bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of measures of good agricultural practice to control diffuse N pollution originated from livestock manure
Authors: Čustović Hamid , Đikić Mirha , Ljuša Melisa
Published: March 2016

The polluting effects of organic farm wastes can occur in a number of different ways and therefore require a broad range of approaches to control. For example, all watercourses (notably lakes, ponds, rivers, streams and field ditches) adjacent to the production, storage or application of organic wastes are potentially at risk of point source pollution. This risk is different from the diffuse pollution that occurs when the microbial breakdown of manure applied to the soil occurs out of phase with the N uptake of a growing crop and leads to nitrate leaching. Bosnia and Herzegovina is divided into basic river basins as follows: Una, Vrbas, Bosna and Drina flow to the Sava River, which drains into the Danube, while the Neretva, Trebišnjica and Cetina flow to the Adriatic Sea. The biggest emission of organic pollution, then nitrogen and phosphorous is from the Bosna River basin (around 20%). This is followed by Una (15%), Sava (13%), Drina (12.5%), and Vrbas (around 10%). About 30% of above mentioned pollutants goes to the catchment of Adriatic Sea. The spatial distribution of emission is in accordance with the size of the river basin, and the size of the river basin is in accordance with other parameters (population, agricultural activities, cattle-breeding). Exceptions are the river basins of Sava and Ukrina with a bigger concentration of population and more intensive agricultural activities.
The history of broomcorn millet (Panicum miliaceum L.) in the Carpathian-basin in the mirror of archaeobotanical remains I. from the beginning until the Roman age
Authors: Gyulai Ferenc
Published: March 2016

The domestication of broomcorn millet based on latest archaeobotanical investigations occurred in the arid areas of North China and in same time in Central Asia. The knowledge of cultivation of broomcorn millet the Carpathian Basin before the 6th thousand BC. Since this time in all archaeological ages are available but in different frequency. Broomcorn millet was a widespread and favoured cereal. Knowing the eating habits of nomadic and semi-nomadic people, this find is expected, as broomcorn millet is a favoured cereal with a short growing season and rapid development requiring relatively little tending. This is expected as broomcorn millet was a key crop for Hungarians in the Middle Ages. A significant amount was grown traditionally by Hungarians through time until the appearance of maize, the new gruel plant. In the first part will be present the history of broomcorn millet in the Carpathian Basin from the beginning until the Roman Age.
Cryopreservation of sperm of the Adriatic grayling (Thymallus thymallus) and the marble trout (Salmo marmoratus) from the Soča river in Slovenia
Authors: Horváth Ákos , Jesenšek Dušan , Snoj Aleš , Csorbai Balázs , Bokor Zoltán , Urbányi Béla
Published: March 2016

A cryopreservation protocol was tested on the sperm of genetically distinct Adriatic grayling (Thymallus thymallus) and the Natura2000-listed marble trout (Salmo marmoratus) from the Soča River basin in Slovenia. Sperm was frozen in an extender composed of 200 mM glucose, 40 mM KCl, 30 mM Tris (pH 8.0) and 10% methanol as a cryoprotectant in the vapour of liquid nitrogen. Sperm dilution ratios of 1:1, 1:4 and 1:9 were tested. The cooling rate was 57 ± 1°Cmin-1 in all cases. In the grayling, the highest ratio of eyed eggs (74 ± 4 % vs. 69 ± 6 % in the control) and the highest hatch percentage (63 ± 6 % vs. 56 ± 10 % in the control) was observed with a dilution ratio of 1:1. In the marble trout, the highest percentage of eyed eggs (84 ± 4 % vs. 88 ± 3 in the control) and the highest hatch rate (70 ± 3 % vs. 76 ± 2 % in the control) was again found using the 1:1 dilution ratio of the sperm. In both species, individual sperm samples had a significant effect on the results. Sperm-to-egg ratios ranging from 2.5 to 5.7 × 104 spermatozoa per egg yielded satisfactory hatch rates (67 ± 7 % to 73 ± 7 %) in the grayling.
The frequency of genetic rearrangements during carrot (Daucus carota) somatic embryogenesis is dependent on 2,4-D levels and diminished in its absence
Authors: Toldi Ottó , Tóth-Lencsés Kitti , Kovács László , Tóth Zsófia , Mendel Ákos , Kerekes Adrienn , Gyulai Gábor
Published: March 2016

For quantification of genetic variations occurring in plant tissue cultures, DNA sequence alterations and replicon- size changes were monitored through subsequent phases of the model carrot tissue culture system, from the 2,4-D-induced proembryiogenic cell cultures to regenerated plantlets, by RAPD and flow cytometry techniques. Banding patterns of random amplified DNA fragments and ploidy-level distributions of cultured cells were significantly different in the presence and in the absence of 2,4-D. In addition, there were marked differences between the cells induced with lower (1.0 mg/l) and higher (2.5 mg/l) doses of 2,4-D. Among those samples that were cultured in the absence of 2,4-D, the epicotyl (C2), hypocotyl control (H1) and the morphologically normal regenerants (IV2) showed identical banding patterns overlapping with the true-to-type seedling controls (N1, N2). In contrast, treatment of starting explants (H2) with 1.0 mg/l 2,4-D resulted in a marked 82% increase in the number of amplified fragments associated with an appearance of cell lines possessing unusual haploid-like and aneuploid-like DNA contents. The induction with 2.5 mg/l 2,4-D resulted in even greater increase in the number of DNA fragments (~100%) amplified from proembryiogenic cell cultures, while it had no further effect on ploidiy-level distributions compared to the treatment with 1.0 mg/l 2,-D. After the withdrawal of the synthetic auxin, banding patterns and ploidy-level distributions were gradually shifted back to the levels of controls resulting in true-to-type regenerants. Conclusions are in short, the combined use of RAPD and flow cytometry can make quantification of genetic variations typical of dedifferentiated plant cells possible. Quantification opens the window for comprehensive evaluation of different methods, treatments and bioactive compounds.
Archaeobotanical overview of rye (Secale cereale L.) in the Carpathian-basin II. From the migration period until the late Medieval age
Authors: Gyulai Ferenc
Published: March 2016

It seems that rye is a twice domesticated cereal. Then, in the course of the Early Iron Age in Central or Eastern Europe, it is again transformed from weed to crop plant. We summarized the development of rye and his spread in the Carpathian Basin based on archaeobotanical data. The grains of the rye were found always in charcoal form. The rye appeared in Carpathian Basin during the Neolithic Age. Sporadic occurrences of rye were also found in Early Bronze Age Bell Beaker-Csepel Group and Early Iron age Scythian cultures. The prehistoric grains were small and longshaped. In the Prehistoric Ages rye should be exist as weed of hulled wheats. His cultivation started in the Roman Age. The grains found in roman sites are always big and reel shaped like recently. Only a few grains were found in the Migration Period. Among cereals of the conquering Hungarians rye is present. Rye became common product in the Late Medieval Ages. It was grown in a big quantity everywhere, but not independently, but mixed with the wheat.
Accumulation and depletion of fertilizer originated nitrate-N and ammonium-N in deeper soil layers
Authors: Füleky György
Published: March 2016

The leaching process of nitrate was studied in a long-term field experiment at Gödöllő on a brown forest soil started in 1969. 0, 90, 180, 270, 360 kg ha-1 y-1 N doses have been broadcasted as basal fertilization in the form of ammonium-nitrate for 16 years. The test plant was maize in monoculture. In autumn 1989 fertilization was discontinued and alfalfa was sown on the experimental area. In 1995 pseudoacacia was planted into the field. In 1986, 1989, 1994 and 2003 the soils of the treatments were sampled in 6 replications from 0 to 3 meters depth at every 20 cm. The nitrate-N and ammonium-N content of the sample was determined. Increasing the dose of nitrogen fertilization nitrate content in the soil profile increased, as well. About the half of fertilizer nitrogen can be found in the 3 meter layer of the soil profile after 16 years fertilization. Using deep rooting plants the accumulated nitrogen could be used to prevent the leaching losses. Results prove the necessity of a suitable technology preventing nitrate losses. As the experiment shows 100 kg N ha-1 fertilizer nitrogen enough for the maximum crop yield in this area. The amount of nitrate-N exceeding plant demand could be leached into 1-3 meter depth of soil or into deeper horizons.
The influence of cultivation method on the soil’s organic carbon content calculations (Hungarian SOC reference values vs. IPCC defaults)
Authors: Kovács Attila , Horváth Bálint , Fogarassy Csaba
Published: March 2016

In the majority of the IPCC (Intergovernmental Panel on Climate Change) studies the third most significant segment among the activities of the agricultural enterprises is the GHG emission from the soil. It is important to examine how this value could be reduced. Our research aims to find the modeling system which is able to provide us with accurate data regarding the difference of the several cultivation methods and easy to apply on the basis of the facts of practical. IPCC methodology has been applied in the calculation specified with the results of certain Hungarian studies. As an early outcome we have come to see that in comparison with the regular methodology our results showed more precise values. Where the IPCC demonstrates 1-2 t CO2e we were able to witness 8-10 t CO2e on soils with better humus content. Therefore we concluded that accurate values of the changes can only be calculated with the involvement of the local conditions.
Egyszülős családok és túlzott eladósodás
Authors: Gyarmati Andrea , Vályi Réka
Published: March 2016

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Proceedings of conference on Mechanism-Based Development of Natural Products for Human Health
Authors: Roufogalis Basil D , Conigrave Arthur D
Published: March 2016

Mechanism-Based Development of Natural Products in Human Health
Nanotherapeutics to Overcome Conventional Cancer Chemotherapy Limitations
Authors: Chidambaram Moorthi , Manavalan R. , Kathiresan K.
Published: March 2016

Cancer is one of the major causes of death worldwide and chemotherapy is a major therapeutic approach for the treatment which may be used alone or combined with other forms of therapy. However, conventional chemotherapy suffers lack of aqueous solubility, lack of selectivity and multidrug resistance. Nanotherapeutics is rapidly progressing aimed to solve several limitations of conventional drug delivery systems. Nonspecific target of cancer chemotherapy leads to damage rapidly proliferating normal cells and can be significantly reduced through folate and transferrin mediated nanotherapeutics which are aimed to target cancerous cells. Multidrug resistance is challenge in cancer chemotherapy which can be significantly reversed by solid lipid nanoparticles, polymeric nanoparticles, mesoporous silica nanoparticles, nanoparticulated chemosensitizer, nanoparticluated poloxamer and magnetic nanoparticles. Hydrophobic nature of chemotherapeutics leads to poor aqueous solubility and low bioavailability which can be overcome by nanocrystals, albumin based nanoparticles, liposomal formulation, polymeric micelles, cyclodextrin and chitosan based nanoparticles. This review focuses the role of nanotherapeutics to overcome lack of selectivity, multidrug resistance and lack of aqueous solubility of conventional cancer chemotherapy.
Evaluation of Brain Targeting and Mucosal Integrity of Nasally Administrated Nanostructured Carriers of a CNS Active Drug, Clonazepam
Authors: Abdel-Bar Hend Mohamed , Abdel-Reheem Amal Youssef , Awad Gehanne A.S , Mortada Nahed Daoud
Published: March 2016

PURPOSE: The aim of the study was to target clonazepam, a CNS active drug, to the brain through the non-invasive intranasal (in) route using of nanocarriers with proven safety METHOD: in clonazepam nanocarriers were prepared by mixing isopropyl myristate, Tween 80, Cremophor EL or lecithin, polyethylene glycol 200, propylene glycol or ethanol in different ratios with water. in-vitro characterization of the nanocarriers was done by various methods including: polarized light microscopy, particle size determination, viscosity measurements and drug release studies. in-vivo study comparing intranasal and intravenous administration was performed. The drug targeting efficiency (DTE %) and direct nose to brain transport percentage (DTP %) were calculated and nasal integrity assessment was carried out. RESULTS: The obtained formulae had particle size below 100 nm favoring rapid direct nose to brain transport and the time for 100% drug release (T100%) depended on systems composition. Plasma Tmax of clonazepam nanostructured carriers varied from 10-30 min., while their brain Tmax did not exceed 10 min, in comparison with 30 min for iv solution. Although there was no significant difference (p>0.05) between the plasma AUC0-∞ of the different tested nanocarriers and intravenous one, the increase in brain AUC 0 -∞ of different nasal formulations in comparison to that of iv administration (3.6 -7.2 fold) confirms direct nose to brain transport via olfactory region. Furthermore, DTE and DTP% confirmed brain targeting of clonazepam following intranasal administration. CONCLUSION: The results confirmed that intranasal nanocarriers were proved to be safe alternative for iv clonazepam delivery with rapid nose to brain transport.

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.
Pharmacokinetics of Oral Rosiglitazone in Taiwanese and Post Hoc Comparisons with Caucasian, Japanese, Korean, and Mainland Chinese Subjects
Authors: Chu Kai-Min , Hu Oliver Yoa-Pu , Pao Li-Heng , Hsiong Cheng-Huei
Published: March 2016

Purpose. Rosiglitazone, an insulin-sensitizing thiazolidinedione, acts as a ligand for the y-subtype of the peroxisome proliferator-activated receptor in the regulation of glucose homeostasis and lipid metabolism. The aims of this study were to determine the pharmacokinetics of oral rosiglitazone in Taiwanese and to post hoc compare the ethnic differences among Caucasian, Japanese, Korean, and Mainland Chinese. Methods. Twelve Taiwanese healthy male subjects received 4 and 8 mg of rosiglitazone. Similar protocols were used in the previously unpublished studies conducted in 25 Caucasian, 32 Japanese, 8 Korean, and 12 Mainland Chinese healthy male subjects. The 4 mg dose data were used for ethnicity comparisons. Results. The respective pharmacokinetic properties of Taiwanese, Caucasian, Japanese, Korean and Mainland Chinese are: terminal half-life (hr): 4.18 +/- 0.43, 3.96 +/- 1.31, 3.83 +/- 0.78, 4.70 +/- 1.19 and 4.37 +/- 0.63; Cmax (ng/ml): 384.1 +/- 59.3, 260.2 +/- 75.7, 401.9 +/- 102.3, 345.3 +/- 60.6, and 406.2 +/- 52.0; AUC0-inf (h•ng/ml): 2078 +/- 433, 1249 +/- 566, 1901 +/- 397, 1938 +/- 534, and 2158 +/- 498. The Cmax and AUC0-inf of Caucasian were significantly (p = 0.002, 0.008) lower and CL/F and V/F were significantly (p = 0.000, 0.003) higher than those of other races. These differences of Cmax, AUC0-inf, CL/F and V/F between Caucasian and other races became insignificant after normalized by dose and weight. Conclusions. In a given dose by body weight, ethnicity had no significant impact on the pharmacokinetics of rosiglitazone in normal healthy volunteers.
A New Cytotoxic Steroidal Glycoalkaloid from the Methanol Extract of Blumea lacera Leaves
Authors: Akter Raushanara , Uddin Shaikh J. , Tiralongo Joe , Grice I. Darren , Tiralongo Evelin
Published: March 2016

PURPOSE: Blumea lacera (B. lacera) (Asteraceae) is a well-known Bangladeshi medicinal plant. This study aimed to identify and characterize constituents associated with the significant cytotoxic activity of this plant that we reported previously. Here, we describe the isolation and characterization of a new steroidal glycoalkaloid (SGA) 1, the evaluation of its cytotoxic activity, apoptotic potential, and effect on cell cycle in comparison to analogous steroidal glycoalkaloids (SGAs). METHODS: SGA 1 was isolated using C18 SPE and HPLC, and subsequently structurally characterized using 1D and 2D NMR, MS and other spectroscopic methods, along with a comparative inspection of the literature. Cytotoxic activity of 1 and seven SGA analogues and steroidal alkaloids (SAs), (β-solamarine, α-solanine, β-solamargine, α-solasonine, khasianine, solasodine, tomatidine HCl) were evaluated for their cytotoxicity against two healthy (NIH3T3 and VERO) and four human cancer (AGS, HT-29, MCF-7 and MDA-MB-231) cell lines using the MTT assay. Cytotoxic SGAs were further evaluated for apoptosis-inducing potential and cell cycle arresting ability against breast cancer cells (MCF-7) using the FITC Annexin V and propidium iodide (PI) assay. RESULTS: Bioactivity guided fractionation of the methanol extract of B. lacera led to isolation of compound 1: (25R)-3β-{O-β-D-glucopyranosyl-(1→4)-O-α-L-rhamnopyranosyl-(1→4)-[O-α-L-rhamnopyranosyl-(1→2)]-α-L-rhamnopyranosyl}-22αN-spirosol-5-ene. SGA 1 was the most cytotoxic compound against a number of human cancer cell lines with an IC50 of 2.62 µM against MCF-7 cells. It displayed the highest apoptotic potential (32% AV+/PI-) on MCF-7 cells compared to other cytotoxic SGA analogues and a slight, but significant cell cycle arresting effect. CONCLUSIONS: A new SGA 1 was isolated from B. lacera and its cytotoxic activity, as well as that of other SAGs, was evaluated. SAR investigations on SGA 1, in relation to SGA analogues, show that the number and nature of sugar moieties along with the linkages of the sugar to the aglycone are crucial for cytotoxic and apoptotic activity. 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 permeability of bilobalide as probed by microdialysis before and after middle cerebral artery occlusion in mice
Authors: Lang Dorothee , Ude Christian , Wurglics Mario , Schubert-Zsilavecz Manfred , Klein Jochen
Published: March 2016

ABSTRACT. Purpose. Bilobalide is an active constituent of Ginkgo biloba and has shown neuroprotective effects in mice with cerebral ischemia. In the present study, we investigated brain permeability of bilobalide (i) in healthy mice and (ii) in mice before or after stroke. Methods. We have used in vivo microdialysis and LC-MS to estimate extracellular levels of bilobalide. 10 mg/kg of bilobalide was given by i.p. injection to control mice, and 60 minutes before and after middle cerebral artery occlusion (MCAO). Results. Bilobalide was already detectable in brain striatal microdialysates 10 min after i.p. administration and reached maximum levels (19 ng/mL, corresponding to 0.92 µM) after 40 min. Maximum plasma bilobalide levels were 5.9 µM. After an ischemic insult, the drug could be dialysed with similar efficiency as in control mice indicating slow elimination from the ischemic brain. When the drug was given after MCAO, availability in the brain was low, but measurable, at approx. 10% of control values. Conclusions. Our data demonstrate that bilobalide easily crosses the blood brain barrier and reaches extracellular concentrations in the brain that allow efficient interaction with target molecules such as neurotransmitter receptors. Availability of the drug in ischemic tissue is high when given before ischemia, but severely limited after MCAO.
Calebin A: Analytical Development for Pharmacokinetics Study, Elucidation of Pharmacological Activities and Content Analysis of Natural Health Products
Authors: Oliveira Ana Luísa De P. , Martinez Stephanie E. , Nagabushnam Kalyanam , Majeed Muhammed , Alrushaid Samaa , Sayre Casey L. , Davies Neal M.
Published: March 2016

Purpose: To develop a bioanalytical assay using RP-HPLC to quantify the curcuminoid calebin A, to characterize its pharmacokinetics in rats after intravenous (IV) and oral (PO) administration, to identify its pharmacological activities and to evaluate its content in natural health products. Methods: An RP-HPLC method was developed for the detection of calebin A. Separation was carried out using a Phenomenex® Kinetex® C18 column with UV detection at 339 nm. An isocratic mobile phase consisting of acetonitrile and water with 10 mM ammonium formate (pH 7.0) (40:60, v/v) at a flow rate of 0.8 mL/min was employed. Linear standard curves were established and applied in the pharmacokinetic study. Calebin A was administered to male Sprague-Dawley (CD) rats IV (20 mg/kg) or PO (500 mg/kg) (n=4/route of administration). Serum and urine samples were collected for 72 h post dose. In vitro antioxidant activity, anti-inflammatory activity (cyclooxygenase and lipoxygenase inhibition), dipeptidyl peptidase-4 (DPP-4) inhibition and cytochrome P450 inhibitory activties of calebin A were examined using commercial assay kits.  Content analysis of calebin A in 14 natural health products advertised to contain  turmeric were carried out using methanolic extraction. Results: The HPLC method was successfully applied to a pharmacokinetic study of calebin A in rats. After IV and PO administration of calebin A, the compound was detected as the aglycone and a glucuronidated metabolite. Oral bioavailabitily was found to be ~0.5%, serum half-life was ~1-3 h. Calebin A appears to be primarily excreted via non-renal routes. Calebin A possessed concentration-dependent antioxidant activity and DPP-4 inhibition. Calebin A appears to be a non-selective cyclooxygenase inhibitor and also a poor lipoxygenase inhibitor. The curcuminoid displayed  in vitro interactions with  CYP2D6 and CYP1A2. Content analysis of 14  natural health products that claimed to contain turmeric showed that concentration of calebin A was inconsistent among the products. Conclusion: A successful assay was developed for the detection of calebin A using RP-HPLC. Preliminary pharmacokinetic studies indicate that an unoptimised formulation of calebin A has poor oral bioavailability. Calebin A exhibits  various pharmacological activities. 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.
Effect of a 36-month Pharmaceutical Care Program on the Coronary Heart Disease Risk in Elderly Diabetic and Hypertensive Patients
Authors: Obreli Neto Paulo Roque , Marusic Srecko , De Lyra Júnior Divaldo Pereira , Pilger Diogo , Cruciol-Souza Joice Mara , Gaeti Walderez Penteado , Cuman Roberto Kenji Nakamura
Published: March 2016

Purpose. To examine the effect of a pharmaceutical care program on the coronary heart disease risk in elderly diabetic and hypertensive patients. Methods. A total of 200 elderly (> 60 years) diabetic and/or hypertensive patients were recruited into a randomized, controlled, prospective clinical trial with a 36-month follow-up, developed in a public primary health care unit in a municipality in the Brazilian State of Sao Paulo. A range of clinical measurements were evaluated at the baseline and up to 36 months afterwards. The intervention group patients received pharmaceutical care from a clinical pharmacist, whereas the control group patients received their usual care from the medical and nursing staff. The Framingham scoring method was used to estimate changes in the 10-year coronary heart disease risk scores of all the patients. Results. A total of 194 patients completed the study. Significant reductions (p < 0.05) in the mean values (baseline vs. 36 months) for the systolic blood pressure [156.7mmHg vs 133.7mmHg; p
Reversible, Time-Dependent Inhibition of CYP3A-Mediated Metabolism of Midazolam and Tacrolimus by Telaprevir in Human Liver Microsomes
Authors: Chapron Brian , Risler Linda , Phillips Brian , Collins Carol , Thummel Kenneth , Shen Danny
Published: March 2016

Purpose  Telaprevir inhibits CYP3A resulting in drug-drug interactions (DDI) of unprecedented magnitude. We investigated the mechanisms by which telaprevir inhibits the oxidation of midazolam and tacrolimus in human liver microsomes (HLM). Methods  We performed a static mechanistic DDI prediction to evaluate whether previously reported competitive inhibition of CYP3A by telaprevir and its diastereomeric metabolite ― VRT-127394 is sufficient to explain the remarkable reduction in oral clearance observed with oral midazolam and tacrolimus. To further explore the inhibitory mechanisms of telaprevir, we assessed whether telaprevir-mediated inhibition of the oxidation of midazolam and tacrolimus is time-dependent in human liver microsomes, and whether any observed time-dependency was irreversible or reversible in nature. Results  The competitive inhibition model failed to account for the magnitude of telaprevir interactions in human subjects. In comparing HLM incubations with and without a prior 30-min exposure to telaprevir, a respective 4- and 11-fold reduction in IC50 was observed with midazolam and tacrolimus as substrates.  This time-dependent inhibition was shown to be NADPH-dependent. Upon dilution of microsomes following pre-incubation with telaprevir, time-dependent inhibition of midazolam metabolism was completely reversed, whereas partial reversal occurred with tacrolimus. Conclusions  The interaction between telaprevir and midazolam or tacrolimus involves both competitive and time-dependent inhibition. The time-dependent component is not explained by irreversible inactivation of CYP3A. Formation of potent inhibitory metabolites may contribute to the remarkable in vivo inhibitory potency of telaprevir. 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.
Nonclassical Biological Activities of Quinolone Derivatives
Authors: Daneshtalab Mohsen , Ahmed Abeer
Published: March 2016

Quinolones are considered as a big family of multi-faceted drugs; their chemical synthesis is flexible and can be easily adapted to prepare new congeners with rationally devised structures. This is shown by the description of many thousands of derivatives in the literature. Scientists could accurately describe their QSAR, which is essential for effective drug design. This also gave them the chance to discover new and unprecedented activities, which makes quinolones an endless source of hope and enables further development of new clinically useful drugs.

Quinolones are among the most common frameworks present in the bioactive molecules that have dominated the market for more than four decades. Since 1962, 4(1H)-quinolone-3-carboxylic acid derivatives are widely used as antibacterial agents. Quinolones have a broad and potent spectrum of activity and are also used as second-line drugs to treat tuberculosis (TB). Recently, quinolones have been reported to display “nonclassical” biological activities, such as antitumor, anti-HIV-1 integrase, anti- HCV-NS3 helicase and -NS5B-polymerase activities.

The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent and/or an antiviral agent. Indeed, quinolones’ antimicrobial action is distinguishable among antibacterial agents, because they target different type II topoisomerase enzymes. Many derivatives of this family show high activity against bacterial topoisomerases and eukaryotic topoisomerases, and are also toxic to cultured mammalian cells and in vivo tumor models. Moreover, quinolones have shown antiviral activity against HIV and HCV viruses. In this context the quinolones family of drugs seem to link three different biological activities (antibacterial, anticancer, and the antiviral profiles) and the review will also provide an insight into the different mechanisms responsible for these activities among different species.

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.
Pharmacologic Activities¬ of 3’-Hydroxypterostilbene: Cytotoxic, Anti-Oxidant, Anti-Adipogenic, Anti-Inflammatory, Histone Deacetylase and Sirtuin 1 Inhibitory Activity
Authors: Takemoto Jody K , Remsberg Connie M. , Davies Neal M.
Published: March 2016

Purpose: Delineate the selected pharmacodynamics of a naturally occurring stilbene 3’-Hydroxypterostilbene. Objective: Characterize for the first time the pharmacodynamics bioactivity in several in-vitro assays with relevant roles in heart disease, inflammation, cancer, and diabetes etiology and pathophysiology. Methods: 3’-Hydroxypterostilbene was studied in in-vitro assays to identify possible bioactivity. Results: 3’-Hydroxypterostilbene demonstrated anti-oxidant, anti-inflammatory, cytotoxic, anti-adipogenic, histone deacetylase, and sirtuin-1 inhibitory activity. Conclusions: The importance of understanding individual stilbene pharmacologic activities were delineated.  Small changes in chemical structure of stilbene compounds result in significant pharmacodynamic differences. 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.
Statins Reduce Mortality After Non-severe but Not After Severe Pneumonia: A Systematic Review and Meta-Analysis
Authors: Jia Mingwang , Huang Wenjie , Li Li , Xu Zhong , Wu Lichan
Published: March 2016

PURPOSE: The objective of this study was to perform a systematic review and meta-analysis of the effects of statins on mortality for patients with non-severe pneumonia or severe pneumonia. METHODS: PubMed, EMBASE, Cochrane Database of Systematic Reviews, Cochrane central register of controlled trials and Clinicaltrials.gov were searched for the association between statins and non-severe/severe pneumonia. Eligible articles were analyzed in Stata 12.0. RESULTS: The database search yielded a total of 566 potential publications, 24 studies involving 312,309 patients met the eligibility criteria. Pooled unadjusted data showed that statin use was associated with lower mortality after non-severe pneumonia (odds ratio [OR] 0.70, 95% confidence interval [CI], 0.66-0.73), but not severe pneumonia (OR 1.05; 95% CI, 0.86-1.28). However, this protective effect of statins was weakened using adjusted estimates (OR 0.78, 95% CI, 0.75-0.82). Besides, protective effect of statins was attenuated by confounders in a subgroup analysis, especially when accounting for pneumonia severity indicators (OR 0.88; 95% CI, 0.80-0.96). CONCLUSIONS: Statin use was associated with reduced mortality after non-severe pneumonia but not severe pneumonia and this protective effect was weakened in subgroups. 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.
Bioadhesive properties of β-limit dextrin
Authors: QI XIN , Tester Richard F
Published: March 2016

Purpose. β-Limit dextrin has been studied for many years as a means to investigate the internal structures of amylose and amylopectin. However its role as an excipient in the pharmaceutical industry has never been reported. This paper is the first one in a series to explore its potential use as an excipient to aid drug delivery. Methods. The bioadhesive properties of β-limit dextrin were studied using a texture analyser and compared with two well-known bioadhesive polymers – carbopol and chitosan (as controls). Results. The β-limit dextrin has significant mucoadhesive properties; similar to carbopol but superior to chitosan. Conclusions. The nature of β-limit dextrin (a starch derivative) makes it safe to consume and provides a natural alternative when compared with synthetic polymers. In addition, the polysaccharide can be digested by salivary amylase and thus provide a clean mouth feel.
Preventive Effects of Selenium Yeast, Chromium Picolinate, Zinc Sulfate and their Combination on Oxidative Stress, Inflammation, Impaired Angiogenesis and Atherogenesis in Myocardial Infarction in Rats
Authors: AL-Rasheed Nouf M , Attia Hala A , Mohamed Raessa A , Al-Rasheed Nawal M , Al-Amin Maha A
Published: March 2016

Purpose: Accumulating evidences suggest a critical role of trace metal dyshemostasis in oxidative stress and cardiac dysfunction after myocardial infarction (MI). This study investigated the cardioprotective effects of selenium yeast (Se), chromium picolinate Cr(pic)3, zinc sulfate (Zn) and their combination on isoproterenol (ISO)-induced MI. Methods: Rats were divided into six groups: normal control, ISO control, Se-pretreated (0.1 mg/kg), Cr(pic)3-pretreated (400 µg/kg), Zn-pretreated (30 mg/kg) and metal combination-pretreated groups. All metals were administered for 28 days and at the 27th day, MI was induced by subcutaneous injection of ISO (85 mg/kg) once for two consecutive days. Results: ISO control group showed hyperlipidemia, elevation of cardiac biomarkers and lipid peroxidation and increased immunostaining of p47 phox NADPH oxidase subunit in addition to decreased levels of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Cardiac levels of tumor necrosis factor-α (TNF-α) were increased, while vascular endothelial growth factor (VEGF, the major angiogenic factor) was decreased. Pretreatment with Se normalized the cardiac enzymes, lipid peroxidation, GSH, SOD, CAT, GPx, TNF-α and VEGF (P<0.001) and reduced the immunostaining of p47 phox subunit. However, Se failed to correct the dyslipidemia. Cr(pic)3 significantly improved lipid profile (P<0.001) and all other biochemical deviations except for VEGF. Zn, but to lesser extent, reduced the oxidative damage and TNF-α levels and improved both dyslipidemia and angiogenesis. Combination therapy exhibited less prominent protection compared to individual metals. Conclusion: Daily supplementation with trace metals is promising for improving myocardial performance via preventing oxidative damage, induction of angiogenesis, anti-inflammatory and/or anti-hyperlipidemic mechanisms.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.
(S)-[6]-Gingerol enhances glucose uptake in L6 myotubes by activation of AMPK in response to [Ca2+]i
Authors: Li Yiming , Tran Van H , Koolaji Nooshin , Duke Colin , Roufogalis Basil D
Published: March 2016

PURPOSE. The aim of this study was to investigate the mechanism of (S)-[6]-gingerol in promoting glucose uptake in L6 skeletal muscle cells. METHODS. The effect of (S)-[6]-gingerol on glucose uptake in L6 myotubes was examined using 2-[1,2-3H]-deoxy-D-glucose. Intracellular Ca2+ concentration was measured using Fluo-4. Phosphorylation of AMPKα was determined by Western blotting analysis. RESULTS. (S)-[6]-Gingerol time-dependently enhanced glucose uptake in L6 myotubes. (S)-[6]-Gingerol elevated intracellular Ca2+ concentration and subsequently induced a dose- and time-dependent enhancement of threonine172 phosphorylated AMPKα in L6 myotubes via modulation by Ca2+/calmodulin-dependent protein kinase kinase. CONCLUSION. The results indicated that (S)-[6]-gingerol increased glucose uptake in L6 skeletal muscle cells by activating AMPK. (S)-[6]-gingerol, a major component of Zingiber officinale, may have potential for development as an antidiabetic agent. 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.
Flavonols Protect Against UV Radiation-Induced Thymine Dimer Formation in an Artificial Skin Mimic
Authors: Maini Sabia , Fahlman Brian M. , Krol Ed S.
Published: March 2016

Purpose: Exposure of skin to ultraviolet light has been shown to have a number of deleterious effects including photoaging, photoimmunosuppression and photoinduced DNA damage which can lead to the development of skin cancer.  In this paper we present a study on the ability of three flavonols to protect EpiDerm™, an artificial skin mimic, against UV-induced damage. Methods: EpiDerm™ samples were treated with flavonol in acetone and exposed to UVA (100 kJ/m2 at 365 nm) and UVB (9000 J/m2 at 310 nm) radiation.  Secretion of matrix metalloproteinase-1 (MMP-1) and tumor necrosis factor-α (TNF-a) were determined by ELISA, cyclobutane pyrimidine dimers were quantified using LC-APCI-MS. Results: EpiDerm ™ treated topically with quercetin significantly decreased MMP-1 secretion induced by UVA (100 µM) or UVB (200 µM) and TNF-a secretion was significantly reduced at 100 µM quercetin for both UVA and UVB radiation.  In addition, topically applied quercetin was found to be photostable over the duration of the experiment.  EpiDerm™ samples were treated topically with quercetin, kaempferol or galangin (52 µM) immediately prior to UVA or UVB exposure, and the cyclobutane thymine dimers (T-T (CPD)) were quantified using an HPLC-APCI MS/MS method.  All three flavonols significantly decreased T-T (CPD) formation in UVB irradiated EpiDerm™, however no effect could be observed for the UVA irradiation experiments as thymine dimer formation was below the limit of quantitation.  Conclusions: Our results suggest that flavonols can provide protection against UV radiation-induced skin damage through both antioxidant activity and direct photo-absorption. 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.
Mechanism of Dissolution Enhancement and Bioavailability of Poorly Water Soluble Celecoxib by Preparing Stable Amorphous Nanoparticles
Authors: Liu Yinghui , Sun Changshan , Hao Yanru , Jiang Tongying , Zheng Li , Wang Siling
Published: March 2016

Purpose: Nanoparticle engineering offers promising methods for the formulation of poorly water soluble drug compounds. The aim of the present work was to enhance dissolution and oral bioavailability of poorly water-soluble celecoxib (CXB) by preparing stable CXB nanoparticles using a promising method, meanwhile, investigate the mechanism of increasing dissolution of CXB. Methods: CXB nanoparticles were produced by combining the antisolvent precipitation and high pressure homogenization (HPH) approaches in the presence of HPMC E5 and SDS (2:1, w/w). Then the CXB nanosuspensions were converted into dry powders by spray-drying. The effect of process variables on particle size and physical state of CXB were investigated. The physicochemical properties of raw CXB and CXB nanoparticles were characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), X-ray photoelectron spectra (XPS), fourier transform infrared (FT-IR) spectroscopy, diffrential scanning calorimetry (DSC), as well as, measuring the particle size and contact angle. Additionally, the studies of in-vitro drug dissolution and oral bioavailability in beagle dogs of nanoparticles were performed. Results: The images of SEM revealed spherical CXB nanoparticles. The DSC and XRPD results indicated that the antisolvent precipitation process led to the amorphization of CXB. Under storage, the amorphous CXB nanoparticles showed promising physical stability. The XPS data indicated the amorphous CXB nanoparticles exhibited different surface property compared to raw CXB. Hydrogen bonds were formed between the raw CXB and HPMC E5 as proven by the FT-IR spectra. CXB nanoparticles increased the saturation solubility of CXB fourfold. CXB nanoparticles completely dissolved in the dissolution medium of phosphate buffer (pH 6.8, 0.5% SDS) within 5 min, while there was only 30% of raw CXB dissolved. The Cmax and AUC0–24h of CXB nanoparticles were approximately threefold and twofold greater than those of the Celecoxib Capsules, respectively. Conclusions: The process by combining the antisolvent precipitation under sonication and HPH was a promising method to produce small, uniform and stable CXB nanoparticles with markedly enhanced dissolution rate and oral bioavailability due to an increased solubility that is attributed to a combination of amorphization and nanonization with increased surface area, improved wettability and reduced diffusion pathway.
A Simple Method to Extract Whole Apolipoproteins for the Preparation of Discoidal Recombined High Density Lipoproteins as Bionic Nanocarriers for Drug Delivery
Authors: Zhang Wenli , Wang Ji , Jia Junting , Chen Liang , Wu Zimei , Liu Jianping
Published: March 2016

Purpose: To develop a simple method to extract the whole apolipoproteins (apo) including apoA-I in native high density lipoproteins (HDLs) and prepare discoidal Tanshinone IIA-loaded reconstituted HDL (TA-rHDLs) as a dual functional drug delivery system with plaque-site target and therapeutic promises in atherosclerotic lesions. Methods: A method based on isoelectric precipitation coupled with organic solvent precipitation was developed to isolate the whole apolipoproteins (apos). TA-rHDLs were prepared by incubating the resultant apos with liposomes and the incubation conditions were optimized using fluorescence quenching experiment. TA-rHDLs were characterized in terms of size, zeta potential, morphology, interaction between lipid and apos,  safety, and bionic function. Results: The extraction results showed that the yield of the HDL apos was 82.4%, with 59% being apoA-I type, similar ratio of apoA-I in the native apos. TA-rHDL prepared were disc-like with an average diameter of 157.6 ± 4.8 nm, zeta potential of -20.90 ± 0.15 mV, and entrapment efficiency of (90.13 ± 1.4) %. The interaction between the lipids and apos was electrostatic and hydrophobic force and was associated with amino acid sequence. Haemolysis and cytotoxicity assays showed good biocompatibility of TA-rHDL. Sterol efflux assay from macrophages mediated by TA-rHDLs and structure remodeling behavior from discs to spheres proved that TA-rHDL could resemble the biological activity of native nascent HDL irrespective of the size. Conclusions: The simple approach to isolate apos may provide a convenient and economical resource to support the development of rHDL as a potential targeting nanocarrier for lipophilic cardiovascular drugs. 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.
Herb-drug Pharmacokinetic Interaction between Carica Papaya Extract and Amiodarone in Rats
Authors: Rodrigues Márcio , Alves Gilberto , Francisco Joana , Fortuna Ana , Falcão Amílcar
Published: March 2016

Purpose - Carica papaya has been traditionally used worldwide in folk medicine to treat a wide range of ailments in humans, including the management of obesity and digestive disorders. However, scientific information about its potential to interact with conventional drugs is lacking. Thus, this work aimed to investigate the interference of a standardized C. papaya extract (GMP certificate) on the systemic exposure to amiodarone (a narrow therapeutic index drug) in rats. Methods - In the first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of C. papaya (1230 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in the second study, rats were pre-treated for 14 days with C. papaya (1230 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the herbal extract vehicle. Blood samples were collected before dosing and at 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h following amiodarone administration; in addition, at 24 h post-dose, blood and tissues (heart, liver, kidneys and lungs) were also harvested. Thereafter, the concentrations of amiodarone and its major metabolite (mono-N-desethylamiodarone) were determined in plasma and tissue samples employing a high-performance liquid chromatography-diode array detection method previously developed and validated. Results - In both studies was observed a delay in attaining the maximum plasma concentrations of amiodarone (tmax) in the rats treated with the extract. Nevertheless, it must be highlighted the marked increase (60-70%) of the extent of amiodarone systemic exposure (as assessed by AUC0-t and AUC0-∞) in the rats pre-treated with C. papaya comparatively with the control (vehicle) group. Conclusions – The results herein found suggest an herb-drug interaction between C. papaya extract and amiodarone, which clearly increase the drug bioavailability. To reliably assess the clinical impact of these findings appropriate human studies should be conducted.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.
Drug-Drug Interactions Associated with Length of Stay and Cost of Hospitalization
Authors: Moura Cristiano Soares , Acurcio Francisco Assis , Belo Najara Oliveira
Published: March 2016

Purpose To evaluate the prevalence of drug-drug interactions (DDI) in prescriptions of hospitalized patients and to identify risk factors associated. Methods A retrospective cross-sectional analysis of prescription data and medical records from a public hospital in Brazil was conducted to identify potential DDI. An inappropriate drug combination was identified and classified with a standard drug interaction source. The main diagnoses were classified with Charlson Comorbidity Index (CCI). Sex, age, polypharmacy and length of stay, among other variables, were correlated with the frequency of potential DDI. Results The study included 589 patients and 3,585 prescriptions. Thirty-seven percent of the patients were exposed to at least one potential interaction during their stay in the hospital. The most frequent interacting pair was Digoxin+Furosemide (11%). In univariate analysis, several variables were associated with DDI, including sex, age, number of prescribed drugs, length and cost of hospitalization and CCI. Multivariate analysis showed that the adjusted odds of being prescribed a potential DDI among patients in polypharmacy was almost five-fold that of patients taking less than five drugs. Further, length of stay, CCI and cost of hospitalization were independently associated with DDI. Conclusion Analysis of prescription data found that a substantial number of potential DDI were identified. Results of this study indicate that DDI is associated with number of prescribed drugs, increased duration of stay in the hospital and cost, which suggest that DDI are a significant clinical and economic problem. Potential damage to patients could be avoided.