bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between LDL-C Reduction after Coronary Revascularization and Prevention of Recurrence of Cardiovascular Events
Authors: Nishiwaki Tatsuhiro , Satoh Mitsutoshi , Kishi Daisuke , Yoshie Fumihiko , Fukuda Keiko , Ibuki Chikao , Seino Yoshihiko
Published: March 2016

Purpose. The purpose of our study was to optimize lipid-lowering therapy in patients undergoing coronary revascularization and to determine whether the percentage change in low-density lipoprotein-cholesterol (LDL-C) level in the 3 months after coronary revascularization could be used as a predictor of the time to recurrence of coronary artery disease (CAD). Methods. Biochemical values of patients undergoing lipid-lowering therapy after receiving coronary revascularization at the Nippon Medical School Chiba Hokusoh Hospital, Japan, were retrospectively investigated. Recurrence of a cardiovascular event (CVE) was defined by death, myocardial infarction, or angina caused by coronary revascularization more than 3 months after the first event. Results. Of 171 patients under secondary preventive care who had at least one recurrence of a CVE, 75 showed evidence of objective stenotic lesions on coronary angiography. Among these 75 patients, exclusion of those in whom coronary revascularization had not been performed at disease onset, balloon dilatation had been used, serum lipid levels had not been measured, or coronary revascularization had been applied to restenosis left 44 patients suitable for inclusion in the study group. Although the mean value of high density lipoprotein-cholesterol did not change in the 3 months after coronary revascularization, that of (LDL-C) significantly decreased. A significant positive correlation was identified between % decrease in LDL-C and number of days to CVE recurrence. The average LDL-C value (102.8±21.7 mg/dL) in the group of patients with no recurrence within 5 years was significantly lower than that (135.3±46.1 mg/dL) in the recurrence group (P = 0.0088). The % of patients achieving the LDL-C target level (non-recurrence group vs. recurrence group: 50.0% vs. 16.7%; P = 0.032) and the % decrease in LDL-C (31.0%±12.6% vs. 9.6±21.0%, P = 0.0012) were significantly greater in the non-recurrence group than in the recurrence group.

Conclusion. From our present study, a decrease in LDL-C 3 months after revascularization surgery reduces the rate of CVE relapse. The % LDL-C decrease could serve as a useful predictor of CVE recurrence, in addition to LDL-C values and achievement of the LDL-C target level.
Strategies to Prolong the Intravaginal Residence Time of Drug Delivery Systems
Authors: Baloglu Esra , Bernkop-Schnürch Andreas , Karavana Sinem Yaprak , Ay Senyigit Zeynep
Published: March 2016

The vagina has been studied as a favorable site for local and systemic delivery of drugs for female-related conditions. There are a large number of vaginal medications on the market and most of them require frequent application due to their short vaginal residence time. A prolonged vaginal residence time of formulations is therefore a key parameter for improved therapeutic efficacy. Promising approaches to prolong the residence time base on mucoadhesion, in- situ sol-gel transition and mechanical fixation. Mucoadhesive drug delivery systems can be tailored to adhere to the vaginal tissue. In-situ gelling systems offer the advantage of increased viscosity in vaginal cavity and consequently reduce outflow from the vagina. Mechanical fixation needs specially shaped drug delivery systems and reduce the frequency of administration significantly. Within this review an overview on these different strategies and systems is provided. Furthermore, the techniques to evaluate the potential of these systems for prolonged vaginal residence time are described.
Effect of Radical Scavenger N-Tert-Butyl-α-Phenylnitrone on Stroke in a Rat Model Using a Telemetric System
Authors: Saito Kieko , Kobayashi Chinatsu , Ikeda Masahiko
Published: March 2016

We used malignant stroke-prone spontaneously hypertensive rats (M-SHRSP) as a stroke model to explore the effects of the radical scavenger N-tert-butyl-alpha-phenylnitrone (PBN) on stroke. PBN was administrated in drinking water to M-SHRSP. Circadian rhythms in heart rate, blood pressure, and locomotive activity in M-SHRSP were monitored with a telemetric system, in addition to measurement of water intake and body weight. Stroke-onset was assessed by changes in neurological symptoms, water intake, and body weight. Circadian rhythms were basically the same between PBN-treated and control rats several days after stroke onset. Significant differences were seen in blood pressure, relative weight of brain and water intake, heart rate, and locomotive activity between two groups. As a result, no significant difference in age of stroke onset was seen between PBN-treated and control rats, but PBN-treated rats displayed prolonged mean life spans. PBN might be effective in prolonging life span.
Effects of Rivastigmine and Donepezil on Brain Acetylcholine Levels in Acetylcholinesterase-Deficient Mice
Authors: Naik Runa S. , Hartmann Joachim , Kiewert Cornelia , Duysen Ellen G. , Lockridge Oksana , Klein Jochen
Published: March 2016

Purpose. Alzheimer´s disease is characterized by a dysfunction of central cholinergic systems and is treated by inhibitors of acetylcholinesterase (AChE). This study tests the effect of two AChE inhibitors in therapeutic use, rivastigmine and donepezil, in mice that are devoid of AChE (AChE-/- mice). Rivastigmine is an inhibitor of both AChE and butyrylcholinesterase (BChE) whereas donepezil is a selective inhibitor of AChE. Methods. We have used in vivo microdialysis to investigate the effects of the two drugs on the extracellular concentration of acetylcholine (ACh) in the hippocampus of AChE-/- mice. Results. Extracellular ACh levels in the hippocampus were 30-fold elevated in AChE-/- mice compared to wild-type (AChE+/+) animals. Infusion of rivastigmine (1 and 10 µM) caused a further doubling of ACh levels in AChE-/- mice within 90-120 min. In contrast, infusion of donepezil (1 µM) did not affect hippocampal ACh levels in AChE-/- mice although it increased ACh levels more than twofold in wild-type mice. Conclusions. In the absence of AChE, rivastigmine enhances the levels of extracellular ACh by inhibiting BChE. This finding may be of therapeutic relevance because BChE activity is preserved, but AChE activity is strongly decreased, in late-stage Alzheimer´s disease.
Altered Pharmacokinetics of Daunorubicin in Rats with CCl4-Induced Hepatic Injury
Authors: Choi Min-Koo , Song Im-Sook , Kim Dae-Duk , Chung Suk-Jae , Shim Chang-Koo
Published: March 2016

PURPOSE. The effect of CCl4-induced experimental hepatic injury (CCl4-EHI) on the pharmacokinetics of daunorubicin was investigated systemically in rats, in an attempt to elucidate the major determinants of the effect of CCl4-EHI on the pharmacokinetics of the drug. METHODS. CCl4-EHI was induced in rats by a single intraperitoneal injection of CCl4 (1mL/kg rat), and a 24 h fasting period. Daunorubicin was administered intravenously to control and EHI rats at a dose of 11.3 mg/mL/kg and the in vivo pharmacokinetics was studied. The in vitro uptake of the drug into isolated hepatocytes and canalicular liver plasma membrane (cLPM) vesicles, as well as the liver microsomal degradation of the drug, were also determined. RESULTS. The area under the plasma concentration-time curve (AUC) of daunorubicin was increased by 1.6 times, resulting in a 34% decrease in the systemic clearance (CL) in rats with CCl4-EHI. The apparent biliary (CLbile) and urinary (CLurine) clearance of the drug were unchanged, whereas the AUC of daunorubicinol, the major metabolite of daunorubicin, was decreased by 66% in rats with CCl4-EHI. EHI seemed to affect the hepatobiliary elimination of the drug in several ways: the in vitro intrinsic sinusoidal uptake clearance was decreased by 20%; the in vitro intrinsic canalicular excretion clearance of the drug was increased by 1.7 times; and the in vitro liver microsomal degradation of daunorubicin was significantly retarded. CONCLUSIONS. CCl4-EHI appears to impair the hepatic metabolism of daunorubicin, thereby decreasing the CL and increasing the AUC of daunorubicin.
Cranberry Juice Ingestion and Clinical Drug-Drug Interaction Potentials; Review of Case Studies and Perspectives
Authors: Srinivas Nuggehally R
Published: March 2016

Cranberry juice is a popular beverage with many health benefits. It has anthocyanins to supplement dietary needs. Based on in vitro evidence cranberry juice is an inhibitor of CYP enzymes and at higher amounts as potent as ketoconazole (CYP3A) and fluconazole (CYP2C9). There is, however, a discrepancy between in vitro and in vivo observations with respect to a number of substrates (cyclosporine, warfarin, flurbiprofen, tizanidine, diclofenac, amoxicillin, ceflacor); with the exception of a single report on midazolam, where there was a moderate increase in the AUC of midazolam in subjects pre-treated with cranberry juice. However, another study questions the clinical relevancy of in vivo pharmacokinetic interaction between cranberry juice and midazolam. The controversy may be due to a) under in vitro conditions all anthocyanin principles may be available to have a concerted effort in CYP inhibition; however, limited anthocyanin principles may be bioavailable with varying low levels in the in vivo studies; b) a faster clearance of the active anthocyanin principles under in vivo conditions may occur, leading to low threshold levels for CYP inhibition; c) efficient protein binding and/or rapid tissue uptake of the substrate may have precluded the drug availability to the enzymes in the in vivo studies. With respect to pharmacodynamic aspects, while the debate continues on the issue of an interaction between warfarin and cranberry juice, the summation of the pharmacodynamics data obtained in patients and healthy subjects from different prospectively designed and controlled clinical trials does not provide overwhelming support for the existence of a pharmacodynamic drug interaction for normal cranberry juice ingestion. However, it is apparent that consumption of large quantities of cranberry juice (about 1-2 L per day) or cranberry juice concentrates in supplements for an extended time period (>3-4 weeks) may temporally alter the effect of warfarin. Therefore, the total avoidance of cranberry juice by warfarin users may not be warranted by the published studies. However, in certain situations of higher intake of cranberry juice or concentrate there may be a need to monitor both warfarin doses and its effect.

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.
Foresight Scanning: Future Directions of Clinical and Pharmaceutical Research
Authors: Foster Brian C.
Published: March 2016

Foresight Scanning: Future Directions of Clinical and Pharmaceutical Research.

Brian C. Foster, Therapeutic Products Directorate, Health Canada, Ottawa, Ontario, Canada

ABSTRACT

The Canadian Society for Pharmaceutical Sciences Satellite Symposium on Foresight Scanning, May 26 and 27, 2008, Nordegg, Alberta, Canada, focussed on the future directions of clinical and pharmaceutical research. The symposium brought together a group of clinicians, regulatory scientists, researchers and students to examine where clinical, pharmaceutical, and regulatory science might be in 10 to 15 years. Industry, regulatory, analytical, and clinical perspectives were presented and discussed, as well as the impact of exogenous (indirect) and endogenous (direct) change drivers. Unconditional funding was provided by Bayer HealthCare; they had no input on the direction of the meeting or selection of speakers. It was envisioned that the more important endogenous drivers may not be new information or changes in technology, policy, regulation, or health care delivery, but amplification of long-term underlying trends by emergence of new technologies, convergence of existing technologies or new communication and collaboration vehicles such as Web 2.0.
Review of Pharmaceutical Applications of N-Methyl-2-Pyrrolidone
Authors: Jouyban Abolghasem , Fakhree Mohammad Amin Abolghasemi , Shayanfar Ali
Published: March 2016

N-Methyl-2-pyrrolidone (NMP) or Pharmasolve is very strong solubilizing agent and it has important applications in different fields of industry. This review presents NMP physicochemical characteristics, application especially in pharmaceutical sciences, pharmacokinetic and toxicity. Characteristics of NMP such as physicochemical properties, solubilization efficacy, toxicity and adverse effects were compared with other common solvents used in the pharmaceutical industries. This review reveals that NMP is an acceptable pharmaceutical solvent and its efficacy, toxicity, and side effects are comparable with other common solvent.
Antidepressant, Anxiolytic and Antinociceptive Activities of Constituents from Rosmarinus Officinalis
Authors: Abdelhalim Abeer , Karim Nasiara , Chebib Mary , Aburjai Talal , Khan Imran , Johnston Graham A.R. , Hanrahan Jane
Published: March 2016

Purpose. Rosmarinus officinalis, traditionally known as rosemary, has been widely used in traditional medicines and has long been known as the herb of remembrance. However, few studies have investigated the effects of non-volatile components of rosemary on central nervous system function. Methods. Fractionation of R. officinalis led to the isolation of salvigenin, rosmanol and cirsimaritin, which were investigated in mouse models of acute toxicity, antinociception (tail immersion and hot plate tests), depression (tail suspension and forced swim tests) and anxiety (elevated plus maze and light/dark box paradigms). Results. Rosmanol, cirsimaritin and salvigenin were not found to exhibit any signs of acute toxicity (50-200 mg/kg), but elicited antinociceptive, antidepressant and anxiolytic activities. Conclusion. Rosmanol, cirsimaritin and salvigenin, all previously shown to have biphasic modulation of GABAA receptors, demonstrated CNS activity in mouse models of antinociception, antidepressant and anxiolysis. The anxiolytic activity of all three compounds was not ameliorated by flumazenil, but was inhibited by pentylenetetrazol, suggesting a mode of action via GABAA receptors at a site other than the high affinity benzodiazepine binding site. 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 Ketamine on Pulmonary Inflammatory Responses and Survival in Rats Exposed to Polymicrobial Sepsis
Authors: Yu Min , Shao Danbing , Yang Rong , Feng Xiaomei , Zhu Sihai , Xu Jianguo
Published: March 2016

PURPOSE. Ketamine is reported to suppress production of proinflammatory cytokines and activity of nuclear factor-kappa B (NF-?B) after lipopolysaccharide (LPS) stimulation. Our study was designed to investigate the effects of ketamine on pulmonary inflammatory responses and survival in a clinically relevant model of polymicrobial sepsis, induced by cecal ligation and puncture (CLP). METHODS. After the induction of sepsis or sham-operation, animals were treated with ketamine (0.5, 5 or 10 mg/kg) or saline (10 ml/kg) at 3h after operation. At 6 h post-operation, the levels of tumor necrosis factor alpha (TNF-?) and interleukin (IL)-6, activity of NF-?B, expression of Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) of the lungs were measured. And the mortality was recorded for 7 days. RESULTS. TNF-? and IL-6 production, NF-?B activity, TLR2 and TLR4 expression in rat lungs were increased after CLP. Ketamine at the doses of 5 mg/kg and 10 mg/kg suppressed CLP-induced elevation of TNF-? and IL-6 production, NF-?B activity and TLR2 expression.

Ketamine 0.5, 5 and 10 mg/kg inhibited TLR4 expression in sepsis. Ketamine 5mg/kg and 10 mg/kg after CLP improved the survival of rats. CONCLUSIONS. Ketamine at sub-anesthetic doses could suppress the production of inflammatory cytokines such as TNF-? and IL-6, attenuate NF-?B activity, and inhibit TLR2 and TLR4 expression in polymicrobial sepsis. These anti-inflammatory effects of ketamine may correlate with improved survival in sepsis.
Effects of PDE4 Pathway Inhibition in Rat Experimental Stroke
Authors: Yang Fan , Sumbria Rachita K , Xue Dong , Yu Chuanhui , He Dan , Liu Shuo , Paganini-Hill Annlia , Fisher Mark
Published: March 2016

PURPOSE: The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS: Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model. RESULTS: Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p<0.01) and 138% (p<0.05) of control in the ligation and embolic models, respectively. PDE4D knockout rats subjected to embolic stroke showed no change in infarct size compared to wild-type control. CONCLUSIONS: Despite increase in infarct size after global inhibition of the PDE4 pathway with rolipram, specific inhibition of the PDE4D isoform had no effect on experimental stroke. These findings support a role for the PDE4 pathway, independent of the PDE4D isoform, in ischemic stroke pathogenesis. 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.
Safety of Liver Surface Instillation of Plasmid DNA in Normal and Carbon Tetrachloride-Induced Hepatitis Mice
Authors: Fumoto Shintaro , Furukawa Hiroyuki , Nakamura Junzo , Nishida Koyo
Published: March 2016

Purpose. We previously demonstrated liver- and lobe-selective gene transfer following instillation of plasmid DNA (pDNA) onto the liver surface in mice. Safety concerns must be resolved prior to future clinical use. Thus, we investigated safety of liver surface instillation of pDNA in normal and hepatitis mice. Methods. pDNA was instilled onto the liver surface in normal and carbon tetrachloride-induced hepatitis mice. Gene expression (luciferase activity) and serum transaminase activities were measured at appropriate time points. Results. Transfection efficiency and target site selectivity were almost the same between the instillation of pDNA using a micropipette and a catheter. Serum transaminase activities 6 h after instillation of pDNA or a vehicle treatment using a micropipette were significantly higher than the no treatment mice, whereas instillation using a catheter did not raise serum transaminase activities throughout the tested time points, suggesting the safety of instillation using a catheter. This safety was also confirmed in hepatitis mice. A dose escalation study verified that liver surface instillation using a catheter did not raise serum transaminase at high doses with saturation of gene expression not only in normal mice, but also in hepatitis mice, supporting the safety of this method. Conclusions. We demonstrated that liver surface instillation of pDNA using a catheter did not raise serum transaminase activities. Information in this study will be useful for future clinical use of liver surface instillation of pDNA using a catheter.
Potential Complementary Therapy for Adverse Drug Reactions to Sulfonamides: Chemoprotection Against Oxidative and Nitrosative Stress by TCM Constituents and Defined Mixtures
Authors: Zhang Lee , Chen Dao-feng , Xia Xue Yan , Yip Cindy , Rieder Michael John , Bend John Richard
Published: March 2016

PURPOSE: Our working hypothesis is that bioactive phytochemicals that are important constituents of Traditional Chinese Medicine and their defined mixtures have potential as complementary therapy for chemoprotection against adverse drug reactions whose toxicity is not related to the pharmacological action of the drug but where oxidative and nitrosative stress are causative factors. METHODS: In this investigation we measured cytotoxicity, lipid peroxidation, protein carbonylation and ROS/NOS-mediated changes in the disulfide proteome of Jurkat E6.1 cells resulting from exposure to sulfamethoxazole N-hydroxylamine with or without pre-treatment with low µM concentrations of baicalein, crocetin, resveratrol and schisanhenol alone and in defined mixtures to compare the ability of these treatment regimens to protect against ROS/RNS toxicity to Jurkat E6.1 cells in culture. RESULTS: Each of the Traditional Chinese Medicine constituents and defined mixtures tested had significant chemoprotective effects against the toxicity of ROS/RNS formed by exposure of Jurkat E6.1 cells to reactive metabolites of sulfamethoxazole implicated as the causative factors in adverse drug reactions to sulfa drugs used for therapy. At equimolar concentrations, the defined mixtures tended to be more effective chemoprotectants overall than any of the single constituents against ROS/RNs toxicity in this context. CONCLUSIONS: At low µM concentrations, defined mixtures of TCM constituents that contain ingredients with varied structures and multiple mechanisms for chemoprotection have excellent potential for complementary therapy with sulfa drugs to attenuate adverse effects caused by oxidative/nitrosative stress. Typically, such mixtures will have a combination of immediate activity due to short in vivo half-lives of some ingredients cleared rapidly following metabolism by phase 2 conjugation enzymes; and some ingredients with more prolonged half-lives and activity reliant on phase 1 oxidation enzymes for their metabolic clearance. 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.
Nucleoside Transport Inhibition by Dipyridamole Prevents Angiogenesis Impairment by Homocysteine and Adenosine
Authors: Kam Antony , Razmovski-Naumovski Valentina , Zhou Xian , Troung John , Chan Kelvin
Published: March 2016

Purpose: Adenosine plays an important role in the pathogenesis of homocysteine-associated vascular complications. Methods: This study examined the effects of dipyridamole, an inhibitor for nucleoside transport, on impaired angiogenic processes caused by homocysteine and adenosine in human cardiovascular endothelial cell line (EAhy926). Results: The results showed that dipyridamole restored the extracellular adenosine and intracellular S-adenosylhomocysteine concentrations disrupted by the combination of homocysteine and adenosine. Dipyridamole also ameliorated the impaired proliferation, migration and formation of capillary-like tubes of EAhy926 cells caused by the combination of homocysteine and adenosine. Mechanism analysis revealed that dipyridamole induced the phosphorylation of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinases (ERK) and its effect on cell growth was attenuated by the MEK inhibitor, U0126. Conclusion: Dipyridamole protected against impaired angiogenesis caused by homocysteine and adenosine, at least in part, by activating the MEK/ERK signalling pathway, and this could be associated with its effects in suppressing intracellular S-adenosylhomocysteine accumulation.Novelty of the Work: This is the first paper showing that nucleoside transport inhibition by dipyridamole reduced impaired angiogenic process caused by homocysteine and adenosine.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.
The Two Faces of Pharmacokinetics
Authors: Rescigno Aldo
Published: March 2016

There are two main branches of Mathematics: Calculus and Geometry; in Physics there are Constructive Theories and Principle Theories. Similarly in Pharmacokinetics we can build models with two opposite approaches, the bottom-up and the top-down point of view. In this short opinion article I will try to show, with the help of a few examples, the advantages of each one of the two approaches.
Differential Effects of Chrysin on Nitrofurantoin Pharmacokinetics Mediated by Intestinal Breast Cancer Resistance Protein in Rats and Mice
Authors: Kawase Atsushi , Matsumoto Yukako , Hadano Motoshi , Ishii Yui , Iwaki Masahiro
Published: March 2016

PURPOSE: The activities of breast cancer resistance protein (Bcrp/ABCG2) as well as P-glycoprotein (P-gp) and drug-metabolizing enzymes can be inhibited by several flavonoids or drugs in rats. However, the species, gender and regional differences of effects of flavonoids on Bcrp/ABCG2 in rats and mice remain unclear, although Bcrp, like P-gp, is also important in controlling drug absorption and disposition.

METHODS: We used chrysin as a model flavonoid because it possesses anti-inflammatory and antioxidative properties and is used as a dietary supplement. We examined the pharmacokinetics of nitrofurantoin, a specific Bcrp substrate, in rats and mice treated with chrysin. Bcrp mRNA levels were measured in liver, kidney, duodenum, jejunum and ileum in rats and mice.

RESULTS: Plasma concentrations of nitrofurantoin were increased in rats, but not mice, treated with oral chrysin, compared with untreated controls. Intraperitoneal injection of chrysin into rats or mice had little effect on the elimination of nitrofurantoin, compared with untreated animals.

CONCLUSIONS: These results suggest that chrysin-nitrofurantoin interactions occur in the small intestine in rats, but not in mice, possibly due to the higher levels of Bcrp expression in the small intestine in rats, compared with those in mice.
Targeting the Calmodulin-Regulated ErbB/Grb7 Signaling Axis in Cancer Therapy
Authors: Villalobo Antonio , García-Palmero Irene , Stateva Silviya R. , Jellali Karim
Published: March 2016

Signal transduction pathways essential for the survival and viability of the cell and that frequently present aberrant expression or function in tumors are attractive targets for pharmacological intervention in human cancers. In this short review we will describe the regulation exerted by the calcium-receptor protein calmodulin (CaM) on signaling routes involving the family of ErbB receptors - highlighting the epidermal growth factor receptor (EGFR/ErbB1) and ErbB2 - and the adaptor protein Grb7, a downstream signaling component of these receptors. The signaling mechanism of the ErbB/Grb7 axis and the regulation exerted by CaM on this pathway will be described. We will present a brief overview of the current efforts to inhibit the hyperactivity of ErbB receptors and Grb7 in tumors. The currently available information on targeting the CaM-binding site of these signaling proteins will be analyzed, and the pros and cons of directly targeting CaM versus the CaM-binding domain of the ErbB receptors and Grb7 as potential anti-cancer therapy will be discussed.

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.
Changes in omeprazole pharmacokinetics in rats with diabetes induced by alloxan or streptozotocin: Faster clearance of omeprazole due to induction of hepatic CYP1A2 and 3A1
Authors: Lee Dae Young , Lee Myung G. , Shin Hyun Sook , Lee Inchul
Published: March 2016

Purpose. To investigate the effect of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS) on the pharmacokinetics of omeprazole in rats. It has been reported that omeprazole is primarily metabolized via hepatic CYP1A2, 2D1, and 3A1 in rats. The expression and mRNA levels of hepatic CYP1A2 and 3A1 increases in DMIA and DMIS rats, but the expression of hepatic CYP2D1 does not change in DMIS rats. In addition, the metabolic activities of intestinal CYP3A1/2 decreases in DMIS rats. Thus, it could be expected that the pharmacokinetics of omeprazole would be affected by changes in both DMIA and DMIS. Methods. Omeprazole was administered intravenously (20 mg/kg) and orally (40 mg/kg) to DMIA and DMIS rats and their respective controls. Results. After intravenous administration of omeprazole, the CLNR of the drug was significantly faster in DMIA (52.6 versus 67.4 mL/min/kg) and DMIS (50.2 versus 73.0 mL/min/kg) rats than the respective controls. However, after oral administration of omeprazole, the AUC was comparable between each type of diabetic rat and the respective controls. Conclusions. The significantly faster CLNR of intravenous omeprazole could be due to increased expression and mRNA levels of hepatic CYP1A2 and 3A1 in both types of diabetic rat. The comparable AUC of oral omeprazole could be due to a decrease in the intestinal first-pass effect of omeprazole caused by decreased intestinal CYP3A1/2 in diabetic rats. Following both intravenous and oral administration in DMIA and DMIS rats, the pharmacokinetics of omeprazole were similarly altered.
Safety of Anti-Tumor Necrosis Factor Therapies in Arthritis Patients
Authors: Nanau Radu M , Neuman Manuela G
Published: March 2016

Purpose. Inflammatory and rheumatic arthritis remain leading causes of disability worldwide. The arthritis therapeutic area commands the largest market for the prescription of biological and non-steroidal anti-inflammatory drugs (NSAID). Yet biotechnology and pharmaceutical companies conducting research and providing therapeutics in this area frequently face challenges in patient safety.  The purpose of our study was to assess safety of anti-tumor necrosis factor therapies in arthritis patients.  Methods: The present study systematically reviews adverse events of biologicals alone or in the presence of NSAIDs and other immunosuppressant therapeutics such as disease-modifying antirheumatic drugs (DMARD). We assessed the rheumatology literature that included clinical trials with anti-tumor necrosis factor (TNF) biologicals and case reports published between 2010 and 2014.  Results: Currently approved anti-TNF biologicals in arthritis include the monoclonal antibodies infliximab, adalimumab, certolizumab pegol and golimumab, and the fusion protein etanercept. The most frequently-reported adverse event was infection. We grouped the adverse reactions as immune-mediated, hypersensitivity syndrome reactions including cutaneous and hepatic manifestation, neurological, hematological, and malignancy.  Discussion: Most adverse events are due to the failure of host immunological control, which involves susceptibility to the drug itself, or de novo infection or reactivation of a latent bacterial or viral infection, often with a different expression of disease. Drug-induced liver injury associated with anti-TNF biologicals must be kept in mind when evaluating patients with increased liver enzymes.  Conclusion: Risk assessment in individuals undergoing treatment with biologicals represents a step towards achieving a personalized medicine approach to identify those patients that will safely benefit from this therapeutic approach. Patients and physicians must be alert of anti-TNF agents as potential causes of drug-induced liver injury and monitor the therapies. Personalizing therapeutic pharmacovigilance promises to optimize benefits while minimizing side effects.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.
Prodrugs of Antiinfective Agents: A Review
Authors: Piplani Mona , Rana Avtar Chand , Sharma Prabodh Chander
Published: March 2016

Prodrugs are the pharmacologically inactive derivatives of active drugs typically intended to optimize the exposure of active drug at target site, through manipulation of its physicochemical, biopharmaceutical or pharmacokinetic properties. This approach has a number of advantages over conventional drug administration. Antiinfective agents are associated with number of limitations, responsible for their reduced bioavailability. Various antiinfective prodrugs have been synthesized with reduced side effects and improved pharmacological properties. The present paper illustrates different vistas of prodrug approach of antiinfective agents describing brief classification, synthetic approaches, pharmacological aspects and recent patents. It is a very productive area of research and its prologue in human therapy has given triumphant outcomes in improving the clinical and therapeutic effectiveness of 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.
Evaluation of Solid Lipid Nanoparticles as Carriers for Delivery of Hepatitis B Surface Antigen for Vaccination Using Subcutaneous Route
Authors: Mishra Dinesh , Mishra Himanshu , Mishra Pradyumna K. , Nahar Manoj , Dubey Vaibhav , Jain Narendra K.
Published: March 2016

Purpose: Solid lipid nanoparticles (SLN) have emerged as carriers for therapeutic peptides, proteins, antigens and bioactive molecules. We have explored the potential of SLN as carrier for Hepatitis B surface antigen (HBsAg) by surface modifications to enhance their loading efficiency and the cellular uptake, using subcutaneous route.

Methods: Four different formulations of SLN were prepared by solvent injection method and characterized for various physical properties: particle size, surface morphology, shape, zeta potential, polydispersity, X-ray diffraction analysis, release profile and entrapment efficiency. HBsAg loaded SLN were studied for their functional characteristics, in vitro cellular uptake and internalization studies by human dendritic cells, macrophages and fibroblasts, T cell proliferation and TH1/TH2 response. Humoral immune response elicited by subcutaneously administered HBsAg containing SLN formulations were studied in vivo in mice.

Results: Compared to soluble HBsAg; SLN, particularly the mannosylated formulation, showed better cellular uptake, lesser cytotoxicity and induction of greater TH1 type of immune response. They also showed better immunological potential by producing sustained antibody titer.

Conclusion: Mannosylated SLN appears to be promising as carrier for vaccine delivery against hepatitis B as ascertained by in vitro and in vivo studies, however further investigations on humans are required to establish their potential as vaccines against hepatitis B infection.
Curcumin Reduces Tumour Necrosis Factor-Enhanced Annexin V-Positive Microparticle Release in Human Vascular Endothelial Cells
Authors: Kam Antony , Li Kong M , Razmovski-Naumovski Valentina , Nammi Srinivas , Chan Kelvin , Grau Georges E , Li George Q
Published: March 2016

PURPOSE: Circulating microparticles have been highlighted as biomarkers of cardiovascular disease state and progression. The aim of this study was to evaluate the effects of curcumin on microparticle release from endothelial cells undergoing TNF-induced cell activation and apoptosis. METHODS: This study evaluated the effects of curcumin on microparticle release, cytotoxicity, apoptosis, cell adhesion molecule expression and monocyte adhesion in EAhy926 human endothelial cells. RESULTS: The results showed that the numbers of microparticles were increased by tumour necrosis factor (TNF) or the combination of TNF and cycloheximide (CHX). Curcumin attenuated microparticle release caused by TNF or TNF plus CHX treatments. The pretreatment by curcumin not only negated the accelerated cell death and apoptosis caused by TNF and CHX, but also diminished TNF-induced cell activation, as assessed by reduced surface expression of intercellular adhesion molecule 1, and adhesion of monocytes to endothelial monolayers. CONCLUSION: Curcumin reduced microparticle release from endothelial cells undergoing cell activation and apoptosis, which supports its protective role in TNF-associated endothelial dysfunction, and highlights its potential use as a nutraceutical agent for vascular inflammatory diseases. 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.
Influence of Ascorbic Acid Supplementation on Type 2 Diabetes Mellitus in Observational and Randomized Controlled Trials; A Systematic Review with Meta-Analysis
Authors: Tabatabaei-Malazy Ozra , Nikfar Shekoufeh , Larijani Bagher , Abdollahi Mohammad
Published: March 2016

Purpose.There are controversial data regarding the beneficial effects of ascorbic acid (AA) supplementation in type 2 diabetes mellitus (T2DM). In this systematic review, we aimed to criticize the current relevant data from both observational and randomized controlled trials (RCTs). Methods. All observational and RCTs conducted to assess anti-hyperglycemic effects of AA in diabetics, published before January 2013, were included. To obtain all related studies Google Scholar, PubMed, Scopus, IranMedex, and Magiran web databases were searched. Exclusion criteria were animal studies, and studies conducted in Type 1 DM, children or pregnant women. Main outcome measures were fasting blood sugar (FBS), and glycated hemoglobin (HbA1c). According to degree of heterogeneity, fixed or random effect models were employed. Meta-analyses were done using Stats Direct software, version 3.0.97. The quality of included articles and publication bias were also assessed. Results. We selected 38 articles; 26 observational studies and 12 RCTs. Due to severe methodological heterogeneity in all observational studies and some of RCTs, we could pool data from only 5 RCTs in a meta-analysis. Single intake of AA versus placebo showed a significant effect on FBS; with the standardized mean difference (SMD): -20.59, 95% confidence intervals (95% CI): -40.77 to -0.4 (p= 0.04), but non-significant effect on HbA1c; SMD: -0.46, 95% CI: -1.75 to 0.84 (p= 0.4). Effect of other antioxidants with/without AA supplementation on FBSwere nonsignificant; SMD: -4.26 (p= 0.8), and SMD: -12.04 (p= 0.3), respectively. Also, their effect on HbA1c was non-significant; SMD: 0.53 (p= 0.11), and SMD: 0.28 (p= 0.34), respectively. Conclusions. Our study supports the positive effect of AA in reduction of FBS in diabetics, however, due to insufficient evidence ragarding long term safety of AA supplementation and limited number of  RCTs, the long term use of this vitamin for its anti-diabetic properties cannot be strongly recommended. 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.
FERRAMENTAS DE E-LEARNING PARA MELHORIA DO APRENDIZADO EM MEDICINA.
Authors: Oliveira Ricardo José Fonseca de , Silva Afonso Xavier Gomes da , Brigido Alexandra Régia Dantas , Mafaldo Rafaella Santos , Paula Vitor Tavares , Diniz Junior José , Diniz Rosiane Viana Zuza
Published: March 2016

Introdução: As tecnologias de informação e comunicação (TIC) têm sido cada vez mais utilizadas no contexto da educação e vêm se tornando importantes ferramentas no auxílio do processo de ensino-aprendizagem na área da saúde. A Interactive Spaced Education (ISE) vem surgindo como método inovador para otimização do aprendizado em saúde. Objetivo: Investigar o uso da ISE como ferramenta de e-learning para melhoria do aprendizado do estudante de semiologia médica. Métodos: Estudo descritivo realizado com 98 estudantes regularmente matriculados no componente curricular “Iniciação ao Exame Clínico”, do curso de medicina. Os estudantes receberam componentes de ISE contendo itens referentes à semiologia cardiovascular e respiratória, duas vezes por semana, durante 13 semanas. Ao final das 13 semanas, os alunos receberam um questionário semi-estruturado online, contendo quesitos fechados utilizando escala de Likert, além de questões abertas, para avaliar a utilização da ferramenta ISE como adjuvante do aprendizado em semiologia médica. Resultados: A taxa de resposta ao questionário online foi de 67,4% (N=66). A idade média dos participantes foi de 20,9±2,2 anos, com predomínio do sexo masculino (54,5%). A ISE contribuiu para o aprendizado de 98,5% destes (N=65), sendo esta contribuição referente ao aprendizado teórico e prático para 59,1% dos indivíduos (N=37). A maioria dos participantes considerou boa a frequência de liberação semanal dos componentes ISE (N=29, 43,9%). Todos os estudantes indicariam a ISE para outros estudantes como forma de aprendizado. Conclusões: A ISE foi bem aceita como ferramenta de e-learning, importante para o aprendizado na percepção dos estudantes de semiologia médica.
A SÍNTESE POÉTICA COMO UMA FERRAMENTA PARA FEEDBACK NA FORMAÇÃO EM SAÚDE
Authors: Melo Ricardo Henrique Vieira , Vilar Rosana Lúcia Alves , Gouveia Ana Cláudia Galvão Freire , Moreira Francisca Sueli Monte , Fernandes Sônia Maria , Felipe Magna Celi Pereira
Published: March 2016

Este texto relata a experiência de uso da Síntese Poética enquanto instrumento para feedback no processo ensino/aprendizagem contextualizada na articulação entre Academia, Comunidade e Estratégia Saúde da Família, durante a Disciplina Saúde e Cidadania, nos cursos de graduação da área de saúde da Universidade Federal do Rio Grande do Norte (UFRN). Esta disciplina é ofertada durante o primeiro período letivo, contribuindo para a inserção precoce dos alunos nos cenários reais dos serviços de saúde, em Natal (RN). Os poemas são recitados após a execução de projetos de intervenção na comunidade e as narrativas reflexivas discentes, contidas em portfólios de aprendizagem, foram analisadas através da técnica do Discurso do Sujeito Coletivo. Verificamos que esta prática estimulou um circuito de trocas positivas, integrando instrumentos formais da ciência com a realidade social, numa perspectiva interativa centrada no desenvolvimento de habilidades comunicativas, dialógicas e de solidariedade reflexiva frente a situações comuns.
NÓDULOS CANCERÍGENOS SUBCUTÂNEOS NO ESOFAGO: ORIGEM, DETECÇÃO E QUANTIFICAÇÃO
Authors: Costa Diogo Oliveira , Rosa Suélia Siqueira Rodrigues Fleury
Published: March 2016

O Câncer Esofágico (CE) é uma neoplasia maligna com alta taxa de mortalidade de difícil diagnóstico em sua fase inicial, o que diminui a eficiência de seu tratamento. Sua incidência muitas vezes está ligada a fatores culturais, como a ingestão de alimentos e ou bebidas em temperaturas elevadas. Devido à baixa rastreabilidade foi pensado no desenvolvimento de um cateter confeccionado em látex, que é um material biossintético, e esse conter uma matriz de termômetros eletrônicos (LM35), para medição da temperatura esofágica, juntamente com sensores de pressão (Resistor Variável a Força - FSR), além de um circuito eletrônico para a aquisição das leituras dos sensores e um software responsável pelo processamento dos sinais adquiridos e visualização gráfica dos resultados. A partir dos sinais de temperatura obtidos aplica-se o método da Dinâmica Simbólica para visualização e compreensão da dinâmica da temperatura e da pressão em toda a extensão do esôfago. Com esse aparato é esperado obter o modelamento térmico e de pressão para tecidos saudáveis e tecidos afetados pelo CE.
Educational Innovation And Personalized Tutoring In Higher Education: A Personal And Professional Guidance
Authors: Del Pozo-Rubio Raul , Ruiz-Palomino Pablo , Martinez-Canas Ricardo
Published: March 2016

College years determine the essential academic and personal training for students future success. Certainly, higher education period is essential in the development of students as persons, setting out their emotional and intellectual capital and therefore determining their professional and personal life expectations. However, this process generally must be faced with few help and also sometimes students have to create, sometimes blindly, their own path. In this sense, Social Sciences Faculty of Cuenca (Spain) has created a Tutoring Action Program that is designed to provide more supportive, collegial and discipline-specific training for students. This plan defines also a new tutorial role for professors as personal mentors of students. The aim of this paper is to present the new methodology used for the implementation of the Tutorial Action Plan which includes the assignment of this new role attributed to professors, and that consist in advising and guiding the students in those questions that may arise throughout the university degree, as well as advising students to do those things that are most appropriate for their profiles relative to their future labor orientations.
Detecting Successful Student Profiles At An Open University: The Case Of The UNED (Spain)
Authors: Fernandez-Aviles Gema , Perez-Zabaleta Amelia , Martinez-Merino Juan-Luis
Published: March 2016

At present, one of the major issues and most interesting discussions within the European Higher Education Area is the rate of success in university-level study, and therefore the adaptation of todays university education system to societys requirements. Moreover, we have seen significant growth in distance education throughout recent decades, as this type of education takes on a stronger leadership role in countries that are experiencing severe economic crises. Because the National Distance Education University (UNED) is the most important distance university in Spain, and the Economics Degree program has been offered by the School of Economics and Business for the first time, we have attempted to find a correlation between variables which describe student characteristics (age, gender, employment status, manner of admission, and nationality) and success rates in order to determine the influence that these variables have and achieve a better understanding of student success rates.
The Study Abroad Experience: A Crucial Element In Globalizing Business School Programs
Authors: Mangiero George A. , Kraten Michael
Published: March 2016

Globalization is a fundamental reality of modern business practice. Participation in a study abroad program is a crucial element in helping students become well rounded global business leaders; it is an increasingly important element of a well rounded business curriculum. A semester or summer abroad, properly conceived and designed, can provide enormous benefits to the modern business student. A variety of organizations, including the AACSB, Forum EA, IBEX, and MSU-CIBER, emphasize the benefits of the direct immersion of business students in global environments and settings. This paper presents an innovative model, entitled PACK & GO, that describes the key elements of a study abroad program for schools, colleges, and universities of business. The model addresses the philosophy, assessment, curriculum, knowledge, governance, and outcomes features of an effective program. The paper concludes with an illustrative example, as well as recommendations for implementation at other institutions.
Principals Perception Regarding Factors Affecting The Performance Of Teachers
Authors: Akram Muhammad Javaid , Raza Syed Ahmad , Khaleeq Abdur Rehman , Atika Samrana
Published: March 2016

This study investigated the perception of principals on how the factors of subject mastery, teaching methodology, personal characteristics, and attitude toward students affect the performance of teachers at higher secondary level in the Punjab. All principals of higher secondary level in the Punjab were part of the population of the study. From the population, 120 principals were selected as the sample. A questionnaire was developed and validated through pilot testing. The data obtained were tabulated and analyzed by using statistical techniques of mean and standard deviation. The major conclusions of the study were that the factor of subject mastery was perceived to be influencing the performance of teachers maximally, but the factor of attitude toward students was affecting the performance of teachers minimally. The remaining two factors - teaching methodology and personal characteristics - were perceived to be at the intermediary level.