mouse blood was only 3% of the concentration found for the maximum tolerated dose (6.0 mg/kg) of plain CPT. The stability difference between CZ48 and CPT in blood was structurally explained by the geometry of these two molecules. Conclusion. The lack of toxicity of CZ48 at effective doses in mice is attributed to its enhanced stability in their blood.

This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Pre-Clinical Pharmacokinetic and Pharmacodynamic Characterization of Selected Chiral Flavonoids: Pinocembrin and Pinostrobin
Authors: Sayre Casey L. , Alrushaid Samaa , Martinez Stephanie E. , Anderson Hope D. , Davies Neal M.
Published: March 2016

Purpose: Delineate the stereospecific pharmacokinetics and pharmacodynamics of the chiral flavonoids pinocembrin and pinostrobin. Objective: Characterize for the first time the stereoselective pharmacokinetics of two flavonoids, pinocembrin and pinostrobin and their bioactivity in several in vitro assays with relevant roles in heart disease, colon cancer, and diabetes etiology and pathophysiology. Methods: Chiral flavonoids were intravenously and orally administered to male Sprague-Dawley rats. Concentrations in serum and urine were characterized via stereospecific HPLC or LC/MS. Pure enantiomeric forms of each flavonoid were tested, where possible, to identify the stereospecific contribution to bioactivity in comparision to their racemates. Results:  Short half-lives (0.2-6 h) in serum were observed, while a better estimation of half-life (3-26 h) and other pharmacokinetic parameters were observed using urinary data. The flavonoids are predominantly excreted via non-renal routes (fe values of 0.3-4.6 %), and undergo rapid and extensive phase II metabolism. Chiral differences in the chemical structure of these compounds result in significant pharmacodynamic differences. Conclusion: The importance of understanding the stereospecific pharmacokinetics and pharmacodynamics of two chiral flavonoids were delineated.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
In vitro controlled drug release from loaded microspheres - dose regulation through formulation
Authors: Waters Laura Jane , Pavlakis Evangelos
Published: March 2016

ABSTRACT

PURPOSE: Drug release profiles were established for ibuprofen encapsulated within several types of microspheres and a range of dissolution buffer media to study the effect these variables have in controlling the rate and extent of drug release. METHODS: Fatty acid microspheres containing ibuprofen were prepared by a process previously developed and refined to produce microspheres of a known size and composition, namely 80-125 ?m diameter and an excipient to ibuprofen ratio of 3:1. Drug release profiles from these encapsulated formulations were compared with those obtained for the dissolution of ibuprofen alone under the same conditions. RESULTS: Stearic acid microspheres were found to only partially retard the release of ibuprofen over a twenty minute period compared with the dissolution of ibuprofen alone. However, a significant retardation of ibuprofen release was observed with cetostearyl alcohol microspheres over the same period of time. Secondly, drug release profiles for encapsulated ibuprofen were determined using five distinct dissolution buffer media; sodium phosphate, potassium phosphate, citric acid and phosphate mix, MOPS and tris. Significant differences in the extent and rate of drug release were recorded between the different dissolution buffer solutions. These differences were also shown to be independent of variations in pH, temperature, buffer concentrations and the type of cations present. CONCLUSIONS: The presence and choice of microsphere formulation, and the choice of buffer present in the dissolution solution, can influence drug release in vitro, i.e. it is possible to achieve controlled drug release from microspheres. To explain the control achieved through the choice of buffer in solution it is proposed that the buffer anion exerts a stabilising influence on the ibuprofen-microsphere matrix.
Incidence and Predictors of Adverse Drug Reactions Caused by Drug-Drug Interactions in Elderly Outpatients: A Prospective Cohort Study
Authors: Obreli-Neto Paulo Roque , Nobili Alessandro , De Lyra Júnior Divaldo Pereira , Pilger Diogo , Guidoni Camilo Molino , Baldoni André De Oliveira , Cruciol-Souza Joice Mara , Freitas Ana Luiza de Carvalho , Tettamanti Mauro , Gaeti Walderez Penteado , Cuman Roberto Kenji Nakamura
Published: March 2016

Purpose. The primary objective of this study was to investigate the incidence of drug-drug interactions (DDIs) related to adverse drug reactions (ADRs) in elderly outpatients who attended public primary healthcare units in a southeastern region of Brazil. The secondary objective was to investigate the possible predictors of DDI-related ADRs. Methods. A prospective cohort study was conducted between November 1, 2010, and November 31, 2011, in the primary public healthcare system in the Ourinhos micro-region in Brazil. Patients who were at least 60 years old, with at least one potential DDI, were eligible for inclusion in the study. Eligible patients were assessed by clinical pharmacists for DDI-related ADRs for 4 months. The causality of DDI-related ADRs was assessed independently by four clinicians using three decisional algorithms. The incidence of DDI-related ADRs during the study period was calculated. Logistic regression analysis was used to study DDI-related ADR predictors. Results. A total of 433 patients completed the study. The incidence of DDI-related ADRs was 6.5%. A multivariate analysis indicated that the adjusted odds ratios (ORs) rose from 0.91 (95% confidence interval [CI] = 0.75-1.12, p = 0.06) in patients aged 65-69 years to 4.40 (95% CI = 3.00-6.12, p < 0.01) in patients aged 80 years or older. Patients who presented two to three diagnosed diseases presented lower adjusted ORs (OR = 0.93 [95% CI = 0.68-1.18, p = 0.08]) than patients who presented six or more diseases (OR = 1.12 [95% CI = 1.02-2.01, p < 0.01]). Elderly patients who took five or more drugs had a significantly higher risk of DDI-related ADRs (OR = 2.72 [95% CI = 1.92-3.12, p < 0.01]) than patients who took three to four drugs (OR = 0.93 [95% CI = 0.74-1.11, p = 0.06]). No significant difference was found with regard to sex (OR = 1.08 [95% CI 0.48-2.02, p = 0.44]). Conclusion. The incidence of DDI-related ADRs in elderly outpatients was significant, and most of the events presented important clinical consequences. Because clinicians still have difficulty managing this problem, highlighting the factors that increase the risk of DDI-related ADRs is essential. Polypharmacy was found to be a significant predictor of DDI-related ADRs in our sample.

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Paradoxical Signaling Pathways in Developing Thymocytes
Authors: Alshamsan Aws
Published: March 2016

ABSTRACT- Thymocytes are subjected to processes of selection during their life in the thymus; negative selection for autoreactive thymocytes and positive selection for self-MHC restricted self-tolerant cells. Interestingly, signals for positive or negative selection originate from the same receptor. More importantly, evidence showed that both death and survival signals are mediated by the MAPK pathway. The degree and order of ERK activation, but not other MAPK proteins, has been found to be different in either cases of cell fate. Therefore, it is suspected that the kinetics of ERK after activation may dictate cell death or survival. There are two important GEF proteins that are involved in Ras/ERK activation, RasGRP and SOS. It is thought that the level, order and kinetics of ERK are influenced upstream by the type of GEF. This review discusses the role of both GEF proteins in positive and negative selection and how this reflects on ERK activation.

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Antibacterial Alkaloids from Chelidonium Majus Linn (Papaveraceae) Against Clinical Isolates of Methicillin-Resistant Staphylococcus Aureus
Authors: Zuo Guo Ying , Meng Fan Yan , Hao Xiao Yan , Zhang Yun Ling , Wang Gen Chun , Xu Gui Li
Published: March 2016

Purpose. This study describes the antibacterial effect of extracts and compounds isolated from the aerial part of Chelidonium majus Linn. (Papaveraceae) acting against clinical strains of methicillin-resistant Staphylococcus aureus (MRSA). Methods. The activities were evaluated by using the macrobroth dilution method and reported as the MICs/MBCs. Results. Bioassay-guided fractionation of the most active extract from the aerial parts (EtOAc) led to the isolation of benzo[c]phenanthridine-type alkaloids 8-hydroxydihydrosanguinarine (hhS), 8-hydroxydihydrochelerythrine (hhC), which were potently active against MRSA strains. Conclusions. The selective antibacterial activity reported in this paper for 8-hydroxylated benzo[c]phenanthridine-type alkaloids isolated from C.majus opens the possibility that they could be helpful for the developing of new antibacterial agents for treating the infection of MRSA which has created nosocomial problem worldwide.
Pharmacy Record Registration of Acetyl Salicylic Acid (ASA) Prescriptions in Quebec
Authors: Guénette Line , Sirois Caroline
Published: March 2016

Purpose: To determine the extent of which acetyl salicylic acid (ASA) use is included in patients’ pharmacy records. Methods: During an in-home interview, people aged ≥65 years were asked to report all of the medications they had used at least once, including over-the-counter drugs, during the preceding month. Researchers recorded information on the drug name, reason for its use, and whether a physician prescribed it. From the pharmacy records, the drug names, prescription fill dates, quantities supplied, and the numbers of days’ supply were recorded. The level of agreement for ASA use across data sources was assessed using proportions of agreement and kappa coefficients. Results: Of 193 individuals interviewed, 86 reported the use of ASA, including 76 ASA users (88.4%) who said it was prescribed by a physician. Pharmacy medication records indicated that there were 74 users of ASA. The proportion of agreement for ASA use was 93.8%, and kappa coefficient was 0.87 (95% confidence interval: 0.80-0.94). The sensitivity, specificity, and positive predictive value of the pharmacy data were all high. Conclusions: A large proportion of ASA use is documented in pharmacy records in Quebec. Thus, the information regarding ASA use in pharmacy records is reliable. This result may not be reproducible in other settings where pharmaceutical reimbursement rules are different.

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In Extraction and Analysis of Methadone in Exhaled Breath Condensate Using a Validated LC-UV Method; Khoubnasabjafari et al, J Pharm Pharm Sci 18(2) 207-219, 2015, all methadone concentrations should read “µg/mL” rather than “µg/L”.
Authors: Bhatia Rahim
Published: March 2016

ErratumRE: In Extraction and Analysis of Methadone in Exhaled Breath Condensate Using a Validated LC-UV Method; Khoubnasabjafari et al, J Pharm Pharm Sci 18(2) 207-219, 2015, all methadone concentrations should read “µg/mL” rather than “µg/L”.All methadone concentrations should be read as µg/mL rather than µg.
Pharmacy Patrons 'Awareness of Pharmacists' Education and Routine Patient Care Responsibilities
Authors: Oyelami-Adeleye Ifemayowa , Abate Marie A. , Blommel Mathew L.
Published: March 2016

Purpose: To assess the similarities between pharmacists’ and pharmacy patrons’ views of pharmacists’ roles and to explore the extent to which persons actually see pharmacists assuming certain roles. Method: Cross-sectional survey was administered to pharmacists and patients who were filling prescriptions or seeking nonprescription medications in 9 community pharmacies in Morgantown, West Virginia. The survey assessed 11 routine patient care services. Main outcome measures include opinions of pharmacists and patients about responsibility for providing 11 routine care services and the extent to which these services are provided. Results: Pharmacists and patients had similar opinions about services that pharmacists should provide for 7 of the 11 services evaluated. For the other 4 items for which opinions were divergent, the mean scores for the extent to which pharmacists provide these services indicated that pharmacists do not always provide these services. Conclusion: Pharmacy patrons might not attribute certain patient-related functions to pharmacists because pharmacists do not frequently perform these routine care-related services in actual practice.

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Applications of Polymeric and Lipid Nanoparticles in Ophthalmic Pharmaceutical Formulations: Present and Future Considerations
Authors: Almeida Hugo , Amaral Maria Helena , Lobão Paulo , Silva Ana C , Loboa José Manuel Sousa
Published: March 2016

The unique properties and characteristics of ocular tissues and the whole set of defence mechanisms of the ocular globe make the instillation of ocular drugs into a difficult task with a low rate of therapeutic response. One of the challenges for the new generation of ophthalmic pharmaceutical formulations is to increase the bioavailability of drugs administered by the ocular route and, therefore, their therapeutic efficacy. This can be achieved with the use of some strategies that provide an increase in the formulation pre-corneal residence time, mucoadhesion and penetration across the eye tissues. Colloidal carrier systems have been very successfully used for the selective and targeted delivery of drugs for several routes of administration. In this context, nanoparticles prepared with specific polymers or lipids and coated, dispersed or suspended in polymer solutions with mucoadhesion properties or in situ gelling properties will be an excellent strategy that deserves attention and further research. In this review, the characteristics and main properties of polymeric and lipid nanoparticles are discussed and examples and advantages of the application of these colloidal carrier systems for the ophthalmic administration of drugs are presented. The future directions of the research required in this specific field are also presented.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
Profiles of Surface Mosaics on Chronic Lymphocytic Leukemias Distinguish Stable and Progressive Subtypes
Authors: Huang Pauline Yu-Hsiu , Kohnke Philippa , Belov Larissa , Best Giles , Mulligan Stephen Peter , Christopherson Richard Ian
Published: March 2016

Purpose. Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, some patients may survive for many years, while 20-30% of patients progress and may die within several years. Currently, there is not a single procedure that enables accurate prognosis and triaging of those patients who need immediate and aggressive treatment. All CLL cells are characterised by the expression of the B-cell antigens CD19, CD20, CD21, CD22 and CD23, with aberrant expression of the T-cell antigen CD5. Methods. We have developed a CD antibody microarray (DotScan) containing 182 immobilised CD antibodies that has been used to obtain extensive surface profiles of CLL cells obtained from 96 patients. Results. Of these 182 antigens, 27 were significantly differentially expressed between stable, stable-progressive and progressive CLL. Some of these antigens are not expressed on normal B-cells and may be targets for therapeutic antibodies against CLL. Unsupervised hierarchical clustering of the surface profiles from 96 patients showed that those with progressive CLL could be distinguished based solely upon this ‘disease signature’. The sensitivity (proportion of actual positives correctly identified) was 67.9%, the specificity (proportion of negatives correctly identified) was 77.5%, and the accuracy was 71.9%. Conclusions. Considerable effort by a number of research groups has resulted in identification of individual markers for progressive CLL, but their collective use is yet to provide a test that identifies CLL patients at risk. Data presented here provide a basis for development of a simple test using an antibody microarray.

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