bluuebunny/crossref_metadata_2025 huggingface dataset:
Species Differences in the Metabolism and Disposition of Antiviral Nucleoside Analogues: 1. Acyclovir
Authors: de Miranda P. , Good S. S.
Published: May 2015

The acyclic nucleoside analogue, acyclovir, is an antiviral drug with activity against the herpes group of DNA viruses. Clinically, it is used as a selective therapeutic agent for the treatment of herpes simplex and varicella-zoster virus infections. Studies on the disposition of acyclovir, during the course of its preclinical and clinical development, indicated significant species differences in the absorption, metabolism and elimination of the drug. Gastrointestinal absorption was adequate in dogs and in mice; but in rats and primates it was limited to less than 20% of the administered dose. Whereas in some species (mice, rats, and dogs), acyclovir was virtually unmetabolized, significant biotransformation was apparent in guinea pigs, rabbits, and some primates. Acyclovir tissue distribution was extensive and indicated few differences across species. This review summarizes diverse studies on acyclovir absorption, metabolism, and disposition in different species, including humans, and indicates the relevance and importance of such studies in drug development.
Comparison of Antiviral Effects of Zidovudine Phosphoramidate and Phosphorodiamidate Derivatives against HIV and ULV in vitro
Authors: Kinchington D. , Harvey J. J. , O'Connor T. J. , Jones B. C. N. M. , Devine K. G. , Taylor-Robinson D. , Jeffries D. J. , McGuigan C.
Published: May 2015

A number of zidovudine phosphoramidate and phosphorodiamidate derivatives were prepared, including some previously unreported benzyl esterified amino acyl compounds. These were found to be active in vitro against the human immunodeficiency virus (HIV-1), and were tested subsequently in the S+L-tissue culture assay against urethane leukaemia virus (ULV), a murine leukaemia virus (MuLV). The fifteen compounds tested showed a similar range of activity against the two viruses. No active compounds were missed in the MuLV system which was usually more sensitive to antiviral effects. Five compounds showed some toxicity to the mouse cells only. We are using this system in parallel with HIV assays to identify those derivatives which will be tested subsequently against a murine retrovirus in vivo.
Determination of IC50 Values and the Mechanism of Action of HIV-1 RT Inhibitors, by the Use of Carrier Bound Template-Primer, Template, or Primer, with 125I-IUTP as Substrate
Authors: Gronowitz J. S. , Lennerstrand J. , Petterson A. , Neumüller M. , Johansson M. , Kältender C. F. R.
Published: May 2015

A novel reverse transcriptase (RT) assay based on the combined use of macrobead-bound template and 125I-iododeoxyuridine-triphosphate (IUTP) was used to determine the IC50 values of various RT inhibitors. The results showed that this assay and the conventional assay gave similar IC50 values. The introduction of carrier bound template-primer, template, or primer also made it possible to design assays revealing the mechanism of action of various RT inhibitors. Unlabelled inhibitor substance could be incubated with carrier bound template-primer in the presence of excess enzyme, after which the inhibitor was removed and the residual template-primer function was analysed by RT assay. By this procedure it was found that chain elongation terminators like 2′,3′-dideoxy-TTP and 3′-azido-TTP destroyed the template-primer at low concentrations which corresponded to the amount of primer. In contrast, 20–200 times higher concentrations were needed for template-primer destruction when using substances continuously incorporated into the DNA, such as IUTP or TTP. Further, an inhibitor such as phosphonoformic acid (PFA) did not affect the template-primer at all. By excluding the excess RT in the first incubation, it was possible to determine whether or not the template-primer destruction of a given substance was enzyme dependent. Another feature of the macrobead bound template-primer, template, or primer useful for elucidation of the mechanism of action of RT inhibitors is that it can be used to study the interference between an inhibitor and the RTs binding to the template-primer, template, or primer. Briefly, the bead carrying the substrate is incubated with RT in the absence or presence of various inhibitor concentrations, followed by thorough wash. After this the bound RT activity is determined. Such analyses showed that, in contrast to different nucleic acids and oligonucleotides, the classic RT inhibitors either did not interfere or only interfered weakly with the binding of RT to the carrier bound template-primer, template, or primer. Due to the technical simplicity of this novel RT assay it is a far better tool to rapidly screen RT inhibitors than conventional procedures used to date. Further, the use of carrier bound template-primer, template, or primer offers a unique and simple technology for analysis of the mechanisms of action of different RT inhibitors and for analysis of the characteristics of different RT isozymes and mutated RT.
Influence of the Infectious Dose of Simian Immunodeficiency Virus on the Acute Infection in Cynomolgus Monkeys and on the Effect of Treatment with 3′-Fluorothymidine
Authors: Böttiger D. , Vrang L. , Öberg B.
Published: May 2015

Inoculation of cynomolgus monkeys with simian immunodeficiency virus (SIVSM) results in an acute infection with circulating viral antigen. The time for appearance of the viral antigen peak was dependent on the dose of virus given, a reduced dose of virus resulting in a later peak. 3′-Fluorothymidine (FLT) was given at a dose of 3 × 5mg kg−1 day−1 starting 8 h before virus inoculation and then every 8 h for 10 days. In monkeys inoculated with 500–2500 infectious doses of SIVSM no significant effect of treatment with FLT was seen. When the amount of virus was reduced to 100 infectious doses or less, treatment with FLT resulted in a significant delay in the appearance of viral antigen. At an inoculum of 2–10 infectious doses per monkey, FLT treatment showed a prophylactic effect.
Zidovudine Antagonizes the Antiviral Effects of Ganciclovir against Cytomegalovirus Infection in Cultured Cells and in Guinea Pigs
Authors: Feng J. S. , Crouch J. Y. , Tian P. Y. , Lucia H. L. , Hsiung G. D.
Published: May 2015

The antiviral effects of ganciclovir (DHPG) combined with zidovudine (AZT) at several dosages against cytomegalovirus infection were evaluated in cultured cells and in Hartley guinea pigs. Combinations of DHPG and AZT at fixed ratios ranging from 1:0.1 to 1:1 showed reduced antiviral effects of DHPG in cultured human lung fibroblast (HEL) cells and guinea pig embryo (GPE) cells infected with human cytomegalovirus and guinea pig cytomegalovirus, respectively. Synergistic cytotoxicity (CI values < 1) was noted in HEL and GPE cell cultures at all DHPG/AZT combinations tested. In vivo experiments using a fixed ratio at three dosage levels for treatment of GPCMV infected guinea pigs for 5 days did not show significant antagonistic antiviral nor synergistic toxic effects at lower dosages. When GPCMV infected guinea pigs were treated with DHPG and AZT in combinations at 40/20, 40/40 and 40/80 mg kg−1 day 1 for 7 days, a significant increase of GPCMV infectivity titres in the salivary gland, lung and spleen were noted when compared with those animals treated with DHPG 40mg kg−1 day−1 alone. In addition, histopathological findings showed more cytotoxicity in the bone marrow of infected and non-infected animals treated wth DHPG/AZT combinations than animals treated with each drug alone. These results suggest that AZT antagonizes the antiviral effects of DHPG against HCMV and GPCMV replication in cultured cells and GPCMV infection in guinea pigs with increased cytotoxicity in cultured cells and in bone marrow of animals receiving the drug combinations.
Effect upon the anti-HIV Activity of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine of Combination with anti-Herpes Nucleoside Analogues
Authors: Cox S. , Vissgården A. , Wahren B.
Published: May 2015

The treatment of the severe and often life-threatening herpesvirus infections which commonly occur in AIDS patients is complicated by the need to treat simultaneously with drugs directed against the human immunodeficiency virus (HIV). Combining together different drugs in this way can lead to effects upon the activities of the individual drugs, such as synergism or antagonism. The effect upon the anti-HIV activity of 3′-azido-3′-deoxythymidine (AZT) and 3′-fluoro-3′-deoxythymidine (FLT) of combination with the anti-herpesvirus drugs 9-(1,3-dihydroxy-2-propoxymethyl-)guanine (DHPG; ganciclovir) and (-)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine ([-]-2HM-HBG) was investigated.

Neither DHPG nor (-)-2HM-HBG showed antiviral activity against HIV-1 up to 50 [AM. When combined with AZT or FLT at ratios of antiherpes:anti-HIV drug of 10:1 or greater, both DHPG and (-)-2HM-HBG antagonized the anti-HIV activity of AZT and FLT. When combined at a lower ratio (1:1), there was no effect upon the anti-HIV activity of either AZT or FLT. The phosphorylation of FLT was found to be unchanged in the presence of DHPG or (-)-2HM-HBG, indicating that the mechanism of the antagonism was not owing to an effect of DHPG or (-)-2HM-HBG upon the metabolism of the anti-HIV drugs.

The results suggest that combination chemotherapy with the anti-herpes drugs DHPG/(-)-2HM-HBG and AZT/FLT should be used cautiously. The possibility of such antagonistic interactions should be borne in mind when considering the choice of drug and ratio for treatment of herpesvirus infections in AIDS patients on anti-HIV therapy.
Evaluation of Topoisomerase Inhibitors as Potential Antiviral Agents
Authors: Maschera B. , Ferrazzi E. , Rassu M. , Toni M. , Palù G.
Published: May 2015

Anti-eukaryotic topoisomerase drugs, Camptothecin and Etoposide, were tested for their ability of selectively interfering with the replication of simian virus 40 (SV40) DNA. Nalidixic acid was also assayed for a comparison, since the compound has been previously reported to affect papoyavirus growth. Our results indicate that anti-eukaryotic topoisomerase drugs significantly inhibit viral DNA replication but at concentrations that are also toxic for uninfected cells. Etoposide treatment produced a relatively higher number of DNA-protein cross-links in virus-infected cells as compared to uninfected control cells. Nalidixic acid displayed some degree of selectivity for inhibiting SV40 DNA synthesis more effectively than synthesis of cellular DNA without appreciable reduction of cell growth. This activity does not appear to depend on DNA damage or interference with topoisomerase II and deserves further evaluation.
Absolute Configuration of the Antiviral Agent (−)-cis-5-Fluoro-1-[2-Hydroxymethyl)-1,3-Oxathiolan-5-yl]Cytosine
Authors: van Roey P. , Pangborn W. A. , Schinazi R. F. , Painter G. , Liotta D. C.
Published: May 2015

The structure and absolute configuration of (−)- cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (FTC), has been determined by X-ray crystallographic analysis. The results confirm that the L-isomer of the nucleoside analogue is the most active enantiomer and that the correct absolute configuration of (−)-FTC is 5-fluoro-(2′R,5′S)-(−)-1-[2-hydroxymethyl)oxathiolan-5-yl]-fluorocytosine. The two molecules in the asymmetric unit show conformations that combine conformational features of two other classes of potent antiviral nucleosides. Both oxathiolane rings have the 3′-sulphur atom in nearly perfect S3′- exo envelope conformations, similar to what is observed for 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxycytidine. One of the two molecules has a glycosylic link conformation in which the base is eclipsed with the C5′-O1′ bond. This mimics the high- anti conformation that has been observed in the structures of several 2′,3′-didehydro-2′,3′-dideoxypyrimidine nucleosides but is inaccessible for saturated pyrimidine nucleosides. However, the observed conformations cannot be superimposed adequately with other active antiviral nucleosides to suggest a common ‘active site’ conformation.
Pharmacokinetics of Famciclovir in Man
Authors: Pue M. A. , Benet L. Z.
Published: May 2015

This review presents briefly the results of a number of studies conducted in healthy volunteers, designed to investigate the pharmacokinetics of famciclovir, the oral form of the antiviral compound, penciclovir. These studies have shown that famciclovir is absorbed rapidly and extensively following oral administration. Extensive pre-systemic metabolism of famciclovir occurs since compound-related material in plasma consists almost entirely of deacetylated and oxidized metabolites. Little or no parent compound is detected in plasma or urine. The major metabolite of famciclovir is penciclovir. Maximum plasma concentrations of penciclovir are achieved rapidly following oral administration of famciclovir, and total systemic availability of penciclovir is high (77%). Pharmacokinetic parameters for penciclovir are linear over the famciclovir oral dose range 125–750 mg and the penciclovir intravenous dose range 10–20 mg kg−1. The distribution of penciclovir after intravenous administration is consistent with localization out of plasma and into tissues. Penciclovir is eliminated rapidly and almost unchanged by net active tubular secretion and glomerular filtration in the kidneys. The terminal phase elimination half-life of the compound in healthy subjects is approximately 2h. A study in healthy elderly male subjects indicated no clinically significant effects of age on the pharmacokinetics of penciclovir following oral famciclovir administration. Food appears to slow the rate of availability of penciclovir from oral famciclovir, but has no effects on the extent of availability of penciclovir. These data indicate that famciclovir possesses excellent pharmacokinetic properties for the provision of clinically useful concentrations of the antiviral agent penciclovir in the oral treatment of herpesviral infections.
Synthesis and Antiviral Activity of New 3,4-Dihydro-2-Alkoxy-6-Benzyl-4-Oxopyrimidines (DABOs), Specific Inhibitors of Human Immunodeficiency Virus Type 1
Authors: Massa S. , Mai A. , Artico M. , Sbardella G. , Tramontano E. , Loi A. G. , Scano P. , La Colla P.
Published: May 2015

3,4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) have emerged as non-nucleoside inhibitors of human immunodeficiency virus type 1 [Artico et al. (1993), Antiviral Chem Chemother 4: 361-368]. With a view to increasing their potency, a new series of DABO derivatives, differently substituted at positions C-2 and/or C-5 of the pyrimidine ring and 3′ or 3′,5′ of the benzyl moiety, have been synthesized. DABOs were prepared by reacting O-methylisourea with the appropriate methyl 2-alkyl-4-phenylacetylacetate, with formation of 3,4-dihydro-2-methoxy-6-arylmethyl-4-oxopyrimidines. Subsequent displacement of the methoxy group linked at the 2-position of the pyrimidine ring by treatment with alkoxy and cycloalkoxy potassium salts led to the required derivatives. In vitro, the most potent compounds were 12e and 12p, which had an EC50 of 0.8 μM and a selective index of 400.
Potent Inhibition of Herpes Simplex Virus by MDL 101028, a Novel Biphenyl Disulfonic Acid Urea Co-Polymer
Authors: Ahmed S. P. , Cardin A. D. , Bridges C. G. , Jackson R. L. , Mullins M. J. , Tyms A. S.
Published: May 2015

A novel low-molecular-weight sulfonic acid polymer, MDL 101028, was investigated for antiviral activity against herpes simplex virus (HSV) type 1 and type 2 in human embryonic diploid fibroblasts (MRC-5) and in a line of monkey kidney cells (Vero). Potent antiviral activities were obtained when treatment was restricted to the adsorption phase of virus propagation as measured by plaque reduction assay, and this was confirmed by experiments at high multiplicity of infection. Inhibition of virus binding to host cells by MDL 101028 was compared to that of heparin, a known antagonist of virus attachment. Both compounds showed dose-dependent inhibition, with IC50 values of 1.1 and 0.43 μg ml−1, respectively. The effect on cell-to-cell fusion was investigated using a syncytial-positive (syn+) phenotypic mutant of HSV-1 (strain 17i). MDL 101028 (3-1 μm) dramatically halted the spread of syncytial lesions; this effect was accompanied by the destruction of the syncytium and regrowth into the lesion by uninfected Vero cells. In contrast, heparin (10 μg ml−1) only partially reduced the spread of syncytia. Protection was also observed with MDL 29797 (100 μg ml−1), an antagonist of glycoprotein maturation. Unexpectedly, only a marginal effect was observed with acyclovir (10 μg ml−1), a potent inhibitor of viral DNA synthesis and HSV growth. As an extension to the current therapy for herpes simplex infection, acyclovir, the potent anti-fusion activity of MDL 101028 may have a clinical use in tissues or organs in which cell-to-cell fusion contributes to the pathology.
Synthesis and anti-HIV Evaluation of Alkyl and Alkoxyethyl Phosphodiester AZT Derivatives
Authors: Calogeropoulou T. , Koufaki M. , Tsotinis A. , Balzarini J. , De Clercq E. , Makriyannis A.
Published: May 2015

A series of new AZT conjugates with alkyl and oxyalkyl ether phospholipids was synthesized and evaluated for inhibitory activities against HIV-1 and HIV-2. The alkoxyethyl derivatives 6a-c proved 3- to 5-fold more active against HIV-1 and HIV-2 than the alkyl analogues 6d-f. A trend for higher activity with longer alkyl side-chains was observed. However, the analogues with the shortest chain possessed the most favourable therapeutic index.
Multiple Mutations in the Human Immunodeficiency Virus Protease Gene Are Responsible for Decreased Susceptibility to Protease Inhibitors
Authors: King R. W. , Garber S. , Winslow D. L. , Reid C. , Bacheler L. T. , Anton E. , Otto M. J.
Published: May 2015

The protease (PR) of the human immunodeficiency virus (HIV) is essential for replication of the virus, and accordingly has become an attractive target for the development of an antiretroviral drug. We have previously reported that passage of HIV-1 in the presence of increasing concentrations of the C-2 symmetrical, linear diol P9941 resulted in the isolation of virus with a valine-to-alanine change at position 82 (V82A) of the PR, and reduced sensitivity to certain PR inhibitors. In this study, we passaged four different variants of HIV-1 in increasing concentrations of XM323, and isolated variants with reduced sensitivity to inhibitors of PR. Twenty-three passages of HIV-1 (RF) in the presence of XM323 resulted in a variant that exhibited an approximately 100-fold reduction in susceptibility to XM323 and that contained V82F and I84V changes. When two other viruses, HIV-1 (RF41D2) and HIV-1(RF41E4), previously derived from HIV-1 (RF) by passage in the presence of P9941, were passaged in the presence of XM323, variants with V82A/L97V and M46L/V82A/L97V changes, respectively, were obtained. The M46L/V82A/L97V variant showed a 6-fold reduction in sensitivity to XM323, whereas the susceptibility of the V82A/L97V mutant remained unchanged. Seventeen passages of a clinical isolate of HIV-1, HIV-1 (Pat.E), in the presence of XM323 produced a V82F/L97V mutant with an approximately 9-fold reduction in sensitivity to XM323.
Synergistic Inhibition of Human Immunodeficiency Virus Type 1 in vitro by 6-0-butanoylcastanospermine (MDL 28574) in Combination with Inhibitors of the Virus-Encoded Reverse Transcriptase and Proteinase
Authors: Taylor D. L. , Brennan T. M. , Bridges C. G. , Kang M. S. , Tyms A. S.
Published: May 2015

The anti-human immunodeficiency virus type 1 (HIV-1) activity of the α-glucosidase 1 inhibitor 6-0-butanoylcastanospermine (MDL 28574) was assessed in combination with the 2′,3′-dideoxynucleoside analogues zidovudine (AZT), didanosine (ddl) and zalcitabine (ddC). MDL 28574 was also evaluated in combination with the non-nucleoside reverse transcriptase (RT) inhibitor nevirapine and the HIV proteinase inhibitor saquinavir (Ro-31-8959). Drug interactions were examined by the isobologram technique and by calculating combination indices (C.l.s). In all cases synergistic inhibition of HIV-1 replication was observed. In three-drug combinations, a marked synergistic antiviral effect was also observed, with C.I. values in the range 0.35-0.44 for MDL 28574 in combination with AZT and nevirapine, and in the range 0.34-0.67 for MDL 28574 in combination with AZT and saquinavir. Moreover, the combination of MDL 28574 with other drugs did not produce detrimental effects on cell division. MDL 28574 is currently in clinical trials and may have an important role in combination chemotherapy for HIV infections.
Inhibition of the Production of HIV-1 from Chronically Infected H9 Cells by Metal Compounds and Their Complexes with L-cysteine or N-acetyl-L-cysteine
Authors: Mahmood N. , Burke A. , Hussain S. , Anner R. M. , Anner B. M.
Published: May 2015

A number of metal compounds and their complexes with cysteine and N-acetyl-cysteine (NAC) were tested for their ability to inhibit HIV replication in vitro, specifically in chronically infected H9 cells (which produce virus continuously). Out of seven metal compounds tested, only bismuth nitrate and bismuth sodium tartrate inhibited virus production in chronically infected H9 cells. The complexes made with metals and cysteine or NAC had slightly improved selective indices.
Lymphatic Targeting of anti-HIV Nucleosides: Distribution of 3′-azido-3′-deoxythymidine (AZT) and 3′-azido-2′,3′-dideoxyuridine (AZdU) after Administration of Dipalmitoylphosphatidyl Prodrugs to Mice
Authors: Manouilov K. K. , Fedorov I. I. , Boudinot F. D. , White C. A. , Kotra L. P. , Schinazi R. F. , Hong Chung , Chu Chung K.
Published: May 2015

Human immunodeficiency virus appears to be proliferating within the lymphatic system throughout the period of clinical latency. Targeting of anti-HIV compounds to the lymphatic tissue may therefore provide therapeutic benefits. The purpose of this investigation was to determine the distribution of 3′-azido-3′-deoxythymidine (AZT) and 3′-azido-2′,3′-dideoxyuridine (AZdU) in lymph nodes in a mouse model after administration of the lipophilic prodrugs dipalmitoylphosphatidyl-azidodeoxythymidine (DPP-AZT) and dipalmitoylphosphatidyl-azidodideoxyuridine (DPP-AZdU). Mice received 50 mg kg−1 of parent nucleoside and 164 mg kg−1 of DPP-AZT (equivalent to 50 mg kg−1 AZT) intravenously or orally and 180mg kg−1 DPP-AZdU (equivalent to 50 mg kg−1 AZdU) orally. Serum, neck, axillary and mesenteric lymph nodes were collected at selected times and AZT and AZdU concentrations were determined by HPLC. The disposition of AZT and AZdU in serum and lymph nodes was significantly altered after intravenous and oral administration of DPP-AZT and oral administration of DPP-AZdU when compared to that after administration of parent nucleoside. Lower peak concentrations of AZT and AZdU were observed in serum and lymph nodes after administration of the phospholipid prodrugs. However, DPP-AZT and DPP-AZdU produced consistently higher concentrations of AZT and AZdU, respectively, 2-3 h after prodrug administration. Half-life values for both nucleosides in serum and lymph nodes were significantly greater after prodrug administration. Greater AUC values for nucleosides were noted in neck (AZT and AZdU) and mesenteric (AZT) lymph nodes after administration of prodrugs compared with values obtained for parent drugs. Furthermore, relative lymph node exposure to AZT and AZdU in the lymph nodes was greater after administration of prodrug than after administration of parent compound. Thus, DPP-AZT and DPP-AZdU show potential as useful prodrugs for the delivery of AZT and AZdU to the lymphatic system.
Pharmacokinetics of the anti-HIV Bicyclam SID791 (JM3100) in Rabbits, as Determined by both Analytical and Bio-Assay Methods
Authors: Witvrouw Myriam , Seifert J.-M. , Henson G.W. , Martellucci S.A. , Desmyter J. , De Clercq E.
Published: May 2015

The serum levels of the bicyclam derivative 1,1′-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-etraazacyclotetradecane octahydrochloride dihydrate [SID791 (JM3100)], a potent inhibitor of HIV replication (De Clercq et al., 1994) were determined in rabbits using two different methods. A method based on the UV-absorption of the Cu-complex of SID791 was used to analyse by HPLC the serum drug concentrations, and an antiviral activity bio-assay was performed to investigate whether the drug in the rabbit serum was in an available active form. After subcutaneous (sc) administration of SID791 to rabbits at 25 mg kg−1 of body weight, the compound was cleared from the serum in a bi-exponential manner (β1-half-lives: 67 and 69 min; β2-half-lives: 320 and 245 min; distribution volumes: 0.40 and 0.37 I; total body clearance: 0.30 and 0.29 I h−1; and AUC: 83.3 and 86.2 h μg ml−1, as determined by HPLC and bio-assay, respectively). Thus, very similar kinetic parameters were noted if serum drug concentrations were determined by HPLC analysis or bio-assay, suggesting that in the rabbit serum the drug is present as an antiviral active agent.
Antipicornavirus Drugs: Current Status
Authors: Diana GD , Pevear DC
Published: May 2015

Considerable efforts have been made over the past several years to discover a broad-spectrum antipicornavirus agent. The X-ray crystal structure of several rhinovirus serotypes, as well as a coxsackievirus, has provided valuable information with respect to the virus structure as well as the location of the binding site of several capsid-binding compounds. This has aided in the design of broad-spectrum compounds. Several potential drug candidates have reached clinical status and some progress has been made in achieving efficacy. However, none of these compounds has as yet become a marketable drug. This review summarizes the current status of efforts in this area.
Syntheses and Biological Evaluation of 5′-O-Myristoyl Derivatives of Thymidine against Human Immunodeficiency Virus
Authors: Parang K , Wiebe LI , Knaus EE
Published: May 2015

A series of 5′- Oacyl derivatives of thymidine (dThd) were prepared by direct acylation of thymidine using the Mitsunobu reaction. Further reaction of the bromo analogues with sodium azide gave azido ester analogues. Anti-human immunodeficiency virus type 1 (HIV-1) activities were determined against HIV-infected T4 lymphocytes. 5′- O-(12-Azidododecanoyl)thymidine exhibited moderate activity (EC50 4.6 μM) against HIV-infected T4 lymphocytes. 5- O-(2-Bromotetradecanoyl)-thymidine was found to be the most stable ester (t1/2 15.3 min) to hydrolysis by porcine liver esterase in vitro. Partition coefficients (P) in n-octanol-phosphate buffer were determined (log10 P range 4.15–6.72) and compared with the theoretical values calculated (log10 P 3.96–6.53) using the PALLAS program. Anti-HIV structure-activity data suggest that the experimental partition coefficient should be in the log10 P 4.6–4.8 range for optimum anti-HIV activity. The structures of these thymidine analogues were optimized using molecular mechanics (MM+ force field) and semi-empirical quantum mechanics PM3 calculations. The moderately active compounds adopted a similar C-2′ endo sugar conformation and exhibited similar energies for the lowest energy conformer. A quantitative structure-activity relationship (QSAR) regression equation was developed, based on the optimized structures and anti-HIV data using the SciQSAR program, which showed that log P was a determinant of anti-HIV activity.
In vitro Sequential Selection and Characterization of Human Immunodeficiency Virus Type 1 Variants with Reduced Sensitivity to Hydroxyethylurea Protease Inhibitors
Authors: Potts KE , Smidt ML , Tucker SP , Stiebel TR , McDonald JJ , Stallings WC , Bryant ML
Published: May 2015

In vitro resistance to the human immunodeficiency virus (HIV) protease inhibitors SC-52151 and SC-55389A was evaluated in an in vitro sequential selection scheme. HIVRF variants were selected for reduced sensitivity to SC-52151 and subsequently passaged in both SC-52151 and a structurally different hydroxyethylurea protease inhibitor, SC-55389A, to select for dual-resistant virus. SC-52151 selection alone resulted in a 23-fold reduction in virus sensitivity whereas selection in both inhibitors resulted in 34- and eightfold reductions in virus sensitivity to SC-52151 and SC-55389A, respectively. Sequence analysis of the protease gene revealed that SC-52151 -resistant virus had a Gly to Val substitution at residue 48 (G48V) and, in 58% of subclones, an accompanying Val to Ala substitution at residue 82 (V82A). Dual-resistant virus had both G48V and V82A substitutions present and, in the majority of subclones, an lle to Thr and/or Leu to Pro substitution at residues 54 and 63, respectively. Drug susceptibility assays with limiting dilution-cloned HIVRFR (G48V/V82A) and HIVRFRR (G48V/154T/L63P/V82A) viruses demonstrated moderate to high-level cross-resistance to additional structurally non-related protease inhibitors. Recombinant HIVHXB2 proviral clones with G48V, L63P and V82A substitutions showed that one active site mutation was permissible, but the presence of both G48V and V82A substitutions together significantly reduced infectious virus production. Insight into the contributions of the observed substitutions to drug resistance is presented in molecular modelling studies.
In vitro Anti-Human Immunodeficiency Virus and Anti-Hepatitis B Virus Activities and Pharmacokinetic Properties of Heterodinucleoside Phosphates Containing AZT or ddC
Authors: Peghini PA , Zahner R , Kuster H , Schott H , Schwendener RA
Published: May 2015

In vitro activities, against human immunodeficiency virus (HIV)- and hepatitis B virus (HBV)-infected cells, of four amphiphilic heterodinucleoside phosphates containing 3′-azido-2′,3′-dideoxythymidine (AZT) or 2′,3′-dideoxycytidine (ddC) as antiviral monomers were evaluated. The four compounds were N4-hexadecyl-2′-deoxyribocytidylyl-(3′→5′)-3′-azido-2′,3′-deoxythymidine (N4-hxddC-AZT), N4-palmitoyl-2′-deoxyribocytidylyl-(3′→5′)-3′-azido-2′,3′-deoxythymidine (N4-pamdC-AZT), N4-hexadecyl-2′-deoxycytidylyl-(3′→5′)-2′,3′-dideoxycytidine (N4-hxddC-ddC) and 2′-deoxythymidylyl-(3′→5′)-N4-palmitoyl-2′,3′-dideoxycytidine (dT-N4-pamddC). All four dimers were active against HIV, dT-N4-pamddC being the most active and least toxic. dT-N4-pamddC also exhibited strong antiviral effects against a panel of eight AZT-resistant HIV strains. The ddC-containing heterodimers incorporated in liposomes additionally inhibited HBV replication by 50–80% in HepG2 2.2.15 cells. AZT and the AZT-containing dimers were ineffective. Differences in pharmacokinetic properties between the antiviral monomers and the heterodimers were evaluated using liposomal formulations of3H-labelled AZT heterodimers as model compounds. The cellular distribution of AZT in H9 cells was predominantly cytoplasmic, whereas the amphiphilic dimers were distributed more evenly throughout the cytoplasm, nuclear membranes and microsomes. Blood levels of the heterodimers decreased at a rate two- to threefold slower than AZT and the areas-under-the-curves were five- to sevenfold higher for N4-pamdC-AZT and N4-hxddC-AZT, respectively. Compared to AZT, the peak levels of the dimers were three to four times higher in blood and five to six times higher in the liver. Analysis of blood samples showed that 34% of N4-pamdC-AZT was metabolized to AZT, whereas only 9% of N4-hxddC-AZT released AZT. Considering the antiviral potency and the favourable pharmacokinetic properties of the heterodimers, these compounds merit further exploration as antiviral drugs.
Imidazo[1,5-b]Pyridazine-D4T Conjugates: Synthesis and Anti-Human Immunodeficiency Virus Evaluation
Authors: Renoud-Grappin M , Fossey C , Fontaine G , Ladurée D , Aubertin AM , Kirn A
Published: May 2015

In an attempt to combine the human immunodeficiency virus type 1 (HIV-D-inhibitory capacity of 2′,3 -dideoxy-2,3 -didehydronucleoside analogues [nucleoside reverse transcriptase (RT) inhibitors; NRTI] and non-nucleoside RT inhibitors (NNRTI), we have designed, synthesized and evaluated for their anti-HIV activity several heterodimers of the general formula [d4T]-NH-(CH2)n-NH-[imidazo[1,5–b]pyridazine]. The synthesis of these heterodimers was conducted in three parts. The first part focused on the synthesis of the NRTI. The second part was devoted to the NNRTI and the NNRTI linked to appropriate spacers; [NNRTI]-NH-(CH2)n-NH2. In the third part, the condensation between the NRTI and the [NNRTI]-NH-(CH2)n-NH2 was performed. The in vitro inhibitory activities against HIV-1 of the [d4T]-NH-(CH2)n-NH-[imidazo[1,5–b]pyridazine] heterodimers were found to be comparable to that of d4T (stavudine) in HIV-infected cells. Moreover, the heterodimers were endowed with anti-HlV-2 activity and with anti-nevirapine-resistant HIV-1 activity. None of the heterodimers proved markedly cytotoxic to CEM-SS or MT-4 cells. There was not a clear trend toward antiviral potency on lengthening the methylene spacer in the [d4T]-NH-(CH2)n-NH-[imidazo[1,5–b]pyridazine] heterodimers.
Treatment of Visna Virus Infection in Lambs with the Acyclic Nucleoside Phosphonate Analogue 9-(2-Phosphonylmethoxyethyl)Adenine (PMEA)
Authors: Thormar H , Georgsson G , Gunnarsson E , Naesens L , Torsteinsdóttir S , Balzarini J , De Clercq E
Published: May 2015

Nucleoside and nucleotide analogues, which are inhibitors of human immunodeficiency virus reverse transcriptase, are highly active inhibitors of visna virus replication in cell cultures. One such analogue, the acyclic nucleoside phosphonate PMEA, has also been found to have a prophylactic effect on visna virus infection in lambs. In the present study, lambs were injected subcutaneously with 10 mg/kg PMEA three times a week starting 4 weeks after inoculation with visna virus, when brain infection had been established. After 3 weeks of treatment there was a reduction in the amount of virus isolated from blood cells of PMEA-treated lambs compared to controls and during the remaining 7 months of drug treatmentthere was significantly less virus isolated from the blood cells of treated lambs than of controls. Antibody response against visna virus was also slower in the treated than in the untreated control group. On the other hand, there was no difference in the amount of virus isolated from various organs of the two groups and the severity of CNS lesions in sheep treated with PMEA for 8 months was comparable to that found in untreated controls, even though PMEA reached concentrations in the cerebrospinal fluid which were well in excess of the EC50 value of the drug for visna virus.
Gonococcal tenosynovitis in two HIV-infected heterosexual men: delayed diagnoses following negative urine nucleic acid amplification testing
Authors: Shaw Jonathan W , Flegg Peter , Sweeney John
Published: May 2015

With recent increases in annual gonorrhoea incidence and disproportionately high infection rates amongst men who have sex with men, the clinical picture of disseminated gonococcal infection is changing. We present two cases where consideration of, and investigation for, disseminated Neisseria gonorrhoeae infection provided the answer when routine inpatient diagnostics had been unsuccessful.
Lifetime suicide attempt history, quality of life, and objective functioning among HIV/AIDS patients with alcohol and illicit substance use disorders
Authors: Walter Kimberly N , Petry Nancy M
Published: May 2015

This cross-sectional study evaluated lifetime prevalence of suicide attempts in 170 HIV/AIDS patients with substance use disorders and the impact of suicide attempt history on subjective indices of quality of life and objective indices of cognitive and physical functioning. All patients met the diagnostic criteria for past-year cocaine or opioid use disorders and 27% of patients also had co-occurring alcohol use disorders. Compared to their counterparts without a history of a suicide attempt, patients with a history of a suicide attempt (n = 60, 35.3%) had significantly poorer emotional and cognitive quality of life scores ( ps < .05), but not physical, social, or functional/global quality-of-life scores. Lifetime suicide attempt status was unrelated to objective indices of cognitive functioning, but there was a non-significant trend ( p = .07) toward lower viral loads in those with a lifetime suicide attempt relative to those without. The findings indicate that suicide attempt histories are prevalent among HIV/AIDS patients with substance use disorders and relate to poorer perceived emotional and cognitive quality of life, but not objective functioning. HIV/AIDS patients with substance use disorders should be screened for lifetime histories of suicide attempts and offered assistance to improve perceived emotional and cognitive functioning.
Sexually acquired Salmonella Typhi urinary tract infection
Authors: Wielding Sally , Scott Gordon
Published: May 2015

We report a case of isolated urinary Salmonella enterica serotype Typhi in an HIV-positive man who has sex with men. He was clinically well and blood and stool cultures were negative, indicating that this may have been a sexually acquired urinary tract infection.
Language varieties and youthful involvement in Indonesian fiction
Authors: Djenar Dwi Noverini , Ewing Michael C
Published: May 2015

This article explores new functions served by language varieties in fiction. Focusing our analysis on two types of texts in Indonesian – teen fiction and comics – we examine the interplay between standard and colloquial varieties to show how they are used together with non-verbal elements to promote youthful involvement. We identify three ways in which involvement is created in the texts: through free indirect discourse, non-verbal cues, and the gradual building of empathy indicated by shifting perspectives. We show that shifts from narrator’s to character’s perspective are shifts in alignment. By shifting to colloquial language, the narrator aligns their perspective with that of both the character and the reader, thus blurring the divisions between them. Non-verbal cues can also signal a shift in narrator roles, from a teller to a keen commentator and interlocutor who directly addresses the reader and invites them to share story-world experience. The frequent shifts between varieties represent a new style of writing which gives salience to the role of narrator as agent with a double persona: an anonymous agent who tells the reader about the characters in relation to the unfolding events, and an agent-participant who makes their presence known to the reader through direct address and evaluative commentary.
Violently Entertained: A Meta-Analysis of the Effects of Mediated Violence on Enjoyment
Authors: Rasul Azmat
Published: May 2015

This meta-analysis addressed the effects of mediated violence on the enjoyment audiences experienced after exposure to a diverse array of entertainment programmes. Published journal articles were collected and effect sizes were analyzed to examine if there were differences in the enjoyment of violent content. Through the lens of a fixed effects model, the results indicated that the morality of audiences and nature of visual media did not impact enjoyment of violence and the selected studies shared a statistically significant common effect size ( d = 0.33). Although synthesized data signified a fairly homogenous effect of mediated violence on enjoyment, the studies employing morality and video games as moderators were heterogeneous. The current study offered guidelines for further inquiry to explicate the nature of heterogeneity and generalizability of the study results.
Online Participation and Self-presentation in Social Networking Sites: A Study of Selective Users of India
Authors: Patra Santosh K.
Published: May 2015

The study explores users’ online presentation and participation in social networking sites (SNSs). The major purpose is to find out as to how people participate in online media and ensure their presence in the context of ‘we’ and ‘they’ in SNSs. By adopting purposive sampling method, a total of 150 respondents have been selected in the age group of 15–22 and data has been collected by using both qualitative and quantitative techniques. In this study, attempts have also been made to assess as to how people consider their presence in different online groups and SNSs. In order to measure online users’ participation in SNSs, their motivation to use SNSs and their tendency to present themselves in SNSs, different categories, emerged from the research, have been deliberated upon. Questions concerning reasons for online users to participate in defined online activities and ensure their presence by presenting themselves in different groups have also been considered.
Assessing the sociology of sport: On sports mega-events and capitalist modernity
Authors: Horne John
Published: May 2015

On the 50th anniversary of the ISSA and IRSS, one of the leading international scholars on sport and consumer culture, John Horne, considers the trajectory and challenges of research on sports mega-events and their place in capitalist modernity. In anchoring work on this topic in Roche’s definition of mega-events, Horne notes that sports mega-events are important symbolic, economic, and political elements in the orientation of nations to stake their place in global society. Fundamental issues about the concept of ‘mega-event’ pose challenges for scholars as questions remain over what qualifies as a sports mega-event and how ‘lived experience’ with such events transacts with media spectacularization and characterization. The essay closes by posing broader questions for further investigation about the economic, political, and social risks and benefits of sports mega-events and how these events may portend and relate to changing relations of economic and political power on a global scale.
Assessing the sociology of sport: On action sport and the politics of identity
Authors: Wheaton Belinda
Published: May 2015

On the 50th anniversary of the ISSA and IRSS, Belinda Wheaton, a key figure in understanding emerging, high-risk, and lifestyle sports and their cultures, assesses developments in the sociology of sport that concern the politics of identity and action sport. In reflecting on the trajectory of inquiry, Wheaton notes the struggles of scholars to determine what constitutes sport and reflects on the ways in which action sport both challenges and reproduces dominant relations and meanings. Because many forms of action and informal sport continue to grow rapidly and outpace the expansion of many traditional sports in many Western nations, they represent an important lens for understanding sport in contemporary settings because they are characterized by boundary-crossing activities that traverse sport and art, play and games. Key challenges for the field include understanding the paradoxes that come with commercialization and professionalization as well as understanding how emergent sport subcultures may evolve in non-Western settings. Key on the agenda for the future will be a need for scholars to continue to expose the political formations and to link identity politics in emergent sport to broader structural forces to better understand power and inequality.
Assessing the sociology of sport: On media and representations of sportswomen
Authors: Bruce Toni
Published: May 2015

On the 50th anniversary of the ISSA and IRSS, Toni Bruce – one of the leading scholars in understanding how media fashion gendered understandings of sport – considers the development of sociology of sport research on media with particular focus on representations of sportswomen. The trajectory of research strategies to study media representations of sportswomen has evolved, to become interdisciplinary, intersectional and theoretically sophisticated. A key challenge for sociology of sport research, both generally and with regards to media specifically, has been to gain traction and exposure beyond the boundaries of the field. While media-centred studies have risen on the research agenda, new challenges remain in engaging understandings of increasingly interactive media in the experience of sport. The future of research on media and sportswomen will face ongoing challenges, given the consistency of mainstream media marginalization of women’s sport; such findings portend the need to broaden the sociological frame to include a ‘psychodynamic dimension’ to understand better how emerging theoretical interest in affect or emotion may help explain how well worn representational grooves about women and sport have remained surprisingly entrenched in culture.
Assessing the sociology of sport: On indigeneity, politics of identity and Australian sports
Authors: Hallinan Chris
Published: May 2015

On the 50th anniversary of the ISSA and IRSS, Chris Hallinan, a leading international scholar on the political and economic contexts of sport, considers the role of indigeneity and the politics of identity in Australian sports. The trajectory of inquiry departed from biocentric strands in human movement studies to extend the legacy of sociology of sport to critical analyses of racism, racialisation, the politics of ethnic identities, and their connection to the politics of Australian identities. Postcolonial studies in this area of inquiry progressed through stages, first considering racism encountered by Aboriginal athletes, moving to critical indigenous sport studies and assessments of how indigenous sport might counter prevailing Anglo-Australian nationalist discourse, to a more recent stage, where the dynamics have been assessed by indigenous sport scholars. It is argued that the future of sociology of sport research on indigeneity and the politics of identities resides in a growing reflexivity that considers whether approaches may reproduce the ‘shackles of colonialism,’ a key element in awareness that may lead to policies to help redress the underrepresentation of Indigenous peoples in leadership and management in sport.
Assessing the sociology of sport: On sports violence and ways of seeing
Authors: Young Kevin
Published: May 2015

On the 50th anniversary of the ISSA and IRSS, a scholar central to the understanding of deviance and violence in sport, Kevin Young, considers the trajectory, challenges and future for research on sport violence. He notes that the sociology of sports violence has been surprisingly limited in its scope, with focus often on football hooliganism and ice hockey tactics. In considering the challenges of sport-related violence, Young notes confounding issues of access and candor in reporting, and interrogates Berger’s notion of ‘ways of seeing’ to provoke new lenses for approaching and understanding the cultures and contexts of violence in sport. In addition, it is argued that using an approach that combines criminology, social justice and community health concerns is crucial to sociological inquiry. The essay closes with key arguments for the study of sport-related violence to ‘open the lens’ by looking beyond the ‘predictable crucibles’ of the UK and North America to examine the permutations of culturally embedded violence that link to sport across the globe.
Assessing the sociology of sport: On globalization and the diffusion of sport
Authors: Maguire Joseph
Published: May 2015

On the 50th anniversary of the ISSA and IRSS, a key foundational scholar on the increasing globalization of sport, Joseph Maguire, considers larger questions about the diffusion of sport in light of the tendencies of globalization. The essay considers the ‘current state of play’ about the ‘known dimensions’ of the globalization of sport, commenting on how British and European influences on standards and conventions gave way to North American (in particular, US) influences on increasing professional norms and the embedding of commodification. In considering challenges to the West and to Western scholars of sport and globalization, the Soviet bloc’s sustained challenges to Western dominance are noted, as are non-Western successes in select sports and recent Chinese success accelerated by the 2008 Beijing Olympic Games. The essay closes by considering five priorities in future directions for research on sport and globalization, all stemming from inquiry about continuities and changes in the global sport power elite and the ways in which this is both understood and resisted.