bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory Effects of Heterogeneous Dextran Sulphate Compounds on Simian Type D Retrovirus in vitro
Authors: Tsai C-C. , Follis K. E. , Yarnall M.
Published: May 2015

Nine heterogeneous dextran sulphate compounds were tested in vitro for their ability to inhibit a type D simian retrovirus (SRV-2) known to cause simian acquired immunodeficiency syndrome (SAIDS). Dextran sulphate, a sulphated polysaccharide, is available commercially in a variety of molecular weights ranging from 5000 (5K) to 500000 (500K). Of the four 500K compounds tested, three completely blocked replication and infectivity of SRV-2. Of the remaining five compounds tested, only three completely inhibited the virus. Cytotoxic effects also varied even among compounds of the same mol. wt. All nine compounds were further tested in combination with azidothymidine (AZT) or dideoxycytidine (ddC) for possible additive, synergistic or antagonistic effects at reduced concentrations of both drugs. Six dextran sulphate compounds showed slight additive or synergistic effects with AZT, while no effects were seen with ddC. The results suggest that the antiretroviral activity of dextran sulphate depends on the particular chemical preparation of the compound and is not entirely dependent on mol. wt. Thus, it is important to be aware of the inhibitory and cytotoxic variability in heterogeneous dextran sulphate compounds when considering the potential use of this drug, either alone or in combination, as an antiretroviral agent in vivo.
Investigation of Topoisomerase Inhibitors for Activity against Human Immunodeficiency Virus: Inhibition by Coumermycin A1
Authors: Tachedjian G. , Tyssen D. , Locarnini S. , Gust I. , Birch C.
Published: May 2015

Representative DNA gyrase inhibitors, eukaryotic topoisomerase I and II inhibitors and DNA cleaving or binding compounds were screened for their activity against human immunodeficiency virus (HIV) replication in MT-2 cells, with the HIV supercoiled DNA form as the proposed target. Of 17 compounds, only the DNA gyrase inhibitor coumermycin A1 was active. This inhibition was observed for two HIV isolates in both MT-2 cells and peripheral blood leucocytes, and could not be attributed to cytotoxicity. Coumermycin A1 did not inhibit HIV reverse transcriptase activity in an in vitro assay at concentrations that inhibited HIV replication in infected cells; its precise mechanism of action remains to be elucidated.
Dose-Dependent Pharmacokinetics of 3′-azido-2′,3′-dideoxyuridine in Rats
Authors: Boudinot F. D. , Srivatsan V. , Chu C. K. , Schinazi R. F.
Published: May 2015

The pharmacokinetics of 3′-azido-2′,3′-dideoxyuridine (AzddU; CS-87), an inhibitor of human immunodeficiency virus (HIV) replication in vitro, were characterized in rats. AzddU was administered intravenously at doses of 10, 50, 100 and 250mgkg−1. Plasma and urine AzddU concentrations were measured by HPLC. Plasma AzddU concentrations declined in a biexponential fashion with a terminal half-life of approximately 1.5h. The disposition of AzddU was independent of dose over the dosage range of 10–100mgkg−1; however, the pharmacokinetics of the nucleoside exhibited non-linearities after 250mgkg−1. Over the dose range of 10–100mgkg−1 AzddU, total clearance and renal clearance averaged 2.13lh−1kg−1 and 1.46lh−1kg−1, respectively. Total clearance was significantly lower after 250mgkg−1 ( CIT = 1.32lh−1kg−1) owing to a decreased renal clearance ( CIR = 0.69lh−1kg−1) of AzddU. Renal clearance exceeded glomerular filtration rate, indicating that active renal tubular secretion was involved in the renal excretion of the compound. The maximum transport capacity ( Tmax) and the Michaelis–Menton constant ( Km) for the tubular secretion mechanism were 142.2mg h−1 and 60.4mg l−1, respectively. The high values for Tmax and Km explain the high renal clearance of AzddU and the linearity of renal excretion over a wide range of drug concentrations. However, at very high AzddU concentrations active tubular secretion is saturable. Nonrenal clearance was independent of dose with a mean value of 0.66lh−1kg−1. Steady-state volume of distribution was similar at all doses averaging 1.05lkg−1. Thus, the disposition of AzddU is linear over the dose range of 10–100mgkg−1, but becomes dose dependent with decreases in renal and total clearances after 250mgkg−1 AzddU.
Improved Delivery through Biological Membranes. Synthesis, Characterization and Antiviral Activity of a Series of Ribavirin Chemical Delivery Systems: 5 and Carboxamide Derivatives
Authors: Bhagrath M. , Sidwell R. , Czako K. , Seyda K. , Anderson W. , Bodor N. , Brewster M. E.
Published: May 2015

A number of 1-methyl-1,4-dihydrotrigonellinate derivatives of ribavirin and various ribavirin esters were prepared as potential brain-targeting delivery forms. Systemic administration of a model system (1-[5′-(1-methyl-3-carbonyl-1,4-dihydropyridine)-2′,3′-bis-O-isobutyrate-β-D-ribofuranosyl]1,2,4-triazol-3-carboxamide) resulted in a significant brain concentration of the corresponding pyridinium salt. Antiviral testing accomplished with the aid of a mouse model, in which a Phlebovirus (Punta Toro virus) was intracranially inoculated, showed that while ribavirin itself was without effect, several ribavirin chemical delivery systems (CDS) exerted significant activity. These responses included increased number of survivors and increased mean survival time. It is suggested that the CDS approach may improve the efficacy of ribavirin towards various RNA viral encephalitis diseases.
Treatment of Acute SIV infection in cynomolgus Monkeys with 2′,3′-dideoxyinosine (ddl) and 2′,3′-dideoxythymidiene (d4T)
Authors: Böttiger D. , Ljungdahl-Ståhle E. , Öberg B.
Published: May 2015

2′,3′-dideoxyinosine (ddl) and 2′,3′-dideoxythymidiene (d4T) have been reported to inhibit the multiplication of human immunodeficiency virus (HIV) in patients, ddl and d4T were administered subcutaneously to cynomolgus monkeys starting 8 h prior to inoculation with 10–50 infectious doses of simian immunodeficiency virus (SIVSM). ddl, at a daily dose of 3 × 3.6 mg kg−1 for 10 days significantly delayed the appearance of SIVSM p24/26 antigen. A significant delay in the appearance of SIVSM p24/26 antigen was also seen when using a daily dose of 3 × 1 mg kg −1 of d4T for 10 days. Neither ddl nor d4T prevented SIVSM infection despite administration prior to virus inoculation.
Rapid Prescreening for Antiviral Agents against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. II. Porphyrins Reacting with the V3 Loop of gp120
Authors: Neurath A. R. , Strick N. , Haberfield P. , Jiang S.
Published: May 2015

Recent observations that haernin inhibited the replication of the human immunodeficiency virus (HIV-1) and the reaction between the HIV-1 envelope glycoprotein gp120 and antibodies specific for the V3 hypervariable loop of this glycoprotein were an enticement to determine whether or not additional porphyrins had similar activities. Several porphyrin derivatives, particularly meso-tetra (4-carboxyphenyl) porphine, were more potent inhibitors of HIV-1 replication than haernin. They blocked the binding of homologous antibodies to synthetic peptides corresponding to V3 hypervariable loops of 21 distinct HIV-1 isolates, and inhibited the replication in lymphocytic (MT-2) and promonocyte (U937) cell lines of several HIV-1 isolates, tested (IIIB, RF, SF-2, and MN). Compounds with inhibitory activity had a tetrapyrrole ring and, carboxyl or sulphonate groups. However, antiviral activity depended on minor structural difference's between distinct derivatives endowed with these two features. Metalloporphyrins had a drastically reduced antiviral activity in comparison with the corresponding porphyrins. An understanding of the relationship between the structure of porphyrins and their antiviral effects, perceptible from the results presented, is expected to lead to the design of additional derivatives with more potent antiviral activity and to unravelling of molecular details involved in the association between the V3 loop of gp120 and antiviral compounds targeted to this loop.
Species Differences in the Metabolism and Disposition of Antiviral Nucleoside Analogues: 2. Zidovudine
Authors: Good S. S. , de Miranda P.
Published: May 2015

Preclinical and clinical studies on the disposition of zidovudine, a thymidine analogue with potent activity against human immunodeficiency virus, identified significant species differences in the metabolism and elimination of the drug. Zidovudine was extensively metabolized to the 5′-O-glucuronide in man and other primates. Rabbits and dogs were intermediate in their extent of biotransformation to the glucuronide conjugate, whereas rats and mice excreted the drug largely unchanged. Decreased metabolism was compensated by increased renal elimination, such that plasma elimination phase half-lives for zidovudine were similar (0.6–1.1 h) in all species. Rapid and extensive absorption and considerable penetration into tissues were also observed for all species studied. Only in the brain and testes were drug levels less than in plasma, although effective antiviral concentrations of zidovudine were achieved in brain and CSF. This review summarizes the variety of studies of the absorption, distribution, metabolism, and elimination of zidovudine in several species, including humans.
Activity of Penciclovir in Combination with Azido-Thymidine, Ganciclovir, Acyclovir, Foscarnet and Human Interferons against Herpes Simplex Virus Replication in Cell Culture
Authors: Sutton D. , Taylor J. , Bacon T. H. , Boyd M. R.
Published: May 2015

Combinations of penciclovir (PCV) with other antiviral agents (acyclovir, ACV; ganciclovir, GCV; foscarnet, PFA; azido-thymidine, AZT) or with human interferons (HulFN-α,β,γ) were tested for inhibitory activity against herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) in cell culture. The antiviral interactions observed between combinations of PCV with ACV or GCV were purely additive. Combinations of PCV with HulFNs demonstrated highly synergistic anti-herpesvirus activity; some synergy was also detected between PCV and PFA against HSV-1. High concentrations of AZT inhibited the antiviral activity of PCV; this antagonism was competitive. In more detailed studies it was demonstrated that high concentrations of AZT also inhibited the antiviral activity of ACV, and that ACV was more sensitive to this antagonism than PCV. It was concluded that the antagonism was unlikely to have clinical significance.
Polymerase Domains of Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Herpes Simplex Virus Type 1 DNA Polymerase: Their Predicted Three-Dimensional Structures and some Putative Functions in Comparison with E. Coli DNA Polymerase I. A Critical Survey
Authors: Lindborg B.
Published: May 2015

Hypothetical three-dimensional models for the entire polymerase domain of HIV-1 reverse transcriptase (HIV RT) and conserved regions of HSV-1 DNA polymerase (HSV pol) were created, primarily from literature data on mutations and principles of protein structure, and compared with those of E. coli DNA polymerase I (E. coli pol I). The corresponding parts, performing similar functions, were found to be analogous, not homologous, in structure with different β topologies and sequential arrangement. The polymerase domain of HSV pol is shown to form an anti-parallel β-sheet with α-helices, but with a topology different from that of the Klenow fragment of E. coli pol I. The main part of the polymerase domain of HIV RT is made up of a basically parallel β-sheet and α-helices with a topology similar to the nucleotide-binding p21 ras proteins. The putative functions of some conserved or invariant amino acids in the three polymerase families are discussed.
Interaction of 5-Methoxymethyl-2′-Deoxyuridine Triphosphate with DNA Polymerases: Effects of the 5-Substituent and Comparison with the Deoxycytidine Derivative
Authors: Aduma P. J. , Gupta S. V. , Stuart A. L.
Published: May 2015

5-Methoxymethyl-2′-deoxyuridine (MMdUrd) is a selective anti-herpes agent that is dependent upon initial phosphorylation by Herpes simplex virus-induced deoxythymidine kinase. In order to determine its mechanism of action, MMdUrd was converted to the 5′-triphosphate (MMdUTP) and the nature of interaction of MMdUTP and dTTP with DNA polymerase of E. coli, HSV-1, and human α was investigated. The order of utilization of deoxyuridine analogues by bacterial and HSV-1 DNA polymerases for DNA synthesis was: dTTP > MMdUTP. In contrast, 5-methoxymethyl-2′-deoxycytidine-5′-triphosphate (MMdCTP) was a better substrate for HSV DNA polymerase compared to dCTP. MMdUTP is a competitive inhibitor of HSV-1 DNA polymerase with respect to dTTP incorporation (Ki = 2.9 × 10−6M). The IC50 values of MMdUTP for both HSV and human αDNA polymerases were 4.5 × 10 −6M. These data suggest that the selective activity of MMdUrd is due to its preferential phosphorylation by viral thymidine kinase and not at the DNA polymerase level. These results may also account for the difference in anti-HSV activity between MMdUrd and its deoxycytidine analogue.
Inhibition of Formation of Rev-RRE Complex by Pyronin Y
Authors: Schröder H. C. , Ushijima H. , Bek A. , Merz H. , Pfeifer K. , Müller W. E. G.
Published: May 2015

The interaction of pyronin Y, an RNA intercalating drug, with the binding of Rev protein from human immunodeficiency virus type 1 (HIV-1) to Rev-responsive element (RRE)-containing env RNA was studied. In gel retardation assays, recombinant Rev protein tightly bound to in vitro transcribed RRE RNA. Nitrocellulose-filter-binding studies revealed a dissociation constant of ≈(1–2) = 10−10M (Pfeifer et al., 1991). Pyronin Y efficiently suppressed formation of the Rev-RRE complex. At a concentration of 1 μg ml−1, complex formation was almost completely inhibited. Electron microscopy showed that Rev oligomerizes in the presence of RRE-containing RNA with the formation of short rod-like structures or long filaments, depending on the length of the transcript. Assembly of Rev protein along RRE-containing RNAs was abolished after addition of pyronin Y. Thus pyronin Y represents the first compound described to inhibit Rev-RRE complex formation.
Footprinting Studies on the Sequence-Selective Binding of Tilorone to DNA
Authors: Bailly C. , Waring M. J.
Published: May 2015

DNAase I footprinting has been used to investigate sequence selectivity in the binding of the antiviral fluorenone derivative tilorone to DNA. Using the 160 base pair EcoRI-AvaI tyr T restriction fragment and the 166 base pair EcoRI-BstEII ptyr 2 restriction fragment, obtained respectively from the Plasmids pKMΔ-98 and pMLB 1048, it is shown that tilorone binds to DNA with a preference for alternating purine-pyrimidine sequences. Enhancement of DNAase I cleavage occurs at homopolymeric A and T stretches and, to a lesser extent, at GC-rich clusters suggesting that the drug discriminates against these sequences. However, tilorone has only limited selectivity and can bind reasonably well to many types of DNA sequences. By comparison with the footprinting patterns produced by a variety of intercalating agents, it appears that tilorone protects from DNAase I cleavage the same sequences as the intercalating drug ethidium bromide. Using diethylpyrocarbohate and osmium tetroxide as probes for chemical reactivity we can perceive deformation in the structure of DNA induced by tilorone binding. Results from enzymic and chemical probing experiments are compared and discussed with respect to the likely intercalative mode of binding of tilorone to DNA.
Inhibition of HIV-1-Induced Cytopathogenicity, Syncytium Formation, and Virus-Cell Binding by Naphthalenedisulphonic Acids through Interaction with the Viral Envelope gp120 Glycoprotein
Authors: Baba M. , Schols D. , Mohan P. , De Clercq E. , Shigeta S.
Published: May 2015

Bis-naphthalenedisulphonic acid derivatives with a biphenyl spacer, 4,4′-[4,4′-biphenyldiylbis(sulphonyl-amino)]bis(5-hydroxy-2,7-naphthalenedisulphonic acid) and 3,3′-[4,4′-biphenyldiylbis(sulphonyl-amino)]bis(1,5-naphthalenedisulphonic acid), have previously been reported as potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in cell culture. These compounds have also proved inhibitory to syncytium formation in cocultures of MOLT-4 cells with HIV-1-infected HUT-78 cells. They also inhibit the binding of HIV-1 virions to MT-4 cells as determined by a flow cytometric (FACS) method. Further studies on their mechanism of action by the FACS have revealed that the compounds inhibit the binding of anti-gp120 monoclonal antibody to the viral envelope glycoprotein gp120. Binding of OKT4A/Leu3a monoclonal antibody to the cellular CD4 receptor is not affected by the compounds. These results suggest that the anti-HIV-1 activity of the naphthalenedisulphonic acid derivatives can be attributed to inhibition of the gp120-CD4 interaction through binding of the compounds to the viral gp120 antigen.
An Overview of the Further Evaluation of Penciclovir against Herpes Simplex Virus and Varicella-Zoster Virus in Cell Culture Highlighting Contrasts with Acyclovir
Authors: Bacon T. H. , Schinazi R. F.
Published: May 2015

The antiviral action of penciclovir against herpes simplex virus (HSV) and varicella-zoster virus (VZV) in cell culture is reviewed. Acyclovir was included for comparison in most of the experiments described. Whilst these two acyclic nucleoside derivatives share a mode of action which is qualitatively similar, quantitative differences were revealed in certain cell culture experiments, and the objective of subsequent biochemical studies was to account for these differences. Where possible, the conditions selected for the cell culture experiments were clinically relevant. The relative antiviral activities of penciclovir and acyclovir were compared using four distinct assays against a single strain of HSV-1 in MRC-5 cells. Some differences in relative potency were observed between the assays and possible reasons for this are discussed. In a subsequent study the initial multiplicity of infection (MOI) was shown to be inversely related to the potency of penciclovir against HSV-1 in both a virus-yield reduction assay and an antigen-inhibition assay, although this relationship was not observed in the viral DNA inhibition assay. Because the determination of infectious virus yields was considered to be a particularly useful measure of antiviral efficacy, further virus yield experiments were conducted. Consistently better activity was observed with penciclovir in a series of experiments with clinical isolates of HSV-1 and HSV-2 in which MRC-5 cells were treated continuously with test compounds following infection at 0.01 p.f.u. cell−1. Furthermore, marked differences were observed between penciclovir and acyclovir when the treatment period was reduced to as little as 2 h and effects on subsequent infectious virus replication or viral DNA synthesis were monitored; unlike acyclovir, there was prolonged inhibition of HSV replication in cultures which had been exposed to penciclovir for short periods. The triphosphate of penciclovir is considerably more stable than acyclovir-triphosphate within HSV-infected cells, and therefore this difference probably accounts for the prolonged antiviral activity observed in cell culture. Prolonged inhibition of VZV DNA synthesis by penciclovir is also reported in this review. Finally, the antiviral activity of combinations of penciclovir with other antiviral agents or with human interferons (HuIFN-α, β, γ) is reviewed. There was marked synergy between penciclovir and HuIFN-α and HuIFN-β against HSV-1 and HSV-2 and possible clinical implication of these results are discussed.
Activity of Famciclovir and Penciclovir in HSV-Infected Animals: A Review
Authors: Sutton D. , Kern E.R.
Published: May 2015

Penciclovir is a potent and highly selective antiherpesvirus agent. Both penciclovir and its oral form, famciclovir, are being evaluated in clinical studies. The activity of penciclovir and famciclovir against herpes simplex virus types 1 and 2 (HSV-1, HSV-2) infections in animals is reviewed. Penciclovir showed potent activity in a variety of cutaneous, genital and systemic HSV infections in mice and guinea-pigs when given either topically or by systemic administration by the subcutaneous, intravenous or oral routes. Comparisons of treatment with famciclovir and penciclovir demonstrated that the improved bioavailability of penciclovir following oral administration of famciclovir resulted in improved efficacy. In addition, there is good evidence to suggest that virus replication within the central nervous system is reduced following treatment with either penciclovir or famciclovir. The relative antiviral potencies in mouse cells and pharmacokinetic properties in mice suggested that acyclovir would be more efficacious than either penciclovir or famciclovir against HSV infections in mice. However, penciclovir and famciclovir in general were at least as effective as acyclovir against cutaneous, genital and intranasal infections. Moreover, in mice infected intraperitoneally with HSV-1, as with systemic administration of penciclovir, orally administered famciclovir, even when administered less frequently, was more active than equivalent treatment with acyclovir. This is consistent with the high stability of intracellular penciclovir-triphosphate within herpesvirus-infected cells and the prolonged activity of penciclovir in cell culture. The excellent pharmacokinetic properties of famciclovir in man coupled with the prolonged activity of penciclovir suggest that famciclovir will be effective in clinical use at both a lower dose and a reduced dosage frequency than acyclovir.
Inhibition of Infection of T-Cells with Human Immunodeficiency Virus Type 1 by Dideoxynucleosides Conjugated with Oligopeptides
Authors: Shimizu N. S. , Handa A. , Shimizu N. G. , Ikeda R. , Uchiyama T. , Achiwa K. , Hoshino H.
Published: May 2015

We conjugated nucleoside derivatives that have anti-HIV-1 activities with oligopeptides that should bind to the gp120 of the HIV-1 virion, and examined their anti-HIV-1 activities. These derivates included 3′-azido-2′,3′-dideoxythymidine (AZT), 2′,3′-dideoxyuridine (ddU), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxyinosine (ddI) and 2′,3′-dideoxyadenine (ddA). Dipeptides consisting of N-carbomethoxy-carbonyl-prolyl-phenylalanylbenzyl ester (CPF) and oligopeptides derived from the complementarity-determining region 2 (CDR2) of domain 1 of CD4 were synthesized. The N-terminals of these peptides were conjugated with the 5′OH of AZT, ddU, ddC, ddl or ddA through carbonyl moieties. CPF conjugated with AZT, ddC, ddl or ddA through two-carbonyl moieties exhibited powerful anti-HIV-1 activity, which was similar to that of the respective nucleosides when compared at the same molar concentration. No complex compound connected by a one-carbonyl moiety had anti-HIV-1 activity, whereas a tetrapeptide or octapeptide of the CDR2 region combined with AZT did have such activity. The toxicity of these CPF-containing compounds to human peripheral blood lymphocytes was slightly weaker than the toxicities of the corresponding nucleosides lacking CPF. Antiviral nucleosides containing oligopeptides may be used as lead compounds in an effort to isolate more effective and less cytotoxic anti-HIV-1 agents.
The use of 5′-Phosphate Derivatives of Nucleoside Analogues as Inhibitors of HIV-1 Replication
Authors: Nillroth U. , Vrang L. , Ahlsen G. , Besidsky Y. , Chattopadhyaya J. , Ugi I. , Danielson U. H.
Published: May 2015

A series of phosphate esters of nucleoside analogues was synthesized and tested for anti-HIV activity in cell culture. A number of these compounds were potent inhibitors of HIV-replication with ED50 ≥ 10 nM.

The most potent compounds were phosphate esters of the most potent nucleosides, 3′-fluoro-3′-deoxythymidine (FLT) and 3′-azido-3′-deoxythymidine (AZT). In cell culture, the inhibition by one of these derivatives was shown to be reversed by thymidine. Also, the AZT analogue was less active against AZT-resistant virus. None of the compounds tested was directly inhibitory of HIV reverse transcriptase.

The compounds were found to be labile; the rate of hydrolysis and the identity of the products varied depending on the substituents on the phosphorus atom. Activation of the most active analogue, FLT-5′-(methoxyglycinyl S-(N-methylcarbamoylmethyl))thiophosphate (JCA-304), involved a pH-dependent hydrolysis, which increased with increasing pH. The hydrolysis was not dependent on HIV proteinase, the presence of MT4 cells or enzymatic activity originating from the culture medium. The product of hydrolysis of JCA-304 was the free nucleoside (FLT); FLT-5′-monophosphate was not detected. The corresponding acyclovir analogue was not active against thymidine-kinase-deficient herpes simplex virus in Vero cells. Hydrolysis of FLT-5′-(S-(N-methylcarbamoylmethyl))thiophosphate (JCA-319) was observed in cell culture medium but not in buffer at the same pH. The product was identified as FLT-5′-monophosphate. Neither of these compounds was seen as an intermediate in the hydrolysis of JCA-304.

The results suggest that the compounds are prodrugs activated by a non-enzymatic hydrolysis and a cytosolic phosphorylation yielding potent inhibitors of HIV reverse transcriptase. The cellular stability of substituted 5′-phosphate derivatives cannot be predicted from their behaviour in buffer or from the hydrolysis of closely related analogues.
Inhibition by azidothymidine triphosphate of reverse transcriptase from paired AZT-susceptible and -resistant primary isolates of human immunodeficiency virus type 1
Authors: Cox S. W. , Corrigan G. , Palmer S.
Published: May 2015

The kinetics and inhibition by 3′-azido-3′-deoxythymidine triphosphate (AZT-TP) of reverse transcriptase (RT) from paired AZT-susceptible and -resistant primary isolates of HIV-1 taken from patients before and after therapy were examined in vitro. The resistant isolates showed mutations in the RT at positions 67, 70, 215 and 219, and also in one case at positions 41 and 215. No changes in the Vmax, the Km for dTTP or the Ki for AZT-TP of a magnitude sufficient to account for the observed development of resistance to AZT in primary isolates from these patients were found.
Efficacy and Toxicity of Long-Term Administration of 2′,3′-dideoxycytidine in the LP-BM5 Murine-Induced Immunodeficiency Model
Authors: Brandi G. , Casabianca A. , Schiavano G.F. , Rossi L. , Fraternale A. , Albano A. , Magnani M.
Published: May 2015

The LP-BM5 murine retrovirus-induced immunodeficiency model was used to evaluate the efficacy and toxicity of long-term 2′,3′-dideoxycytidine (DDC) therapy. A mean plasma drug concentration of 0.2 + 0.02 μm of DDC for 3 months was found to reduce splenomegaly, lymphoadenopathy and hypergammaglobulinemia in infected mice. However, DDC also reduced spleen weight in control mice and spleen haemopoiesis in both infected and uninfected animals. In the bone marrow the most prominent feature of DDC treatment was a marked reduction of megakariocytes, while in the liver an hepatocellular vacuolation was evident in uninfected animals. DDC reduced, but did not prevent, LP-BM5 integration in lymph node DNA and Pr 60gag expression in spleen lymphocytes and bone marrow cells. Furthermore, DDC reduced the mitochondrial DNA content and restored the mitogen proliferation of T cells but not that of B cells in infected mice. Thus, DDC appears to be of some, but limited, efficacy in murine AIDS, with a toxicity profile involving more cell types than previously thought.
Progress in the Clinical Management of Herpesvirus Infections
Authors: Griffiths P.D.
Published: May 2015

Antiviral drug discovery has produced a series of drugs active against herpesviruses in vitro. Several of these are now licensed and/or have been used in clinical practice. This article reviews the mechanisms of action of acyclovir, ganciclovir, penciclovir, sorivudine and foscarnet, the development of resistance to these drugs and their pharmacokinetic and cellular toxicities. Based upon the natural histories of HSV, VZV and CMV, treatment objectives for each virus are discussed and the performance of each drug matched against these objectives. Overall, it is concluded that the perfect drug for treating herpesviruses does not exist, but that significant progress has been made towards controlling several herpesvirus diseases. It is suggested that further progress will require not just improved drug discovery programmes, but also an understanding of different pathogeneses and an appreciation by practising physicians that antiviral drugs must be given early in the infectious process to achieve the best results.
Host Cell Dependence of Human Immunodeficiency Virus Type-1 Drug Resistance Profiles and Tissue Culture Selection Patterns
Authors: Salomon H. , Gu Z. , Gao Q. , Nagai K. , Hiscott J. , Wainberg M. A.
Published: May 2015

Clinical isolates of the human immunodeficiency virus type 1 (HIV-1) displayed differential sensitivity to antiviral nucleosides depending on the type of host cell employed for viral propagation. Viruses derived from the peripheral blood mononuclear cells (PBMC) of subjects on prolonged 3′-azido-3′-deoxythymidine (AZT) therapy behaved as AZT-resistant when tested in either cord blood mononuclear cells or MT-4 cells but as relatively drug-sensitive in the U-937 monocytic cell line. Viruses derived from monocytes/ macrophages of the same individuals behaved as drug-sensitive in all cells tested. It was also shown that cloned recombinant viruses, which contained defined resistance-conferring mutations at either position 65 or 184 in the HIV pol gene, were generally less susceptible to each of 2′-3′-dideoxyinosine (ddl), 2′,3′-dideoxycytidine (ddC) and the (-)enantiomer of 2′,3′-dideoxy-3′thiacytidine (3TC) in MT-4 cells than in any of PBMC, cord blood mononuclear cells (CBMC) or Jurkat cells. Finally, resistance against each of AZT, ddl and ddC could be selected for more easily using MT-4 cells than CBMC or Jurkat lymphocytes and not at all with the U-937 monocytic cell line.
Inhibition of Herpes Simplex Virus Type-1 Multiplication by Meliacine, a Peptide of Plant Origin
Authors: Villamil S. M. , Alché L. E. , Coto C. E.
Published: May 2015

Meliacine, a peptide isolated from leaves of Melia azedarach L., exhibited potent activity against herpes simplex type 1 (HSV-1). The in vitro selective indices for pre- and post-treatment were 937.5 and 2500, respectively. Analysis of early events following infection showed that meliacine did not affect viral adsorption and penetration. Meliacine strongly inhibited specific infected-cell polypeptides (ICPs) produced late in infection. The antiviral activity, which is attributed mainly to this selective effect, was also demonstrated in an immunofluorescence assay.
In vitro Evaluation of the Anti-Picornavirus Activities of New Synthetic Flavonoids
Authors: Desideri N. , Conti C. , Sestili I. , Tomao P. , Stein M. L. , Orsi N.
Published: May 2015

Substituted oxazolinylflavons and oxazolinylflavanones were synthesized in order to compare their anti-picornavirus activities with those of related natural and synthetic compounds. The antiviral potencies of the new compounds were evaluated against rhino-virus type 1B and poliovirus type 2 by a plaque reduction assay in HeLa cell cultures. Among the substituted flavanones only 6-chloro-4′-oxazolinylflavanone showed activity against both viruses. A comparison of the effects of 3-substituted flavones indicated that the presence of a 3-methoxy group enhances the activity against rhinovirus, while the presence of a 3-hydroxy group enhances the activity against poliovirus.
Antiviral Activities and Pharmacokinetics of Penciclovir and Famciclovir in Pekin Ducks Chronically Infected with Duck Hepatitis B Virus
Authors: Tsiquaye K.N. , Sutton D. , Maung M. , Boyd M.R.
Published: May 2015

Famciclovir (FCV) is the oral form of the potent and selective antiherpesvirus agent penciclovir (PCV). In order to provide more information on the spectrum of activity of PCV, the activities of FCV and PCV against duck hepatitis B virus (DHBV) in chronically infected ducks were examined. As part of this investigation, the oral pharmacokinetics of FCV and PCV were determined in ducks. Oral treatment of DHBV-infected ducks (twice daily for 21 days) with either PCV (20 mg kg−1 or 100 mg kg−1) or FCV (5 mg kg−1 or 25 mg kg−1) suppressed virus replication, as measured by both plasma viral DNA and DNA polymerase levels. Both markers were reduced to undetectable levels within 4 days of the start of treatment, and after the cessation of treatment there was a delay of 2 to 8 days before plasma DHBV DNA and DNA polymerase levels began to increase, indicating that virus replication had resumed. The demonstration of efficacy of PCV and its oral form FCV against DHBV suggested that the two compounds may have clinical benefits. against human hepatitis B virus. Clinical trials are currently ongoing.
Differential Susceptibility of Several Drug-Resistant Strains of Herpes Simplex Virus Type 2 to Various Antiviral Compounds
Authors: Andrei G , Snoeck R , De Clercq E
Published: May 2015

Drug-resistant herpes simplex virus type 2 (HSV-2) strains were obtained under the selective pressure of acyclovir, ganciclovir, brivudin, foscamet, 2-phosphonyl-methoxyethyl (PME) derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP), and 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) derivatives of adenine (HPMPA) and cytosine (HPMPC; cidofovir). A significant degree of cross-resistance between HPMPC and HPMPA on the one hand, and between PMEA, PMEDAP and foscarnet on the other, was noted, suggesting a different mode of interaction of the PME and HPMP derivatives at the DNA polymerase level. The results described here with HSV-2 agree with the published results for HSV-1 and human cytomegalovirus.
Random-effects meta-analysis: the number of studies matters
Authors: Guolo Annamaria , Varin Cristiano
Published: May 2015

This paper investigates the impact of the number of studies on meta-analysis and meta-regression within the random-effects model framework. It is frequently neglected that inference in random-effects models requires a substantial number of studies included in meta-analysis to guarantee reliable conclusions. Several authors warn about the risk of inaccurate results of the traditional DerSimonian and Laird approach especially in the common case of meta-analysis involving a limited number of studies. This paper presents a selection of likelihood and non-likelihood methods for inference in meta-analysis proposed to overcome the limitations of the DerSimonian and Laird procedure, with a focus on the effect of the number of studies. The applicability and the performance of the methods are investigated in terms of Type I error rates and empirical power to detect effects, according to scenarios of practical interest. Simulation studies and applications to real meta-analyses highlight that it is not possible to identify an approach uniformly superior to alternatives. The overall recommendation is to avoid the DerSimonian and Laird method when the number of meta-analysis studies is modest and prefer a more comprehensive procedure that compares alternative inferential approaches. R code for meta-analysis according to all of the inferential methods examined in the paper is provided.
‘The World Beach Project’ Going Viral: Measuring Online Influence—Case Study of the Victoria and Albert Online Museum Project
Authors: Grincheva Natalia
Published: May 2015

This study aims to explore the influence of social media platforms employed by the internationally recognized museum, the Victoria and Albert Museum (V&A) in London, in the development and implementation of its famous online participatory project—the World Beach Project. The research looks at the behaviour, size and geographic distribution of international audiences present in various social media spaces of the V&A, particularly in relation to the project. The research intends to assess the influence of social media on the global audience by evaluating online audience engagement with the project through quantitative research, behavioural study and qualitative enquiry. The article consists of two major parts. The first section proposes and explains a theoretical model of online influence—understood in this project as international audience’s engagement with and in the social media spaces of the museum. Drawing on traditional museum visitor studies research and emerging methodological approaches utilized in the online world, this part of the article tries to identify and explain the main metric components of the online audience’s engagement. The second part of the article tests this model and provides detailed analysis of the online project explored in this study through its online outreach across different social media platforms.
Assessing the sociology of sport: On critical sport sociology and sport management
Authors: Knoppers Annelies
Published: May 2015

On the 50th anniversary of the ISSA and IRSS, Annelies Knoppers, one of the leading scholars in understanding the culture of sport in organizational settings, considers how the critical lens of sociology can enhance and mesh with research on sport management. Knoppers argues that there have been lost opportunities and understandings from the little overlap between scholars publishing in journals in the sociology of sport and sport management. Using the topic of gender and leadership, she describes the benefits that might result from using a sociological lens and a ‘critical reflexivity’ to study power and social inequalities in sport management and organizations. Consideration is given to how critical understandings about gender can enhance organizational effectiveness by valuing ‘hybridity’ in leadership styles. The essay closes with arguments for a critical intersectional approach to the study of sport management with recognition that ‘disciplinary’ practices shape the wielding of leadership power within organizations.
Assessing the sociology of sport: On sport and exercise
Authors: Markula Pirkko
Published: May 2015

On the 50th anniversary of the ISSA and IRSS, Pirkko Markula, a leading poststructuralist scholar, assesses the trajectory, challenges, and future for sociology of sport research on exercise, fitness and physical cultures. The trajectory of more openly politicized examinations of power in sport as cultural studies entered Anglo-American sociology of sport in the 1990s coincided with an expanded focus on the cultures of physical activity and exercise, notably with critique of the feminine body ideal in the fitness industry. Key challenges for the future include mending a ‘disconnect’ in the tensions between critical analysis and actual physical activity education and practices, furthering scholarly commitment to interdisciplinarity, and for poststructuralist theorizing to reach beyond sport studies to serve as a platform for thinking differently about exercise practices and scientific understandings of the moving body.
Assessing the sociology of sport: On race and diaspora
Authors: Carrington Ben
Published: May 2015

On the 50th anniversary of the ISSA and IRSS, a key foundational scholar on the intersection of race and sport, Ben Carrington, reflects on the field as a whole and the notion of “diaspora” in understanding race and sport. In considering the trajectory of the sociology of sport, questions are raised about whether a coherent field has ever existed. Noting relative failures in getting “mainstream sociology” to take sport seriously, the challenges ahead are for a field that is necessarily a “multifaceted” entity, and one that ironically has never been more impactful while at its weakest institutional moment. Noting the paradox between the relative little consideration given to sport in the main sociology journals in the US and UK in contrast with the sociology of sport having successfully established self-reproducing and self-referencing spaces of critical enquiry, a key challenge for the field continues to be in its search for a “scholarly place;” it is less than clear whether the banner of “the sociology of sport” continues to resonate in the face of the neo-liberal assaults on critical scholarship within higher education. The concept of “diaspora,” surprisingly ignored in the study of sport, will be increasingly important in the future as it will enable critical race scholars to problematize the often Eurocentric and teleological underpinning of globalization theory in relation to sport; considerations of diaspora will fuel more meaningful accounts of how sport reconnects geographically dispersed groups and changes identities and subjectivities in hostile circumstances.
Assessing the sociology of sport: On theory relevance and action research
Authors: Chalip Laurence
Published: May 2015

On the 50th anniversary of the ISSA and IRSS, one of the leading scholars of the study of sport organizations, management, and policy, Laurence Chalip, considers the crucial intersection of the sociology of sport with its applications in the real world. Reflecting on how a 1989 call for the development of an applied sociology of sport by Yiannakis was not well-received by a sociology of sport scholarly community (concerned that political and marketplace imperatives might diminish its interpretive and critical agenda) Chalip outlines pragmatic and moral grounds for needing an applied sociology of sport. Posing that the challenges of the sociology of sport entail both embracing the nexus of application and theory, and the development of new conceptual tools, it is argued that an applied sociology of sport can, counter to conventional wisdom, challenge the status and functioning of privilege and power in sport. A key challenge of servicing clients in consultancies and applications is realizing that applied sociology of sport cannot be a-theoretical, but instead demands being multiply theoretical. Looking to the future, it is noted that the dearth of action research by sport scholars has been noteworthy, and that the simultaneous engagement of theory with practice, which has been inadequately developed, represents an opportunity that should not be missed.
Material symmetry group and constitutive equations of micropolar anisotropic elastic solids
Authors: Eremeyev Victor A , Pietraszkiewicz Wojciech
Published: May 2015

We discuss the material symmetry group of the micropolar continuum and related consistently simplified constitutive equations. Following Eremeyev and Pietraszkiewicz ( Int J Solid Struct 2012; 49: 1993–2005; Generalized continua as models for materials, Heidelberg: Springer, 2013, 77–90) we extend the definition of the group proposed by Eringen and Kafadar ( Continuum physics, vol. 4, New York, NY: Academic Press, 1976, 1–75) by taking into account the microstructure curvature tensor as well as different transformation properties of polar (true) and axial (pseudo) tensors. Our material symmetry group consists of ordered triples of tensors which make the strain energy density of the micropolar continuum invariant under change of the reference placement. Within micropolar solids we discuss the isotropic, hemitropic, orthotropic, transversely isotropic and clinotropic materials and give explicitly the consistently reduced representations of the strain energy density.
Deformation of an elastic magnetizable square rod due to a uniform electric current inside the rod and an external transverse magnetic field
Authors: Dhaba AR El , Ghaleb AF , Placidi L
Published: May 2015

We find the deformation and stresses in an infinite rod of an electric conducting material with square normal cross-section, carrying uniform electric current and subjected to an external, initially uniform magnetic field. The complete solution of the uncoupled problem is obtained using a boundary integral method. The results are discussed in detail.
A mathematical model for longitudinal wave propagation in a magnetoelastic hollow circular cylinder of anisotropic material under the influence of initial hydrostatic stress
Authors: Abd-alla Abo-el-nour N , Alshaikh Fatimah , Giorgio Ivan , Della Corte Alessandro
Published: May 2015

In this paper, we built a mathematical model to study the influence of the initial stress on propagation of longitudinal waves in a hollow infinite circular cylinder in the presence of an axial initial magnetic field. The elastic cylinder is assumed to be made of a tetragonal system material. The problem is described by the equations of elasticity, taking into account the effect of the initial stress and the electro-magnetic equations of Maxwell. This requires the solution of the equations of motion in cylindrical coordinates with the z-axis directed along the axis of the cylinder. The displacement components will be obtained by founding the analytical solutions of the motion’s equations. The frequency equations have been obtained in the form of a determinant involving Bessel functions. The roots of the frequency equation give the values of the characteristic circular frequency parameters of the first three modes for various geometries when the initial hydrostatic stress is compression or tension. These roots, which correspond to various modes, are numerically calculated and presented graphically. This study shows that waves in a solid body propagating under the influence of an initial stress can differ significantly from those propagating in the absence of the initial stress. The results of this research are used in analyzing the relationship between magnetic field, the initial stress and the frequency equation and could lead to discussions for using the magnetic field and the initial stress in ultrasound imaging.
Associations of Maternal and Infant Testosterone and Cortisol Levels With Maternal Depressive Symptoms and Infant Socioemotional Problems
Authors: Cho June , Su Xiaogang , Phillips Vivien , Holditch-Davis Diane
Published: May 2015

This study examined the associations of testosterone and cortisol levels with maternal depressive symptoms and infant socioemotional (SE) problems that are influenced by infant gender. A total of 62 mothers and their very-low-birth weight (VLBW) infants were recruited from a neonatal intensive care unit at a tertiary medical center in the southeast United States. Data were collected at three time points (before 40 weeks’ postmenstrual age [PMA] and at 3 months and 6 months of age corrected for prematurity). Measures included infant medical record review, maternal interview, biochemical assays of salivary hormone levels in mother-VLBWinfant pairs, and standard questionnaires. Generalized estimating equations with separate analyses for boys and girls showed that maternal testosterone level was negatively associated with depressive symptoms in mothers of boys, whereas infant testosterone level was negatively associated with maternal report of infant SE problems in girls after controlling for characteristics of mothers and infants and number of days post birth of saliva collection. Not surprisingly, the SE problems were positively associated with a number of medical complications. Mothers with more depressive symptoms reported that their infants had more SE problems. Mothers with higher testosterone levels reported that girls, but not boys, had fewer SE problems. In summary, high levels of testosterone could have a protective role for maternal depressive symptoms and infant SE problems. Future research need to be directed toward clinical application of these preliminary results.