bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac Autonomic Dysfunction in Patients With Infantile Spasm and the Effect of Adrenocorticotropic Hormone Treatment
Authors: Gencpinar Pinar , Kocabas Abdullah , Duman Özgür , Dündar Nihal Olgaç , Haspolat Senay , Kardelen Fırat
Published: May 2015

Infantile spasm is an age-dependent epileptic-encephalopathy syndrome. Cardiac autonomic function is frequently altered in epilepsy. In this study, we examined heart rate variability in patients with infantile spasm before and after treatment. Nineteen patients with infantile spasm and 13 healthy comparisons were enrolled in the study. Cardiac rhythm was recorded with a Holter device for 24 hours before adrenocorticotropic hormone (ACTH) (Synacthen depot) and B6 vitamin administration and 1 month after treatment. Heart rate variability analysis found lower heart rate variability parameters in patients with infantile spasm at the onset of the syndrome, prior to treatment with ACTH. The time domain parameters of heart rate variability values showed a statistically significant increase following ACTH treatment. Our data suggest that patients with infantile spasm exhibit lower heart rate variability parameters, and the treatment of spasms with ACTH and B6 together diminished the autonomic dysfunction in our cohort.
Exploring the Experiences of Abuse of College Students With Disabilities
Authors: Findley Patricia A. , Plummer Sara-Beth , McMahon Sarah
Published: May 2015

Intimate partner violence and sexual assault of college students has garnered increased attention and publicity. Current studies have focused primarily on general campus populations with little to no attention to students with disabilities. While studies suggest the rate of abuse of individuals with disabilities is similar or higher compared to the general population, there remains a lack of focus on this issue. Individuals with disabilities are at particularly high risk for abuse, both through typical forms of violence (physical, sexual, emotional, and economic) and those that target one’s disability. In an effort highlight and explore this issue further, an exploratory study was conducted to learn the rates of abuse among university students who have identified as having a disability. This is a cross-sectional survey of 101 students of students with disabilities from a large northeastern public university. Experiences of abuse were measured through the use of the Abuse Assessment Screen- Disability (AAS-D) scale. Students were asked about experiences of physical, sexual, psychological, and disability related abuse within the last year and help seeking behaviors when an incident of abuse occurred. We found that 22 % of participants reported some form of abuse over the last and nearly 62% (n= 63) had experienced some form of physical or sexual abuse before the age of 17. Those who were abused in the past year, 40% reported little or no knowledge of abuse-related resources and only 27% reported the incident. Authors discuss implications results have for programs and policies on campus for individuals with disabilities.
Examining the Intersection of Bullying and Physical Relationship Violence Among New York City High School Students
Authors: Peters Zachary J. , Hatzenbuehler Mark L. , Davidson Leslie L.
Published: May 2015

Research is just beginning to explore the intersection of bullying and relationship violence. The relationship between these forms of youth aggression has yet to be examined in diverse urban centers, including New York City (NYC). This study seeks to identify intersections of joint victimization from bullying and electronic bullying (e-bullying) with physical relationship violence (pRV). This study examines data from the NYC Youth Risk Behavior Survey (YRBS), a representative sample of NYC public high school students, to assess the concurrent victimization from bullying at school and e-bullying with pRV, operationalized as physical violence by a dating partner in the past 12 months. Students who reported being bullied at school and e-bullied had increased odds (bullied: OR = 2.5, 95% CI [2.1, 2.9]; e-bullied: OR = 3.0, 95% CI [2.6, 3.5]) of also being victimized by pRV compared with those who did not report being bullied or e-bullied. In logistic regression models, being bullied at school and being e-bullied remained significant predictors of students’ odds of reporting pRV (bullied: AOR = 2.6, 95% CI [2.2, 3.1]; e-bullied: AOR = 3.0, 95% CI [2.5, 3.6]) while controlling for race, gender, sexual orientation, and age. This research is the first to assess the intersection of victimization from bullying and e-bullying with pRV in a large, diverse, random sample of urban high school students. In this sample, students who report being bullied or e-bullied are more likely also to report pRV than students who have not been bullied or e-bullied. This research has potential implications for educators, adolescent health and social service providers, and policy makers to tailor programs and enact policies that jointly address bullying and pRV. Future studies are needed to longitudinally assess both victimization from and perpetration of bullying and pRV.
The effect of perforations on the stress wave propagation characteristics of multilayered materials
Authors: Tasdemirci Alper , Kara Ali
Published: May 2015

The effect of perforated interlayers on the stress wave transmission of multilayered materials was investigated both experimentally and numerically using the Split Hopkinson pressure bar (SHPB) testing. The multilayer combinations consisted of a ceramic face plate and a glass/epoxy backing plate with a laterally constrained low modulus solid or perforated rubber and Teflon interlayer. The perforations on rubber interlayer delayed the stress rise time and reduced the magnitude of the transmitted stress wave at low strains, while the perforations allowed the passage of relatively high transmitted stresses at large strains similar to the solid rubber interlayer. It was concluded that the effect of perforations were somewhat less pronounced in Teflon interlayer configuration, arising from its relatively low Poisson’s ratio. It was finally shown that SHPB testing accompanied with the numerical simulations can be used to analyze the effect of compliant interlayer insertion in the multilayered structures.
Experimental and numerical investigation of the effect of interlayer on the damage formation in a ceramic/composite armor at a low projectile velocity
Authors: Tasdemirci A , Tunusoglu G
Published: May 2015

The damage formation in a multilayered armor system without and with an interlayer (rubber, Teflon, and aluminum foam) between the front face ceramic layer and the composite backing plate were investigated experimentally and numerically. The projectile impact tests were performed in a low-velocity projectile impact test system and the numerical studies were implemented using the nonlinear finite element code LS-DYNA. The results of numerical simulations showed that the stress wave transmission to the composite backing plate decreased significantly in Teflon and foam interlayer armor configurations. Similar to without interlayer configuration, the rubber interlayer configuration led to the passage of relatively high stress waves to the composite backing plate. This was mainly attributed to the increased rubber interlayer impedance during the impact event. The numerical results of reduced stress wave transmission to the backing plate and the increased damage formation in the ceramic front face layer with the use of Teflon and foam interlayer was further confirmed experimentally.
Characterization of Complementary and Alternative Medicine-Related Consultations in an Academic Drug Information Service
Authors: Gregory Philip J. , Jalloh Mohamed A. , Abe Andrew M. , Hu James , Hein Darren J.
Published: May 2015

Purpose:

To characterize requests received through an academic drug information consultation service related to complementary and alternative medicines.

Methods:

A retrospective review and descriptive analysis of drug information consultations was conducted.

Results:

A total of 195 consultations related to complementary and alternative medicine were evaluated. All consultation requests involved questions about dietary supplements. The most common request types were related to safety and tolerability (39%), effectiveness (38%), and therapeutic use (34%). Sixty-eight percent of the requests were from pharmacists. The most frequent consultation requests from pharmacists were questions related to drug interactions (37%), therapeutic use (37%), or stability/compatibility/storage (34%). Nearly 60% of complementary and alternative medicine-related consultation requests were able to be completely addressed using available resources. Among review sources, Natural Medicines Comprehensive Database, Clinical Pharmacology, Micromedex, and Pharmacist’s Letter were the most common resources used to address consultations.

Conclusion:

Utilization of a drug information service may be a viable option for health care professionals to help answer a complementary and alternative medicine-related question. Additionally, pharmacists and other health care professionals may consider acquiring resources identified to consistently answering these questions.
Depressive Symptoms and Disability Risk Among Older White and Latino Adults by Nativity Status
Authors: Bowen Mary Elizabeth , Ruch Alexandra
Published: May 2015

Objective: To examine how the relationship between depressive symptoms and disability may vary by nativity status in later life. Method: This nationally representative prospective study of community-dwelling adults age 51 years and older in the Health and Retirement Study (1998-2010) used hierarchical linear modeling to examine how depressive symptoms (Center for Epidemiological Symptoms of Depression) and disability (instrumental activities of daily living [IADL]; activities of daily living [ADL]) vary by nativity status (U.S.- vs. foreign-born), accounting for changes in social support, health behaviors, and health conditions. Results: Depressive symptoms were associated with increased IADL and ADL disability among Latinos compared with Whites; foreign-born Latinos had lower than expected depressive symptom–related IADL and ADL (0.82; p ≤ .001) disability. Discussion: Given that U.S.-born Latinos had similar or poorer depressive symptom–related disability outcomes than Whites, interventions focused on early detection and treatment of depressive symptoms for this group are warranted and may improve disablement outcomes.
Long-Term BMI Trajectories and Health in Older Adults
Authors: Zajacova Anna , Huzurbazar Snehalata , Greenwood Mark , Nguyen Huong
Published: May 2015

Objective: This project contributes to the emerging research that aims to identify distinct body mass index (BMI) trajectory types in the population. We identify clusters of long-term BMI curves among older adults and determine how the clusters differ with respect to initial health. Method: Health and Retirement Study cohort ( N = 9,893) with BMI information collected in up to 10 waves (1992-2010) is analyzed using a powerful cutting-edge approach: hierarchical clustering of BMI functions estimated via the Principal Analysis by Conditional Expectations (PACE) algorithm. Results: Three BMI trajectory clusters emerged for each gender: stable, gaining, and losing. The initial health of the gaining and stable groups in both genders was comparable; the losing cluster experienced significantly poorer health at baseline. Discussion: BMI trajectories among older adults cluster into distinct types in both genders, and the clusters vary substantially in initial health. Weight loss but not gain is associated with poor initial health in this age group.
Trajectories of Aging Long-Term Mexican American Heroin Injectors
Authors: Cepeda Alice , Nowotny Kathryn M. , Valdez Avelardo
Published: May 2015

Objective: To examine the applicability of the “maturing out” theory to a sample of aging Mexican American men who are long-term heroin injectors. Method: Ethnographic data were collected as part of a cross-sectional study of aging Mexican American heroin users in Houston with 20 current heroin users. Results: Findings indicate that dysfunctions that emerge in the heroin lifestyle lead not to cessation but rather to “maturing in,” a specific process of social readjustment that returns the heroin user to a stable maintenance pattern of use instead of a recovery phase. This process of paradoxical maturing out can be attributed to the unconditional social support provided to the heroin user by family, peers, and the tecato subculture embedded in Mexican American communities. Discussion: Results highlight the implications for the intersection of heroin-related conditions, natural age-related impairments, and cognitive functioning that make this population increasingly susceptible to adverse health consequences.
Depressed Mood in Middle-Aged and Older Adults in Europe and the United States
Authors: Mojtabai Ramin
Published: May 2015

Objective: To compare self-ratings of depressed mood in middle-aged and older adults in the United States and nine European countries after adjustment by anchoring vignettes. Method: Samples were drawn from three large surveys of middle-aged and older adults: the U.S. Health and Retirement Study, the English Longitudinal Study of Aging (ELSA), and the Survey of Health, Ageing and Retirement in Europe. Self-ratings of depressed mood were compared across countries before and after adjustment by anchoring vignettes depicting cases with different levels of depressed mood. Results: Compared with Europeans as a group, Americans rated both the cases presented in the vignettes and themselves as more depressed. However, after adjustment by vignette ratings, Americans appeared to be less depressed than their counterparts in all but two European countries. Discussion: Cultural differences in mental health norms reflected in vignette rating may partly explain between-country differences in self-reported depressive symptoms and perhaps other psychiatric complaints.
Analysing policy failure as an argumentative strategy in the policymaking process: A pragmatist perspective
Authors: Zittoun Philippe
Published: May 2015

The purpose of this article is to focus on policy failure as a concept that stakeholders use. Our article will first address how researchers define failure to explore some different dimensions of the concept. Second, we will highlight the political and subjective dimension relative to how policymakers use the concept of failure as critical judgement. Last, we will show that while failure is a critical judgement, it should not be overlooked by researchers seeking to understand the policy process. In this article, we argue that stakeholders’ production and use of critical judgement play a fundamental role in policymaking.
Attribute and technology value mapping for conceptual product design phase
Authors: Georgiou Aris , Haritos George , Fowler Moyra , Imani Yasmin
Published: May 2015

The main focus of this paper is how the concept design phase of the product development process can be improved by using an objective data-driven approach in selecting a final concept design to progress further. A quantitative new test-bed ‘Product Optimisation Value Engineering’ (PROVEN) is presented to critically assess new and evolving powertrain technologies at the concept design phase. The new test-bed has the ability to define a technology value map to assess multiple technical options as a function of its attributes, whose precise values can be determined at a given cost. A mathematical model that incorporates a highly adaptable, data-driven and multi-attribute value approach to product specification and conceptual design is developed, novel to the concept design process. This creates a substantially optimised product offering to the market, reducing overall development costs while achieving customer satisfaction.
Clustering techniques applied to a high-speed train pantograph–catenary subsystem for electric arc detection and classification
Authors: Barmada Sami , Tucci Mauro , Menci Mauro , Romano Francesco
Published: May 2015

Assessment of the current collection properties of a pantograph–catenary system mounted on a train is of great importance. Excessive electric arcing can lead to wear of the system components, and, at the same time, it can be an index of wear status. In this paper we investigate the possibility of detecting arcing events in the pantograph–catenary collection system without the need of additional equipment installed on-board the train. Data that is currently measured and recorded for modern high-speed trains (i.e. voltage and current) are analysed in order to detect and quantify electric arcs and shed light on the current collection quality of the pantograph–catenary system. This work was performed in cooperation with Trenitalia s.p.a. who provided the data it collects on-board high-speed trains in regular passenger service.
State-led versus community-initiated: stormwater drainage and informal settlement intervention in Johannesburg, South Africa
Authors: Adegun Olumuyiwa Bayode
Published: May 2015

In two informal settlements in Johannesburg, South Africa, stormwater drainage interventions were investigated and compared. In the case of Elias Motsoaledi settlement, the intervention was state-led; in Slovo Park settlement it involved community-based initiatives. Both settlements are vulnerable to runoff-related disturbances. State-led stormwater management interventions in informal settlements are embedded in a context that can create various concerns and contradictions, participatory challenges, and political influence. Community-initiated approaches can also have limitations and coping strategies can be minimally effective. The state’s central role is clear from both cases and it highlights the need for integration between the state-led and communitarian approaches towards co-producing meaningful drainage and infrastructural intervention in informal settlements.
Targets of Amphotericin B Methyl Ester (AME) in the Inhibition of Infection of Different Cell Lines by HIV-1
Authors: Pontani D. , Plescia O. J. , Schaffner C. P. , Sun D. , Shahied S. I. , Sarin P. S.
Published: May 2015

The effect of amphotericin B methyl ester (AME) on human immunodeficiency virus (HIV-1) was examined in vitro in cultures of H9, Molt-3 and human peripheral blood lymphocytes acutely infected with HIV. AME inactivates HIV-1 at non-cytotoxic concentrations ranging from 10–100 μg ml−1, and protects pretreated target cells from the cytopathic effects of the virus. AME inhibits the cell to cell spread of virus, as shown by the blocking of syncytia formation in Molt-3 cells, and the reduction in the level of virus expression in cultured peripheral blood leukocytes from an AIDS patient. These results suggest AME may be an effective chemotherapeutic agent in the treatment of AIDS patients, and, because of its unique mode of action may act cooperatively with other AIDS chemotherapeutics.
A Therapeutic Panorama of the Spongiform Encephalopathies
Authors: Brown P.
Published: May 2015

The spongiform encephalopathies are a group of uniformly fatal, transmissible amyloidoses of humans and animals, for which the causative agents have not yet been precisely defined; in some respects they resemble viruses, but in other respects appear to be replicating host polypeptides. A vast array of anti-infective and other drugs has been studied in animal models, among which a few membrane-active compounds (heteropolyanions and amphotericin B) consistently prolong the course of infection, and occasionally even prevent the illness. However, because no form of therapy has any effect when given after the disease becomes clinically manifest, and because there is no laboratory test to detect preclinical infection, therapeutic efforts in humans have been predictably unsuccessful. If infection and disease turn out to depend upon the pathological accumulation of an amyloidogenic host protein, the prospects for future therapy may include genetic engineering and perhaps even the ‘poisoning’ of protein crystal growth.
Synthesis and anti-HIV Activity of Some Novel Phosphorodiamidate Derivatives of 3′-azido-3′-deoxythymidine (AZT)
Authors: Jones B. C. N. M. , McGuigan C. , O'Connor T. J. , Jeffries D. J. , Kinchington D.
Published: May 2015

The reaction of 3′-azido-3′-deoxythymidine (AZT) with phosphoryl chloride followed by amino acid methyl esters gave novel diamidate derivatives of AZT 5′-monophosphate (AZTMP). It was hoped that the 5′-phosphorodiamidates might act as membrane-soluble prodrugs of the bio-active free nucleotides of AZT. Five different amino acids were employed, covering a range of structures and polarities. The reaction was also conducted with propylamine, and with diethylamine. The derivatives were tested for their inhibitory effect on human immunodeficiency virus type 1 (HIV-1) proliferation in a human lymphoblastoid cell line. The amino acid derivatives were potent inhibitors of viral proliferation, small changes in structure leading to marked changes in activity.
Trial of Antisense RNA Inhibition of HIV Replication and Gene Expression
Authors: Shimada T. , Fujii H. , Maier B. , Hayashi S. , Mitsuya H. , Broder S. , Nienhuis A. W.
Published: May 2015

We examined the feasibility of antisense RNA inhibition of human immunodeficiency virus (HIV) replication. In the first experiment, we established CD4+ T-cell lines constitutively expressing various antisense HIV sequences using the retrovirus-mediated gene transfer technique. These cell lines were tested for their ability to withstand HIV de novo infection. In this challenge assay, however, we could not detect any significant difference in the survival rate between these genetically engineered cell lines and control T cells. In the second approach, the effects of antisense sequences on Tat expression were studied by monitoring the activities of reporter enzymes. A functional Tat expression vector and the antisense sequence expression vector were co-introduced into HeLa cells stably transfected with either the HIV-long terminal repeat (LTR) directed chloramphenicol acetyltransferase (CAT) or luciferase. Although the concentration of the antisense RNA was at least 10-fold higher than that of the sense Tat mRNA in cells, these antisense sequences could not inhibit transactivation of HIV-LTR. Regulation of HIV gene expression has proven to be very complicated and Tat transactivation of the HIV-LTR is extraordinarily strong. Consequently, it may be difficult to block HIV replication by the antisense strategy.
Anti-HIV-1 Activity of CD4 Synthetic Oligopeptides Representative of the Putative gp120 Binding Site
Authors: Cereda P. M. , Palù G. , Rassu M. , Toni M. , Malwood W. , Dettin M. , di Bello C.
Published: May 2015

Two CD4 oligopeptides, corresponding to residues (37–53) and (37–55) of the V1 domain of CD4, which recent structural studies propose as the most likely binding site of HIV-1 gp120, have been chemically synthesized by solid-phase techniques, modified by the addition of two side-chain protected cysteines at both termini and purified by HPLC. Their ability to inhibit the infectivity of human immunodeficiency virus type 1 (HIV-1) (HTLV-IIIB, RF and GB8 strains) in different cell lines was monitored by the production of progeny virus, p24 and reverse transcriptase activity in the culture supernatants and by electron microscopy. The results indicated that the peptides inhibited HIV-1 infectivity in a dose-dependent fashion without any detectable cytotoxicity.
Suppression of HIV-1 Replication by a 4-H-Quinolizine Derivative
Authors: Ohnota H. , Ushijima H. , Morikawa S. , Momose D. , Kurashina Y. , Kitamura T.
Published: May 2015

A novel derivative of 4-H-quinolizine, 3-cyano-1-ethoxycarbonyl-4-imino-2-isopropyl-4-H-quinolizine (KAV-397), was discovered to inhibit replication of human immunodeficiency virus type 1 (HIV-1) in T-lymphocyte cell lines. HIV-infected T cells proliferated at the same growth rate as uninfected cells for at least 8 days when the cells were co-cultivated with KAV-397, while infected control cells died in 3 or 4 days. This compound inhibited reverse transcriptase (RT) activity of HIV-1 but did not compete with either deoxythymidine triphosphate substrates nor template-primers. It had no or little effect on RT activities of HIV-2, avian leukosis virus (ALV) and murine leukaemia virus (MuLV). Regarding eukaryotic DNA-dependent DNA polymerases, it significantly suppressed chicken DNA polymerase α and slightly suppressed γ but not murine DNA polymerase β.
1-(Ethoxymethyl)-6-(Phenylselenenyl)Pyrimidines with Activity against Human Immunodeficiency Virus Types 1 and 2
Authors: Goudgaon N. M. , McMillan A. , Schinazi R. F.
Published: May 2015

The reaction of chloromethyl ethyl ether with bis(trimethylsilyl)uracil derivatives yield 1-(ethoxymethyl)pyrimidines 1a–d in good yield. Lithiation of 1a–d with lithium diisopropylamide at −78°C, followed by reaction with diphenyl diselenide as an electrophile, gave 1-(ethoxymethyl)-6-(phenylselenenyl)ura-cils 2a–d in 70–80% yield. The 6-phenylselenenyl acyclic pyrimidines 2b and 2d exhibited selective in vitro activity against HIV-1 and HIV-2 in primary human lymphocytes. The most potent compound was 1-(ethoxymethyl)-6-(phenylselenenyl)-5-ethyluracil 2d with a median effective concentration of 17 nM in primary human lymphocytes and no discernable cytotoxicity in these cells or rapidly dividing CEM and Vero cells. Well characterized AZT-resistant virus was modestly (3 to 12-fold increase) cross-resistant to compounds 2b and 2d.
Naturally Occurring Pyrrolizidines: Inhibition of α-Glucosidase 1 and Anti-HIV Activity of One Stereoisomer
Authors: Taylor D. L. , Nash R. , Fellows L. E. , Kang M. S. , Tyms A. S.
Published: May 2015

Alexine, a naturally occurring pyrrolizidine alkaloid, isolated from Alexa leiopetala, and four stereoisomers, isolated from Castanospermum australe, were investigated for inhibitory activity against the growth of HIV-1. Only treatment with the 7,7a-diepialexine restricted virus growth (IC50 0.38 mm) although it was less active than the indolizidine alkaloid castanospermine (IC50 0.02 mm). The antiviral effects of 7,7a-diepialexine, like castanospermine, correlated with the inhibitory activity against purified pig kidney α-glucosidase 1 of the glycoprotein processing enzymes and the reduced cleavage of the precursor HIV-1 glycoprotein gp160.
Amino- and Hydroxytetraphenylporphyrins with Activity against the Human Immunodeficiency Virus
Authors: Dixon D. W. , Kim M. S. , Kumar V. , Obara G. , Marzilli L. G. , Schinazi R. F.
Published: May 2015

A series of amino- and hydroxytetraphenylporphyrin derivatives was found to have activity against the human immunodeficiency virus type 1 (HIV-1) in human peripheral blood mononuclear cells. Activity tends to be associated with increased hydrophilicity of the porphyrins for the porphyrins with one substituent on each phenyl ring but there is no clear pattern for the porphyrins with two substituents on each phenyl ring. The antiviral activity of certain porphyrins has been demonstrated in the absence of light, suggesting a non-photochemical process. Whereas only some of the porphyrins that inhibit HIV-1 in culture inhibit HIV-1 reverse transcriptase in a cell-free system, none of those tested inhibit DNA polymerase α.
Famciclovir and Penciclovir. The Mode of Action of Famciclovir Including Its Conversion to Penciclovir
Authors: Hodge R. A. Vere
Published: May 2015

Famciclovir is the oral form of penciclovir, a highly selective antiherpesvirus agent. Both famciclovir and penciclovir are being evaluated in clinical studies. This review covers the conversion of famciclovir to penciclovir, the formation and stability of penciclovir-triphosphate, its effect on herpesvirus DNA polymerases and the inhibition of viral DNA synthesis in cell cultures.

The conversion of famciclovir into penciclovir is described, emphasising work with human tissues and including the elucidation of the structures of its chiral monoacetylated derivatives. To reflect its metabolism during oral absorption, famciclovir was incubated in duodenal contents, extracts of intestinal wall and liver, and in blood. The major metabolic route was by de-acetylation followed by oxidation of the purine to form penciclovir. This work with human tissues was predictive of the major metabolic pathway in humans.

Penciclovir is phosphorylated much more efficiently than acyclovir in herpesvirus-infected cells yet the host cell kinases phosphorylate the two compounds to a small but comparable extent. This highly preferential metabolism in herpesvirus infected cells is a major factor in its selective antiviral activity. The ( S) enantiomer of penciclovir-triphosphate is the major metabolite and it has good stability in HSV-1, HSV-2, and VZV infected cells. At the high concentrations found in infected cells, penciclovir-triphosphate was an effective inhibitor of viral DNA polymerases and of viral DNA synthesis. The efficient entrapment of the active moiety can account for the markedly better antiviral activity of penciclovir than acyclovir when infected cell cultures were treated for a short time. Such assays reflect more closely the clinical situation after oral dosing than do standard assays in which the test compounds are present continuously. The role of these studies in compound selection and development is discussed.
Antiviral 9-[2-(Phosphonomethylthio)Alkoxy]purines
Authors: Harnden M.R. , Jennings L.J.
Published: May 2015

A series of 9-[2-(phosphonomethylthio)alkoxy]purine analogues of recently reported antiviral 9-[2-(phosphonomethoxy)alkoxy]purines (Duckworth et al., 1991) has been prepared and evaluated as antiviral agents. 9–[2-(Phosphonomethylthio)ethoxy]guanine (8) has potent activity against herpesviruses, and (R)-9-[3-hydroxy-2-(phosphonomethylthio)propoxy]guanine (37) has potent and selective activity against visna virus and good activity against HIV-1.
Activity of a Sulfated Polysaccharide Extracted from the Red Seaweed Aghardhiella Tenera against Human Immunodeficiency Virus and Other Enveloped Viruses
Authors: Witvrouw M. , Este J. A. , Mateu M. Q. , Reymen D. , Andrei G. , Snoeck R. , Ikeda S. , Pauwels R. , Bianchini N. V. , Desmyter J. , De Clercq E.
Published: May 2015

A galactan sulfate (GS) was isolated from an aqueous extract of the red seaweed Aghardhiella tenera and partially purified. GS inhibited the cytopathic effect of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in MT-4 cells at concentrations 10-fold higher than those required for the inhibition by dextran sulfate (MW 5000) of the cytopathic effect of HIV-1 and HIV-2 (50% inhibitory concentrations: 0.5 and 0.05 μg ml−1, respectively). GS suppressed syncytium formation between MOLT-4 cells and persistently HIV-1- or HIV-2-infected HUT-78 cells at concentrations higher than 5 μg ml−1. Like dextran sulfate (DS) and aurintricarboxylic acid (ATA), GS inhibited the binding of HIV-1 to the cells and the binding of anti-gp120 mAb to HIV-1 gp120. Like DS and ATA, GS proved active not only against HIV-1 and HIV-2 but also against other enveloped viruses, i.e. herpes-, toga-, arena-, myxo- and rhabdoviruses. GS represents a natural polysaccharide with broad-spectrum activity against a number of important viral pathogens.
Kinetic Interaction of the Diphosphates of 9-(2-phosphonylmethoxyethyl)adenine and Other anti-HIV Active Purine Congeners with HIV Reverse Transcriptase and Human DNA Polymerases α, β and γ
Authors: Cherrington J. M. , Allen S. J. W. , Bischofberger N. , Chen M. S.
Published: May 2015

The inhibitory effects of the diphosphates of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and its analogues on HIV reverse transcriptase and human DNA polymerases α, β, and γ have been studied. The analogues investigated are the diphosphates of 9-(2-phosphonylmethoxypropyl)adenine (PMPApp), 9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine (PMPDAPpp), and (2R,5R)-9-[2,5-dihydro-5-(phosphonyl methoxy)-2-furanyl]adenine (D4APpp). These four compounds are much more inhibitory to HIV reverse transcriptase when an RNA template rather than a DNA template is used. The Ki, values for the four compounds range from 11 to 22 nM with an RNA template. The Ki, values for ddCTP and AZTTP are 54 nM and 8 nM, respectively. PMEApp and its analogues show varying degrees of inhibition of the human DNA polymerases. The Ki, values for PMEApp, PMPApp and PMPDAPpp against DNA polymerase α are in the micromolar range, while D4APpp is a poor inhibitor of this enzyme with a Ki, value of 65.9 μM. The inhibition of DNA polymerase β by PMEApp, PMPApp and D4APpp is minimal, while PMPDAPpp shows higher inhibition of DNA polymerase β with a Ki, value of 9.71 μM. The Ki, values for PMEApp and D4APpp against DNA polymerase γ are submicromolar, while PMPApp and PMPDAPpp are much less inhibitory to this enzyme. For comparison, ddCTP was found to be a more potent inhibitor of DNA polymerases β and γ than the diphosphates of PMEA and its analogues.
A Comparative Study of 5-ethyl-2′-Deoxyuridine and Selected Lipophilic 5,6-Dihydro Double/Triple Prodrugs
Authors: Cheraghali A. M. , Kumar R. , Morin K. W. , De Clercq E. , Knaus E. E. , Wiebe L. I.
Published: May 2015

(+)- Trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-5′-O-valeryl-2′-deoxyuridine (3) and (+)- trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-3′,5′-di-O-valery[-2′-deoxyuridine (4) were synthesized in 55% and 8.6% yield, respectively, by esterification of the 5′-hydroxyl group of (+)- trans-(5R,6R)-5-bromo-5-ethyl-6-ethoxy-5,6-dihydro-2′-deoxyuridine (2) using valeryl chloride. [4-14C]-3 and [4-14C]-4 were synthesized in 79% and 64% chemical and radiochemical yield, respectively, by similar esterifications of [4-14C]-2.

The double prodrug 3 was readily hydrolysed (> 95% in 8 min) to 5-ethyl-2′-deoxyuridine (EDU) by porcine liver esterase in vitro. The biotransformations of 2 and 3 were studied following i.v. injection of a 0.4 mmol/kg i.v. dose to male Balb/c mice. The single prodrug 2 was rapidly cleared (<10 min) from the blood. The area under the blood concentration-time curve (AUC) for EDU, as a metabolite of 2, was higher (2.1 ± 0.4 μmol.h.g−1) than the AUC observed when EDU itself was injected (1.7 ± 0.2 μmol.h.g−1). The double prodrug 3 provided a sustained high concentration of EDU in blood, with an AUC for EDU, as a metabolite of 3, of 1.8 ± 0.2 μmol.hr.g−1. 5′-O-Valeryl-5-ethyl-2′-deoxyuridine and 3 were both detected in blood samples collected up to 35 min post i.v. injection. 5-Ethyluracil and 5-(1-hydroxyethyl)-uracil were identified as secondary metabolites of EDU, 2 and 3. Compared to [4-14C]-EDU, i.v. injection of [4-14C]-3 or [4-14C]-4 provided significantly higher (P < 0.001) radioactivity levels in the brain, but neither EDU, 2 or 3 protected mice against intracerebral herpes simplex virus infection.

Hepatic uptakes of 2, 3 and 4, in mice, were similar to each other despite the respective substantial increases in both molecular weight and lipophilicity of this series. In rats, biliary excretion over the 0-4 h period after i.v. injection accounted for only 2.9-3.9% of the injected dose for these prodrugs.
Effects of Plant-Derived Polysaccharides on Murine Cytomegalovirus and Encephalomyocarditis Virus Infections in Mice
Authors: Smee D. F. , Verbiscar A. J.
Published: May 2015

Polysaccharides from three plant species, Astragalus brachycentrus (AV222), Astragalus echidnaeformis (AV224) and Sterculia urens (AV223), which are devoid of in vitro antiviral activity, were evaluated in mouse models of murine cytomegalovirus and encephalomyocarditis virus infections. AV223 and AV224 were very potent agents, protecting mice from mortality at intraperitoneal doses between 3.2 and 100 mgkg−1 day−1 treatments. Treatment with compounds needed to be started one day prior to virus inoculation for maximum protective benefit. Treatments starting after virus inoculation were ineffective. No detectable toxicity was apparent in mice treated with up to 100 mg of each polysaccharide per kg of body weight. Interferon was not detected in mouse sera from polysaccharide-treated mice, suggesting a different mode of immuno-enhancement may be responsible for the antiviral effects observed.
Scopadulciol is an Inhibitor of Herpes Simplex Virus Type 1 and a Potentiator of Aciclovir
Authors: Hayashi Kyoko , Hayashi Toshimitsu
Published: May 2015

The antiviral activity of scopadulciol (SDC), a tetracyclic diterpenoid with a chemical structure related to that of aphidicolin, isolated from Scoparia dulcis, was studied in vitro against herpes simplex virus type 1 (HSV-1). SDC was found to inhibit the virus replication as shown by reduction of virus production. The action was not due to the inhibition of viral DNA polymerase activity and virus penetration, but might involve, at least in part, a virucidal effect. SDC did not suppress the viral protein synthesis of infected cells when added at an early stage of HSV-1 replication, but did when added later. When aciclovir (ACV) and SDC were evaluated in combination for antiviral activity against HSV-1 replication and cytotoxicity, these drugs inhibited viral replication in HeLa cells synergistically, but the same combination did not produce synergistic cytotoxicity in HeLa cells. Studies of the deoxynucleotide pool sizes revealed that SDC increased the intracellular dNTP pools and ACV triphosphate level significantly in infected cells when the cells were treated with the combination. These results could account for the synergistic action between SDC and ACV.
Antiviral Activity of a Sulphated Polysaccharide Extracted from the Marine Pseudomonas and Marine Plant Dinoflagellata against Human Immunodeficiency Viruses and other Enveloped Viruses
Authors: Hashimoto K. , Kodama E. , Mori S. , Watanabe J. , Baba M. , Okutani K. , Matsuda M. , Shigeta S.
Published: May 2015

A natural sulphated mucopolysaccharide (OKU40), extracted from a marine plant Dinoflagellata, and an artificial sulphated polysaccharide (OKU41), prepared from a marine Pseudomonas, displayed antiviral activities against several enveloped viruses. OKU40 and OKU41 were found to be homogenous in electrophoresis and sedimation velocity and had a molecular weight of 8.0 × 1065.0 × 105respectively. The sulphation rate of OKU40 and OKU41 was 8.9% and 5.4%, respectively. Each OKU40 and OKU41 inhibited the cytopathic effect of human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2) and zidovudineresistant HIV-1 in MT-4 cells at similar concentrations to those of dextran sulphate (molecular weight: 5000) (50% inhibitory concentrations: 0.86-1.95 μg mL−1), whereas these compounds did not affect the growth and viability of mock-infected MT-4 cells at concentrations up to 500 μg mL−1. These compounds proved inhibitory not only to HIV-1 and HIV-2 but also to other enveloped viruses, i.e. herpes simplex virus type 1, influenza virus A and B, respiratory syncytial virus and measles virus. OKU40 and OKU41 suppressed syncytium formation induced by cocultivation of MOLT-4/IIIb and MOLT-4 cells at concentrations higher than 20 μg mL−1. Although OKU41 inhibited the binding of HIV-1 to the host cells and the binding of anti-gp120 monoclonal antibody to HIV-1 gp120, OKU40 did not inhibit these bindings, suggesting that the mechanism of anti-HIV activity of OKU40 and OKU41 may be primarily due to the inhibition of virus-cell fusion and viral adsorption to the host cells, respectively. Furthermore, these compounds did not inhibit to the blood coagulation process at a concentration that was significantly inhibitory to HIV replication. The compounds appear to have an interesting potential as virucidal agents.
Synthesis and Evaluation of Some Symmetrical Phosphate Dimer Derivatives of 3′-Modified Nucleosides as Potential anti-HIV Agents
Authors: McGuigan C. , Tsang H.-W. , Mahmood N. , Hay A. J.
Published: May 2015

Novel symmetrical nucIeotide-(5′,5′)-dimers of 3′-O-acetylthymidine, 3′-O-methylthymidine, 3′-O-ethylthymidine, 3′-O-n-propylthymidine and 3′-azido-3′-deoxythymidine (AZT) were synthesized as membrane soluble pro-drugs. These were prepared using phosphorodichloridate chemistry and were characterised by spectroscopic and analytical data. In-vitro evaluation of the derivatives in cells acutely infected with the human immunodeficiency virus (HIV-1) demonstrated a range of activities. These derivatives were generally found to display poor inhibition of HIV proliferation. Derivatives containing AZT moieties were found to be potent, but such compounds were less active than the parent nucleoside. The data indicated that the AZT-containing compounds act primarily via the release of the free nucleoside. However, in some cases, the dimers of certain inactive nucleoside analogues were found to be active. In these cases, release of the nucleoside alone cannot account for the activity.
Synthesis and Anti-HIV Activity of some Novel Chain-Extended Phosphoramidate Derivatives of d4T (Stavudine): Esterase Hydrolysis as a Rapid Predictive Test for Antiviral Potency
Authors: McGuigan C , Tsang H-W , Sutton PW , De Clercq E , Balzarini J
Published: May 2015

Novel chain-extended nucleoside phosphoramidates of the anti-human immunodeficiency virus (HIV) drug d4T (stavudine) have been prepared as possible membrane-permeable prodrugs of the bio-active free 5′-monophosphates. Phosphorochloridate chemistry gave the target compounds in moderate to high yields, and all materials were fully characterized by spectroscopic and analytical methods. The compounds are related to the previously reported phenyl methoxyalaninyl derivative of d4T, which was shown to be a potent and selective inhibitor of HIV. In this study theamino acid nitrogen and ester moieties were separated by methylene spacers of between two and six carbon atoms. In vitro evaluation of these compounds indicated an almost complete lack of anti-HIV activity, the compounds being several orders of magnitude less potent than the corresponding α-amino acid derivatives. The reasons for the virtual lack of anti-HIV activity appear to involve poor enzyme-mediated hydrolysis.
Anti-Human Immunodeficiency Virus Drug Combination Strategies
Authors: Vandamme A-M , Van Vaerenbergh K , De Clercq E
Published: May 2015

It is now generally accepted that mono- and bitherapy for human immunodeficiency virus type 1 (HIV-1) infection are only transiently efficient mainly due to virus drug resistance. To obtain a sustained benefit from antiviral therapy, current guidelines recommend at least triple-drug combinations, or the so-called highly active antiretroviral therapy (HAART). In some patients, HAART can be problematic, either because it is difficult to remain compliant or because previous suboptimum therapies have limited the choice of drugs. For compliant drug-naive patients, HAART should be able to offer long-term virus suppression, when changing from first- to second- to third-line HAART at drug failure. Long-term treatment might ultimately result in multi-drug resistant virus leaving few options for salvage therapy. HIV drug resistance testing to guide this salvage therapy and the development of new drugs to allow new options will therefore remain priorities in anti-HIV drug research.
Strategies for Antiviral Drug Discovery
Authors: Jones PS
Published: May 2015

The need for antiviral drugs is growing rapidly as more viral diseases are recognized. The methods used to discover these drugs have evolved considerably over the past 40 years and the overall process of discovery can be broken down into sub-processes which include lead generation, lead optimization and lead development. Various methods are now employed to ensure these processes are carried out efficiently. For lead generation, screening methodologies have developed to the extent where hundreds of thousands of compounds can be screened against a particular target. An alternative approach is to use the structures of enzyme substrates as a starting point for drug discovery. Much use is now made of X-ray crystallographic data of target–inhibitor complexes for the optimization of lead structures, and methods for preparing libraries of compounds to assist both generation and optimization of leads are welldeveloped. The methods used to predict and improve the pharmacokinetic properties of compounds are also changing rapidly. Finally, novel approaches to antiviral therapy using oligonucleotide-based compounds or modulating the host immune response are also being explored. This review discusses these approaches, provides examples of where their application has been successful and sets them against a historical background.
Allosteric Inhibitors against HIV-1 Reverse Transcriptase: Design and Synthesis of MKC-442 Analogues Having an Ω-Functionalized Acyclic Structure
Authors: Tanaka H , Walker RT , Hopkins AL , Ren J , Jones EY , Fujimoto K , Hayashi M , Miyasaka T , Baba M , Stammers DK , Stuart DI
Published: May 2015

Based on X-ray crystallographic analysis of MKC-442/human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) complex, analogues in which the N1-substituent is replaced with ω-functionalized alkyl groups were designed to improve the affinity for the enzyme. Synthesis of these compounds was carried out starting from MKC-442 by a sequence of reactions (N3-protection, removal of N1-ethoxymethyl group, alkylation, and N3-deprotection). The compounds were evaluated for anti-HIV activity. Structure–activity relationships are discussed in terms of the possible interaction with the enzyme.
3-Hydroxyphthaloyl β-Lactoglobulin. IV. Antiviral Activity in the Mouse Model of Genital Herpesvirus Infection
Authors: Kokuba H , Aurelian L , Neurath AR
Published: May 2015

The spread of sexually transmitted infections caused by herpes simplex virus type 2 (HSV-2) has continued unabated despite educational efforts generated in response to the human immunodeficiency virus (HIV) epidemic. Given the absence of effective vaccines, this indicates the need to develop prophylactic measures such as topical antiviral agents. Chemical modification of bovine β-lactoglobulin (β-LG), the major protein of whey, by hydroxyphthalic anhydride (3HP) led to the generation of a potent HIV-1 inhibitor designated 3HP-β-LG. This agent was shown to also have antiviral activity against HSV-2 and HSV-1 in vitro. Recent studies indicate that 3HP-β-LG binds to HSV-1 virions, which, at least in part, involves the viral glycoprotein gE. Here we show that 3HP-β-LG inhibits HSV-2 infection in the mouse model of genital HSV-2 infection. Simultaneous exposure to HSV-2 and 3HP-β-LG caused a significant decrease in the proportion of infected animals (27% virus shedding, 5% lesion development and 0% fatality for 3HP-β-LG as compared to 80% shedding, 60% lesion development and 53% fatality in micetreated with PBS). The proportion of animals with HSV-2 infection after treatment with β-LG was similar to that in the PBS-treated group. Pretreatment with 3HP-β-LG formulated in a gel, which prolongs the presence of the agent in the vagina, also significantly reduced the proportion of HSV-2-infected mice (5% virus shedding, 5% lesion development and 0% fatality for 3HP-β-LG as compared to 70% shedding, 60% lesion development and 40% fatality in vehicle-treated mice). These differences were significant ( P≤0.0005, 0.002 and 0.008 for shedding, lesion development and fatality, respectively). Virus titres in the minority of mice that developed infection were similar to those in untreated mice. HSV-2 infection was not inhibited by treatment of an ongoing infection, indicating that 3HP-β-LG interferes with the initial infection. These data suggest that 3HP-β-LG may be an efficacious agent for preventing vaginal transmission of genital herpesvirus infections.