bluuebunny/crossref_metadata_2025 huggingface dataset:
An Overview of Antiretroviral Agents for Treating HIV Infection in Paediatric Population
Authors: Melo Rita , Lemos Agostinho , Preto António J. , Bueschbell Beatriz , Matos-Filipe Pedro , Barreto Carlos , Almeida José G. , Silva Rúben D.M. , Correia João D.G. , Moreira Irina S.
Published: September 2018

Paediatric Acquired ImmunoDeficiency Syndrome (AIDS) is a life-threatening and infectious disease in which the Human Immunodeficiency Virus (HIV) is mainly transmitted through Mother-To- Child Transmission (MTCT) during pregnancy, labour and delivery, or breastfeeding. This review provides an overview of the distinct therapeutic alternatives to abolish the systemic viral replication in paediatric HIV-1 infection. Numerous classes of antiretroviral agents have emerged as therapeutic tools for downregulation of different steps in the HIV replication process. These classes encompass Non- Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs), Nucleoside/Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs/NtRTIs), INtegrase Inhibitors (INIs), Protease Inhibitors (PIs), and Entry Inhibitors (EIs). Co-administration of certain antiretroviral drugs with Pharmacokinetic Enhancers (PEs) may boost the effectiveness of the primary therapeutic agent. The combination of multiple antiretroviral drug regimens (Highly Active AntiRetroviral Therapy - HAART) is currently the standard therapeutic approach for HIV infection. So far, the use of HAART offers the best opportunity for prolonged and maximal viral suppression, and preservation of the immune system upon HIV infection. Still, the frequent administration of high doses of multiple drugs, their inefficient ability to reach the viral reservoirs in adequate doses, the development of drug resistance, and the lack of patient compliance compromise the complete HIV elimination. The development of nanotechnology-based drug delivery systems may enable targeted delivery of antiretroviral agents to inaccessible viral reservoir sites at therapeutic concentrations. In addition, the application of Computer-Aided Drug Design (CADD) approaches has provided valuable tools for the development of anti-HIV drug candidates with favourable pharmacodynamics and pharmacokinetic properties.
Pyridine and Pyrimidine Derivatives as Privileged Scaffolds in Biologically Active Agents
Authors: Chiacchio Maria Assunta , Iannazzo Daniela , Romeo Roberto , Giofrè Salvatore V. , Legnani Laura
Published: September 2018

Pyridine and pyrimidine derivatives have received great interest in recent pharmacological
research, being effective in the treatment of various malignancies, such as myeloid
leukemia, breast cancer and idiopathic pulmonary fibrosis. Most of the FDA approved drugs
show a pyridine or pyrimidine core bearing different substituents. The aim of this review is to
describe the most recent reports in this field, with reference to the newly discovered pyridineor
pyrimidine-based drugs, to their synthesis and to the evaluation of the most biologically
active derivatives. The corresponding benzo-fused heterocyclic compounds, i.e. quinolines
and quinazolines, are also reported.
Alzheimer's Disease-Like Pathologies and Cognitive Impairments Induced by Formaldehyde in Non-Human Primates
Authors: Zhai Rongwei , Rizak Joshua , Zheng Na , He Xiaping , Li Zhenhui , Yin Yong , Su Tao , He Yingge , He Rongqiao , Ma Yuanye , Yang Meifeng , Wang Zhengbo , Hu Xintian
Published: September 2018

Background:

Formaldehyde (FA) has been implicated in Alzheimer’s disease (AD) pathology
as an age-related factor and as a protein cross-linker known to aggregate Amyloid-Beta (Aβ) and tau
protein in vitro. Higher levels of FA have also been found in patients with greater cognitive impairment
and in AD patient brains.

Objective:

To directly evaluate the effect of chronically elevated FA levels on the primate brain with
respect to AD pathological markers.

Method:

Young rhesus macaques (5-8 yrs, without AD related mutations) were given chronic intracerebroventricular
(i.c.v.) injections of FA or vehicle over a 12-month period. Monkeys were monitored for
changes in cognitive ability and evaluated post-mortem for common AD pathological markers.

Results:

Monkeys injected with FA were found to have significant spatial working memory impairments.
Histopathological analysis revealed the presence of amyloid-β+ neuritic-like plaques, neurofibrillary
tangle-like formations, increased tau protein phosphorylation, neuronal loss and reactive gliosis in
three memory (and AD) related brain areas (the hippocampus, entorhinal cortex and prefrontal cortex
(PFC)) of monkeys receiving i.c.v. injections of FA. ELISA assays revealed that the amounts of pT181
and Aβ42 were markedly higher in the PFC and hippocampus of FA treated monkeys.

Conclusion:

FA was found to induce major AD-like pathological markers and cognitive impairments in
young rhesus monkeys independent of genetic predispositions. This suggests FA may play a significant
role in the initiation and progression of the disease.
Crosstalk between Gut Microbiota and Central Nervous System: A Focus on Alzheimer's Disease
Authors: Junges Vilma M. , Closs Vera E. , Nogueira Guilherme M. , Gottlieb Maria G.V.
Published: September 2018

The role of diet and gut microbiota in the pathophysiology of neurodegenerative diseases,
such as Alzheimer's, has recently come under intense investigation. Studies suggest that human gut microbiota
may contribute to the modulation of several neurochemical and neurometabolic pathways,
through complex systems that interact and interconnect with the central nervous system. The brain and
intestine form a bidirectional communication axis, or vice versa, they form an axis through bi-directional
communication between endocrine and complex immune systems, involving neurotransmitters and hormones.
Above all, studies suggest that dysbiotic and poorly diversified microbiota may interfere with the
synthesis and secretion of neurotrophic factors, such as brain-derived neurotrophic factor, gammaaminobutyric
acid and N-methyl D-Aspartate receptors, widely associated with cognitive decline and
dementia. In this context, the present article provides a review of the literature on the role of the gutbrain
axis in Alzheimer's disease.
Cordycepin Downregulates Cdk-2 to Interfere with Cell Cycle and Increases Apoptosis by Generating ROS in Cervical Cancer Cells: in vitro and in silico Study
Authors: Tania Mousumi , Shawon Jakaria , Saif Kazi , Kiefer Rudolf , Khorram Mahdi Safaei , Halim Mohammad A. , Khan Md. Asaduzzaman
Published: September 2018

Background: Cordycepin is a small molecule from medicinal mushroom Cordyceps, which has been reported for anticancer properties.  Objective: In this study, we have focused on the investigation of cordycepin effect on cervical cancer cells with further clarification of possible molecular mechanism.  Method: We have used cell viability and cell counting assay for cytotoxic effect of cordycepin, flow cytometric assay of apoptosis and cell cycle, and quantitative PCR (qPCR) and Western blotting for the determination of target gene expression. Molecular docking and Molecular dynamics simulation were used for in silico analysis of cordycepin affinity to target protein(s).  Results: Treatment of cordycepin controlled SiHa and HeLa cervical cancer cell growth, increased the rate of their apoptosis, and interfered with cell cycle, specifically elongated S-phase. qPCR results indicated that there was a downregulation of cell cycle proteins CDK-2, CYCLIN-A2 and CYCLIN-E1 in mRNA level by cordycepin treatment but no significant change was observed in pro-apoptotic or antiapoptotic proteins. The intracellular reactive oxygen species (ROS) level in cordycepin treated cells was increased significantly, implying that apoptosis might be induced by ROS. Western blot analysis confirmed significant decrease of Cdk-2 and mild decrease of Cyclin-E1 and Cyclin-A2 by cordycepin, which might be responsible for regulating cell cycle. Molecular docking indicated high binding affinity of cordycepin against Cdk-2. Molecular dynamics simulation further confirmed that the docked pose of cordycepin-Cdk-2 complex remained within the binding pocket for 10 ns.  Conclusion: Our study suggests that cordycepin is effective against cervical cancer cells, and regulating cell cycle via cell cycle proteins, especially downregulating Cdk-2, and inducing apoptosis by generating ROS are among the mechanisms of anticancer activities of cordycepin.
c-Myc Inhibitor 10074-G5 Induces Murine and Human Hematopoietic Stem and Progenitor Cell Expansion and HDR Modulator Rad51 Expression
Authors: Aksoz Merve , Albayrak Esra , Aslan Galip Servet , Turan Raife Dilek , Alyazici Lamia Yazgi , Siyah Pınar , Tuysuz Emre Can , Canikyan Serli , Yucel Dogacan , Meric Neslihan , Gulbas Zafer , Sahin Fikrettin , Kocabas Fatih
Published: September 2018

Background:

c-Myc plays a major role in the maintenance of glycolytic metabolism and hematopoietic stem cell (HSC) quiescence.

Objective:

Targeting modulators of HSC quiescence and metabolism could lead to HSC cell cycle entry with concomitant expansion.

Methods and Results:

Here we show that c-Myc inhibitor 10074-G5 treatment leads to 2-fold increase in murine LSKCD34low HSC compartment post 7 days. In addition, c-Myc inhibition increases CD34+ and CD133+ human HSC number. c-Myc inhibition leads to downregulation of glycolytic and cyclindependent kinase inhibitor (CDKI) gene expression ex vivo and in vivo. In addition, c-Myc inhibition upregulates major HDR modulator Rad51 expression in hematopoietic cells. Besides, c-Myc inhibition does not alter proliferation kinetics of endothelial cells, fibroblasts or adipose-derived mesenchymal stem cells, however, it limits bone marrow derived mesenchymal stem cell proliferation. We further demonstrate that a cocktail of c-Myc inhibitor 10074-G5 along with tauroursodeoxycholic acid (TUDCA) and i-NOS inhibitor L-NIL provides a robust HSC maintenance and expansion ex vivo as evident by induction of all stem cell antigens analyzed. Intriguingly, the cocktail of c-Myc inhibitor 10074-G5, TUDCA and L-NIL improves HDR related gene expression.

Conclusion:

These findings provide tools to improve ex vivo HSC maintenance and expansion, autologous HSC transplantation and gene editing through modulation of HSC glycolytic and HDR pathways.
Aminopyridines and Acetyl-DL-leucine: New Therapies in Cerebellar Disorders
Authors: Kalla Roger , Strupp Michael
Published: September 2018

Cerebellar ataxia is a frequent and often disabling syndrome severely impairing motor
functioning and quality of life. Patients suffer from reduced mobility, and restricted autonomy, experiencing
an even lower quality of life than, e.g., stroke survivors. Aminopyridines have been
demonstrated viable for the symptomatic treatment of certain forms of cerebellar ataxia. This article
will give an outline of the present pharmacotherapy of different cerebellar disorders. As a current
key-therapy for the treatment of downbeat nystagmus 4-aminopyridine (4-AP) is suggested for the
treatment of downbeat nystagmus (5–10 mg Twice a day [TID]), a frequent type of persisting nystagmus,
due to a compromise of the vestibulo-cerebellum. Studies with animals have demonstrated,
that a nonselective blockage of voltage-gated potassium channels (mainly Kv1.5) increases Purkinje-
cell (PC) excitability. In episodic ataxia type 2 (EA2), which is frequently caused by mutations
of the PQ-calcium channel, the efficacy of 4-AP (5–10 mg TID) has been shown in a randomized
controlled trial (RCT). 4-AP was well tolerated in the recommended dosages. 4-AP was also effective
in elevating symptoms in cerebellar gait ataxia of different etiologies (2 case series).

A new treatment option for cerebellar disease is the amino-acid acetyl-DL-leucine, which has significantly
improved cerebellar symptoms in three case series. There are on-going randomized controlled
trials for cerebellar ataxia (acetyl-DL-leucine vs placebo; ALCAT), cerebellar gait disorders
(SR-form of 4-AP vs placebo; FACEG) and EA2 (sustained-release/SR-form of 4-AP vs acetazolamide
vs placebo; EAT2TREAT), which will provide new insights into the pharmacological treatment
of cerebellar disorders.
Neuroregeneration in Parkinson’s Disease: From Proteins to Small Molecules
Authors: Sidorova Yulia A. , Volcho Konstantin P. , Salakhutdinov Nariman F.
Published: September 2018

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, the lifetime risk of developing this disease is 1.5%. Motor diagnostic symptoms of PD are caused by degeneration of nigrostriatal dopamine neurons. There is no cure for PD and current therapy is limited to supportive care that partially alleviates disease signs and symptoms. As diagnostic symptoms of PD result from progressive degeneration of dopamine neurons, drugs restoring these neurons may significantly improve treatment of PD.  Method: A literature search was performed using the PubMed, Web of Science and Scopus databases to discuss the progress achieved in the development of neuroregenerative agents for PD. Papers published before early 2018 were taken into account.  Results: Here, we review several groups of potential agents capable of protecting and restoring dopamine neurons in cultures or animal models of PD including neurotrophic factors and small molecular weight compounds.  Conclusion: Despite the promising results of in vitro and in vivo experiments, none of the found agents have yet shown conclusive neurorestorative properties in PD patients. Meanwhile, a few promising biologicals and small molecules have been identified. Their further clinical development can eventually give rise to disease-modifying drugs for PD. Thus, intensive research in the field is justified.
The Biology of β-D-mannuronic acid (M2000) on Human Dendritic Cell Based on MicroRNA-155 and MicroRNA-221
Authors: Tabrizian Nakisa , Fard Nazanin Arjomand , Farazmand Ali , Eftekhari Rahil , Zavareh Farzaneh Tofighi , Mirshafiey Abbas
Published: September 2018

Background: The aim of this study was to evaluate the effect of ß-Dmannuronic
acid (M2000) on related miRNAs to dendritic cells (DCs) differentiation.
DC-based immunosuppressive drugs can suppress the progression of autoimmune
diseases, however, their notable side effects in increasing the risk of infectious diseases
and cancers should be considered. The β-D-mannuronic acid, as a novel non-steroidal
anti-inflammatory agent, has been tested in various experimental models.

Method: The effect of M2000 on expression of miRNA-155 and miRNA-221 was
examined. To investigate how M2000 affects differentiation of human dendritic DCs in a
defined inflammatory environment, human peripheral blood mononuclear cells were
isolated from healthy blood and the monocytes were purified using anti-CD14
microbeads. The so isolated monocytes were subsequently incubated in the presence of
M2000 in two different doses (3 and 6 mMol/well) adding granulocyte-macrophage
colony-stimulating factor (GM-CSF) and interleukin-4 for inducing monocytes to
immature DC and lipopolysaccharide for running DC differentiation. The expression of
miRNA-155 and miRNA-221 were examined with Real Time PCR.

Results: The results demonstrate that M2000 has no significant side effect on expression
of miR-155 and miR-221 in both immature DC and mature DC process in vitro.

Conclusion: Our findings show that β-D-mannuronic acid is a safe agent which has no
adverse effect on regulatory miRNA-155 and miRNA-221 in dendritic cells.
Studying the Gut Microbiome of Latin America and Hispanic/Latino Populations. Insight into Obesity and Diabetes: Systematic Review
Authors: Elena Romero-Ibarguengoitia Maria , Gabriela Garcia-Dolagaray , Arnulfo Gonzalez-Cantu , Enrique Caballero Augusto
Published: September 2018

Background:

People from Latin America (LA) and the Hispanic/Latino community living in
the United States (LUS) exhibit a high prevalence of diabetes (DM) and obesity (OB). The Gut Microbiome
(GM) is capable of altering energy regulation and glucose metabolism, but for the expression of
these diseases a combination of multiple factors such as ethnicity, genetic and nutritional factors are required.
A systematic research was conducted to understand if the prevalence of OB and/or DM has an
interaction with the GM in LA and LUS.

Methods:

Research was conducted in PubMed, Web of Science, Scielo, Embase and Google Scholar
for articles between 1990 and 2017. It was restricted to human studies published in English, Spanish, or
Portuguese that applied genetic techniques to study the GM in LA or LUS and discussed the association
with OB and/or DM.

Results:

Different gut Firmicutes/Bacteroidetes relationships in several populations from LA influenced
by geography, diet and lifestyles interacted with OB. Healthy people from the Mexico and US
border had the same imbalance between Firmicutes and Bacteroidetes found in OB or Type 2 DM.
High levels of Bacteroides and a reduced proportion of Prevotella, Megamonas, and Acidaminococcus
were found in newly diagnosed type 1 DM. Once the patient was treated with insulin, an increase of
Prevotella levels was seen. Inverse Firmicutes/Bacteroidetes relationship was reported before the development
of Type 1 DM.

Conclusion:

An important relation between GM and OB and/or DM exists in LA and LUS. Further
elucidation of pathophysiologic mechanisms is required.
Synthesis and Structural Elucidation of Novel Benzothiazole Derivatives as Anti-tubercular Agents: In-silico Screening for Possible Target Identification
Authors: Venugopala Katharigatta N. , Chandrashekharappa Sandeep , Pillay Melendhran , Bhandary Subhrajyoti , Kandeel Mahmoud , Mahomoodally Fawzi M. , Morsy Mohamed A. , Chopra Deepak , Aldhubiab Bandar E. , Attimarad Mahesh , Alwassil Osama I. , Harsha Sree , Mlisana Koleka , Odhav Bharti
Published: September 2018

Background:

Benzothiazole derivatives are known for anti-TB properties. Based on the
known anti-TB benzothiazole pharmacophore, in the present study, we described the synthesis,
structural elucidation, and anti-tubercular screening of a series of novel benzothiazole (BNTZ) derivatives
(BNTZ 1–7 and BNTZ 8–13).

Objective:

The study aims to carry out the development of benzothiazole based anti-TB compounds.

Methods:

Title compounds are synthesized by microwave method and purified by column chromatography.
Characterization of the compounds is achieved by FT-IR, NMR (1H and 13C), LCMS
and elemental analysis. Screening of test compounds for anti-TB activity is achieved by Resazurin
Microplate Assay (REMA) Plate method.

Results:

It was noted that the BNTZ compound with an isoquinoline nucleus (BNTZ 9) exhibited
remarkable anti-tubercular activity at 8 &µg/mL against both the susceptible strain H37Rv and the
multi-drug resistant tuberculosis strains of Mycobacterium tuberculosis. On the other hand, the
BNTZ compound with a naphthalene nucleus (BNTZ 2) revealed anti-tubercular activity at 6
µg/mL and 11 &µg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis
strains of M. tuberculosis, respectively. One of the selected BNTZ derivatives BNTZ 13
was used for single crystal X-ray studies.

Conclusion:

To identify the appropriate target for potent BNTZ compounds from the series, molecular
modeling studies revealed the multiple strong binding of several BNTZs with mycobacterium
lysine-ɛ-aminotransferase and decaprenyl-phosphoryl-β-D-ribose 2&'-oxidase. The interaction
is derived by forming favorable hydrogen bonds and stacking interactions. This new class of
BNTZ compounds gave promising anti-tubercular actions in the low micromolar range, and can be
further optimized on a structural basis to develop promising, novel, BNTZ pharmacophore-based
anti-tubercular drugs.
Design, Synthesis, and Biological Evaluation of Novel Thiazolyl Substituted Bis-pyrazole Oxime Derivatives with Potent Antitumor Activities by Selectively Inducing Apoptosis and ROS in Cancer Cells
Authors: Xiong Biao , Chen Shi , Zhu Peng , Huang Meiling , Gao Weijie , Zhu Rui , Qian Jianqiang , Peng Yanfu , Zhang Yanan , Dai Hong , Ling Yong
Published: September 2018

Background:

A large number of pyrazole derivatives have different biological activities
such as anticancer, antimicrobial, anti-inflammatory, analgesic and antiepileptic activity.
Among them, pyrazole oximes have attracted much attention due to their potential pharmacological
activities, particularly anticancer activities.

Objective:

Our goal is to synthesize novel thiazolyl substituted bis-pyrazole oxime derivatives
with potent antitumor activities by selectively inducing apoptosis and Reactive Oxygen Species
(ROS) accumulation in cancer cells.

Methods:

Eighteen bis-pyrazole oximes were synthesized by conjugating thiazolyl substituted
pyrazoles with pyrazoxime. The target compounds were characterized by 1HNMR, 13C NMR, and
HRMS, and screened for their antiproliferative activity against four cancer cells in MTT assay.
The most potent compound was examined for its inhibitory effect and ROS accumulation in both
cancer cells HCT116 and normal intestinal epithelial cells CCD841. Finally, the most potent
compound was further evaluated for its apoptotic induction by flow cytometry analysis and immunoblot
analysis of apoptosis-related proteins and DNA damage proteins.

Results:

Most compounds displayed potent antiproliferative activity against four cancer cell lines
in vitro, displaying potencies superior to 5-FU. In particular, the most potent compound 13l selectively
inhibited proliferation of colorectal cancer HCT116 cells but not normal colon CCD841
cells. Furthermore, compound 13l also selectively promoted intracellular ROS accumulation in
HCT116 which was involved in 13l inhibition of cancer cell proliferation and induction of cell
apoptosis. Finally, compound 13l also dose-dependently induced cancer cell apoptosis by regulating
apoptotic and DNA damage related proteins expressions.

Conclusion:

Our synthetic bis-pyrazole oxime derivatives possess potent antitumor activities by
selectively inducing apoptosis and ROS accumulation in cancer cells, which may hold great
promise as therapeutic agents for the treatment of human cancers.
A Novel Simultaneous Estimation of Sofosbuvir and Velpatasvir in Human Plasma by Liquid Chromatography Tandem-Mass Spectrometry after Protein Precipitation Method
Authors: Narenderan S.T. , Babu Basuvan , Gokul T. , Meyyanathan Subramania Nainar
Published: September 2018

Objective:

The aim of the present work is to achieve a novel highly sensitive chromatographic
method for the simultaneous determination of hepatitis C agents, sofosbuvir and velpatasvir
from human plasma using ritonavir as an internal standard.

Methods:

Chromatographic separation was achieved using Hypersil C18 column (50mm x 4.6mm, 3μm)
with an isocratic elution mode using the mobile phase composition 10 mM ammonium formate buffer
(pH 5.0): acetonitrile (20:80 v/v) pumped at a flow rate of 0.5 ml/min. The detection was carried out by
tandem mass spectrometry using Multiple Reaction Monitoring (MRM) positive Electrospray Ionization
(ESI) with proton adducts at m/z 530.10 > 243.10, 883.40 > 114.0 and 721.25 > 197.0.

Results:

The method validated as per USFDA guidelines with respect to linearity, accuracy, and precision
was found to be acceptable over the concentration range of 0.2–2000 ng/ml and 5-2000 ng/ml for
sofosbuvir and velpatasvir respectively and the method was found to be highly sensitive and selective.

Conclusion:

The developed tandem mass spectrometric method is robust and can be applied for the
monitoring of plasma levels of the analyzed drug in preclinical and clinical pharmacokinetic studies.
Tissue Distribution of Active Principles from Alpiniae Oxyphyllae Fructus Extract: An Experimental Study in Rats
Authors: Wen Qi , Li Hai-Long , Mai Shi-Ying , Tan Yin-Feng , Chen Feng
Published: September 2018

Background:

Alpiniae Oxyphyllae Fructus (Yizhi in Chinese) have been widely used as an
herbal medicine for the treatment of diuresis, enuresis and diarrhea in China. Many studies have deciphered
some potential underlying mechanisms for its anti-diarrheal effects. However, tissue distribution
of Yizhi constituents is warranted because pharmacological receptors are frequently located in tissues.
Moreover, it is also interesting to know about the potential correlation between behavior in drug distribution
and the observed pharmacological response. The aim of this study is to investigate tissue distribution
behaviors of Yizhi constituents after oral administration of Yizhi extract to rats, focusing on 10
active principles.

Methods:

Twenty four male Sprague Dawley rats were given orally the Yizhi extract and fourteen tissue
samples were collected after being killed by bleeding from the abdominal aorta under ether anesthesia
at different time-points. The resulting tissues were excised and homogenized. Based on our previous
reports, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to quantify
the target analytes, as well as phase II metabolites, in the various biosamples.

Results:

Almost all the targeted Yizhi active principles and some glucuronidated metabolites were
qualitatively measured in rat stomach, small intestine, large intestine, as well as liver. Nootkatone,
yakuchinone A and tectochrysin were observed in the rat brain. In other rat tissues, these analytes had
lower exposure or could not be detected. Consistently, quantitative analysis revealed that the Yizhi active
principles dominantly distributed into gastrointestinal tissues followed by liver, the overall exposure
levels ranking as follows: stomach > small intestine > large intestine > liver. Tissue concentrationtime
profiles of the test active principles in rat stomach, small intestine, and large intestine were bimodal
with two concentration peaks occurring at 0.5 and 4h after oral administration, respectively. The
exposure levels in rat kidney and bladder were quite low.

Conclusion:

The active principles of Yizhi were specially distributed into gastrointestinal tissues after
oral administration of its ethanol extract to rats. The tissue distribution behaviors partly supported its
anti-diarrheal effects from a pharmacokinetic opinion. This paper will be useful as the starting point for
studying the pharmacological activities of this traditional herb.
Non-Invasive Extraction of Gabapentin for Therapeutic Drug Monitoring by Reverse Iontophoresis: Effect of pH, Ionic Strength, and Polyethylene Glycol 400 in the Receiving Medium
Authors: Giri Tapan Kumar , Chakrabarty Subhasis , Ghosh Bijaya
Published: September 2018

Background:

Monitoring of plasma concentrations is a necessity for narrow therapeutic index
potent drugs. Development of non-invasive methods can save the patients from the trauma of needles
and hence is considered as a research priority.

Introduction:

Gabapentin, an anti-epileptic drug requires therapeutic monitoring because of its narrow
therapeutic index. The objective of the study was to develop a suitable method for the non-invasive
extraction of gabapentin for the same.

Methods:

Transdermal reverse iontophoresis was performed using pig ear skin as a barrier membrane.
Three compartment iontophoretic cells were used for the extraction study. Extractions were carried out
under low intensity electric field (current intensity- 0.5 mA/cm2, electrical field approximately 5 V).
The donor compartment was charged with aqueous gabapentin (10 µg/ml in phosphate buffer of pH
7.4). For studying the effect of receiving vehicle (pH, ionic strength, and enhancer) on the extraction
efficiency of gabapentin, the two receiver chambers were charged with media having varying concentration
of these factors. Drug content was determined by HPLC.

Results:

Compared to other pHs, cumulative extraction of gabapentin at pH 5 was significantly higher
at both anode and cathode (p<0.001). At low ionic strength, extraction of gabapentin increased linearly
with the increase in concentration of ions up to a certain value but at very high ionic strength the pattern
reversed. Similar results were obtained with enhancer (polyethylene glycol 400). Extraction increased
with increase in polyethylene glycol 400 up to 3% and then decreased.

Conclusion:

Extraction flux can be optimized by manipulation of the receiver media.
Preparation and Characterization of Four Major Novel Degradation Products of Pralatrexate Injection and Validation of HPLC-UV Method
Authors: Prabhakara Sastry Regella Venkata Rama , Venkatesan Chidambaram Subramanian , Sastry Bhetanabhotla Sarveswara , Sathiyanarayanan Singaram , Murali Sanapati
Published: September 2018

Background:

Four major degradation products (1-4) of pralatrexate injection were formed
under hydrolytic and light stress conditions. The impurities 1 and 2 were the potential photo degradation
products and the impurities 3 and 4 were the potential hydrolytic degradation products.

Objective:

To prepare and characterize the novel degradation impurities 1, 2, 3 and 4 of pralatrexate
injection using NMR, HR MS and IR techniques; and to develop and validate stability indicating analytical
reverse phase HPLC-UV method for quantitative simultaneous determination of potential
degradation impurities, related substances of pralatrexate and pralatrexate active in pralatrexate liquid
formulation.

Methods:

Gradient HPLC-UV method was developed for the quantification of degradation impurities,
related substances and pralatrexate in pralatrexate injection. The separation was achieved on C18 column
(250 mm X 4.6 mm, 5µm) using a mobile phase composed of sodium dihydrogen phosphate
monohydrate in water (pH 3.0; 0.01M) and methanol. The components were monitored by the UVvisible
detector at 242 nm with a flow rate of 1.0 mL/min.

Results:

The method validation parameters such as accuracy, selectivity, linearity, LOD, LOQ, precision,
ruggedness and robustness were demonstrated successfully for pralatrexate and its degradation
impurities. The stability-indicating capability of the developed HPLC method was demonstrated by
adequate separation of all potential pralatrexate related substances from pralatrexate stressed drug
product samples.

Conclusion:

The developed stability indicating HPLC method was found to be suitable for the simultaneous
quantitative determination of potential degradation impurities and related substances of pralatrexate
and pralatrexate active in pralatrexate liquid formulation.
Synthesis of Spiro-Isoxazolidine Derivatives of Methyl α-Isocostate
Authors: Zaki Mohamed , Oukhrib Abdelouahd , Loubidi Mohammed , El Hakmaoui Ahmed , Hiebel Marie-Aude , Akssira Mohammed , Berteina-Raboin Sabine
Published: September 2018

Background:

In recent decades, natural products are an important source of chemotherapeutics
as more than half of the effective cancer drugs can be traced to natural origins.

Objective:

Moreover, the modification of natural products is one of the most common and fruitful
approaches to obtain novel therapeutic agents in medicinal chemistry.

Method:

Continuing with a research project based on the support of Moroccan plant resources. we
report herein the use of α-isocostic acid extracted in enantiomerically pure form from Dittrichia viscosa
as a convenient starting material for the synthesis of new eudesmane derivatives.

Results:

Novel spiro derivatives with a natural scaffold were prepared. Spiro-isoxazolidine derivatives
were generated on the exocyclic double bond adjacent to the ester α,β-unsaturated function by 1,3-dipolar
cycloaddition of methyl α-isocostate 1 derived from sesquiterpenic isocostic acid, with nitrones 2.

Conclusion:

This procedure allowed us to generate enantiomerically pure spiro compounds in one
diastereoisomer form with a limited number of steps. These compounds were fully characterized by
spectroscopic methods.
Mussel-inspired Polymers: Recent Trends
Authors: Moulay Saad
Published: September 2018

Background:

A number of natural and synthetic polymers were subjected to functionalization with catechol-containing modifiers, mimicking the chemical structure of Mytilus foot proteins of marine mussel, and affording materials with specific properties that are related to their adhesion ability.

Objective:

This review highlights the various applications of mussel-inspired polymers, worked out within the last five years, in separation processes, hydrogels making, and biomedicals.

Method and Results:

Marine mussel-inspired polymers were fashioned either by direct synthesis from catechol-containing monomers or chemical modification of existing polymers. Mostly, the catechol units attached to the polymer matrixes are 3,4-dihydroxyphenyl-L-alanine and dopamine.

Conclusion:

Michael addition and/or Schiff base reaction between catechol-containing molecules units and polyamines afford efficient separative membranes. Hydrogel-making from catecholcontaining polymers can be easily realized via oxidation with oxidants and coordination with transition metal ions.
Assessment of spatial distributions of some climate indices in Iraq
Authors: Al-Zamili Hanan S. , Al-Lami Alaa M.
Published: September 2018

Aridity is one of the main factors which distinguish the climate of a region and has significant influence on human activities. This study investigated the spatial distribution of the aridity indices to determine the climate conditions in Iraq over the period (1981-2015), depending on the data of the air temperature and rainfall which obtained from 28 stations distributed through Iraq. The used aridity indices are: Lang, Erinc, Emberger, UNEP, De Martonne and Thornthwaite. The spatial distribution was determined using inverse distance weighting (IDW) interpolated method. The results of aridity indices analysis shows that the hyper-arid, arid, and semi-arid categories are predominant with almost (91%) to (100%) of the country’s area. Dry sub-humid, moist sub-humid and humid categories occupies less than (10%) with most of indices at stations of (Arbil, Sulaymaniyah, and Salahaddin). To evaluate the seasonal spatial distributions, De Martonne was utilized. During winter, the climate types ranged from semi-arid to very-humid, while at spring season from arid to humid. Autumn season dominated by arid at (97%) of study area. The summer season was the driest compared with the other seasons. The change point for aridity indices was detected by using the cumulative sum charts (CUSUMs), it is found for the most stations in (1997). Consequently, the spatial distribution for the aridity indices were analyzed through two periods (1981-1997 and 1998-2015), this analysis showed that the arid and hyper-arid areas were increased in the second period compared with the first period with obvious extension toward the north of Iraq.
A study of some cloud microphysical parameters over Iraq using satellite data
Authors: Fadhil Murtadha A. , Al-Jumaily Kais J.
Published: September 2018

Studying clouds is a top priority among many atmospheric scientists because clouds are one of the greatest unknown factors in predicting changes in the Earth’s climate. Clouds play an important role in maintaining the energy balance because they can reflect, absorb, and radiate energy. The aim of this research is to investigate the properties of clouds over Iraq using data acquired by the Moderate Resolution Imaging Spectroradiometer (MODIS)on board Aqua Satellite for water and ice clouds. The results showed that daily mean cloud top pressure patterns during spring months are higher than other months and cloud top temperature patterns reached their highest values during summer months. The results also indicated that the ice cloud effective particle radius is relatively large during summer while cloud optical thickness assume its largest values in winter months. It was found that the highest values of precipitation rate over Iraq occurred during March to mid-April. Correlation aanalysis between optical thickness and liquid water path over Iraq that these two parameters are positively correlated and the correlation for water cloud was better that that for ice clouds. Case studies of heavy precipitation events over Iraq showed that the maximum values of the most cloud properties variables were located ahead of the storm center.
YILDIRIM DARBELERİNİN SİLAHLI İNSANSIZ HAVA ARAÇLARI (SİHA) ÜZERİNDEKİ DOLAYLI ETKİLERİNİN ANALİZİ
Authors: NİŞANCI Muhammet Hilmi , TEŞNELİ Ahmet Yahya , TEŞNELİ Nigar Berna
Published: September 2018

Yıldırımın elektronik sistemler üzerindeki dolaylı etkilerini ortadan
kaldırmak ya da en aza indirgemek için başta hava olmak üzere kara ve deniz
taşıtlarının tasarımlarında yıldırım darbe riskleri göz önüne alınmaktadır. Bu
çalışmada yıldırım darbelerinin askeri alanda kullanımları yaygınlaşan silahlı
insansız hava araçları (SİHA) üzerindeki dolaylı etkileri incelenmiştir. Tipik
bir SİHA üç boyutlu olarak modellenmiş ve bilgisayar tabanlı benzetimler ile nümerik
olarak analiz edilmiştir. Yıldırım darbesi SİHA’da bulunan farklı yakalama çubuklarına
ayrı ayrı uygulanarak oluşturduğu geri dönüş darbe akımı elde edilmiştir. Geri
dönüş darbe akımının sebep olduğu elektromanyetik (EM) alan şiddeti ve yüzey
akım dağılımları bulunarak elektriksel sürekliliğe sahip olması gereken
yıldırım akım yolları belirlenmiştir. Ayrıca PEC, Alüminyum ve Karbon fiber
takviyeli kompozit ile kaplanmış SİHA’lar için geri dönüş darbe akımları
karşılaştırılmıştır.
A 12-Week Electronic Mentoring Employment Preparation Intervention for Youth With Physical Disabilities: Pilot Feasibility Randomized Controlled Trial (Preprint)
Authors: Lindsay Sally , Cagliostro Elaine , Leck Joanne , Stinson Jennifer
Published: September 2018

BACKGROUND

Youth with disabilities are at high risk of unemployment compared with youth without disabilities. They often encounter challenges in accessing vocational programs that meet their needs. One promising approach that could help to address barriers that youth encounter while also enhancing social support is through electronic mentoring (e-mentoring). Although there is an increase in e-mentoring for youth with disabilities, little is known about its impact for youth with physical disabilities.

OBJECTIVE

This study aimed to assess the acceptability and initial impact of a Web-based peer electronic mentor employment intervention for youth with physical disabilities.

METHODS

The Empowering Youth Towards Employment intervention was evaluated using a pilot randomized controlled trial (RCT). Youth, aged 15-21 years, with physical disabilities were randomly assigned to an intervention (ie, mentored) or control (ie, not mentored) group. Trained mentors (ie, near peers) with a physical disability led the online discussion forums and provided peer support and resources for 12 modules (1 topic per week over 12 weeks). Primary outcomes focused on self-determination, career maturity, and social support. We also explored program adherence and dosage, participant satisfaction, and areas for improvement.

RESULTS

A total of 13 youth (mean age 17.3 years, SD 1.88; 54%, 7/13 female) completed the RCT. In the intervention group (n=9), 56% (5/9) of the youth were females, and in the control group (n=4), 50% (2/4) of the youth were female. Participants reported satisfaction with the program and that it was feasible and acceptable. Participants’ mean engagement level with the program was 5.22 (SD 2.48) for the intervention group and 5.40 (SD 4.56) for controls. Participants in the intervention group demonstrated significant improvements in self-determination (t12=2.49; P<.04) compared with the control group. No adverse events were reported.

CONCLUSIONS

The Empowering Youth Towards Employment is a promising intervention that enhances self-determination among youth with physical disabilities.

CLINICALTRIAL

ClinicalTrials.gov NCT02522507; https://clinicaltrials.gov/ct2/show/NCT02522507 (Archived by WebCite at http://www.webcitation.org/6uD58Pvjc)
A Social Media Website (Supporting Our Valued Adolescents) to Support Treatment Uptake for Adolescents With Depression and/or Anxiety and Their Parents: Protocol for a Pilot Randomized Controlled Trial (Preprint)
Authors: Radovic Ana , Li Yaming , Landsittel Douglas , Stein Bradley D , Miller Elizabeth
Published: September 2018

BACKGROUND

Few adolescents who experience depression or anxiety connect to mental health treatment. Supporting Our Valued Adolescents (SOVA) is a stakeholder-informed technology intervention that consists of 2 blog-format websites—one for adolescents and another for parents. SOVA is designed to intervene on targets, which may increase the mental health treatment uptake when adolescents with depression or anxiety are identified in primary care settings.

OBJECTIVE

This study aims to describe the protocol for a pilot randomized controlled trial designed to refine recruitment and retention strategies, document intervention fidelity and implementation outcomes, and assess changes in health beliefs and knowledge, emotional or informational support, and parent-adolescent communication quality in adolescents and their parents.

METHODS

Adolescents identified with symptoms of depression or anxiety, for which a health care provider recommends treatment, and their parents will be recruited from clinics where adolescents are seen for primary care. Adolescent-parent dyads will be randomized at 1:1 to both receive the SOVA websites and enhanced usual care or enhanced usual care alone. Baseline measures and 6-week and 3-month outcomes will be collected by Web-based self-report surveys and electronic health record review. The main pilot outcome is the 6-week study retention rate. Analyses will also assess changes in health beliefs and knowledge, emotional support, and parent-adolescent communication in both adolescents and their parents.

RESULTS

The project was funded in 2017. Recruitment commenced in April 2018 and enrollment is ongoing, with completion anticipated at the end of 2019 with subsequent plans for data analysis and publication submission in early 2020.

CONCLUSIONS

The findings of this research will inform the design of a multisite hybrid effectiveness-implementation randomized controlled trial examining the effectiveness and optimal implementation strategies for using SOVA in community primary care settings.

CLINICALTRIAL

ClinicalTrials.gov NCT03318666; https://clinicaltrials.gov/ct2/show/NCT03318666

INTERNATIONAL REGISTERED REPOR

PRR1-10.2196/12117
Use of Free-Living Step Count Monitoring for Heart Failure Functional Classification: Validation Study (Preprint)
Authors: Baril Jonathan-F. , Bromberg Simon , Moayedi Yasbanoo , Taati Babak , Manlhiot Cedric , Ross Heather Joan , Cafazzo Joseph
Published: September 2018

BACKGROUND

The New York Heart Association (NYHA) functional classification system has poor inter-rater reproducibility. A previously published pilot study showed a statistically significant difference between the daily step counts of heart failure (with reduced ejection fraction) patients classified as NYHA functional class II and III as measured by wrist-worn activity monitors. However, the study’s small sample size severely limits scientific confidence in the generalizability of this finding to a larger heart failure (HF) population.

OBJECTIVE

This study aimed to validate the pilot study on a larger sample of patients with HF with reduced ejection fraction (HFrEF) and attempt to characterize the step count distribution to gain insight into a more objective method of assessing NYHA functional class.

METHODS

We repeated the analysis performed during the pilot study on an independently recorded dataset comprising a total of 50 patients with HFrEF (35 NYHA II and 15 NYHA III) patients. Participants were monitored for step count with a Fitbit Flex for a period of 2 weeks in a free-living environment.

RESULTS

Comparing group medians, patients exhibiting NYHA class III symptoms had significantly lower recorded 2-week mean daily total step count (3541 vs 5729 [steps], P=.04), lower 2-week maximum daily total step count (10,792 vs 5904 [steps], P=.03), lower 2-week recorded mean daily mean step count (4.0 vs 2.5 [steps/minute], P=.04,), and lower 2-week mean and 2-week maximum daily per minute step count maximums (88.1 vs 96.1 and 111.0 vs 123.0 [steps/minute]; P=.02 and .004, respectively).

CONCLUSIONS

Patients with NYHA II and III symptoms differed significantly by various aggregate measures of free-living step count including the (1) mean and (2) maximum daily total step count as well as by the (3) mean of daily mean step count and by the (4) mean and (5) maximum of the daily per minute step count maximum. These findings affirm that the degree of exercise intolerance of NYHA II and III patients as a group is quantifiable in a replicable manner. This is a novel and promising finding that suggests the existence of a possible, completely objective measure of assessing HF functional class, something which would be a great boon in the continuing quest to improve patient outcomes for this burdensome and costly disease.
Reading Level and Suitability of Congestive Heart Failure (CHF) Education in a Mobile App (CHF Info App): Descriptive Design Study (Preprint)
Authors: Athilingam Ponrathi , Jenkins Bradlee , Redding Barbara A
Published: September 2018

BACKGROUND

Education at the time of diagnosis or at discharge after an index illness is a vital component of improving outcomes in congestive heart failure (CHF). About 90 million Americans have limited health literacy and have a readability level at or below a 5th-grade level, which could affect their understanding of education provided at the time of diagnosis or discharge from hospital.

OBJECTIVE

The aim of this paper was to assess the suitability and readability level of a mobile phone app, the CHF Info App.

METHODS

A descriptive design was used to assess the reading level and suitability of patient educational materials included in the CHF Info App. The suitability assessment of patient educational materials included in the CHF Info App was independently assessed by two of the authors using the 26-item Suitability Assessment of Materials (SAM) tool. The reading grade level for each of the 10 CHF educational modules included in the CHF Info App was assessed using the comprehensive online Text Readability Consensus Calculator based on the seven most-common readability formulas: the Flesch Reading Ease Formula, the Gunning Fog Index, the Flesch-Kincaid Grade Level Formula, the Coleman-Liau Index, the Simplified Measure of Gobbledygook Index, the Automated Readability Index, and the Linsear Write Formula. The reading level included the text-scale score, the ease-of-reading score, and the corresponding grade level.

RESULTS

The educational materials included in the CHF Info App ranged from a 5th-grade to an 8th-grade reading level, with a mean of a 6th-grade level, which is recommended by the American Medical Association. The SAM tool result demonstrated adequate-to-superior levels in all four components assessed, including content, appearance, visuals, and layout and design, with a total score of 77%, indicating superior suitability.

CONCLUSIONS

The authors conclude that the CHF Info App will be suitable and meet the recommended health literacy level for American adult learners. Further testing of the CHF Info App in a longitudinal study is warranted to determine improvement in CHF knowledge.