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Sample records for evaluate anti-hiv therapy

  1. Therapeutic genes for anti-HIV/AIDS gene therapy.

    PubMed

    Bovolenta, Chiara; Porcellini, Simona; Alberici, Luca

    2013-01-01

    The multiple therapeutic approaches developed so far to cope HIV-1 infection, such as anti-retroviral drugs, germicides and several attempts of therapeutic vaccination have provided significant amelioration in terms of life-quality and survival rate of AIDS patients. Nevertheless, no approach has demonstrated efficacy in eradicating this lethal, if untreated, infection. The curative power of gene therapy has been proven for the treatment of monogenic immunodeficiensies, where permanent gene modification of host cells is sufficient to correct the defect for life-time. No doubt, a similar concept is not applicable for gene therapy of infectious immunodeficiensies as AIDS, where there is not a single gene to be corrected; rather engineered cells must gain immunotherapeutic or antiviral features to grant either short- or long-term efficacy mostly by acquisition of antiviral genes or payloads. Anti-HIV/AIDS gene therapy is one of the most promising strategy, although challenging, to eradicate HIV-1 infection. In fact, genetic modification of hematopoietic stem cells with one or multiple therapeutic genes is expected to originate blood cell progenies resistant to viral infection and thereby able to prevail on infected unprotected cells. Ultimately, protected cells will re-establish a functional immune system able to control HIV-1 replication. More than hundred gene therapy clinical trials against AIDS employing different viral vectors and transgenes have been approved or are currently ongoing worldwide. This review will overview anti-HIV-1 infection gene therapy field evaluating strength and weakness of the transgenes and payloads used in the past and of those potentially exploitable in the future.

  2. Liposomes as nanocarriers for anti-HIV therapy.

    PubMed

    Chopra, Shruti; Venkatesan, Natarajan; Betageri, Guru V

    2013-10-01

    Globally, in the last three decades of medical research, the use of liposomes as carrier for anti-HIV/AIDS drugs is gaining prominence. These potential anti-HIV nanocarriers are concentric lipid bilayers which can be fabricated to protect molecules and to target the drugs to specific sites, which is the reason behind their popularity in the antiretroviral drug delivery. The development of an effective drug delivery system such as liposomes presents an opportunity to circumvent the many challenges associated with antiretroviral drug therapy. The physiochemical properties of liposomes such as size, charge, and lipid composition significantly affect the liposomal efficiency. These nanocarriers offer advantages such as drug loading both in aqueous region and within the bilayer of the vesicles, act as solubilizing agents, protect drug from degradation in the body, allow modification of the pharmacokinetic and tissue distribution patterns of the drug, provide drug targeting, and have low immunogenicity, biocompatibility, and cell specificity. Different types of liposome-based delivery systems, such as cationic, anionic, sterically stabilized, and immunoliposomes, have been studied for the anti-HIV/AIDS drug delivery. Liposomes, however, face challenges with regard to their use in antiretroviral drug delivery such as limited hydrophilic drug-loading capacity, issues related to physical and biologic stability, poor scale-up, cost, short shelf life, and toxicity. Numerous patented strategies have been granted in the USA and around the world related to these anti-HIV nanocarriers. In the present article, we have discussed the general physiological aspects of the HIV infection, relevance of the nanocarrier, liposomes, in the treatment of this disease and some recently awarded US patents and patent applications of these liposomal delivery systems for anti-HIV drugs.

  3. Investigating the psychosocial impact of anti-HIV combination therapies.

    PubMed

    Lee, K; Solts, B; Burns, J

    2002-12-01

    Developments in anti-HIV medication have meant that people with HIV/AIDS are now living longer, with some authors arguing that HIV should now be defined as a manageable rather than terminal illness. However uncertainty about the long-term efficacy of such treatments remains. This research aimed to examine the psychosocial impact of the new treatments and to explore whether, and in what ways, they affect psychological wellbeing. Clients were also asked about their use of services and whether they thought services should be changing in response to new pharmacological treatments. A semi-structured interview schedule was developed to elicit the views of six service users. From multiple readings of the qualitative data generated, prominent themes were identified suggesting that participants had ambivalent feelings about taking antiretroviral combination therapy and that being well with HIV raised a number of difficult issues. Four main themes were revealed: (1) disruptions in daily living: antiretrovirals as intrusions to life, (2) the tablets as a visible marker for HIV infection, (3) tempered optimism and increasing horizons, (4) an uncertain and fragile future: life without benefits and services. The results were discussed in terms of limitations of the current study and suggestions for further research.

  4. Criticality of timing for anti-HIV therapy initiation.

    PubMed

    Castiglione, Filippo; Paci, Paola

    2010-01-01

    The time of initiation of antiretroviral therapy in HIV-1 infected patients has a determinant effect on the viral dynamics. The question is, how far can the therapy be delayed? Is sooner always better? We resort to clinical data and to microsimulations to forecast the dynamics of the viral load at therapy interruption after prolonged antiretroviral treatment. A computational model previously evaluated, produces results that are statistically adherent to clinical data. In addition, it allows a finer grain analysis of the impact of the therapy initiation point to the disease course. We find a swift increase of the viral density as a function of the time of initiation of the therapy measured when the therapy is stopped. In particular there is a critical time delay with respect to the infection instant beyond which the therapy does not affect the viral rebound. Initiation of the treatment is beneficial because it can down-regulate the immune activation, hence limiting viral replication and spread.

  5. Anti-HIV Antibody Responses and the HIV Reservoir Size during Antiretroviral Therapy

    PubMed Central

    Lee, Sulggi A.; Bacchetti, Peter; Chomont, Nicolas; Fromentin, Remi; Lewin, Sharon R.; O’Doherty, Una; Palmer, Sarah; Richman, Douglas D.; Siliciano, Janet D.; Yukl, Steven A.; Deeks, Steven G.; Burbelo, Peter D.

    2016-01-01

    Background A major challenge to HIV eradication strategies is the lack of an accurate measurement of the total burden of replication-competent HIV (the “reservoir”). We assessed the association of anti-HIV antibody responses and the estimated size of the reservoir during antiretroviral therapy (ART). Methods We evaluated anti-HIV antibody profiles using luciferase immunoprecipitation systems (LIPS) assay in relation to several blood-based HIV reservoir measures: total and 2-LTR DNA (rtPCR or droplet digital PCR); integrated DNA (Alu PCR); unspliced RNA (rtPCR), multiply-spliced RNA (TILDA), residual plasma HIV RNA (single copy PCR), and replication-competent virus (outgrowth assay). We also assessed total HIV DNA and RNA in gut-associated lymphoid tissue (rtPCR). Spearman correlations and linear regressions were performed using log-transformed blood- or tissue-based reservoir measurements as predictors and log-transformed antibody levels as outcome variables. Results Among 51 chronically HIV-infected ART-suppressed participants (median age = 57, nadir CD4+ count = 196 cells/mm3, ART duration = 9 years), the most statistically significant associations were between antibody responses to integrase and HIV RNA in gut-associated lymphoid tissue (1.17 fold-increase per two-fold RNA increase, P = 0.004) and between antibody responses to matrix and integrated HIV DNA in resting CD4+ T cells (0.35 fold-decrease per two-fold DNA increase, P = 0.003). However, these associations were not statistically significant after a stringent Bonferroni-adjustment of P<0.00045. Multivariate models including age and duration of ART did not markedly alter results. Conclusions Our findings suggest that anti-HIV antibody responses may reflect the size of the HIV reservoir during chronic treated HIV disease, possibly via antigen recognition in reservoir sites. Larger, prospective studies are needed to validate the utility of antibody levels as a measure of the total body burden of HIV

  6. Fluorinated betulinic acid derivatives and evaluation of their anti-HIV activity.

    PubMed

    Li, Jizhen; Goto, Masuo; Yang, Xiaoming; Morris-Natschke, Susan L; Huang, Li; Chen, Chin-Ho; Lee, Kuo-Hsiung

    2016-01-01

    Several fluorinated derivatives of the anti-HIV maturation agent bevirimat (1) were synthesized and evaluated for anti-HIV replication activity. The modified positions were the C-2, C-3, C-28, and C-30 positions, either directly on the betulinic acid (2) skeleton or in the attached side chains. Compound 18, which has a trifluoromethyl group added to C-30 of its isopropenyl group, exhibited similar potency to 1 against HIV-1NL4-3. In total, our current studies support our prior conclusion that C-30 allylic modification is unlikely to be a pharmacophore for anti-HIV activity, but could be a meaningful route to manipulate other properties of 2-related compounds.

  7. Stem cell based anti-HIV Gene therapy

    PubMed Central

    Kitchen, Scott G.; Shimizu, Saki; An, Dong Sung

    2011-01-01

    Human stem cell-based therapeutic intervention strategies for treating HIV infection have recently undergone a renaissance as a major focus of investigation. Unlike most conventional antiviral therapies, genetically engineered hematopoietic stem cells possess the capacity for prolonged self-renewal that would continuously produce protected immune cells to fight against HIV. A successful strategy therefore has the potential to stably control and ultimately eradicate HIV from patients by a single or minimal treatment. Recent progress in the development of new technologies and clinical trials sets the stage for the current generation of gene therapy approaches to combat HIV infection. In this review, we will discuss two major approaches that are currently underway in the development of stem cell-based gene therapy to target HIV: One that focuses on the protection of cells from productive infection with HIV, and the other that focuses on targeting immune cells to directly combat HIV infection. PMID:21247612

  8. Evaluation of Atazanavir and Darunavir Interactions with Lipids for Developing pH-responsive Anti-HIV Drug Combination Nanoparticles

    PubMed Central

    Duan, Jinghua; Freeling, Jennifer P.; Koehn, Josefin; Shu, Cuiling; Ho, Rodney J. Y.

    2014-01-01

    We evaluated two HIV protease inhibitors, atazanavir and darunavir, for pH-dependent solubility, lipid binding, and drug release from lipid nanoparticles. Both atazanavir and darunavir incorporated into lipid nanoparticles composed of pegylated and non-pegylated phospholipids with nearly 100% efficiency, but only atazanavir lipid nanoparticles formed stable lipid-drug particles and exhibited pH-dependent drug release. Darunavir lipid nanoparticles were unstable and formed mixed micelles at low drug-lipid concentrations, and thus are not suitable for lipid-drug particle development. When atazanavir lipid nanoparticles were prepared with ritonavir, a metabolic and cellular membrane exporter inhibitor, and tenofovir, an HIV reverse transcriptase inhibitor, stable, scalable, and reproducible anti-HIV drug combination lipid nanoparticles were produced. Drug incorporation efficiencies of 85.5 ± 8.2, 85.1 ± 7.1, and 6.1 ± 0.8 % for atazanavir, ritonavir, and tenofovir, respectively, were achieved. Preliminary primate pharmacokinetic studies with these pH-responsive anti-HIV drug combination lipid nanoparticles administered subcutaneously produced detectable plasma concentrations that lasted for 7 days for all three drugs. These anti-HIV lipid nanoparticles could be developed as a long-acting targeted antiretroviral therapy. PMID:24948204

  9. Conditional Cytotoxic Anti-HIV Gene Therapy for Selectable Cell Modification.

    PubMed

    Garg, Himanshu; Joshi, Anjali

    2016-05-01

    Gene therapy remains one of the potential strategies to achieve a cure for HIV infection. One of the major limitations of anti-HIV gene therapy concerns recovering an adequate number of modified cells to generate an HIV-proof immune system. Our study addresses this issue by developing a methodology that can mark conditional vector-transformed cells for selection and subsequently target HIV-infected cells for elimination by treatment with ganciclovir (GCV). We used the herpes simplex virus thymidine kinase (TK) mutant SR39, which is highly potent at killing cells at low GCV concentrations. This gene was cloned into a conditional HIV vector, pNL-GFPRRESA, which expresses the gene of interest as well as green fluorescent protein (GFP) in the presence of HIV Tat protein. We show here that TK-SR39 was more potent that wild-type TK (TK-WT) at eliminating infected cells at lower concentrations of GCV. As the vector expresses GFP in the presence of Tat, transient expression of Tat either by Tat RNA transfection or transduction by a nonintegrating lentiviral (NIL) vector marked the cells with GFP for selection. In cells selected by this strategy, TK-SR39 was more potent at limiting virus replication than TK-WT. Finally, in Jurkat cells modified and selected by this approach, infection with CXCR4-tropic Lai virus could be suppressed by treatment with GCV. GCV treatment limited the number of HIV-infected cells, virus production, as well as virus-induced cytopathic effects in this model. We provide proof of principle that TK-SR39 in a conditional HIV vector can provide a safe and effective anti-HIV strategy. PMID:26800572

  10. Evaluation of PD 404,182 as an Anti-HIV and Anti-Herpes Simplex Virus Microbicide

    PubMed Central

    Chamoun-Emanuelli, Ana M.; Bobardt, Michael; Moncla, Bernard; Mankowski, Marie K.; Ptak, Roger G.

    2014-01-01

    PD 404,182 (PD) is a synthetic compound that was found to compromise HIV integrity via interaction with a nonenvelope protein viral structural component (A. M. Chamoun et al., Antimicrob. Agents Chemother. 56:672–681, 2012). The present study evaluates the potential of PD as an anti-HIV microbicide and establishes PD's virucidal activity toward another pathogen, herpes simplex virus (HSV). We show that the anti-HIV-1 50% inhibitory concentration (IC50) of PD, when diluted in seminal plasma, is ∼1 μM, similar to the IC50 determined in cell culture growth medium, and that PD retains full anti-HIV-1 activity after incubation in cervical fluid at 37°C for at least 24 h. In addition, PD is nontoxic toward vaginal commensal Lactobacillus species (50% cytotoxic concentration [CC50], >300 μM), freshly activated human peripheral blood mononuclear cells (CC50, ∼200 μM), and primary CD4+ T cells, macrophages, and dendritic cells (CC50, >300 μM). PD also exhibited high stability in pH-adjusted Dulbecco's phosphate-buffered saline with little to no activity loss after 8 weeks at pH 4 and 42°C, indicating suitability for formulation for transportation and storage in developing countries. Finally, for the first time, we show that PD inactivates herpes simplex virus 1 (HSV-1) and HSV-2 at submicromolar concentrations. Due to the prevalence of HSV infection, the ability of PD to inactivate HSV may provide an additional incentive for use as a microbicide. The ability of PD to inactivate both HIV-1 and HSV, combined with its low toxicity and high stability, warrants additional studies for the evaluation of PD's microbicidal candidacy in animals and humans. PMID:24217696

  11. Is wetter better? An evaluation of over-the-counter personal lubricants for safety and anti-HIV-1 activity.

    PubMed

    Dezzutti, Charlene S; Brown, Elizabeth R; Moncla, Bernard; Russo, Julie; Cost, Marilyn; Wang, Lin; Uranker, Kevin; Kunjara Na Ayudhya, Ratiya P; Pryke, Kara; Pickett, Jim; Leblanc, Marc-André; Rohan, Lisa C

    2012-01-01

    Because lubricants may decrease trauma during coitus, it is hypothesized that they could aid in the prevention of HIV acquisition. Therefore, safety and anti-HIV-1 activity of over-the-counter (OTC) aqueous- (n = 10), lipid- (n = 2), and silicone-based (n = 2) products were tested. The rheological properties of the lipid-based lubricants precluded testing with the exception of explant safety testing. Six aqueous-based gels were hyperosmolar, two were nearly iso-osmolar, and two were hypo-osmolar. Evaluation of the panel of products showed Gynol II (a spermicidal gel containing 2% nonoxynol-9), KY Jelly, and Replens were toxic to Lactobacillus. Two nearly iso-osmolar aqueous- and both silicone-based gels were not toxic toward epithelial cell lines or ectocervical or colorectal explant tissues. Hyperosmolar lubricants demonstrated reduction of tissue viability and epithelial fracture/sloughing while the nearly iso-osmolar and silicon-based lubricants showed no significant changes in tissue viability or epithelial modifications. While most of the lubricants had no measurable anti-HIV-1 activity, three lubricants which retained cell viability did demonstrate modest anti-HIV-1 activity in vitro. To determine if this would result in protection of mucosal tissue or conversely determine if the epithelial damage associated with the hyperosmolar lubricants increased HIV-1 infection ex vivo, ectocervical tissue was exposed to selected lubricants and then challenged with HIV-1. None of the lubricants that had a moderate to high therapeutic index protected the mucosal tissue. These results show hyperosmolar lubricant gels were associated with cellular toxicity and epithelial damage while showing no anti-viral activity. The two iso-osmolar lubricants, Good Clean Love and PRÉ, and both silicone-based lubricants, Female Condom 2 lubricant and Wet Platinum, were the safest in our testing algorithm.

  12. Is wetter better? An evaluation of over-the-counter personal lubricants for safety and anti-HIV-1 activity.

    PubMed

    Dezzutti, Charlene S; Brown, Elizabeth R; Moncla, Bernard; Russo, Julie; Cost, Marilyn; Wang, Lin; Uranker, Kevin; Kunjara Na Ayudhya, Ratiya P; Pryke, Kara; Pickett, Jim; Leblanc, Marc-André; Rohan, Lisa C

    2012-01-01

    Because lubricants may decrease trauma during coitus, it is hypothesized that they could aid in the prevention of HIV acquisition. Therefore, safety and anti-HIV-1 activity of over-the-counter (OTC) aqueous- (n = 10), lipid- (n = 2), and silicone-based (n = 2) products were tested. The rheological properties of the lipid-based lubricants precluded testing with the exception of explant safety testing. Six aqueous-based gels were hyperosmolar, two were nearly iso-osmolar, and two were hypo-osmolar. Evaluation of the panel of products showed Gynol II (a spermicidal gel containing 2% nonoxynol-9), KY Jelly, and Replens were toxic to Lactobacillus. Two nearly iso-osmolar aqueous- and both silicone-based gels were not toxic toward epithelial cell lines or ectocervical or colorectal explant tissues. Hyperosmolar lubricants demonstrated reduction of tissue viability and epithelial fracture/sloughing while the nearly iso-osmolar and silicon-based lubricants showed no significant changes in tissue viability or epithelial modifications. While most of the lubricants had no measurable anti-HIV-1 activity, three lubricants which retained cell viability did demonstrate modest anti-HIV-1 activity in vitro. To determine if this would result in protection of mucosal tissue or conversely determine if the epithelial damage associated with the hyperosmolar lubricants increased HIV-1 infection ex vivo, ectocervical tissue was exposed to selected lubricants and then challenged with HIV-1. None of the lubricants that had a moderate to high therapeutic index protected the mucosal tissue. These results show hyperosmolar lubricant gels were associated with cellular toxicity and epithelial damage while showing no anti-viral activity. The two iso-osmolar lubricants, Good Clean Love and PRÉ, and both silicone-based lubricants, Female Condom 2 lubricant and Wet Platinum, were the safest in our testing algorithm. PMID:23144863

  13. Is Wetter Better? An Evaluation of Over-the-Counter Personal Lubricants for Safety and Anti-HIV-1 Activity

    PubMed Central

    Dezzutti, Charlene S.; Brown, Elizabeth R.; Moncla, Bernard; Russo, Julie; Cost, Marilyn; Wang, Lin; Uranker, Kevin; Kunjara Na Ayudhya, Ratiya P.; Pryke, Kara; Pickett, Jim; LeBlanc, Marc-André; Rohan, Lisa C.

    2012-01-01

    Because lubricants may decrease trauma during coitus, it is hypothesized that they could aid in the prevention of HIV acquisition. Therefore, safety and anti-HIV-1 activity of over-the-counter (OTC) aqueous- (n = 10), lipid- (n = 2), and silicone-based (n = 2) products were tested. The rheological properties of the lipid-based lubricants precluded testing with the exception of explant safety testing. Six aqueous-based gels were hyperosmolar, two were nearly iso-osmolar, and two were hypo-osmolar. Evaluation of the panel of products showed Gynol II (a spermicidal gel containing 2% nonoxynol-9), KY Jelly, and Replens were toxic to Lactobacillus. Two nearly iso-osmolar aqueous- and both silicone-based gels were not toxic toward epithelial cell lines or ectocervical or colorectal explant tissues. Hyperosmolar lubricants demonstrated reduction of tissue viability and epithelial fracture/sloughing while the nearly iso-osmolar and silicon-based lubricants showed no significant changes in tissue viability or epithelial modifications. While most of the lubricants had no measurable anti-HIV-1 activity, three lubricants which retained cell viability did demonstrate modest anti-HIV-1 activity in vitro. To determine if this would result in protection of mucosal tissue or conversely determine if the epithelial damage associated with the hyperosmolar lubricants increased HIV-1 infection ex vivo, ectocervical tissue was exposed to selected lubricants and then challenged with HIV-1. None of the lubricants that had a moderate to high therapeutic index protected the mucosal tissue. These results show hyperosmolar lubricant gels were associated with cellular toxicity and epithelial damage while showing no anti-viral activity. The two iso-osmolar lubricants, Good Clean Love and PRÉ, and both silicone-based lubricants, Female Condom 2 lubricant and Wet Platinum, were the safest in our testing algorithm. PMID:23144863

  14. Potential anti-HIV agents from marine resources: an overview.

    PubMed

    Vo, Thanh-Sang; Kim, Se-Kwon

    2010-11-29

    Human immunodeficiency virus (HIV) infection causes acquired immune deficiency syndrome (AIDS) and is a global public health issue. Anti-HIV therapy involving chemical drugs has improved the life quality of HIV/AIDS patients. However, emergence of HIV drug resistance, side effects and the necessity for long-term anti-HIV treatment are the main reasons for failure of anti-HIV therapy. Therefore, it is essential to isolate novel anti-HIV therapeutics from natural resources. Recently, a great deal of interest has been expressed regarding marine-derived anti-HIV agents such as phlorotannins, sulfated chitooligosaccharides, sulfated polysaccharides, lectins and bioactive peptides. This contribution presents an overview of anti-HIV therapeutics derived from marine resources and their potential application in HIV therapy.

  15. Potential Anti-HIV Agents from Marine Resources: An Overview

    PubMed Central

    Vo, Thanh-Sang; Kim, Se-Kwon

    2010-01-01

    Human immunodeficiency virus (HIV) infection causes acquired immune deficiency syndrome (AIDS) and is a global public health issue. Anti-HIV therapy involving chemical drugs has improved the life quality of HIV/AIDS patients. However, emergence of HIV drug resistance, side effects and the necessity for long-term anti-HIV treatment are the main reasons for failure of anti-HIV therapy. Therefore, it is essential to isolate novel anti-HIV therapeutics from natural resources. Recently, a great deal of interest has been expressed regarding marine-derived anti-HIV agents such as phlorotannins, sulfated chitooligosaccharides, sulfated polysaccharides, lectins and bioactive peptides. This contribution presents an overview of anti-HIV therapeutics derived from marine resources and their potential application in HIV therapy. PMID:21339954

  16. Anti-HIV-1 activity of eight monofloral Iranian honey types.

    PubMed

    Behbahani, Mandana

    2014-01-01

    Monofloral Iranian honeys from eight floral sources were analyzed to determine their anti-HIV-1 activities as well as their effects on lymphocyte proliferation. The Peripheral Blood Mononuclear Cells (PBMCs) used in this study were prepared from five healthy volunteers who were seronegative for HIV, HCV, HBV and TB. The anti-HIV-1 activity of eight different honeys was performed by quantitative polymerase chain reaction (PCR) assay and high pure viral nucleic acid kit. The results demonstrated that monofloral honeys from Petro selinum sativum, Nigella sativa, Citrus sinensis, Zataria multiflora, Citrus aurantium and Zizyphus mauritiana flowers had potent anti-HIV-1 activity with half maximal effective concentration (EC50) values of 37.5, 88, 70, 88, 105 and 5 µg/ml respectively. However, monofloral Iranian honeys from Astragalus gummifer and Chamaemelum nobile flowers had weak anti-HIV-1 activity. The frequency and intensity of CD4 expression on PBMCs increased in the presence of all honey types. CD19 marker were also increased after the treatment with monofloral honeys from Z. multiflora and N. sativa. The anti-HIV-1 agent in monofloral honeys from P. sativum, N. sativa, Z. multiflora and Z. mauritiana flowers was detected by spectroscopic analysis as methylglyoxal. Time of drug addition studies demonstrated that the inhibitory effect of methylglyoxal is higher on the late stage of HIV-1 infection. The result demonstrated that methylglyoxal isolated from monofloral honey types is a good candidate for preclinical evaluation of anti-HIV-1 therapies. PMID:25333699

  17. Toward a durable anti-HIV gene therapy based on RNA interference.

    PubMed

    Berkhout, Ben

    2009-09-01

    Basic research in the field of molecular biology led to the discovery of the mechanism of RNA interference (RNAi) in Caenorhabditis elegans in 1998. RNAi is now widely appreciated as an important gene control mechanism in mammals, and several RNAi-based gene-silencing applications have already been used in clinical trials. In this review I will discuss RNAi approaches to inhibit the pathogenic human immunodeficiency virus type 1 (HIV-1), which establishes a chronic infection that would most likely require a durable gene therapy approach. Viruses, such as HIV-1, are particularly difficult targets for RNAi attack because they mutate frequently, which allows viral escape by mutation of the RNAi target sequence. Combinatorial RNAi strategies are required to prevent viral escape. PMID:19796072

  18. RD2-MolPack-Chim3, a Packaging Cell Line for Stable Production of Lentiviral Vectors for Anti-HIV Gene Therapy

    PubMed Central

    Stornaiuolo, Anna; Piovani, Bianca Maria; Bossi, Sergio; Zucchelli, Eleonora; Corna, Stefano; Salvatori, Francesca; Mavilio, Fulvio; Bordignon, Claudio; Rizzardi, Gian Paolo

    2013-01-01

    Abstract Over the last two decades, several attempts to generate packaging cells for lentiviral vectors (LV) have been made. Despite different technologies, no packaging clone is currently employed in clinical trials. We developed a new strategy for LV stable production based on the HEK-293T progenitor cells; the sequential insertion of the viral genes by integrating vectors; the constitutive expression of the viral components; and the RD114-TR envelope pseudotyping. We generated the intermediate clone PK-7 expressing constitutively gag/pol and rev genes and, by adding tat and rd114-tr genes, the stable packaging cell line RD2-MolPack, which can produce LV carrying any transfer vector (TV). Finally, we obtained the RD2-MolPack-Chim3 producer clone by transducing RD2-MolPack cells with the TV expressing the anti-HIV transgene Chim3. Remarkably, RD114-TR pseudovirions have much higher potency when produced by stable compared with transient technology. Most importantly, comparable transduction efficiency in hematopoietic stem cells (HSC) is obtained with 2-logs less physical particles respect to VSV-G pseudovirions produced by transient transfection. Altogether, RD2-MolPack technology should be considered a valid option for large-scale production of LV to be used in gene therapy protocols employing HSC, resulting in the possibility of downsizing the manufacturing scale by about 10-fold in respect to transient technology. PMID:23767932

  19. RD2-MolPack-Chim3, a packaging cell line for stable production of lentiviral vectors for anti-HIV gene therapy.

    PubMed

    Stornaiuolo, Anna; Piovani, Bianca Maria; Bossi, Sergio; Zucchelli, Eleonora; Corna, Stefano; Salvatori, Francesca; Mavilio, Fulvio; Bordignon, Claudio; Rizzardi, Gian Paolo; Bovolenta, Chiara

    2013-08-01

    Over the last two decades, several attempts to generate packaging cells for lentiviral vectors (LV) have been made. Despite different technologies, no packaging clone is currently employed in clinical trials. We developed a new strategy for LV stable production based on the HEK-293T progenitor cells; the sequential insertion of the viral genes by integrating vectors; the constitutive expression of the viral components; and the RD114-TR envelope pseudotyping. We generated the intermediate clone PK-7 expressing constitutively gag/pol and rev genes and, by adding tat and rd114-tr genes, the stable packaging cell line RD2-MolPack, which can produce LV carrying any transfer vector (TV). Finally, we obtained the RD2-MolPack-Chim3 producer clone by transducing RD2-MolPack cells with the TV expressing the anti-HIV transgene Chim3. Remarkably, RD114-TR pseudovirions have much higher potency when produced by stable compared with transient technology. Most importantly, comparable transduction efficiency in hematopoietic stem cells (HSC) is obtained with 2-logs less physical particles respect to VSV-G pseudovirions produced by transient transfection. Altogether, RD2-MolPack technology should be considered a valid option for large-scale production of LV to be used in gene therapy protocols employing HSC, resulting in the possibility of downsizing the manufacturing scale by about 10-fold in respect to transient technology.

  20. GACPAT HIV 1 + 2: a simple, inexpensive assay to screen for, and discriminate between, anti-HIV 1 and anti-HIV 2.

    PubMed

    Parry, J V; Connell, J A; Reinbott, P; Garcia, A B; Avillez, F; Mortimer, P P

    1995-01-01

    A simple and cheap assay suitable for screening for anti-HIV 1 and anti-HIV 2 and discriminating between them was evaluated. In it specimens are incubated in U-bottomed microplate wells coated with anti-human IgG for 30 min at room temperature. After washing, 100 microliters of a 1 in 50 dilution of HIV 1-coated gelatin particles (Serodia-HIV 1/2, Fujirebio) are added. Settling patterns are read on the second day: A positive reaction is indicated by adherence of the particles and a negative by a button. The HIV 1 particles are then washed away and HIV 2 particles added. Anti-HIV 2 reaction patterns are read on the third day. To assess the performance of the modified "GACPAT HIV 1 + 2" assay a panel of 1,621 serum/plasma specimens was used. It comprised validated anti-HIV 1 positive (n = 220), anti-HIV 2 positive (n = 214), dual anti-HIV 1/anti-HIV 2 positive (n = 11), and anti-HIV negative (n = 1,176) serum/plasma specimens. All 434 specimens that contained anti-HIV 1 or anti-HIV 2 reacted positively with the homologous particles. The 11 dually positive specimens reacted positively with both HIV 1 and HIV 2 particles. Five (2.3%) anti-HIV 1 and five (2.3%) anti-HIV 2 positive specimens gave positive reactions with both particle types, but none of the five cross-reactive anti-HIV 2 specimens were dually reactive when the order of particle addition was reversed.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Anti-AIDS agents 85. Design, synthesis, and evaluation of 1R,2R-dicamphanoyl-3,3-dimethyldihydropyrano-[2,3-c]xanthen-7(1H)-one (DCX) derivatives as novel anti-HIV agents

    PubMed Central

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Huang, Li; Ho, Phong; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung

    2011-01-01

    In this study, 1R,2R-dicamphanoyl-3,3-dimethydihydropyrano[2,3-c]xanthen-7(1H)-one (DCX) derivatives were designed and synthesized as novel anti-HIV agents against both wild-type and nonnucleoside reverse transcriptase (RT) inhibitor-resistant HIV-1 (RTMDR-1) strains. Twenty-four DCX analogs (6-29) were synthesized and evaluated against the non-drug-resistant HIV-1 NL4-3 strain, and selected analogs were also screened for their ability to inhibit the RTMDR-1 strain. Compared with the control 2-ethyl-3′,4′-di-O-(-)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (2-EDCP, 2), one of the best anti-HIV coumarin derivatives in our prior study, three DCX compounds (7, 12, and 22) showed better activity against both HIV strains with an EC50 range of 0.062 – 0.081 μM, and five additional compounds (8, 11, 16, 18, and 21) exhibited comparable anti-HIV potency. Six DCX analogs (7, 11-12, 18, and 21-22) also showed enhanced selectivity index (SI) values in comparison to the control. Structure-activity relationship (SAR) information suggested that the extended conjugated system of the pyranoxanthone skeleton facilitates the interaction of the small DCX molecule within the viral binding pocket, consequently leading to enhanced anti-HIV activity and selectivity. Compared to DCP compounds, DCX analogs are a more promising new class of anti-HIV agents. PMID:22063755

  2. Cyclotriazadisulfonamides: promising new CD4-targeted anti-HIV drugs.

    PubMed

    Vermeire, Kurt; Schols, Dominique

    2005-08-01

    It is imperative to continue efforts to identify novel effective therapies that can assist in containing the spread of HIV. Recently acquired knowledge about the HIV entry process points to new strategies to block viral entry. For most HIV strains, the successful infection of their target cells is mainly dependent on the presence of the CD4 surface molecule, which serves as the primary virus receptor. The attachment of the viral envelope to this cellular CD4 receptor can be considered as an ideal target with multiple windows of opportunity for therapeutic intervention. Therefore, drugs that interfere with the CD4 receptor, and thus inhibit viral entry, may be promising agents for the treatment of AIDS. The CD4-targeted HIV entry inhibitors cyclotriazadisulfonamides represent a novel class of small molecule antiviral agents with a unique mode of action. The lead compound, CADA, specifically interacts with the cellular CD4 receptor and is active against a wide variety of HIV strains at submicromolar levels when evaluated in different cell-types such as T cells, monocytes and dendritic cells. Moreover, a strict correlation has been demonstrated between anti-HIV activity and CD4 interaction of about 20 different CADA analogues. In addition, CADA acted synergistically in combination with all other FDA-approved anti-HIV drugs as well as with compounds that target the main HIV co-receptors. In this article, the characteristics of cyclotriazadisulfonamide compounds are presented and the possible application of CADA as a microbicide is also discussed. PMID:15980096

  3. Design, Synthesis, and Biological Evaluation of 1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole Derivatives as Anti-HIV-1 Agents.

    PubMed

    Ashok, Penta; Lu, Cui-Lin; Chander, Subhash; Zheng, Yong-Tang; Murugesan, Sankarnarayanan

    2015-06-01

    A novel series of 1-(thiophen-2-yl)-9H-pyrido [3,4-b]indole derivatives were synthesized using DL-tryptophan as starting material. All the compounds were characterized by spectral analysis such as (1) H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV-1 replication. Among the reported analogues, compound 7g exhibited significant anti-HIV activity with EC(50) 0.53 μm and selectivity index 483; compounds 7e, 7i, and 7o displayed moderate activity with EC(50) 3.8, 3.8, and 2.8 μm and selectivity index >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV-1(IIIB) infected cell line C8166 with EC50 1.1 μm. In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug-likeness, and drug score of the synthesized analogues.

  4. Design, Synthesis, and Biological Evaluation of Novel 2-(Pyridin-3-yloxy)acetamide Derivatives as Potential Anti-HIV-1 Agents.

    PubMed

    Huang, Boshi; Li, Xiao; Zhan, Peng; De Clercq, Erik; Daelemans, Dirk; Pannecouque, Christophe; Liu, Xinyong

    2016-02-01

    Through a structure-based molecular hybridization and bioisosterism approach, a series of novel 2-(pyridin-3-yloxy)acetamide derivatives were designed, synthesized, and evaluated for their anti-HIV activities in MT-4 cell cultures. Biological results showed that three compounds (Ia, Ih, and Ij) exhibited moderate inhibitory activities against wild-type (wt) HIV-1 strain (IIIB ) with EC50 values ranging from 8.18 μm to 41.52 μm. Among them, Ij was the most active analogue possessing an EC50 value of 8.18 μm. To further confirm the binding target, four compounds were selected to implement an HIV-1 RT inhibitory assay. In addition, preliminary structure-activity relationship (SAR) analysis and some predicted physicochemical properties of three active compounds Ia, Ih, and Ij were discussed in detail. Molecular docking studies were also carried out to investigate the binding modes of Ij and the lead compound GW678248 in the binding pocket of RT, which provided beneficial information for further rational design of non-nucleoside reverse transcriptase inhibitors.

  5. Inhibition of in vivo HIV infection in humanized mice by gene therapy of human hematopoietic stem cells with a lentiviral vector encoding a broadly neutralizing anti-HIV antibody.

    PubMed

    Joseph, Aviva; Zheng, Jian Hua; Chen, Ken; Dutta, Monica; Chen, Cindy; Stiegler, Gabriela; Kunert, Renate; Follenzi, Antonia; Goldstein, Harris

    2010-07-01

    Due to the inherent immune evasion properties of the HIV envelope, broadly neutralizing HIV-specific antibodies capable of suppressing HIV infection are rarely produced by infected individuals. We examined the feasibility of utilizing genetic engineering to circumvent the restricted capacity of individuals to endogenously produce broadly neutralizing HIV-specific antibodies. We constructed a single lentiviral vector that encoded the heavy and light chains of 2G12, a broadly neutralizing anti-HIV human antibody, and that efficiently transduced and directed primary human B cells to secrete 2G12. To evaluate the capacity of this approach to provide protection from in vivo HIV infection, we used the humanized NOD/SCID/gamma(c)(null) mouse model, which becomes populated with human B cells, T cells, and macrophages after transplantation with human hematopoietic stem cells (hu-HSC) and develops in vivo infection after inoculation with HIV. The plasma of the irradiated NOD/SCID/gamma(c)(null) mice transplanted with hu-HSC transduced with the 2G12-encoding lentivirus contained 2G12 antibody, likely secreted by progeny human lymphoid and/or myeloid cells. After intraperitoneal inoculation with high-titer HIV-1(JR-CSF), mice engrafted with 2G12-transduced hu-HSC displayed marked inhibition of in vivo HIV infection as manifested by a profound 70-fold reduction in plasma HIV RNA levels and an almost 200-fold reduction in HIV-infected human cell numbers in mouse spleens, compared to control hu-HSC-transplanted NOD/SCID/gamma(c)(null) mice inoculated with equivalent high-titer HIV-1(JR-CSF). These results support the potential efficacy of this new gene therapy approach of using lentiviral vectors encoding a mixture of broadly neutralizing HIV antibodies for the treatment of HIV infection, particularly infection with multiple-drug-resistant isolates.

  6. Evaluation of a new fourth generation enzyme-linked immunosorbent assay, the LG HIV Ag-Ab Plus, with a combined HIV p24 antigen and anti-HIV-1/2/O screening test.

    PubMed

    Yeom, Joon-Sup; Jun, Gyo; Chang, Young; Sohn, Mi-Jin; Yoo, Seungbum; Kim, Eunkyung; Ryu, Seung-Ho; Kang, Hee-Jung; Kim, Young-A; Ahn, Sun-Young; Cha, Je-Eun; Youn, Sung-Tae; Park, Jae-Won

    2006-11-01

    The LG HIV Ag-Ab Plus, a new fourth generation diagnostic assay for HIV infection, was evaluated in comparison to the Enzygnost HIV Integral, an established fourth generation HIV assay. The LG assay showed 100% sensitivity with 109 samples with anti-HIV-1, anti-HIV-2 or anti-HIV-1 group O reactivity. It also detected correctly all 51 positives on three BBI performance panels, slightly outperforming the Enzygnost HIV Integral, which detected 50. The specificity of the LG HIV Ag-Ab Plus was 99.9% with 999 sera from healthy blood donors, which was slightly inferior to the performance of the Enzygnost HIV Integral, which had 100% specificity. The LG assay showed 100% specificity with 81 specimens with underlying diseases including hepatitis B, demonstrating a low risk of cross-reactivity with other infections. The reduction of the diagnostic window by the LG HIV Ag-Ab Plus, compared to a third generation HIV assay, was 6.3 days. The LG assay also showed sufficiently high intra-person and inter-person reproducibility. The overall performance of this new fourth generation HIV assay was adequate for screening and diagnosis of HIV infection.

  7. Anti-HIV Drug-Combination Nanoparticles Enhance Plasma Drug Exposure Duration as Well as Triple-Drug Combination Levels in Cells Within Lymph Nodes and Blood in Primates

    PubMed Central

    Freeling, Jennifer P.; Koehn, Josefin; Shu, Cuiling; Sun, Jianguo

    2015-01-01

    Abstract HIV patients on combination oral drug therapy experience insufficient drug levels in lymph nodes, which is linked to viral persistence. Following success in enhancing lymph node drug levels and extending plasma residence time of indinavir formulated in lipid nanoparticles, we developed multidrug anti-HIV lipid nanoparticles (anti-HIV LNPs) containing lopinavir (LPV), ritonavir (RTV), and tenofovir (PMPA). These anti-HIV LNPs were prepared, characterized, scaled up, and evaluated in primates with a focus on plasma time course and intracellular drug exposure in blood and lymph nodes. Four macaques were subcutaneously administered anti-HIV LNPs and free drug suspension in a crossover study. The time course of the plasma drug concentration as well as intracellular drug concentrations in blood and inguinal lymph nodes were analyzed to compare the effects of LNP formulation. Anti-HIV LNPs incorporated LPV and RTV with high efficiency and entrapped a reproducible fraction of hydrophilic PMPA. In primates, anti-HIV LNPs produced over 50-fold higher intracellular concentrations of LPV and RTV in lymph nodes compared to free drug. Plasma and intracellular drug levels in blood were enhanced and sustained up to 7 days, beyond that achievable by their free drug counterpart. Thus, multiple antiretroviral agents can be simultaneously incorporated into anti-HIV lipid nanoparticles to enhance intracellular drug concentrations in blood and lymph nodes, where viral replication persists. As these anti-HIV lipid nanoparticles also prolonged plasma drug exposure, they hold promise as a long-acting dosage form for HIV patients in addressing residual virus in cells and tissue. PMID:25402233

  8. Targeting anti-HIV drugs to the CNS

    PubMed Central

    Rao, Kavitha S; Ghorpade, Anuja; Labhasetwar, Vinod

    2009-01-01

    The development of antiretroviral drugs over the past couple of decades has been commendable due to the identification of several new targets within the overall Human Immunodeficiency Virus (HIV) replication cycle. However, complete control over HIV/Acquired Immune Deficiency Syndrome is yet to be achieved. This is because the current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. This occurs because most anti-HIV drugs do not accumulate in certain cellular and anatomical reservoirs including the Central Nervous System (CNS). Insufficient delivery of anti-HIV drugs to the CNS is attributed to their low permeability across the blood-brain-barrier (BBB). Hence, low and sustained viral replication within the CNS continues even during prolonged antiretroviral drug therapy. Therefore, developing novel approaches that are targeted at enhancing the CNS delivery of anti-HIV drugs are required. In this review, we discussed the potential of nanocarriers and the role of cell-penetrating peptides in enhancing drug delivery to the CNS. Such drug delivery approaches could also lead to higher drug delivery to other cellular and anatomical reservoirs where the virus harbor than with conventional treatment, thus providing an effective therapy to eliminate the virus completely from the body. PMID:19566446

  9. Anti-HIV-1 activity of flavonoid myricetin on HIV-1 infection in a dual-chamber in vitro model.

    PubMed

    Pasetto, Silvana; Pardi, Vanessa; Murata, Ramiro Mendonça

    2014-01-01

    HIV infection by sexual transmission remains an enormous global health concern. More than 1 million new infections among women occur annually. Microbicides represent a promising prevention strategy that women can easily control. Among emerging therapies, natural small molecules such as flavonoids are an important source of new active substances. In this study we report the in vitro cytotoxicity and anti-HIV-1 and microbicide activity of the following flavonoids: Myricetin, Quercetin and Pinocembrin. Cytotoxicity tests were conducted on TZM-bl, HeLa, PBMC, and H9 cell cultures using 0.01-100 µM concentrations. Myricetin presented the lowest toxic effect, with Quercetin and Pinocembrin relatively more toxic. The anti-HIV-1 activity was tested with TZM-bl cell plus HIV-1 BaL (R5 tropic), H9 and PBMC cells plus HIV-1 MN (X4 tropic), and the dual tropic (X4R5) HIV-1 89.6. All flavonoids showed anti-HIV activity, although Myricetin was more effective than Quercetin or Pinocembrin. In TZM-bl cells, Myricetin inhibited ≥90% of HIV-1 BaL infection. The results were confirmed by quantification of HIV-1 p24 antigen in supernatant from H9 and PBMC cells following flavonoid treatment. In H9 and PBMC cells infected by HIV-1 MN and HIV-1 89.6, Myricetin showed more than 80% anti-HIV activity. Quercetin and Pinocembrin presented modest anti-HIV activity in all experiments. Myricetin activity was tested against HIV-RT and inhibited the enzyme by 49%. Microbicide activities were evaluated using a dual-chamber female genital tract model. In the in vitro microbicide activity model, Myricetin showed promising results against different strains of HIV-1 while also showing insignificant cytotoxic effects. Further studies of Myricetin should be performed to identify its molecular targets in order to provide a solid biological foundation for translational research.

  10. Anti-HIV-1 Activity of Flavonoid Myricetin on HIV-1 Infection in a Dual-Chamber In Vitro Model

    PubMed Central

    Pasetto, Silvana; Pardi, Vanessa; Murata, Ramiro Mendonça

    2014-01-01

    HIV infection by sexual transmission remains an enormous global health concern. More than 1 million new infections among women occur annually. Microbicides represent a promising prevention strategy that women can easily control. Among emerging therapies, natural small molecules such as flavonoids are an important source of new active substances. In this study we report the in vitro cytotoxicity and anti-HIV-1 and microbicide activity of the following flavonoids: Myricetin, Quercetin and Pinocembrin. Cytotoxicity tests were conducted on TZM-bl, HeLa, PBMC, and H9 cell cultures using 0.01–100 µM concentrations. Myricetin presented the lowest toxic effect, with Quercetin and Pinocembrin relatively more toxic. The anti-HIV-1 activity was tested with TZM-bl cell plus HIV-1 BaL (R5 tropic), H9 and PBMC cells plus HIV-1 MN (X4 tropic), and the dual tropic (X4R5) HIV-1 89.6. All flavonoids showed anti-HIV activity, although Myricetin was more effective than Quercetin or Pinocembrin. In TZM-bl cells, Myricetin inhibited ≥90% of HIV-1 BaL infection. The results were confirmed by quantification of HIV-1 p24 antigen in supernatant from H9 and PBMC cells following flavonoid treatment. In H9 and PBMC cells infected by HIV-1 MN and HIV-1 89.6, Myricetin showed more than 80% anti-HIV activity. Quercetin and Pinocembrin presented modest anti-HIV activity in all experiments. Myricetin activity was tested against HIV-RT and inhibited the enzyme by 49%. Microbicide activities were evaluated using a dual-chamber female genital tract model. In the in vitro microbicide activity model, Myricetin showed promising results against different strains of HIV-1 while also showing insignificant cytotoxic effects. Further studies of Myricetin should be performed to identify its molecular targets in order to provide a solid biological foundation for translational research. PMID:25546350

  11. Diagnosis of human immunodeficiency virus (HIV) infection: multicenter evaluation of a newly developed anti-HIV 1 and 2 enzyme immunoassay.

    PubMed Central

    Hess, G; Avillez, F; Lourenco, M H; D'Agostino, F; Cambie, G; Piot, P; Vercauteren, G; Michl, U; Melchior, W; Bayer, H

    1994-01-01

    A new anti-human immunodeficiency virus type 1 and 2 (anti-HIV 1 and 2) test is described. It uses recombinant p24 and peptides covering gp32, gp41, and gp120 to identify HIV-1 and HIV-2 infections. This test has been shown to be specific (99.5%) and sensitive (99.8%). In this respect, the assay was equal or superior to anti-HIV 1 and 2 tests run as references. The test was able to discriminate sera from patients with HIV infections from those from uninfected individuals with excellence; it also exerted high intra- and interassay precisions. The "modular" concept of the test allows the use of single components (gp32 or gp41) to separate between HIV-2 and HIV-1 infections, respectively. PMID:8150950

  12. Anti-AIDS agents 86. Synthesis and anti-HIV evaluation of 2',3'-seco-3'-nor DCP and DCK analogues.

    PubMed

    Chen, Ying; Cheng, Ming; Liu, Fa-Qiang; Xia, Peng; Qian, Keduo; Yu, Donglei; Xia, Yi; Yang, Zheng-Yu; Chen, Chin-Ho; Morris-Natschke, Susan L; Lee, Kuo-Hsiung

    2011-10-01

    In a continuing study of novel anti-HIV agents with drug-like structures and properties, 30 1'-O-, 1'-S-, 4'-O- and 4'-substituted-2',3'-seco-3'-nor DCP and DCK analogues (8-37) were designed and synthesized. All newly synthesized seco-compounds were screened against HIV-1(NL4-3) and a multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR) strain in the TZM-bl cell line, using seco-DCK (7) and 2-ethyl-DCP (4) as controls. Several compounds (14, 18, 19, 22-24, and 32) exhibited potent anti-HIV activity with EC(50) values ranging from 0.93 to 1.93 μM and therapeutic index (TI) values ranging from 20 to 39. 1'-O-Isopropoxy-2',3'-seco-3'-nor-DCP (12) showed the greatest potency among the newly synthesized compounds with EC(50) values of 0.47 and 0.88 μM, and TI of 96 and 51, respectively, against HIV-1(NL4-3) and RTMDR strains. The seco-compounds exhibited better chemical stability in acidic conditions compared with DCP and DCK compounds. Overall, the results suggested that seco-DCP analogues with simplified structures may be more favorable for development as novel anti-HIV candidates.

  13. Synthesis and Biological Evaluation of Macrocyclized Betulin Derivatives as a Novel Class of Anti-HIV-1 Maturation Inhibitors

    PubMed Central

    Tang, Jun; Jones, Stacey A.; Jeffery, Jerry L.; Miranda, Sonia R.; Galardi, Cristin M.; Irlbeck, David M.; Brown, Kevin W.; McDanal, Charlene B.; Han, Nianhe; Gao, Daxin; Wu, Yongyong; Shen, Bin; Liu, Chunyu; Xi, Caiming; Yang, Heping; Li, Rui; Yu, Yajun; Sun, Yufei; Jin, Zhimin; Wang, Erjuan; Johns, Brian A.

    2014-01-01

    A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery. However, the synthetic challenge to access this structural class is high and hinders the exploration of macrocycles. In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established. The macrocycle containing compounds showed equal potency compared to bevirimat in multiple HIV-1 antiviral assays. The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed. PMID:25250097

  14. Synthesis and Anti-HIV-1 Evaluation of Some Novel MC-1220 Analogs as Non-Nucleoside Reverse Transcriptase Inhibitors.

    PubMed

    Loksha, Yasser M; Pedersen, Erik B; Loddo, Roberta; La Colla, Paolo

    2016-05-01

    Some novel MC-1220 analogs were synthesized by condensation of 4,6-dichloro-N-methylpyrimidin-2-amine derivatives (1a,b and 15) and/or 4-chloro-6-methoxy-N,N,5-trimethylpyrimidin-2-amine (2a) with the sodium salt of 2,6-difluorophenylacetonitrile followed by treatment with aqueous sodium hydroxide in methanol, alkylation, reduction, halogenation, and/or acidic hydrolysis. All synthesized compounds were evaluated for their activity against HIV-1. The most active compound in this study was compound 7, which showed activity against HIV-1 comparable to that of MC-1220. The only difference in structure between compound 7 and MC-1220 is a fluoro atom instead of a CH3 group. PMID:26996241

  15. [Development of anti-HIV agents based on chemical biology].

    PubMed

    Tamamura, Hirokazu

    2012-01-01

    Recently, highly active anti-retroviral therapy (HAART), which involves a combinational use of reverse transcriptase inhibitors and HIV protease inhibitors, has brought us a great success in the clinical treatment of AIDS patients. However, HAART has several serious clinical problems. These drawbacks encouraged us to find novel drugs and increase repertoires of anti-HIV agents with various action mechanisms. The recent disclosing of the dynamic supramolecular mechanism in HIV-entry has provided potentials to find a new type of drugs. To date, we have synthesized HIV-entry inhibitors, especially coreceptor CXCR4 antagonists. In addition, CD4 mimics in consideration of synergic effects with other entry inhibitors or neutralizing antibodies have been developed. The development of the above anti-HIV agents is based on the concept of reverse chemical genomics, in which target molecules are fixed. On the other hand, based on the concept of forward chemical genomics, in which active compounds are searched according to the screening of random libraries, effective peptide leads such as integrase inhibitors derived from fragment peptides of HIV-1 Vpr have been discovered. As such, from a point of view on chemical biology, anti-HIV leads have been found utilizing reverse and forward chemical genomics. Furthermore, antibody-based therapy or AIDS vaccine is still thought to be a promising treatment. Thus, peptidic antigen molecules based on artificial remodeling of the dynamic structures of a surface protein gp41 in HIV fusion have been developed. The present chemical biology approaches would be essential for discovery of anti-HIV agents in consideration of cocktail therapy of AIDS.

  16. Synthesis and bioevaluation of substituted chalcones, coumaranones and other flavonoids as anti-HIV agents.

    PubMed

    Cole, Amy L; Hossain, Sandra; Cole, Alex M; Phanstiel, Otto

    2016-06-15

    A series of chalcone, flavone, coumaranone and other flavonoid compounds were screened for their anti HIV-1 activity in two cell culture models using TZM-bl and PM1 cells. Within the systems evaluated, the most promising compounds contained either an α- or β-hydroxy-carbonyl motif within their structure (e.g., 8 and 9). Efficacious substituents were identified and used to design new HIV inhibitors with increased potency and lower cytotoxicity. Of the scaffolds evaluated, specific chalcones were found to provide the best balance between anti-HIV potency and low host cell toxicity. Chalcone 8l was shown to inhibit different clinical isolates of HIV in a dose-dependent manner (e.g., IC50 typically⩽5μM). Inhibition of HIV infection experiments using TZM-bl cells demonstrated that chalcone 8l and flavonol 9c had IC50 values of 4.7μM and 10.4μM, respectively. These insights were used to design new chalcones 8o and 8p. Rewardingly, chalcones 8o and 8p (at 10μM) each gave >92% inhibition of viral propagation without impacting PM1 host cell viability. Inhibition of viral propagation significantly increased (60-90%) when PM1 cells were pre-incubated with chalcone 8o, but not with the related flavonol 9c. These results suggested that chalcone 8o may be of value as both a HIV prophylactic and therapy. In summary, O-benzyl-substituted chalcones were identified as promising anti-HIV agents for future investigation. PMID:27161874

  17. Naturally derived anti-HIV agents.

    PubMed

    Asres, Kaleab; Seyoum, Ameha; Veeresham, Ciddi; Bucar, Franz; Gibbons, Simon

    2005-07-01

    The urgent need for new anti-HIV/AIDS drugs is a global concern. In addition to obvious economical and commercial hurdles, HIV/AIDS patients are faced with multifarious difficulties associated with the currently approved anti-HIV drugs. Adverse effects, the emergence of drug resistance and the narrow spectrum of activity have limited the therapeutic usefulness of the various reverse transcriptase and protease inhibitors that are currently available on the market. This has driven many scientists to look for new anti-retrovirals with better efficacy, safety and affordability. As has always been the case in the search for cures, natural sources offer great promise. Several natural products, mostly of plant origin have been shown to possess promising activities that could assist in the prevention and/or amelioration of the disease. Many of these anti-HIV agents have other medicinal values as well, which afford them further prospective as novel leads for the development of new drugs that can deal with both the virus and the various disorders that characterize HIV/AIDS. The aim of this review is to report new discoveries and updates pertaining to anti-HIV natural products. In the review anti-HIV agents have been classified according to their chemical classes rather than their target in the HIV replicative cycle, which is the most frequently encountered approach. Perusal of the literature revealed that most of these promising naturally derived anti-HIV compounds are flavonoids, coumarins, terpenoids, alkaloids, polyphenols, polysaccharides or proteins. It is our strong conviction that the results and experiences with many of the anti-HIV natural products will inspire and motivate even more researchers to look for new leads from plants and other natural sources. PMID:16161055

  18. Lectins with anti-HIV activity: a review.

    PubMed

    Akkouh, Ouafae; Ng, Tzi Bun; Singh, Senjam Sunil; Yin, Cuiming; Dan, Xiuli; Chan, Yau Sang; Pan, Wenliang; Cheung, Randy Chi Fai

    2015-01-01

    Lectins including flowering plant lectins, algal lectins, cyanobacterial lectins, actinomycete lectin, worm lectins, and the nonpeptidic lectin mimics pradimicins and benanomicins, exhibit anti-HIV activity. The anti-HIV plant lectins include Artocarpus heterophyllus (jacalin) lectin, concanavalin A, Galanthus nivalis (snowdrop) agglutinin-related lectins, Musa acuminata (banana) lectin, Myrianthus holstii lectin, Narcissus pseudonarcissus lectin, and Urtica diocia agglutinin. The anti-HIV algal lectins comprise Boodlea coacta lectin, Griffithsin, Oscillatoria agardhii agglutinin. The anti-HIV cyanobacterial lectins are cyanovirin-N, scytovirin, Microcystis viridis lectin, and microvirin. Actinohivin is an anti-HIV actinomycete lectin. The anti-HIV worm lectins include Chaetopterus variopedatus polychaete marine worm lectin, Serpula vermicularis sea worm lectin, and C-type lectin Mermaid from nematode (Laxus oneistus). The anti-HIV nonpeptidic lectin mimics comprise pradimicins and benanomicins. Their anti-HIV mechanisms are discussed. PMID:25569520

  19. Lectins with anti-HIV activity: a review.

    PubMed

    Akkouh, Ouafae; Ng, Tzi Bun; Singh, Senjam Sunil; Yin, Cuiming; Dan, Xiuli; Chan, Yau Sang; Pan, Wenliang; Cheung, Randy Chi Fai

    2015-01-01

    Lectins including flowering plant lectins, algal lectins, cyanobacterial lectins, actinomycete lectin, worm lectins, and the nonpeptidic lectin mimics pradimicins and benanomicins, exhibit anti-HIV activity. The anti-HIV plant lectins include Artocarpus heterophyllus (jacalin) lectin, concanavalin A, Galanthus nivalis (snowdrop) agglutinin-related lectins, Musa acuminata (banana) lectin, Myrianthus holstii lectin, Narcissus pseudonarcissus lectin, and Urtica diocia agglutinin. The anti-HIV algal lectins comprise Boodlea coacta lectin, Griffithsin, Oscillatoria agardhii agglutinin. The anti-HIV cyanobacterial lectins are cyanovirin-N, scytovirin, Microcystis viridis lectin, and microvirin. Actinohivin is an anti-HIV actinomycete lectin. The anti-HIV worm lectins include Chaetopterus variopedatus polychaete marine worm lectin, Serpula vermicularis sea worm lectin, and C-type lectin Mermaid from nematode (Laxus oneistus). The anti-HIV nonpeptidic lectin mimics comprise pradimicins and benanomicins. Their anti-HIV mechanisms are discussed.

  20. Natural Products as Anti-HIV Agents and Role in HIV-Associated Neurocognitive Disorders (HAND): A Brief Overview.

    PubMed

    Kurapati, Kesava Rao V; Atluri, Venkata S; Samikkannu, Thangavel; Garcia, Gabriella; Nair, Madhavan P N

    2015-01-01

    As the threat of Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) persists to rise, effective drug treatments are required to treat the infected people. Even though combination antiretroviral therapy (cART) provides stable viral suppression, it is not devoid of undesirable side effects, especially in persons undergoing long-term treatment. The present therapy finds its limitations in the emergence of multidrug resistance and accordingly finding new drugs and novel targets is the need of the hour to treat the infected persons and further to attack HIV reservoirs in the body like brain, lymph nodes to achieve the ultimate goal of complete eradication of HIV and AIDS. Natural products such as plant-originated compounds and plant extracts have enormous potential to become drug leads with anti-HIV and neuroprotective activity. Accordingly, many research groups are exploring the biodiversity of the plant kingdom to find new and better anti-HIV drugs with novel mechanisms of action and for HIV-associated neurocognitive disorders (HAND). The basic challenge that still persists is to develop viral replication-targeted therapy using novel anti-HIV compounds with new mode of action, accepted toxicity and less resistance profile. Against this backdrop, the World Health Organization (WHO) suggested the need to evaluate ethno-medicines for the management of HIV/AIDS. Consequently, there is need to evaluate traditional medicine, particularly medicinal plants and other natural products that may yield effective and affordable therapeutic agents. Although there are a good number of reports on traditional uses of plants to treat various diseases, knowledge of herbal remedies used to manage HIV/AIDS and HAND are scanty, vague and not well documented. In this review, plant substances showing a promising action that is anti-HIV and HAND will be explored along with what they interact. Since some plant substances are also known to modulate several cellular

  1. Natural Products as Anti-HIV Agents and Role in HIV-Associated Neurocognitive Disorders (HAND): A Brief Overview

    PubMed Central

    Kurapati, Kesava Rao V.; Atluri, Venkata S.; Samikkannu, Thangavel; Garcia, Gabriella; Nair, Madhavan P. N.

    2016-01-01

    As the threat of Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) persists to rise, effective drug treatments are required to treat the infected people. Even though combination antiretroviral therapy (cART) provides stable viral suppression, it is not devoid of undesirable side effects, especially in persons undergoing long-term treatment. The present therapy finds its limitations in the emergence of multidrug resistance and accordingly finding new drugs and novel targets is the need of the hour to treat the infected persons and further to attack HIV reservoirs in the body like brain, lymph nodes to achieve the ultimate goal of complete eradication of HIV and AIDS. Natural products such as plant-originated compounds and plant extracts have enormous potential to become drug leads with anti-HIV and neuroprotective activity. Accordingly, many research groups are exploring the biodiversity of the plant kingdom to find new and better anti-HIV drugs with novel mechanisms of action and for HIV-associated neurocognitive disorders (HAND). The basic challenge that still persists is to develop viral replication-targeted therapy using novel anti-HIV compounds with new mode of action, accepted toxicity and less resistance profile. Against this backdrop, the World Health Organization (WHO) suggested the need to evaluate ethno-medicines for the management of HIV/AIDS. Consequently, there is need to evaluate traditional medicine, particularly medicinal plants and other natural products that may yield effective and affordable therapeutic agents. Although there are a good number of reports on traditional uses of plants to treat various diseases, knowledge of herbal remedies used to manage HIV/AIDS and HAND are scanty, vague and not well documented. In this review, plant substances showing a promising action that is anti-HIV and HAND will be explored along with what they interact. Since some plant substances are also known to modulate several cellular

  2. Quinobene, a new potent anti-HIV agent.

    PubMed

    Gruszecka-Kowalik, E; Haugwitz, R D; Zalkow, L H

    1992-09-30

    A simple synthesis of the sulfonated azo dye Quinobene (3) and its derivatives, as well as the results of their evaluation in anti-HIV screening have been described. Thus, reacting the diazonium salt of 4,4'-diaminostilbene-2,2'-disulfonic acid with 8-hydroxyquinoline-5-sulfonic acid yielded the readily isolable title compound. The lithium and tetramethylammonium salts of Quinobene and its complexes with Cu(II), Zn(II), Mg(II) were also prepared. In vitro tests showed considerable activity of these compounds against HIV-1.

  3. Anti-HIV screening for cell-penetrating peptides using chloroquine and identification of anti-HIV peptides derived from matrix proteins.

    PubMed

    Mizuguchi, Takaaki; Ohashi, Nami; Nomura, Wataru; Komoriya, Mao; Hashimoto, Chie; Yamamoto, Naoki; Murakami, Tsutomu; Tamamura, Hirokazu

    2015-08-01

    Previously, compounds which inhibit the HIV-1 replication cycle were found in overlapping peptide libraries covering the whole sequence of an HIV-1 matrix (MA) protein constructed with the addition of an octa-arginyl group. The two top lead compounds are sequential fragments MA-8L and MA-9L. In the present study, the addition of chloroquine in cell-based anti-HIV assays was proven to be an efficient method with which to find anti-HIV compounds among several peptides conjugated by cell-penetrating signals such as an octa-arginyl group: the conjugation of an octa-arginyl group to individual peptides contained in whole proteins in combination with the addition of chloroquine in cells is a useful assay method to search active peptides. To find more potent fragment peptides, individual peptides between MA-8L and MA-9L, having the same peptide chain length but with sequences shifted by one amino acid residue, were synthesized in this paper and their anti-HIV activity was evaluated with an anti-HIV assay using chloroquine. As a result, the peptides in the C-terminal side of the series, which are relatively close to MA-9L, showed more potent inhibitory activity against both X4-HIV-1 and R5-HIV-1 than the peptides in the N-terminal side.

  4. [Advances in the study on anti-HIV lignan compounds].

    PubMed

    Qin, Hao; Gao, Li; Guo, Jun

    2012-09-01

    Lignan compounds have a variety of pharmacological activities. The mechanism of anti-HIV lignans is through affecting a particular aspect of HIV replication cycle, thus inhibiting viral replication and infection. Lignan is divided into four categories based on different anti-HIV detection methods. In this paper, we summarize the advance in the study on anti-HIV lignan compounds in last two decades.

  5. Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues.

    PubMed

    West, Anthony P; Scharf, Louise; Horwitz, Joshua; Klein, Florian; Nussenzweig, Michel C; Bjorkman, Pamela J

    2013-06-25

    Advances in single-cell antibody cloning methods have led to the identification of a variety of broadly neutralizing anti-HIV-1 antibodies. We developed a computational tool (Antibody Database) to help identify critical residues on the HIV-1 envelope protein whose natural variation affects antibody activity. Our simplifying assumption was that, for a given antibody, a significant portion of the dispersion of neutralization activity across a panel of HIV-1 strains is due to the amino acid identity or glycosylation state at a small number of specific sites, each acting independently. A model of an antibody's neutralization IC50 was developed in which each site contributes a term to the logarithm of the modeled IC50. The analysis program attempts to determine the set of rules that minimizes the sum of the residuals between observed and modeled IC50 values. The predictive quality of the identified rules may be assessed in part by whether there is support for rules within individual viral clades. As a test case, we analyzed antibody 8ANC195, an anti-glycoprotein gp120 antibody of unknown specificity. The model for this antibody indicated that several glycosylation sites were critical for neutralization. We evaluated this prediction by measuring neutralization potencies of 8ANC195 against HIV-1 in vitro and in an antibody therapy experiment in humanized mice. These experiments confirmed that 8ANC195 represents a distinct class of glycan-dependent anti-HIV-1 antibody and validated the utility of computational analysis of neutralization panel data.

  6. Synthesis and anti-HIV evaluation of hybrid-type prodrugs conjugating HIV integrase inhibitors with d4t by self-cleavable spacers containing an amino acid residue.

    PubMed

    Fossey, Christine; Huynh, Ngoc-Trinh; Vu, Anh-Hoang; Vidu, Anamaria; Zarafu, Irina; Laduree, Daniel; Schmidt, Sylvie; Laumond, Geraldine; Aubertin, Anne-Marie

    2007-10-01

    In an attempt to combine the anti-HIV inhibitory capacity of reverse transcriptase (RT) inhibitors (NRTIs) and integrase (IN) inhibitors (INIs), several heterodimer analogues of the previously reported [d4T]-PABC-[INI] and [d4T]-OABC-[INI] prototypes have been prepared. In these novel series, we wished to extend our results to conjugates which incorporated an enzymatically labile aminoacid unit (L-alanine) connected to d4T through a self-immolative para- or ortho-aminobenzyl carbonate (PABC or OABC) spacer. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable to that of the [L-708,906]-PABC-[d4T] Heterodimer A prototype. However, although the compounds proved inhibitory to HIV-1, they were less potent than the parent compounds from which they were derived.

  7. Synthesis and Anti-HIV-1 Activity Evaluation for Novel 3a,6a-Dihydro-1H-pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives.

    PubMed

    Liu, Guan-Nan; Luo, Rong-Hua; Zhou, Yu; Zhang, Xing-Jie; Li, Jian; Yang, Liu-Meng; Zheng, Yong-Tang; Liu, Hong

    2016-01-01

    The search for new molecular constructs that resemble the critical two-metal binding pharmacophore and the halo-substituted phenyl functionality required for HIV-1 integrase (IN) inhibition represents a vibrant area of research within drug discovery. As reported herein, we have modified our recently disclosed 1-[2-(4-fluorophenyl)ethyl]-pyrrole-2,5-dione scaffolds to design 35 novel compounds with improved biological activities against HIV-1. These new compounds show single-digit micromolar antiviral potencies against HIV-1 and low toxicity. Among of them, compound 9g and 15i had potent anti-HIV-1 activities (EC50 < 5 μM) and excellent therapeutic index (TI, CC50/EC50 > 100). These two compounds have potential as lead compounds for further optimization into clinical anti-HIV-1 agents. PMID:27617994

  8. Anti-HIV activity of Indian medicinal plants.

    PubMed

    Sabde, Sudeep; Bodiwala, Hardik S; Karmase, Aniket; Deshpande, Preeti J; Kaur, Amandeep; Ahmed, Nafees; Chauthe, Siddheshwar K; Brahmbhatt, Keyur G; Phadke, Rasika U; Mitra, Debashis; Bhutani, Kamlesh Kumar; Singh, Inder Pal

    2011-07-01

    Acquired immunodeficiency syndrome patients face great socio-economic difficulties in obtaining treatment. There is an urgent need for new, safe, and cheap anti-HIV agents. Traditional medicinal plants are a valuable source of novel anti-HIV agents and may offer alternatives to expensive medicines in future. Various medicinal plants or plant-derived natural products have shown strong anti-HIV activity and are under various stages of clinical development in different parts of the world. The present study was directed towards assessment of anti-HIV activity of various extracts prepared from Indian medicinal plants. The plants were chosen on the basis of similarity of chemical constituents with reported anti-HIV compounds or on the basis of their traditional usage as immunomodulators. Different extracts were prepared by Soxhlet extraction and liquid-liquid partitioning. Ninety-two extracts were prepared from 23 plants. Anti-HIV activity was measured in a human CD4+ T-cell line, CEM-GFP cells infected with HIV-1NL4.3. Nine extracts of 8 different plants significantly reduced viral production in CEM-GFP cells infected with HIV-1NL4.3. Aegle marmelos, Argemone mexicana, Asparagus racemosus, Coleus forskohlii, and Rubia cordifolia demonstrated promising anti-HIV potential and were investigated for their active principles. PMID:21365365

  9. Glycosystems in nanotechnology: Gold glyconanoparticles as carrier for anti-HIV prodrugs.

    PubMed

    Chiodo, Fabrizio; Marradi, Marco; Calvo, Javier; Yuste, Eloisa; Penadés, Soledad

    2014-01-01

    The therapeutic approach for the treatment of HIV infection is based on the highly active antiretroviral therapy (HAART), a cocktail of antiretroviral drugs. Notwithstanding HAART has shown different drawbacks like toxic side effects and the emergence of viral multidrug resistance. Nanotechnology offers new tools to improve HIV drug treatment and prevention. In this scenario, gold nanoparticles are an interesting chemical tool to design and prepare smart and efficient drug-delivery systems. Here we describe the preparation and antiviral activity of carbohydrate-coated gold nanoparticles loaded with anti-HIV prodrug candidates. The nucleoside reverse transcriptase inhibitors abacavir and lamivudine have been converted to the corresponding thiol-ending ester derivatives and then conjugated to ~3 nm glucose-coated gold nanoparticles by means of "thiol-for-thiol" ligand place exchange reactions. The drugs-containing glyconanoparticles were characterized and the pH-mediated release of the drug from the nanoparticle has been determined. The antiviral activity was tested by evaluating the replication of NL4-3 HIV in TZM-bl infected cells. The proof-of-principle presented in this work aims to introduce gold glyconanoparticles as a new multifunctional drug-delivery system in the therapy against HIV.

  10. Glycosystems in nanotechnology: Gold glyconanoparticles as carrier for anti-HIV prodrugs.

    PubMed

    Chiodo, Fabrizio; Marradi, Marco; Calvo, Javier; Yuste, Eloisa; Penadés, Soledad

    2014-01-01

    The therapeutic approach for the treatment of HIV infection is based on the highly active antiretroviral therapy (HAART), a cocktail of antiretroviral drugs. Notwithstanding HAART has shown different drawbacks like toxic side effects and the emergence of viral multidrug resistance. Nanotechnology offers new tools to improve HIV drug treatment and prevention. In this scenario, gold nanoparticles are an interesting chemical tool to design and prepare smart and efficient drug-delivery systems. Here we describe the preparation and antiviral activity of carbohydrate-coated gold nanoparticles loaded with anti-HIV prodrug candidates. The nucleoside reverse transcriptase inhibitors abacavir and lamivudine have been converted to the corresponding thiol-ending ester derivatives and then conjugated to ~3 nm glucose-coated gold nanoparticles by means of "thiol-for-thiol" ligand place exchange reactions. The drugs-containing glyconanoparticles were characterized and the pH-mediated release of the drug from the nanoparticle has been determined. The antiviral activity was tested by evaluating the replication of NL4-3 HIV in TZM-bl infected cells. The proof-of-principle presented in this work aims to introduce gold glyconanoparticles as a new multifunctional drug-delivery system in the therapy against HIV. PMID:24991287

  11. Development of an implantable infusion pump for sustained anti-HIV drug administration.

    PubMed

    Baert, Lieven; Schueller, Laurent; Tardy, Yanik; Macbride, Doug; Klooster, Gerben van't; Borghys, Herman; Clessens, Ellen; Van Den Mooter, Guy; Van Gyseghem, Elke; Van Remoortere, Pieter; Wigerinck, Piet; Rosier, Jan

    2008-05-01

    Factors such as insufficient drug potency, non-compliance and restricted tissue penetration contribute to incomplete suppression of Human Immunodeficiency Virus (HIV) and the difficulty to control this infection. Infusion via standard catheters can be a source of infection, which is potentially life threatening in these patients. We developed an implantable infusion pump, allowing to accommodate large volumes (16-50mL) of high viscous solutions (up to 23.96mPas at 39 degrees C) of anti-HIV agents and providing sustained release of medication: a standard Codman 3000 pump, which was initially developed to release aqueous solutions ( approximately 0.7mPas) into the spinal cord such as for pain medication, was transformed for release of viscous solutions up to 40mPas by adapting the diameter of the capillary flow restrictor, the capillary length and way of catheterisation--by placing the indwelling catheter in the vena cava. A pilot study of the pump implanted in 2 dogs showed continuous steady-state release of the protease inhibitor darunavir (25mg/dog/day administered for 25 days), thereby achieving plasma concentration levels of approximately 40ng/mL. Steady-state plasma levels were reproducible after monthly refill of the pumps. In conclusion, the implantable adapted Codman 3000 constant-flow infusion pump customized to anti-HIV therapy allows sustained release of anti-HIV medication and may represent an opportunity to reduce the pill burden and complexity of dosing schemes associated with common anti-HIV therapy.

  12. DNA Triplex-Based Complexes Display Anti-HIV-1-Cell Fusion Activity

    PubMed Central

    Xu, Liang; Zhang, Tao; Xu, Xiaoyu; Chong, Huihui; Lai, Wenqing; Jiang, Xifeng; Wang, Chao

    2015-01-01

    DNA triplexes with hydrophobic modifications were designed and evaluated for their activity as inhibitors of the cell fusion of human immunodeficiency virus type 1 (HIV-1). Triplex inhibitors displayed low micromolar activities in the cell–cell fusion assay and nanomolar activities in the anti-HIV-1 pseudovirus test. Helix structure and the presence of sufficient numbers of hydrophobic regions were essential for the antifusion activity. Results from native polyacrylamide gel electrophoresis and a fluorescent resonance energy transfer-based inhibitory assay indicated that these triplexes may interact with the primary pocket at the glycoprotein 41 (gp41) N-heptad repeat, thereby inhibiting formation of the HIV-1 gp41 6-helical bundle. Triplex-based complexes may represent a novel category of HIV-1 inhibitors in anti-HIV-1 drug discovery. PMID:26192705

  13. [Evaluation of the analytic performance of blood collection tubes (BD Vacutainer SST) for the screening of anti-HIV, anti-HTLV, anti-HCV, anti-HBc, anti-CMV antibodies, and of HBs, P24 HIV antigens, and of alanine aminotransferase].

    PubMed

    Gobin, E; Desruelle, J M; Vigier, J P

    2001-02-01

    The Laboratory of Viral Diseases Immunology (Laboratoire d'Immunologie des Maladies Virales) of the Northern Region Blood Bank (Etablissement Français du Sang Nord de France) performs between 180.000 and 200.000 viral blood qualifications per year. The use of a serum gel separator evacuated tube should contribute to improve the quality of the pre-analytical phase. However, it must not impact negatively the analytical performances. We evaluated such tube within our specific environment and with the various reagents used in routine. The open study compared the BD Vacutainer plain tube (7 mL, non siliconised) with the BD Vacutainer SST tube (6 mL siliconised with serum gel separator) against the anti-HIV, anti-HTLV, anti-HCV, anti-HBc, anti-HBs, anti-CMV antibodies, the HBs, HIV P24 antigen and the alanine aminotransferase. The study objectives were to find potential gel interference; to verify the diagnostic sensitivity, reagents specificity, and reproducibility. The results analysis show: equivalent performances with the anti-HIV Ab (Anti HIV 1/2 recombinant--Biotest et Genscreen HIV 1/2--Sanofi), anti HIV WB Ab (New Lav Blot 1--Sanofi), anti-HBs Ab (Enzygnost anti-HBs micro--Behring), anti-HBc Ab (HBc Elisa Test System--Ortho), anti-CMV Ab (Enzygnost anti-CMV IgG + M--Behring) kits; lower performances with: The Vironostika HIV Uni Form II plus 0--Organon kit with a -3.5% signal decrease around the ratio R = 2.7 for positive anti-HIV Ab. The Elisa test System 3 Ag HBs-Ortho kit with an increase of the mean ratio of the negative Ag HBs samples; better performances with: the Vironostika HIV 1 Antigen--Organon kit with a +10% signal increase around the threshold ratio R = 1 for positive Ag HIV samples. This deserves further study to verify that the specificity is maintained. The HTLV Type 1 et 2 EIA--Ortho kit with +8% signal increase around the ratio R = 2 for positive anti-HTLV Ab samples without change of the specificity. The Ortho HCV 3.0 Elisa Test System and

  14. Unciaphenol, an Oxygenated Analogue of the Bergman Cyclization Product of Uncialamycin Exhibits Anti-HIV Activity.

    PubMed

    Williams, David E; Bottriell, Helen; Davies, Julian; Tietjen, Ian; Brockman, Mark A; Andersen, Raymond J

    2015-11-01

    Unciaphenol (2), an oxygenated analogue of the Bergman cyclization product of the enediyne uncialamycin (1), has been isolated along with 1 from cultures of the actinomycete Streptomyces uncialis. It is proposed that the C-22 OH substituent in 2 might arise from the attack of a nucleophilic oxygen species on the p-benzyne diradical intermediate IA in the Bergman cyclization of 1. 2 shows in vitro anti-HIV activity against viral strains that are resistant to clinically utilized anti-retroviral therapies.

  15. Henrin A: A New Anti-HIV Ent-Kaurane Diterpene from Pteris henryi.

    PubMed

    Li, Wan-Fei; Wang, Juan; Zhang, Jing-Jie; Song, Xun; Ku, Chuen-Fai; Zou, Juan; Li, Ji-Xin; Rong, Li-Jun; Pan, Lu-Tai; Zhang, Hong-Jie

    2015-11-24

    Henrin A (1), a new ent-kaurane diterpene, was isolated from the leaves of Pteris henryi. The chemical structure was elucidated by analysis of the spectroscopic data including one-dimensional (1D) and two-dimensional (2D) NMR spectra, and was further confirmed by X-ray crystallographic analysis. The compound was evaluated for its biological activities against a panel of cancer cell lines, dental bacterial biofilm formation, and HIV. It displayed anti-HIV potential with an IC50 value of 9.1 µM (SI = 12.2).

  16. Henrin A: A New Anti-HIV Ent-Kaurane Diterpene from Pteris henryi

    PubMed Central

    Li, Wan-Fei; Wang, Juan; Zhang, Jing-Jie; Song, Xun; Ku, Chuen-Fai; Zou, Juan; Li, Ji-Xin; Rong, Li-Jun; Pan, Lu-Tai; Zhang, Hong-Jie

    2015-01-01

    Henrin A (1), a new ent-kaurane diterpene, was isolated from the leaves of Pteris henryi. The chemical structure was elucidated by analysis of the spectroscopic data including one-dimensional (1D) and two-dimensional (2D) NMR spectra, and was further confirmed by X-ray crystallographic analysis. The compound was evaluated for its biological activities against a panel of cancer cell lines, dental bacterial biofilm formation, and HIV. It displayed anti-HIV potential with an IC50 value of 9.1 µM (SI = 12.2). PMID:26610490

  17. Design, synthesis and anti-HIV activity of novel quinoxaline derivatives.

    PubMed

    Patel, Saloni B; Patel, Bhumika D; Pannecouque, Christophe; Bhatt, Hardik G

    2016-07-19

    In order to design novel anti-HIV agents, pharmacophore modelling, virtual screening, 3D-QSAR and molecular docking studies were performed. Pharmacophore model was generated using 17 structurally diverse molecules using DISCOtech followed by refinement with GASP module of Sybyl X. The best model containing four features; two donor sites, one acceptor atom and one hydrophobic region; was used as a query for virtual screening in NCI database and 6 compounds with Qfit value ≥98 were retrieved. The quinoxaline ring which is the bio-isostere of pteridine ring, retrieved as a hit in virtual screening, was selected as a core moiety. 3D-QSAR was carried on thirty five 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide derivatives. Contour map analysis of best CoMFA and CoMSIA model suggested incorporation of hydrophobic, bulky and electronegative groups to increase potency of the designed compounds. 50 quinoxaline derivatives with different substitutions were designed on basis of both ligand based drug design approaches and were mapped on the best pharmacophore model. From this, best 32 quinoxaline derivatives were docked onto the active site of integrase enzyme and in-silico ADMET properties were also predicted. From this data, synthesis of top 7 quinoxaline derivatives was carried out and were characterized using Mass, (1)H-NMR and (13)C-NMR spectroscopy. Purity of compounds were checked using HPLC. These derivatives were evaluated for anti-HIV activity on III-B strain of HIV-1 and cytotoxicity studies were performed on VERO cell line. Two quinoxaline derivatives (7d and 7e) showed good results, which can be further explored to develop novel anti-HIV agents.

  18. Design, synthesis and anti-HIV activity of novel quinoxaline derivatives.

    PubMed

    Patel, Saloni B; Patel, Bhumika D; Pannecouque, Christophe; Bhatt, Hardik G

    2016-07-19

    In order to design novel anti-HIV agents, pharmacophore modelling, virtual screening, 3D-QSAR and molecular docking studies were performed. Pharmacophore model was generated using 17 structurally diverse molecules using DISCOtech followed by refinement with GASP module of Sybyl X. The best model containing four features; two donor sites, one acceptor atom and one hydrophobic region; was used as a query for virtual screening in NCI database and 6 compounds with Qfit value ≥98 were retrieved. The quinoxaline ring which is the bio-isostere of pteridine ring, retrieved as a hit in virtual screening, was selected as a core moiety. 3D-QSAR was carried on thirty five 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide derivatives. Contour map analysis of best CoMFA and CoMSIA model suggested incorporation of hydrophobic, bulky and electronegative groups to increase potency of the designed compounds. 50 quinoxaline derivatives with different substitutions were designed on basis of both ligand based drug design approaches and were mapped on the best pharmacophore model. From this, best 32 quinoxaline derivatives were docked onto the active site of integrase enzyme and in-silico ADMET properties were also predicted. From this data, synthesis of top 7 quinoxaline derivatives was carried out and were characterized using Mass, (1)H-NMR and (13)C-NMR spectroscopy. Purity of compounds were checked using HPLC. These derivatives were evaluated for anti-HIV activity on III-B strain of HIV-1 and cytotoxicity studies were performed on VERO cell line. Two quinoxaline derivatives (7d and 7e) showed good results, which can be further explored to develop novel anti-HIV agents. PMID:27105027

  19. Synthetic galactomannans with potent anti-HIV activity.

    PubMed

    Budragchaa, Davaanyam; Bai, Shiming; Kanamoto, Taisei; Nakashima, Hideki; Han, Shuqin; Yoshida, Takashi

    2015-10-01

    Ring-opening polymerization of a new 1,6-anhydro disaccharide monomer, 1, 6-anhydro-2, 3-di-O-benzyl-4-O-(2', 3', 4', 6'-tetra-O-benzyl-α-d-galactopyranosyl)-α-d-mannopyranose, was carried out using PF5 as a catalyst under high vacuum at -60°C to give galactose branched mannopyranan (synthetic galactomannan), 4-O-α-d-galactopyranosyl-(1→6)-α-d-mannopyranan, after debenzylation with Na in liquid NH3. The ring-opening copolymerization with 1, 6-anhydro-tri-O-benzyl-α-d-mannopyranose in various feeds was also performed to give synthetic galactomannans with various proportions of galactose branches. After sulfation, sulfated synthetic galactomannans were found to have anti-HIV activity and cytotoxicity as high and low as those of standard curdlan and dextran sulfates, respectively, which are potent anti-HIV sulfated polysaccharides with low cytotoxicity. The anti-HIV mechanism of sulfated synthetic galactomannans used by poly-l-lysine as a model peptide of the HIV surface protein was estimated by using SPR, DSL, and zeta potential measurements, revealing the electrostatic interaction between negatively charged sulfate groups and positively charged amino groups.

  20. Synthetic galactomannans with potent anti-HIV activity.

    PubMed

    Budragchaa, Davaanyam; Bai, Shiming; Kanamoto, Taisei; Nakashima, Hideki; Han, Shuqin; Yoshida, Takashi

    2015-10-01

    Ring-opening polymerization of a new 1,6-anhydro disaccharide monomer, 1, 6-anhydro-2, 3-di-O-benzyl-4-O-(2', 3', 4', 6'-tetra-O-benzyl-α-d-galactopyranosyl)-α-d-mannopyranose, was carried out using PF5 as a catalyst under high vacuum at -60°C to give galactose branched mannopyranan (synthetic galactomannan), 4-O-α-d-galactopyranosyl-(1→6)-α-d-mannopyranan, after debenzylation with Na in liquid NH3. The ring-opening copolymerization with 1, 6-anhydro-tri-O-benzyl-α-d-mannopyranose in various feeds was also performed to give synthetic galactomannans with various proportions of galactose branches. After sulfation, sulfated synthetic galactomannans were found to have anti-HIV activity and cytotoxicity as high and low as those of standard curdlan and dextran sulfates, respectively, which are potent anti-HIV sulfated polysaccharides with low cytotoxicity. The anti-HIV mechanism of sulfated synthetic galactomannans used by poly-l-lysine as a model peptide of the HIV surface protein was estimated by using SPR, DSL, and zeta potential measurements, revealing the electrostatic interaction between negatively charged sulfate groups and positively charged amino groups. PMID:26076622

  1. A new vinyl selenone-based domino approach to spirocyclopropyl oxindoles endowed with anti-HIV RT activity.

    PubMed

    Palomba, M; Rossi, L; Sancineto, L; Tramontano, E; Corona, A; Bagnoli, L; Santi, C; Pannecouque, C; Tabarrini, O; Marini, F

    2016-02-14

    Herein, we disclose a general and flexible access to spirocyclopropyl oxindoles by a domino Michael/intramolecular nucleophilic substitution pathway with variously substituted vinyl selenones and enolizable oxindoles in aqueous sodium hydroxide solution. The spirocyclopropyl oxindole being a privileged scaffold, some of the synthesized compounds were selected for biological evaluation. Compound showed selective anti-HIV-1 activity thanks to its ability to inhibit the reverse transcriptase.

  2. Marine natural products with anti-HIV activities in the last decade.

    PubMed

    Zhou, Xuefeng; Liu, Juan; Yang, Bin; Lin, Xiuping; Yang, Xian-Wen; Liu, Yonghong

    2013-01-01

    Marine organisms have been proven to be excellent sources of biologically active compounds against HIV. This review gives an overview of 132 natural products from marine sources obtained during the last decade (2002-2011), which exhibit anti-HIV activity toward different biological targets. Sponges contribute more than half of all anti-HIV natural products from marine organisms, mainly as alkaloids and cyclic depsipeptides. In addition, some macromolecules are considered as potential anti-HIV agents, including lectins from algae and marine invertebrates, as well as sulfated polysaccharides from algae. In the reviewed marine natural products, many active ingredients act as HIV entry inhibitors, one class of new anti-HIV agents, and may be regarded as potential candidates for the development of novel anti-HIV agents. The other features of development in the marine original anti-HIV natural products in this ten years are also discussed.

  3. Aaptamine derivatives with antifungal and anti-HIV-1 activities from the South China Sea sponge Aaptos aaptos.

    PubMed

    Yu, Hao-Bing; Yang, Fan; Sun, Fan; Li, Jing; Jiao, Wei-Hua; Gan, Jian-Hong; Hu, Wen-Zhen; Lin, Hou-Wen

    2014-12-01

    Five new alkaloids of aaptamine family, compounds (1-5) and three known derivatives (6-8), have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated by spectroscopic analyses, as well as by comparison with the literature data. Compounds 1-2 are characterized with triazapyrene lactam skeleton, whereas compounds 4-5 share an imidazole-fused aaptamine moiety. These compounds were evaluated in antifungal and anti-HIV-1 assays. Compounds 3, 7, and 8 showed antifungal activity against six fungi, with MIC values in the range of 4 to 64 μg/mL. Compounds 7-8 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 μM.

  4. The utility of self-emulsifying oil formulation to improve the poor solubility of the anti HIV drug CSIC

    PubMed Central

    2013-01-01

    Background CSIC (5-chloro-3-phenylsulfonylindole-2-carboxamide), a non-nucleoside reverse transcriptase inhibitor (NNRTI) has not been advanced as a therapeutic anti-HIV candidate drug due to its low aqueous solubility and poor bioavailability. Objective The objective of this work was to formulate CSIC into self-emulsifying oil formulations for the purpose of improving its aqueous solubility and evaluating in vitro antiretroviral activity. Methods CSIC self-emulsifying oil formulations (SEFs) were formulated and evaluated for droplet size, zeta potential, polydispersity index (PDI), viscosity, emulsification time, stability and bioactivity. Results Results showed significantly improved solubility of CSIC in the SEFs.The concentration of co-surfactant affected the droplet size, zeta potential and polydispersity index. In vitro bioactivity studies showed that the CSIC SEFs retained full anti-HIV activity. Conclusion The in vitro data from this first attempt to formulate CSIC SEFs suggest that improvement on the aqueous solubility of CSIC through this delivery system may accentuate its antiretroviral effectiveness in vivo via bioavailability enhancement. The formulation is therefore intended as an oral anti-HIV agent for prophylactic and therapeutic uses. PMID:23721408

  5. Synthesis of zidovudine derivatives with anti-HIV-1 and antibacterial activities.

    PubMed

    Senthilkumar, Palaniappan; Long, Jing; Swetha, Raparla; Shruthi, Vaidyanathan; Wang, Rui-Rui; Preethi, Srinivasan; Yogeeswari, Perumal; Zheng, Yong-Tang; Sriram, Dharmarajan

    2009-02-01

    Twelve novel zidovudine derivatives were prepared by modifying 5 '-hydroxyl group of sugar moiety (1-8) and 5-methyl group of thymidine nucleus (9-12) and characterized spectrally. The compounds were evaluated for anti-HIV-1, antitubercular and antibacterial activities. Compound (3-azido-tetrahydro-5- (3,4-dihydro-5-methyl-2,4-dioxopyrimidin-1(2H)-yl)furan-2-yl)methyl 7-(4-(2-phenylacetoyloxy)-3,5- dimethylpiperazin-1-yl)-5-(2-phenylacetoyloxyamino)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (5) was found to be the most potent anti-HIV-1 agent with EC(50) of 0.0012 microM against HIV-1(IIIB) and CC(50) of 34.05 microM against MT-4 with selectivity index of 28,375. Compound 5 inhibited Mycobacterium tuberculosis with MIC of 1.72 microM and inhibited four pathogenic bacteria with MIC of less than 1 microM. PMID:19219739

  6. Development of water-soluble polyanionic carbosilane dendrimers as novel and highly potent topical anti-HIV-2 microbicides

    NASA Astrophysics Data System (ADS)

    Briz, Verónica; Sepúlveda-Crespo, Daniel; Diniz, Ana Rita; Borrego, Pedro; Rodes, Berta; de La Mata, Francisco Javier; Gómez, Rafael; Taveira, Nuno; Muñoz-Fernández, Mª Ángeles

    2015-08-01

    The development of topical microbicide formulations for vaginal delivery to prevent HIV-2 sexual transmission is urgently needed. Second- and third-generation polyanionic carbosilane dendrimers with a silicon atom core and 16 sulfonate (G2-S16), napthylsulfonate (G2-NS16) and sulphate (G3-Sh16) end-groups have shown potent and broad-spectrum anti-HIV-1 activity. However, their antiviral activity against HIV-2 and mode of action have not been probed. Cytotoxicity, anti-HIV-2, anti-sperm and antimicrobial activities of dendrimers were determined. Analysis of combined effects of triple combinations with tenofovir and raltegravir was performed by using CalcuSyn software. We also assessed the mode of antiviral action on the inhibition of HIV-2 infection through a panel of different in vitro antiviral assays: attachment, internalization in PBMCs, inactivation and cell-based fusion. Vaginal irritation and histological analysis in female BALB/c mice were evaluated. Our results suggest that G2-S16, G2-NS16 and G3-Sh16 exert anti-HIV-2 activity at an early stage of viral replication inactivating the virus, inhibiting cell-to-cell HIV-2 transmission, and blocking the binding of gp120 to CD4, and the HIV-2 entry. Triple combinations with tenofovir and raltegravir increased the anti-HIV-2 activity, consistent with synergistic interactions (CIwt: 0.33-0.66). No vaginal irritation was detected in BALB/c mice after two consecutive applications for 2 days with 3% G2-S16. Our results have clearly shown that G2-S16, G2-NS16 and G3-Sh16 have high potency against HIV-2 infection. The modes of action confirm their multifactorial and non-specific ability, suggesting that these dendrimers deserve further studies as potential candidate microbicides to prevent vaginal/rectal HIV-1/HIV-2 transmission in humans.

  7. Anti HIV-1 flavonoid glycosides from Ochna integerrima.

    PubMed

    Reutrakul, Vichai; Ningnuek, Niwat; Pohmakotr, Manat; Yoosook, Chalobon; Napaswad, Chanita; Kasisit, Jitra; Santisuk, Thawatchai; Tuchinda, Patoomratana

    2007-06-01

    Bioassay-guided fractionation of the anti-HIV-1 active EtOAc extract from leaves and twigs of Ochna integerrima led to the isolation of five new flavonoid glycosides 1 - 5, five known flavonoids 6 - 10, and two known flavonoid glycosides 11 and 12. Structures were determined based on spectroscopic analyses. 6- gamma, gamma-Dimethylallyldihydrokaempferol 7- O- beta-D-glucoside (1), 6-gamma, gamma-dimethylallylquercetin 7- O- beta- D-glucoside (3), 6-(3-hydroxy-3-methylbutyl)taxifolin 7- O- beta-D-glucoside (4), 6-(3-hydroxy-3-methylbutyl)quercetin 7- O-beta-D-glucoside (5), and 6-gamma, gamma-dimethylallyltaxifolin 7-O-beta-D-glucoside (11) showed anti-HIV-1 activities in the syncytium assay using the (Delta Tat/rev)MC99 virus and the 1A2 cell line system with EC(50) values ranging from 14.0 - 102.4 microg/mL. Furthermore, ochnaflavone 7''-O-methyl ether (7) and 2'', 3''-dihydroochnaflavone 7''-O-methyl ether (8) were very active; they exerted activities in the syncytium assay with EC(50) values of 2.0 and 0.9 microg/mL, respectively, and likewise inhibited HIV-1 reverse transcriptase (RT) with IC(50) values of 2.0 and 2.4 microg/mL, respectively.

  8. Nanomedicine in the development of anti-HIV microbicides.

    PubMed

    das Neves, José; Nunes, Rute; Rodrigues, Francisca; Sarmento, Bruno

    2016-08-01

    Prevention plays an invaluable role in the fight against HIV/AIDS. The use of microbicides is considered an interesting potential approach for topical pre-exposure prophylaxis of HIV sexual transmission. The prospects of having an effective product available are expected to be fulfilled in the near future as driven by recent and forthcoming results of clinical trials. Different dosage forms and delivery strategies have been proposed and tested for multiple microbicide drug candidates presently at different stages of the development pipeline. One particularly interesting approach comprises the application of nanomedicine principles to the development of novel anti-HIV microbicides, but its implications to efficacy and safety are not yet fully understood. Nanotechnology-based systems, either presenting inherent anti-HIV activity or acting as drug nanocarriers, may significantly influence features such as drug solubility, stability of active payloads, drug release, interactions between active moieties and virus/cells, intracellular drug delivery, drug targeting, safety, antiviral activity, mucoadhesive behavior, drug distribution and tissue penetration, and pharmacokinetics. The present manuscript provides a comprehensive and holistic overview of these topics as relevant to the development of vaginal and rectal microbicides. In particular, recent advances pertaining inherently active microbicide nanosystems and microbicide drug nanocarriers are discussed.

  9. Particle agglutination test "Serodia HIV-1/2" as a novel anti-HIV-1/2 screening test: comparative study on 3311 serum samples.

    PubMed

    Poljak, M; Zener, N; Seme, K; Kristancic, L

    1997-01-01

    Enzyme immunoassays are most widely used screening tests for antibodies to human immunodeficiency viruses (HIV). Nevertheless, the need of simpler, noninstrumented tests is evident in many parts of the world, where laboratory facilities and trained personnel are limited, and HIV incidence is high. A recently developed variant of gelatin-particle agglutination tests, Serodia HIV-1/2 (Fujirebio Inc., Tokyo, Japan), is one of such simple and noninstrumented tests. To evaluate its utility, 3311 serum samples (281 anti-HIV-1 positive, 8 anti-HIV-2 positive and 3022 anti-HIV-1/2 negative) obtained from 2632 individuals from Slovenia, other parts of former Yugoslavia and Senegal were investigated. No false-negative results and only one false-positive result were obtained during the procedures, giving overall sensitivity and specificity of the particle agglutination test of 100% and 99.97%, respectively. We have concluded that Serodia HIV-1/2 test is highly specific and sensitive for detection of anti-HIV-1/2 antibodies, suitable for small blood banks and for epidemiological surveys.

  10. Ligand-Based Virtual Screening in a Search for Novel Anti-HIV-1 Chemotypes.

    PubMed

    Kurczyk, Agata; Warszycki, Dawid; Musiol, Robert; Kafel, Rafał; Bojarski, Andrzej J; Polanski, Jaroslaw

    2015-10-26

    In a search for new anti-HIV-1 chemotypes, we developed a multistep ligand-based virtual screening (VS) protocol combining machine learning (ML) methods with the privileged structures (PS) concept. In its learning step, the VS protocol was based on HIV integrase (IN) inhibitors fetched from the ChEMBL database. The performances of various ML methods and PS weighting scheme were evaluated and applied as VS filtering criteria. Finally, a database of 1.5 million commercially available compounds was virtually screened using a multistep ligand-based cascade, and 13 selected unique structures were tested by measuring the inhibition of HIV replication in infected cells. This approach resulted in the discovery of two novel chemotypes with moderate antiretroviral activity, that, together with their topological diversity, make them good candidates as lead structures for future optimization.

  11. A new sulfated beta-galactan from clams with anti-HIV activity.

    PubMed

    Amornrut, C; Toida, T; Imanari, T; Woo, E R; Park, H; Linhardt, R; Wu, S J; Kim, Y S

    1999-09-15

    A new polysaccharide composed of galactan sulfate with a beta-(1-->3)-glycosidic linkage has been isolated from the marine clam species Meretrix petechialis. The polysaccharide was homogeneous in its composition containing D-galactose. The glycosidic linkage was examined by 2D DQF-COSY and 2D NOESY spectroscopy. The coupling constant of anomeric proton was 7.8 Hz, suggesting a beta-galacto configuration. The downfield shift of H-2 of galactose residue demonstrated the presence of 2-O-sulfonate group. TQF-COSY confirmed that the C-6 position was substituted with a sulfonate group. The anti-HIV activity of the polysaccharides has been evaluated by the inhibition of syncytia formation. The fusion index and percentage fusion inhibition of sulfated galactan were 0.34 and 56% at 200 micrograms/mL.

  12. Electronic structure and spectroscopic properties of anti-HIV active aminophenols

    NASA Astrophysics Data System (ADS)

    Bazyl', O. K.; Artyukhov, V. Ya.; Maier, G. V.; Tolstorozhev, G. B.; Raichenok, T. F.; Skornyakov, I. V.; Shadyro, O. I.; Sorokin, V. L.; Ksendzova, G. A.

    2012-02-01

    We have measured the absorption and fluorescence spectra and fluorescence quantum yields of sulphone-containing anti-HIV active o-aminophenol molecules in an inert solvent, hexane, and in a polar solvent, acetonitrile. We have studied IR Fourier-transform spectra and examined structural features of o-aminophenols with different substituents in solutions and crystals. Functional groups of molecules that are involved in the formation of hydrogen bonds have been revealed. Proton acceptor properties of o-aminophenol molecules have been theoretically evaluated using the method of molecular electrostatic potential. Using quantum chemistry methods, we have calculated and interpreted absorption and fluorescence spectra of o-aminophenols. Calculation data are compared with experimental results. We have determined the main channels and mechanisms of photophysical relaxation processes in o-aminophenols.

  13. 2-Aminothiazolones as Anti-HIV Agents That Act as gp120-CD4 Inhibitors

    PubMed Central

    Tiberi, Marika; Tintori, Cristina; Ceresola, Elisa Rita; Fazi, Roberta; Zamperini, Claudio; Calandro, Pierpaolo; Franchi, Luigi; Selvaraj, Manikandan; Botta, Lorenzo; Sampaolo, Michela; Saita, Diego; Ferrarese, Roberto; Clementi, Massimo

    2014-01-01

    We report here the synthesis of 2-aminothiazolones along with their biological properties as novel anti-HIV agents. Such compounds have proven to act through the inhibition of the gp120-CD4 protein-protein interaction that occurs at the very early stage of the HIV-1 entry process. No cytotoxicity was found for these compounds, and broad antiviral activities against laboratory strains and pseudotyped viruses were documented. Docking simulations have also been applied to predict the mechanism, at the molecular level, by which the inhibitors were able to interact within the Phe43 cavity of HIV-1 gp120. Furthermore, a preliminary absorption, distribution, metabolism, and excretion (ADME) evaluation was performed. Overall, this study led the basis for the development of more potent HIV entry inhibitors. PMID:24614386

  14. A Randomized Trial to Assess Anti-HIV Activity in Female Genital Tract Secretions and Soluble Mucosal Immunity Following Application of 1% Tenofovir Gel

    PubMed Central

    Torres, N. Merna; Fazzari, Melissa J.; Cho, Sylvia; Kalyoussef, Sabah; Shust, Gail; Mesquita, Pedro M. M.; Louissaint, Nicolette; Chen, Jianmeng; Cohen, Hillel W.; Diament, Erin C.; Lee, Anna C.; Soto-Torres, Lydia; Hendrix, Craig W.; Herold, Betsy C.

    2011-01-01

    Background Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition. Methods 30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood. Results A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid Emax pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators. Conclusions Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay

  15. Flazinamide, a novel {beta}-carboline compound with anti-HIV actions

    SciTech Connect

    Wang Yunhua; Tang Jianguo; Wang Ruirui; Yang Liumeng; Dong Zejun; Du Li; Shen Xu; Liu Jikai; Zheng Yongtang . E-mail: zhengyt@mail.kiz.ac.cn

    2007-04-20

    A {beta}-carboline compound, flazin isolated from Suillus granulatus has been shown weak anti-HIV-1 activity. Based on the structure of flazin, flazinamide [1-(5'- hydromethyl-2'-furyl)-{beta}-carboline-3-carboxamide] was synthesized and its anti-HIV activities were evaluated in the present study. The cytotoxicity of flazinamide was about 4.1-fold lower than that of flazin. Flazinamide potently reduced syncytium formation induced by HIV-1IIIB with EC50 value of 0.38 {mu}M, the EC50 of flazinamide was about 6.2-fold lower than that of flazin. Flazinamide also inhibited HIV-2ROD and HIV-2CBL-20 infection with EC50 values of 0.57 and 0.89 {mu}M, respectively. Flazinamide reduced p24 antigen expression in HIV-1IIIB acute infected C8166 and in clinical isolated strain HIV-1KM018 infected PBMC, with EC50 values of 1.45 and 0.77 {mu}M, respectively. Flazinamide did not suppress HIV-1 replication in chronically infected H9 cells. Flazinamide blocked the fusion between normal cells and HIV-1 or HIV-2 chronically infected cells. It weakly inhibited activities of recombinant HIV-1 reverse transcriptase, protease or integrase at higher concentrations. In conclusion, the conversion of the carboxyl group in 3 position of flazin markedly enhanced the anti-viral activity (TI value increased from 12.1 to 312.2) and flazinamide might interfere in the early stage of HIV life cycle.

  16. In vitro testing of African traditional medicines for cytotoxic, immune modulatory and anti-HIV activities.

    PubMed

    Gqaleni, Nceba; Ngcobo, Mlungisi; Parboosing, Raveen; Naidoo, Anneta

    2012-01-01

    African Traditional Medicines (ATMs) serve as a major source of primary healthcare for African people. The reasons for their use range from easy access, affordability, beliefs in traditional systems and long term safety. ATMs have been used to treat individuals infected with HIV and therefore need scientific validation; a view supported by Traditional Health Practitioners (THPs). This study aimed to evaluate the in vitro cytotoxicity, immune modulatory and anti-HIV activities of traditional multiple herbal preparations from local THPs. Ugambu, Ihashi, Product Nene, Product Blue, SPNa and SDKc ATM were supplied by local THPs. Changes in adenosine triphosphate (ATP) & glutathione (GSH) over 24 hours were measured using luminometry. Changes in 12 cytokines were assayed using an ELISA-based absorbance assay. Protective effects against HIV killing of MT-4 cells were tested using the XTT assay and antiviral activity was measured using an HIV-1 viral load assay. Cyclosporine and AZT were used as positive controls. Ugambu, Ihashi, Product Nene and SDKc induced a dose dependent toxicity on treated PBMCs by reducing ATP and GSH at high doses (p< 0.001). These medicinal preparations, along with SPNa, showed immunomodulatory activity by significantly (p< 0.001) changing the secretion of pro-inflammatory cytokines. Product Blue stimulated the levels of ATP and GSH in treated PBMCs at all doses however this product did not show any immunomodulatory activity on cytokine secretion when compared to control cells. Ugambu, Ihashi, Product Nene showed promising anti-HIV activity relative to AZT (p< 0.01). This study has shown that some of these traditional medicinal preparations have at least one or all the properties of immunostimulation, immunomodulation or antiretroviral effects. The mechanism of action of the shown activities should further be investigated.

  17. Synthesis and biological evaluation of phosphoramidate prodrugs of two analogues of 2-deoxy-d-ribose-1-phosphate directed to the discovery of two carbasugars as new potential anti-HIV leads.

    PubMed

    Hamon, Nadège; Slusarczyk, Magdalena; Serpi, Michaela; Balzarini, Jan; McGuigan, Christopher

    2015-02-15

    2-Deoxy-α-d-ribose-1-phosphate is of great interest as it is involved in the biosynthesis and/or catabolic degradation of several nucleoside analogues of biological and therapeutic relevance. However due to the lack of a stabilising group at its 2-position, it is difficult to synthesize stable prodrugs of this compound. In order to overcome this lack of stability, the synthesis of carbasugar analogues of 2-deoxyribose-1-phosphate was envisioned. Herein the preparation of a series of prodrugs of two carbocyclic analogues of 2-deoxyribose-1-phosphate using the phosphoramidate ProTide technology, along with their biological evaluation against HIV and cancer cell proliferation, is reported.

  18. Evaluation of family therapy.

    PubMed

    Nielsen, Nanna

    2006-01-01

    Because children of mentally disordered parents have an increased risk of becoming subjects of mental disorder and psychological problems, adult psychiatry has increasingly paid attention to the patients' parental skills. This study includes 31 families with children younger than 18 years of age where the parents were admitted to family therapy in an open psychiatric ward. The average number of sessions was seven, and the diagnoses of severe stress and of adjustment disorder were the most common. The aim of the study was to measure changes in the family climate during the period of therapy. The instrument used was the Family Environment Scale (FES), a self-rating questionnaire that measures the parents' experience of family environment. The change of family environment is related to its influence on children's well-being and development. The study finds that family therapy has resulted in positive changes of the parents' experience of the family climate.

  19. Testing of viscous anti-HIV microbicides using Lactobacillus

    PubMed Central

    Moncla, B.J.; Pryke, K.; Rohan, L. C.; Yang, H.

    2012-01-01

    The development of topical microbicides for intravaginal use to prevent HIV infection requires that the drugs and formulated products be nontoxic to the endogenous vaginal Lactobacillus. In 30 min exposure tests we found dapivirine, tenofovir and UC781 (reverse transcriptase inhibitor anti-HIV drugs) as pure drugs or formulated as film or gel products were not deleterious to Lactobacillus species; however, PSC-RANTES (a synthetic CCR5 antagonist) killed 2 strains of Lactobacillus jensenii. To demonstrate the toxicity of formulated products a new assay was developed for use with viscous and non-viscous samples that we have termed the Lactobacillus toxicity test. We found that the vortex mixing of vaginal Lactobacillus species can lead to reductions in bacterial viability. Lactobacillus can survive brief, about 2 sec, but viability declines with increased vortex mixing. The addition of heat inactivated serum or bovine serum albumin, but not glycerol, prevented the decrease in bacterial viability. Bacillus atrophaeus spores also demonstrated loss of viability upon extended mixing. We observed that many of the excipients used in film formulation and the films themselves also afford protection from the killing during vortex mixing. This method is of relevance for toxicity for cidal activities of viscous products. PMID:22226641

  20. G-Quadruplex Forming Oligonucleotides as Anti-HIV Agents.

    PubMed

    Musumeci, Domenica; Riccardi, Claudia; Montesarchio, Daniela

    2015-09-22

    Though a variety of different non-canonical nucleic acids conformations have been recognized, G-quadruplex structures are probably the structural motifs most commonly found within known oligonucleotide-based aptamers. This could be ascribed to several factors, as their large conformational diversity, marked responsiveness of their folding/unfolding processes to external stimuli, high structural compactness and chemo-enzymatic and thermodynamic stability. A number of G-quadruplex-forming oligonucleotides having relevant in vitro anti-HIV activity have been discovered in the last two decades through either SELEX or rational design approaches. Improved aptamers have been obtained by chemical modifications of natural oligonucleotides, as terminal conjugations with large hydrophobic groups, replacement of phosphodiester linkages with phosphorothioate bonds or other surrogates, insertion of base-modified monomers, etc. In turn, detailed structural studies have elucidated the peculiar architectures adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. An overview of the state-of-the-art knowledge of the relevance of putative G-quadruplex forming sequences within the viral genome and of the most studied G-quadruplex-forming aptamers, selectively targeting HIV proteins, is here presented.

  1. Evaluation of Anti-HIV-1 Mutagenic Nucleoside Analogues*

    PubMed Central

    Vivet-Boudou, Valérie; Isel, Catherine; El Safadi, Yazan; Smyth, Redmond P.; Laumond, Géraldine; Moog, Christiane; Paillart, Jean-Christophe; Marquet, Roland

    2015-01-01

    Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the concept of “lethal mutagenesis” that prompted us to synthesize pyrimidine nucleoside analogues with antiviral activity in cell culture consistent with an accumulation of deleterious mutations in the HIV-1 genome. However, testing all potentially mutagenic compounds in cell-based assays is tedious and costly. Here, we describe two simple in vitro biophysical/biochemical assays that allow prediction of the mutagenic potential of deoxyribonucleoside analogues. The first assay compares the thermal stabilities of matched and mismatched base pairs in DNA duplexes containing or not the nucleoside analogues as follows. A promising candidate should display a small destabilization of the matched base pair compared with the natural nucleoside and the smallest gap possible between the stabilities of the matched and mismatched base pairs. From this assay, we predicted that two of our compounds, 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine, should be mutagenic. The second in vitro reverse transcription assay assesses DNA synthesis opposite nucleoside analogues inserted into a template strand and subsequent extension of the newly synthesized base pairs. Once again, only 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine are predicted to be efficient mutagens. The predictive potential of our fast and easy first line screens was confirmed by detailed analysis of the mutation spectrum induced by the compounds in cell culture because only compounds 5-hydroxymethyl-2′-deoxyuridine and 5-hydroxymethyl-2′-deoxycytidine were found to increase the mutation frequency by 3.1- and 3.4-fold, respectively. PMID:25398876

  2. Comparison of three quantification methods for the TZM-bl pseudovirus assay for screening of anti-HIV-1 agents.

    PubMed

    Xing, Liying; Wang, Shunyi; Hu, Qin; Li, Jingtao; Zeng, Yi

    2016-07-01

    The TZM-bl pseudovirus assay is commonly used to evaluate the efficacy of neutralizing antibodies and small molecular inhibitors in HIV-1 research. Here, to determine the optimal measurement method for screening anti-HIV-1 inhibitors, we compared three measurement methods based on firefly luciferase and β-galactosidase activities. The 50% tissue culture infective doses (TCID50) of the pseudoviruses were determined using the luciferase, β-galactosidase colorimetric, and 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside (X-gal) staining assays. Three commercial reverse-transcriptase inhibitors (azidothymidine, nevirapine, and lamivudine) were tested as reference drugs to compare the reproducibility, linear correlation, and half maximal inhibitory concentration (IC50) values determined using these methods. In the TCID50 assay, the sensitivity of β-galactosidase colorimetric assay was almost 562 times lower than that of the other two methods. Reproducible dose-response curves were obtained for the inhibitors with all methods; the IC50 values of the inhibitors were not significantly different. Linear regression analysis showed linear correlation between methods. Compared to the β-galactosidase colorimetric assay, the other two methods have the advantage of high sensitivity and are less affected by interference. In conclusion, the luciferase and X-gal staining assays, which can be applied either alone or combined, are recommended for anti-HIV-1 inhibitor screening. PMID:27016178

  3. Array-in-well platform-based multiplex assay for the simultaneous detection of anti-HIV- and treponemal-antibodies, and Hepatitis B surface antigen.

    PubMed

    Talha, Sheikh M; Saviranta, Petri; Hattara, Liisa; Vuorinen, Tytti; Hytönen, Jukka; Khanna, Navin; Pettersson, Kim

    2016-02-01

    Multiplex assays detecting sets of related clinical analytes simultaneously can save considerable amount of time and resources. Array-in-well (AIW) is a powerful platform for the multiplex detection of different analytes where microarrays can be printed at the bottom of microtiter wells, thus combining the potential of microarrays with the ease of handling microtiter wells. We have developed a single-step AIW assay for the simultaneous screening of HIV, Treponema pallidum subspecies pallidum (causing syphilis) and Hepatitis B virus infections targeting the specific detection of anti-HIV- and treponemal-antibodies and Hepatitis B surface antigen (HBsAg), respectively, using two different fluorescent label technologies i.e. DyLight 633 and europium nanoparticle. Double-antigen assay formats were used for anti-HIV- and treponemal-antibody detection that can simultaneously detect both IgG and IgM, and thus reduce the window period of detection. AIW assay was evaluated with well characterized serum/plasma samples (n=111), and the qualitative results were in near complete agreement with those of the reference assays. The AIW assay exhibited 100% sensitivities for all three analytes, and 100% specificities for anti-HIV antibodies and HBsAg, and 98.6% specificity for treponemal antibodies. The limit of detection of HBsAg in AIW assay was 0.18 ng/ml. This high performing AIW assay has the potential to be used as a multiplex screening test for these three infections.

  4. Pure drug and polymer based nanotechnologies for the improved solubility, stability, bioavailability and targeting of anti-HIV drugs.

    PubMed

    Sharma, Puneet; Garg, Sanjay

    2010-03-18

    The impact of human immunodeficiency virus (HIV) infection has been devastating with nearly 7400 new infections every day. Although, the advent of highly active antiretroviral therapy (HAART) has made a tremendous contribution in reducing the morbidity and mortality in developed countries, the situation in developing countries is still grim with millions of people being infected by this disease. The new advancements in the field of nanotechnology based drug delivery systems hold promise to improve the situation. These nanoscale systems have been successfully employed in other diseases such as cancer, and therefore, we now have a better understanding of the practicalities and technicalities associated with their clinical development. Nanotechnology based approaches offer some unique opportunities specifically for the improvement of water solubility, stability, bioavailability and targeting of antiretroviral drugs. This review presents discussion on the contribution of pure drug and polymer based nanotechnologies for the delivery anti-HIV drugs.

  5. Deformation density components analysis of fullerene-based anti-HIV drugs.

    PubMed

    Fakhraee, Sara; Souri, Maryam

    2014-11-01

    Deformation density analysis is performed on fullerene-based anti-HIV agents to investigate the influence of charge redistribution on the capability of binding to HIV enzymes. Two types of HIV inhibitors including malonic acid- and amino acid-type C60 derivatives are considered to study. Total deformation density and its components including orbital relaxation and kinetic energy pressure are obtained for C60 derivatives. The deformation natural orbitals for each component of deformation density are assessed and their amounts of charge displacement are quantified to evaluate the binding affinity of HIV inhibitors. The results show that the orbital relaxation plays a more prominent role in deformation of electron density of studied compounds. Among the considered drugs, the amino acid-type derivatives, N-(carboxymethyl)-2,5-dicarboxylic fulleropyrrolidines, show the most charge displacement. Moreover, the investigation into the deformation density of amino acid-type functional groups on C60 reveals that the connection of functional groups to the 5,6-ring junction results more displaced charge than the connection to the 6,6-ring junction.

  6. In vitro anti-HIV-1 activity of fucoidan from Sargassum swartzii.

    PubMed

    Dinesh, Subramaniam; Menon, Thangam; Hanna, Luke E; Suresh, V; Sathuvan, M; Manikannan, M

    2016-01-01

    Sargassum swartzii, a marine brown algae with wide range of biological properties belongs to the family Sargassaceae. Bioactive fucoidan fractions (CFF, FF1 and FF2) were isolated from S. swartzii and characterized by linear gradient anion-exchange chromatography and FT-IR. The characterized fucoidan fractions contained mainly sugars, sulfate and uronic acid. In the present study, anti-HIV-1 property of the fucoidan fractions was investigated. Fraction FF2 was found to exhibit significant anti-HIV-1 activity at concentrations of 1.56 and 6.25 μg/ml as observed by >50% reduction in HIV-1 p24 antigen levels and reverse transcriptase activity. Fucoidan fractions have no cytotoxic effects on PBMCs at the concentration range of 1.56-1000 μg/ml. These results suggest that fucoidan fractions could have inhibitory activity against HIV and has potential as an anti-HIV-1 agent.

  7. Anti-HIV-1 activity of a tripodal receptor that recognizes mannose oligomers.

    PubMed

    Rivero-Buceta, Eva; Carrero, Paula; Casanova, Elena; Doyagüez, Elisa G; Madrona, Andrés; Quesada, Ernesto; Peréz-Pérez, María Jesús; Mateos, Raquel; Bravo, Laura; Mathys, Leen; Noppen, Sam; Kiselev, Evgeny; Marchand, Christophe; Pommier, Yves; Liekens, Sandra; Balzarini, Jan; Camarasa, María José; San-Félix, Ana

    2015-12-01

    The glycoprotein gp120 of the HIV-1 viral envelope has a high content in mannose residues, particularly α-1,2-mannose oligomers. Compounds that interact with these high-mannose type glycans may disturb the interaction between gp120 and its (co)receptors and are considered potential anti-HIV agents. Previously, we demonstrated that a tripodal receptor (1), with a central scaffold of 1,3,5-triethylbenzene substituted with three 2,3,4-trihydroxybenzoyl groups, selectively recognizes α-1,2-mannose polysaccharides. Here we present additional studies to determine the anti-HIV-1 activity and the mechanism of antiviral activity of this compound. Our studies indicate that 1 shows anti-HIV-1 activity in the low micromolar range and has pronounced gp120 binding and HIV-1 integrase inhibitory capacity. However, gp120 binding rather than integrase inhibition seems to be the primary mechanism of antiviral activity of 1. PMID:26540494

  8. Novel anti-HIV peptides containing multiple copies of artificially designed heptad repeat motifs

    SciTech Connect

    Shi Weiguo; Qi Zhi; Pan Chungen; Xue Na; Debnath, Asim K.; Qie Jiankun; Jiang Shibo Liu Keliang

    2008-10-03

    The peptidic anti-HIV drug T20 (Fuzeon) and its analog C34 share a common heptad repeat (HR) sequence, but they have different functional domains, i.e., pocket- and lipid-binding domains (PBD and LBD, respectively). We hypothesize that novel anti-HIV peptides may be designed by using artificial sequences containing multiple copies of HR motifs plus zero, one or two functional domains. Surprisingly, we found that the peptides containing only the non-natural HR sequences could significantly inhibit HIV-1 infection, while addition of PBD and/or LBD to the peptides resulted in significant improvement of anti-HIV-1 activity. These results suggest that these artificial HR sequences, which may serve as structural domains, could be used as templates for the design of novel antiviral peptides against HIV and other viruses with class I fusion proteins.

  9. In vitro anti-HIV-1 activity of fucoidan from Sargassum swartzii.

    PubMed

    Dinesh, Subramaniam; Menon, Thangam; Hanna, Luke E; Suresh, V; Sathuvan, M; Manikannan, M

    2016-01-01

    Sargassum swartzii, a marine brown algae with wide range of biological properties belongs to the family Sargassaceae. Bioactive fucoidan fractions (CFF, FF1 and FF2) were isolated from S. swartzii and characterized by linear gradient anion-exchange chromatography and FT-IR. The characterized fucoidan fractions contained mainly sugars, sulfate and uronic acid. In the present study, anti-HIV-1 property of the fucoidan fractions was investigated. Fraction FF2 was found to exhibit significant anti-HIV-1 activity at concentrations of 1.56 and 6.25 μg/ml as observed by >50% reduction in HIV-1 p24 antigen levels and reverse transcriptase activity. Fucoidan fractions have no cytotoxic effects on PBMCs at the concentration range of 1.56-1000 μg/ml. These results suggest that fucoidan fractions could have inhibitory activity against HIV and has potential as an anti-HIV-1 agent. PMID:26472515

  10. Synthesis and Anti-HIV Activity of Novel 4'-Trifluoromethylated 5'-Deoxycarbocyclic Nucleoside Phosphonic Acids.

    PubMed

    Jee, Jun-Pil; Kim, Seyeon; Hong, Joon Hee

    2015-01-01

    Efficient synthetic route to novel 4'-trifluoromethylated 5'-deoxycarbocyclic nucleoside phosphonic acids was described from α-trifluoromethyl-α,β-unsaturated ester. Coupling of purine nucleosidic bases with cyclopentanol using a Mitsunobu reaction gave the nucleoside intermediates which were further phosphonated and hydrolyzed to reach desired nucleoside analogs. Synthesized nucleoside analogs were tested for anti-HIV activity as well as cytotoxicity. Adenine analog 22 shows significant anti-HIV activity (EC50 = 8.3 μM) up to 100 μM.

  11. Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue

    PubMed Central

    Roy, Upal; Ding, Hong; Pilakka-Kanthikeel, Sudheesh; Raymond, Andrea D; Atluri, Venkata; Yndart, Adriana; Kaftanovskaya, Elena M; Batrakova, Elena; Agudelo, Marisela; Nair, Madhavan

    2015-01-01

    The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT). Being the largest lymphoid organ, GALT plays a key role in early HIV infection and host–pathogen interaction. Many different treatment options have been proposed to eradicate the virus from GALT. However, it becomes difficult to deliver traditional drugs to the GALT because of its complex physiology. In this regard, we developed a polymer-based Pluronic nanocarrier containing anti-HIV drug called efavirenz (EFV) targeting Microfold cells (M-cells) in the GALT. M-cells are specialized epithelial cells that are predominantly present in the GALT. In this work, we have exploited this paracellular transport property of M-cells for targeted delivery of Pluronic nanocarrier tagged EFV, bioconjugated with anti-M-cell-specific antibodies to the GALT (nanodrug). Preliminary characterization showed that the nanodrug (EFV-F12-COOH) is of 140 nm size with 0.3 polydispersion index, and the zeta potential of the particles was −19.38±2.2 mV. Further, drug dissolution study has shown a significantly improved sustained release over free drugs. Binding potential of nanodrug with M-cell was also confirmed with fluorescence microscopy and in vitro uptake and release studies. The anti-HIV activity of the nanodrug was also significantly higher compared to that of free drug. This novel formulation was able to show sustained release of EFV and inhibit the HIV-1 infection in the GALT compared to the free drug. The present study has potential for our in vivo targeted nanodrug delivery system by combining traditional enteric-coated capsule technique via oral administration. PMID:26425084

  12. Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue.

    PubMed

    Roy, Upal; Ding, Hong; Pilakka-Kanthikeel, Sudheesh; Raymond, Andrea D; Atluri, Venkata; Yndart, Adriana; Kaftanovskaya, Elena M; Batrakova, Elena; Agudelo, Marisela; Nair, Madhavan

    2015-01-01

    The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT). Being the largest lymphoid organ, GALT plays a key role in early HIV infection and host-pathogen interaction. Many different treatment options have been proposed to eradicate the virus from GALT. However, it becomes difficult to deliver traditional drugs to the GALT because of its complex physiology. In this regard, we developed a polymer-based Pluronic nanocarrier containing anti-HIV drug called efavirenz (EFV) targeting Microfold cells (M-cells) in the GALT. M-cells are specialized epithelial cells that are predominantly present in the GALT. In this work, we have exploited this paracellular transport property of M-cells for targeted delivery of Pluronic nanocarrier tagged EFV, bioconjugated with anti-M-cell-specific antibodies to the GALT (nanodrug). Preliminary characterization showed that the nanodrug (EFV-F12-COOH) is of 140 nm size with 0.3 polydispersion index, and the zeta potential of the particles was -19.38±2.2 mV. Further, drug dissolution study has shown a significantly improved sustained release over free drugs. Binding potential of nanodrug with M-cell was also confirmed with fluorescence microscopy and in vitro uptake and release studies. The anti-HIV activity of the nanodrug was also significantly higher compared to that of free drug. This novel formulation was able to show sustained release of EFV and inhibit the HIV-1 infection in the GALT compared to the free drug. The present study has potential for our in vivo targeted nanodrug delivery system by combining traditional enteric-coated capsule technique via oral administration.

  13. Safety and anti-HIV assessments of natural vaginal cleansing products in an established topical microbicides in vitro testing algorithm

    PubMed Central

    2010-01-01

    Background At present, there is no effective vaccine or other approved product for the prevention of sexually transmitted human immunodeficiency virus type 1 (HIV-1) infection. It has been reported that women in resource-poor communities use vaginally applied citrus juices as topical microbicides. These easily accessible food products have historically been applied to prevent pregnancy and sexually transmitted diseases. The aim of this study was to evaluate the efficacy and cytotoxicity of these substances using an established topical microbicide testing algorithm. Freshly squeezed lemon and lime juice and household vinegar were tested in their original state or in pH neutralized form for efficacy and cytotoxicity in the CCR5-tropic cell-free entry and cell-associated transmission assays, CXCR4-tropic entry and fusion assays, and in a human PBMC-based anti-HIV-1 assay. These products were also tested for their effect on viability of cervico-vaginal cell lines, human cervical explant tissues, and beneficial Lactobacillus species. Results Natural lime and lemon juice and household vinegar demonstrated anti-HIV-1 activity and cytotoxicity in transformed cell lines. Neutralization of the products reduced both anti-HIV-1 activity and cytotoxicity, resulting in a low therapeutic window for both acidic and neutralized formulations. For the natural juices and vinegar, the IC50 was ≤ 3.5 (0.8-3.5)% and the TC50 ≤ 6.3 (1.0-6.3)%. All three liquid products inhibited viability of beneficial Lactobacillus species associated with vaginal health. Comparison of three different toxicity endpoints in the cervical HeLa cell line revealed that all three products affected membrane integrity, cytosolic enzyme release, and dehydrogenase enzyme activity in living cells. The juices and vinegar also exerted strong cytotoxicity in cervico-vaginal cell lines, mainly due to their acidic pH. In human cervical explant tissues, treatment with 5% lemon or lime juice or 6% vinegar induced

  14. Aspernigrins with anti-HIV-1 activities from the marine-derived fungus Aspergillus niger SCSIO Jcsw6F30.

    PubMed

    Zhou, Xuefeng; Fang, Wei; Tan, Suiyi; Lin, Xiuping; Xun, Tianrong; Yang, Bingjie; Liu, Shuwen; Liu, Yonghong

    2016-01-15

    Two new 2-benzylpyridin-4-one containing metabolites, aspernigrins C (3) and D (4), together with six known compounds (1, 2, and 5-8), were isolated from the marine-derived fungus Aspergillus niger SCSIO Jcsw6F30. The structures of the new compounds were determined by NMR, MS, and optical rotation analyses. All the isolated compounds were evaluated for their inhibitory activities against infection with HIV-1 SF162 in TZM-bl cells. Malformin C (5) showed the strongest anti-HIV-1 activity with IC50 of 1.4±0.06μM (selectivity index, 11.4), meanwhile aspernigrin C (3) also exhibited potent activity with IC50 of 4.7±0.4μM (selectivity index, 7.5).

  15. Synthesis and in vitro anti-HIV-1 activity of a series of N-arylsulfonyl-3-propionylindoles.

    PubMed

    Che, Zhiping; Tian, Yuee; Hu, Zhenjie; Chen, Yingwu; Liu, Shengming; Chen, Genqiang

    2016-01-01

    Fifteen N-arylsulfonyl-3-propionylindoles (3a-o) were prepared and preliminarily evaluated as in vitro inhibitors of human immunodeficiency virus type-1 (HIV-1). Three compounds 3c, 3g and 3i exhibited potent anti-HIV-1 activity with effective concentration (EC(50)) values of 0.8, 4.0 and 1.2 μg/mL, and therapeutic index (TI) values of 11.7, 16.6 and 84.1, respectively. N-(m-Nitro)phenylsulfonyl-3-propionyl-6-methylindole (3i) exhibited the most promising and best activity against HIV-1 replication. The cytotoxicity of these compounds was assessed as well. PMID:27124676

  16. Evaluation of the Efficacy And Toxicity of RNAs Targeting HIV-1 Production for Use in Gene or Drug Therapy.

    PubMed

    Scarborough, Robert J; Adams, Kelsey L; Del Corpo, Olivier; Daher, Aïcha; Gatignol, Anne

    2016-01-01

    Small RNA therapies targeting post-integration steps in the HIV-1 replication cycle are among the top candidates for gene therapy and have the potential to be used as drug therapies for HIV-1 infection. Post-integration inhibitors include ribozymes, short hairpin (sh) RNAs, small interfering (si) RNAs, U1 interference (U1i) RNAs and RNA aptamers. Many of these have been identified using transient co-transfection assays with an HIV-1 expression plasmid and some have advanced to clinical trials. In addition to measures of efficacy, small RNAs have been evaluated for their potential to affect the expression of human RNAs, alter cell growth and/or differentiation, and elicit innate immune responses. In the protocols described here, a set of transient transfection assays designed to evaluate the efficacy and toxicity of RNA molecules targeting post-integration steps in the HIV-1 replication cycle are described. We have used these assays to identify new ribozymes and optimize the format of shRNAs and siRNAs targeting HIV-1 RNA. The methods provide a quick set of assays that are useful for screening new anti-HIV-1 RNAs and could be adapted to screen other post-integration inhibitors of HIV-1 replication. PMID:27684275

  17. Semi-synthesis of oxygenated dolabellane diterpenes with highly in vitro anti-HIV-1 activity.

    PubMed

    Pardo-Vargas, Alonso; Ramos, Freddy A; Cirne-Santos, Claudio Cesar; Stephens, Paulo Roberto; Paixão, Izabel Christina Palmer; Teixeira, Valeria Laneuville; Castellanos, Leonardo

    2014-09-15

    Research on dolabellane diterpenes of brown algae Dictyota spp. has shown that these diterpenoids have strong anti-HIV-1 activity, but there are not data about antiviral activity of dolabellane diterpenes isolated from octocorals, which are antipodes of those isolated from the brown algae. Dolabellanes 13-keto-1(R),11(S)-dolabella-3(E),7(E),12(18)-triene (1) and β-Araneosene (2) were isolated from the Caribbean octocoral Eunicea laciniata, and both showed low anti-HIV-1 activity and low toxicity. Since it was shown that oxygenated dolabellanes from algae have better anti-HIV-1 activity, in this work some derivatives of the main dolabellane of E. laciniata1 were obtained by epoxidation (3), epoxide opening (4), and allylic oxidation (5). The derivatives showed significant improvement in the anti-HIV-1potency (100-fold), being compounds 3 and 5 the most active ones. Their high antiviral activities, along with their low cytotoxicity, make them promissory antiviral compounds; and it is worth noting that the absolute configuration at the ring junction in the dolabellane skeleton does not seem to be determinant in the antiviral potency of these diterpeneoids. PMID:25176328

  18. Semi-synthesis of oxygenated dolabellane diterpenes with highly in vitro anti-HIV-1 activity.

    PubMed

    Pardo-Vargas, Alonso; Ramos, Freddy A; Cirne-Santos, Claudio Cesar; Stephens, Paulo Roberto; Paixão, Izabel Christina Palmer; Teixeira, Valeria Laneuville; Castellanos, Leonardo

    2014-09-15

    Research on dolabellane diterpenes of brown algae Dictyota spp. has shown that these diterpenoids have strong anti-HIV-1 activity, but there are not data about antiviral activity of dolabellane diterpenes isolated from octocorals, which are antipodes of those isolated from the brown algae. Dolabellanes 13-keto-1(R),11(S)-dolabella-3(E),7(E),12(18)-triene (1) and β-Araneosene (2) were isolated from the Caribbean octocoral Eunicea laciniata, and both showed low anti-HIV-1 activity and low toxicity. Since it was shown that oxygenated dolabellanes from algae have better anti-HIV-1 activity, in this work some derivatives of the main dolabellane of E. laciniata1 were obtained by epoxidation (3), epoxide opening (4), and allylic oxidation (5). The derivatives showed significant improvement in the anti-HIV-1potency (100-fold), being compounds 3 and 5 the most active ones. Their high antiviral activities, along with their low cytotoxicity, make them promissory antiviral compounds; and it is worth noting that the absolute configuration at the ring junction in the dolabellane skeleton does not seem to be determinant in the antiviral potency of these diterpeneoids.

  19. Plant-derived triterpenoids and analogues as antitumor and anti-HIV agents†

    PubMed Central

    Kuo, Reen-Yen; Qian, Keduo; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung

    2013-01-01

    This article reviews the antitumor and anti-HIV activities of naturally occurring triterpenoids, including the lupane, ursane, oleanane, lanostane, dammarane, and miscellaneous scaffolds. Structure–activity relationships of selected natural compounds and their synthetic derivatives are also discussed. PMID:19779642

  20. Antibacterial, anti-HIV-1 protease and cytotoxic activities of aqueous ethanolic extracts from Combretum adenogonium Steud. Ex A. Rich (Combretaceae)

    PubMed Central

    2012-01-01

    Background Records have shown that Combretum adenogonium Steud. Ex A. Rich (Combretaceae) is used in traditional medicine systems of several tribes in Tanzania. This study focused on the investigation of antibacterial activity, anti-HIV-1 protease activity, toxicity properties and classes of phytochemicals in extracts from C. adenogonium Steud. Ex A. Rich (Combretaceae) to evaluate potential of these extracts for development as herbal remedies. Methods Dried plant material were ground to fine powder and extracted using 80% aqueous ethanol to afford root, leaf and stem bark extracts. The extracts were assayed for anti-HIV-1 protease activities, antibacterial activities using microdilution methods and cytotoxicity using brine shrimps lethality assay. Screening for major phytochemical classes was carried out using standard chemical tests. Results All extracts exhibited antibacterial activity to at least one of the test bacteria with MIC-values ranging from 0.31-5.0 mg/ml. Two extracts, namely, root and stem bark exhibited anti-HIV-1 PR activity with IC50 values of 24.7 and 26.5 μg/ml, respectively. Stem bark and leaf extracts showed mild toxicity with LC50 values of 65.768 μg/ml and 76.965 μg/ml, respectively, whereas roots were relatively non-toxic (LC50 = 110.042 μg/ml). Phytochemical screening of the extracts indicated presence of flavonoids, terpenoids, alkaloids, tannins, glycosides and saponins. Conclusion These results provide promising baseline information for the potential development of C. adenogonium extracts in treatment of bacterial and HIV/AIDS-related opportunistic infections. PMID:23013240

  1. Anti-HIV-1 Activity of Elafin Is More Potent than Its Precursor's, Trappin-2, in Genital Epithelial Cells

    PubMed Central

    Drannik, Anna G.; Nag, Kakon; Yao, Xiao-Dan; Henrick, Bethany M.; Jain, Sumiti; Ball, T. Blake; Plummer, Francis A.; Wachihi, Charles; Kimani, Joshua

    2012-01-01

    Cervicovaginal lavage fluid (CVL) is a natural source of anti-HIV-1 factors; however, molecular characterization of the anti-HIV-1 activity of CVL remains elusive. In this study, we confirmed that CVLs from HIV-1-resistant (HIV-R) compared to HIV-1-susceptible (HIV-S) commercial sex workers (CSWs) contain significantly larger amounts of serine antiprotease trappin-2 (Tr) and its processed form, elafin (E). We assessed anti-HIV-1 activity of CVLs of CSWs and recombinant E and Tr on genital epithelial cells (ECs) that possess (TZM-bl) or lack (HEC-1A) canonical HIV-1 receptors. Our results showed that immunodepletion of 30% of Tr/E from CVL accounted for up to 60% of total anti-HIV-1 activity of CVL. Knockdown of endogenous Tr/E in HEC-1A cells resulted in significantly increased shedding of infectious R5 and X4 HIV-1. Pretreatment of R5, but not X4 HIV-1, with either Tr or E led to inhibition of HIV-1 infection of TZM-bl cells. Interestingly, when either HIV-1 or cells lacking canonical HIV-1 receptors were pretreated with Tr or E, HIV-1 attachment and transcytosis were significantly reduced, and decreased attachment was not associated with altered expression of syndecan-1 or CXCR4. Determination of 50% inhibitory concentrations (IC50) of Tr and E anti-HIV-1 activity indicated that E is ∼130 times more potent than its precursor, Tr, despite their equipotent antiprotease activities. This study provides the first experimental evidence that (i) Tr and E are among the principal anti-HIV-1 molecules of CVL; (ii) Tr and E affect cell attachment and transcytosis of HIV-1; (iii) E is more efficient than Tr regarding anti-HIV-1 activity; and (iv) the anti-HIV-1 effect of Tr and E is contextual. PMID:22345469

  2. A combination of molecular dynamics and docking calculations to explore the binding mode of ADS-J1, a polyanionic compound endowed with anti-HIV-1 activity.

    PubMed

    Manetti, Fabrizio; Tintori, Cristina; Armand-Ugón, Mercedes; Clotet-Codina, Imma; Massa, Silvio; Ragno, Rino; Esté, José A; Botta, Maurizio

    2006-01-01

    The HIV-1 entry process is an important target for the design of new pharmaceuticals for the multidrug therapy of AIDS. A lot of polyanionic compounds, such as polysulfonated and polysulfated, are reported in the literature for their ability to block early stages of HIV-1 replication. Several studies have been performed to elucidate the mechanism of the anti-HIV-1 activity of sulfated polysaccharides and polyanions in general, including binding to cell surface CD4 and interfering with the gp120-coreceptor interaction. Here, we show molecular modeling investigations on ADS-J1, a polyanionic compound with anti-HIV activity that is able to interfere with gp120-coreceptor interactions. Agreeing with experimental data, computer simulations suggested that the V3 loop of gp120 was the preferential binding site for ADS-J1 onto HIV-1. Moreover, mutations induced by the inhibitor significantly changed the stereoelectronic properties of the gp120 surface, justifying a marked drop in the affinity of ADS-J1 toward an ADS-J1-resistant HIV-1 strain.

  3. From docking false-positive to active anti-HIV agent.

    PubMed

    Barreiro, Gabriela; Kim, Joseph T; Guimarães, Cristiano R W; Bailey, Christopher M; Domaoal, Robert A; Wang, Ligong; Anderson, Karen S; Jorgensen, William L

    2007-11-01

    Virtual screening of the Maybridge library of ca. 70 000 compounds was performed using a similarity filter, docking, and molecular mechanics-generalized Born/surface area postprocessing to seek potential non-nucleoside inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (NNRTIs). Although known NNRTIs were retrieved well, purchase and assaying of representative, top-scoring compounds from the library failed to yield any active anti-HIV agents. However, the highest-ranked library compound, oxadiazole 1, was pursued as a potential "near-miss" with the BOMB program to seek constructive modifications. Subsequent synthesis and assaying of several polychloro-analogs did yield anti-HIV agents with EC50 values as low as 310 nM. The study demonstrates that it is possible to learn from a formally unsuccessful virtual-screening exercise and, with the aid of computational analyses, to efficiently evolve a false positive into a true active. PMID:17918923

  4. Synthesis of the anti-HIV agent (-)-hyperolactone C by using oxonium ylide formation-rearrangement.

    PubMed

    Hodgson, David M; Man, Stanislav

    2011-08-22

    Starting from readily available (S)-styrene oxide an asymmetric synthesis is described of the naturally occurring anti-HIV spirolactone (-)-hyperolactone C, which possesses adjacent fully substituted stereocenters. The key step involves a stereocontrolled Rh(II) -catalysed oxonium ylide formation-[2,3] sigmatropic rearrangement of an α-diazo-β-ketoester bearing allylic ether functionality. From the resulting furanone, an acid-catalysed lactonisation and dehydrogenation gives the natural product. PMID:21766363

  5. Flueggether A and Virosinine A, Anti-HIV Alkaloids from Flueggea virosa.

    PubMed

    Zhang, Hua; Zhu, Kong-Kai; Han, Ying-Shan; Luo, Cheng; Wainberg, Mark A; Yue, Jian-Min

    2015-12-18

    Two new alkaloids, flueggether A (1) and virosinine A (2), were isolated from a Chinese medicinal plant, Flueggea virosa. Their structures were assigned via spectroscopic methods with the absolute configurations of 1 and 2 being established by X-ray diffraction analysis and calculated electronic circular dichroism data, respectively. Compound 1 represents the first example with an ether bridge of Securinega alkaloid oligomers, and 2 bears a new heterocyclic backbone. Both alkaloids showed mild in vitro anti-HIV activity.

  6. In vitro anti-HIV-1 activity of salicylidene acylhydrazide compounds.

    PubMed

    Forthal, Donald N; Phan, Tran B; Slepenkin, Anatoly V; Landucci, Gary; Chu, Hencelyn; Elofsson, Mikael; Peterson, Ellena

    2012-10-01

    Salicylidene acylhydrazide compounds have been shown to inhibit bacterial pathogens, including Chlamydia and Neisseria gonorrhoeae. If such compounds could also target HIV-1, their potential use as topical microbicides to prevent sexually transmitted infections would be considerable. In this study, the in vitro anti-HIV-1 activity, cytotoxicity and mechanism of action of several salicylidene acylhydrazides were determined. Inhibitory activity was assessed using TZM-bl cells and primary peripheral blood mononuclear cells (PBMCs) as targets for HIV-1 infection. Antiviral activity was measured against cell-free and cell-associated virus and in vaginal fluid and semen simulants. Since the antibacterial activity of salicylidene acylhydrazides is reversible by Fe(2+), the ability of Fe(2+) and other cations to reverse the anti-HIV-1 activity of the compounds was determined. Real-time PCR was also employed to determine the stage affected in the HIV-1 replication cycle. Four compounds with 50% inhibitory concentrations against HIV-1 of 1-7 μM were identified. In vitro toxicity varied but was generally limited. Activity was similar against three R5 clade B primary isolates and whether the target for virus replication was TZM-bl cells or PBMCs. Compounds inhibited cell-free and cell-associated virus and were active in vaginal fluid and semen simulants. Fe(2+), but not other cations, reversed the anti-HIV-1 effect. Finally, the inhibitory effect of the compounds occurred at a post-integration step. In conclusion, salicylidene acylhydrazides were identified with in vitro anti-HIV-1 activity in the micromolar range. The activity of these compounds against other sexually transmitted pathogens makes them potential candidates to formulate for use as a broad-spectrum topical genital microbicide. PMID:22819150

  7. Characterization of permeability, stability and anti-HIV-1 activity of decitabine and gemcitabine divalerate prodrugs

    PubMed Central

    Clouser, Christine L; Bonnac, Laurent; Mansky, Louis M; Patterson, Steven E

    2015-01-01

    Background Over 25 drugs have been approved for the treatment of HIV-1 replication. All but one of these drugs is delivered as an oral medication. Previous studies have demonstrated that two drugs, decitabine and gemcitabine, have potent anti-HIV-1 activities and can work together in synergy to reduce HIV-1 infectivity via lethal mutagenesis. For their current indications, decitabine and gemcitabine are delivered intravenously. Methods As an initial step towards the clinical translation of these drugs for the treatment of HIV-1 infection, we synthesized decitabine and gemcitabine prodrugs in order to increase drug permeability, which has generally been shown to correlate with increased bioavailability in vivo. In the present study we investigated the permeability, stability and anti-HIV-1 activity of decitabine and gemcitabine prodrugs and selected the divalerate esters of each as candidates for further investigation. Results Our results provide the first demonstration of divalerate prodrugs of decitabine and gemcitabine that are readily permeable, stable and possess anti-HIV-1 activity. Conclusions These observations predict improved oral availability of decitabine and gemcitabine, and warrant further study of their ability to reduce HIV-1 infectivity in vivo. PMID:23994876

  8. Predicting anti-HIV activity of TIBO derivatives: a computational approach using a novel topological descriptor.

    PubMed

    Sardana, Satish; Madan, Anil Kumar

    2002-08-01

    A novel highly discriminating adjacency-cum-distance-based topological descriptor, termed the adjacent eccentric distance sum index, has been conceptualized and its discriminating power investigated with regard to the anti-HIV activity of 4,5,6,7-tetrahydro-imidazo-[4,5,1- jk] [1,4] benzodiazepin-2 (1 H)-one (TIBO) derivatives. The discriminating power of the adjacent eccentric distance sum index was compared with that of the eccentric connectivity index - another adjacency-cum-distance-based topological descriptor. The values of the eccentric connectivity index and the adjacent eccentric distance sum index of each of 121 analogues comprising the data set were computed and active ranges were identified. Subsequently, a biological activity was assigned to each analogue involved in the data set and this was then compared with the reported anti-HIV activity. Excellent correlations were observed between anti-HIV activity and both the topological descriptors. Although the overall accuracy of prediction was found to be approximately 84% in case of the eccentric connectivity index and approximately 86% in case of adjacent eccentric distance sum index, the predictability using the adjacent eccentric distance sum index in the active range itself was >92%. The proposed index offers a vast potential for structure-activity/property studies.

  9. Identification of anti-HIV and anti-reverse transcriptase activity from Tetracera scandens.

    PubMed

    Kwon, Hyeok Sang; Park, Jung Ae; Kim, Joo-Hwan; You, Ji Chang

    2012-03-01

    We report here that an ethanol extract of Tetracera scandens, a Vietnamese medicinal plant, has anti-HIV activity and possesses strong inhibitory activity against HIV-1 reverse transcriptase (RTase). Using a MT-4 cell-based assay, we found that the T. scandens extract inhibited effectively HIV virus replication with an IC(50) value in the range of 2.0-2.5 μg/ml while the cellular toxicity value (CC50) was more than 40-50 μg/ml concentration, thus yielding a minimum specificity index of 20-fold. Moreover, the anti-HIV efficacy of the T. scandens extract was determined to be due, in part, to its potent inhibitory activity against HIV-1 RTase activity in vitro. The inhibitory activity against the RTase was further confirmed by probing viral cDNA production, an intermediate of viral reverse transcription, in virus-infected cells using quantitative DNA-PCR analysis. Thus, these results suggest that T. scandens can be a useful source for the isolation and development of new anti- HIV-1 inhibitor(s). [BMB reports 2012; 45(3): 165-170]. PMID:22449703

  10. Parthenium hysterophorus: A Probable Source of Anticancer, Antioxidant and Anti-HIV Agents

    PubMed Central

    Kumar, Shashank; Chashoo, Gousia; Saxena, Ajit K.; Pandey, Abhay K.

    2013-01-01

    The present work reports the anticancer, antioxidant, lipo-protective, and anti-HIV activities of phytoconstituents present in P. hysterophorus leaf. Dried leaf samples were sequentially extracted with nonpolar and polar solvents. Ethanol fraction showed noticeable cytotoxic activity (81–85%) in SRB assay against MCF-7 and THP-1 cancer cell lines at 100 μg/ml concentration, while lower activity was observed with DU-145 cell line. The same extract exhibited 17–98% growth inhibition of HL-60 cancer cell lines in MTT assay, showing concentration dependent response. Ethanol extract caused 12% reduction in mitochondrial membrane potential and 10% increment in sub G1 population of HL-60 cell lines. Several leaf fractions, namely, ethyl acetate, ethanol, and aqueous fractions exhibited considerable reducing capability at higher concentrations. Most of the extracts demonstrated appreciable (>75%) metal ion chelating and hydroxyl radical scavenging activities at 200 µg/ml. All the extracts except aqueous fraction accounted for about 70–80% inhibition of lipid peroxidation in rat liver homogenate indicating protective response against membrane damage. About 40% inhibition of reverse transcriptase (RT) activity was observed in hexane fraction in anti-HIV assay at 6.0 µg/ml concentration. The study showed that phytochemicals present in P. hysterophorus leaf have considerable potential as cytotoxic and antioxidant agents with low to moderate anti-HIV activity. PMID:24350290

  11. Assessment of Anti-HIV-1 Antibodies in Oral and Nasal Compartments of Volunteers From 3 Different Populations.

    PubMed

    Bergin, Philip J; Langat, Robert; Omosa-Manyonyi, Gloria; Farah, Bashir; Ouattara, Gina; Park, Harriet; Coutinho, Helen; Laufer, Dagna; Fast, Pat; Verlinde, Carl; Bizimana, Jean; Umviligihozo, Gisele; Nyombayire, Julien; Ingabire, Rosine; Kuldanek, Kristin; Cox, Josephine; McMorrow, Martin; Fidler, Sarah; Karita, Etienne; Gilmour, Jill; Anzala, Omu

    2016-10-01

    In this study, we assessed the feasibility of collecting standardized nasal and salivary samples at centers in Nairobi (Kenya), Kigali (Rwanda), and London (United Kingdom) using different collection devices and media (synthetic absorptive matrices versus flocked swabs, and Salimetrics oral swabs versus whole oral fluid collection). We detected anti-Gag (p24) and envelope (gp140) antibodies in both nasal fluid and salivary collections from all HIV-infected individuals, and cross-reactive anti-p24 antibodies were detected in 10% of HIV-uninfected individuals enrolled at one site. Collections from the nasal turbinates were comparable with samples collected deeper in the nasopharyngeal tract, and the yield of anti-p24 IgA in the whole oral fluid samples was higher than in samples collected from the parotid gland. We noted a trend toward reduced levels of anti-HIV antibody in the volunteers receiving anti-retroviral therapy. Levels of antibodies were stable over multiple collection visits. Overall, this study shows that nasal and salivary samples can be collected in a standardized manner over repeated visits in both low- and high-resource settings. These methods may be used in support for future HIV vaccine clinical trials. PMID:27243901

  12. Decoding the membrane activity of the cyclotide kalata B1: the importance of phosphatidylethanolamine phospholipids and lipid organization on hemolytic and anti-HIV activities.

    PubMed

    Henriques, Sónia Troeira; Huang, Yen-Hua; Rosengren, K Johan; Franquelim, Henri G; Carvalho, Filomena A; Johnson, Adam; Sonza, Secondo; Tachedjian, Gilda; Castanho, Miguel A R B; Daly, Norelle L; Craik, David J

    2011-07-01

    Cyclotides, a large family of cyclic peptides from plants, have a broad range of biological activities, including insecticidal, cytotoxic, and anti-HIV activities. In all of these activities, cell membranes seem likely to be the primary target for cyclotides. However, the mechanistic role of lipid membranes in the activity of cyclotides remains unclear. To determine the role of lipid organization in the activity of the prototypic cyclotide, kalata B1 (kB1), and synthetic analogs, their bioactivities and affinities for model membranes were evaluated. We found that the bioactivity of kB1 is dependent on the lipid composition of target cell membranes. In particular, the activity of kB1 requires specific interactions with phospholipids containing phosphatidylethanolamine (PE) headgroups but is further modulated by nonspecific peptide-lipid hydrophobic interactions, which are favored in raft-like membranes. Negatively charged phospholipids do not favor high kB1 affinity. This lipid selectivity explains trends in antimicrobial and hemolytic activities of kB1; it does not target bacterial cell walls, which are negatively charged and lacking PE-phospholipids but can insert in the membranes of red blood cells, which have a low PE content and raft domains in their outer layer. We further show that the anti-HIV activity of kB1 is the result of its ability to target and disrupt the membranes of HIV particles, which are raft-like membranes very rich in PE-phospholipids.

  13. d- and l-2′,3′-Didehydro-2′,3′-Dideoxy-3′-Fluoro-Carbocyclic Nucleosides: Synthesis, Anti-HIV Activity and Mechanism of Resistance

    PubMed Central

    Wang, Jianing; Jin, Yunho; Rapp, Kimberly L.; Schinazi, Raymond F.; Chu, Chung K.

    2008-01-01

    Introducing 2′-fluoro substitution on the 2′,3′-double bond in carbocyclic nucleosides has provided biologically interesting compounds with potent anti-HIV activity. As an extension of our previous works in the discovery of anti-HIV agents, d- and l-2′,3′-unsaturated 3′-fluoro carbocyclic nucleosides were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. Among the synthesized l-series nucleosides, compounds 18, 19, 26, 28 exhibited moderate antiviral activity (EC50 7.1 μM, 6.4 μM, 10.3 μM and 20.7 μM, respectively), while among the d-series, the guanosine analogue (35, d-3′-F-C-d4G) exhibited the most potent anti-HIV activity (EC50 0.4 μM, EC90 2.8 μM). However, the guanosine analogue 35 was cross-resistant to the lamivudine-resistant variants (HIV-1M184V). Molecular modeling studies suggest that hydrophobic interaction as well as hydrogen bonding stabilize the binding of compound 35 in the active site of wild type HIV reverse transcriptase (HIV-RT). In the case of l-nucleosides, these two effects are opposite which results in a loss of binding affinity. According to the molecular modeling studies, cross-resistance of d-3′-F-C-d4G (35) to M184V mutant may be caused by the realignment of the primer and template in the HIV-RTM184V interaction, which destabilizes the RT-inhibitor triphosphate complex, resulting in a significant reduction in anti-HIV activity of the d-guanine derivative 35. PMID:17373782

  14. Short communication: Anti-HIV-1 envelope immunoglobulin Gs in blood and cervicovaginal samples of Beninese commercial sex workers.

    PubMed

    Batraville, Laurie-Anne; Richard, Jonathan; Veillette, Maxime; Labbé, Annie-Claude; Alary, Michel; Guédou, Fernand; Kaufmann, Daniel E; Poudrier, Johanne; Finzi, Andrés; Roger, Michel

    2014-11-01

    Characterization of the immune correlates of protection against HIV infection is crucial for the development of preventive strategies. This study examined HIV-1 envelope (Env) glycoproteins, specifically immunoglobulin G (IgG), in systemic and mucosal compartments of female Beninese commercial sex workers (CSWs). Samples of 23 HIV-1-positive and 20 highly exposed HIV-1-seronegative (HESN) CSWs were studied. HIV-1 Env-specific IgG detection in sera and cervicovaginal lavages (CVLs) from the study population was done by cell-based ELISA. The HIV neutralizing activity was evaluated with a neutralization assay. The HIV-1-specific antibody-dependent cellular cytotoxicity (ADCC) response of the cohort was measured with a FACS-based assay evaluating the ADCC-mediated elimination of gp120-coated target cells. No anti-HIV-1 Env-specific IgG neutralizing or ADCC activities were detected in samples from HESN CSWs. Samples from HIV-1-infected CSWs presented ADCC activity in both sera and CVLs. Anti-Env IgG from sera and CVLs from HIV-1-infected CSWs preferentially recognized Env in its CD4-bound conformation. HIV-1-infected CSWs have ADCC-mediating IgG that preferentially recognizes Env in its CD4-bound conformation at the mucosal site.

  15. Synthesis and anti-HIV-1 screening of novel N'-(1-(aryl)ethylidene)-2-(5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(1H)-yl)acetohydrazides.

    PubMed

    Aslam, Sana; Ahmad, Matloob; Zia-Ur-Rehman, Muhammad; Montero, Catherine; Detorio, Mervi; Parvez, Masood; Schinazi, Raymond F

    2014-11-01

    A novel series of N'-(1-(aryl)ethylidene)-2-(5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(1H)-yl)acetohydrazides was synthesized. The synthesis was carried out by thermal method as well as ultrasonic bath to reduce reaction time and to enhance product yields. The synthesized compounds were characterized by spectroscopic techniques like NMR, infrared and EIMS. The structure of compound 5w was elucidated by X-ray crystallography. The titled compounds were evaluated for anti-human immunodeficiency virus type 1 (anti-HIV-1) and cytotoxic activities. Biological studies indicated that amongst these compounds, 5a, b, j, h and i showed the activity with median effective concentration (EC50) values less than 20 μM. Compound 5i exhibited the most potent anti-HIV-1 activity (EC50 = 3.2 μM) while 5h showed anti-HIV-1 activity (EC50 = 3.8 μM) with no toxicity at all in primary human lymphocytes, CEM and VERO cells.

  16. Synthesis and anti-HIV activity of (-)-β-D-(2R,4R) 1,3-dioxolane 2,6-diamino purine (DAPD) (Amdoxovir) and (-)-β-D-(2R,4R) 1,3-dioxolane guanosine (DXG) prodrugs

    PubMed Central

    Narayanasamy, Janarthanan; Pullagurla, Manik R.; Sharon, Ashoke; Wang, Jianing; Schinazi, Raymond F.; Chu, Chung K.

    2007-01-01

    Prodrugs of (-)-β-D-(2R,4R)-1,3-dioxolane-2,6-diamino purine (DAPD), organic salts of DAPD, 5′-l-valyl DAPD and N-1 substituted (-)-β-D-(2R,4R)-1,3-dioxolane guanosine (DXG) have been synthesized with the objective of finding molecules which might be superior to DAPD and DXG in solubility as well as pharmacologic profiles. Synthesized prodrugs were evaluated for anti-HIV activity against HIV-1LAI in primary human lymphocytes (PBM cells) as well as their cytotoxicity in PBM, CEM and Vero cells. DAPD prodrugs, modified at the C6 position of the purine ring, demonstrated several folds of enhanced anti-HIV activity in comparison to the parent compound DAPD without increasing the toxicity. The presence of alkyl amino groups at the C6 position of the purine ring increased the antiviral potency several folds, and the most potent compound (-)-β-D-(2R,4R)-1,3-dioxolane-2-amino-6-aminoethyl purine (8) was 17 times more potent than that of DAPD. 5′-l-Valyl DAPD 20 and organic acid salts 21-24 also exhibited enhanced anti-HIV activity in comparison to DAPD, while DXG prodrugs 16-17 exhibited lower potency than that of DXG or DAPD. PMID:17532483

  17. Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2',2'-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents.

    PubMed

    Zhou, Ting; Shi, Qian; Chen, Chin-Ho; Zhu, Hao; Huang, Li; Ho, Phong; Lee, Kuo-Hsiung

    2010-09-15

    In a continued study, 23 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5-27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 microM to 0.14 microM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 microM; TI 310 and 200, respectively), and were twofold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 microM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5-10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates.

  18. An alternative approach to confirming anti-HIV reactivity: a multi-country collaborative study.

    PubMed Central

    Mortimer, J.

    1992-01-01

    The confirmation of positive screening assay reactions for antibodies to human immunodeficiency virus type 1 (anti-HIV-1) by Western blot is expensive and often gives indeterminate results. We therefore carried out a collaborative study to investigate the confirmation of screening assay reactions using a second screening assay. For this purpose, seven laboratories prospectively tested sequential specimens, using at least one additional screening assay, until about 50 confirmed anti-HIV-1-positive specimens had been identified in each test centre. The reactions of 16 assays were analysed in pairs (assay A and assay B), using assay B on specimens reactive in assay A: A+/B+ reactions were considered positive and A-, negative anti-HIV results. These outcomes were compared with those obtained using confirmatory Western blot. In all, 7950 specimens were tested, and 359 were reported as positive by the laboratories. Within the test centres, eight screening assay pairings gave rise to no false-positive or false-negative results, and these combinations were at least as accurate as a single screening assay followed by Western blot. From 6.3% to 8.3% of the Western blot results were indeterminate. The number of specimens examined was too small to justify recommending for general use named pairs of screening assays; the choice of these would, in any case, depend on local conditions. However, individual laboratory managers may wish to investigate the large potential savings to be made by confirming HIV infection using a second screening assay on initially reactive specimens. If the more sensitive screening assay is used first, the sensitivity of this approach may be improved by further investigation of specimens that react as A+B-. PMID:1486672

  19. Synthesis of 9-substituted derivatives of berberine as anti-HIV agents.

    PubMed

    Bodiwala, Hardik S; Sabde, Sudeep; Mitra, Debashis; Bhutani, Kamlesh Kumar; Singh, Inder Pal

    2011-04-01

    Naturally occurring protoberberine alkaloids, berberine and berberrubine along with 9-substituted derivatives of berberine were assessed for the anti-human immunodeficiency virus (HIV) activity. Berberine was found to be the most active compound with an EC(50) of 0.13 μM against HIV-1 NL4.3 virus in CEM-GFP cell lines. Berberrubine and two other compounds were found to be less active than berberine, at the same time they were less toxic than berberine. Enzyme based assay suggested that the anti-HIV activity of berberine and its analogs might be due to RTase inhibitory activity and some additional mechanisms.

  20. Synthesis of optically pure dioxolane nucleosides and their anti-HIV activity

    SciTech Connect

    Siddigui, M.A.; Evans, C.; Jin, H.L.; Tse, A.; Brown, W.; Nguyen-Ba, N.; Mansour, T.S.; Cameron, J.M.

    1993-12-31

    The clinical candidate 3TC, 1, possessing non-natural absolute stereochemistry is a potent and non-toxic inhibitor of a key enzyme, reverse transcriptase, involved in the replicative cycle of the HIV. Selective inhibition of both HIV and HBV is seen. In view of the authors` interest in finding correlation between stereochemistry and antiviral activity, several enantiomerically pure dioxolane nucleosides, 2, were synthesized and assayed. The discussion will focus on (a) the synthesis of optically pure dioxolane sugars from L-ascorbic acid, (b) enzymatic resolution of purine dioxolane nucleosides, (c) anti HIV-1 activity in MT-4 cells.

  1. Core-structure-inspired asymmetric addition reactions: enantioselective synthesis of dihydrobenzoxazinone- and dihydroquinazolinone-based anti-HIV agents.

    PubMed

    Li, Shen; Ma, Jun-An

    2015-11-01

    Dihydrobenzoxazinones and dihydroquinazolinones are the core units present in many anti-HIV agents, such as Efavirenz, DPC 961, DPC 963, and DPC 083. All these molecules contain a trifluoromethyl moiety at the quaternary stereogenic carbon center with S configuration. The enantioselective addition of carbon nucleophiles to ketones or cyclic ketimines could serve as a key step to access these molecules. This tutorial review provides an overview of significant advances in the synthesis of dihydrobenzoxazinone- and dihydroquinazolinone-based anti-HIV agents and relative analogues, with an emphasis on asymmetric addition reactions for the establishment of the CF3-containing quaternary carbon centers.

  2. Coating flow of non-Newtonian anti-HIV microbicide vehicles

    NASA Astrophysics Data System (ADS)

    Park, Su Chan; Szeri, Andrew; Verguet, Stéphane; Katz, David; Weiss, Aaron

    2008-11-01

    Elastohydrodynamic lubrication over soft substrates is of importance for the drug delivery functions of vehicles for anti-HIV topical microbicides. These are intended to inhibit transmission into vulnerable mucosa, e.g. in the vagina. First generation prototype microbicides have gel vehicles, which spread after insertion and coat luminal surfaces. Effectiveness derives from potency of the active ingredients and completeness and durability of coating. Delivery vehicle rheology, luminal biomechanical properties and the force due to gravity influence the coating mechanics. We develop a framework for understanding the relative importance of boundary squeezing and body forces on the extent and speed of the coating that results. In the case of a shear-thinning fluid, the Carreau number also plays a role. Numerical solutions are developed for a range of conditions and materials. Results are interpreted with respect to tradeoffs between wall elasticity, longitudinal forces, bolus viscosity and bolus volume. These provide initial insights of practical value for formulators of non-Newtonian gel delivery vehicles for anti-HIV microbicidal formulations.

  3. Anti-HIV activity of fucoidans from three brown seaweed species.

    PubMed

    Thuy, Thanh Thi Thu; Ly, Bui Minh; Van, Tran Thi Thanh; Quang, Ngo Van; Tu, Ho Cam; Zheng, Yue; Seguin-Devaux, Carole; Mi, Bilan; Ai, Usov

    2015-01-22

    Fucoidans are sulfated polysaccharides derived from marine brown algae. In the current work the anti-HIV activity of three fucoidans, extracted from three brown seaweeds Sargassum mcclurei, Sargassum polycystum and Turbinara ornata and collected from Nha Trang bay, Vietnam was investigated. Fucoidans extracted from the three species displayed similar antiviral activities with a mean IC50 ranging from 0.33 to 0.7 μg/ml while displaying no cell toxicity. Our results showed that the anti-HIV activity of fucoidans is not primarily linked to the sulfate content and the appropriate position of sulfate groups in the fucoidan backbones was also not associated with the antiviral activity. Fucoidans inhibited HIV-1 infection when they were pre-incubated with the virus but not with the cells, and not after infection, blocking the early steps of HIV entry into target cells. These data contribute to a better understanding of the influence of fucoidans structural characteristics on their biological activity.

  4. Double Variational Binding—(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV Pyrimidine Ligands

    PubMed Central

    Putz, Mihai V.; Dudaș, Nicoleta A.; Isvoran, Adriana

    2015-01-01

    Variational quantitative binding–conformational analysis for a series of anti-HIV pyrimidine-based ligands is advanced at the individual molecular level. This was achieved by employing ligand-receptor docking algorithms for each molecule in the 1,3-disubstituted uracil derivative series that was studied. Such computational algorithms were employed for analyzing both genuine molecular cases and their simplified molecular input line entry system (SMILES) transformations, which were created via the controlled breaking of chemical bonds, so as to generate the longest SMILES molecular chain (LoSMoC) and Branching SMILES (BraS) conformations. The study identified the most active anti-HIV molecules, and analyzed their special and relevant bonding fragments (chemical alerts), and the recorded energetic and geometric docking results (i.e., binding and affinity energies, and the surface area and volume of bonding, respectively). Clear computational evidence was also produced concerning the ligand-receptor pocket binding efficacies of the LoSMoc and BraS conformation types, thus confirming their earlier presence (as suggested by variational quantitative structure-activity relationship, variational-QSAR) as active intermediates for the molecule-to-cell transduction process. PMID:26295229

  5. Sulfated Polysaccharides in Marine Sponges: Extraction Methods and Anti-HIV Activity

    PubMed Central

    Esteves, Ana I. S.; Nicolai, Marisa; Humanes, Madalena; Goncalves, Joao

    2011-01-01

    The extraction, fractionation and HIV-1 inhibition potential of polysaccharides extracted from three species of marine sponges, Erylus discophorus, Cliona celata and Stelletta sp., collected in the Northeastern Atlantic, is presented in this work. The anti-HIV activity of 23 polysaccharide pellets and three crude extracts was tested. Crude extracts prepared from Erylus discophorus specimens were all highly active against HIV-1 (90 to 95% inhibition). Cliona celata pellets showed low polysaccharide content (bellow 38.5%) and almost no anti-HIV activity (<10% inhibition). Stelletta sp. pellets, although quite rich in polysaccharide (up to 97.3%), showed only modest bioactivity (<36% HIV-1 inhibition). Erylus discophorus pellets were among the richest in terms of polysaccharide content (up to 98%) and the most active against HIV-1 (up to 95% inhibition). Chromatographic fractionation of the polysaccharide pellet obtained from a specimen of Erylus discophorus (B161) yielded only modestly active fractions. However, we could infer that the active molecule is most probably a high molecular weight sulfated polysaccharide (>2000 kDa), whose mechanism is possibly preventing viral attachment and entry (fusion inhibitor). PMID:21339952

  6. Anti-AIDS agents 87. New bio-isosteric dicamphanoyl-dihydropyranochromone (DCP) and dicamphanoyl-khellactone (DCK) analogues with potent anti-HIV activity.

    PubMed

    Liu, Hong-Shan; Xu, Shi-Qing; Cheng, Ming; Chen, Ying; Xia, Peng; Qian, Keduo; Xia, Yi; Yang, Zheng-Yu; Chen, Chin-Ho; Morris-Natschke, Susan L; Lee, Kuo-Hsiung

    2011-10-01

    Six 3'R,4'R-di-O-(S)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) and two 3'R,4'R-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives were designed, synthesized, and evaluated for inhibition of HIV-1(NL4-3) replication in TZM-bl cells. 2-Ethyl-2'-monomethyl-1'-oxa- and -1'-thia-DCP (5a, 6a), as well as 2-ethyl-1'-thia-DCP (7a) exhibited potent anti-HIV activity with EC(50) values of 30, 38 and 54 nM and therapeutic indexes of 152.6, 48.0 and 100.0, respectively, which were better than or comparable to those of the lead compound 2-ethyl-DCP in the same assay. 4-Methyl-1'-thia-DCK (8a) also showed significant inhibitory activity with an EC(50) of 128 nM and TI of 237.9.

  7. Cytotoxic, antitopoisomerase IIα, and anti-HIV-1 activities of triterpenoids isolated from leaves and twigs of Gardenia carinata.

    PubMed

    Kongkum, Naowarat; Tuchinda, Patoomratana; Pohmakotr, Manat; Reutrakul, Vichai; Piyachaturawat, Pawinee; Jariyawat, Surawat; Suksen, Kanoknetr; Akkarawongsapat, Radeekorn; Kasisit, Jitra; Napaswad, Chanita

    2013-04-26

    Eight new cycloartane triterpenoids (1-8), named carinatins A-H, and the known compounds secaubryolide (9) and dikamaliartane D (10) were isolated from the leaves and twigs of Gardenia carinata. Their structures were determined on the basis of spectroscopic methods. Cytotoxic, antitopoisomerase IIα, and anti-HIV-1 activities of compounds 1-7, 9, and 10 were investigated.

  8. Design, Synthesis and antiHIV activity of Novel Isatine-Sulphonamides.

    PubMed

    Selvam, P; Murugesh, N; Chandramohan, M; Debyser, Z; Witvrouw, M

    2008-11-01

    A series of novel isatine-sulphonamide derivatives have been synthesized by combining isatin derivatives with sulphonamides. The structure of the synthesized compounds were elucidated by spectral analysis (IR, NMR and Mass). Investigation of anti-HIV activity was done against HIV-1(IIIB) in MT-4 cells and HIV integrase inhibitory activity. 4-(1-acetyl-5-methyl-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (SPIII-5ME-AC) inhibits the HIV Integrase enzymatic activity as both over all and strand transfer reaction and 4-(1-benzoyl-5-chloro-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzene sulfonamide (SPIII-5Cl-BZ) exhibits 36 percent maximum protection against HIV-1 at sub toxic concentration.

  9. Design, Synthesis and antiHIV activity of Novel Isatine-Sulphonamides

    PubMed Central

    Selvam, P.; Murugesh, N.; Chandramohan, M.; Debyser, Z.; Witvrouw, M.

    2008-01-01

    A series of novel isatine-sulphonamide derivatives have been synthesized by combining isatin derivatives with sulphonamides. The structure of the synthesized compounds were elucidated by spectral analysis (IR, NMR and Mass). Investigation of anti-HIV activity was done against HIV-1(IIIB) in MT-4 cells and HIV integrase inhibitory activity. 4-(1-acetyl-5-methyl-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (SPIII-5ME-AC) inhibits the HIV Integrase enzymatic activity as both over all and strand transfer reaction and 4-(1-benzoyl-5-chloro-2-oxoindolin-3-ylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzene sulfonamide (SPIII-5Cl-BZ) exhibits 36 percent maximum protection against HIV-1 at sub toxic concentration. PMID:21369440

  10. Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV.

    PubMed

    De Clercq, Erik

    2009-04-01

    In 2008, 25 years after the human immunodeficiency virus (HIV) was discovered as the then tentative aetiological agent of acquired immune deficiency syndrome (AIDS), exactly 25 anti-HIV compounds have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir); non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine, efavirenz and etravirine); protease inhibitors (PIs: saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir); cell entry inhibitors [fusion inhibitors (FIs: enfuvirtide) and co-receptor inhibitors (CRIs: maraviroc)]; and integrase inhibitors (INIs: raltegravir). These compounds should be used in drug combination regimens to achieve the highest possible benefit, tolerability and compliance and to diminish the risk of resistance development.

  11. Electrochemical impediometric detection of anti-HIV drug taking gold nanorods as a sensing interface.

    PubMed

    Narang, Jagriti; Malhotra, Nitesh; Singh, Gajendra; Pundir, C S

    2015-04-15

    In present work, gold nanorods were used for amplification of electrochemical sensing of anti-HIV replication drug i.e. deferiprone. Gold nanorods (nano Au) deposited onto pencil graphite electrode (PGE) has been utilized for covalent immobilization of horse radish peroxidase (HRP), via glutaraldehyde (Glu), for deferiprone detection using impedimetric technique. Gold nanorods (nano Au) prepared were characterized by TEM and XRD. The resulting nano Au sensor exhibited a good response to deferiprone with a wide linear range (0.005-1000µM) and a low detection limit 0.005µM. The biosensor also showed a short response time (within 15s). In addition, the biosensor exhibited high reproducibility, good storage stability and anti-interference ability. The applicability of the nano Au sensor is to determine deferiprone level in spiked urine and serum samples. PMID:25437372

  12. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges.

    PubMed

    Gautam, Rajeev; Nishimura, Yoshiaki; Pegu, Amarendra; Nason, Martha C; Klein, Florian; Gazumyan, Anna; Golijanin, Jovana; Buckler-White, Alicia; Sadjadpour, Reza; Wang, Keyun; Mankoff, Zachary; Schmidt, Stephen D; Lifson, Jeffrey D; Mascola, John R; Nussenzweig, Michel C; Martin, Malcolm A

    2016-05-01

    Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg(-1)) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9 - 12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission.

  13. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges.

    PubMed

    Gautam, Rajeev; Nishimura, Yoshiaki; Pegu, Amarendra; Nason, Martha C; Klein, Florian; Gazumyan, Anna; Golijanin, Jovana; Buckler-White, Alicia; Sadjadpour, Reza; Wang, Keyun; Mankoff, Zachary; Schmidt, Stephen D; Lifson, Jeffrey D; Mascola, John R; Nussenzweig, Michel C; Martin, Malcolm A

    2016-05-01

    Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg(-1)) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9 - 12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission. PMID:27120156

  14. Stem cell-based therapies for HIV/AIDS.

    PubMed

    Pernet, Olivier; Yadav, Swati Seth; An, Dong Sung

    2016-08-01

    One of the current focuses in HIV/AIDS research is to develop a novel therapeutic strategy that can provide a life-long remission of HIV/AIDS without daily drug treatment and, ultimately, a cure for HIV/AIDS. Hematopoietic stem cell-based anti-HIV gene therapy aims to reconstitute the patient immune system by transplantation of genetically engineered hematopoietic stem cells with anti-HIV genes. Hematopoietic stem cells can self-renew, proliferate and differentiate into mature immune cells. In theory, anti-HIV gene-modified hematopoietic stem cells can continuously provide HIV-resistant immune cells throughout the life of a patient. Therefore, hematopoietic stem cell-based anti-HIV gene therapy has a great potential to provide a life-long remission of HIV/AIDS by a single treatment. Here, we provide a comprehensive review of the recent progress of developing anti-HIV genes, genetic modification of hematopoietic stem progenitor cells, engraftment and reconstitution of anti-HIV gene-modified immune cells, HIV inhibition in in vitro and in vivo animal models, and in human clinical trials. PMID:27151309

  15. Rational design, synthesis, anti-HIV-1 RT and antimicrobial activity of novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one derivatives.

    PubMed

    Chander, Subhash; Wang, Ping; Ashok, Penta; Yang, Liu-Meng; Zheng, Yong-Tang; Murugesan, Sankaranarayanan

    2016-08-01

    In the present study, fifteen novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one (6a-o) derivatives were designed as inhibitor of HIV-1 RT using ligand based drug design approach and in-silico evaluated for drug-likeness properties. Designed compounds were synthesized, characterized and in-vitro evaluated for RT inhibitory activity against wild HIV-1 RT strain. Among the tested compounds, four compounds (6a, 6b, 6j and 6o) exhibited significant inhibition of HIV-1 RT (IC50⩽10μg/ml). All synthesized compounds were also evaluated for anti-HIV-1 activity as well as cytotoxicity on T lymphocytes, in which compounds 6b and 6l exhibited significant anti-HIV activity (EC50 values 4.72 and 5.45μg/ml respectively) with good safety index. Four compounds (6a, 6b, 6j and 6o) found significantly active against HIV-1 RT in the in-vitro assay were in-silico evaluated against two mutant RT strains as well as one wild strain. Further, titled compounds were evaluated for in-vitro antibacterial (Escherichia coli, Pseudomonas putida, Staphylococcus aureus and Bacillus cereus) and antifungal (Candida albicans and Aspergillus niger) activities.

  16. [HPLC enantioseparation, absolute configuration determination and anti-HIV-1 activity of (±)-F18 enantiomers].

    PubMed

    Zhang, Lei-lei; Xue, Hai; Li, Li; Lu, Xiao-fan; Chen, Zhi-wei; Lu, Gang

    2015-06-01

    Racemic (±)-F18 (10-chloromethyl-11-demethyl-12-oxo-calanolide A), an analog of nature product (+)-calanolide A, is a new anti-HIV-1 nonnucleoside reverse transcript inhibitor (NNRTI). A successful enantioseparation of (±)-F18 offering (R)-F18 and (S)-F18 was achieved by a chiral stationary phase prepared HPLC. Their absolute configurations were determined by measurement of their electronic circular dichroisms combined with modem quantum-chemical calculations. Further investigation revealed that (R)-F18 and (S)-F18 shared a similar anti-HIV activities, however, (R)-F18 was more potent than (S)-F18 against wild-type virus, K101E mutation and P225H mutation pseudoviruses. PMID:26521445

  17. Coating flow of an anti-HIV microbicide gel: boundary dilution and yield stress

    NASA Astrophysics Data System (ADS)

    Szeri, Andrew J.; Tasoglu, Savas; Park, Su Chan; Katz, David F.

    2010-11-01

    A recent study has confirmed, for the first time, that a vaginal gel formulation of the antiretroviral drug Tenofovir, when topically applied, significantly inhibits sexual HIV transmission to women [1]. However, the gel for this drug, and anti-HIV microbicide gels in general, have not been designed using an understanding of how gel spreading govern successful drug delivery. Elastohydrodynamic lubrication theory can be applied to model spreading of microbicide gels [2]. Here, we extend our initial analysis: we incorporate a yield stress, and we model the effects of gel dilution due to contact with vaginal fluid produced at the gel-tissue interface. Our model developed in [2] is supplemented with a convective-diffusive transport equation to characterize dilution, and solved using a multi-step scheme in a moving domain. The association between local dilution of gel and rheological properties is obtained experimentally. To model the common yield stress property of gels, we proceed by scaling analysis first. This establishes the conditions for validity of lubrication theory of a shear thinning yield stress fluid. This involves further development of the model in [2], incorporating a biviscosity model.[4pt] [1] Karim, et al., Science, 2010.[0pt] [2] Szeri, et al., Phy. of Fluids, 2008.

  18. Transgenic Production of an Anti HIV Antibody in the Barley Endosperm.

    PubMed

    Hensel, Goetz; Floss, Doreen M; Arcalis, Elsa; Sack, Markus; Melnik, Stanislav; Altmann, Friedrich; Rutten, Twan; Kumlehn, Jochen; Stoger, Eva; Conrad, Udo

    2015-01-01

    Barley is an attractive vehicle for producing recombinant protein, since it is a readily transformable diploid crop species in which doubled haploids can be routinely generated. High amounts of protein are naturally accumulated in the grain, but optimal endosperm-specific promoters have yet to be perfected. Here, the oat GLOBULIN1 promoter was combined with the legumin B4 (LeB4) signal peptide and the endoplasmic reticulum (ER) retention signal (SE)KDEL. Transgenic barley grain accumulated up to 1.2 g/kg dry weight of recombinant protein (GFP), deposited in small roundish compartments assumed to be ER-derived protein bodies. The molecular farming potential of the system was tested by generating doubled haploid transgenic lines engineered to synthesize the anti-HIV-1 monoclonal antibody 2G12 with up to 160 μg recombinant protein per g grain. The recombinant protein was deposited at the periphery of protein bodies in the form of a mixture of various N-glycans (notably those lacking terminal N-acetylglucosamine residues), consistent with their vacuolar localization. Inspection of protein-A purified antibodies using surface plasmon resonance spectroscopy showed that their equilibrium and kinetic rate constants were comparable to those associated with recombinant 2G12 synthesized in Chinese hamster ovary cells.

  19. Transgenic Production of an Anti HIV Antibody in the Barley Endosperm

    PubMed Central

    Hensel, Goetz; Floss, Doreen M.; Arcalis, Elsa; Sack, Markus; Melnik, Stanislav; Altmann, Friedrich; Rutten, Twan; Kumlehn, Jochen; Stoger, Eva; Conrad, Udo

    2015-01-01

    Barley is an attractive vehicle for producing recombinant protein, since it is a readily transformable diploid crop species in which doubled haploids can be routinely generated. High amounts of protein are naturally accumulated in the grain, but optimal endosperm-specific promoters have yet to be perfected. Here, the oat GLOBULIN1 promoter was combined with the legumin B4 (LeB4) signal peptide and the endoplasmic reticulum (ER) retention signal (SE)KDEL. Transgenic barley grain accumulated up to 1.2 g/kg dry weight of recombinant protein (GFP), deposited in small roundish compartments assumed to be ER-derived protein bodies. The molecular farming potential of the system was tested by generating doubled haploid transgenic lines engineered to synthesize the anti-HIV-1 monoclonal antibody 2G12 with up to 160 μg recombinant protein per g grain. The recombinant protein was deposited at the periphery of protein bodies in the form of a mixture of various N-glycans (notably those lacking terminal N-acetylglucosamine residues), consistent with their vacuolar localization. Inspection of protein-A purified antibodies using surface plasmon resonance spectroscopy showed that their equilibrium and kinetic rate constants were comparable to those associated with recombinant 2G12 synthesized in Chinese hamster ovary cells. PMID:26461955

  20. Transgenic Production of an Anti HIV Antibody in the Barley Endosperm.

    PubMed

    Hensel, Goetz; Floss, Doreen M; Arcalis, Elsa; Sack, Markus; Melnik, Stanislav; Altmann, Friedrich; Rutten, Twan; Kumlehn, Jochen; Stoger, Eva; Conrad, Udo

    2015-01-01

    Barley is an attractive vehicle for producing recombinant protein, since it is a readily transformable diploid crop species in which doubled haploids can be routinely generated. High amounts of protein are naturally accumulated in the grain, but optimal endosperm-specific promoters have yet to be perfected. Here, the oat GLOBULIN1 promoter was combined with the legumin B4 (LeB4) signal peptide and the endoplasmic reticulum (ER) retention signal (SE)KDEL. Transgenic barley grain accumulated up to 1.2 g/kg dry weight of recombinant protein (GFP), deposited in small roundish compartments assumed to be ER-derived protein bodies. The molecular farming potential of the system was tested by generating doubled haploid transgenic lines engineered to synthesize the anti-HIV-1 monoclonal antibody 2G12 with up to 160 μg recombinant protein per g grain. The recombinant protein was deposited at the periphery of protein bodies in the form of a mixture of various N-glycans (notably those lacking terminal N-acetylglucosamine residues), consistent with their vacuolar localization. Inspection of protein-A purified antibodies using surface plasmon resonance spectroscopy showed that their equilibrium and kinetic rate constants were comparable to those associated with recombinant 2G12 synthesized in Chinese hamster ovary cells. PMID:26461955

  1. Glycosylated enfuvirtide: a long-lasting glycopeptide with potent anti-HIV activity.

    PubMed

    Cheng, Shuihong; Chang, Xuesong; Wang, Yan; Gao, George F; Shao, Yiming; Ma, Liying; Li, Xuebing

    2015-02-12

    Many peptide-based therapeutics have short circulatory half-lives. We report here that the pharmacokinetics of an anti-HIV peptide drug enfuvirtide (ENF) can be dramatically improved by a chemical glycosylation approach. A set of glycosylated ENFs with varying glycosylation sites and glycan structures were synthesized. Among these, a sialic acid-introduced peptide (SL-ENF) demonstrated a 15-fold extended half-life in rats relative to ENF (T1/2: 23.1 vs 1.5 h), and its antiviral potency was comparable to that of ENF (EC50: 2 vs 3 nM). SL-ENF bound to a functional fragment of the HIV fusogenic protein gp41 and formed complexes with high affinity and α-helicity, revealing the mechanism behind its potent antiviral activity. Because it is widely accepted in biology that glycosylation protects proteins from denaturation and proteases, our approach may be useful for the development of novel protein and peptide drugs with enhanced pharmaceutical properties.

  2. Anti-HIV microRNA expression in a novel Indian cohort

    PubMed Central

    Dey, Rakesh; Soni, Kartik; Saravanan, Shanmugam; Balakrishnan, Pachamuthu; Kumar, Vikram; Boobalan, Jayaseelan; Solomon, Sunil Suhas; Scaria, Vinod; Solomon, Suniti; Brahmachari, Samir K.; Pillai, Beena

    2016-01-01

    HIV-1 replication inside host cells is known to be regulated by various host factors. Host miRNAs, by virtue of its normal functioning, also regulate HIV-1 RNA expression by either directly targeting virus mRNAs or indirectly by regulating host proteins that HIV-1 uses for own replication. Therefore, it is highly possible that with differential miRNA expression, rate of disease progression will vary in HIV-1 infected individuals. In this study we have compared expression of a panel of 13 reported anti-HIV miRNAs in human PBMCs from long term non progressors (LTNPs), regular progressors and rapid progressors. We found that LTNPs have substantial lower expression of miR-382-5p that positively correlates with viral loads. Combinatorial regulation is highly probable in dictating differential disease progression as average expression of miR-382-5p and miR-155-5p can substantially distinguish LTNP individuals from regular progressors. PMID:27320691

  3. Preventing sexual transmission of HIV: anti-HIV bioregulatory and homeostatic components of commercial sexual lubricants.

    PubMed

    Nguyen, D; Lee, H; Poast, J; Cloyd, M W; Baron, S

    2004-01-01

    Certain safe over-the-counter (OTC) sexual lubricants such as Astroglide, KY Liquid, Replens, Vagisil, ViAmor, and Wet Stuff inhibit both cell-free HIV and the production of HIV by infected leukocytes in vitro even in the presence of seminal fluid. To identify which components of the lubricants were active against HIV, we tested five components (glycerin, methylparaben, propylparaben, polyquaternium-32, and propylene glycol). The paraben preservatives and propylene glycol in the lubricants did not inhibit HIV, while the common natural homeostatic metabolite, glycerin, and the thickener polyquaternium-32 did strongly inactivate infectious HIV and HIV-infected leukocytes. Activity against HIV and HIV-infected cells by glycerin was stable through 24 hours at 37 degrees C. Glycerin and polyquaternium-32 were active at minimum concentrations of approximately 2% and 0.01%, respectively--well within the highest FDA safety guidelines. Both active components disrupted infected leukocytes within 5 minutes which resulted in inhibition of infectious HIV production by infected leukocytes of greater than 25 to 100-fold. These components do not disrupt vaginal epithelial cells in vivo. These components also rapidly inactivate cell-free HIV by 10- to 30-fold. Thus, we may conclude that the active components of the OTC lubricants are glycerin and polyquaternium-32. Using these components, OTC sexual lubricants could be reformulated to optimize their anti-HIV activity. Furthermore, clinical trials of these lubricants and components seem to be indicated because of their FDA safety level, wide availability, and low cost.

  4. Structural Insights into the Anti-HIV Activity of the Oscillatoria agardhii Agglutinin Homolog Lectin Family*

    PubMed Central

    Koharudin, Leonardus M. I.; Kollipara, Sireesha; Aiken, Christopher; Gronenborn, Angela M.

    2012-01-01

    Oscillatoria agardhii agglutinin homolog (OAAH) proteins belong to a recently discovered lectin family. All members contain a sequence repeat of ∼66 amino acids, with the number of repeats varying among different family members. Apart from data for the founding member OAA, neither three-dimensional structures, information about carbohydrate binding specificities, nor antiviral activity data have been available up to now for any other members of the OAAH family. To elucidate the structural basis for the antiviral mechanism of OAAHs, we determined the crystal structures of Pseudomonas fluorescens and Myxococcus xanthus lectins. Both proteins exhibit the same fold, resembling the founding family member, OAA, with minor differences in loop conformations. Carbohydrate binding studies by NMR and x-ray structures of glycan-lectin complexes reveal that the number of sugar binding sites corresponds to the number of sequence repeats in each protein. As for OAA, tight and specific binding to α3,α6-mannopentaose was observed. All the OAAH proteins described here exhibit potent anti-HIV activity at comparable levels. Altogether, our results provide structural details of the protein-carbohydrate interaction for this novel lectin family and insights into the molecular basis of their HIV inactivation properties. PMID:22865886

  5. Transient swelling behavior and drug delivery from a dissolving film deploying anti-HIV microbicide

    NASA Astrophysics Data System (ADS)

    Tasoglu, Savas; Katz, David F.; Szeri, Andrew J.

    2010-11-01

    Despite more than two decades of HIV vaccine research, there is still no efficacious HIV vaccine. Very recently, a research group has shown that a microbicide gel formulation of antiretroviral drug Tenofovir, significantly inhibits HIV transmission to women [1]. However, there is a widespread agreement that more effective and diverse drug delivery vehicles must be developed. In this setting, there is now great interest in developing different delivery vehicles such as vaginal rings, gels, and films. Here, we develop a model for transient fluid uptake and swelling behavior, and subsequent dissolution and drug deployment from a film containing anti-HIV microbicide. In the model, the polymer structural relaxation via water uptake is assumed to follow first order kinetics. In the case of a film loaded with an osmotically active solute, the kinetic equation is modified to account for the osmotic effect. The transport rate of solvent and solute within the matrix is characterized by a diffusion equation. After the matrix is relaxed to a specified concentration of solvent, lubrication theory and convective-diffusive transport are employed for flow of the liquefied matrix and drug dispersion respectively. [1] Karim, et al., Science, 2010.

  6. Effects of dilution on elastohydrodynamic coating flow of an anti-HIV microbicide vehicle

    NASA Astrophysics Data System (ADS)

    Szeri, Andrew; Park, Su Chan; Tasoglu, Savas; Katz, David F.

    2009-11-01

    Elastohydrodynamic lubrication over soft substrates characterizes the drug delivery of anti-HIV topical microbicides carried in gel vehicles. These gels are under development to prevent HIV transmission into vulnerable vaginal mucosa during intercourse. Their effectiveness depends on completeness and durability of coating, as well as on the active ingredients. Here we investigate the influence of dilution by vaginal fluid on the coating flows that serve to protect the user. The effects of dilution by vaginal fluid simulant are assessed through rheological experiments at variable dilution of the gel vehicle. This involves determination of the way parameters in a Carreau model of a shear-thinning gel are modified by dilution. The changes in coating are determined from a computational model, based on dilution rheology measured in the laboratory. The elastohydrodynamic lubrication model of Szeri, et al. Physics of Fluids (2008) is supplemented with a convective-diffusive transport equation to handle dilution, and solved using a multi-step scheme in a moving domain.

  7. Preventing sexual transmission of HIV: anti-HIV bioregulatory and homeostatic components of commercial sexual lubricants.

    PubMed

    Nguyen, D; Lee, H; Poast, J; Cloyd, M W; Baron, S

    2004-01-01

    Certain safe over-the-counter (OTC) sexual lubricants such as Astroglide, KY Liquid, Replens, Vagisil, ViAmor, and Wet Stuff inhibit both cell-free HIV and the production of HIV by infected leukocytes in vitro even in the presence of seminal fluid. To identify which components of the lubricants were active against HIV, we tested five components (glycerin, methylparaben, propylparaben, polyquaternium-32, and propylene glycol). The paraben preservatives and propylene glycol in the lubricants did not inhibit HIV, while the common natural homeostatic metabolite, glycerin, and the thickener polyquaternium-32 did strongly inactivate infectious HIV and HIV-infected leukocytes. Activity against HIV and HIV-infected cells by glycerin was stable through 24 hours at 37 degrees C. Glycerin and polyquaternium-32 were active at minimum concentrations of approximately 2% and 0.01%, respectively--well within the highest FDA safety guidelines. Both active components disrupted infected leukocytes within 5 minutes which resulted in inhibition of infectious HIV production by infected leukocytes of greater than 25 to 100-fold. These components do not disrupt vaginal epithelial cells in vivo. These components also rapidly inactivate cell-free HIV by 10- to 30-fold. Thus, we may conclude that the active components of the OTC lubricants are glycerin and polyquaternium-32. Using these components, OTC sexual lubricants could be reformulated to optimize their anti-HIV activity. Furthermore, clinical trials of these lubricants and components seem to be indicated because of their FDA safety level, wide availability, and low cost. PMID:15786693

  8. [Investigation of HHV-8 prevalence in anti-HIV-1 positive patients in Istanbul, Turkey].

    PubMed

    Karlı, Bahar; Onel, Mustafa; Eraksoy, Haluk; Ağaçfidan, Ali

    2013-07-01

    Human herpes virus-8 (HHV-8) infections are associated with Kaposi's Sarcoma (KS), Multiple Castleman disease and primary effusion lymphoma, and particularly important in HIV/AIDS and transplantation patients. The aim of this prospective study was to detect HHV-8 prevalence in HIV-1-infected patients,in a Turkish population. A total of 85 anti-HIV-1 positive patients (53 male, 32 female; age range: 1-70 years) diagnosed at Istanbul Faculty of Medicine, Infectious Diseases and Clinical Microbiology Department were included in the study. In 45 (53%) of the patients HIV-RNA was detectable and viral loads were between 20-10.000.000 copies/ml. HHV-8-specific IgG antibodies were screened by using a commercial ELISA kit (Advanced Biotechnologies Inc, USA), and the presence of HHV-8 nucleic acids were investigated by PCR (Roche Diagnostics, Germany) in the blood samples obtained from patients. HHV-8 IgG was detected in 28.2% (24/85) of the anti-HIV-1 positive patients, and HHV-8 DNA was detected in 3.5% (3/85). One of the three HHV-8 DNA positive cases was seropositive as well. Twenty-five percent of the seropositive patients were female (6/24) and 75% were male (18/24). Of three HHV-8 DNA positive cases, two were male and one was female. The distribution of HHV-8 seropositivity rates according to the age groups were as follows; 1/3 for 1-10 years, 1/2 for 11-20 years, 3/8 for 21-30 years, 7/27 for 31-40 years, 9/30 for 41-50 years, 1/9 for 51-60 years, and 2/6 for 61-70 years. The highest seropositivity rate was detected in 41-50 age group (9/24, 37.5%), followed by 31-40 age group (7/24, 29.2%), presenting statistically significant differences between the other age groups (p< 0.05). HHV-8 DNA was detected in only 1 (4.2%) out of 24 IgG seropositive patients. HIV viral loads of the two HHV-8 seronegative patients whose HHV-8 DNA levels of < 500 copy/ml, were < 20 copy/ml and 1250 copy/ml, respectively. HIV-RNA load of the other patient with HHV-8 IgG positivity and 2240

  9. Syndecan-Fc Hybrid Molecule as a Potent In Vitro Microbicidal Anti-HIV-1 Agent▿

    PubMed Central

    Bobardt, Michael D.; Chatterji, Udayan; Schaffer, Lana; de Witte, Lot; Gallay, Philippe A.

    2010-01-01

    In the absence of a vaccine, there is an urgent need for the development of safe and effective topical microbicides to prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In this study, we proposed to develop a novel class of microbicides using syndecan as the antiviral agent. Specifically, we generated a soluble syndecan-Fc hybrid molecule by fusing the ectodomain of syndecan-1 to the Fc domain of a human IgG. We then tested the syndecan-Fc hybrid molecule for various in vitro microbicidal anti-HIV-1 properties. Remarkably, the syndecan-Fc hybrid molecule possesses multiple attractive microbicidal properties: (i) it blocks HIV-1 infection of primary targets including T cells, macrophages, and dendritic cells (DC); (ii) it exhibits a broad range of antiviral activity against primary HIV-1 isolates, multidrug resistant HIV-1 isolates, HIV-2, and simian immunodeficiency virus (SIV); (iii) it prevents transmigration of HIV-1 through human primary genital epithelial cells; (iv) it prevents HIV-1 transfer from dendritic cells to CD4+ T cells; (v) it is potent when added 2 h prior to addition of HIV-1 to target cells; (vi) it is potent at a low pH; (vii) it blocks HIV-1 infectivity when diluted in genital fluids; and (viii) it prevents herpes simplex virus infection. The heparan sulfate chains of the syndecan-Fc hybrid molecule are absolutely required for HIV-1 neutralization. Several lines of evidence suggest that the highly conserved Arg298 in the V3 region of gp120 serves as the locus for the syndecan-Fc hybrid molecule neutralization. In conclusion, this study suggests that the syndecan-Fc hybrid molecule represents the prototype of a new generation of microbicidal agents that may have promise for HIV-1 prevention. PMID:20439611

  10. A rationally engineered anti-HIV peptide fusion inhibitor with greatly reduced immunogenicity.

    PubMed

    Brauer, Frances; Schmidt, Kerstin; Zahn, Roland C; Richter, Cornelia; Radeke, Heinfried H; Schmitz, Jörn E; von Laer, Dorothee; Egerer, Lisa

    2013-02-01

    Peptides derived from the C-terminal heptad repeat 2 (HR2) region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very efficient HIV-1 fusion inhibitors. We previously developed innovative gene therapeutic approaches aiming at the direct in vivo production of C peptides from genetically modified host cells and found that T cells expressing membrane-anchored or secreted C peptides are protected from HIV-1 infection. However, an unwanted immune response against such antiviral peptides may significantly impair clinical efficacy and pose safety risks to patients. To overcome this problem, we engineered a novel C peptide, V2o, with greatly reduced immunogenicity and excellent antiviral activity. V2o is based on the chimeric C peptide C46-EHO, which is derived from the HR2 regions of HIV-2(EHO) and HIV-1(HxB2) and has broad anti-HIV and anti-simian immunodeficiency virus activity. Antibody and major histocompatibility complex class I epitopes within the C46-EHO peptide sequence were identified by in silico and in vitro analyses. Using rational design, we removed these epitopes by amino acid substitutions and thus minimized antigenicity and immunogenicity considerably. At the same time, the antiviral activity of the deimmunized peptide V2o was preserved or even enhanced compared to that of the parental C46-EHO peptide. Thus, V2o is an ideal candidate, especially for those novel therapeutic approaches for HIV infection that involve direct in vivo production of antiviral C peptides. PMID:23147734

  11. Technology evaluation: cystic fibrosis therapy, Genzyme.

    PubMed

    Cockett, M I

    1999-04-01

    Genzyme is developing therapies to replace the defective forms of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein in CF patients. The company is developing a gene therapy, as well as a recombinant production of CFTR for protein replacement therapy. Both approaches have been granted orphan drug status by the FDA [156348]. The results of several clinical trials were discussed at the first annual meeting of the American Society of Gene Therapy in May 1998. A single dose nasal administration was well tolerated by volunteers, but had disappointing efficacy. In a study completed at the Royal Brompton Hospital, London, a single dose aerosol application of GL-67:DOPE was administered to eight patients, while another eight received GL-67:DOPE plus pCF1-CFTR. In the second group, a moderate increase in the potential difference in the lung was observed, with a slight trend towards bacterial adherence normalization in the airway cells. Seven of the patients in the second group, and three patients who received lipid alone, developed, flu-like symptoms within 24 h. A trial at the University of Alabama, using the same formulation, showed that flu-like symptoms developed in six of eight patients by day two, and in all patients by day seven [290120]. In 1995, the company began a clinical safety trial involving delivery of a normal CF gene to the patient's lungs via an adenovirus vector. The administration involves the inhalation of an aerosol containing the vector or, separately, delivery to one lobe of the patient's lung via a bronchoscope [191678]. To evaluate additional delivery methods for the gene, Genzyme has an exclusive research agreement for the use of Vical's cytofectins as non-viral delivery vectors for CFTR. Also under investigation are delivery systems for the nasal epithelium using liposomes or lipid-DNA complexes. These protocols are being developed in collaboration with the National Heart & Lung Institute, London, and an undisclosed

  12. Anti-HIV-1 nanotherapeutics: promises and challenges for the future.

    PubMed

    Mahajan, Supriya D; Aalinkeel, Ravikumar; Law, Wing-Cheung; Reynolds, Jessica L; Nair, Bindukumar B; Sykes, Donald E; Yong, Ken-Tye; Roy, Indrajit; Prasad, Paras N; Schwartz, Stanley A

    2012-01-01

    The advent of highly active antiretroviral therapy (HAART) has significantly improved the prognosis for human immunodeficiency virus (HIV)-infected patients, however the adverse side effects associated with prolonged HAART therapy use continue. Although systemic viral load can be undetectable, the virus remains sequestered in anatomically privileged sites within the body. Nanotechnology-based delivery systems are being developed to target the virus within different tissue compartments and are being evaluated for their safety and efficacy. The current review outlines the various nanomaterials that are becoming increasingly used in biomedical applications by virtue of their robustness, safety, multimodality, and multifunctionality. Nanotechnology can revolutionize the field of HIV medicine by not only improving diagnosis, but also by improving delivery of antiretrovirals to targeted regions in the body and by significantly enhancing the efficacy of the currently available antiretroviral medications.

  13. A Rapid, Self-confirming Assay for HIV: Simultaneous Detection of Anti-HIV Antibodies and Viral RNA

    PubMed Central

    Chen, Zongyuan; Zhu, Hui; Malamud, Daniel; Barber, Cheryl; Ongagna, Yhombi Yvon Serge; Yasmin, Rubina; Modak, Sayli; Janal, Malvin N.; Abrams, William R.; Montagna, Richard A.

    2016-01-01

    Objective We developed a microfluidic system to simultaneously detect host anti-HIV antibodies and viral RNA in the same specimen in order to satisfy two important diagnostic criteria, especially within resource-limited settings. First, the system can detect acute HIV infection and allow immediate confirmation of a seropositive screening result by detection of HIV RNA. It also addresses the well-known "seroconversion window" during early HIV infection when antibodies are not yet detectable and viral loads are at their highest. Methods We first developed and optimized two separate manual assays for the detection of host anti-HIV antibodies and viral RNA and then converted them to the microfluidic system. We optimized a commercially available serologic assay to run within the microfluidic device while we incorporated the isothermal LAMP assay to detect the presence of viral RNA. The microfluidic device and instrumentation were developed to simultaneously perform both assays without any user intervention. Results The finalized system consists of a disposable injection molded and film-laminated microfluidic CARD disposable device and a portable, software controlled instrument, which together can automatically perform all steps of both assays without any user intervention after the initial loading of samples and reagents. The microfluidic CARD cartridge has multiple microchannels, valves, pumps and reservoirs, which perform the immunoassay, isolates viral RNA for detection by magnetic bead based purification, and Reverse Transcriptase loop-mediated isothermal amplification (RT-LAMP). The microfluidic system was able to detect host anti-HIV antibodies and viral RNA in either a blood or saliva sample. Conclusion The ability to detect antibodies and simultaneously confirm a seropositive HIV-RNA result provides healthcare workers with a complete and accurate appraisal of a patient's infection status in the earliest stages of the disease and represents an important tool for

  14. Docking of anti-HIV-1 oxoquinoline-acylhydrazone derivatives as potential HSV-1 DNA polymerase inhibitors

    NASA Astrophysics Data System (ADS)

    Yoneda, Julliane Diniz; Albuquerque, Magaly Girão; Leal, Kátia Zaccur; Santos, Fernanda da Costa; Batalha, Pedro Netto; Brozeguini, Leonardo; Seidl, Peter R.; de Alencastro, Ricardo Bicca; Cunha, Anna Cláudia; de Souza, Maria Cecília B. V.; Ferreira, Vitor F.; Giongo, Viveca A.; Cirne-Santos, Cláudio; Paixão, Izabel C. P.

    2014-09-01

    Although there are many antiviral drugs available for the treatment of herpes simplex virus (HSV) infections, still the synthesis of new anti-HSV candidates is an important strategy to be pursued, due to the emergency of resistant HSV strains mainly in human immunodeficiency virus (HIV) co-infected patients. Some 1,4-dihydro-4-oxoquinolines, such as PNU-183792 (1), show a broad spectrum antiviral activity against human herpes viruses, inhibiting the viral DNA polymerase (POL) without affecting the human POLs. Thus, on an ongoing antiviral research project, our group has synthesized ribonucleosides containing the 1,4-dihydro-4-oxoquinoline (quinolone) heterocyclic moiety, such as the 6-Cl derivative (2), which is a dual antiviral agent (HSV-1 and HIV-1). Molecular dynamics simulations of the complexes of 1 and 2 with the HSV-1 POL suggest that structural modifications of 2 should increase its experimental anti-HSV-1 activity, since its ribosyl and carboxyl groups are highly hydrophilic to interact with a hydrophobic pocket of this enzyme. Therefore, in this work, comparative molecular docking simulations of 1 and three new synthesized oxoquinoline-acylhydrazone HIV-1 inhibitors (3-5), which do not contain those hydrophilic groups, were carried out, in order to access these modifications in the proposition of new potential anti-HSV-1 agents, but maintaining the anti-HIV-1 activity. Among the docked compounds, the oxoquinoline-acylhydrazone 3 is the best candidate for an anti-HSV-1 agent, and, in addition, it showed anti-HIV-1 activity (EC50 = 3.4 ± 0.3 μM). Compounds 2 and 3 were used as templates in the design of four new oxoquinoline-acylhydrazones (6-9) as potential anti-HSV-1 agents to increase the antiviral activity of 2. Among the docked compounds, oxoquinoline-acylhydrazone 7 was selected as the best candidate for further development of dual anti-HIV/HSV activity.

  15. Functional advantage of educated KIR2DL1(+) natural killer cells for anti-HIV-1 antibody-dependent activation.

    PubMed

    Gooneratne, S L; Center, R J; Kent, S J; Parsons, M S

    2016-04-01

    Evidence from the RV144 HIV-1 vaccine trial implicates anti-HIV-1 antibody-dependent cellular cytotoxicity (ADCC) in vaccine-conferred protection from infection. Among effector cells that mediate ADCC are natural killer (NK) cells. The ability of NK cells to be activated in an antibody-dependent manner is reliant upon several factors. In general, NK cell-mediated antibody-dependent activation is most robust in terminally differentiated CD57(+) NK cells, as well as NK cells educated through ontological interactions between inhibitory killer immunoglobulin-like receptors (KIR) and their major histocompatibility complex class I [MHC-I or human leucocyte antigen (HLA-I)] ligands. With regard to anti-HIV-1 antibody-dependent NK cell activation, previous research has demonstrated that the epidemiologically relevant KIR3DL1/HLA-Bw4 receptor/ligand combination confers enhanced activation potential. In the present study we assessed the ability of the KIR2DL1/HLA-C2 receptor/ligand combination to confer enhanced activation upon direct stimulation with HLA-I-devoid target cells or antibody-dependent stimulation with HIV-1 gp140-pulsed CEM.NKr-CCR5 target cells in the presence of an anti-HIV-1 antibody source. Among donors carrying the HLA-C2 ligand for KIR2DL1, higher interferon (IFN)-γ production was observed within KIR2DL1(+) NK cells than in KIR2DL1(-) NK cells upon both direct and antibody-dependent stimulation. No differences in KIR2DL1(+) and KIR2DL1(-) NK cell activation were observed in HLA-C1 homozygous donors. Additionally, higher activation in KIR2DL1(+) than KIR2DL1(-) NK cells from HLA-C2 carrying donors was observed within less differentiated CD57(-) NK cells, demonstrating that the observed differences were due to education and not an overabundance of KIR2DL1(+) NK cells within differentiated CD57(+) NK cells. These observations are relevant for understanding the regulation of anti-HIV-1 antibody-dependent NK cell responses.

  16. L-selectin and P-selectin are novel biomarkers of cervicovaginal inflammation for preclinical mucosal safety assessment of anti-HIV-1 microbicide.

    PubMed

    Zhong, Maohua; He, Benxia; Yang, Jingyi; Bao, Rong; Zhang, Yan; Zhou, Dihan; Chen, Yaoqing; Li, Liangzhu; Han, Chen; Yang, Yi; Sun, Ying; Cao, Yuan; Li, Yaoming; Shi, Wei; Jiang, Shibo; Zhang, Xiaoyan; Yan, Huimin

    2012-06-01

    A major obstacle thwarting preclinical development of microbicides is the lack of a validated biomarker of cervicovaginal inflammation. Therefore, the present study aims to identify novel noninvasive soluble markers in a murine model for assessment of microbicide mucosal safety. By performing cytokine antibody array analysis, we identified two adhesion molecules, L-selectin and P-selectin, which significantly increased when mucosal inflammation was triggered by nonoxynol-9 (N9), an anti-HIV-1 microbicide candidate that failed clinical trials, in a refined murine model of agent-induced cervicovaginal inflammation. We found that patterns of detection of L-selectin and P-selectin were obviously different from those of the two previously defined biomarkers of cervicovaginal inflammation, monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6). The levels of these two soluble selectins correlated better than those of MCP-1 and IL-6 with the duration and severity of mucosal inflammation triggered by N9 and two approved proinflammatory compounds, benzalkonium chloride (BZK) and sodium dodecyl sulfate (SDS), but not by two nonproinflammatory compounds, carboxymethyl celluose (CMC; microbicide excipients) and tenofovir (TFV; microbicide candidate). These data indicated that L-selectin and P-selectin can serve as additional novel cervicovaginal inflammation biomarkers for preclinical mucosal safety evaluation of candidate microbicides for the prevention of infection with HIV and other sexually transmitted pathogens. PMID:22391529

  17. Highly water-soluble lipophilic prodrugs of the anti-HIV nucleoside analogue 2',3'-dideoxycytidine and its 3'-fluoro derivative.

    PubMed

    Kerr, S G; Kalman, T I

    1992-05-29

    The synthesis of a novel series of lipophilic prodrug derivatives of the anti-HIV drugs 2',3'-dideoxycytidine (ddC, 1) and 3'-fluoro-ddC (2), involving N4-substitution with (N,N-dialkylamino)methylene side chains, is described. The increase in the partition coefficients for the prodrug series, compared to those of the parent drugs 1 and 2, ranged from 1.5- to 122-fold and from 1.6- to 175-fold, respectively. At pH 7.4, 37 degrees C, the hydrolytic t1/2 values ranged from 2 to 52 h, the diisopropyl derivatives (3d and 4d) being most stable in the series. 3d and 4d were greater than or equal to 4-fold and 1.7-fold more soluble in water than 1 and 2, respectively. The in vitro antiretroviral activities of 3d, 4a, and 4d were evaluated; the results indicate efficient prodrug-to-drug conversion under the assay conditions. The results of this investigation demonstrate that it is indeed feasible to chemically modify certain nucleoside analogues with inferior solubility properties to simultaneously achieve significantly enhanced lipid and water solubility.

  18. Altertoxins with potent anti-HIV activity from Alternaria tenuissima QUE1Se, a fungal endophyte of Quercus emoryi.

    PubMed

    Bashyal, Bharat P; Wellensiek, Brian P; Ramakrishnan, Rajesh; Faeth, Stanley H; Ahmad, Nafees; Gunatilaka, A A Leslie

    2014-11-01

    Screening of a small library of natural product extracts derived from endophytic fungi of the Sonoran desert plants in a cell-based anti-HIV assay involving T-cells infected with the HIV-1 virus identified the EtOAc extract of a fermentation broth of Alternaria tenuissima QUE1Se inhabiting the stem tissue of Quercus emoryi as a promising candidate for further investigation. Bioactivity-guided fractionation of this extract led to the isolation and identification of two new metabolites, altertoxins V (1) and VI (2) together with the known compounds, altertoxins I (3), II (4), and III (5). The structures of 1 and 2 were determined by detailed spectroscopic analysis and those of 3-5 were established by comparison with reported data. When tested in our cell-based assay at concentrations insignificantly toxic to T-cells, altertoxins V (1), I (3), II (4), and III (5) completely inhibited replication of the HIV-1 virus at concentrations of 0.50, 2.20, 0.30, and 1.50 μM, respectively. Our findings suggest that the epoxyperylene structural scaffold in altertoxins may be manipulated to produce potent anti-HIV therapeutics.

  19. Molecular cloning and anti-HIV-1 activities of APOBEC3s from northern pig-tailed macaques (Macaca leonina).

    PubMed

    Zhang, Xiao-Liang; Song, Jia-Hao; Pang, Wei; Zheng, Yong-Tang

    2016-07-18

    Northern pig-tailed macaques (NPMs, Macaca leonina) are susceptible to HIV-1 infection largely due to the loss of HIV-1-restricting factor TRIM5α. However, great impediments still exist in the persistent replication of HIV-1 in vivo, suggesting some viral restriction factors are reserved in this host. The APOBEC3 proteins have demonstrated a capacity to restrict HIV-1 replication, but their inhibitory effects in NPMs remain elusive. In this study, we cloned the NPM A3A-A3H genes, and determined by BLAST searching that their coding sequences (CDSs) showed 99% identity to the corresponding counterparts from rhesus and southern pig-tailed macaques. We further analyzed the anti-HIV-1 activities of the A3A-A3H genes, and found that A3G and A3F had the greatest anti-HIV-1 activity compared with that of other members. The results of this study indicate that A3G and A3F might play critical roles in limiting HIV-1 replication in NPMs in vivo. Furthermore, this research provides valuable information for the optimization of monkey models of HIV-1 infection. PMID:27469256

  20. Molecular cloning and anti-HIV-1 activities of APOBEC3s from northern pig-tailed macaques (Macaca leonina)

    PubMed Central

    ZHANG, Xiao-Liang; SONG, Jia-Hao; PANG, Wei; ZHENG, Yong-Tang

    2016-01-01

    Northern pig-tailed macaques (NPMs, Macaca leonina) are susceptible to HIV-1 infection largely due to the loss of HIV-1-restricting factor TRIM5α. However, great impediments still exist in the persistent replication of HIV-1 in vivo, suggesting some viral restriction factors are reserved in this host. The APOBEC3 proteins have demonstrated a capacity to restrict HIV-1 replication, but their inhibitory effects in NPMs remain elusive. In this study, we cloned the NPM A3A-A3H genes, and determined by BLAST searching that their coding sequences (CDSs) showed 99% identity to the corresponding counterparts from rhesus and southern pig-tailed macaques. We further analyzed the anti-HIV-1 activities of the A3A-A3H genes, and found that A3G and A3F had the greatest anti-HIV-1 activity compared with that of other members. The results of this study indicate that A3G and A3F might play critical roles in limiting HIV-1 replication in NPMs in vivo. Furthermore, this research provides valuable information for the optimization of monkey models of HIV-1 infection. PMID:27469256

  1. In vitro anti-HIV-1 activities of kaempferol and kaempferol-7-O-glucoside isolated from Securigera securidaca

    PubMed Central

    Behbahani, M.; Sayedipour, S.; Pourazar, A.; Shanehsazzadeh, M.

    2014-01-01

    Previously, we reported that the kaempferol and kaempferol-7-O-glucoside isolated from Securigera securidaca showed potent anti-HSV activity. In the present study the anti-HIV-1 activities of kaempferol and kaempferol-7-O-glucoside are investigated at different concentrations (100, 50, 25 and 10 μg/ml) using HIV-1 p24 Antigen kit. Real-time Polymerase chain reaction (RT-PCR) assay was also used for quantification of full range of virus load observed in treated and untreated cells. According to the results of RT- PCR, tested compounds at a concentration of 100 μg/ml exerted potent inhibitory effect. Time of drug addition experiments demonstrated that these compounds exerted their inhibitory effects on the early stage of HIV infection. The results also showed potent anti-HIV-1 reverse transcriptase activity. Antiviral activity of kaempferol-7-O-glucoside was more pronounced than that of kaempferol. These findings demonstrate that kaempferol-7-O-glucoside could be considered as a new potential drug candidate for the treatment of HIV infection which requires further assessments. PMID:26339261

  2. In vitro anti-HIV-1 activities of kaempferol and kaempferol-7-O-glucoside isolated from Securigera securidaca.

    PubMed

    Behbahani, M; Sayedipour, S; Pourazar, A; Shanehsazzadeh, M

    2014-01-01

    Previously, we reported that the kaempferol and kaempferol-7-O-glucoside isolated from Securigera securidaca showed potent anti-HSV activity. In the present study the anti-HIV-1 activities of kaempferol and kaempferol-7-O-glucoside are investigated at different concentrations (100, 50, 25 and 10 μg/ml) using HIV-1 p24 Antigen kit. Real-time Polymerase chain reaction (RT-PCR) assay was also used for quantification of full range of virus load observed in treated and untreated cells. According to the results of RT- PCR, tested compounds at a concentration of 100 μg/ml exerted potent inhibitory effect. Time of drug addition experiments demonstrated that these compounds exerted their inhibitory effects on the early stage of HIV infection. The results also showed potent anti-HIV-1 reverse transcriptase activity. Antiviral activity of kaempferol-7-O-glucoside was more pronounced than that of kaempferol. These findings demonstrate that kaempferol-7-O-glucoside could be considered as a new potential drug candidate for the treatment of HIV infection which requires further assessments. PMID:26339261

  3. Sampling of Glycan-Bound Conformers by the Anti-HIV Lectin Oscillatoria agardhii agglutinin in the Absence of Sugar.

    PubMed

    Carneiro, Marta G; Koharudin, Leonardus M I; Ban, David; Sabo, T Michael; Trigo-Mourino, Pablo; Mazur, Adam; Griesinger, Christian; Gronenborn, Angela M; Lee, Donghan

    2015-05-26

    Lectins from different sources have been shown to interfere with HIV infection by binding to the sugars of viral-envelope glycoproteins. Three-dimensional atomic structures of a number of HIV-inactivating lectins have been determined, both as free proteins and in glycan-bound forms. However, details on the mechanism of recognition and binding to sugars are elusive. Herein we focus on the anti-HIV lectin OAA from Oscillatoria agardhii: We show that in the absence of sugars in solution, both the sugar-free and sugar-bound protein conformations that were observed in the X-ray crystal structures exist as conformational substates. Our results suggest that glycan recognition occurs by conformational selection within the ground state; this model differs from the popular "excited-state" model. Our findings provide further insight into molecular recognition of the major receptor on the HIV virus by OAA. These details can potentially be used for the optimization and/or development of preventive anti-HIV therapeutics. PMID:25873445

  4. Proton minibeam radiation therapy: Experimental dosimetry evaluation

    SciTech Connect

    Peucelle, C.; Martínez-Rovira, I.; Prezado, Y.; Nauraye, C.; Patriarca, A.; Hierso, E.; Fournier-Bidoz, N.

    2015-12-15

    Purpose: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy (RT) approach that allies the inherent physical advantages of protons with the normal tissue preservation observed when irradiated with submillimetric spatially fractionated beams. This dosimetry work aims at demonstrating the feasibility of the technical implementation of pMBRT. This has been performed at the Institut Curie - Proton Therapy Center in Orsay. Methods: Proton minibeams (400 and 700 μm-width) were generated by means of a brass multislit collimator. Center-to-center distances between consecutive beams of 3200 and 3500 μm, respectively, were employed. The (passive scattered) beam energy was 100 MeV corresponding to a range of 7.7 cm water equivalent. Absolute dosimetry was performed with a thimble ionization chamber (IBA CC13) in a water tank. Relative dosimetry was carried out irradiating radiochromic films interspersed in a IBA RW3 slab phantom. Depth dose curves and lateral profiles at different depths were evaluated. Peak-to-valley dose ratios (PVDR), beam widths, and output factors were also assessed as a function of depth. Results: A pattern of peaks and valleys was maintained in the transverse direction with PVDR values decreasing as a function of depth until 6.7 cm. From that depth, the transverse dose profiles became homogeneous due to multiple Coulomb scattering. Peak-to-valley dose ratio values extended from 8.2 ± 0.5 at the phantom surface to 1.08 ± 0.06 at the Bragg peak. This was the first time that dosimetry in such small proton field sizes was performed. Despite the challenge, a complete set of dosimetric data needed to guide the first biological experiments was achieved. Conclusions: pMBRT is a novel strategy in order to reduce the side effects of RT. This works provides the experimental proof of concept of this new RT method: clinical proton beams might allow depositing a (high) uniform dose in a brain tumor located in the center of the brain (7.5 cm depth

  5. "Who's to Blame?": An Activity to Stimulate Reflection about Anti-HIV Stigma in an Undergraduate Course on the HIV Epidemic

    ERIC Educational Resources Information Center

    Beshers, Sarah C.

    2007-01-01

    A classroom-based activity was created to help undergraduate students in a course about the HIV epidemic explore and better understand the nature and scope of anti-HIV stigma. The activity asks students to assess the extent of their sympathy for several people living with HIV disease when given only a brief statement about how each person became…

  6. Screening of anti-HIV-1 inophyllums by HPLC-DAD of Calophyllum inophyllum leaf extracts from French Polynesia Islands.

    PubMed

    Laure, Frédéric; Raharivelomanana, Phila; Butaud, Jean-François; Bianchini, Jean-Pierre; Gaydou, Emile M

    2008-08-22

    Various pyranocoumarins, calophyllolide, inophyllums B, C, G(1), G(2) and P, from Calophyllum inophyllum (Clusiaceae) leaves of French Polynesia (Austral, Marquesas, Society and Tuamotu archipelagos) have been determined in 136 leaf extracts using a high pressure liquid chromatography-UV-diode array detection (HPLC-UV-DAD) technique. Results show a wide range in chemical composition within trees growing on eighteen islands. The use of multivariate statistical analyses (PCA) shows geographical distribution of inophyllums and indicate those rich in HIV-1 active (+)-inophyllums. Inophyllum B and P contents (0.0-39.0 and 0.0-21.8 mg kg(-1), respectively) confirm the chemodiversity of this species within the large area of French Polynesia. The study suggests the presence of interesting chemotypes which could be used as plant source for anti-HIV-1 drugs. PMID:18706320

  7. Detection of anti-HIV-1 IgG antibodies in whole saliva by GACELISA and Western blot assays.

    PubMed

    Matee, M I; Lyamuya, E F; Simon, E; Mbena, E C; Kagoma, C; Samaranayake, L P; Scheutz, F

    1996-05-01

    The present study, based on 158 HIV seropositives and 167 HIV seronegatives, demonstrates that saliva collected with the Omni-SAL device and tested with GACELISA (an IgG antibody capture ELISA) is an effective non-invasive alternative to serum for anti-HIV IgG antibody screening. The study also shows that a conventional serum Western blot kit can be used, with slight modifications, for confirmatory testing of saliva specimens. Collecting saliva with the Omni-SAL device had a very good acceptance rate among Tanzanian subjects, and although this diagnostic method is not yet known by the general public, 65% of the study participants preferred to give saliva instead of blood for HIV testing.

  8. A New Neolignan, and the Cytotoxic and Anti-HIV-1 Activities of Constituents from the Roots of Dasymaschalon sootepense.

    PubMed

    Hongthong, Sakchai; Kuhakarn, Chutima; Jaipetch, Thaworn; Piyachaturawat, Pawinee; Jariyawat, Surawat; Suksen, Kanoknetr; Limthongkul, Jitra; Nuntasaen, Narong; Reutrakul, Vichai

    2016-06-01

    Bioassay-guided isolation from the ethyl acetate extract of Dasymaschalon sootepense roots led to the isolation of twelve compounds including a new dihydrobenzo-furan neolignan, (+)-(2S,3S)-2,3-dihydro-2-(3,4-dimethoxyphenyl)-3-methylbenzofuran-5-carbaldehyde (5), and eleven known compounds (1-4, and 6-12). The chemical structures and stereochemistry of all the isolated compounds were established by spectroscopic techniques. The known compounds 4 and 6 have been fully characterized spectroscopically, including their absolute configurations. Cytotoxic and anti-HIV-1 reverse transcriptase (RT) activities of compounds 1-3, 5 and 8-12 were determined. Among compounds screened, compounds 2, 3 and 10 displayed weak cytotoxic activity with ED50 values ranging from 9.6-47.5 μM and only compound 2 was found weakly active against HIV-1 RT with an IC50 value of 323.2 μM. PMID:27534123

  9. Voltammetric detection of anti-HIV replication drug based on novel nanocomposite gold-nanoparticle-CaCO3 hybrid material.

    PubMed

    Narang, Jagriti; Malhotra, Nitesh; Singh, Gajendra; Pundir, C S

    2015-05-01

    A novel bionanocomposite, horse radish peroxidase- gold-nanoparticle-Calcium carbonate (HRP-AuNPs-CaCO3), hybrid material was encapsulated by silica sol on a glassy carbon electrode (GCE). The fabricated modified electrode was used as a novel voltammetric sensor for electrochemical sensing of anti-HIV replication drug i.e. deferiprone. The surface morphology of the modified electrode was characterized by scanning electron microscopy (SEM). Results obtained from the voltammetric measurements show that HRP-AuNPs-CaCO3 modified GCE offers a selective and sensitive electrochemical sensor for the determination of deferiprone. Under experimental conditions, the proposed voltammetric sensor has a linear response range from 0.01 to 10,000 μM with a detection limit of 0.01 μM. Furthermore, the fabricated sensor was successfully applied to determine deferiprone level in spiked urine and serum samples. PMID:25416586

  10. Inculcating safe sex attitudes in South African adolescents: a directive for the government's anti-HIV/AIDS policy.

    PubMed

    D'Souza, Jayesh

    2010-01-01

    South Africa has one of the highest rates of HIV/AIDS in the world. Much blame for this has been laid on the apathy of the South African government and the cultural traits of South Africans. AIDS prevention research calls for early childhood education to raise awareness of the causes, dangers, and prevention of HIV/AIDS. This study involved surveys among a select sample of South African adolescents to determine their sexual attitudes before and after a cognitive-behavioral intervention. Overall, the results did not make a significant difference in their attitudes, suggesting pre-adolescent sex education might prove to be a more useful tool in anti-HIV/AIDS education. Risky sexual behavior, under the influence of alcohol, also serves as a warning to educate young consumers of alcohol.

  11. Expression, purification and identification of CtCVNH, a novel anti-HIV (Human Immunodeficiency Virus) protein from Ceratopteris thalictroides.

    PubMed

    Sun, Junbo; Su, Yingjuan; Wang, Ting

    2013-04-08

    CVN (cyanovirin-N) is an anti-HIV protein. CVNH (cyanovirin-N homology) represents its homology. In a previous study, we first reported the full-length sequences of the CVNH gene cloned from Ceratopteris thalictroides. Based on the finding, the coding sequence of CtCVNH was optimized in the study, and then a pET prokaryotic expression vector was constructed. The purification and identification of CtCVNH protein were investigated, as well. SDS-PAGE analysis indicated that a 31 kDa protein was overexpressed and mainly accumulated in the soluble fraction. Only a single protein was obtained after the Ni- nitrilotriacetic acid (NTA) affinity chromatography. The purified protein was identified to be the recombinant CtCVNH by both Western blot and peptide mass fingerprinting analysis.

  12. A model of transluminal flow of an anti-HIV microbicide vehicle: Combined elastic squeezing and gravitational sliding

    NASA Astrophysics Data System (ADS)

    Szeri, Andrew J.; Park, Su Chan; Verguet, Stéphane; Weiss, Aaron; Katz, David F.

    2008-08-01

    Elastohydrodynamic lubrication over soft substrates is of importance in a number of biomedical problems: From lubrication of the eye surface by the tear film, to lubrication of joints by synovial fluid, to lubrication between the pleural surfaces that protect the lungs and other organs. Such flows are also important for the drug delivery functions of vehicles for anti-HIV topical microbicides. These are intended to inhibit transmission into vulnerable mucosa, e.g., in the vagina. First generation prototype microbicides have gel vehicles, which spread after insertion and coat luminal surfaces. Effectiveness derives from potency of the active ingredients and completeness and durability of coating. Delivery vehicle rheology, luminal biomechanical properties, and the force due to gravity influence the coating mechanics. We develop a framework for understanding the relative importance of boundary squeezing and body forces on the extent and speed of the coating that results. A single dimensionless number, independent of viscosity, characterizes the relative influences of squeezing and gravitational acceleration on the shape of spreading in the Newtonian case. A second scale, involving viscosity, determines the spreading rate. In the case of a shear-thinning fluid, the Carreau number also plays a role. Numerical solutions were developed for a range of the dimensionless parameter and compared well with asymptotic theory in the limited case where such results can be obtained. Results were interpreted with respect to trade-offs between wall elasticity, longitudinal forces, bolus viscosity, and bolus volume. These provide initial insights of practical value for formulators of gel delivery vehicles for anti-HIV microbicidal formulations.

  13. Mapping the Vif-A3G interaction using peptide arrays: a basis for anti-HIV lead peptides.

    PubMed

    Reingewertz, Tali H; Britan-Rosich, Elena; Rotem-Bamberger, Shahar; Viard, Mathias; Jacobs, Amy; Miller, Abigail; Lee, Ji Youn; Hwang, Jeeseong; Blumenthal, Robert; Kotler, Moshe; Friedler, Assaf

    2013-06-15

    Human apolipoprotein-B mRNA-editing catalytic polypeptide-like 3G (A3G) is a cytidine deaminase that restricts retroviruses, endogenous retro-elements and DNA viruses. A3G plays a key role in the anti-HIV-1 innate cellular immunity. The HIV-1 Vif protein counteracts A3G mainly by leading A3G towards the proteosomal machinery and by direct inhibition of its enzymatic activity. Both activities involve direct interaction between Vif and A3G. Disrupting the interaction between A3G and Vif may rescue A3G antiviral activity and inhibit HIV-1 propagation. Here, mapping the interaction sites between A3G and Vif by peptide array screening revealed distinct regions in Vif important for A3G binding, including the N-terminal domain (NTD), C-terminal domain (CTD) and residues 83-99. The Vif-binding sites in A3G included 12 different peptides that showed strong binding to either full-length Vif, Vif CTD or both. Sequence similarity was found between Vif-binding peptides from the A3G CTD and NTD. A3G peptides were synthesized and tested for their ability to counteract Vif action. A3G 211-225 inhibited HIV-1 replication in cell culture and impaired Vif dependent A3G degradation. In vivo co-localization of full-length Vif with A3G 211-225 was demonstrated by use of FRET. This peptide has the potential to serve as an anti-HIV-1 lead compound. Our results suggest a complex interaction between Vif and A3G that is mediated by discontinuous binding regions with different affinities.

  14. Anti-HIV-1 antibody-dependent cellular cytotoxicity mediated by hyperimmune bovine colostrum IgG.

    PubMed

    Kramski, Marit; Lichtfuss, Gregor F; Navis, Marjon; Isitman, Gamze; Wren, Leia; Rawlin, Grant; Center, Rob J; Jaworowski, Anthony; Kent, Stephen J; Purcell, Damian F J

    2012-10-01

    Antibodies with antibody-dependent cellular cytotoxicity (ADCC) activity play an important role in protection against HIV-1 infection, but generating sufficient amounts of antibodies to study their protective efficacy is difficult. HIV-specific IgG can be easily and inexpensively produced in large quantities using bovine colostrum. We previously vaccinated cows with HIV-1 envelope gp140 and elicited high titers of anti-gp140-binding IgG in colostrum. In the present study, we determined whether bovine antibodies would also demonstrate specific cytotoxic activity. We found that bovine IgG bind to Fcγ-receptors (FcγRs) on human neutrophils, monocytes, and NK cells in a dose-dependent manner. Antibody-dependent killing was observed in the presence of anti-HIV-1 colostrum IgG but not nonimmune colostrum IgG. Killing was dependent on Fc and FcγR interaction since ADDC activity was not seen with F(ab')(2) fragments. ADCC activity was primarily mediated by CD14(+) monocytes with FcγRIIa (CD32a) as the major receptor responsible for monocyte-mediated ADCC in response to bovine IgG. In conclusion, we demonstrate that bovine anti-HIV colostrum IgG have robust HIV-1-specific ADCC activity and therefore offer a useful source of antibodies able to provide a rapid and potent response against HIV-1 infection. This could assist the development of novel Ab-mediated approaches for prevention of HIV-1 transmission. PMID:22730083

  15. CCL20/MIP3a is a Novel Anti-HIV-1 Molecule of the Human Female Reproductive Tract

    PubMed Central

    Ghosh, Mimi; Shen, Zheng; Schaefer, Todd M.; Fahey, John V.; Gupta, Phalguni; Wira, Charles R.

    2013-01-01

    Problem CCL20/MIP3α is a chemokine for immature dendritic cells as well as an antibacterial against gram-positive and gram-negative bacteria. The role of CCL20/MIP3α as an antiviral is unknown. In this study, we have examined the production of CCL20/MIP3α by epithelial cells from the upper female reproductive tract as well as its activity as an antiviral molecule. Method of study Primary uterine and Fallopian tube epithelial cells were treated with Poly(I:C) and CCL20/MIP3α mRNA and protein was measured by Real-time RT-PCR and ELISA assays. Anti-HIV activity was determined using an indicator cell line TZM-bl and quantified by using a luminometer. Results Primary uterine and Fallopian tube epithelial cells produce CCL20/MIP3α constitutively and the production is enhanced following stimulation with viral double-stranded RNA mimic Poly(I:C). Recombinant CCL20/MIP3α was able to inhibit both T-cell-tropic X4/IIIB and macrophage-tropic R5/BaL HIV-1 when virus was directly incubated with CCL20/MIP3α but not when CCL20/MIP3α was added to cells either prior to infection or post-infection. This suggests that the mechanism of inhibition is likely to be a direct interaction between HIV-1 and CCL20/MIP3α. Conclusion This study demonstrates that CCL20/MIP3α is an important endogenous anti-HIV-1 microbicide of the female reproductive tract. PMID:19527233

  16. Cross-reactive lysis of human targets infected with prototypic and clinical human immunodeficiency virus type 1 (HIV-1) strains by murine anti-HIV-1 IIIB env-specific cytotoxic T lymphocytes.

    PubMed Central

    Chada, S; DeJesus, C E; Townsend, K; Lee, W T; Laube, L; Jolly, D J; Chang, S M; Warner, J F

    1993-01-01

    To evaluate the ability of murine anti-human immunodeficiency virus type 1 (HIV-1) IIIB env cytotoxic T lymphocytes (CTL) to recognize and lyse HIV-1-infected cells, we have constructed a human cell line (Hu/Dd) expressing both the CD4 receptor and the murine H-2Dd major histocompatibility complex (MHC) class I protein. This cell line can be productively infected with HIV-1 and can also function as a target for murine CD8+, class I MHC-restricted CTL directed against the envelope glycoprotein of HIV-1 IIIB. The ability of BALB/c anti-HIV-1 IIIB env CTL to specifically recognize and lyse Hu/Dd target cells infected with divergent HIV-1 strains was tested by using both prototypic and clinical HIV-1 strains. CTL generated by immunization of mice with syngeneic cells expressing either the native or V3 loop-deleted (delta V3) envelope glycoprotein from HIV-1 IIIB were able to recognize and specifically lyse Hu/Dd target cells infected with the HIV-1 prototypic isolates IIIB, MN, WMJ II, SF2, and CC as well as several HIV-1 clinical isolates. These results demonstrate that CTL determinants for HIV-1 env exist outside the hypervariable V3 region, anti-HIV-1 IIIB env CTL appear to recognize common determinants on diverse HIV-1 strains, and classification of HIV-1 strains based on neutralizing antibody reactivities does not appear to correspond to CTL recognition and lysis. The results suggest that the cell-mediated components of the immune system may have a broader recognition of divergent HIV-1 strains than do the humoral components. Images PMID:8497058

  17. Evaluation of ventilatory therapy for acid aspiration.

    PubMed

    Flint, L; Gosdin, G; Carrico, C J

    1975-10-01

    Aspiration of hydrochloric acid in experimental animals results in severe, progressive hypoxia which is due to intrapulmonary shunting and depressed cardiac output. This preparation is useful therefore in studying the therapy of hypoxia. Mongrel dogs were subjected to acid aspiration and the effects of several ventilatory patterns on intrapulmonary shunt fractions and lung water accumulation observed. The combination of large tidal volumes (30 c.c. per kilogram) with positive end-expiratory pressure was effective in preventing intrapulmonary shunting and other ventilatory patterns were ineffective. Pulmonary edema uniformly followed acid aspiration and was not affected by ventilatory therapy. When ventilatory therapy was delayed for 4 hours, the progression of shunting apparently was limited, but the existing shunt was not reduced.

  18. Evaluating College Student Interest in Pet Therapy

    ERIC Educational Resources Information Center

    Adamle, Kathleen N.; Riley, Tracy A.; Carlson, Tracey

    2009-01-01

    The first year of college can be extremely stressful, especially for students residing on campus. Objective: The authors obtained information from college freshmen about their relationships with pets and investigated interest in a pet therapy program as social support for transient stressful periods. Participants: As part of a university…

  19. Evaluating Nicotine Replacement Therapy and Stage-Based Therapies in a Population-Based Effectiveness Trial

    ERIC Educational Resources Information Center

    Velicer, Wayne F.; Friedman, Robert H.; Fava, Joseph L.; Gulliver, Suzy B.; Keller, Stefan; Sun, Xiaowu; Ramelson, Harley; Prochaska, James O.

    2006-01-01

    Pharmacological interventions for smoking cessation are typically evaluated using volunteer samples (efficacy trials) but should also be evaluated in population-based trials (effectiveness trials). Nicotine replacement therapy (NRT) alone and in combination with behavioral interventions was evaluated on a population of smokers from a New England…

  20. Synthesis and anti-HIV-1 activity of a series of 1-alkoxy-5-alkyl-6-(arylthio)uracils.

    PubMed

    Kim, D K; Gam, J; Kim, Y W; Lim, J; Kim, H T; Kim, K H

    1997-07-18

    A series of 1-alkoxy-5-alkyl-6-(arylthio)uracils was synthesized and tested for their ability to inhibit HIV-1 replication. Treatment of 2-alkyl-3,3-bis(methylthio)acryloyl chlorides (5a-e) with AgOCN in benzene followed by reaction of the resulting isocyanates 6a-e with an appropriate alkoxyamine gave N-alkoxy-N'-((2-alkyl-3,3-bis(methylthio)acryloyl)ureas (10a-z) in good to excellent yields. Cyclization of 10a-z in AcOH containing a catalytic amount of p-TsOH produced 1-alkoxy-5-alkyl-6-(methylthio)uracils (11a-z). Oxidation of 11a-z with 3-chloroperoxybenzoic acid in CH2Cl2 resulted in high yields of 1-alkoxy-5-alkyl-6-(methylsulfonyl)uracils (12a-x and 12z) and 1-(benzyloxy)-6-(methylsulfinyl)thymine (12y), which were subsequently reacted with an appropriate arenethiol in ethanolic NaOH solution to afford 1-alkoxy-5-alkyl-6-(arylthio)uracils (14-49). Substitution at the 3- and 5-positions of the C-6-(phenylthio) ring by two methyl groups significantly increased its original anti-HIV-1 activity (EC50: 6-((3,5-dimethylphenyl)thio)-5-isopropyl-1-propoxyuracil (18), 0.064 microM; 6-((3,5-dimethylphenyl)thio)-1-(3-hydroxypropoxy)-5-isopropyluracil++ + (23), 0.19 microM). Among the various alkoxy substituents at the N-1, the propoxy group was the most beneficial for improving the anti-HIV-1 activity. The 1-propoxy derivative 18 proved to be the most potent inhibitor of HIV-1 replication, followed by the 1-(3-hydroxypropoxy) derivative 23. Introduction of an isopropyl group at C-5 of the uracil base also remarkably enhanced the activity. When compound 18 was incubated with a rat liver homogenate preparation, no metabolite was observed, thus confirming the metabolic stability of the N-O bond in these 1-alkoxyuracils.

  1. [Screening tests combined with p24 antigen and anti-HIV antibodies in early detection of HIV-1].

    PubMed

    Laperche, S; Maniez-Montreuil, M; Couroucé, A M

    2000-06-01

    The five available p24 Ag/anti-HIV combined tests were compared to the six third-generation anti-HIV assays mainly used in blood transfusion centers. Among 70 selected HIV-1 positive samples (12 samples from early infected blood donors and 58 from ten commercial panels), 59 were positive with at least one assay. False negative results were observed for zero to six samples with p24 Ag/Ab assays versus seven to 19 with antibody (Ab) tests. In five cases, one or more combined assays gave a positive signal later than the most sensitive Ab screening test. One sample with a high p24 Ag titer was missed by one combined test. The mean time delay between the most sensitive test and the second one was 0.3 to 2 days. The p24 Ag limit of detection was investigated with seven dilutions of the HIV Ag reference. The threshold of the p24 Ag detection was found to be between 65 and 250 pg/mL of HIV Ag. For four of the five combined assays, p24 Ag detectability was assessed with dilutions of infected culture cell supernatants from 13 HIV-1 different genotype strains exhibiting HIV Ag titers from 300 to 450 pg/mL. One of the four combined assays gave negative results but close to the cut-off for three supernatant dilutions (1 B, 1 F, 1 HIV-1/O) and one missed the HIV-1/O dilution. The p24 Ag/Ab combined assays permit an earlier diagnosis of HIV infection than third generation assays even if the yield in terms of reduction of the window period is moderate. They are less sensitive than p24 Ag screening assays for the detection of this marker. Consequently, the p24 Ag/Ab assays have not been used for the diagnosis of a primary infection instead of p24 Ag screening tests. They must be considered only as good tools for the detection of HIV infection.

  2. Prothymosin-α Variants Elicit Anti-HIV-1 Response via TLR4 Dependent and Independent Pathways

    PubMed Central

    Gusella, G. Luca; Teixeira, Avelino; Aberg, Judith; Uversky, Vladimir N.; Mosoian, Arevik

    2016-01-01

    Background Prothymosin α (ProTα) (isoform 2: iso2) is a widely distributed, small acidic protein with intracellular and extracellular-associated functions. Recently, we identified two new ProTα variants with potent anti-HIV activity from CD8+ T cells and cervicovaginal lavage. The first is a splice variant of the ProTα gene known as isoB and the second is the product of ProTα pseudogene 7 (p7). Similarly to iso2, the anti-HIV activity of both variants is mediated by type I IFN. Here we tested whether the immunomodulatory activity of isoB and p7 are also TLR4 dependent and determined their kinetic of release in response to HIV-1 infection. Methods Type I, type III, TNF-α and IL-6 mRNA inducing activity was determined in macrophages from wild type and TLR4 knockout mice treated with recombinant ProTα variants. Supernatants from mock and HIV infected cells were analyzed by mass spectrometry in positive and negative modes for the presence of ProTα variants. In silico structural and functional analysis of ProTα variants were performed. Results We show that both isoB and p7 upregulate IFN-β, IFN-λ1, IL-6, TNF-α and RANTES mRNAs in primary human macrophages. The potent stimulation of IFN-β by the recombinant ProTα variants in human macrophages is dependent on the TLR4 pathway, whereas the induction of TNF-α and IL-6 may also occur independently of TLR4, suggesting the interaction of ProTα variants with other signaling molecules/receptors. In silico analyses confirmed that the novel isoB and p7 variants are intrinsically disordered proteins, which lack the NLS and mass spectrometry showed release of ProTα variants within minutes post HIV-1 infection. These features are consistent with the function of ProTα variants as damage associate molecular patterns (DAMPs). Conclusions Our findings indicate that ProTα variants strongly inhibit viral replication mainly, but not exclusively, through TLR4 signaling and that they are released within minutes of viral

  3. Cancer Therapy Evaluation Program | Office of Cancer Genomics

    Cancer.gov

    The Cancer Therapy Evaluation Program (CTEP) seeks to improve the lives of cancer patients by finding better treatments, control mechanisms, and cures for cancer. CTEP funds a national program of cancer research, sponsoring clinical trials to evaluate new anti-cancer agents.

  4. Breathing evaluation and retraining in manual therapy.

    PubMed

    McLaughlin, Laurie

    2009-07-01

    Patients with back and neck pain commonly seek body work yet there are some who do not experience full recovery with the typical tool kit of manual therapy, education and exercise, suggesting the need for additional clinical approaches. Epidemiological literature linking back pain with breathing difficulties suggests one possibility. Altered motor control associated with back and neck pain appears to negatively impact breathing mechanics, which may have negative consequences on respiratory chemistry. Changes in respiratory chemistry can have profound effects on body system function. Altered breathing has been recognized for many years as a potential source of a wide variety of unexplained symptoms. There has been controversy around accurate diagnosis with symptoms and questionnaires often being the only methods used. Capnography, which is routinely used in critical care settings, offers an objective measure of respiratory chemistry providing physiological data on which to base a diagnosis of poor breathing. Capnography can also be used as biofeedback to guide breathing retraining.

  5. Introduction of germline residues improves the stability of anti-HIV mAb 2G12-IgM

    PubMed Central

    Chromikova, Veronika; Mader, Alexander; Hofbauer, Stefan; Göbl, Christoph; Madl, Tobias; Gach, Johannes S.; Bauernfried, Stefan; Furtmüller, Paul G.; Forthal, Donald N.; Mach, Lukas; Obinger, Christian; Kunert, Renate

    2015-01-01

    Immunoglobulins M (IgMs) are gaining increasing attention as biopharmaceuticals since their multivalent mode of binding can give rise to high avidity. Furthermore, IgMs are potent activators of the complement system. However, they are frequently difficult to express recombinantly and can suffer from low conformational stability. Here, the broadly neutralizing anti-HIV-1 antibody 2G12 was class-switched to IgM and then further engineered by introduction of 17 germline residues. The impact of these changes on the structure and conformational stability of the antibody was then assessed using a range of biophysical techniques. We also investigated the effects of the class switch and germline substitutions on the ligand-binding properties of 2G12 and its capacity for HIV-1 neutralization. Our results demonstrate that the introduced germline residues improve the conformational and thermal stability of 2G12-IgM without altering its overall shape and ligand-binding properties. Interestingly, the engineered protein was found to exhibit much lower neutralization potency than its wild-type counterpart, indicating that potent antigen recognition is not solely responsible for IgM-mediated HIV-1 inactivation. PMID:25748881

  6. Predicting anti-HIV-1 activity of 6-arylbenzonitriles: computational approach using superaugmented eccentric connectivity topochemical indices.

    PubMed

    Dureja, Harish; Gupta, Sunil; Madan, A K

    2008-02-01

    Highly discriminating adjacency-cum-distance based topochemical indices termed as superaugmented eccentric connectivity topochemical indices for quantitative structure-activity and structure-property relationships (QSAR/QSPR) have been conceptualized in the present study. These indices were found to exhibit high sensitivity towards the presence and relative position of heteroatom(s), exceptionally high discriminating power and negligible degeneracy for all possible structures of five vertices containing one heteroatom. Utility of these indices was investigated for development of models for prediction of anti-human immunodeficiency virus (HIV)-1 activity using a data set comprising 81 differently substituted 6-arylbenzonitriles. The values of the superaugmented eccentric connectivity topochemical indices of all the analogues comprising the data set were computed using an in-house computer program. The resultant data was analyzed and suitable models were developed after identification of the active ranges. Subsequently, a biological activity was assigned to each analogue using these models which was then compared with the reported anti-HIV-1 activity. The accuracy of prediction was found to be approximately 81% for all the three topochemical models. High sensitivity towards presence and relative position of heteroatom(s), exceptionally high discriminating power amalgamated with low degeneracy offer proposed topochemical indices vast potential for isomer discrimination, similarity/dissimilarity, drug design, quantitative structure-activity/structure-property relationships, lead optimization and combinatorial library design.

  7. Anti-HIV-1 protease- and HIV-1 integrase activities of Thai medicinal plants known as Hua-Khao-Yen.

    PubMed

    Tewtrakul, Supinya; Itharat, Arunporn; Rattanasuwan, Pranee

    2006-04-21

    Ethanolic- and water extracts from five species of Thai medicinal plants known as Hua-Khao-Yen were tested for their inhibitory effects against HIV-1 protease (HIV-PR) and HIV-1 integrase (HIV-1 IN). The result revealed that the ethanolic (EtOH) extract of Smilax corbularia exhibited anti-HIV-1 IN activity with an IC50 value of 1.9 microg/ml, followed by the water extract of Dioscorea birmanica (IC50 = 4.5 microg/ml), the EtOH extract of Dioscorea birmanica (IC50 = 4.7 microg/ml), the water extract of Smilax corbularia (IC50 = 5.4 microg/ml), the EtOH extract of Smilax glabra (IC50 = 6.7 microg/ml) and the water extract of Smilax glabra (IC50 = 8.5 microg/ml). The extracts of Pygmaeopremna herbacea and Dioscorea membranacea were apparently inactive (IC50 > 100 microg/ml). Interestingly, only the EtOH extract of Dioscorea membranacea showed appreciable activity (IC50 = 48 microg/ml) against HIV-1 PR, while the other extracts possessed mild activity. This result strongly supported the basis for the use of Smilax corbularia and Dioscorea membranacea for AIDS treatment by Thai traditional doctors. PMID:16406414

  8. Activation of the human nuclear xenobiotic receptor PXR by the reverse transcriptase-targeted anti-HIV drug PNU-142721

    SciTech Connect

    Cheng, Yuan; Redinbo, Matthew R.

    2012-10-09

    The human pregnane X receptor (PXR) is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. PXR responds to a structurally diverse variety of endogenous and xenobiotic compounds, and coordinates the expression of genes central to the metabolism and excretion of potentially harmful chemicals, including human therapeutics. The reverse transcriptase inhibitor PNU-142721 has been designed to treat human immunodeficiency virus (HIV) infection. Although this compound has anti-HIV activity, it was established using cell-based assays that PNU-142721 is an efficacious PXR agonist. We present here the 2.8 {angstrom} resolution crystal structure of the human PXR ligand-binding domain in complex with PNU-142721. PXR employs one hydrogen bond and fourteen van der Waals contacts to interact with the ligand, but allows two loops adjacent to the ligand-binding pocket to remain disordered in the structure. These observations highlight the role structural flexibility plays in PXR's promiscuous responses to xenobiotics. The crystal structure also explains why PNU-173575, a thiomethyl metabolite of PNU-142721, exhibits enhanced PXR activation relative to the unmodified compound and why PNU-142721 can also activate rat PXR. Taken together, the results presented here elucidate the structural basis for PXR activation by PNU-142721 and related chemicals.

  9. DNA topoisomerase IIα inhibitory and anti-HIV-1 flavones from leaves and twigs of Gardenia carinata.

    PubMed

    Kongkum, Naowarat; Tuchinda, Patoomratana; Pohmakotr, Manat; Reutrakul, Vichai; Piyachaturawat, Pawinee; Jariyawat, Surawat; Suksen, Kanoknetr; Yoosook, Chalobon; Kasisit, Jitra; Napaswad, Chanita

    2012-03-01

    Four new flavones, 5,2'-dihydroxy-7,3',4',5'-tetramethoxyflavone (1), 5,2',5'-trihydroxy-7,3',4'-trimethoxyflavone (2), 5,7,2',5'-tetrahydroxy-6,3',4'-trimethoxyflavone (3) and 5,2',5'-trihydroxy-6,7,3',4'-tetramethoxyflavone (4), along with the known 5,3'-dihydroxy-6,7,4',5'-tetramethoxyflavone (5), 5,7,3',5'-tetrahydroxy-6,4'-dimethoxyflavone (6), syringaldehyde, vanillic acid and scopoletin were isolated from the leaves and twigs of Gardenia carinata (Rubiaceae). Their structures were determined by spectroscopic methods. Flavone 2 exhibited cytotoxic activity against P-388 and MCF-7 cell lines, while 3, 5 and 6 were active only in P-388 cell line. All active compounds were found to inhibit DNA topoisomerase IIα activity, which may be responsible for the observed cytotoxicity. Flavones 1-3, 5 and 6 also exhibited anti-HIV-1 activity in the anti-syncytium assay using (∆Tat/rev)MC99 virus and 1A2 cell line system; 2 was most potent. Only flavones 1 and 6 showed considerably activity against HIV-1 reverse transcriptase.

  10. Rationally designed anti-HIV peptides containing multifunctional domains as molecule probes for studying the mechanisms of action of the first and second generation HIV fusion inhibitors.

    PubMed

    Qi, Zhi; Shi, Weiguo; Xue, Na; Pan, Chungen; Jing, Weiguo; Liu, Keliang; Jiang, Shibo

    2008-10-31

    We have previously shown that the first generation human immunodeficiency virus (HIV) fusion inhibitor T20 (Fuzeon) contains a critical lipid-binding domain (LBD), whereas C34, another anti-HIV peptide derived from the gp41 C-terminal heptad repeat, consists of an important pocket-binding domain (PBD), and both share a common 4-3 heptad repeat (HR) sequence (Liu, S., Jing, W., Cheung, B., Lu, H., Sun, J., Yan, X., Niu, J., Farmar, J., Wu, S., and Jiang, S. (2007) J. Biol. Chem. 282, 9612-9620). T1249, the second generation HIV fusion inhibitor, has both LBD and PBD but a different HR sequence, suggesting that these three anti-HIV peptides may have distinct mechanisms of action. Here we rationally designed a set of peptides that contain multiple copies of a predicted HR sequence (5HR) or the HR sequence plus either LBD (4HR-LBD) or PBD (PBD-4HR) or both (PBD-3HR-LBD), and we compared their anti-HIV-1 activity and biophysical properties. We found that the peptide 5HR exhibited low-to-moderate inhibitory activity on HIV-1-mediated cell-cell fusion, whereas addition of LBD and/or PBD to the HR sequence resulted in a significant increase of the anti-HIV-1 activity. The peptides containing PBD, including PBD-4HR and PBD-3HR-LBD, could form a stable six-helix bundle with the N-peptide N46 and effectively blocked the gp41 core formation, whereas the peptides containing LBD, e.g. 4HR-LBD and PBD-3HR-LBD, could interact with the lipid vehicles. These results suggest that the HR sequence in these anti-HIV peptides acts as a structure domain and is responsible for its interaction with the HR sequence in N-terminal heptad repeat, whereas PBD and LBD are critical for interactions with their corresponding targets. T20, C34, and T1249 may function like 4HR-LBD, PBD-4HR, and PBD-3HR-LBD, respectively, to interact with different target sites for inhibiting HIV fusion and entry. Therefore, this study provides important information for understanding the mechanisms of action of the

  11. Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends.

    PubMed

    Zhan, Peng; Pannecouque, Christophe; De Clercq, Erik; Liu, Xinyong

    2016-04-14

    The early effectiveness of combinatorial antiretroviral therapy (cART) in the treatment of HIV infection has been compromised to some extent by rapid development of multidrug-resistant HIV strains, poor bioavailability, and cumulative toxicities, and so there is a need for alternative strategies of antiretroviral drug discovery and additional therapeutic agents with novel action modes or targets. From this perspective, we first review current strategies of antiretroviral drug discovery and optimization, with the aid of selected examples from the recent literature. We highlight the development of phosphate ester-based prodrugs as a means to improve the aqueous solubility of HIV inhibitors, and the introduction of the substrate envelope hypothesis as a new approach for overcoming HIV drug resistance. Finally, we discuss future directions for research, including opportunities for exploitation of novel antiretroviral targets, and the strategy of activation of latent HIV reservoirs as a means to eradicate the virus. PMID:26509831

  12. A Critical Evaluation of Nicotine Replacement Therapy for Teenage Smokers.

    ERIC Educational Resources Information Center

    Patten, Christi A.

    2000-01-01

    Evaluates the appropriateness and feasibility of nicotine replacement therapy (NRT) in teenage smokers. Available forms of NRT, theoretical rationale and efficacy of NRT, ethical considerations, and the feasibility of NRT in teenage smokers are addressed. Several characteristics similar to adult nicotine dependent smokers have been found in teen…

  13. Evaluation of combined therapy in carcinoma of the bladder.

    PubMed

    Kagan, A R; Gilbert, H A

    1978-01-01

    A number of studies are considered in order to evaluate the benefits of combined treatment for patients with Stage B2C transitional carcinoma of the bladder. It is found that for a variety of reasons, such treatment is not shown to be beneficial; the conclusion is that routine combined preoperative therapy is investigative but cannot be recommended as a community standard.

  14. Structural Determinants for the Selective Anti-HIV-1 Activity of the All-β Alternative Conformer of XCL1

    PubMed Central

    Guzzo, Christina; Fox, Jamie C.; Miao, Huiyi; Volkman, Brian F.

    2015-01-01

    ABSTRACT HIV-1 replication is regulated in vivo by a complex network of cytokines and chemokines. XCL1/lymphotactin, a unique metamorphic chemokine, was recently identified as a broad-spectrum endogenous HIV-1 inhibitor that blocks viral entry via direct interaction with the gp120 envelope glycoprotein. HIV-1 inhibition by XCL1 requires access to the alternative all-β conformation, which interacts with glycosaminoglycans (GAGs) but not with the specific XCL1 receptor, XCR1. To investigate the structural determinants of the HIV-inhibitory function of XCL1, we performed a detailed structure-function analysis of a stabilized all-β variant, XCL1 W55D. Individual alanine substitutions of two basic residues within the 40s' loop, K42 and R43, abrogated the ability of XCL1 to bind to the viral envelope and block HIV-1 infection; moreover, a loss of HIV-inhibitory function, albeit less marked, was seen upon individual mutation of three additional basic residues: R18, R35, and K46. In contrast, mutation of K42 to arginine did not cause any loss of function, suggesting that the interaction with gp120 is primarily electrostatic in nature. Strikingly, four of these five residues cluster to form a large (∼350 Å2) positively charged surface in the all-β XCL1 conformation, whereas they are dissociated in the classic chemokine fold, which is inactive against HIV-1, providing a structural basis for the selective antiviral activity of the alternatively folded XCL1. Furthermore, we observed that changes to the N-terminal domain, which is proximal to the cluster of putative HIV-1 gp120-interacting residues, also affect the antiviral activity of XCL1. Interestingly, the complement of residues involved in HIV-1 blockade is partially overlapping, but distinct from those involved in the GAG-binding function of XCL1. These data identify key structural determinants of anti-HIV activity in XCL1, providing new templates for the development of HIV-1 entry inhibitors. IMPORTANCE The host

  15. The effects of inhomogeneous boundary dilution on the coating flow of an anti-HIV microbicide vehicle

    NASA Astrophysics Data System (ADS)

    Tasoglu, Savas; Peters, Jennifer J.; Park, Su Chan; Verguet, Stéphane; Katz, David F.; Szeri, Andrew J.

    2011-09-01

    A recent study in South Africa has confirmed, for the first time, that a vaginal gel formulation of the antiretroviral drug Tenofovir, when topically applied, significantly inhibits sexual HIV transmission to women [Karim et al., Science 329, 1168 (2010)]. However, the gel for this drug and anti-HIV microbicide gels in general have not been designed using an understanding of how gel spreading and retention in the vagina govern successful drug delivery. Elastohydrodynamic lubrication theory can be applied to model spreading of microbicide gels [Szeri et al., Phys. Fluids 20, 083101 (2008)]. This should incorporate the full rheological behavior of a gel, including how rheological properties change due to contact with, and dilution by, ambient vaginal fluids. Here, we extend our initial analysis, incorporating the effects of gel dilution due to contact with vaginal fluid produced at the gel-tissue interface. Our original model is supplemented with a convective-diffusive transport equation to characterize water transport into the gel and, thus, local gel dilution. The problem is solved using a multi-step scheme in a moving domain. The association between local dilution of gel and rheological properties is obtained experimentally, delineating the way constitutive parameters of a shear-thinning gel are modified by dilution. Results show that dilution accelerates the coating flow by creating a slippery region near the vaginal wall akin to a dilution boundary layer, especially if the boundary flux exceeds a certain value. On the other hand, if the diffusion coefficient of boundary fluid is increased, the slippery region diminishes in extent and the overall rate of gel spreading decreases.

  16. Characterization of the phenotypic and lymphokine profile associated with strong CD8+ anti-HIV-1 suppressor activity (CASA)

    PubMed Central

    Wilkinson, J; Zaunders, J J; Carr, A; Guillemin, G; Cooper, D A

    2002-01-01

    A panel of 22 CD8+ T cell lines, with a broad range of CD8+ anti-HIV-1 suppressor activity (CASA) were generated from a single patient with HIV-1 infection. CD8+ T cell lines with either strong or weak CASA were examined and compared for cell surface and intracellular markers, constitutive chemokine and lymphokine mRNA levels and inducible lymphokine expression. Strong CASA significantly correlated with CD8+ T cell lines that highly coexpressed the molecule CD28+ (r = 0·52, P = 0·01) and Ki67+ (r = 0·88, P = 0·02), with strong CASA CD8+ T cell lines demonstrating significantly higher (P < 0·05) expression of CD8+CD28+ and CD8+Ki67+ compared to those with weak activity. No such correlations or findings were observed for the markers CD38, HLA-DR, CD57 or perforin. The Th1 cytokines were expressed at greater levels than the Th2 cytokines, with strong CASA significantly associated with an increased inducible level of IL-2 production (P = 0·05). Constitutive RANTES, IP-10 and I-309 mRNA expression were significantly (P < 0·05) elevated in CD8+ T cell lines exhibiting strong CASA compared to those with weak CASA. There was no significant difference in the mRNA expression of the lymphokines IL-2, 4, 5, 8, 9, 10, 14, 15, or chemokines MIP-1α, MIP-1β, MCP-1, and Ltn. Strong CASA was therefore associated with rapidly replicating CD8+ T cells of the phenotype CD8+CD28+Ki67+ that expressed greater levels of IL-2 and the ligands RANTES and I-309. PMID:11882045

  17. Dynamic features of apo and bound HIV-Nef protein reveal the anti-HIV dimerization inhibition mechanism.

    PubMed

    Moonsamy, Suri; Bhakat, Soumendranath; Soliman, Mahmoud E S

    2015-01-01

    The first account on the dynamic features of Nef or negative factor, a small myristoylated protein located in the cytoplasm believes to increase HIV-1 viral titer level, is reported herein. Due to its major role in HIV-1 pathogenicity, Nef protein is considered an emerging target in anti-HIV drug design and discovery process. In this study, comparative long-range all-atom molecular dynamics simulations were employed for apo and bound protein to unveil molecular mechanism of HIV-Nef dimerization and inhibition. Results clearly revealed that B9, a newly discovered Nef inhibitor, binds at the dimeric interface of Nef protein and caused significant separation between orthogonally opposed residues, namely Asp108, Leu112 and Gln104. Large differences in magnitudes were observed in the radius of gyration (∼1.5 Å), per-residue fluctuation (∼2 Å), C-alpha deviations (∼2 Å) which confirm a comparatively more flexible nature of apo conformation due to rapid dimeric association. Compared to the bound conformer, a more globally correlated motion in case of apo structure of HIV-Nef confirms the process of dimeric association. This clearly highlights the process of inhibition as a result of ligand binding. The difference in principal component analysis (PCA) scatter plot and per-residue mobility plot across first two normal modes further justifies the same findings. The in-depth dynamic analyses of Nef protein presented in this report would serve crucial in understanding its function and inhibition mechanisms. Information on inhibitor binding mode would also assist in designing of potential inhibitors against this important HIV target. PMID:26355431

  18. Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection.

    PubMed

    Ramezani, Ali; Dubrovsky, Larisa; Pushkarsky, Tatiana; Sviridov, Dmitri; Karandish, Sara; Raj, Dominic S; Fitzgerald, Michael L; Bukrinsky, Michael

    2015-09-01

    Previous studies demonstrated that liver X receptor (LXR) agonists inhibit human immunodeficiency virus (HIV) replication by upregulating cholesterol transporter ATP-binding cassette A1 (ABCA1), suppressing HIV production, and reducing infectivity of produced virions. In this study, we extended these observations by analyzing the effect of the LXR agonist T0901317 [N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide] on the ongoing HIV infection and investigating the possibility of using LXR agonist for pre-exposure prophylaxis of HIV infection in a humanized mouse model. Pre-exposure of monocyte-derived macrophages to T0901317 reduced susceptibility of these cells to HIV infection in vitro. This protective effect lasted for up to 4 days after treatment termination and correlated with upregulated expression of ABCA1, reduced abundance of lipid rafts, and reduced fusion of the cells with HIV. Pre-exposure of peripheral blood leukocytes to T0901317 provided only a short-term protection against HIV infection. Treatment of HIV-exposed humanized mice with LXR agonist starting 2 weeks postinfection substantially reduced viral load. When eight humanized mice were pretreated with LXR agonist prior to HIV infection, five animals were protected from infection, two had viral load at the limit of detection, and one had viral load significantly reduced relative to mock-treated controls. T0901317 pretreatment also reduced HIV-induced dyslipidemia in infected mice. In conclusion, these results reveal a novel link between LXR stimulation and cell resistance to HIV infection and suggest that LXR agonists may be good candidates for development as anti-HIV agents, in particular for pre-exposure prophylaxis of HIV infection.

  19. Evaluation of neutron radiation field in carbon ion therapy

    NASA Astrophysics Data System (ADS)

    Xu, Jun-Kui; Su, You-Wu; Li, Wu-Yuan; Yan, Wei-Wei; Chen, Xi-Meng; Mao, Wang; Pang, Cheng-Guo

    2016-01-01

    Carbon ions have significant advantages in tumor therapy because of their physical and biological properties. In view of the radiation protection, the safety of patients is the most important issue in therapy processes. Therefore, the effects of the secondary particles produced by the carbon ions in the tumor therapy should be carefully considered, especially for the neutrons. In the present work, the neutron radiation field induced by carbon ions was evaluated by using the FLUKA code. The simulated results of neutron energy spectra and neutron dose was found to be in good agreement with the experiment data. In addition, energy deposition of carbon ions and neutrons in tissue-like media was studied, it is found that the secondary neutron energy deposition is not expected to exceed 1% of the carbon ion energy deposition in a typical treatment.

  20. Evaluation of a sponge-on therapy for canine scabies.

    PubMed

    Folz, S D; Kratzer, D D; Kakuk, T J; Rector, D L

    1984-03-01

    Forty dogs (20 treated, 20 controls) were utilized to evaluate a new treatment for naturally acquired canine scabies. A liquid concentrate formulation of amitraz was diluted and applied as a sponge-on therapy. Ninety-four percent of the dogs treated with the scabicide were cleared of mites and returned to clinical normality with a single topical treatment; one dog was retreated, cleared of mites and was also returned to normality. All dogs treated with the miticide responded clinically, therefore the treatment also may be useful when trial therapy is necessary to differentially diagnose the disease. The miticide was well tolerated by all dogs, and there was no evidence of dermal or ocular irritation. Topical treatment with the liquid concentrate was efficacious and safe as a therapy for naturally acquired canine scabies. Placebo controls did not improve clinically and these animals retained their mite populations.

  1. PolyICLC Exerts Pro- and Anti-HIV Effects on the DC-T Cell Milieu In Vitro and In Vivo.

    PubMed

    Aravantinou, Meropi; Frank, Ines; Hallor, Magnus; Singer, Rachel; Tharinger, Hugo; Kenney, Jessica; Gettie, Agegnehu; Grasperge, Brooke; Blanchard, James; Salazar, Andres; Piatak, Michael; Lifson, Jeffrey D; Robbiani, Melissa; Derby, Nina

    2016-01-01

    Myeloid dendritic cells (mDCs) contribute to both HIV pathogenesis and elicitation of antiviral immunity. Understanding how mDC responses to stimuli shape HIV infection outcomes will inform HIV prevention and treatment strategies. The long double-stranded RNA (dsRNA) viral mimic, polyinosinic polycytidylic acid (polyIC, PIC) potently stimulates DCs to focus Th1 responses, triggers direct antiviral activity in vitro, and boosts anti-HIV responses in vivo. Stabilized polyICLC (PICLC) is being developed for vaccine adjuvant applications in humans, making it critical to understand how mDC sensing of PICLC influences HIV infection. Using the monocyte-derived DC (moDC) model, we sought to describe how PICLC (vs. other dsRNAs) impacts HIV infection within DCs and DC-T cell mixtures. We extended this work to in vivo macaque rectal transmission studies by administering PICLC with or before rectal SIVmac239 (SIVwt) or SIVmac239ΔNef (SIVΔNef) challenge. Like PIC, PICLC activated DCs and T cells, increased expression of α4β7 and CD169, and induced type I IFN responses in vitro. The type of dsRNA and timing of dsRNA exposure differentially impacted in vitro DC-driven HIV infection. Rectal PICLC treatment similarly induced DC and T cell activation and pro- and anti-HIV factors locally and systemically. Importantly, this did not enhance SIV transmission in vivo. Instead, SIV acquisition was marginally reduced after a single high dose challenge. Interestingly, in the PICLC-treated, SIVΔNef-infected animals, SIVΔNef viremia was higher, in line with the importance of DC and T cell activation in SIVΔNef replication. In the right combination anti-HIV strategy, PICLC has the potential to limit HIV infection and boost HIV immunity. PMID:27603520

  2. PolyICLC Exerts Pro- and Anti-HIV Effects on the DC-T Cell Milieu In Vitro and In Vivo

    PubMed Central

    Hallor, Magnus; Singer, Rachel; Tharinger, Hugo; Kenney, Jessica; Gettie, Agegnehu; Grasperge, Brooke; Blanchard, James; Salazar, Andres; Lifson, Jeffrey D.; Robbiani, Melissa; Derby, Nina

    2016-01-01

    Myeloid dendritic cells (mDCs) contribute to both HIV pathogenesis and elicitation of antiviral immunity. Understanding how mDC responses to stimuli shape HIV infection outcomes will inform HIV prevention and treatment strategies. The long double-stranded RNA (dsRNA) viral mimic, polyinosinic polycytidylic acid (polyIC, PIC) potently stimulates DCs to focus Th1 responses, triggers direct antiviral activity in vitro, and boosts anti-HIV responses in vivo. Stabilized polyICLC (PICLC) is being developed for vaccine adjuvant applications in humans, making it critical to understand how mDC sensing of PICLC influences HIV infection. Using the monocyte-derived DC (moDC) model, we sought to describe how PICLC (vs. other dsRNAs) impacts HIV infection within DCs and DC-T cell mixtures. We extended this work to in vivo macaque rectal transmission studies by administering PICLC with or before rectal SIVmac239 (SIVwt) or SIVmac239ΔNef (SIVΔNef) challenge. Like PIC, PICLC activated DCs and T cells, increased expression of α4β7 and CD169, and induced type I IFN responses in vitro. The type of dsRNA and timing of dsRNA exposure differentially impacted in vitro DC-driven HIV infection. Rectal PICLC treatment similarly induced DC and T cell activation and pro- and anti-HIV factors locally and systemically. Importantly, this did not enhance SIV transmission in vivo. Instead, SIV acquisition was marginally reduced after a single high dose challenge. Interestingly, in the PICLC-treated, SIVΔNef-infected animals, SIVΔNef viremia was higher, in line with the importance of DC and T cell activation in SIVΔNef replication. In the right combination anti-HIV strategy, PICLC has the potential to limit HIV infection and boost HIV immunity. PMID:27603520

  3. Formulation, In Vitro and In Vivo Pharmacokinetics of Anti-HIV Vaginal Bioadhesive Gel

    PubMed Central

    Chatterjee, A; Bhowmik, B B; Thakur, Y S

    2011-01-01

    Inexpensive and female-controlled pre-exposure prophylaxis strategies to prevent mucosal transmission of the virus, is urgently needed with the rising prevalence of human immunodeficiency virus (HIV-1 and HIV2) infections in women. Zidovudine-loaded bioadhesive vaginal gel may become one of the very useful strategies, as it can be used not only for controlled release but also for enhancing bioavailability. Drug delivery through vaginal gel is a promising area for continued research with the aim of achieving controlled release with enhanced bioavailability over longer periods of time. The aim of the study was to develop a newer prolong releasing Zidovudine (AZT) bioadhesive vaginal gel to treat HIV infections with increased patient convenience. AZT-loaded bioadhesive vaginal gel was prepared successfully by using cold mechanical method. F3 formulation containing carbopol–HPMC (1:3) was selected and evaluated in order to achieve objectives of this study. In vitro drug release study of F3 showed in 24 h drug released following case I Fickian (n ≤ 0.5) transport mechanism, and in vivo drug release was found much better (Tmax), (Cmax), and bioavailability (F) comparison with oral pour drug solution. It was also showed good extrudability, spreadability, and bioadhesive strength. A generalized protocol, for the further research, in this area will surely expected to yield significant outcome with improved drug delivery system. PMID:21731351

  4. Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

    PubMed Central

    Scott, Yanille M.; Park, Seo Young

    2015-01-01

    Broadly neutralizing monoclonal antibodies (nAbs) specific for HIV are being investigated for use in HIV prevention. Due to their ability to inhibit HIV attachment to and entry into target cells, nAbs may be suitable for use as topical HIV microbicides. As such, they would present an alternative intervention for individuals who may not benefit from using antiretroviral-based products for HIV prevention. We theorize that nAbs can inhibit viral transmission through mucosal tissue, thus reducing the incidence of HIV infection. The efficacy of the PG9, PG16, VRC01, and 4E10 antibodies was evaluated in an ex vivo human model of mucosal HIV transmission. nAbs reduced HIV transmission, causing 1.5- to 2-log10 reductions in HIV replication in ectocervical tissues and ≈3-log10 reductions in HIV replication in colonic tissues over 21 days. These antibodies demonstrated greater potency in colonic tissues, with a 50-fold higher dose being required to reduce transmission in ectocervical tissues. Importantly, nAbs retained their potency and reduced viral transmission in the presence of whole semen. No changes in tissue viability or immune activation were observed in colonic or ectocervical tissue after nAb exposure. Our data suggest that topically applied nAbs are safe and effective against HIV infection of mucosal tissue and support further development of nAbs as a topical microbicide that could be used for anal as well as vaginal protection. PMID:26596954

  5. Evaluating an Educational Module on Home Inotrope Therapy.

    PubMed

    Lockman-Samkowiak, Jodie; Brenner, Phyllis S; Dunn, Deborah S; Qureshi, Elena

    2015-01-01

    Educating home health nurses presents significant challenges for nurse educators because of the vast geographical areas served and the types of patient cared for. The integration of technology into the home health care arena offers new and innovative opportunities to address the ongoing educational needs of nurses as required by accrediting bodies. This exploratory study evaluated a Web-based educational module on home inotrope therapy in regard to nurses' perceived knowledge and confidence. PMID:26126142

  6. Transient spreading and swelling behavior of a gel deploying an anti-HIV topical microbicide.

    PubMed

    Tasoglu, Savas; Katz, David F; Szeri, Andrew J

    2012-11-01

    Drug delivery of topical microbicidal molecules against HIV offers promise as a modality to prevent sexual transmission of the virus. Success of any microbicide product depends, in an interactive way, upon its drug (the microbicide active pharmaceutical ingredient, API) and its delivery system (e.g. a gel, film or intravaginal ring). There is a widespread agreement that more effective drug delivery vehicles, as well as better APIs, must be developed to improve the efficacy of microbicide products. Non-Newtonian gels are primary microbicide vehicles, but those to date have been created with limited understanding of how their properties govern their spreading and retention in the vagina, which, in turn, govern successful drug delivery. Here, we apply fundamental fluid mechanical and physicochemical transport theory to help better understand how successful microbicide API delivery depends upon properties of a gel and the vaginal environment. We address several critical components of this complex process, including: elastohydrodynamic flow of the bolus of a non-Newtonian fluid; and mass transfer due to inhomogeneous dilution of the gel by vaginal fluid contacting it along a moving boundary (the locally deforming vaginal epithelial surface). Local dilution of gel alters local rheological properties. We evaluated this experimentally, delin-eating the way that constitutive parameters of a shear-thinning gel are modified by dilution. We supplement the Reynolds lubrication equation with a mass conservation equation to model diluting fluid movement across the moving vaginal epithelial surface and into the gel bolus. This is a physicochemically complex phenomenon that is not well understood. We implement a boundary flux model based upon the elevated hydrodynamic pressures in the cells. Results show that this model produces fluxes that lie within the range of mean values that have been reported. Further experimental characterization of the vaginal wall is required for a more

  7. Transient swelling, spreading, and drug delivery by a dissolved anti-HIV microbicide-bearing film

    NASA Astrophysics Data System (ADS)

    Tasoglu, Savas; Rohan, Lisa C.; Katz, David F.; Szeri, Andrew J.

    2013-03-01

    There is a widespread agreement that more effective drug delivery vehicles with more alternatives, as well as better active pharmaceutical ingredients (APIs), must be developed to improve the efficacy of microbicide products. For instance, in tropical regions, films are more appropriate than gels due to better stability of drugs at extremes of moisture and temperature. Here, we apply fundamental fluid mechanical and physicochemical transport theory to help better understand how successful microbicide API delivery depends upon properties of a film and the human reproductive tract environment. Several critical components of successful drug delivery are addressed. Among these are: elastohydrodynamic flow of a dissolved non-Newtonian film; mass transfer due to inhomogeneous dilution of the film by vaginal fluid contacting it along a moving boundary (the locally deforming vaginal epithelial surface); and drug absorption by the epithelium. Local rheological properties of the film are dependent on local volume fraction of the vaginal fluid. We evaluated this experimentally, delineating the way that constitutive parameters of a shear-thinning dissolved film are modified by dilution. To develop the mathematical model, we integrate the Reynolds lubrication equation with a mass conservation equation to model diluting fluid movement across the moving vaginal epithelial surface and into the film. This is a complex physicochemical phenomenon that is not well understood. We explore time- and space-varying boundary flux model based upon osmotic gradients. Results show that the model produces fluxes that are comparable to experimental data. Further experimental characterization of the vaginal wall is required for a more precise set of parameters and a more sophisticated theoretical treatment of epithelium.

  8. Evaluation of Low-Level Laser Therapy in TMD Patients.

    PubMed

    Ayyildiz, Simel; Emir, Faruk; Sahin, Cem

    2015-01-01

    Light amplification by stimulated emission of radiation (laser) is one of the most recent treatment modalities in dentistry. Low-level laser therapy (LLLT) is suggested to have biostimulating and analgesic effects through direct irradiation without causing thermal response. There are few studies that have investigated the efficacy of laser therapy in temporomandibular disorders (TMD), especially in reduced mouth opening. The case report here evaluates performance of LLLT with a diode laser for temporomandibular clicking and postoperative findings were evaluated in two cases of TMD patients. First patient had a history of limited mouth opening and pain in temporomandibular joint (TMJ) region since nine months. Second patient's main complaint was his restricted mouth opening, which was progressed in one year. LLLT was performed with a 685 nm red probed diode laser that has an energy density of 6.2 J/cm(2), three times a week for one month, and application time was 30 seconds (685 nm, 25 mW, 30 s, 0.02 Hz, and 6.2 J/cm(2)) (BTL-2000, Portative Laser Therapy Device). The treatment protocol was decided according to the literature. One year later patients were evaluated and there were no changes. This application suggested that LLLT is an appropriate treatment for TMD related pain and limited mouth opening and should be considered as an alternative to other methods. PMID:26587294

  9. Evaluation of Low-Level Laser Therapy in TMD Patients

    PubMed Central

    Ayyildiz, Simel; Emir, Faruk; Sahin, Cem

    2015-01-01

    Light amplification by stimulated emission of radiation (laser) is one of the most recent treatment modalities in dentistry. Low-level laser therapy (LLLT) is suggested to have biostimulating and analgesic effects through direct irradiation without causing thermal response. There are few studies that have investigated the efficacy of laser therapy in temporomandibular disorders (TMD), especially in reduced mouth opening. The case report here evaluates performance of LLLT with a diode laser for temporomandibular clicking and postoperative findings were evaluated in two cases of TMD patients. First patient had a history of limited mouth opening and pain in temporomandibular joint (TMJ) region since nine months. Second patient's main complaint was his restricted mouth opening, which was progressed in one year. LLLT was performed with a 685 nm red probed diode laser that has an energy density of 6.2 J/cm2, three times a week for one month, and application time was 30 seconds (685 nm, 25 mW, 30 s, 0.02 Hz, and 6.2 J/cm2) (BTL-2000, Portative Laser Therapy Device). The treatment protocol was decided according to the literature. One year later patients were evaluated and there were no changes. This application suggested that LLLT is an appropriate treatment for TMD related pain and limited mouth opening and should be considered as an alternative to other methods. PMID:26587294

  10. Assessing Patients’ Cognitive Therapy Skills: Initial Evaluation of the Competencies of Cognitive Therapy Scale

    PubMed Central

    Strunk, Daniel R.; Hollars, Shannon N.; Adler, Abby D.; Goldstein, Lizabeth A.; Braun, Justin D.

    2014-01-01

    In Cognitive Therapy (CT), therapists work to help patients develop skills to cope with negative affect. Most current methods of assessing patients’ skills are cumbersome and impractical for clinical use. To address this issue, we developed and conducted an initial psychometric evaluation of self and therapist reported versions of a new measure of CT skills: the Competencies of Cognitive Therapy Scale (CCTS). We evaluated the CCTS at intake and post-treatment in a sample of 67 patients participating in CT. The CCTS correlated with a preexisting measure of CT skills (the Ways of Responding Questionnaire) and was also related to concurrent depressive symptoms. Across CT, self-reported improvements in CT competencies were associated with greater changes in depressive symptoms. These findings offer initial evidence for the validity of the CCTS. We discuss the CCTS in comparison with other measures of CT skills and suggest future research directions. PMID:25408560

  11. Assessing Patients' Cognitive Therapy Skills: Initial Evaluation of the Competencies of Cognitive Therapy Scale.

    PubMed

    Strunk, Daniel R; Hollars, Shannon N; Adler, Abby D; Goldstein, Lizabeth A; Braun, Justin D

    2014-10-01

    In Cognitive Therapy (CT), therapists work to help patients develop skills to cope with negative affect. Most current methods of assessing patients' skills are cumbersome and impractical for clinical use. To address this issue, we developed and conducted an initial psychometric evaluation of self and therapist reported versions of a new measure of CT skills: the Competencies of Cognitive Therapy Scale (CCTS). We evaluated the CCTS at intake and post-treatment in a sample of 67 patients participating in CT. The CCTS correlated with a preexisting measure of CT skills (the Ways of Responding Questionnaire) and was also related to concurrent depressive symptoms. Across CT, self-reported improvements in CT competencies were associated with greater changes in depressive symptoms. These findings offer initial evidence for the validity of the CCTS. We discuss the CCTS in comparison with other measures of CT skills and suggest future research directions.

  12. Autoreactivity and Exceptional CDR Plasticity (but Not Unusual Polyspecificity) Hinder Elicitation of the Anti-HIV Antibody 4E10

    PubMed Central

    Finton, Kathryn A. K.; Larimore, Kevin; Larman, H. Benjamin; Friend, Della; Correnti, Colin; Rupert, Peter B.; Elledge, Stephen J.; Greenberg, Philip D.; Strong, Roland K.

    2013-01-01

    The broadly-neutralizing anti-HIV antibody 4E10 recognizes an epitope in the membrane-proximal external region of the HIV envelope protein gp41. Previous attempts to elicit 4E10 by vaccination with envelope-derived or reverse-engineered immunogens have failed. It was presumed that the ontogeny of 4E10-equivalent responses was blocked by inherent autoreactivity and exceptional polyreactivity. We generated 4E10 heavy-chain knock-in mice, which displayed significant B cell dysregulation, consistent with recognition of autoantigen/s by 4E10 and the presumption that tolerance mechanisms may hinder the elicitation of 4E10 or 4E10-equivalent responses. Previously proposed candidate 4E10 autoantigens include the mitochondrial lipid cardiolipin and a nuclear splicing factor, 3B3. However, using carefully-controlled assays, 4E10 bound only weakly to cardiolipin-containing liposomes, but also bound negatively-charged, non-cardiolipin-containing liposomes comparably poorly. 4E10/liposome binding was predominantly mediated by electrostatic interactions rather than presumed hydrophobic interactions. The crystal structure of 4E10 free of bound ligands showed a dramatic restructuring of the combining site, occluding the HIV epitope binding site and revealing profound flexibility, but creating an electropositive pocket consistent with non-specific binding of phospholipid headgroups. These results strongly suggested that antigens other than cardiolipin mediate 4E10 autoreactivity. Using a synthetic peptide library spanning the human proteome, we determined that 4E10 displays limited and focused, but unexceptional, polyspecificity. We also identified a novel autoepitope shared by three ER-resident inositol trisphosphate receptors, validated through binding studies and immunohistochemistry. Tissue staining with 4E10 demonstrated reactivity consistent with the type 1 inositol trisphosphate receptor as the most likely candidate autoantigen, but is inconsistent with splicing factor 3B3

  13. D77, one benzoic acid derivative, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular LEDGF/p75

    SciTech Connect

    Du Li; Zhao Yaxue; Chen, Jing; Yang Liumeng; Zheng Yongtang; Tang Yun Shen Xu Jiang Hualiang

    2008-10-10

    Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. Since LEDGF/p75 plays an important role in HIV integration, disruption of the LEDGF/p75 interaction with IN has provided a special interest for anti-HIV agent discovery. In this work, we reported that a benzoic acid derivative, 4-[(5-bromo-4-{l_brace}[2,4-dioxo-3-(2-oxo-2-phenylethyl) -1,3-thiazolidin-5-ylidene]methyl{r_brace}-2-ethoxyphenoxy)methyl]benzoic acid (D77) could potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution thus exhibiting antiretroviral activity. Molecular docking with site-directed mutagenesis analysis and surface plasmon resonance (SPR) binding assays has clarified possible binding mode of D77 against HIV-1 integrase. As the firstly discovered small molecular compound targeting HIV-1 integrase interaction with LEDGF/p75, D77 might supply useful structural information for further anti-HIV agent discovery.

  14. Zirconium phosphatidylcholine-based nanocapsules as an in vivo degradable drug delivery system of MAP30, a momordica anti-HIV protein.

    PubMed

    Caizhen, Guo; Yan, Gao; Ronron, Chang; Lirong, Yang; Panpan, Chu; Xuemei, Hu; Yuanbiao, Qiao; Qingshan, Li

    2015-04-10

    An essential in vivo drug delivery system of a momordica anti-HIV protein, MAP30, was developed through encapsulating in chemically synthesized matrices of zirconium egg- and soy-phosphatidylcholines, abbreviated to Zr/EPC and Zr/SPC, respectively. Matrices were characterized by transmission electron microscopy and powder X-ray diffractometry studies. Zr/EPC granule at an approximate diameter of 69.43±7.78 nm was a less efficient encapsulator than the granule of Zr/SPC. Interlayer spacing of the matrices encapsulating MAP30 increased from 8.8 and 9.7 Å to 7.4 and 7.9 nm, respectively. In vivo kinetics on degradation and protein release was performed by analyzing the serum sampling of intravenously injected SPF chickens. The first order and biphasic variations were obtained for in vivo kinetics using equilibrium dialysis. Antimicrobial and anti-HIV assays yielded greatly decreased MIC50 and EC50 values of nanoformulated MAP30. An acute toxicity of MAP30 encapsulated in Zr/EPC occurred at a single intravenous dose above 14.24 mg/kg bw in NIH/KM/ICR mice. The folding of MAP30 from Zr/EPC sustained in vivo chickens for more than 8 days in high performance liquid chromatography assays. These matrices could protect MAP30 efficiently with strong structure retention, lowered toxicity and prolonged in vivo life.

  15. Evaluation of intakes of transuranics influenced by chelation therapy

    SciTech Connect

    LaBone, T.R.

    1994-02-01

    Once an intake of transuranics occurs, there are only three therapeutic procedures available to the physician for reducing the intake and mitigating the dose: excision of material from wounds, removal of material from the lungs with lavage, and chelation therapy. The only chelation agents approved in the United States for the treatment of occupational intakes of transuranics are the zinc and calcium salts of diethylene-triamine-pentaacetic acid, better known as Zn-DTPA and Ca-DTPA. In the past 35 years, approximately 3000 doses of DTPA have been administrated to over 500 individuals who had intakes of transuranics. The drug is considered to be quiet safe and has few side effects. For the internal dosimetrist, perhaps the most important aspects of chelation therapy is that if enhances the excretion rate of a transuranic and perturbs the shape of the urinary excretion curve. These perturbations last for months and are so great that standard urinary excretion models cannot be used to evaluate the intake. We review here a method for evaluating intakes of transuranics influenced by chelation therapy that has been used with some degree of success at the Savannah River Site for over 20 years.

  16. Does structural commonality of metal complex formation by PAC-1 (anticancer), DHBNH (anti-HIV), AHL (autoinducer), and UCS1025A (anticancer) denote mechanistic similarity? Signal transduction and medical aspects.

    PubMed

    Kovacic, Peter

    2008-01-01

    There is an urgent need of novel approaches to drugs in the cancer, HIV, and bacterial areas. Increasing resistance to conventional therapies is observed. This minireview provides novel insights for drugs in these three areas. The agents PAC-1 (anticancer), DHBNH (anti-HIV), AHL (autoinducer), and UCS1025A (anticancer) have recently attracted attention due to considerable potential based on new approaches. PAC-1 activates procaspase-3 to caspase-3, resulting in induction of apoptosis in tumor cells. DHBNH binds to a newly revealed site on HIV reverse transcriptase. The drug mainly inhibits RNase H (RNA-cleaving). AHLs comprise an important class that participates in bacterial cell communication. UCS1025A is a fungus-derived inhibitor of the enzyme telomerase, present in cancer cells, which is crucially involved in tumor cell immortality. All four agents possess chelating sites for metal binding, which has not been appreciated. In PAC-1 and DHBNH, the coordinating portion is similar to salicylaldehyde semicarbazone. For AHL and UCS1025A, the metal-binding moiety is a beta -ketoamide. Metal complexes of heavier metals are well-known electron transfer (ET) functionalities that can generate reactive oxygen species. Hence, it is reasonable to hypothesize a commonality in mechanism based on metal ET. Differences in receptor binding can result, in part, in diverse physiological responses. There is considerable literature that addresses involvement of signal transduction with the various physiologically active agents discussed herein. Thus, cell communication appears to play an important role in the biochemistry of these endogenous and exogenous substances. Details of cell signaling are presented for complexes of metals (Fe, Cu, Ni, and As), telomerase, caspase-3, and RNase. In addition, practical medical aspects are discussed.

  17. CT evaluation of effects of cranial radiation therapy in children

    SciTech Connect

    Davis, P.C.; Hoffman, J.C. Jr.; Pearl, G.S.; Braun, I.F.

    1986-09-01

    A retrospective evaluation was completed of 49 children who received conventional cranial radiation therapy for primary central nervous system and/or skull-base neoplasia and who had follow-up CT studies. In these children, abnormalities in normal parenchyma away from the tumor itself were surprisingly frequent, with or without chemotherapy. Generalized volume loss or atrophy was the most frequent abnormality (51%), but in this population it may have resulted from a variety of causes. Calcification in nontumorous parenchyma was common (28%) with or without chemotherapy. The most frequent site of calcification was subcortical at the gray-white junction. Calcification was progressive over 1-2 years and correlated pathologically with mineralizing microangiopathy and dystrophic calcification with demyelination. White-matter abnormalities other than those associated with shunt malfunction and tumor edema occurred in 26% of the patients. Both white-matter abnormalities and calcification occurred predominantly in younger children, particularly those under 3 years old at the time of radiation therapy. Of the 21 children who received chemotherapy in this series, only two received methotrexate. White-matter abnormalities and calcifications occurred with similar frequency in children with and without chemotherapy; thus, radiation therapy is the most likely cause of these findings.

  18. Technology evaluation: VEGF165 gene therapy, Valentis Inc.

    PubMed

    Morse, M A

    2001-02-01

    Valentis Inc, formerly GeneMedicine, is developing a vascular endothelial growth factor (VEGF165) non-viral gene therapy using its proprietary PINC polymer for plasmid condensation. Two physician-initiated phase II angioplasty trials are ongoing, one for treating peripheral vascular disease and one for treating coronary artery disease [281714], [347153]. In February 2000, the trials were expected to be completed in the fourth quarter of 2000 [356225]; however, in October 2000, it was reported that the trial for peripheral vascular disease would be completed in the first quarter of 2001 [385232]. In March 2000, Valentis initiated a trial incorporating Valentis's DOTMA-based cationic lipid gene delivery system and the VEGF165 gene with Eurogene's local collar-reservoir delivery device. The trial is designed to demonstrate that the VEGF165 gene, delivered locally to the outside surface of a blood vessel, will transfect and express in the smooth muscle cells of the vessel wall [360683]. In March 1999, Valentis was awarded with a Phase II SBIR grant of $686,260. The aim of grant was to advance the development of non-viral gene therapies for ischemia. Specifically, Valentis intended to select an optimal promoter to be used with the VEGF expression plasmid. Valentis also intended to evaluate the gene therapy system in a rabbit ischemia model and complete the necessary preclinical studies for submission of an IND [318137]. PMID:11249737

  19. Laser therapies for onychomycosis - critical evaluation of methods and effectiveness.

    PubMed

    Francuzik, W; Fritz, K; Salavastru, C

    2016-06-01

    The number of medical devices designed specifically to treat onychomycosis has recently increased, although their mechanism of action is not clear. We evaluated available laser therapies for onychomycosis by reviewing the existing literature. Twenty-two reports, published in peer-reviewed journals and as white papers out of 926 initial search results conveyed enough details to be included in this study. In most cases, the methodology of the trials described in the papers we reviewed was not comprehensive and the reporting of outcomes was not unified. We therefore found it hard to compare different clinical trials to one another. The majority of studies (81.82%) reported using an Nd:YAG laser device to treat onychomycosis. A total of 47.37% of the studies which used a 1064 device (and 47.83% of all studies we reviewed) reported that all treated patients responded positively to laser therapy. A total of 60% of studies reported achieving a complete cure (no clinical symptoms, nor negative mycology) in at least 50% of the treated patients. A low number of adverse events and their mild intensity were consistently reported across all studies, which makes this form of therapy particularly attractive to patients with contraindications for receiving systemic antifungal medication. In order to achieve more unified, comparable studies in the future, we suggest that researchers report a minimum set of outcome measurements: the calculation of the infected nail area pre- and posttreatment, as well as the number of patients achieving mycological, clinical and complete cures.

  20. Innovative therapies: general aspects and ethical criteria for evaluating protocols.

    PubMed

    Petrini, C

    2013-01-01

    There are many ways of interpreting the notion of "innovation" with reference to therapeutics. The term is generally given a wide meaning, encompassing anything that brings something new. From the ethical point of view the definition of "innovation" is of key importance, for example when dealing with a major problem such as the evaluation of protocols that propose "innovative" therapies. There is currently debate as to whether this should be accomplished using the same procedures typically applied to experimental research protocols, or by following quite different procedures when "innovation" is involved. The present article offers an overview of the notion of "innovation" in the context of biomedical research, together with some considerations and proposals for evaluating it from the ethical viewpoint.

  1. An evaluation of antimicrobial therapy for undifferentiated bovine respiratory disease

    PubMed Central

    Bateman, Ken G.; Martin, S. Wayne; Shewen, Patricia E.; Menzies, Paula I.

    1990-01-01

    A field trial of antimicrobial therapy for cases of undifferentiated bovine respiratory disease (UBRD) in beef calves was conducted at four Ontario feedlots. The primary purpose of the trial was to evaluate the efficacy of three different antimicrobials (oxytetracycline, penicillin, and trimethoprim-sulfadoxine) in the treatment of UBRD occurring within the first 28 days postarrival. The response, relapse, and case fatality rates overall were 85.7%, 14.8%, and 1.4%, respectively, and were not significantly different among the three antimicrobials evaluated. Weight gains of calves treated with the different drugs were not statistically different over the feeding period. Calves that suffered a relapse posttreatment were first treated significantly earlier (p<0.001) in the postarrival period than those that did not relapse. Considered together, treated calves gained significantly less (p<0.05) over the first 28 days and throughout the entire feeding period than controls that were never sick. Cases of UBRD that responded to therapy and did not relapse had rates of gain that were not significantly different from the controls. PMID:17423676

  2. A Pilot Evaluation of an Art Therapy Program for Refugee Youth from Burma

    ERIC Educational Resources Information Center

    Kowitt, Sarah Dorothy; Emmerling, Dane; Gavarkavich, Diane; Mershon, Claire-Helene; Linton, Kristin; Rubesin, Hillary; Agnew-Brune, Christine; Eng, Eugenia

    2016-01-01

    Art therapy is a promising form of therapy to address mental health concerns for refugee youth. This article describes the development and implementation of a pilot evaluation of an art therapy program for refugee adolescents from Burma currently living in the United States. Evaluation activities were based on the Centers for Disease Control and…

  3. The Low-Cost Compound Lignosulfonic Acid (LA) Exhibits Broad-Spectrum Anti-HIV and Anti-HSV Activity and Has Potential for Microbicidal Applications

    PubMed Central

    D’huys, Thomas; Petrova, Mariya I.; Lebeer, Sarah; Snoeck, Robert; Andrei, Graciela; Schols, Dominique

    2015-01-01

    Objectives Lignosulfonic acid (LA), a low-cost lignin-derived polyanionic macromolecule, was extensively studied for its anti-HIV and anti-HSV activity in various cellular assays, its mechanism of viral inhibition and safety profile as potential microbicide. Results LA demonstrated potent inhibitory activity of HIV replication against a wide range of R5 and X4 HIV strains and prevented the uptake of HIV by bystander CD4+ T cells from persistently infected T cells in vitro (IC50: 0.07 – 0.34 μM). LA also inhibited HSV-2 replication in vitro in different cell types (IC50: 0.42 – 1.1 μM) and in rodents in vivo. Furthermore, LA neutralized the HIV-1 and HSV-2 DC-SIGN-mediated viral transfer to CD4+ T cells (IC50: ∼1 μM). In addition, dual HIV-1/HSV-2 infection in T cells was potently blocked by LA (IC50: 0.71 μM). No antiviral activity was observed against the non-enveloped viruses Coxsackie type B4 and Reovirus type 1. LA is defined as a HIV entry inhibitor since it interfered with gp120 binding to the cell surface of T cells. Pretreatment of PBMCs with LA neither increased expression levels of cellular activation markers (CD69, CD25 and HLA-DR), nor enhanced HIV-1 replication. Furthermore, we found that LA had non-antagonistic effects with acyclovir, PRO2000 or LabyA1 (combination index (CI): 0.46 – 1.03) in its anti-HSV-2 activity and synergized with tenofovir (CI: 0.59) in its anti-HIV-1 activity. To identify mechanisms of LA resistance, we generated in vitro a mutant HIV-1 NL4.3LAresistant virus, which acquired seven mutations in the HIV-1 envelope glycoproteins: S160N, V170N, Q280H and R389T in gp120 and K77Q, N113D and H132Y in gp41. Additionally, HIV-1 NL4.3LAresistant virus showed cross-resistance with feglymycin, enfuvirtide, PRO2000 and mAb b12, four well-described HIV binding/fusion inhibitors. Importantly, LA did not affect the growth of vaginal Lactobacilli strains. Conclusion Overall, these data highlight LA as a potential and unique low

  4. A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats

    SciTech Connect

    Li, Xiaoguang; Qian, Hua; Miyamoto, Fusako; Kawaji, Kumi; Hattori, Toshio; Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka; and others

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. Black-Right-Pointing-Pointer The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. Black-Right-Pointing-Pointer In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1{sub IIIB} and HIV-1{sub BaL} as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1{sub IIIB} activity, whereas fusion inhibitors showed both anti-HIV-1{sub IIIB} and anti-HIV-1{sub BaL} activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, 'phenotypic drug evaluation', may be applicable for the evaluation of various antiviral drugs in vivo.

  5. Evaluating cost benefits of combination therapies for advanced melanoma

    PubMed Central

    Jensen, Ivar S.; Zacherle, Emily; Blanchette, Christopher M.; Zhang, Jie; Yin, Wes

    2016-01-01

    Background: Although a number of monoimmunotherapies and targeted therapies are available to treat BRAF+ advanced melanoma, response rates remain relatively low in the range of 22–53% with progression-free survival (PFS) in the range of 4.8–8.8 months. Recently, combination targeted therapies have improved response rates to about 66–69%, PFS to 11.0–12.6 months and overall survival (OS) to 25.1–25.6 months. While combination immunotherapies have improved response rates of 67 compared with 19–29% with monotherapies and improved PFS of 11.7 compared with 4.4–5.8 months with monotherapies, the OS benefit is yet to be established in phase 3 trials. As healthcare costs continue to rise, US payers have a predominant interest in assessing the value of available treatments. Therefore, a cost-benefit model was developed to evaluate the value of treating BRAF+ advanced melanoma with two combination therapies: nivolumab + ipilimumab (N+I) and dabrafenib + trametinib (D+T). Scope: The model was used to estimate total costs, total costs by expenditure category, cost per month of PFS and cost per responder for the payer, and societal perspectives of treating advanced melanoma patients with the BRAF V600 mutation using combination targeted therapy (D+T) or combination immunotherapy (N+I). The model followed patients from initiation of treatment to the point of progression or death. Deterministic and probabilistic sensitivity analyses were conducted to evaluate the robustness of the results and to understand the dispersion of simulated results. Findings: Based on a hypothetical payer with one million covered lives, it was expected that fourteen metastatic melanoma patients with the BRAF V600 mutation would be treated each year. Cost-benefit with N+I and D+T was simulated from the payer perspective. The cost per month of PFS for N+I was $22,162, while that for D+T was $17,716 (−$4,446 cost difference); the cost per responder for N+I was $388,746 and that for D+T was

  6. Suramin analogues with a 2-phenylbenzimidazole moiety as partial structure; potential anti HIV- and angiostatic drugs, 2: Sulfanilic acid-, benzenedisulfonic acid-, and naphthalenetrisulfonic acid analogues.

    PubMed

    Kreimeyer, A; Müller, G; Kassack, M; Nickel, P; Gagliardi, A R

    1998-03-01

    The synthesis of suramin analogues bearing a 2-phenyl-benzimidazole moiety is described. Aminoarene sulfonic acids 2a-e are acylated with 3,4-dinitrobenzoyl chloride 3 yielding the amides 4a-e which are hydrogenated to the corresponding diamines 5a-e. These are treated with 3-nitrobenzaldehyde, yielding the azomethines 7a-e and their isomers 8a-e and 9a-e. Key step in the synthesis of the target compounds 12a-e is the oxidation of the azomethines with oxygen to the benzimidazoles 10a-e. These are hydrogenated to the amines 11a-e reacting with phosgene to yield the symmetric ureas 12a-e. Results of the anti-HIV, cytostatic, and antiangiogenic screening are presented.

  7. LC-MS/MS structural characterization of stress degradation products including the development of a stability indicating assay of Darunavir: An anti-HIV drug.

    PubMed

    Rao, R Nageswara; Ramachandra, B; Sravan, B; Khalid, Sara

    2014-02-01

    Darunavir, an anti-HIV drug was subjected to forced degradation under acid, base, thermal and neutral hydrolysis, oxidation and photolysis as prescribed by ICH guidelines. Four major degradation products were formed under acid and base hydrolysis, while stable under neutral and thermal hydrolysis, oxidative and photolysis. The drug and its degradation products were separated on Hiber, LiChrospher® 60, RP-select B, C8 column (250mm×4.6mm i.d., 5μm) using 10mM ammonium acetate: acetonitrile (52:48, v/v) as mobile phase in an isocratic elution mode by LC. The degradation products were characterized by LC-MS/MS and fragmentation pathways were proposed. The proposed structures of degradation products were confirmed by HRMS and the LC method was validated with respect to specificity, linearity, accuracy, recovery, LOD and LOQ. PMID:24252722

  8. Evaluating localized prostate cancer and identifying candidates for focal therapy.

    PubMed

    Sartor, A Oliver; Hricak, Hedvig; Wheeler, Thomas M; Coleman, Jonathan; Penson, David F; Carroll, Peter R; Rubin, Mark A; Scardino, Peter T

    2008-12-01

    accurate staging, grading, and tumor localization needed for a focal therapy program. Nevertheless, for men with minimal cancer who are amenable to active surveillance or focal therapy, consensus about the most accurate biopsy strategy has not yet been reached. Imaging, particularly magnetic resonance imaging and magnetic resonance spectroscopic imaging, has been used to assess men with early-stage prostate cancer. Large-volume cancers can be seen reasonably well, but small lesions have been difficult to detect reliably or measure accurately. Factors such as voxel resolution, organ movement, biopsy artifact, and benign changes have limited the consistent estimation of the quantitative tumor volume. Nevertheless, magnetic resonance imaging and magnetic resonance spectroscopic imaging can aid in evaluating patients with prostate cancer being considered for focal therapy by providing additional evidence that the patient does not harbor an otherwise undetected high-risk, aggressive cancer. In some cases, imaging can usefully identify the location of even a limited-sized index cancer. When imaging findings are substantiated by mapping biopsy results, confidence in the accurate characterization of the cancer is enhanced. Correlating the imaging results with tissue changes during and after treatment can be of use in monitoring the ablative effects in the prostate and in assessing for tumor recurrence. More work is necessary before staging studies can uniformly characterize a prostate cancer before therapy, much less reliably identify and locate small-volume cancer within the prostate. However, exploring the role of focal ablation as a therapeutic option for selected men with low-risk, clinically localized, prostate cancer need not await the emergence of perfectly accurate staging studies, any more than the application of radical surgery or radiotherapy have. Modern biopsy strategies, combined with optimal imaging and nomograms to estimate the pathologic stage and risk, taken

  9. A New Activity of Anti-HIV and Anti-tumor Protein GAP31: DNA Adenosine Glycosidase – Structural and Modeling Insight into its Functions

    SciTech Connect

    Li, H.; Huang, P; Zhang, D; Sun, Y; Chen, H; Zhang, J; Huang, P; Kong, X; Lee-Huang, S

    2010-01-01

    We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA.

  10. A new activity of anti-HIV and anti-tumor protein GAP31: DNA adenosine glycosidase - Structural and modeling insight into its functions

    SciTech Connect

    Li, Hui-Guang; Huang, Philip L.; Zhang, Dawei; Sun, Yongtao; Chen, Hao-Chia; Zhang, John; Huang, Paul L.; Kong, Xiang-Peng; Lee-Huang, Sylvia

    2010-01-01

    We report here the high-resolution atomic structures of GAP31 crystallized in the presence of HIV-LTR DNA oligonucleotides systematically designed to examine the adenosine glycosidase activity of this anti-HIV and anti-tumor plant protein. Structural analysis and molecular modeling lead to several novel findings. First, adenine is bound at the active site in the crystal structures of GAP31 to HIV-LTR duplex DNA with 5' overhanging adenosine ends, such as the 3'-processed HIV-LTR DNA but not to DNA duplex with blunt ends. Second, the active site pocket of GAP31 is ideally suited to accommodate the 5' overhanging adenosine of the 3'-processed HIV-LTR DNA and the active site residues are positioned to perform the adenosine glycosidase activity. Third, GAP31 also removes the 5'-end adenine from single-stranded HIV-LTR DNA oligonucleotide as well as any exposed adenosine, including that of single nucleotide dAMP but not from AMP. Fourth, GAP31 does not de-purinate guanosine from di-nucleotide GT. These results suggest that GAP31 has DNA adenosine glycosidase activity against accessible adenosine. This activity is distinct from the generally known RNA N-glycosidase activity toward the 28S rRNA. It may be an alternative function that contributes to the antiviral and anti-tumor activities of GAP31. These results provide molecular insights consistent with the anti-HIV mechanisms of GAP31 in its inhibition on the integration of viral DNA into the host genome by HIV-integrase as well as irreversible topological relaxation of the supercoiled viral DNA.

  11. Therapy response evaluation with positron emission tomography-computed tomography.

    PubMed

    Segall, George M

    2010-12-01

    Positron emission tomography-computed tomography with F-18-fluorodeoxyglucose is widely used for evaluation of therapy response in patients with solid tumors but has not been as readily adopted in clinical trials because of the variability of acquisition and processing protocols and the absence of universal response criteria. Criteria proposed for clinical trials are difficult to apply in clinical practice, and gestalt impression is probably accurate in individual patients, especially with respect to the presence of progressive disease and complete response. Semiquantitative methods of determining tissue glucose metabolism, such as standard uptake value, can be a useful descriptor for levels of tissue glucose metabolism and changes in response to therapy if technical quality control measures are carefully maintained. The terms partial response, complete response, and progressive disease are best used in clinical trials in which the terms have specific meanings and precise definitions. In clinical practice, it may be better to use descriptive terminology agreed upon by imaging physicians and clinicians in their own practice. PMID:21147376

  12. Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy

    PubMed Central

    Drusano, George L.; Adams, Jonathan R.; Rodriquez, Jaime L.; Jambunathan, Kalyani; Baluya, Dodge L.; Brown, David L.; Kwara, Awewura; Mirsalis, Jon C.; Hafner, Richard; Louie, Arnold

    2015-01-01

    ABSTRACT Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. PMID:26530386

  13. Evaluating current trends in psychiatric music therapy: a descriptive analysis.

    PubMed

    Silverman, Michael J

    2007-01-01

    Approximately 21% of music therapists report working in the mental health field, more so than another other specific client population category (AMTA, 2005). The purpose of this study was to descriptively evaluate psychiatric music therapists and their institutions, philosophies, interventions, and clinical objectives. A survey was designed and posted online or mailed to music therapists who did not have email addresses in the 2005 Member Sourcebook (AMTA, 2005). A total of 176 psychiatric music therapists completed various parts of the survey for an overall response rate of 42.9%. Respondents reported working a mean of 11.3 years in the psychiatric setting, being Board-Certified Music Therapists for 13.3 years, and working at their institution for 8.4 years. Most respondents (90.6%) indicated they did not have a music therapist as a supervisor. Group music therapy was the dominant modality in psychiatric institutions for music therapists. Respondents indicated they read music therapy journals (80%) and other types of psychiatric periodicals (57.1%), presented educational sessions at conferences (44.6%), conducted in-services for hospital staff (64.8%), worked with an interdisciplinary treatment team (77.9%), and trained practica students (43.5%) and interns (37.4%). Respondents also indicated that although most were not bilingual (85.7%), they still worked with non-English speaking consumers (58.2%). Participants noted that they enjoyed working with the psychiatric population and felt they had a positive influence on treatment as indicated by Likert-type scales. Respondents reported using primarily behavioral or psychodynamic approaches but considered their primary psychological philosophy as eclectic. Participants predominantly indicated they addressed goal areas such as socialization, communication, self-esteem, coping skills, and stress reduction/management. Participants noted they employed a variety of music therapy techniques such as music assisted relaxation

  14. Computer-aided therapy in aphasia therapy: evaluation of assignment criteria.

    PubMed

    Schröder, Christina; Schupp, Wilfried; Seewald, Barbara; Haase, Ingo

    2007-12-01

    Recent studies in neurorehabilitation research show that success in aphasia therapy is linked to a high treatment frequency. Computer-aided therapy offers a solution to the dilemma of increasing therapy frequency while maintaining or reducing the load on therapists' resources. Until now it has, however, been unclear which patients can reasonably be treated with computer-aided therapy. The study investigates therapists' indication choices of a new computer-aided training programme designed to supplement conventional speech therapy for aphasics (EvoCare therapy, Dr Hein GmbH, Nuremberg, Germany). The goal was to ascertain which patients were suitable for the training and which (individual) allocation criteria played a role in the therapists' decision for or against the new therapy concept. The study is an explorative prospective application study in inpatient rehabilitation care. To determine the allocation criteria, comprehensive medical, psychosocial and neurolinguistic questionnaires were used. The speech therapists were surveyed separately. Forty-nine of the 75 patients were treated with EvoCare therapy; the others received purely conventional speech therapy. Patients chosen for computer-aided therapy suffered more frequently from problems with everyday mobility and serious neurolinguistic disorders. Type and extent of brain damage, degree of reliance on caregivers, sensomotoric and cognitive deficits and depression were irrelevant to the allocation. PMID:17975448

  15. Fluorescence guided evaluation of photodynamic therapy as acne treatment

    NASA Astrophysics Data System (ADS)

    Ericson, Marica B.; Horfelt, Camilla; Cheng, Elaine; Larsson, Frida; Larko, Olle; Wennberg, Ann-Marie

    2005-08-01

    Photodynamic therapy (PDT) is an attractive alternative treatment for patients with acne because of its efficiency and few side effects. Propionibacterium acnes (P.acnes) are bacteria present in the skin, which produce endogenous porphyrins that act as photosensitisers. In addition, application of aminolaevulinic acid or its methyl ester (mALA) results in increased accumulation of porphyrins in the pilosebaceous units. This makes it possible to treat acne with PDT. This initial study investigates the possibility of fluorescence imaging as assessment tool in adjunct to PDT of patients with acne. Twenty-four patients with acne on the cheeks have been treated with PDT with and without mALA. Fluorescence images have been obtained before and after treatment. The clinical acne score was assessed as base line before PDT, and at every follow up visit. Additionally the amount of P.acnes was determined. The clinical evaluation showed a general improvement of acne, even though no difference between treatment with and without mALA was observed. By performing texture analysis and multivariate data analsysis on the fluorescence images, the extracted texture features were found to correlate with the corresponding clinical assessment (67%) and amount of P.acnes (72%). The analysis showed that features describing the highly fluorescent pores could be related to the clinical assessment. This result suggests that fluorescence imaging can be used as an objective assessment of acne, but further improvement of the technique is possible, for example by including colour images.

  16. Evaluation of an electroconvulsive therapy service in a general hospital.

    PubMed

    Lamont, Scott; Brunero, Scott; Barclay, Christopher; Wijeratne, Chanaka

    2011-06-01

    There has been much recent literature on the technical parameters of electroconvulsive therapy (ECT) with regard to improving efficacy and minimizing adverse effects, but relatively little on ECT service delivery. This paper will discuss the development and characteristics of an ECT service at a teaching hospital in metropolitan Sydney, New South Wales, Australia. A mixture of qualitative and quantitative methods, including a selective literature review and audit of ECT use were used. The results of the audit were compared with the 2007 revision of the Royal Australian and New Zealand College of Psychiatrists' clinical memorandum on ECT. We discuss issues, such as the optimal site for ECT delivery, ECT mental health nurse coordinator role, credentialing of psychiatrists, registrar supervision, and the development of an ECT committee. A significant finding of the audit was that the majority of patients were treated under the New South Wales Mental Health Act, and voluntary patients were more likely to have a diagnosis of a depressive disorder, whereas involuntary patients were more likely to have a non-mood disorder diagnosis. This study has shown that auditing of ECT practices and services by mental health nurses is essential for quality improvement processes. The audit highlighted areas of service delivery that should be subject to review and evaluation against professional standards.

  17. Process and Outcome Evaluation of an Art Therapy Program for People Living with HIV/AIDS

    ERIC Educational Resources Information Center

    Feldman, Matthew B.; Betts, Donna J.; Blausey, Daniel

    2014-01-01

    Program evaluation offers an opportunity for improving the implementation and impact of art therapy. This article describes a process and outcomes evaluation of an art therapy program within the mental health services unit of a community-based organization for people living with HIV/AIDS. The aims were to assess utilization patterns and program…

  18. Structural insights into the specific anti-HIV property of actinohivin: structure of its complex with the α(1–2)mannobiose moiety of gp120

    SciTech Connect

    Hoque, M. Mominul; Suzuki, Kaoru; Tsunoda, Masaru; Jiang, Jiandong; Zhang, Fang; Takahashi, Atsushi; Ohbayashi, Naomi; Zhang, Xiaoxue; Tanaka, Haruo; Ōmura, Satoshi; Takénaka, Akio

    2012-12-01

    X-ray analysis of anti-HIV actinohivin in complex with the target α(1-2)mannobiose moiety of high-mannose type glycans attached to HIV-1 gp120 reveals that the three rotamers generated with 120 rotations around the molecular pseudo-rotation axis are packed randomly in the unit cell according to the P2{sub 1}2{sub 1}2{sub 1} symmetry to exhibit an apparent space group P2{sub 1}3 as the statistical structure. However, the high-resolution X-ray structure shows the detailed interaction geometry for specific binding. Actinohivin (AH) is an actinomycete lectin with a potent specific anti-HIV activity. In order to clarify the structural evidence for its specific binding to the α(1–2)mannobiose (MB) moiety of the D1 chains of high-mannose-type glycans (HMTGs) attached to HIV-1 gp120, the crystal structure of AH in complex with MB has been determined. The AH molecule is composed of three identical structural modules, each of which has a pocket in which an MB molecule is bound adopting a bracket-shaped conformation. This conformation is stabilized through two weak C—H⋯O hydrogen bonds facilitated by the α(1–2) linkage. The binding features in the three pockets are quite similar to each other, in accordance with the molecular pseudo-threefold symmetry generated from the three tandem repeats in the amino-acid sequence. The shape of the pocket can accept two neighbouring hydroxyl groups of the O{sup 3} and O{sup 4} atoms of the equatorial configuration of the second mannose residue. To recognize these atoms through hydrogen bonds, an Asp residue is located at the bottom of each pocket. Tyr and Leu residues seem to block the movement of the MB molecules. Furthermore, the O{sup 1} atom of the axial configuration of the second mannose residue protrudes from each pocket into an open space surrounded by the conserved hydrophobic residues, suggesting an additional binding site for the third mannose residue of the branched D1 chain of HMTGs. These structural features

  19. Anti-HIV IgA Isotypes: Differential Virion Capture and Inhibition of Transcytosis are Linked to Prevention of Mucosal R5 SHIV Transmission

    PubMed Central

    Watkins, Jennifer D.; Sholukh, Anton M.; Mukhtar, Muhammad M.; Siddappa, Nagadenahalli B.; Lakhashe, Samir K.; Kim, Mikyung; Reinherz, Ellis L.; Gupta, Sandeep; Forthal, Donald N.; Sattentau, Quentin; Villinger, Francois; Corti, Davide; Ruprecht, Ruth M.

    2014-01-01

    Objective Although passive immunization with anti-HIV-1 Env IgG1 neutralizing monoclonal Abs (nmAbs) prevented simian-human immunodeficiency virus (SHIV) infection in rhesus monkeys (RMs), IgA nmAbs have not been tested. Here, we sought to determine whether human anti-HIV-1 dimeric (d)IgA1, dIgA2, and IgG1 differ in their ability to prevent mucosal R5 SHIV acquisition in RMs. Design DIgA1, dIgA2, and IgG1 versions of nmAb HGN194 were applied intrarectally (i.r.) in three RM groups 30 min before i.r. SHIV challenge. Methods After a control pharmacokinetic study showed that nmAb concentrations in rectal fluids over time were similar for all HGN194 isotypes, control and nmAb-treated animals were challenged i.r. with an R5 SHIV, and viral loads were monitored. Results Unexpectedly, dIgA1 provided the best protection in vivo – although all nmAbs showed similar neutralizing activity in vitro. Five out of the six dIgA1-treated RMs remained virus-free compared to only one out of six animals given dIgA2 (P=0.045 by log rank test) and two out of six RMs treated with IgG1 forms of the nmAb (P=0.12). Protection correlated significantly with virion capture activity by a given nmAb form, as well as inhibition of transcytosis of cell-free virus across an epithelial cell layer in vitro. Conclusions Our data imply that dIgA1-mediated capturing of virions in mucosal secretions and inhibition of transcytosis can provide significant prevention of lentiviral acquisition – over and above direct virus neutralization. Vaccine strategies that induce mucosal IgA, especially IgA1, should be developed as first-line of defense against HIV-1, a virus predominantly transmitted mucosally. PMID:23775002

  20. Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study

    PubMed Central

    Kovari, Helen; Sabin, Caroline A.; Ledergerber, Bruno; Ryom, Lene; Reiss, Peter; Law, Matthew; Pradier, Christian; Dabis, Francois; d'Arminio Monforte, Antonella; Smith, Colette; de Wit, Stephane; Kirk, Ole; Lundgren, Jens D.; Weber, Rainer

    2016-01-01

    Background. Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear. Methods. Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (<2 or ≥2 years) after initiation. Association between development of cLEE and ART exposure was investigated using Poisson regression. Results. Among 21 485 participants observed for 105 413 person-years (PY), 6368 developed cLEE (incidence 6.04/100 PY; 95% confidence interval [CI], 5.89–6.19). Chronic liver enzyme elevation was associated with short-and long-term exposure to didanosine (<2 years rate ratio [RR] = 1.29, 95% CI, 1.11–1.49; >2 years RR = 1.26, 95% CI, 1.13–1.41); stavudine (<2 years RR = 1.51, 95% CI, 1.26–1.81; >2 years RR = 1.17, 95% CI, 1.03–1.32), and tenofovir disoproxil fumarate (<2 years RR = 1.55, 95% CI, 1.40–1.72; >2 years RR = 1.18, 95% CI, 1.05–1.32), but only short-term exposure to nevirapine (<2 years RR = 1.44, 95% CI, 1.29–1.61), efavirenz (<2 years RR = 1.14, 95% CI, 1.03–1.26), emtricitabine (<2 years RR = 1.18, 95% CI, 1.04–1.33), and atazanavir (<2 years RR = 1.20, 95% CI, 1.04–1.38). Chronic liver enzyme elevation was not associated with use of lamivudine, abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE. Conclusions. Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be

  1. Predicting the short-term risk of diabetes in HIV-positive patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study

    PubMed Central

    Petoumenos, Kathy; Worm, Signe W; Fontas, Eric; Weber, Rainer; De Wit, Stephane; Bruyand, Mathias; Reiss, Peter; El-Sadr, Wafaa; Monforte, Antonella D'Arminio; Friis-Møller, Nina; Lundgren, Jens D; Law, Matthew G

    2012-01-01

    Introduction HIV-positive patients receiving combination antiretroviral therapy (cART) frequently experience metabolic complications such as dyslipidemia and insulin resistance, as well as lipodystrophy, increasing the risk of cardiovascular disease (CVD) and diabetes mellitus (DM). Rates of DM and other glucose-associated disorders among HIV-positive patients have been reported to range between 2 and 14%, and in an ageing HIV-positive population, the prevalence of DM is expected to continue to increase. This study aims to develop a model to predict the short-term (six-month) risk of DM in HIV-positive populations and to compare the existing models developed in the general population. Methods All patients recruited to the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study with follow-up data, without prior DM, myocardial infarction or other CVD events and with a complete DM risk factor profile were included. Conventional risk factors identified in the general population as well as key HIV-related factors were assessed using Poisson-regression methods. Expected probabilities of DM events were also determined based on the Framingham Offspring Study DM equation. The D:A:D and Framingham equations were then assessed using an internal-external validation process; area under the receiver operating characteristic (AUROC) curve and predicted DM events were determined. Results Of 33,308 patients, 16,632 (50%) patients were included, with 376 cases of new onset DM during 89,469 person-years (PY). Factors predictive of DM included higher glucose, body mass index (BMI) and triglyceride levels, and older age. Among HIV-related factors, recent CD4 counts of<200 cells/µL and lipodystrophy were predictive of new onset DM. The mean performance of the D:A:D and Framingham equations yielded AUROC of 0.894 (95% CI: 0.849, 0.940) and 0.877 (95% CI: 0.823, 0.932), respectively. The Framingham equation over-predicted DM events compared to D:A:D for lower glucose and lower

  2. Evaluation of an Anger Therapy Intervention for Incarcerated Adult Males

    ERIC Educational Resources Information Center

    Vannoy, Steven D.; Hoyt, William T.

    2004-01-01

    An anger therapy intervention was developed for incarcerated adult males. The therapy was an extension of cognitive-behavioral approaches, incorporating principles and practices drawn from Buddhist psychology. Adult males from a Midwestern low-security prison were randomly assigned to either a treatment group (n= 16) or a waiting list control…

  3. High throughput virtual screening and in silico ADMET analysis for rapid and efficient identification of potential PAP248-286 aggregation inhibitors as anti-HIV agents

    NASA Astrophysics Data System (ADS)

    Malik, Ruchi; Bunkar, Devendra; Choudhary, Bhanwar Singh; Srivastava, Shubham; Mehta, Pakhuri; Sharma, Manish

    2016-10-01

    Human semen is principal vehicle for transmission of HIV-1 and other enveloped viruses. Several endogenous peptides present in semen, including a 39-amino acid fragments of prostatic acid phosphatase (PAP248-286) assemble into amyloid fibrils named as semen-derived enhancer of viral infection (SEVI) that promote virion attachment to target cells which dramatically enhance HIV virus infection by up to 105-fold. Epigallocatechin-3-gallate (EGCG), a polyphenolic compound, is the major catechin found in green tea which disaggregates existing SEVI fibers, and inhibits the formation of SEVI fibers. The aim of this study was to screen a number of relevant polyphenols to develop a rational approach for designing PAP248-286 aggregation inhibitors as potential anti-HIV agents. The molecular docking based virtual screening results showed that polyphenolic compounds 2-6 possessed good docking score and interacted well with the active site residues of PAP248-286. Amino acid residues of binding site namely; Lys255, Ser256, Leu258 and Asn265 are involved in binding of these compounds. In silico ADMET prediction studies on these hits were also found to be promising. Polyphenolic compounds 2-6 identified as hits may act as novel leads for inhibiting aggregation of PAP248-286 into SEVI.

  4. Burkholderia oklahomensis agglutinin is a canonical two-domain OAA-family lectin: structures, carbohydrate binding and anti-HIV activity.

    PubMed

    Whitley, Matthew J; Furey, William; Kollipara, Sireesha; Gronenborn, Angela M

    2013-05-01

    Burkholderia oklahomensis EO147 agglutinin (BOA) is a 29 kDa member of the Oscillatoria agardhii agglutinin (OAA) family of lectins. Members of the OAA family recognize high-mannose glycans, and, by binding to the HIV envelope glycoprotein 120 (gp120), block the virus from binding to and entering the host cell, thereby inhibiting infection. OAA-family lectins comprise either one or two homologous domains, with a single domain possessing two glycan binding sites. We solved the structure of BOA in the ligand-free form as well as in complex with four molecules of 3α,6α-mannopentaose, the core unit of the N-linked high-mannose structures found on gp120 in vivo. This is the first structure of a double-domain OAA-family lectin in which all four binding sites are occupied by ligand. The structural details of the BOA-glycan interactions presented here, together with determination of affinity constants and HIV inactivation data, shed further light onto the structure-function relationship in this important class of anti-HIV proteins.

  5. Expression of a Recombinant Anti-HIV and Anti-Tumor Protein, MAP30, in Nicotiana tobacum Hairy Roots: A pH-Stable and Thermophilic Antimicrobial Protein

    PubMed Central

    Moghadam, Ali; Niazi, Ali; Afsharifar, Alireza; Taghavi, Seyed Mohsen

    2016-01-01

    In contrast to conventional antibiotics, which microorganisms can readily evade, it is nearly impossible for a microbial strain that is sensitive to antimicrobial proteins to convert to a resistant strain. Therefore, antimicrobial proteins and peptides that are promising alternative candidates for the control of bacterial infections are under investigation. The MAP30 protein of Momordica charantia is a valuable type I ribosome-inactivating protein (RIP) with anti-HIV and anti-tumor activities. Whereas the antimicrobial activity of some type I RIPs has been confirmed, less attention has been paid to the antimicrobial activity of MAP30 produced in a stable, easily handled, and extremely cost-effective protein-expression system. rMAP30-KDEL was expressed in Nicotiana tobacum hairy roots, and its effect on different microorganisms was investigated. Analysis of the extracted total proteins of transgenic hairy roots showed that rMAP30-KDEL was expressed effectively and that this protein exhibited significant antibacterial activity in a dose-dependent manner. rMAP30-KDEL also possessed thermal and pH stability. Bioinformatic analysis of MAP30 and other RIPs regarding their conserved motifs, amino-acid contents, charge, aliphatic index, GRAVY value, and secondary structures demonstrated that these factors accounted for their thermophilicity. Therefore, RIPs such as MAP30 and its derived peptides might have promising applications as food preservatives, and their analysis might provide useful insights into designing clinically applicable antibiotic agents. PMID:27459300

  6. Virus burden in long-term survivors of human immunodeficiency virus (HIV) infection is a determinant of anti-HIV CD8+ lymphocyte activity.

    PubMed

    Ferbas, J; Kaplan, A H; Hausner, M A; Hultin, L E; Matud, J L; Liu, Z; Panicali, D L; Nerng-Ho, H; Detels, R; Giorgi, J V

    1995-08-01

    Persons infected with human immunodeficiency virus (HIV) for > 8 years were studied to delineate virologic and immunologic attributes of long-term survival. Whereas those with 300-700 CD4+ cells/microL often had circulating cytotoxic T lymphocytes (CTL) against HIV antigens, those with > 1000 CD4+ cells/microL did not. The subjects with > 1000 CD4+ cells/microL had low virus burden, low levels of Gag-specific CTL precursors, and minimal CD8+ cell activation. Overall, elevated levels of CD8+ cells, CD38 antigen expression on CD8+ cells, and anti-HIV functions were correlated with increased virus burden, provirus load, and HIV plasma RNA levels. A factor that suppressed HIV replication was spontaneously secreted from CD8+ cells of most subjects but not from those with high CD4+ cell counts. CD8+ cell activities, therefore, may reflect chronic viral stimulation of the immune system. Long-term survivors with high levels of CD4+ cells maintained control of viral replication but lacked the CD8+ cell activities.

  7. Expression of a Recombinant Anti-HIV and Anti-Tumor Protein, MAP30, in Nicotiana tobacum Hairy Roots: A pH-Stable and Thermophilic Antimicrobial Protein.

    PubMed

    Moghadam, Ali; Niazi, Ali; Afsharifar, Alireza; Taghavi, Seyed Mohsen

    2016-01-01

    In contrast to conventional antibiotics, which microorganisms can readily evade, it is nearly impossible for a microbial strain that is sensitive to antimicrobial proteins to convert to a resistant strain. Therefore, antimicrobial proteins and peptides that are promising alternative candidates for the control of bacterial infections are under investigation. The MAP30 protein of Momordica charantia is a valuable type I ribosome-inactivating protein (RIP) with anti-HIV and anti-tumor activities. Whereas the antimicrobial activity of some type I RIPs has been confirmed, less attention has been paid to the antimicrobial activity of MAP30 produced in a stable, easily handled, and extremely cost-effective protein-expression system. rMAP30-KDEL was expressed in Nicotiana tobacum hairy roots, and its effect on different microorganisms was investigated. Analysis of the extracted total proteins of transgenic hairy roots showed that rMAP30-KDEL was expressed effectively and that this protein exhibited significant antibacterial activity in a dose-dependent manner. rMAP30-KDEL also possessed thermal and pH stability. Bioinformatic analysis of MAP30 and other RIPs regarding their conserved motifs, amino-acid contents, charge, aliphatic index, GRAVY value, and secondary structures demonstrated that these factors accounted for their thermophilicity. Therefore, RIPs such as MAP30 and its derived peptides might have promising applications as food preservatives, and their analysis might provide useful insights into designing clinically applicable antibiotic agents. PMID:27459300

  8. A Model Plan for the Supervision and Evaluation of Therapy Services in Educational Settings. TIES: Therapy in Educational Settings.

    ERIC Educational Resources Information Center

    Reed, Penny; And Others

    The manual serves as a model for school districts developing procedures for supervising and evaluating their therapy services. The narrative is addressed to therapists rather than supervisors so that school districts can photocopy or adapt sections of the manual and assemble customized manuals for therapists in their programs. The first chapter,…

  9. Noise evaluation of Compton camera imaging for proton therapy

    NASA Astrophysics Data System (ADS)

    Ortega, P. G.; Torres-Espallardo, I.; Cerutti, F.; Ferrari, A.; Gillam, J. E.; Lacasta, C.; Llosá, G.; Oliver, J. F.; Sala, P. R.; Solevi, P.; Rafecas, M.

    2015-02-01

    Compton Cameras emerged as an alternative for real-time dose monitoring techniques for Particle Therapy (PT), based on the detection of prompt-gammas. As a consequence of the Compton scattering process, the gamma origin point can be restricted onto the surface of a cone (Compton cone). Through image reconstruction techniques, the distribution of the gamma emitters can be estimated, using cone-surfaces backprojections of the Compton cones through the image space, along with more sophisticated statistical methods to improve the image quality. To calculate the Compton cone required for image reconstruction, either two interactions, the last being photoelectric absorption, or three scatter interactions are needed. Because of the high energy of the photons in PT the first option might not be adequate, as the photon is not absorbed in general. However, the second option is less efficient. That is the reason to resort to spectral reconstructions, where the incoming γ energy is considered as a variable in the reconstruction inverse problem. Jointly with prompt gamma, secondary neutrons and scattered photons, not strongly correlated with the dose map, can also reach the imaging detector and produce false events. These events deteriorate the image quality. Also, high intensity beams can produce particle accumulation in the camera, which lead to an increase of random coincidences, meaning events which gather measurements from different incoming particles. The noise scenario is expected to be different if double or triple events are used, and consequently, the reconstructed images can be affected differently by spurious data. The aim of the present work is to study the effect of false events in the reconstructed image, evaluating their impact in the determination of the beam particle ranges. A simulation study that includes misidentified events (neutrons and random coincidences) in the final image of a Compton Telescope for PT monitoring is presented. The complete chain of

  10. Noise evaluation of Compton camera imaging for proton therapy.

    PubMed

    Ortega, P G; Torres-Espallardo, I; Cerutti, F; Ferrari, A; Gillam, J E; Lacasta, C; Llosá, G; Oliver, J F; Sala, P R; Solevi, P; Rafecas, M

    2015-03-01

    Compton Cameras emerged as an alternative for real-time dose monitoring techniques for Particle Therapy (PT), based on the detection of prompt-gammas. As a consequence of the Compton scattering process, the gamma origin point can be restricted onto the surface of a cone (Compton cone). Through image reconstruction techniques, the distribution of the gamma emitters can be estimated, using cone-surfaces backprojections of the Compton cones through the image space, along with more sophisticated statistical methods to improve the image quality. To calculate the Compton cone required for image reconstruction, either two interactions, the last being photoelectric absorption, or three scatter interactions are needed. Because of the high energy of the photons in PT the first option might not be adequate, as the photon is not absorbed in general. However, the second option is less efficient. That is the reason to resort to spectral reconstructions, where the incoming γ energy is considered as a variable in the reconstruction inverse problem. Jointly with prompt gamma, secondary neutrons and scattered photons, not strongly correlated with the dose map, can also reach the imaging detector and produce false events. These events deteriorate the image quality. Also, high intensity beams can produce particle accumulation in the camera, which lead to an increase of random coincidences, meaning events which gather measurements from different incoming particles. The noise scenario is expected to be different if double or triple events are used, and consequently, the reconstructed images can be affected differently by spurious data. The aim of the present work is to study the effect of false events in the reconstructed image, evaluating their impact in the determination of the beam particle ranges. A simulation study that includes misidentified events (neutrons and random coincidences) in the final image of a Compton Telescope for PT monitoring is presented. The complete chain of

  11. "Hyper-response" evaluated by 3D echocardiography after cardiac resynchronization therapy.

    PubMed

    Hotta, Viviane Tiemi; Vieira, Marcelo Luiz Campos; Rassi, Daniela do Carmo; Nishioka, Silvana Angelina D'orio; Martinelli Filho, Martino; Mathias, Wilson

    2011-06-01

    Cardiac resynchronization therapy consists of a promising treatment for patients with severe heart failure, but about 30% of patients do not exhibit clinical improvement with this procedure. However, approximately 10% of patients undergoing this therapy may have hyperresponsiveness, and three-dimensional echocardiography can provide an interesting option for the selection and evaluation of such patients. PMID:21789343

  12. Evaluating Animal-Assisted Therapy in Group Treatment for Child Sexual Abuse

    ERIC Educational Resources Information Center

    Dietz, Tracy J.; Davis, Diana; Pennings, Jacquelyn

    2012-01-01

    This study evaluates and compares the effectiveness of three group interventions on trauma symptoms for children who have been sexually abused. All of the groups followed the same treatment protocol, with two of them incorporating variations of animal-assisted therapy. A total of 153 children ages 7 to 17 who were in group therapy at a Child…

  13. Designing, Implementing, and Evaluating a Group Therapy for Underserved Populations

    ERIC Educational Resources Information Center

    Waltman, Scott H.; Hetrick, Holly; Tasker, Tamara E.

    2012-01-01

    This article presents the case of a mindfulness-based group therapy that was implemented in a residential treatment facility. The case presented comprised a group of adolescent males with disruptive behavior disorders. The group was designed to be appropriate for the unique demographics of the clients, with the intent to help the clients enhance…

  14. Evaluation of combination therapy in animal models of cerebral ischemia.

    PubMed

    O'Collins, Victoria E; Macleod, Malcolm R; Donnan, Geoffrey A; Howells, David W

    2012-04-01

    Combination therapy has been identified as a promising strategy to improve stroke management. We conducted a systematic review and meta-analysis of evidence from animal models of ischemic stroke to determine whether combining treatments improved efficacy. Multiple databases were searched and data were extracted from focal ischemia experiments comparing control groups, single treatments, and combination treatments. Of 11,430 papers identified, 142 met the inclusion criteria; these tested 126 treatments in 373 experiments using 8,037 animals (I(2)=85 to 96%). Taken together, single treatments reduced infarct size by 20% and improved neurological score by 12% compared with control; a second therapy improved efficacy by an additional 18% and 25%, respectively. Publication bias may affect combination efficacy for infarct size but not neurological score. Combining thrombolysis with other therapies may extend the time window from 4.4 to 8 hours in animal models, although testing beyond 6 hours is required to confirm this. Benefits of additional therapy decreased as the efficacy of the primary treatment increased, with combination efficacy reaching a ceiling at 60% to 80% protection. Combining treatments may bring benefits and extend the time window for treatment. More evidence is needed due to potential publication bias and heterogeneity.

  15. Alleviating Communication Apprehension through Rational Emotive Therapy: A Comparative Evaluation.

    ERIC Educational Resources Information Center

    Watson, Arden K.; Dodd, Carley H.

    Albert Ellis's Rational Emotive Therapy (RET), which assumes that a person can change an emotional disturbance by discovering and disputing the irrational ideas giving rise to that emotion, has been used effectively in treating public speaking anxiety. To compare RET with other treatments for communication apprehension, 52 high communication…

  16. Evaluation of Group Cognitive Behavioral Therapy for Adults with ADHD

    ERIC Educational Resources Information Center

    Bramham, Jessica; Young, Susan; Bickerdike, Alison; Spain, Deborah; McCartan, Denise; Xenitidis, Kiriakos

    2009-01-01

    Objective: A brief cognitive behavioral therapy (CBT) group intervention was designed to treat comorbid anxiety, depression, and low self-esteem and self-efficacy in adults with ADHD. It was hypothesised that participants would gain knowledge about ADHD, experience a reduction in comorbid symptoms, and benefit from the supportive aspect of group…

  17. Animal-assisted therapy: evaluation and implementation of a complementary therapy to improve the psychological and physiological health of critically ill patients.

    PubMed

    DeCourcey, Mary; Russell, Anne C; Keister, Kathy J

    2010-01-01

    Animal-assisted therapy has gained widespread support in a variety of health care settings, including critical care units. This article seeks to review some of the current animal-assisted therapy, define a structured program, and evaluate the potential ability of the therapy to enhance the progress and health of our patients.

  18. Novel near-infrared BiFC systems from a bacterial phytochrome for imaging protein interactions and drug evaluation under physiological conditions.

    PubMed

    Chen, Minghai; Li, Wei; Zhang, Zhiping; Liu, Sanying; Zhang, Xiaowei; Zhang, Xian-En; Cui, Zongqiang

    2015-04-01

    Monitoring protein-protein interactions (PPIs) in live subjects is critical for understanding these fundamental biological processes. Bimolecular fluorescence complementation (BiFC) provides a good technique for imaging PPIs; however, a BiFC system with a long wavelength remains to be pursued for in vivo imaging. Here, we conducted systematic screening of split reporters from a bacterial phytochrome-based, near-infrared fluorescent protein (iRFP). Several new near-infrared phytochrome BiFC systems were built based on selected split sites including the amino acids residues 97/98, 99/100, 122/123, and 123/124. These new near-infrared BiFC systems from a bacterial phytochrome were verified as powerful tools for imaging PPIs under physiological conditions in live cells and in live mice. The interaction between HIV-1 integrase (IN) and cellular cofactor protein Lens epithelium-derived growth factor (LEDGF/p75) was visualized in live cells using the newly constructed iRFP BiFC system because of its important roles in HIV-1 integration and replication. Because the HIV IN-LEDGF/p75 interaction is an attractive anti-HIV target, drug evaluation assays to inhibit the HIV IN-LEDGF/p75 interaction were also performed using the newly constructed BiFC system. The results showed that compound 6 and carbidopa inhibit the HIV IN-LEDGF/p75 interaction in a dose-dependent manner under physiological conditions in the BiFC assays. This study provides novel near-infrared BiFC systems for imaging protein interactions under physiological conditions and provides guidance for splitting other bacterial phytochrome-like proteins to construct BiFC systems. The study also provides a new method for drug evaluation in live cells based on iRFP BiFC systems and supplies some new information regarding candidate drugs for anti-HIV therapies.

  19. Evaluation of a compact tinnitus therapy by electrophysiological tinnitus decompensation measures.

    PubMed

    Low, Yin Fen; Argstatter, Heike; Bolay, Hans Volker; Strauss, Daniel J

    2008-01-01

    Large-scale neural correlates of the tinnitus decompensation have been identified by using wavelet phase stability criteria of single sweep sequences of auditory late responses (ALRs). Our previous work showed that the synchronization stability in ALR sequences might be used for objective quantification of the tinnitus decompensation and attention which link to Jastreboff tinnitus model. In this study, we intend to provide an objective evaluation for quantifying the effect of music therapy in tinnitus patients. We examined neural correlates of the attentional mechanism in single sweep sequences of ALRs in chronic tinnitus patients who underwent compact therapy course by using the maximum entropy auditory paradigm. Results by our measure showed that the extent of differentiation between attended and unattended conditions improved significantly after the therapy. It is concluded that the wavelet phase synchronization stability of ALRs single sweeps can be used for the objective evaluation of tinnitus therapies, in this case the compact tinnitus music therapy. PMID:19163872

  20. Controlling drug efficiency by encapsulation into carbon nanotubes: A theoretical study of the antitumor Cisplatin and the anti-HIV TIBO molecules

    NASA Astrophysics Data System (ADS)

    Bessrour, R.; Belmiloud, Y.; Hosni, Z.; Tangour, B.

    2012-06-01

    From the beginning of last century, Paul Ehrlich, a specialist in the immune system and the Nobel Prize (1908) had raised the possibility of "magic bullets" can directly address, in an organism, drugs in a particular area of the body, sparing all other parts of side effects. Carbon nanotubes (CNTs) have particular property to cross cell membranes easily. In an effort to optimize the use of CNT as drug nanocarriers, we divided our study into two parts. In the first, our concern was to find the minimum diameter of a single wall CNT can encapsulate an anticancer drug that iscisplatin without altering its geometry in order conserve its therapeutic power. Behavior of one and two Cisplatin(Cp) molecules confined in capped and opened single-walled carbon nanotubes (CNTs) is studied by means of ab-initio calculations. Single molecule binding energies clearly exhibit encapsulation dependence on tube diameters that range from 6.26 Å to 12.04 Å. A weak stabilization energy of the Cp@(11,0) equal to -70 kcal.mol-1 has been obtained corresponding to a CNT's diameter of 8.5Å. We noticed that Cisplatin molecule changes shape when encapsulated into CNTs' whose diameters are less than 7.6 Å. In the presence of a second Cisplatin molecule in the (10,0) CNT, preferred position stays parallel to CNT's axis leading to a linear density of roughly 1588 molecules/μm of CNT's length corresponding to a linear density of 7.9 10-19 g/μm. The 195Pt chemical shift tensors are calculated using GIAO method. NMR calculations reveal that Platinum chemical shift is sensitive to CNT's diameter and is linearly correlated to confinement energy. 195Pt chemical shift measurement may be a direct method to access to the diameter of the encapsulating CNT's and to control the amount of drug molecule transported by this CNT. In the second part, the opposite has been sought is to say how the use of nanotubes with different diameters can control the change in a geometry of an anti-HIV drug that is TIBO

  1. Experimental models for evaluating antithrombotic therapies in replantation microsurgery.

    PubMed

    Cooley, B C; Gould, J S

    1987-01-01

    A variety of anticoagulation and antiplatelet aggregation agents are in use clinically, and in applications to microvascular surgery, a clear choice for the most effective therapy has not been determined. Models of vascular trauma combined with microvascular anastomosis have been developed for comparing the efficacy of these agents in maintaining vascular patency. In a rat model of microvascular thrombosis, heparin effectively prevents occlusion in both arteries and veins, at clinical levels of administration. Aspirin helps prevent thrombosis, but not as well as heparin. These results support the beneficial effect of antithrombotic drug therapies, and suggest a more potent role of the heparin-inhibited fibrin clot over platelet aggregation in creating thrombotic occlusion of small vessels.

  2. Purification and characterization of a novel antifungal protein with antiproliferation and anti-HIV-1 reverse transcriptase activities from Peganum harmala seeds.

    PubMed

    Ma, Xiaojin; Liu, Dongliang; Tang, Haishu; Wang, Yan; Wu, Ting; Li, Yang; Yang, Jie; Yang, Jianhua; Sun, Surong; Zhang, Fuchun

    2013-02-01

    A novel antifungal protein, designated as PHP, was isolated from the seeds of Peganum harmala, by cationic exchange chromatography on Resource S column and gel filtration on Sephadex 75 10/300 GL column. PHP was found to form a homodimer of about 16 kDa. Isoelectric focusing polyacrylamide gel electrophoresis analysis showed that the isoelectric point of PHP was ∼8.4. The N-terminal 20-amino acid sequence of PHP, ITCPQVTQSLAPCVPYLISG, resembles the non-specific lipid transfer proteins in certain plants. PHP exhibited lipid-binding activity. Furthermore, PHP exerted antifungal activity against Alternaria alternate, Penicillium degitatum, Rhizopus stuolonifer, and Magnaporthe grisea, and its antifungal activity was stable in the temperature range 4-60°C, and in the pH range 4-10. It inhibited the mycelial growth in A. alternate, P. degitatum, R. stuolonifer, and M. grisea with 50% inhibitory concentration (IC(50)) of 1.5, 37.5, 8.44, and 12.19 μM, respectively. PHP was also able to inhibit the proliferation of esophagus carcinoma (Eca-109), cervical carcinoma (HeLa), gastric carcinoma (MGC-7), and melanoma (B16) cells with IC(50) of 0.7, 2.74, 3.13, and 1.47 μM, respectively. Moreover, PHP significantly inhibited HIV-1 reverse transcriptase (RT) with an IC(50) of 1.26 μM. It did not have hemagglutinating and antibacterial activities. In conclusion, a novel antifungal protein with antiproliferation and anti-HIV-1 RT activities was obtained from P. harmala seeds.

  3. Fc-glycosylation influences Fcγ receptor binding and cell-mediated anti-HIV activity of monoclonal antibody 2G12.

    PubMed

    Forthal, Donald N; Gach, Johannes S; Landucci, Gary; Jez, Jakub; Strasser, Richard; Kunert, Renate; Steinkellner, Herta

    2010-12-01

    Interactions between the Fc segment of IgG and FcγRs on a variety of cells are likely to play an important role in the anti-HIV activity of Abs. Because the nature of the glycan structure on the Fc domain is a critical determinant of Fc-FcγR binding, proper Fc glycosylation may contribute to Ab-mediated protection. We have generated five different glycoforms of the broadly HIV-1-neutralizing mAb 2G12 in wild-type and glycoengineered plants and Chinese hamster ovary cells. Plant-derived 2G12 exhibited highly homogeneous glycosylation profiles with a single dominant N-glycan species. Using flow cytometry with FcγR-expressing cell lines, all 2G12 glycoforms demonstrated similar binding to FcγRI, FcγRIIa, and FcγRIIb. In contrast, two glycoforms derived from glycoengineered plants that lack plant-specific xylose and core α1,3-fucose, and instead carry human-like glycosylation with great uniformity, showed significantly enhanced binding to FcγRIIIa compared with Chinese hamster ovary or wild-type plant-derived 2G12. Using surface plasmon resonance, we show that binding of 2G12 to FcγRIIIa is markedly affected by core fucose, irrespective of its plant-specific α1,3 or mammalian-type α1,6 linkage. Consistent with this finding, 2G12 glycoforms lacking core fucose (and xylose) mediated higher antiviral activity against HIV-1 or simian immunodeficiency virus as measured by Ab-dependent cell-mediated virus inhibition. This is, to our knowledge, the first demonstration that specific alterations of Fc glycosylation can improve antiviral activity. Such alterations may result in better immunotherapeutic reagents. Moreover, biasing vaccine-induced immune responses toward optimal Fc glycosylation patterns could result in improved vaccine efficacy. PMID:21041724

  4. Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses.

    PubMed

    Hancock, Gemma; Yang, Hongbing; Yorke, Elisabeth; Wainwright, Emma; Bourne, Victoria; Frisbee, Alyse; Payne, Tamika L; Berrong, Mark; Ferrari, Guido; Chopera, Denis; Hanke, Tomas; Mothe, Beatriz; Brander, Christian; McElrath, M Juliana; McMichael, Andrew; Goonetilleke, Nilu; Tomaras, Georgia D; Frahm, Nicole; Dorrell, Lucy

    2015-02-01

    Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for

  5. Radionuclide methods for evaluating the results of thrombolytic therapy

    SciTech Connect

    Zaret, B.L.; Wackers, F.J.

    1987-08-01

    In summary, a variety of nuclear techniques may be used to investigate the effects of thrombolytic therapy and myocardial reperfusion. Assessments of global and regional ventricular function, myocardial perfusion, and metabolic integrity are available and appear to add substantially to conventional assessment. Timing of studies appears to be critical. Complementary data can be obtained in both the acute and convalescent phase of myocardial infarction. 49 references.

  6. Behavioral and endocrinological evaluation of music therapy for elderly patients with dementia.

    PubMed

    Suzuki, Mizue; Kanamori, Masao; Watanabe, Motoko; Nagasawa, Shingo; Kojima, Emi; Ooshiro, Hajime; Nakahara, Daiichirou

    2004-03-01

    The present study investigated the effectiveness of music therapy for dementia patients using endocrinological and behavioral evaluations. The study comprised 10 patients with senile dementia who received music therapy; six had Alzheimer's dementia and four had vascular dementia. Music therapy was performed twice a week for 8 consecutive weeks (16 sessions). As a result, total scores on the Mini-Mental State Examination (MMSE) did not significantly change, but the scores of a subscale, "language", improved significantly. According to the Multidimensional Observation Scale For Elderly Subjects (MOSES), scores for "irritability" decreased significantly. Regarding changes in salivary chromogranin A (CgA) levels, the average was significantly decreased before session 16 compared to after this. These results suggest that the combination of endocrinological measurements, behavioral evaluations and functional assessment methods are useful in evaluating the effects of music therapy in persons with senile dementia.

  7. The Anti-HIV Microbicide Candidate RC-101 Inhibits Pathogenic Vaginal Bacteria Without Harming Endogenous Flora or Mucosa

    PubMed Central

    Eade, Colleen R.; Cole, Amy L.; Diaz, Camila; Rohan, Lisa C.; Parniak, Michael A.; Marx, Preston; Tarwater, Patrick M.; Gupta, Phalguni; Cole, Alexander M.

    2012-01-01

    Problem Vaginal microbicides represent a promising approach for preventing heterosexual HIV transmission. However, preclinical evaluation should be conducted to ensure that microbicides will be safe for human cells and healthy microflora of the female reproductive tract. One microbicide candidate, RC-101, has been effective and well-tolerated in preliminary cell culture and macaque models. However, the effect of RC-101 on primary vaginal tissues and resident vaginal microflora requires further evaluation. Method of Study We treated primary vaginal tissues and vaginal bacteria, both pathogenic and commensal, with RC-101 to investigate effects of this microbicide. Results RC-101 was well-tolerated by host tissues, and also by commensal vaginal bacteria. Simultaneously, pathogenic vaginal bacteria, which are known to increase susceptibility to HIV acquisition, were inhibited by RC-101. Conclusions By establishing vaginal microflora, the specific antibacterial activity of RC-101 may provide a dual mechanism of HIV protection. These findings support advancement of RC-101 to clinical trials. PMID:23167830

  8. Powder for reconstitution of the anti-HIV-1 drug TMC278 - Formulation development, stability and animal studies.

    PubMed

    Van Gyseghem, Elke; Pendela, Murali; Baert, Lieven; Rosier, Jan; Van 't Klooster, Gerben; De Man, Hilde; Bouche, Marie-Paule; Schueller, Laurent; Van Remoortere, Pieter; Wigerinck, Piet; Adams, Erwin; Hoogmartens, Jos; Van den Mooter, Guy

    2008-11-01

    Powders for reconstitution of the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 with low water solubility were developed by using a spray-dry technology. Their flexible dosing ability makes them suitable for patients looking for a different approach for antiretroviral (ARV) therapy. The selection of formulation excipients was based on their potential to create and maintain supersaturation solubility of TMC278 in 0.01 M HCl. Suitable water-soluble carriers for TMC278 were selected by a supersaturation screening to formulate powders for reconstitution by spray-drying. The selected powders for reconstitution were compared to clinical tablets of TMC278.HCl, in vitro using dissolution and stability testing, and in vivo through administration to beagle dogs, fed immediately after dosing. The spray-dried powders for reconstitution made up of TMC278/PVP-VA 64 1:9 (w/w) and TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w) showed ease of suspendability, nearly complete dissolution of the drug and acceptable stability after one month storage at 25 and 40 degrees C. In dogs, TMC278 was more slowly absorbed from tablets than from the suspended powders for reconstitution. Compared to the tablet, the relative bioavailability obtained with the powders ranged between 69% and 89% for TMC278/PVP-VA 64 1:9 (w/w) and between 85% and 157% for TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w). The absence of differences in vivo and in vitro between the powders made an eventual choice very difficult, yet their advantageous in vivo behaviour and flexible dosing possibility may provide a starting point for paediatric formulations.

  9. [The management of dialysis patients seropositive for HBsAg, anti-HCV, or anti-HIV antibodies].

    PubMed

    Fabrizi, Fabrizio; Messa, Piergiorgio

    2012-01-01

    Infections by hepatitis B or hepatitis C virus are still common among patients on maintenance dialysis in Western countries. The natural history of HBV and HCV in the dialysis population remains unclear; however, there is good evidence showing an adverse impact of an anti-HCV seropositive status on survival in dialysis patients. A recent meta-analysis of observational studies (n=7, 11,589 unique patients) reported that anti-HCV-positive patients on dialysis had a higher mortality rate than those who were anti-HCV negative (adjusted hazard ratio=1.35, 95% confidence interval, 1.13; 1.59, p<0.001). This was in part attributed to a higher frequency of chronic hepatitis C and its attending complications (cirrhosis and hepatocellular carcinoma). In addition, HCV appeared to have a negative influence on quality of life. Recent clinical guidelines by the KDIGO Study Group have not suggested the isolation of anti-HCV-positive patients on maintenance dialysis. Standard precautions and specific procedures against the transmission of blood-borne agents have been recommended to control HCV infection within dialysis units. Isolation by dialysis machines, staff and rooms has been strongly recommended to control HBV. Vaccination is an important tool against transmission of HBV infection among patients on maintenance dialysis; however, the immune response towards the hepatitis B vaccine in uremic patients remains unsatisfactory. Monotherapy with lamivudine is currently used for dialysis patients with hepatitis B whereas combination antiviral therapy (pegylated interferon plus ribavirin) is the standard of care for hepatitis C in the dialysis population, even if various side effects have been observed.

  10. beta-estradiol attenuates the anti-HIV-1 efficacy of Stavudine (D4T) in primary PBL

    PubMed Central

    Zhang, Mingjie; Huang, Qingsheng; Huang, Yong; Wood, Owen; Yuan, Weishi; Chancey, Caren; Daniel, Sylvester; Rios, Maria; Hewlett, Indira; Clouse, Kathleen A; Dayton, Andrew I

    2008-01-01

    Background Female hormones are known to play an important role in predisposition for many infectious diseases. Recent work suggests there are gender effects in HIV/AIDS progression. Here we ask whether the sex steroid hormone β-estradiol affects the replication of HIV-1 or the efficacy of a common anti-retroviral drug, Stavudine (D4T). Results Human PBL were infected with HIV-1 in the presence or absence of combinations of sex steroid hormones and the anti-retroviral drug, D4T. After seven days in culture, viral supernatants were assayed for HIV-1 p24 protein. β-estradiol resulted in a modest inhibition of HIV-1 replication of ~26%. However, 2 nM β-estradiol increased the amount of HIV-1 replication in the presence of 50 nM D4T from a baseline of 33% (+/- SE = 5.4) to 74% (+/- SE = 5.4) of control virus levels in the absence of drug. Both results were statistically highly significant (p < 0.001). β-estradiol did not increase the replication of a D4T-resistant strain of HIV in the presence of D4T. The effects were unlikely to be due to general cell inhibition or toxicity because these concentrations of drug and hormone cause no cytotoxicity in PBL as measured by trypan blue exclusion. Conclusion β-estradiol inhibited both HIV-1 replication in primary human PBL and the antiretroviral efficacy of D4T in PBL cultures. To optimize antiretroviral drug therapy, it may be necessary to monitor patient hormonal status. PMID:18808673

  11. Evaluating complementary and alternative therapies for cancer patients.

    PubMed

    Cassileth, B R

    1999-01-01

    "Complementary and alternative" therapies are actually a vast collection of disparate, unrelated regimens and products, ranging from adjunctive modalities that effectively enhance quality of life and promising antitumor herbal remedies now under investigation, to bogus therapies that claim to cure cancer and that harm not only directly, but also indirectly by encouraging patients to avoid or postpone effective cancer care. Complementary therapies such as music and massage, herbal teas to aid digestion and relieve nausea, yoga, tai chi, meditation, and the many other well-documented techniques that relieve stress and enhance well-being should be made available to patients to augment and ease the experience of cancer treatment and recovery. Many time-tested herbal and diet-based remedies are now being studied for their abilities to induce or extend remission without toxicity. At the same time, lack of government regulatory authority leaves consumers at the mercy of those who promote unproved remedies, scores of which the grocery store and pharmacy shelves. Many of these over-the-counter products contain harmful ingredients. Herb-drug interactions, only some of which are documented, occur with frequency and are sufficiently problematic to require that patients stop taking herbal remedies prior to surgery (to prevent interactions with anesthetics and anticoagulant effects); before radiation (due to potential for increased photosensitivity); and during courses of chemotherapy (to prevent product-drug interactions). Moreover, both good information and misinformation that appear in printed materials and on the Internet appeal to better educated consumers, who are, in fact, the most likely to try complementary and alternative methods.

  12. Evaluation of Staphylococcus aureus Eradication Therapy in Vascular Surgery

    PubMed Central

    Donker, J. M. W.; van Rijen, M. M. L.; Kluytmans, J. A. J. W.; van der Laan, L.

    2016-01-01

    Introduction Surgical site infections (SSI) are a serious complication in vascular surgery which may lead to severe morbidity and mortality. Staphylococcus aureus nasal carriage is associated with increased risk for development of SSIs in central vascular surgery. The risk for SSI can be reduced by perioperative eradication of S. aureus carriage in cardiothoracic and orthopedic surgery. This study analyzes the relation between S. aureus eradication therapy and SSI in a vascular surgery population. Methods A prospective cohort study was performed, including all patients undergoing vascular surgery between February 2013 and April 2015. Patients were screened for S. aureus nasal carriage and, when tested positive, were subsequently treated with eradication therapy. The presence of SSI was recorded based on criteria of the CDC. The control group consisted of a cohort of vascular surgery patients in 2010, who were screened, but received no treatment. Results A total of 444 patients were screened. 104 nasal swabs were positive for S. aureus, these patients were included in the intervention group. 204 patients were screened in the 2010 cohort. 51 tested positive and were included in the control group. The incidence of S. aureus infection was 5 out of 51 (9.8%) in the control group versus 3 out of 104 in the eradication group (2.2%; 95% confidence interval 0.02–1.39; P = 0.13). A subgroup analysis showed that the incidence of S. aureus infection was 3 out of 23 (13.0%) in the control group in central reconstructive surgery versus 0 out of 44 in the intervention group (P = 0.074). The reduction of infection pressure by S. aureus was stronger than the reduction of infection pressure by other pathogens (exact maximum likelihood estimation; OR = 0.0724; 95% CI: 0.001–0.98; p = 0.0475). Conclusion S. aureus eradication therapy reduces the infection pressure of S. aureus, resulting in a reduction of SSIs caused by S. aureus. PMID:27529551

  13. Evaluating complementary and alternative therapies for cancer patients.

    PubMed

    Cassileth, B R

    1999-01-01

    "Complementary and alternative" therapies are actually a vast collection of disparate, unrelated regimens and products, ranging from adjunctive modalities that effectively enhance quality of life and promising antitumor herbal remedies now under investigation, to bogus therapies that claim to cure cancer and that harm not only directly, but also indirectly by encouraging patients to avoid or postpone effective cancer care. Complementary therapies such as music and massage, herbal teas to aid digestion and relieve nausea, yoga, tai chi, meditation, and the many other well-documented techniques that relieve stress and enhance well-being should be made available to patients to augment and ease the experience of cancer treatment and recovery. Many time-tested herbal and diet-based remedies are now being studied for their abilities to induce or extend remission without toxicity. At the same time, lack of government regulatory authority leaves consumers at the mercy of those who promote unproved remedies, scores of which the grocery store and pharmacy shelves. Many of these over-the-counter products contain harmful ingredients. Herb-drug interactions, only some of which are documented, occur with frequency and are sufficiently problematic to require that patients stop taking herbal remedies prior to surgery (to prevent interactions with anesthetics and anticoagulant effects); before radiation (due to potential for increased photosensitivity); and during courses of chemotherapy (to prevent product-drug interactions). Moreover, both good information and misinformation that appear in printed materials and on the Internet appeal to better educated consumers, who are, in fact, the most likely to try complementary and alternative methods. PMID:11198952

  14. Spectroscopic evaluation of photodynamic therapy of the intraperitoneal cavity

    NASA Astrophysics Data System (ADS)

    Finlay, Jarod C.; Sandell, Julia L.; Zhu, Timothy C.; Lewis, Robert; Cengel, Keith A.; Hahn, Stephen M.

    2010-02-01

    We present the results of spectroscopic measurements of diffuse reflectance and fluorescence before and after photodynamic therapy of healthy canine peritoneal cavity. Animals were treated intra-operatively after iv injection of the benzoporphyrin derivative (BPD). The small bowel was treated using a uniform light field projected by a microlens-tipped fiber. The cavity was then filled with scattering medium and the remaining organs were treated using a moving diffuser. Diffuse reflectance and fluorescence measurements were made using a multi-fiber optical probe positioned on the surface of various tissues within the cavity before and after illumination. The measured data were analyzed to quantify hemoglobin concentration and oxygenation and sensitizer concentration.

  15. Effect of Methamphetamine on Spectral Binding, Ligand Docking and Metabolism of Anti-HIV Drugs with CYP3A4

    PubMed Central

    Ande, Anusha; Wang, Lei; Vaidya, Naveen K.; Li, Weihua; Kumar, Santosh; Kumar, Anil

    2016-01-01

    -boosted antiretroviral therapy, in HIV-1-infected individuals who abuse methamphetamine. PMID:26741368

  16. Effect of Methamphetamine on Spectral Binding, Ligand Docking and Metabolism of Anti-HIV Drugs with CYP3A4.

    PubMed

    Nookala, Anantha R; Li, Junhao; Ande, Anusha; Wang, Lei; Vaidya, Naveen K; Li, Weihua; Kumar, Santosh; Kumar, Anil

    2016-01-01

    -boosted antiretroviral therapy, in HIV-1-infected individuals who abuse methamphetamine.

  17. Anti-AIDS agents. 60. Substituted 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) analogues as potent anti-HIV agents.

    PubMed

    Yu, Donglei; Chen, Chin-Ho; Brossi, Arnold; Lee, Kuo-Hsiung

    2004-07-29

    Synthesis of positional isomers is a commonly used technique in drug design. Accordingly, based on prior SAR studies of 3'R,4'R-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK, 1) analogues, a series of mono- and disubstituted chromone derivatives of 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP, 4) were designed and synthesized. Together with 1 and 4-methyl DCK (2), all newly synthesized DCP analogues (4-21) were screened for anti-HIV-1 activity against a non-drug-resistant strain in H9 lymphocytes and a multiple reverse transcriptase (RT) inhibitor-resistant strain in the MT4 cell line. Several DCP analogues (4, 5, 7, 8, 13, and 17) exhibited extremely high anti-HIV activity in the non-drug-resistant strain assay, with EC(50) values ranging from 0.00032 to 0.0057 microM and remarkable therapeutic indexes (TI) ranging from 5.6 x 10(3) to 1.16 x 10(5), which were similar to those of 2 (EC(50) 0.0059 microM, TI > 6.6 x 10(3)) and better than those of 1 (EC(50) 0.049 microM, TI > 328). Even more promisingly, some DCP analogues also showed activity against a multi-RT inhibitor-resistant strain, HIV-1 RTMDR1, whereas most DCK analogues did not. The most significant compound was 8, with an EC(50) value of 0.06 microM and TI of 718 against the multi-RT inhibitor-resistant HIV-1 strain. Compounds 9 and 10 also showed good activity with an EC(50) value of 0.14 microM, and TIs of 272 and >111, respectively. 2-Ethyl DCP (8) exhibited the best anti-HIV activity in both assays. Further development of 8-related compounds as clinical trial candidates is warranted.

  18. A better model of acute pancreatitis for evaluating therapy.

    PubMed Central

    Schmidt, J; Rattner, D W; Lewandrowski, K; Compton, C C; Mandavilli, U; Knoefel, W T; Warshaw, A L

    1992-01-01

    Existing models of acute pancreatitis have limitations to studying novel therapy. Whereas some produce mild self-limited pancreatitis, others result in sudden necrotizing injury. The authors developed an improved model providing homogeneous moderately severe injury by superimposing secretory hyperstimulation on minimal intraductal bile acid exposure. Sprague-Dawley rats (n = 231) received low-pressure intraductal glycodeoxycholic acid (GDOC) at very low (5 or 10 mmol/L) concentrations followed by intravenous cerulein. Cerulein or GDOC alone caused only very mild inflammation. However, GDOC combined with cerulein was uniformly associated with more edema (p less than 0.0005), acinar necrosis (p less than 0.01), inflammation (p less than 0.006), and hemorrhage (p less than 0.01). Pancreatic injury was further increased and death was potentiated by increasing volume and duration of intraductal low-dose GDOC infusion. There was significant morphologic progression between 6 and 24 hours. The authors conclude that (1) combining minimal intraductal bile acid exposure with intravenous hyperstimulation produces homogeneous pancreatitis of intermediate severity that can be modulated at will; (2) the injury is progressive over at least 24 hours with finite mortality rate; (3) the model provides superior opportunity to study innovative therapy. Images FIG. 3. FIG. 4. FIG. 5. FIG. 6. FIG. 7. PMID:1731649

  19. Evaluation of National Institute for Learning Development and Discovery Educational Therapy Program

    ERIC Educational Resources Information Center

    Frimpong, Prince Christopher

    2014-01-01

    In Maryland, some Christian schools have enrolled students with learning disabilities (LDs) but do not have any interventional programs at the school to help them succeed academically. The purpose of this qualitative program evaluation was to evaluate the National Institute for Learning Development (NILD) and Discovery Therapy Educational Program…

  20. Formative Evaluation Research of Art-Based Supervision in Art Therapy Training

    ERIC Educational Resources Information Center

    Fish, Barbara J.

    2008-01-01

    Image making is a common component of art therapy supervision but its use has not yet been formally evaluated. This article describes formative evaluation research used to investigate student responses to art-based supervision in which response art was used as a primary method to contain, explore, or express clinical work. Art-based supervision,…

  1. Impact Evaluation of a Cognitive Behavioral Group Therapy Model in Brazilian Sexually Abused Girls

    ERIC Educational Resources Information Center

    Habigzang, Luisa Fernanda; Damasio, Bruno Figueiredo; Koller, Silvia Helena

    2013-01-01

    This study evaluated the impact of a cognitive behavioral group therapy model in Brazilian girls who had experienced sexual abuse. The effect of the waiting period before treatment and the enduring effectiveness of the treatment after six and 12 months were also evaluated. Forty-nine female sexual abuse victims between the ages of 9 and 16…

  2. Evaluating Photodynamic Therapy Efficacy Using Laser Induced Breakdown Spectroscopy

    NASA Astrophysics Data System (ADS)

    Fekry, O.; El-Batanouny, M. H.; El-Begawy, M. B.; Harith, M. A.

    2011-09-01

    Laser-induced breakdown spectroscopy (LIBS), is an excellent tool for trace elemental analysis, was exploited for a detecting concentrations of calcium and magnesium in malignant tissues before and after PDT. Calcium and magnesium concentrations are known tobe high in malignancy. Tissues were injected with methylene blue photosensitizer with concentrations 0.5%, 1% and 2%. Two different light sources were used with two different energy densities/each light sources. The results showed a decrease in tissue elements content after PDT application for both calcium and magnesium compared to before PDT application as shown in the tissue spectral lines' intensities which has been reflected in. Type of light source showed no effect on tissue elements content which showed slight differences among the different energy densities. It has been shown that LIBS technique can be adopted method to monitor tumor photodynamic therapy applications.

  3. Evaluation of social marketing of oral rehydration therapy.

    PubMed

    Koul, P B; Murali, M V; Gupta, P; Sharma, P P

    1991-09-01

    Attempts, at social marketing of oral rehydration therapy (ORT) through television, in changing the knowledge and practice of mothers with regard to its use was assessed. One hundred and eighty seven consecutive mothers (38 excluded due to non use of ORT) were administered a preplanned questionnaire to assess their socio-economic profile, educational status, concept of diarrhea and correct use of ORT. Fifty nine mothers who watched these programmes on TV regularly formed the study group. These were compared with 90 mothers who had gained such knowledge from non-television sources. The correct application of knowledge of ORT was significantly better in study group compared with control group. The educational status of mothers had a positive impact on motivation to use ORT at home in the study group. Mass media campaigns through "TV spots" is an effective way of improving knowledge of mothers on ORT in a developing country.

  4. Evaluation of social marketing of oral rehydration therapy.

    PubMed

    Koul, P B; Murali, M V; Gupta, P; Sharma, P P

    1991-09-01

    Attempts, at social marketing of oral rehydration therapy (ORT) through television, in changing the knowledge and practice of mothers with regard to its use was assessed. One hundred and eighty seven consecutive mothers (38 excluded due to non use of ORT) were administered a preplanned questionnaire to assess their socio-economic profile, educational status, concept of diarrhea and correct use of ORT. Fifty nine mothers who watched these programmes on TV regularly formed the study group. These were compared with 90 mothers who had gained such knowledge from non-television sources. The correct application of knowledge of ORT was significantly better in study group compared with control group. The educational status of mothers had a positive impact on motivation to use ORT at home in the study group. Mass media campaigns through "TV spots" is an effective way of improving knowledge of mothers on ORT in a developing country. PMID:1802837

  5. Evaluation of absorbed dose in Gadolinium neutron capture therapy

    NASA Astrophysics Data System (ADS)

    Abdullaeva, Gayane; Djuraeva, Gulnara; Kim, Andrey; Koblik, Yuriy; Kulabdullaev, Gairatulla; Rakhmonov, Turdimukhammad; Saytjanov, Shavkat

    2015-02-01

    Gadolinium neutron capture therapy (GdNCT) is used for treatment of radioresistant malignant tumors. The absorbed dose in GdNCT can be divided into four primary dose components: thermal neutron, fast neutron, photon and natural gadolinium doses. The most significant is the dose created by natural gadolinium. The amount of gadolinium at the irradiated region is changeable and depends on the gadolinium delivery agent and on the structure of the location where the agent is injected. To de- fine the time dependence of the gadolinium concentration ρ(t) in the irradiated region the pharmacokinetics of gadolinium delivery agent (Magnevist) was studied at intratumoral injection in mice and intramuscular injection in rats. A polynomial approximation was applied to the experimental data and the influence of ρ(t) on the relative change of the absorbed dose of gadolinium was studied.

  6. Development and evaluation of a virtual intensive therapy unit - VITU.

    PubMed

    Theodoropoulos, A; Kneebone, R; Dornan, B; Leonard, R; Bello, F

    2007-01-01

    Complex and safety critical healthcare environments like the Intensive Therapy Unit demand highly skilled professionals efficiently interacting with their technologically advanced surroundings and with each other. The ITU environment is daunting to newcomers and contains considerable potential for harm by inexpert treatment. In spite of this, current training is largely workplace based and depends upon observation and supervised practice with real patients. We propose the development of a distributed collaborative environment that recreates key elements of critical care. Centred on a 'virtual bedspace', team members will care for the patient in a way that accurately reflects actual practice and therefore minimises any learning gap. Graded exposure to increasing levels of complexity will ensure that collaborative learning takes place alongside each participant's clinical experience and complements it appropriately.

  7. Aerosol therapy in bronchopulmonary disease. A critical evaluation.

    PubMed

    OLSEN, A M

    1962-04-01

    AEROSOL THERAPY HAS THREE PRINCIPAL OBJECTIVES: Mobilization of bronchial secretions, relief of bronchospasm and topical chemotherapy. It has become an important tool in the treatment of bronchopulmonary diseases. The equipment for inhalation therapy, however, should be adequate. Both large-capacity and small-capacity nebulizers must be available, and they must be the kind that will produce a mist with most of its particles only 0.5 to 2.5 micra in diameter. These nebulizers may be used alone or in conjunction with a variety of appliances that will deliver the aerosols to the respiratory tract. The use of humidifying agents as aerosols is extremely helpful in patients with retained bronchopulmonary secretions. In some patients who have particularly thick or gelatinous secretions and in patients with mucoviscidosis, ordinary water or saline solution is often not enough. Hypertonic saline may be of value in these cases, and it is suggested that half-molar (2.9 per cent) saline be administered in 10 per cent propylene glycol. In these cases, preparations containing detergents (tyloxypal) or other preparations containing enzymes (desoxyribonuclease or trypsin) may be given by the aerosol technique, with care not to cause irritation. The bronchodilator aerosol agents are of proved benefit in the treatment of bronchospastic disorders and are indicated in most cases of asthma and in those cases of emphysema in which there is definite evidence of associated bronchospasm. The value of the aerosol method of administering chemotherapeutic and antibiotic drugs has probably been overrated, and it is suspected that much of the benefit previously attributed to the therapeutic agent was actually a result of humidification and liquefaction.

  8. The Alpha Stem Cell Clinic: A Model for Evaluating and Delivering Stem Cell-Based Therapies

    PubMed Central

    DeWitt, Natalie D.; Feigal, Ellen G.

    2012-01-01

    Summary Cellular therapies require the careful preparation, expansion, characterization, and delivery of cells in a clinical environment. There are major challenges associated with the delivery of cell therapies and high costs that will limit the companies available to fully evaluate their merit in clinical trials, and will handicap their application at the present financial environment. Cells will be manufactured in good manufacturing practice or near-equivalent facilities with prerequisite safety practices in place, and cell delivery systems will be specialized and require well-trained medical and nursing staff, technicians or nurses trained to handle cells once delivered, patient counselors, as well as statisticians and database managers who will oversee the monitoring of patients in relatively long-term follow-up studies. The model proposed for Alpha Stem Cell Clinics will initially use the capacities and infrastructure that exist in the most advanced tertiary medical clinics for delivery of established bone marrow stem cell therapies. As the research evolves, they will incorporate improved procedures and cell preparations. This model enables commercialization of medical devices, reagents, and other products required for cell therapies. A carefully constructed cell therapy clinical infrastructure with the requisite scientific, technical, and medical expertise and operational efficiencies will have the capabilities to address three fundamental and critical functions: 1) fostering clinical trials; 2) evaluating and establishing safe and effective therapies, and 3) developing and maintaining the delivery of therapies approved by the Food and Drug Administration, or other regulatory agencies. PMID:23197634

  9. Evaluation of Helicobacter Pylori eradication in pediatric patients by triple therapy plus lactoferrin and probiotics compared to triple therapy alone

    PubMed Central

    2012-01-01

    Background To evaluate whether the addition of a probiotic could improve Helicobacter pylori (H.P.) eradication rates and reduce the side effects of treatment in children. Methods Between July 2008 and July 2011 all patients with a clinical, laboratory and endoscopic diagnosis of H.P. positive gastritis referred to our Unit were included in the study. Patients suffering from allergy to any of drugs used in the study, with previous attempts to eradicate H.P. and those who received antibiotics, PPIs or probiotics within 4 weeks were excluded from the present study. Patients were randomized into two therapy regimens (group A and B): both groups received standard triple treatment (omeprazole, amoxicillin and clarithromycin) while only group B patients were also given a probiotic (Probinul - Cadigroup). Patients compliance was evaluated at the end of the treatment. Successful eradication was defined as a negative 13 C-urea breath test (C13-ubt) result four weeks after therapy discontinuation. Results A total of 68 histopathologically proven H.P.-infection children (32 male and 36 females) were included in the study. All of the patients in both groups used more than 90% of the therapies and no patients were lost at follow up. All side effects were selflimiting and disappeared once the therapy was terminated. Epigastric pain was observed in 6 (17.6%) group A vs 2 (5.8%) group B patients (P<0.05), nausea in 3 (8.8%) group A vs 1 (2.9%) group B patients (P<0.05); vomiting and diarrhea were observed in 2(5.8%) and 8 (23.5%) group A patients, respectively and never in group B (P<0.05). There was no significant difference between the two groups in terms of constipation (5.8% in group A and B). Four weeks after the completion of therapy, 56/68 patients (82.3%) tested negative for H.P. on C13-ubt. H.P. was eradicated in 26 patients (76.4%) in group A and in 30 patients (88.2%) in group B. There was no significantly difference in the rate of H.P. eradication between group A and

  10. Impact of region contouring variability on image-based focal therapy evaluation

    NASA Astrophysics Data System (ADS)

    Gibson, Eli; Donaldson, Ian A.; Shah, Taimur T.; Hu, Yipeng; Ahmed, Hashim U.; Barratt, Dean C.

    2016-03-01

    Motivation: Focal therapy is an emerging low-morbidity treatment option for low-intermediate risk prostate cancer; however, challenges remain in accurately delivering treatment to specified targets and determining treatment success. Registered multi-parametric magnetic resonance imaging (MPMRI) acquired before and after treatment can support focal therapy evaluation and optimization; however, contouring variability, when defining the prostate, the clinical target volume (CTV) and the ablation region in images, reduces the precision of quantitative image-based focal therapy evaluation metrics. To inform the interpretation and clarify the limitations of such metrics, we investigated inter-observer contouring variability and its impact on four metrics. Methods: Pre-therapy and 2-week-post-therapy standard-of-care MPMRI were acquired from 5 focal cryotherapy patients. Two clinicians independently contoured, on each slice, the prostate (pre- and post-treatment) and the dominant index lesion CTV (pre-treatment) in the T2-weighted MRI, and the ablated region (post-treatment) in the dynamic-contrast- enhanced MRI. For each combination of clinician contours, post-treatment images were registered to pre-treatment images using a 3D biomechanical-model-based registration of prostate surfaces, and four metrics were computed: the proportion of the target tissue region that was ablated and the target:ablated region volume ratio for each of two targets (the CTV and an expanded planning target volume). Variance components analysis was used to measure the contribution of each type of contour to the variance in the therapy evaluation metrics. Conclusions: 14-23% of evaluation metric variance was attributable to contouring variability (including 6-12% from ablation region contouring); reducing this variability could improve the precision of focal therapy evaluation metrics.

  11. HIV-1 Tat Promotes Integrin-Mediated HIV Transmission to Dendritic Cells by Binding Env Spikes and Competes Neutralization by Anti-HIV Antibodies

    PubMed Central

    Monini, Paolo; Cafaro, Aurelio; Srivastava, Indresh K.; Moretti, Sonia; Sharma, Victoria A.; Andreini, Claudia; Chiozzini, Chiara; Ferrantelli, Flavia; Cossut, Maria R. Pavone.; Tripiciano, Antonella; Nappi, Filomena; Longo, Olimpia; Bellino, Stefania; Picconi, Orietta; Fanales-Belasio, Emanuele; Borsetti, Alessandra; Toschi, Elena; Schiavoni, Ilaria; Bacigalupo, Ilaria; Kan, Elaine; Sernicola, Leonardo; Maggiorella, Maria T.; Montin, Katy; Porcu, Marco; Leone, Patrizia; Leone, Pasqualina; Collacchi, Barbara; Palladino, Clelia; Ridolfi, Barbara; Falchi, Mario; Macchia, Iole; Ulmer, Jeffrey B.; Buttò, Stefano; Sgadari, Cecilia; Magnani, Mauro; Federico, Maurizio P. M.; Titti, Fausto; Banci, Lucia; Dallocchio, Franco; Rappuoli, Rino; Ensoli, Fabrizio; Barnett, Susan W.; Garaci, Enrico; Ensoli, Barbara

    2012-01-01

    Use of Env in HIV vaccine development has been disappointing. Here we show that, in the presence of a biologically active Tat subunit vaccine, a trimeric Env protein prevents in monkeys virus spread from the portal of entry to regional lymph nodes. This appears to be due to specific interactions between Tat and Env spikes that form a novel virus entry complex favoring R5 or X4 virus entry and productive infection of dendritic cells (DCs) via an integrin-mediated pathway. These Tat effects do not require Tat-transactivation activity and are blocked by anti-integrin antibodies (Abs). Productive DC infection promoted by Tat is associated with a highly efficient virus transmission to T cells. In the Tat/Env complex the cysteine-rich region of Tat engages the Env V3 loop, whereas the Tat RGD sequence remains free and directs the virus to integrins present on DCs. V2 loop deletion, which unshields the CCR5 binding region of Env, increases Tat/Env complex stability. Of note, binding of Tat to Env abolishes neutralization of Env entry or infection of DCs by anti-HIV sera lacking anti-Tat Abs, which are seldom present in natural infection. This is reversed, and neutralization further enhanced, by HIV sera containing anti-Tat Abs such as those from asymptomatic or Tat-vaccinated patients, or by sera from the Tat/Env vaccinated monkeys. Thus, both anti-Tat and anti-Env Abs are required for efficient HIV neutralization. These data suggest that the Tat/Env interaction increases HIV acquisition and spreading, as a mechanism evolved by the virus to escape anti-Env neutralizing Abs. This may explain the low effectiveness of Env-based vaccines, which are also unlikely to elicit Abs against new Env epitopes exposed by the Tat/Env interaction. As Tat also binds Envs from different clades, new vaccine strategies should exploit the Tat/Env interaction for both preventative and therapeutic interventions. PMID:23152803

  12. The evaluation of gastroesophageal reflux before and after medical therapies

    SciTech Connect

    Malmud, L.S.; Fisher, R.S.

    1981-07-01

    Gastroesophageal scintigraphy is a quantitative technique that can be employed to detect and quantitate gastroesophageal reflux before and after the application of therapeutic modalities, including change in body position, bethanechol, atropine, antacids, and antacid-alginate compounds. Five groups of 10-15 patients each were studied before and after using each therapeutic modality and before and after atropine. The results were compared to the patient's symptomatology and to the acid reflux test. Gastroesophageal scintigraphy was performed following oral administration of 300 microCi 99mTc-sulfur colloid in 300 ml acidified orange juice. Thirty-second gamma camera images were obtained as the gastroesophageal gradient was increased from approximately 10 to 35 mm Hg at 5 mm Hg increments using an inflatable abdominal binder. Data were processed using a digital computer. Reflux was reduced by change in position from recumbent to upright, and by the use of subcutaneous bethanechol, oral antacid, or oral antacidalginate compound. Atropine increased reflux. Gastroesophageal scintigraphy is more sensitive than fluoroscopy, correlates well with clinical symptomatology, and is a reliable and convenient technique for the quantitative estimation of reflux before and after therapy.

  13. Behavior therapy in drug abuse treatment: review and evaluation.

    PubMed

    Stitzer, M L; Bigelow, G E; McCaul, M E

    1985-01-01

    The goal of drug abuse treatment is to decrease the dominance of drug-related behaviors while enhancing the dominance of alternative socially acceptable behaviors. The behavioral techniques of extinction, satiation, and punishment can be used to suppress undesirable behaviors, and reinforcement can be used to enhance desirable behaviors. Methadone maintenance offers unique advantages for treatment of opiate abuse since methadone satiates the drug abuser, thereby reducing the reinforcing efficacy of illicit opiate drugs, while also serving as a reinforcer whose delivery in the treatment setting can be used in contingent arrangements. Short-term efficacy has been demonstrated in studies that used contingent treatment termination or contingent dose decreases as punishing events and contingent dose increases or contingent take-home privileges as reinforcing events to promote reductions in drug use and cooperation with clinic rules. Systematic use of dose adjustments and take-home privileges may be a useful adjunct to methadone maintenance treatment, having a positive impact both on client outcomes and clinic operation. Rehabilitation efforts might also benefit if delivery of reinforcers available at the clinic is contingent upon participation in skills training and therapy programs or community activities outside the drug abuse clinic. PMID:3929125

  14. Immune-based therapies in brief.

    PubMed

    2000-03-01

    Immune-based therapy is considered by many to be the "holy grail" of AIDS research. Most successful therapies to date have been anti-HIV drugs that suppress reproduction of HIV, the virus that causes AIDS. Success, however, usually comes at the price of many side effects. Researchers and patients alike have longed for therapy that doesn't so much try to wage war against the virus, but rather strengthens the weakening immune response associated with AIDS. The hope is that such an approach might be more natural or less toxic. Although health food stores offer an abundance of products that claim to "boost" or "strengthen" immunity, those are mostly just advertising claims. Helping the immune system in its battle against HIV is far more complex than simply "boosting" anything.

  15. Preclinical Evaluation of Bioabsorbable Polyglycolic Acid Spacer for Particle Therapy

    SciTech Connect

    Akasaka, Hiroaki; Sasaki, Ryohei; Miyawaki, Daisuke; Mukumoto, Naritoshi; Sulaiman, Nor Shazrina Binti; Nagata, Masaaki; Yamada, Shigeru; Murakami, Masao; Demizu, Yusuke; Fukumoto, Takumi

    2014-12-01

    Purpose: To evaluate the efficacy and safety of a polyglycolic acid (PGA) spacer through physical and animal experiments. Methods and Materials: The spacer was produced with surgical suture material made of PGA, forming a 3-dimensional nonwoven fabric. For evaluation or physical experiments, 150-MeV proton or 320-MeV carbon-ion beams were used to generate 60-mm width of spread-out Bragg peak. For animal experiments, the abdomens of C57BL/6 mice, with or without the inserted PGA spacers, were irradiated with 20 Gy of carbon-ion beam (290 MeV) using the spread-out Bragg peak. Body weight changes over time were scored, and radiation damage to the intestine was investigated using hematoxylin and eosin stain. Blood samples were also evaluated 24 days after the irradiation. Long-term thickness retention and safety were evaluated using crab-eating macaques. Results: No chemical or structural changes after 100 Gy of proton or carbon-ion irradiation were observed in the PGA spacer. Water equivalency of the PGA spacer was equal to the water thickness under wet condition. During 24 days' observation after 20 Gy of carbon-ion irradiation, the body weights of mice with the PGA spacer were relatively unchanged, whereas significant weight loss was observed in those mice without the PGA spacer (P<.05). In mice with the PGA spacer, villus and crypt structure were preserved after irradiation. No inflammatory reactions or liver or renal dysfunctions due to placement of the PGA spacer were observed. In the abdomen of crab-eating macaques, thickness of the PGA spacer was maintained 8 weeks after placement. Conclusions: The absorbable PGA spacer had water-equivalent, bio-compatible, and thickness-retaining properties. Although further evaluation is warranted in a clinical setting, the PGA spacer may be effective to stop proton or carbon-ion beams and to separate normal tissues from the radiation field.

  16. Assembling different antennas of the gp120 high mannose-type glycans on gold nanoparticles provides superior binding to the anti-HIV antibody 2G12 than the individual antennas.

    PubMed

    Chiodo, Fabrizio; Enríquez-Navas, Pedro M; Angulo, Jesús; Marradi, Marco; Penadés, Soledad

    2015-03-20

    In order to re-build Man9GlcNAc2 clusters of the HIV gp120 glycoprotein, ∼2 nm gold glyconanoparticles (GNPs) were coated with the synthetic partial structures of Man9, the tetramannoside Manα1-2Manα1-2Manα1-3Manα1- and the pentamannoside Manα1-2Manα1-3[Manα1-2Manα1-6]Manα1-. Their interactions with the anti-HIV broadly neutralizing antibody 2G12 were studied by surface plasmon resonance (SPR)-based biosensors and saturation transfer difference (STD)-NMR spectroscopy. A synergistic effect of the tetra- and pentamannosides multimerized on a same GNP was observed. The assembly of these antennas of the gp120 high-mannose type glycan on GNPs provided superior binding to the anti-HIV antibody 2G12 with respect to GNPs carrying only the individual oligomannosides. The results presented in this work provide new molecular information on the interactions between clusters of oligomannosides and 2G12 that could help in the design of a carbohydrate-based vaccine against HIV.

  17. QSAR Study on Anti-HIV-1 Activity of 4-Oxo-1,4-dihydroquinoline and 4-Oxo-4H-pyrido[1,2-a]pyrimidine Derivatives Using SW-MLR, Artificial Neural Network and Filtering Methods

    PubMed Central

    Hajimahdi, Zahra; Ranjbar, Amin; Abolfazl Suratgar, Amir; Zarghi, Afshin

    2015-01-01

    Predictive quantitative structure–activity relationship was performed on the novel4-oxo-1,4-dihydroquinoline and 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives to explore relationship between the structure of synthesized compounds and their anti-HIV-1 activities. In this way, the suitable set of the molecular descriptors was calculated and the important descriptors using the variable selections of the stepwise technique were selected. Multiple linear regression (MLR) and artificial neural network (ANN) as nonlinear system were used for constructing QSAR models. The predictive quality of the quantitative structure–activity relationship models was tested for an external set of five compounds, randomly chosen out of 25 compounds. The findings exhibited that stepwise-ANN model was more efficient at prediction activity of both training and test sets with high statistical qualities. Based on QSAR models results, electronegativity, the atomic masses, the atomic van der Waals volumes, the molecular symmetry and polarizability were found to be important factors controlling the anti-HIV-1 activity. PMID:26185507

  18. [Torticollis spasmodicus, blepharospasm and hemifacial spasm. Subjective evaluation of therapy by patients].

    PubMed

    Birner, P; Schnider, P; Müller, J; Wissel, J; Fuchs, I; Auff, E

    1999-10-01

    Injections with botulinum toxin type A (BTX) are considered the first-line treatment for spasmodic torticollis (ST), blepharospasm (BL) and hemifacial spasm (HFS). Because BTX brings only temporary and partial relief, patients frequently try other additional therapies to minimize their symptoms. The subjective rating of all therapies ever tried by patients with ST, BL and HFS was evaluated by using a simple questionnaire. Two hundred questionnaires were considered (112 TS, 54 BL, 34 HFS). BTX was rated subjectively the best therapy in all three diagnostic groups (median: 2 = good effect). Despite Citalopram and physiotherapy (median: 3 = average effect), all other therapies were rated with a median of > or = 4 (= minimal effect). Patients with ST tried 7.7, patients with BL 2.4 and patients with HFS 2.6 different types of therapy. In conclusion, BTX is the most effective treatment for patients with ST, BL and HFS, as rated subjectively. Further evaluation of therapies additional to BTX injections is recommended.

  19. Evaluation and Targeted Therapy of Voiding Dysfunction in Children.

    PubMed

    Palmer, Lane S

    2016-06-01

    Significant strides have been made over the past two decades in more precisely evaluating and managing children with voiding complaints. A thorough history should offer insight into the possible causes for the presenting complaints and this should be supplemented by physical examination, urine studies, and select imaging. Uroflowmetry and external sphincter electromyography with measurement of postvoid residual urine should allow for accurate diagnosis using categories offered by the International Children's Continence Society. This ability to make an accurate diagnosis should naturally lead to the use of treatment options (urotherapy, pharmacotherapy, biofeedback, and neuromodulation) that specifically target the responsible cause of the complaints rather than simply their symptoms.

  20. Evaluating the cost of therapy for restenosis: considerations for brachytherapy.

    PubMed

    Weintraub, W S

    1996-11-01

    Costs have become increasingly important in medicine in recent years as demand for services has outstripped readily available resources. Clinical microeconomics offers an approach to understanding cost and outcomes in an environment of economic scarcity. In this article the types of costs and methods for determining cost are presented. In addition, methods for assessing outcome and outcome in relation to cost are developed. Restenosis after coronary angioplasty is a prime example of a clinical problem requiring economic evaluation. This is because it results in little serious morbidity except for recurrent chest pain, but it has serious economic consequences which occur some time after the original angioplasty. This makes the economic assessment of restenosis complicated. The application of health care microeconomic principles to brachytherapy for restenosis in the coronary arteries is presented. PMID:8960526

  1. Cryoultrasound therapy and tendonitis in athletes: a comparative evaluation versus laser CO2 and t.e.ca.r. therapy.

    PubMed

    Costantino, Cosimo; Pogliacomi, Francesco; Vaienti, Enrico

    2005-04-01

    Aim of this study is to compare the different kinds of tendonitis in athletes using cryoultrasound therapy, lasertherapy CO2 and t.e.ca.r. therapy (transfert energetic capacitive and resistive). Forty five athletes were selected; they were all affected by severe insertional tendonitis of the Achilles tendon (15 of them), of the patellar tendon (15 of them) and of the epicondylar region (15 of them) during the last two months. They were divided into three groups. The first group underwent a treatment of 12 lasertherapy CO2 sessions, the second group 12 cryoultrasound therapy sessions and the last group 12 t.e.ca.r. therapy sessions. Each patient was registered by an independent observer according to the pain before (initial V.A.S.) and after treatment (final V.A.S.) using the analogic visual range from 0 (lack of pain) to 10 (unbearable pain) and the indicator of efficacy (difference between initial V.A.S. and final V.A.S./initial V.A.S.x 100). The obtained results were expressed as a difference between the two V.A.S. values and as a parameter of effectiveness (value ranging from 0 to 100) in order to correlate the initial condition of the patients with the performed physiotherapic treatment. The obtained V.A.S. score was submitted to statistic evaluation by analysis of variance through repeated measures, taking into consideration a value of p<0.05. Possible differences among the group of patients were shown by analysis of variance through one single way by comparison among groups. Every patient benefited from the treatment. Analyzing the initial and final V.A.S. values in the three groups, statistically significant variations emerged (p<0.05). A meaningful difference resulted among the different kinds of treatment; a marked difference was noticed between laser CO2 and cryoultrasound therapy (p<0.01). No statistically significant differences were observed between t.e.ca.r. and laser CO2 therapy or between t.e.ca.r. and cryoultrasound therapy. It must be admitted

  2. Quality and Reporting of Cluster Randomized Controlled Trials Evaluating Occupational Therapy Interventions

    PubMed Central

    Tokolahi, Ema; Hocking, Clare; Kersten, Paula; Vandal, Alain C.

    2015-01-01

    Growing use of cluster randomized control trials (RCTs) in health care research requires careful attention to study designs, with implications for the development of an evidence base for practice. The objective of this study is to investigate the characteristics, quality, and reporting of cluster RCTs evaluating occupational therapy interventions to inform future research design. An extensive search of cluster RCTs evaluating occupational therapy was conducted in several databases. Fourteen studies met our inclusion criteria; four were protocols. Eleven (79%) justified the use of a cluster RCT and accounted for clustering in the sample size and analysis. All full studies reported the number of clusters randomized, and five reported intercluster correlation coefficients (50%): Protocols had higher compliance. Risk of bias was most evident in unblinding of participants. Statistician involvement was associated with improved trial quality and reporting. Quality of cluster RCTs of occupational therapy interventions is comparable with those from other areas of health research and needs improvement. PMID:27504689

  3. Quantitative Measures for Evaluation of Ultrasound Therapies of the Prostate

    NASA Astrophysics Data System (ADS)

    Kobelevskiy, Ilya; Burtnyk, Mathieu; Bronskill, Michael; Chopra, Rajiv

    2010-03-01

    Development of non-invasive techniques for prostate cancer treatment requires implementation of quantitative measures for evaluation of the treatment results. In this paper. we introduce measures that estimate spatial targeting accuracy and potential thermal damage to the structures surrounding the prostate. The measures were developed for the technique of treating prostate cancer with a transurethral ultrasound heating applicators guided by active MR temperature feedback. Variations of ultrasound element length and related MR imaging parameters such as MR slice thickness and update time were investigated by performing numerical simulations of the treatment on a database of ten patient prostate geometries segmented from clinical MR images. Susceptibility of each parameter configuration to uncertainty in MR temperature measurements was studied by adding noise to the temperature measurements. Gaussian noise with zero mean and standard deviation of 0, 1, 3 and 5° C was used to model different levels of uncertainty in MR temperature measurements. Results of simulations for each parameter configuration were averaged over the database of the ten prostate patient geometries studied. Results have shown that for update time of 5 seconds both 3- and 5-mm elements achieve appropriate performance for temperature uncertainty up to 3° C, while temperature uncertainty of 5° C leads to noticeable reduction in spatial accuracy and increased risk of damaging rectal wall. Ten-mm elements lacked spatial accuracy and had higher risk of damaging rectal wall compared to 3- and 5-mm elements, but were less sensitive to the level of temperature uncertainty. The effect of changing update time was studied for 5-mm elements. Simulations showed that update time had minor effects on all aspects of treatment for temperature uncertainty of 0° C and 1° C, while temperature uncertainties of 3° C and 5° C led to reduced spatial accuracy, increased potential damage to the rectal wall, and

  4. Clinical parameters for evaluating biological response modifier therapy.

    PubMed

    Hamblin, T J

    1989-01-01

    Evaluating response in cancer is a well established practice, depending on the recognition of complete response, partial response, stable disease and progressive disease. For chemotherapeutic drugs, only those patients achieving a complete response experience an increase in survival. Partial response merely indicates that the drug has some activity in that disease. What the patient wants is not active drugs but prolonged survival with good quality of life. It is well recognised that tumours may remain dormant for many years, and that even those patients with complete responses to chemotherapy usually have minimal residual disease. It is assumed that such minimal disease is controlled and held in check by a biological process. The principal aim of biological response modifiers is to enhance this effect so as to control an even larger tumour load. It therefore follows that removal of all tumour is not the only benefit, and that stable disease and even slower progression might translate to longer survival. Survival curves are the acid test and we should expect longer survival even for those patients failing to achieve complete response if we are to establish that life imprisonment is as effective in cancer treatment as capital punishment.

  5. Utilizing ambulatory blood pressure recordings to evaluate antihypertensive drug therapy.

    PubMed

    White, W B

    1992-04-30

    Until recently, the efficacy and pharmacodynamics of antihypertensive agents were assessed by resting blood pressure measurements in the doctor's office or a research clinic. The limitations of the office or clinic blood pressure measurement include the lack of representation (from recording only 1 point of time in the dosing schedule), the effects of the doctor's office on the patient's blood pressure, and, perhaps more relevant, observer bias. Ambulatory monitoring of the blood pressure has gained worldwide acceptance as an alternative method to assess antihypertensive drug efficacy and the time-effect relation of a drug. The ambulatory monitoring devices have been refined and are smaller, more precise, and more reliable than earlier recording models. Although there are no reference standards for analysis of ambulatory blood pressure data, international consensus groups are presently addressing this problem. Key roles for ambulatory blood pressure recordings in clinical trials of antihypertensive agents now include determination of the entry criteria for patients, improving the assessment of peak/trough pharmacodynamics in the patient's own environment (including nocturnal/sleep readings), and evaluating efficacy through calculation of the hypertensive burden, or blood pressure load. PMID:1575177

  6. A Comparison of Methods Used to Evaluate Intakes of Transuranics Influenced by Chelation Therapy

    SciTech Connect

    La Bone, T.

    2002-05-14

    A comparison of methods is used to evaluate the intake of transuranics influenced by chelation therapy. The purpose of this paper is to introduce the mechanistic method by using it to validate Hall's method and Jech's method. This is accomplished by using the mechanistic method to generate a known set of data suitable for benchmarking all three methods.

  7. Implementing Cognitive Behavioral Therapy for Chronic Fatigue Syndrome in a Mental Health Center: A Benchmarking Evaluation

    ERIC Educational Resources Information Center

    Scheeres, Korine; Wensing, Michel; Knoop, Hans; Bleijenberg, Gijs

    2008-01-01

    Objective: This study evaluated the success of implementing cognitive behavioral therapy (CBT) for chronic fatigue syndrome (CFS) in a representative clinical practice setting and compared the patient outcomes with those of previously published randomized controlled trials (RCTs) of CBT for CFS. Method: The implementation interventions were the…

  8. Music Therapy Evaluation Study for Department of Health and Welfare Demonstration Projects.

    ERIC Educational Resources Information Center

    Kenny, Carolyn, Ed.

    Reported are the findings of a project to evaluate the effectiveness of music therapy with disturbed or otherwise handicapped individuals in a number of different clinical settings. Following an introduction which outlines the project's objectives, a brief section discusses research methodology. The remainder of the document includes a larger…

  9. Art Enrichment: Evaluating a Collaboration between Head Start and a Graduate Art Therapy Program

    ERIC Educational Resources Information Center

    Klorer, P. Gussie; Robb, Megan

    2012-01-01

    Head Start, a U.S. federally funded program, prepares children for school through early childhood intervention in social-emotional and cognitive arenas. This article describes program evaluation survey results from the past 5 years of an 18-year collaboration between a university graduate art therapy program and 8 Head Start centers. Graduate art…

  10. Evaluation of an Occupational Therapy Mentorship Program: Effects on Therapists' Skills and Family-Centered Behavior

    ERIC Educational Resources Information Center

    King, Gillian; Tam, Cynthia; Fay, Linda; Pilkington, Martha; Servais, Michelle; Petrosian, Hasmik

    2011-01-01

    There is growing interest in understanding the usefulness of mentorship programs for children's rehabilitation service providers. This evaluation study examined the effects of an occupational therapy mentorship program on the skills and behaviors of 8 new and 17 experienced occupational therapists practicing at a regional children's rehabilitation…

  11. Acceptance and Commitment Therapy for Self-Stigma around Sexual Orientation: A Multiple Baseline Evaluation

    ERIC Educational Resources Information Center

    Yadavaia, James E.; Hayes, Steven C.

    2012-01-01

    This study evaluated the effectiveness of 6 to 10 sessions of Acceptance and Commitment Therapy (ACT) for self-stigma around sexual orientation linked to same-sex attraction (what has generally been referred to as internalized homophobia; IH) in a concurrent multiple-baseline across-participants design. Three men and 2 women showed sizeable…

  12. An Art Program Evaluation of Daily Life Therapy for Children with Autism

    ERIC Educational Resources Information Center

    Talusan-Dunn, Rowena

    2012-01-01

    The author evaluated a private school's art program in 2009-2010 that used Daily Life Therapy (DLT) for students diagnosed with autism spectrum disorders (ASD). Significant increases in numbers of persons diagnosed with ASD have been noted in the last two decades. Several methodologies claim success in programming for children with ASD, but lack…

  13. Synthesis, Anti-HIV Activity, and Metabolic Stability of New Alkenyldiarylmethane (ADAM) HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

    PubMed Central

    Deng, Bo-Liang; Hartman, Tracy L.; Buckheit, Robert W.; Pannecouque, Christophe; De Clercq, Erik; Fanwick, Phillip E.; Cushman, Mark

    2008-01-01

    Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are part of the combination therapy currently used to treat HIV infection. Based on analogy with known HIV-1 NNRT inhibitors, eighteen novel alkenyldiarylmethanes (ADAMs) containing 5-chloro-2-methoxyphenyl, 3-cyanophenyl or 3-fluoro-5-trifluoromethylphenyl groups were synthesized and evaluated as HIV inhibitors. Their stabilities in rat plasma have also been investigated. Although introducing 5-chloro-2-methoxyphenyl, or 3-fluoro-5-trifluoromethylphenyl groups into alkenyldiarylmethanes does not maintain the antiviral potency, the structural modification of alkenyldiarylmethanes with a 3-cyanophenyl substituent can be made without a large decrease in activity. The oxazolidinonyl group was introduced into the alkenyldiarylmethane framework and found to confer enhanced metabolic stability in rat plasma. PMID:16162014

  14. Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor.

    PubMed

    Dousson, Cyril; Alexandre, François-René; Amador, Agnès; Bonaric, Séverine; Bot, Stéphanie; Caillet, Catherine; Convard, Thierry; da Costa, Daniel; Lioure, Marie-Pierre; Roland, Arlène; Rosinovsky, Elodie; Maldonado, Sébastien; Parsy, Christophe; Trochet, Christophe; Storer, Richard; Stewart, Alistair; Wang, Jingyang; Mayes, Benjamin A; Musiu, Chiara; Poddesu, Barbara; Vargiu, Luana; Liuzzi, Michel; Moussa, Adel; Jakubik, Jocelyn; Hubbard, Luke; Seifer, Maria; Standring, David

    2016-03-10

    Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant.

  15. Development of Lentiviral Vectors Simultaneously Expressing Multiple siRNAs Against CCR5, vif and tat/rev Genes for an HIV-1 Gene Therapy Approach.

    PubMed

    Spanevello, Francesca; Calistri, Arianna; Del Vecchio, Claudia; Mantelli, Barbara; Frasson, Chiara; Basso, Giuseppe; Palù, Giorgio; Cavazzana, Marina; Parolin, Cristina

    2016-04-19

    Gene therapy holds considerable promise for the functional cure of HIV-1 infection and, in this context, RNA interference (RNAi)-based approaches represent powerful strategies. Stable expression of small interfering RNAs (siRNAs) targeting HIV genes or cellular cofactors has the potential to render HIV-1 susceptible cells resistant to infection. To inhibit different steps of virus life cycle, self-inactivating lentiviral vectors expressing multiple siRNAs targeting the CCR5 cellular gene as well as vif and tat/rev viral transcripts, under the control of different RNA polymerase III promoters (U6, 7SK, H1) were developed. The use of a single RNA polymerase III promoter driving the expression of a sequence giving rise to three siRNAs directed against the selected targets (e-shRNA) was also investigated. Luciferase assay and inhibition of HIV-1 replication in human Jurkat T-cell line were adopted to select the best combination of promoter/siRNA. The efficacy of selected developed combinatorial vectors in interfering with viral replication was evaluated in human primary CD4(+) T lymphocytes. We identified two effective anti-HIV combinatorial vectors that conferred protection against R5- and X4- tropic viruses. Overall, our results showed that the antiviral effect is influenced by different factors, including the promoter used to express the RNAi molecules and the selected cassette combination. These findings contribute to gain further insights in the design of RNAi-based gene therapy approaches against HIV-1 for clinical application.

  16. Structural and Thermodynamic Basis of Epitope Binding by Neutralizing and Nonneutralizing Forms of the Anti-HIV-1 Antibody 4E10

    PubMed Central

    Rujas, Edurne; Gulzar, Naveed; Morante, Koldo; Tsumoto, Kouhei; Scott, Jamie K.

    2015-01-01

    ABSTRACT The 4E10 antibody recognizes the membrane-proximal external region (MPER) of the HIV-1 Env glycoprotein gp41 transmembrane subunit, exhibiting one of the broadest neutralizing activities known to date. The neutralizing activity of 4E10 requires solvent-exposed hydrophobic residues at the apex of the complementarity-determining region (CDR) H3 loop, but the molecular basis for this requirement has not been clarified. Here, we report the cocrystal structures and the energetic parameters of binding of a peptide bearing the 4E10-epitope sequence (4E10ep) to nonneutralizing versions of the 4E10 Fab. Nonneutralizing Fabs were obtained by shortening and decreasing the hydrophobicity of the CDR-H3 loop (termed ΔLoop) or by substituting the two tryptophan residues of the CDR-H3 apex with Asp residues (termed WDWD), which also decreases hydrophobicity but preserves the length of the loop. The analysis was complemented by the first crystal structure of the 4E10 Fab in its ligand-free state. Collectively, the data ruled out major conformational changes of CDR-H3 at any stage during the binding process (equilibrium or transition state). Although these mutations did not impact the affinity of wild-type Fab for the 4E10ep in solution, the two nonneutralizing versions of 4E10 were deficient in binding to MPER inserted in the plasma membrane (mimicking the environment faced by the antibody in vivo). The conclusions of our structure-function analysis strengthen the idea that to exert effective neutralization, the hydrophobic apex of the solvent-exposed CDR-H3 loop must recognize an antigenic structure more complex than just the linear α-helical epitope and likely constrained by the viral membrane lipids. IMPORTANCE The broadly neutralizing anti-HIV-1 4E10 antibody blocks infection caused by nearly all viral strains and isolates examined thus far. However, 4E10 (or 4E10-like) antibodies are rarely found in HIV-1-infected individuals or elicited through vaccination

  17. The Utility of 3D Ultramicroscopy for Evaluating Cellular Therapies After Spinal Cord Injury

    PubMed Central

    Ghosh, M.; Jährling, N.; Henao, M.C.; Dodt, H-U; Pearse, D.D.

    2012-01-01

    Cell therapies have shown promise for repairing the injured spinal cord in experimental models and are now being evaluated in clinical trials for the treatment of human spinal cord injury (SCI). To date, experimental evaluation of implanted cell survival, migration, and integration within the injured central nervous system (CNS) of animals has been technically demanding, requiring tissue sectioning, staining, imaging, and manual reconstruction of 2-dimensional (2D) specimens in 3 dimensions (3D). Not only are these histological procedures laborious and fraught with processing artifacts during manual 3D reconstruction, but they are time-intensive. Herein we describe the utility of 3D ultramicroscopy for assessment of cell therapies after SCI, a new state-of-the-art imaging modality in which whole brain and spinal cord samples are optically sectioned to allow evaluation of intact, macroscopic specimens with microscopic resolution. PMID:23459000

  18. Ectopic expression of anti-HIV-1 shRNAs protects CD8{sup +} T cells modified with CD4ζ CAR from HIV-1 infection and alleviates impairment of cell proliferation

    SciTech Connect

    Kamata, Masakazu; Kim, Patrick Y.; Ng, Hwee L.; Ringpis, Gene-Errol E.; Kranz, Emiko; Chan, Joshua; O'Connor, Sean; Yang, Otto O.; Chen, Irvin S.Y.

    2015-07-31

    Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity to immune effector T cells. As an HIV-1-specific CAR, CD4ζ CAR has been extensively tested in vitro as well as in clinical trials. T cells modified with this CAR mediated highly potent anti-HIV-1 activities in vitro and were well-tolerated in vivo, but exerted limited effects on viral load and reservoir size due to poor survival and/or functionality of the transduced cells in patients. We hypothesize that ectopic expression of CD4ζ on CD8{sup +} T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8{sup +} T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8{sup +} T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24{sup Gag} in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8{sup +} T cells was reduced relative to control cells upon HIV-1 infection. To protect these cells from HIV-1 infection, we co-expressed two anti-HIV-1 shRNAs previously developed by our group together with CD4ζ. This combination vector was able to suppress HIV-1 infection without impairing HIV-1-dependent effector activities of CD4ζ. In addition, the number of CD4ζ-modified CD8{sup +} T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8{sup +} T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. - Highlights: • Ectopic expression of CD4ζ CAR in CD8{sup +} T cells renders them susceptible to HIV-1 infection. • Co-expression of two anti-HIV-1 shRNAs protects CD4ζ CAR-modified CD8{sup +} T cells from HIV-1 infection. • Protecting CD4ζ CAR-modified CD8{sup +} T cells from HIV-1 infection suppresses its cytopathic effect.

  19. Evaluation of Leber's hereditary optic neuropathy patients prior to a gene therapy clinical trial

    PubMed Central

    Yang, Shuo; Yang, Hong; Ma, Si-qi; Wang, Shuai-shuai; He, Heng; Zhao, Min-jian; Li, Bin

    2016-01-01

    Abstract Gene therapy may be a promising approach for the treatment of Leber hereditary optic neuropathy. The aim of this study was to evaluate patients with this condition who were recruited into an upcoming gene therapy clinical trial and to assess any changes in the detection parameters to provide support for the clinical trial. Sixteen patients with Leber hereditary optic neuropathy were evaluated using visual function tests 12 months before the initiation of gene therapy. Then, the results of visual acuity (VA), visual field (VF), RNFL (retinal nerve fiber layer) thickness, and Pattern-reversal Visual evoked potential (PR-VEP) were compared and analyzed. A total of 32 eyes of 16 patients were evaluated. Based on the best-corrected visual acuity (BCVA), 24 eyes were relatively stable compared with the baseline evaluation, and 8 eyes had significant changes, including 5 eyes that showed improvement and 3 eyes that showed impairment. In all eyes, the changes in the best-corrected visual acuity were significantly correlated with the changes in the visual field index (VFI), mean defect (MD), and P100 of the visual evoked potential. In the eyes with relatively stable BCVA and those with an obvious improvement in the BCVA, only the visual mean defect showed a significant change; the other indicators were not significantly different. Aside from the patients showing a tendency of spontaneous improvement, the others were in accordance with the requirement. The effects of Leber hereditary optical neuropathy (LHON) gene therapy should be evaluated primarily based on visual acuity. Additionally, visual field, neural fiber thickness, and electrophysiology should be considered in the evaluation. PMID:27749593

  20. Systematic evaluation of methyl ester bioisosteres in the context of developing alkenyldiarylmethanes (ADAMs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) for anti-HIV-1 chemotherapy.

    PubMed

    Hoshi, Ayako; Sakamoto, Takeshi; Takayama, Jun; Xuan, Meiyan; Okazaki, Mari; Hartman, Tracy L; Buckheit, Robert W; Pannecouque, Christophe; Cushman, Mark

    2016-07-01

    The alkenyldiarylmethanes (ADAMs) are a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting HIV-1. Four chemically and metabolically stabilized ADAMs incorporating N-methoxyimidoyl halide replacements of the methyl esters of the lead compound were previously reported. In this study, twenty-five new ADAMs were synthesized in order to investigate the biological consequences of installing nine different methyl ester bioisosteres at three different locations. Attempts to define a universal rank order of methyl ester bioisosteres and discover the 'best' one in terms of inhibitory activity versus HIV-1 reverse transcriptase (RT) led to the realization that the potencies are critically dependent on the surrounding structure at each location, and therefore the definition of universal rank order is impossible. This investigation produced several new non-nucleoside reverse transcriptase inhibitors in which all three of the three methyl esters of the lead compound were replaced by methyl ester bioisosteres, resulting in compounds that are more potent as HIV-1 RT inhibitors and antiviral agents than the lead compound itself and are expected to also be more metabolically stable than the lead compound. PMID:27234889

  1. A Mathematical Model of Antiretroviral Therapy Evaluation for HIV Type 1

    NASA Astrophysics Data System (ADS)

    Raimundo, Silvia Martorano; Venturino, Ezio; Mo Yang, Hyun

    2009-09-01

    Treating HIV-infected patients with a combination of several antiretroviral drugs can lead to emergence of the drug-resistant strain. This work proposes a mathematical model to evaluate the emergence of HIV-1 drug resistant during antiretroviral therapy. The model assumes that all susceptible individuals who can be infected by the wildtype strain (sensible to the treatment) or by drug-resistant virus receive antiretroviral therapy. Patients on treatment regimen can evolve to a state of success or failure and for the individuals in therapeutic fail the therapeutic schema is changed. The analysis of system is performed. The existence and stability of the steady states are considered. We address an analytical expression for the reproductive number in a community where antiretroviral therapy are widely used to treat HIV and where both drug sensitive and drug resistant strains are co-circulating.

  2. Evaluating animal-assisted therapy in group treatment for child sexual abuse.

    PubMed

    Dietz, Tracy J; Davis, Diana; Pennings, Jacquelyn

    2012-01-01

    This study evaluates and compares the effectiveness of three group interventions on trauma symptoms for children who have been sexually abused. All of the groups followed the same treatment protocol, with two of them incorporating variations of animal-assisted therapy. A total of 153 children ages 7 to 17 who were in group therapy at a Child Advocacy Center participated in the study. Results indicate that children in the groups that included therapy dogs showed significant decreases in trauma symptoms including anxiety, depression, anger, post-traumatic stress disorder, dissociation, and sexual concerns. In addition, results show that children who participated in the group with therapeutic stories showed significantly more change than the other groups. Implications and suggestions for further research are discussed.

  3. Economic Evaluation of Endoscopic Sinus Surgery versus Continued Medical Therapy for Refractory Chronic Rhinosinusitis

    PubMed Central

    Rudmik, Luke; Soler, Zachary M.; Mace, Jess C.; Schlosser, Rodney J.; Smith, Timothy L.

    2014-01-01

    Objective To evaluate the long-term cost-effectiveness of endoscopic sinus surgery (ESS) compared to continued medical therapy for patients with refractory chronic rhinosinusitis (CRS). Study Design Cohort-style Markov decision tree economic evaluation Methods The economic perspective was the US third party payer with a 30 year time horizon. The two comparative treatment strategies were: 1) ESS followed by appropriate postoperative medical therapy and 2) continued medical therapy alone. Primary outcome was the incremental cost per quality adjusted life year (QALY). Costs were discounted at a rate of 3.5% in the reference case. Multiple sensitivity analyses were performed including differing time-horizons, discounting scenarios, and a probabilistic sensitivity analysis (PSA). Results The reference case demonstrated that the ESS strategy cost a total of $48,838.38 and produced a total of 20.50 QALYs. The medical therapy alone strategy cost a total of $28,948.98 and produced a total of 17.13 QALYs. The incremental cost effectiveness ratio (ICER) for ESS versus medical therapy alone is $5,901.90 per QALY. The cost-effectiveness acceptability curve from the PSA demonstrated that there is 74% certainty that the ESS strategy is the most cost-effective decision for any willingness to pay threshold greater then $25,000. The time horizon analysis suggests that ESS becomes the cost-effective intervention within the 3rd year after surgery. Conclusion Results from this study suggest that employing an ESS treatment strategy is the most cost-effective intervention compared to continued medical therapy alone for the long-term management of patients with refractory CRS. PMID:25186499

  4. Dosimetric evaluation of the interplay effect in respiratory-gated RapidArc radiation therapy

    SciTech Connect

    Riley, Craig; Yang, Yong Li, Tianfang; Zhang, Yongqian; Heron, Dwight E.; Huq, M. Saiful

    2014-01-15

    Purpose: Volumetric modulated arc therapy (VMAT) with gating capability has had increasing adoption in many clinics in the United States. In this new technique, dose rate, gantry rotation speed, and the leaf motion speed of multileaf collimators (MLCs) are modulated dynamically during gated beam delivery to achieve highly conformal dose coverage of the target and normal tissue sparing. Compared with the traditional gated intensity-modulated radiation therapy technique, this complicated beam delivery technique may result in larger dose errors due to the intrafraction tumor motion. The purpose of this work is to evaluate the dosimetric influence of the interplay effect for the respiration-gated VMAT technique (RapidArc, Varian Medical Systems, Palo Alto, CA). Our work consisted of two parts: (1) Investigate the interplay effect for different target residual errors during gated RapidArc delivery using a one-dimensional moving phantom capable of producing stable sinusoidal movement; (2) Evaluate the dosimetric influence in ten clinical patients’ treatment plans using a moving phantom driven with a patient-specific respiratory curve. Methods: For the first part of this study, four plans were created with a spherical target for varying residual motion of 0.25, 0.5, 0.75, and 1.0 cm. Appropriate gating windows were applied for each. The dosimetric effect was evaluated using EDR2 film by comparing the gated delivery with static delivery. For the second part of the project, ten gated lung stereotactic body radiotherapy cases were selected and reoptimized to be delivered by the gated RapidArc technique. These plans were delivered to a phantom, and again the gated treatments were compared to static deliveries by the same methods. Results: For regular sinusoidal motion, the dose delivered to the target was not substantially affected by the gating windows when evaluated with the gamma statistics, suggesting the interplay effect has a small role in respiratory-gated Rapid

  5. [The combined DAK therapy of obesity for children and adolescents. Evaluation after 1 year].

    PubMed

    Adam, S; Westenhöfer, J; Rudolphi, B; Kraaibeek, H K

    2008-04-10

    In 2003, the program "The combined DAK therapy of obesity for children and adolescents", funded and conducted by the Deutsche Angestellten Krankenkasse (DAK) (A German Health Insurance Company), has started. The whole treatment lasts for 1 year including an initial inpatient therapy for 6 weeks followed by an outpatient treatment at home that adresses the overweight patients and their families. The therapy contents are developed according to the recommendations of the "Arbeitsgemeinschaft Adipositas im Kindes- und Jugendalter (AGA)". In a prospective cohort study a sample of 604 subjects was studied in order to examine the achievement of the treatment goals weight reduction, behaviour modification and improvement of quality of life. The development of weight was evaluated using BMI-SDS. 44,1% of children and adolescents had a successful weight reduction, they reduced their weight at least by 0,3 BMI-SDS. Furthermore, significant changes of health behaviour, physical fitness and quality of life were observed. However, during the outpatient treatment an impairment of some behaviour changes were observed. Nevertheless, the study has identified significant, positive effects in weight loss, behaviour modifications, changes in physical fitness and in the development of quality of life as a result of the therapy. It is demonstrated that a relapse in "old behaviour" followed by an increase of weight after the inpatient treatment can be avoided bythe subsequent outpatient therapy.

  6. Ectopic expression of anti-HIV-1 shRNAs protects CD8+ T cells modified with CD4ζ CAR from HIV-1 infection and alleviates impairment of cell proliferation

    PubMed Central

    Kamata, Masakazu; Kim, Patrick Y.; Ng, Hwee L.; Ringpis, Gene-Errol E.; Kranz, Emiko; Chan, Joshua; O'Connor, Sean; Yang, Otto O.; Chen, Irvin S.Y.

    2015-01-01

    Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity to immune effector T cells. As an HIV-1-specific CAR, CD4ζ CAR has been extensively tested in vitro as well as in clinical trials. T cells modified with this CAR mediated highly potent anti-HIV-1 activities in vitro and were well-tolerated in vivo, but exerted limited effects on viral load and reservoir size due to poor survival and/or functionality of the transduced cells in patients. We hypothesize that ectopic expression of CD4ζ on CD8+ T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8+ T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8+ T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24Gag in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8+ T cells was reduced relative to control cells upon HIV-1 infection. To protect these cells from HIV-1 infection, we co-expressed two anti-HIV-1 shRNAs previously developed by our group together with CD4ζ. This combination vector was able to suppress HIV-1 infection without impairing HIV-1-dependent effector activities of CD4ζ. In addition, the number of CD4ζ-modified CD8+ T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8+ T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. PMID:25998390

  7. Ectopic expression of anti-HIV-1 shRNAs protects CD8(+) T cells modified with CD4ζ CAR from HIV-1 infection and alleviates impairment of cell proliferation.

    PubMed

    Kamata, Masakazu; Kim, Patrick Y; Ng, Hwee L; Ringpis, Gene-Errol E; Kranz, Emiko; Chan, Joshua; O'Connor, Sean; Yang, Otto O; Chen, Irvin S Y

    2015-07-31

    Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity to immune effector T cells. As an HIV-1-specific CAR, CD4ζ CAR has been extensively tested in vitro as well as in clinical trials. T cells modified with this CAR mediated highly potent anti-HIV-1 activities in vitro and were well-tolerated in vivo, but exerted limited effects on viral load and reservoir size due to poor survival and/or functionality of the transduced cells in patients. We hypothesize that ectopic expression of CD4ζ on CD8(+) T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8(+) T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8(+) T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24(Gag) in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8(+) T cells was reduced relative to control cells upon HIV-1 infection. To protect these cells from HIV-1 infection, we co-expressed two anti-HIV-1 shRNAs previously developed by our group together with CD4ζ. This combination vector was able to suppress HIV-1 infection without impairing HIV-1-dependent effector activities of CD4ζ. In addition, the number of CD4ζ-modified CD8(+) T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8(+) T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. PMID:25998390

  8. An evaluation study of voice therapy in non-organic dysphonia.

    PubMed

    Carding, P N; Horsley, I A

    1992-01-01

    Thirty patients diagnosed as suffering from non-organic dysphonia were assigned to one of three treatment groups: direct therapy, indirect and no treatment for a period of 8 weeks. Therapeutic outcome was evaluated by independent judges, patient self-evaluation, electrolaryngograph ratings and measures of fundamental frequency. The direct treatment group showed the most significant improvement in the return to normal voice functioning followed by the indirect treatment group. One patient in the control group showed improvement without any intervention. This study provides evidence in support of the effectiveness of both direct and indirect therapy in the treatment of non-organic dysphonia and raises questions concerning individual patient responses to these approaches.

  9. Evaluation of Novel Targeted Therapies in Aggressive Biology Sarcoma Patients after progression from US FDA approved Therapies

    PubMed Central

    Subbiah, Vivek; Hess, Kenneth R.; Khawaja, Muhammad Rizwan; Wagner, Michael J.; Tang, Chad; Naing, Aung; Fu, Siqing; Janku, Filip; Piha-Paul, Sarina; Tsimberidou, Apostolia M.; Herzog, Cynthia E.; Ludwig, Joseph A.; Patel, Shreyaskumar; Ravi, Vinod; Benjamin, Robert S.; Meric-Bernstam, Funda; Hong, David S.

    2016-01-01

    Prognosis of patients with advanced sarcoma after progression from FDA approved therapies remains grim. In this study, clinical outcomes of 100 patients with advanced sarcoma who received treatment on novel targeted therapy trials were evaluated. Outcomes of interest included best response, clinical benefit rate, progression-free survival (PFS) and overall survival (OS). Median patient age was 48 years (range 14–80). Patients had received a median of 2 prior lines of systemic treatment. Phase I treatments were anti-VEGF–based (n = 45), mTOR inhibitor–based (n = 15), and anti-VEGF + mTOR inhibitor–based (n = 17) or involved other targets (n = 23). Best responses included partial response (n = 4) and stable disease (n = 57). Clinical benefit rate was 36% (95% confidence interval 27–46%). Median OS was 9.6 months (95% Confidence Interval 8.1–14.2); median PFS was 3.5 months (95% Confidence Interval 2.4–4.7). RMH prognostic score of 2 or 3 was associated with lower median OS (log-rank p-value < 0.0001) and PFS (log-rank p-value 0.0081). Receiving cytotoxic chemotherapy as part of phase I trial was also associated with shorter median OS (log-rank p-value 0.039). Patients with advanced sarcoma treated on phase I clinical trials had a clinical benefit rate of 36% and RMH score predicted survival. PMID:27748430

  10. The feasibility of incorporating Vpx into lentiviral gene therapy vectors

    PubMed Central

    McAllery, Samantha A; Ahlenstiel, Chantelle L; Suzuki, Kazuo; Symonds, Geoff P; Kelleher, Anthony D; Turville, Stuart G

    2016-01-01

    While current antiretroviral therapy has significantly improved, challenges still remain in life-long targeting of HIV-1 reservoirs. Lentiviral gene therapy has the potential to deliver protective genes into the HIV-1 reservoir. However, inefficient reverse transcription (RT) occurs in HIV-1 reservoirs during lentiviral gene delivery. The viral protein Vpx is capable of increasing lentiviral RT by antagonizing the restriction factor SAMHD1. Incorporating Vpx into lentiviral vectors could substantially increase gene delivery into the HIV-1 reservoir. The feasibility of this Vpx approach was tested in resting cell models utilizing macrophages and dendritic cells. Our results showed Vpx exposure led to increased permissiveness of cells over a period that exceeded 2 weeks. Consequently, significant lower potency of HIV-1 antiretrovirals inhibiting RT and integration was observed. When Vpx was incorporated with anti-HIV-1 genes inhibiting either pre-RT or post-RT stages of the viral life-cycle, transduction levels significantly increased. However, a stronger antiviral effect was only observed with constructs that inhibit pre-RT stages of the viral life cycle. In conclusion this study demonstrates a way to overcome the major delivery obstacle of gene delivery into HIV-1 reservoir cell types. Importantly, incorporating Vpx with pre-RT anti-HIV-1 genes, demonstrated the greatest protection against HIV-1 infection. PMID:27790625

  11. The effectiveness of asthma therapy alternatives and evaluating the effectivity of asthma therapy by interleukin-13 and interferon gamma levels in children.

    PubMed

    Karaman, Ozkan; Arli, Ozgun; Uzuner, Nevin; Islekel, Huray; Babayigit, Arzu; Olmez, Duygu; Kose, Suna; Tezcan, Dilek

    2007-01-01

    This study evaluated the superiority of combination therapy over steroid therapy alone by using clinical and laboratory data including interleukin (IL)-13 and interferon (IFN) gamma, which participate in the characteristic inflammation and have not been studied to evaluate the efficiency of asthma treatment sufficiently. Moderate persistent asthma patients, aged 7-17 years were included in the study. Patients were randomized to three groups. Group 1 used inhaled budesonide, group 2 used inhaled budesonide plus inhaled formoterol fumarate, and group 3 used inhaled budesonide and oral montelukast sodium therapy. At the beginning and at the end of the 2nd month a detailed physical examination and clinical evaluation; total IgE levels and total eosinophil count in peripheral venous blood, serum IL-13, and IFN-gamma levels; pulmonary function tests; and an assessment questionnaire (Pediatric Asthma Quality-of-Life Questionnaire with Standardized Activities [PAQLQ{S}] were performed. Sixty-seven patients completed the study. Serum IL-13 levels and PAQLQ(S) scores before the therapy and serum IL-13 levels after the therapy were significantly different between the groups and other parameters did not show any significant differences. Serum IgE level was decreased after the therapy in group I and increased in groups 2 and 3, but the difference was insignificant. In all groups total eosinophil levels were decreased insignificantly. After the therapy, IL-13 levels were decreased in groups 1 and 2 and increased in group 3, but the difference was not statistically significant. When compared with the levels before the therapy IFN-gamma levels were decreased after the therapy but the difference was not statistically significant. When the improvement rates for IgE, total eosinophil, IL-13, and IFN-gamma levels and each parameter of respiratory function tests were compared, there were no significant differences between the therapy groups. In all groups PAQLQ(S) scores were

  12. Dolutegravir: clinical efficacy and role in HIV therapy

    PubMed Central

    Fantauzzi, Alessandra

    2014-01-01

    The human immunodeficiency virus type-1 (HIV-1) integrase enzyme has recently emerged as a primary alternative target to block viral replication, and integrase strand transfer inhibitors (INSTIs) are now considered an alternative ‘third agent’ class of antiretroviral (ARV) drugs. Dolutegravir is the first next-generation INSTI showing some novel and intriguing characteristics: it has a favorable pharmacokinetic profile with a prolonged intracellular halflife, rendering feasible a once daily dosing without the need for pharmacokinetic boosting. Secondly, it is largely metabolized via uridine diphosphate glucuronosyltransferase-1A1 with a minor component of cytochrome P450 isoforms, thus allowing a low grade of drug–drug interactions, so that its metabolic profile consents co-administration with the majority of the other ARV drugs without dose adjustments. Lastly, but no less important, virological studies have clearly demonstrated that dolutegravir has a significant activity against HIV-1 isolates showing raltegravir and/or elvitegravir associated resistance mutations. The attributes of once daily administration and the potential to treat INSTI-resistant viruses make dolutegravir an interesting and promising new agent in the treatment of both naïve and experienced HIV-1 subjects. In this review, the main concerns on dolutegravir efficacy are focused through the analysis of the currently available data from clinical studies in naïve and experienced patients, evaluating its possible place within the anti-HIV-1 drug armamentarium. The development of newer once daily, single tablet coformulations improved drug adherence and maximized the success of ARV therapy. Pharmacokinetic studies and dose-ranging trials suggested that dolutegravir is a good candidate for a single tablet regimen in one or more new coformulated pills that will be available in the near future. PMID:24982751

  13. Safety, effectiveness and economic evaluation of intra-operative radiation therapy: a systematic review

    PubMed Central

    Najafipour, Farshad; Hamouzadeh, Pejman; Arabloo, Jalal; Mobinizadeh, Mohammadreza; Norouzi, Amir

    2015-01-01

    Background: Intra-operative radiation therapy (IORT) is the transfer of a single large radiation dose to the tumor bed during surgery with the final goal of improving regional tumor control. This study aimed to investigate the safety, effectiveness and economic evaluation of intra-operative radiation therapy. Methods: The scientific literature was searched in the main biomedical databases (Centre for Reviews and Dissemination, Cochrane Library and PubMed) up to March 2014. Two independent reviewers selected the papers based on pre-established inclusion criteria, with any disagreements being resolved by consensus. Data were then extracted and summarized in a structured form. Results from studies were analyzed and discussed within a descriptive synthesis. Results: Sixteen studies met the inclusion criteria. It seems that outcomes from using intraoperative radiation therapy can be considered in various kinds of cancers like breast, pancreatic and colorectal cancers. The application of this method may provide significant survival increase only for colorectal cancer, but this increase was not significant for other types of cancer. This technology had low complications; and it is relatively safe. Using intra-operative radiation therapy could potentially be accounted as a cost-effective strategy for controlling and managing breast cancer. Conclusion: According to the existing evidences, that are the highest medical evidences for using intra-operative radiation therapy, one can generally conclude that intra-operative radiation therapy is considered as a relatively safe and cost-effective method for managing early-stage breast cancer and it can significantly increase the survival of patients with colorectal cancer. Also, the results of this study have policy implications with respect to the reimbursement of this technology. PMID:26793649

  14. Computerized PET/CT image analysis in the evaluation of tumour response to therapy

    PubMed Central

    Wang, J; Zhang, H H

    2015-01-01

    Current cancer therapy strategy is mostly population based, however, there are large differences in tumour response among patients. It is therefore important for treating physicians to know individual tumour response. In recent years, many studies proposed the use of computerized positron emission tomography/CT image analysis in the evaluation of tumour response. Results showed that computerized analysis overcame some major limitations of current qualitative and semiquantitative analysis and led to improved accuracy. In this review, we summarize these studies in four steps of the analysis: image registration, tumour segmentation, image feature extraction and response evaluation. Future works are proposed and challenges described. PMID:25723599

  15. Evaluating outcomes of palliative photodynamic therapy: instrument development and preliminary results

    NASA Astrophysics Data System (ADS)

    Goodell, Teresa T.; Bargo, Paulo R.; Jacques, Steven L.

    2002-06-01

    Background: Subjective measures are considered the gold standard in palliative care evaluation, but no studies have evaluated palliative photodynamic therapy (PDT) subjectively. If PDT is to be accepted as a palliative therapy for later-stage obstructing esophageal and lung cancer, evidence of its effectiveness and acceptability to patients must be made known. Study Design/Materials and Methods: This ongoing study's major aim is to evaluate subjective outcomes of PDT in patients with obstructing esophageal and lung cancer. Existing measures of health status, dysphagia and performance status were supplemented with an instrument developed to evaluate PDT symptom relief and side effect burden, the PDT Side Effects Survey (PSES). Results: PDT patients treated with porfimer sodium (Photofrin) and 630-nm light experienced reduced dysphagia grade and stable performance status for at least one month after PDT (N= 10-17), but these effects did not necessarily persist at three months. Fatigue, appetite and quality of life may be the most burdensome issues for these patients. Conclusions: Preliminary data suggest that the PSES is an acceptable and valid tool for measuring subjective outcomes of palliative PDT. This study is the first attempt to systematically evaluate subjective outcomes of palliative PDT. Multi-center outcomes research is needed to draw generalizable conclusions that will establish PDT's effectiveness in actual clinical practice and enhance the wider adoption of PDT as a cancer symptom relief modality.

  16. Evaluation of an Expert System for the Generation of Speech and Language Therapy Plans

    PubMed Central

    López-Nores, Martín; García-Duque, Jorge; Pazos-Arias, José J; Arévalo-Lucero, Daysi

    2016-01-01

    Background Speech and language pathologists (SLPs) deal with a wide spectrum of disorders, arising from many different conditions, that affect voice, speech, language, and swallowing capabilities in different ways. Therefore, the outcomes of Speech and Language Therapy (SLT) are highly dependent on the accurate, consistent, and complete design of personalized therapy plans. However, SLPs often have very limited time to work with their patients and to browse the large (and growing) catalogue of activities and specific exercises that can be put into therapy plans. As a consequence, many plans are suboptimal and fail to address the specific needs of each patient. Objective We aimed to evaluate an expert system that automatically generates plans for speech and language therapy, containing semiannual activities in the five areas of hearing, oral structure and function, linguistic formulation, expressive language and articulation, and receptive language. The goal was to assess whether the expert system speeds up the SLPs’ work and leads to more accurate, consistent, and complete therapy plans for their patients. Methods We examined the evaluation results of the SPELTA expert system in supporting the decision making of 4 SLPs treating children in three special education institutions in Ecuador. The expert system was first trained with data from 117 cases, including medical data; diagnosis for voice, speech, language and swallowing capabilities; and therapy plans created manually by the SLPs. It was then used to automatically generate new therapy plans for 13 new patients. The SLPs were finally asked to evaluate the accuracy, consistency, and completeness of those plans. A four-fold cross-validation experiment was also run on the original corpus of 117 cases in order to assess the significance of the results. Results The evaluation showed that 87% of the outputs provided by the SPELTA expert system were considered valid therapy plans for the different areas. The SLPs

  17. Evaluation of occupational therapy interventions for elderly patients in Swedish acute care: a pilot study.

    PubMed

    Wressle, Ewa; Filipsson, Viveka; Andersson, Lena; Jacobsson, Beatrice; Martinsson, Karin; Engel, Kristina

    2006-12-01

    The aim was to evaluate whether occupational therapy interventions in acute care could improve the elderly patient's perception of ability to manage at home after discharge. A pilot study was performed, including 22 patients in the experimental group and 19 in the control group. Occupational therapy interventions were conducted in the experimental group concerning personal care, information, prescription of assistive devices, planning of discharge, and reporting to primary care or community care. The control group was given no occupational therapy interventions. Structured interviews were performed on discharge and at a follow-up in about 14 weeks after discharge. The two groups were comparable concerning gender, age, days of care, and diagnoses. Patients in the experimental group scored lower on mental health and were more anxious on discharge. However, there was no difference between the groups in managing at home after discharge. Patients in the control group had greater need of further contacts with healthcare after discharge. Due to the small sample interpretations must be made with caution. The findings indicate that occupational therapy interventions in acute care might have a positive effect from the perspective of the elderly patient. These results need to be confirmed in a larger study.

  18. Evaluation of occupational therapy interventions for elderly patients in Swedish acute care: a pilot study.

    PubMed

    Wressle, Ewa; Filipsson, Viveka; Andersson, Lena; Jacobsson, Beatrice; Martinsson, Karin; Engel, Kristina

    2006-12-01

    The aim was to evaluate whether occupational therapy interventions in acute care could improve the elderly patient's perception of ability to manage at home after discharge. A pilot study was performed, including 22 patients in the experimental group and 19 in the control group. Occupational therapy interventions were conducted in the experimental group concerning personal care, information, prescription of assistive devices, planning of discharge, and reporting to primary care or community care. The control group was given no occupational therapy interventions. Structured interviews were performed on discharge and at a follow-up in about 14 weeks after discharge. The two groups were comparable concerning gender, age, days of care, and diagnoses. Patients in the experimental group scored lower on mental health and were more anxious on discharge. However, there was no difference between the groups in managing at home after discharge. Patients in the control group had greater need of further contacts with healthcare after discharge. Due to the small sample interpretations must be made with caution. The findings indicate that occupational therapy interventions in acute care might have a positive effect from the perspective of the elderly patient. These results need to be confirmed in a larger study. PMID:17203670

  19. SU-E-P-07: Evaluation of Productivity Systems for Radiation Therapy

    SciTech Connect

    Ramsey, C; Usynin, A

    2014-06-01

    Purpose: Health systems throughout the United States are under increased financial pressure to reduce operating cost. As a result, productivity models developed by third-party consultants are being used to optimize staff to treatment volumes. The purpose of this study was to critically evaluate productivity systems for radiation oncology. Methods: Staffing efficiency was evaluated using multiple productivity models. The first model evaluated staffing levels using equal weighting of procedure codes and hours worked. A second productivity model was developed using hours worked by job class and relative value units for each procedure code. A third model was developed using the measured procedure times extracted from the electronic medical record, which tracks the wait and treatment times for each patient for each treatment fraction. A MatLab program was developed to query and analyze the daily treatment data. A model was then created to determine any theoretical gains in treatment productivity. Results: Productivity was evaluated for six radiation therapy departments operating nine linear accelerators delivering over 40,000 treatment fractions per year. Third party productivity models that do not take into consideration the unique nature of radiation therapy can be counterproductive. For example, other outpatient departments can compress their daily schedule to decrease the worked hours. This approach was tested using the treatment schedule evaluation tool developed as part of this study. It was determined that the maximum possible savings for treatment schedule compression was $32,000 per year per linac. All annual cost savings would be lost if only two patients per year choose to be treated elsewhere because of limited or restricted appointment times. Conclusion: The use of productivity models in radiation therapy can easily result in a loss of treatment revenue that is greater than any potential cost savings in reduced hours worked by staff.

  20. Structural Insights on the Role of Antibodies in HIV-1 Vaccine and Therapy

    PubMed Central

    West, Anthony P.; Scharf, Louise; Scheid, Johannes F.; Klein, Florian; Bjorkman, Pamela J.; Nussenzweig, Michel C.

    2014-01-01

    Despite 30 years of effort, there is no effective vaccine for HIV-1. However, antibodies can prevent HIV-1 infection in humanized mice and macaques when passively transferred. New single-cell-based methods have uncovered many broad and potent donor-derived antibodies, and structural studies have revealed the molecular bases for their activities. The new data suggest why such antibodies are difficult to elicit and inform HIV-1 vaccine development efforts. In addition to protecting against infection, the newly identified antibodies can suppress active infections in mice and macaques, suggesting they could be valuable additions to anti-HIV-1 therapies and to strategies to eradicate HIV-1 infection. PMID:24529371

  1. Synthesis and evaluation of boron compounds for neutron capture therapy of malignant brain tumors

    SciTech Connect

    Soloway, A.H.; Barth, R.F.

    1990-01-01

    Boron neutron capture therapy offers the potentiality for treating brain tumors currently resistant to treatment. The success of this form of therapy is directly dependent upon the delivery of sufficient numbers of thermal-neutrons to tumor cells which possess high concentrations of B-10. The objective of this project is to develop chemical methodology to synthesize boron-containing compounds with the potential for becoming incorporated into rapidly-dividing malignant brain tumor cells and excluded from normal components of the brain and surrounding tissues, to develope biological methods for assessing the potential of the compound by use of cell culture or intratumoral injection, to develop analytical methodology for measuring boron in cells and tissue using direct current plasma atomic emission spectroscopy (DCP-AES) and alpha track autoradiography, to develop biochemical and HPLC procedures for evaluating compound uptake and tissue half-life, and to develop procedures required to assess both in vitro and vivo efficacy of BNCT with selected compounds.

  2. Evaluation of results of conservative therapy in patients with transient osteoporosis of hip.

    PubMed

    Guler, Olcay; Ozyurek, Selahattin; Cakmak, Selami; Isyar, Mehmet; Mutlu, Serhat; Mahirogullari, Mahir

    2015-09-01

    The present study aimed to review the general characteristics of 18 cases diagnosed with transient osteoporosis of the hip (TOH) in our hospital within a 3-year period and to present their follow-up results after conservative treatment. A retrospective evaluation was made of the treatment and results of follow-up of TOH cases using physical examination and laboratory findings, hip radiographs and magnetic resonance imaging (MRI) and Harris Hip Scores (HHS). The mean duration of complaints of 6 females (mean age, 34.3±4.3 years) and 12 males (mean age, 40.7±10.5 years) was 6.1±2.7 weeks before the treatment. Three female patients had a history of giving birth by cesarean delivery. None of the patients had any history of trauma. MRI revealed increased intensity in T2 sequences and decreased intensity in T1 sequences in the proximal aspect of the femur. None of the patients had subchondral collapse or intra-articular effusion. For 3 female patients who were breastfeeding, no medical therapy was given, but only hyperbaric oxygen (HBO) therapy and forearm crutches. As standard management, the other patients were prevented from weight-bearing with the use of forearm crutches and medical therapy of diclofenac sodium, acetylsalicylic acid, and risedronate sodium was administered and additional HBO therapy. Clinical and radiological improvements were observed in all patients. None of the patients had avascular necrosis (AVN) of the femoral head. There was no record of therapy-related complications. While HHS was 55.6±7.8 before the treatment, it increased to 88.8±5.8 in the 3rd month and to 96.0±1.8 in the 6th month after the treatment. This change in score over time was found to be significant.

  3. Evaluation of low level laser therapy in reducing diabetic polyneuropathy related pain and sensorimotor disorders.

    PubMed

    Bashiri, Homayoon

    2013-01-01

    Over the past three decades physicians have used light level laser therapy (LLLT) for the management and the treatment of diabetic peripheral neuropathy and have obtained results that calls for further investigations. This study aimed to investigate the effectiveness of LLLT in treatment of pain symptoms in patients with diabetic polyneuropathy. In this study 60 patients with diabetic peripheral neuropathy were matched based on their sex, age, BMI, type of diabetes, duration of diabetes, and duration of pain, and randomized to case and control groups based on their established scores on the visual analog scale (VAS) and the Toronto clinical scoring system (TCSS). Cases received laser therapy with wavelength of 78 nm and 2.5 j/cm2 two times a week, each time for 5 min, for one month. During the same period, controls received sham laser therapy. Comparing the differences between the two groups' VAS and TCSS mean scores before the intervention with that of the 2 weeks and 4 weeks after the intervention we were able to see a statistically significant difference between the two groups (P<0.05). On the other hand, when we compared their VAS and TCSS mean scores 4 weeks and 2 weeks after the intervention we did not find any statistically significant difference between the two groups. We achieved the same results when we examined cases' and controls' pre and post VAS and TCSS scores independent from each other; no improvement in the assessment based on their 2 and 4 weeks comparisons tests. Laser therapy resulted in improved neuropathy outcomes in diabetic patients who received it relative to the group that received sham therapy, evaluating before and after LLLT assessments. Further studies are needed to test types of lasers, as well as different dosage and exposure levels required in different phase of neuropathic care, so as to obtain reproducible results. PMID:24026991

  4. Supervision, monitoring and evaluation of nationwide scale-up of antiretroviral therapy in Malawi.

    PubMed Central

    Libamba, Edwin; Makombe, Simon; Mhango, Eustice; de Ascurra Teck, Olga; Limbambala, Eddie; Schouten, Erik J.; Harries, Anthony D.

    2006-01-01

    OBJECTIVE: To describe the supervision, monitoring and evaluation strategies used to assess the delivery of antiretroviral therapy during nationwide scale-up of treatment in Malawi. METHODS: In the first quarter of 2005, the HIV Unit of the Ministry of Health and its partners (the Lighthouse Clinic; Médecins Sans Frontières-Belgium, Thyolo district; and WHO's Country Office) undertook structured supervision and monitoring of all public sector health facilities in Malawi delivering antiretroviral therapy. FINDINGS: Data monitoring showed that by the end of 2004, there were 13,183 patients (5274 (40%) male, 12 527 (95%) adults) who had ever started antiretroviral therapy. Of patients who had ever started, 82% (10 761/13,183) were alive and taking antiretrovirals; 8% (1026/13,183) were dead; 8% (1039/13,183) had been lost to follow up; <1% (106/13,183) had stopped treatment; and 2% (251/13,183) had transferred to another facility. Of those alive and on antiretrovirals, 98% (7098/7258) were ambulatory; 85% (6174/7258) were fit to work; 10% (456/4687) had significant side effects; and, based on pill counts, 96% (6824/7114) had taken their treatment correctly. Mistakes in the registration and monitoring of patients were identified and corrected. Drug stocks were checked, and one potential drug stock-out was averted. As a result of the supervisory visits, by the end of March 2005 recruitment of patients to facilities scheduled to start delivering antiretroviral therapy had increased. CONCLUSION: This report demonstrates the importance of early supervision for sites that are starting to deliver antiretroviral therapy, and it shows the value of combining data collection with supervision. Making regular supervisory and monitoring visits to delivery sites are essential for tracking the national scale-up of delivery of antiretrovirals. PMID:16628306

  5. Client satisfaction of hand therapy intervention: An evaluation of the effectiveness of therapy for clients recovered from complex regional pain syndrome

    PubMed Central

    Zagzoog, Nirmeen; Chinchalkar, Shrikant J; Sumsion, Thelma

    2008-01-01

    Complex regional pain syndrome (CRPS) is a neuropathic pain condition that may develop following trauma to an extremity. Clients treated for CRPS at St Joseph’s Health Care London – Hand and Upper Limb Centre, London, Ontario, were asked to evaluate their level of satisfaction with the treatment they had received by comparing their pain, functional status and emotional status before and after receiving therapy. The results indicated a high level of satisfaction among clients, attributable to the unique nature of the therapy program in use at this facility, where the occupational therapist works in close collaboration with the surgeon and pain specialists, and the therapy regimen is designed for each client individually according to his or her needs. The unique contribution of the present study to the body of clinical literature on CRPS is that it introduces a focus on client functionality and on client satisfaction with therapy received. PMID:19554162

  6. Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy.

    PubMed

    Virani, Sean A; Dent, Susan; Brezden-Masley, Christine; Clarke, Brian; Davis, Margot K; Jassal, Davinder S; Johnson, Christopher; Lemieux, Julie; Paterson, Ian; Sebag, Igal A; Simmons, Christine; Sulpher, Jeffrey; Thain, Kishore; Thavendiranathan, Paaldinesh; Wentzell, Jason R; Wurtele, Nola; Côté, Marc André; Fine, Nowell M; Haddad, Haissam; Hayley, Bradley D; Hopkins, Sean; Joy, Anil A; Rayson, Daniel; Stadnick, Ellamae; Straatman, Lynn

    2016-07-01

    Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients. PMID:27343741

  7. Physical evaluation system to determine medical risk and indicated dental therapy modifications.

    PubMed

    McCarthy, F M; Malamed, S F

    1979-08-01

    The physical evaluation system allows the practitioner to rapidly classify each patient according to medical risk and thus to provide dental treatment comfortably and safely. The evaluation system serves as a guide to the level of dental therapy, deisions of management, and modification of treatment for the medically compromised patient. Extensive use of the ADA physical status classification system in dentistry would allow meaningful studies of morbidity and mortality that are related to various management protocols and could conceivably have an impact on insurance schedules associated with psychosedation modalities and general anethesia on an out patient basis. A physical evaluation system cannot substitute for knowledge and good judgment. Recommended categories of physical status and modification of treatment should not be considered as absolutes, but as guides. Wheras the guidelines may appear to be inflexible, they should not be considered as such. Deviation from recommendations is often justified and is expected.

  8. Evaluating Sarconesiopsis magellanica blowfly-derived larval therapy and comparing it to Lucilia sericata-derived therapy in an animal model.

    PubMed

    Díaz-Roa, Andrea; Gaona, María A; Segura, Nidya A; Ramírez-Hernández, Alejandro; Cortés-Vecino, Jesús A; Patarroyo, Manuel A; Bello, Felio

    2016-02-01

    Larval therapy is used as alternative treatment for hard-to-heal chronic and infected wounds. Lucilia sericata is the most used blowfly species. However, it has been shown recently that Sarconesiopsis magellanica larval excretions and secretions have potent antibacterial activity; this blowfly belongs to the Calliphoridae family. The present work has dealt with evaluating larval therapy using S. magellanica on wounds induced in diabetic rabbits and its action was compared to the effect induced by L. sericata. Twelve New Zealand White rabbits (Oryctolagus cuniculus) were used; they were divided into 4 groups, the first two being treated with larval therapy derived from both aforementioned necrophagous blowflies, an antibiotic was used in the third and the fourth was used as control. All the animals were wounded on the back and infected with Pseudomonas aeruginosa and Staphylococcus aureus. Samples of the secretion from each animal's infected wound were taken and sown on blood agar. The colony forming units were then counted. The PUSH scale was used for the macroscopic evaluation of the wounds. Bacterial control was encountered 48 h post-treatment in the treatments involving larval therapy and to a lesser extent with the antibiotic. Likewise, wound debridement was quicker and more efficient with larval therapy compared to the antibiotic group; however, wound closing time was 23 days in all treatments. The group treated with S. magellanica larvae had relatively quicker evolution until the proliferation phase and the start of maturation, even though there were no significant differences between both blowfly species evaluated here regarding treatments by the end of the treatment period. The present study has validated the diabetic rabbit model for inducing chronic wounds regarding larval therapy and has likewise confirmed the effectiveness of S. magellanica-derived larval therapy as an alternative for curing and healing wounds.

  9. Evaluating Sarconesiopsis magellanica blowfly-derived larval therapy and comparing it to Lucilia sericata-derived therapy in an animal model.

    PubMed

    Díaz-Roa, Andrea; Gaona, María A; Segura, Nidya A; Ramírez-Hernández, Alejandro; Cortés-Vecino, Jesús A; Patarroyo, Manuel A; Bello, Felio

    2016-02-01

    Larval therapy is used as alternative treatment for hard-to-heal chronic and infected wounds. Lucilia sericata is the most used blowfly species. However, it has been shown recently that Sarconesiopsis magellanica larval excretions and secretions have potent antibacterial activity; this blowfly belongs to the Calliphoridae family. The present work has dealt with evaluating larval therapy using S. magellanica on wounds induced in diabetic rabbits and its action was compared to the effect induced by L. sericata. Twelve New Zealand White rabbits (Oryctolagus cuniculus) were used; they were divided into 4 groups, the first two being treated with larval therapy derived from both aforementioned necrophagous blowflies, an antibiotic was used in the third and the fourth was used as control. All the animals were wounded on the back and infected with Pseudomonas aeruginosa and Staphylococcus aureus. Samples of the secretion from each animal's infected wound were taken and sown on blood agar. The colony forming units were then counted. The PUSH scale was used for the macroscopic evaluation of the wounds. Bacterial control was encountered 48 h post-treatment in the treatments involving larval therapy and to a lesser extent with the antibiotic. Likewise, wound debridement was quicker and more efficient with larval therapy compared to the antibiotic group; however, wound closing time was 23 days in all treatments. The group treated with S. magellanica larvae had relatively quicker evolution until the proliferation phase and the start of maturation, even though there were no significant differences between both blowfly species evaluated here regarding treatments by the end of the treatment period. The present study has validated the diabetic rabbit model for inducing chronic wounds regarding larval therapy and has likewise confirmed the effectiveness of S. magellanica-derived larval therapy as an alternative for curing and healing wounds. PMID:26546725

  10. [Behavioral, stress and immunological evaluation methods of music therapy in elderly patients with senile dementia].

    PubMed

    Suzuki, Mizue; Kanamori, Masao; Nagasawa, Shingo; Saruhara, Takayuki

    2005-01-01

    The purpose of this study was to clarify the efficacy of behavioral, stress and immunological evaluation methods in music therapy (MT) with elderly patients with senile dementia. The MT group consisted of 8 elderly patients with dementia and the control group included 8 similarly matched patients. A total of 25 sessions of music therapy were conducted for one hour, twice each week for three months. The Mini-Mental State Exam (MMSE), Gottfries-Brane-Steen Scale (GBS), and Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) were used to evaluate behavioral changes. Saliva Chromogranin A (Cg A) and Immunoglobulin A (Ig A) were used to assess changes in stress and immunological status, respectively. The results of the study were as follows: 1. In GBS, the mean score of "different symptoms common in dementia" improved significantly after MT. 2. The mean Behave-AD score of "paranoid and delusional ideation" was also significantly improved (p<0.05) after the intervention. 3. In the 25th session, mean saliva Cg A was significantly decreased after MT (p<0.05). IgA was slightly increased prior to intervention. Our results suggest that a combination of behavioral, stress and immunological evaluation methods were valuable for assessing changes that occurred during MT for elderly patients with dementia.

  11. Gamma evaluation combined with isocenter optimal matching in intensity modulated radiation therapy quality assurance

    NASA Astrophysics Data System (ADS)

    Bak, Jino; Choi, Jin Hwa; Park, Suk Won; Park, Kwangwoo; Park, Sungho

    2015-12-01

    Two-dimensional (2D) dose comparisons are widely performed by using a gamma evaluation with patient-specific intensity modulated radiation therapy quality assurance (IMRT QA) or dose delivery quality assurance (DQA). In this way, a pass/fail determination is made for a particular treatment plan. When gamma evaluation results are close to the failure criterion, the pass/fail decision may change applying a small shift to the center of the 2D dose distribution. In this study, we quantitatively evaluated the meaning of such a small relative shift in a 2D dose distribution comparison. In addition, we propose the use of a small shift for a pass/fail criterion in gamma analysis, where the concept of isocenter optimal matching (IOM) is applied to IMRT QA of 20 patients. Gamma evaluations were performed to compare two dose distributions, one with and the other without IOM. In-house software was developed in C++ in order to find IOM values including both translational and rotational shifts. Upon gamma evaluation failure, further investigation was initiated using IOM. In this way, three groups were categorized: group 1 for `pass' on gamma evaluation, group 21 for `fail' on the gamma evaluation and `pass' on the gamma the evaluation with IOM, and group 22 for `fail' on the both gamma evaluations and the IOM calculation. IOM results revealed that some failures could be considered as a `pass'. In group 21, 88.98% (fail) of the averaged gamma pass rate changed to 90.45% (pass) when IOM was applied. On average, a ratio of γ ≥ 1 was reduced by 11.06% in 20 patients. We propose that gamma evaluations that do not pass with a rate of 85% to 90% may be augmented with IOM to reveal a potential pass result.

  12. Murine Model Imitating Chronic Wound Infections for Evaluation of Antimicrobial Photodynamic Therapy Efficacy

    PubMed Central

    Fila, Grzegorz; Kasimova, Kamola; Arenas, Yaxal; Nakonieczna, Joanna; Grinholc, Mariusz; Bielawski, Krzysztof P.; Lilge, Lothar

    2016-01-01

    It is generally acknowledged that the age of antibiotics could come to an end, due to their widespread, and inappropriate use. Particularly for chronic wounds alternatives are being thought. Antimicrobial Photodynamic Therapy (APDT) is a potential candidate, and while approved for some indications, such as periodontitis, chronic sinusitis and other niche indications, its use in chronic wounds is not established. To further facilitate the development of APDT in chronic wounds we present an easy to use animal model exhibiting the key hallmarks of chronic wounds, based on full-thickness skin wounds paired with an optically transparent cover. The moisture-retaining wound exhibited rapid expansion of pathogen colonies up to 8 days while not jeopardizing the host survival. Use of two bioluminescent pathogens; methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa permits real time monitoring of the pathogens. The murine model was employed to evaluate the performance of four different photosensitizers as mediators in Photodynamic Therapy. While all four photosensitizers, Rose Bengal, porphyrin TMPyP, New Methylene Blue, and TLD1411 demonstrated good to excellent antimicrobial efficacy in planktonic solutions at 1 to 50 μM concentrations, whereas in in vivo the growth delay was limited with 24–48 h delay in pathogen expansion for MRSA, and we noticed longer growth suppression of P. aeruginosa with TLD1411 mediated Photodynamic Therapy. The murine model will enable developing new strategies for enhancement of APDT for chronic wound infections. PMID:27555843

  13. Murine Model Imitating Chronic Wound Infections for Evaluation of Antimicrobial Photodynamic Therapy Efficacy.

    PubMed

    Fila, Grzegorz; Kasimova, Kamola; Arenas, Yaxal; Nakonieczna, Joanna; Grinholc, Mariusz; Bielawski, Krzysztof P; Lilge, Lothar

    2016-01-01

    It is generally acknowledged that the age of antibiotics could come to an end, due to their widespread, and inappropriate use. Particularly for chronic wounds alternatives are being thought. Antimicrobial Photodynamic Therapy (APDT) is a potential candidate, and while approved for some indications, such as periodontitis, chronic sinusitis and other niche indications, its use in chronic wounds is not established. To further facilitate the development of APDT in chronic wounds we present an easy to use animal model exhibiting the key hallmarks of chronic wounds, based on full-thickness skin wounds paired with an optically transparent cover. The moisture-retaining wound exhibited rapid expansion of pathogen colonies up to 8 days while not jeopardizing the host survival. Use of two bioluminescent pathogens; methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa permits real time monitoring of the pathogens. The murine model was employed to evaluate the performance of four different photosensitizers as mediators in Photodynamic Therapy. While all four photosensitizers, Rose Bengal, porphyrin TMPyP, New Methylene Blue, and TLD1411 demonstrated good to excellent antimicrobial efficacy in planktonic solutions at 1 to 50 μM concentrations, whereas in in vivo the growth delay was limited with 24-48 h delay in pathogen expansion for MRSA, and we noticed longer growth suppression of P. aeruginosa with TLD1411 mediated Photodynamic Therapy. The murine model will enable developing new strategies for enhancement of APDT for chronic wound infections. PMID:27555843

  14. Are complementary therapies and integrative care cost-effective? A systematic review of economic evaluations

    PubMed Central

    Herman, Patricia M; Poindexter, Beth L; Witt, Claudia M; Eisenberg, David M

    2012-01-01

    Objective A comprehensive systematic review of economic evaluations of complementary and integrative medicine (CIM) to establish the value of these therapies to health reform efforts. Data sources PubMed, CINAHL, AMED, PsychInfo, Web of Science and EMBASE were searched from inception through 2010. In addition, bibliographies of found articles and reviews were searched, and key researchers were contacted. Eligibility criteria for selecting studies Studies of CIM were identified using criteria based on those of the Cochrane complementary and alternative medicine group. All studies of CIM reporting economic outcomes were included. Study appraisal methods All recent (and likely most cost-relevant) full economic evaluations published 2001–2010 were subjected to several measures of quality. Detailed results of higher-quality studies are reported. Results A total of 338 economic evaluations of CIM were identified, of which 204, covering a wide variety of CIM for different populations, were published 2001–2010. A total of 114 of these were full economic evaluations. And 90% of these articles covered studies of single CIM therapies and only one compared usual care to usual care plus access to multiple licensed CIM practitioners. Of the recent full evaluations, 31 (27%) met five study-quality criteria, and 22 of these also met the minimum criterion for study transferability (‘generalisability’). Of the 56 comparisons made in the higher-quality studies, 16 (29%) show a health improvement with cost savings for the CIM therapy versus usual care. Study quality of the cost-utility analyses (CUAs) of CIM was generally comparable to that seen in CUAs across all medicine according to several measures, and the quality of the cost-saving studies was slightly, but not significantly, lower than those showing cost increases (85% vs 88%, p=0.460). Conclusions This comprehensive review identified many CIM economic evaluations missed by previous reviews and emerging evidence of cost

  15. Evaluation of Online/Offline Image Guidance/Adaptation Approaches for Prostate Cancer Radiation Therapy

    SciTech Connect

    Qin, An; Sun, Ying; Liang, Jian; Yan, Di

    2015-04-01

    Purpose: To evaluate online/offline image-guided/adaptive treatment techniques for prostate cancer radiation therapy with daily cone-beam CT (CBCT) imaging. Methods and Materials: Three treatment techniques were evaluated retrospectively using daily pre- and posttreatment CBCT images on 22 prostate cancer patients. Prostate, seminal vesicles (SV), rectal wall, and bladder were delineated on all CBCT images. For each patient, a pretreatment intensity modulated radiation therapy plan with clinical target volume (CTV) = prostate + SV and planning target volume (PTV) = CTV + 3 mm was created. The 3 treatment techniques were as follows: (1) Daily Correction: The pretreatment intensity modulated radiation therapy plan was delivered after online CBCT imaging, and position correction; (2) Online Planning: Daily online inverse plans with 3-mm CTV-to-PTV margin were created using online CBCT images, and delivered; and (3) Hybrid Adaption: Daily Correction plus an offline adaptive inverse planning performed after the first week of treatment. The adaptive plan was delivered for all remaining 15 fractions. Treatment dose for each technique was constructed using the daily posttreatment CBCT images via deformable image registration. Evaluation was performed using treatment dose distribution in target and critical organs. Results: Treatment equivalent uniform dose (EUD) for the CTV was within [85.6%, 100.8%] of the pretreatment planned target EUD for Daily Correction; [98.7%, 103.0%] for Online Planning; and [99.2%, 103.4%] for Hybrid Adaptation. Eighteen percent of the 22 patients in Daily Correction had a target dose deficiency >5%. For rectal wall, the mean ± SD of the normalized EUD was 102.6% ± 2.7% for Daily Correction, 99.9% ± 2.5% for Online Planning, and 100.6% ± 2.1% for Hybrid Adaptation. The mean ± SD of the normalized bladder EUD was 108.7% ± 8.2% for Daily Correction, 92.7% ± 8.6% for Online Planning, and 89.4% ± 10.8% for Hybrid

  16. A critical evaluation of the evidence supporting the practice of behavioural vision therapy.

    PubMed

    Barrett, Brendan T

    2009-01-01

    In 2000, the UK's College of Optometrists commissioned a report to critically evaluate the theory and practice of behavioural optometry. The report which followed Jennings (2000; Behavioural optometry--a critical review. Optom. Pract. 1: 67) concluded that there was a lack of controlled clinical trials to support behavioural management strategies. The purpose of this report was to evaluate the evidence in support of behavioural approaches as it stands in 2008. The available evidence was reviewed under 10 headings, selected because they represent patient groups/conditions that behavioural optometrists are treating, or because they represent approaches to treatment that have been advocated in the behavioural literature. The headings selected were: (1) vision therapy for accommodation/vergence disorders; (2) the underachieving child; (3) prisms for near binocular disorders and for producing postural change; (4) near point stress and low-plus prescriptions; (5) use of low-plus lenses at near to slow the progression of myopia; (6) therapy to reduce myopia; (7) behavioural approaches to the treatment of strabismus and amblyopia; (8) training central and peripheral awareness and syntonics; (9) sports vision therapy; (10) neurological disorders and neuro-rehabilitation after trauma/stroke. There is a continued paucity of controlled trials in the literature to support behavioural optometry approaches. Although there are areas where the available evidence is consistent with claims made by behavioural optometrists (most notably in relation to the treatment of convergence insufficiency, the use of yoked prisms in neurological patients, and in vision rehabilitation after brain disease/injury), a large majority of behavioural management approaches are not evidence-based, and thus cannot be advocated.

  17. Physician Evaluation of Internet Health Information on Proton Therapy for Prostate Cancer

    SciTech Connect

    Shah, Anand; Paly, Jonathan J.; Efstathiou, Jason A.; Bekelman, Justin E.

    2013-03-15

    Purpose: Many patients considering prostate cancer (PCa) treatment options report seeking proton beam therapy (PBT) based in part on information readily available on the Internet. There is, however, potential for considerable variation in Internet health information (IHI). We thus evaluated the characteristics, quality, and accuracy of IHI on PBT for PCa. Methods and Materials: We undertook a qualitative research study using snowball-purposive sampling in which we evaluated the top 50 Google search results for “proton prostate cancer.” Quality was evaluated on a 5-point scale using the validated 15-question DISCERN instrument. Accuracy was evaluated by comparing IHI with the best available evidence. Results: Thirty-seven IHI websites were included in the final sample. These websites most frequently were patient information/support resources (46%), were focused exclusively on PBT (51%), and had a commercial affiliation (38%). There was a significant difference in quality according to the type of IHI. Substantial inaccuracies were noted in the study sample compared with best available or contextual evidence. Conclusions: There are shortcomings in quality and accuracy in consumer-oriented IHI on PBT for PCa. Providers must be prepared to educate patients how to critically evaluate IHI related to PBT for PCa to best inform their treatment decisions.

  18. A proposed integrated approach for the preclinical evaluation of phage therapy in Pseudomonas infections.

    PubMed

    Danis-Wlodarczyk, Katarzyna; Vandenheuvel, Dieter; Jang, Ho Bin; Briers, Yves; Olszak, Tomasz; Arabski, Michal; Wasik, Slawomir; Drabik, Marcin; Higgins, Gerard; Tyrrell, Jean; Harvey, Brian J; Noben, Jean-Paul; Lavigne, Rob; Drulis-Kawa, Zuzanna

    2016-01-01

    Bacteriophage therapy is currently resurging as a potential complement/alternative to antibiotic treatment. However, preclinical evaluation lacks streamlined approaches. We here focus on preclinical approaches which have been implemented to assess bacteriophage efficacy against Pseudomonas biofilms and infections. Laser interferometry and profilometry were applied to measure biofilm matrix permeability and surface geometry changes, respectively. These biophysical approaches were combined with an advanced Airway Surface Liquid infection model, which mimics in vitro the normal and CF lung environments, and an in vivo Galleria larvae model. These assays have been implemented to analyze KTN4 (279,593 bp dsDNA genome), a type-IV pili dependent, giant phage resembling phiKZ. Upon contact, KTN4 immediately disrupts the P. aeruginosa PAO1 biofilm and reduces pyocyanin and siderophore production. The gentamicin exclusion assay on NuLi-1 and CuFi-1 cell lines revealed the decrease of extracellular bacterial load between 4 and 7 logs and successfully prevents wild-type Pseudomonas internalization into CF epithelial cells. These properties and the significant rescue of Galleria larvae indicate that giant KTN4 phage is a suitable candidate for in vivo phage therapy evaluation for lung infection applications. PMID:27301427

  19. The rational use of animal models in the evaluation of novel bone regenerative therapies.

    PubMed

    Peric, Mihaela; Dumic-Cule, Ivo; Grcevic, Danka; Matijasic, Mario; Verbanac, Donatella; Paul, Ruth; Grgurevic, Lovorka; Trkulja, Vladimir; Bagi, Cedo M; Vukicevic, Slobodan

    2015-01-01

    Bone has a high potential for endogenous self-repair. However, due to population aging, human diseases with impaired bone regeneration are on the rise. Current strategies to facilitate bone healing include various biomolecules, cellular therapies, biomaterials and different combinations of these. Animal models for testing novel regenerative therapies remain the gold standard in pre-clinical phases of drug discovery and development. Despite improvements in animal experimentation, excessive poorly designed animal studies with inappropriate endpoints and inaccurate conclusions are being conducted. In this review, we discuss animal models, procedures, methods and technologies used in bone repair studies with the aim to assist investigators in planning and performing scientifically sound experiments that respect the wellbeing of animals. In the process of designing an animal study for bone repair investigators should consider: skeletal characteristics of the selected animal species; a suitable animal model that mimics the intended clinical indication; an appropriate assessment plan with validated methods, markers, timing, endpoints and scoring systems; relevant dosing and statistically pre-justified sample sizes and evaluation methods; synchronization of the study with regulatory requirements and additional evaluations specific to cell-based approaches. This article is part of a Special Issue entitled "Stem Cells and Bone".

  20. A proposed integrated approach for the preclinical evaluation of phage therapy in Pseudomonas infections

    NASA Astrophysics Data System (ADS)

    Danis-Wlodarczyk, Katarzyna; Vandenheuvel, Dieter; Jang, Ho Bin; Briers, Yves; Olszak, Tomasz; Arabski, Michal; Wasik, Slawomir; Drabik, Marcin; Higgins, Gerard; Tyrrell, Jean; Harvey, Brian J.; Noben, Jean-Paul; Lavigne, Rob; Drulis-Kawa, Zuzanna

    2016-06-01

    Bacteriophage therapy is currently resurging as a potential complement/alternative to antibiotic treatment. However, preclinical evaluation lacks streamlined approaches. We here focus on preclinical approaches which have been implemented to assess bacteriophage efficacy against Pseudomonas biofilms and infections. Laser interferometry and profilometry were applied to measure biofilm matrix permeability and surface geometry changes, respectively. These biophysical approaches were combined with an advanced Airway Surface Liquid infection model, which mimics in vitro the normal and CF lung environments, and an in vivo Galleria larvae model. These assays have been implemented to analyze KTN4 (279,593 bp dsDNA genome), a type-IV pili dependent, giant phage resembling phiKZ. Upon contact, KTN4 immediately disrupts the P. aeruginosa PAO1 biofilm and reduces pyocyanin and siderophore production. The gentamicin exclusion assay on NuLi-1 and CuFi-1 cell lines revealed the decrease of extracellular bacterial load between 4 and 7 logs and successfully prevents wild-type Pseudomonas internalization into CF epithelial cells. These properties and the significant rescue of Galleria larvae indicate that giant KTN4 phage is a suitable candidate for in vivo phage therapy evaluation for lung infection applications.

  1. A proposed integrated approach for the preclinical evaluation of phage therapy in Pseudomonas infections

    PubMed Central

    Danis-Wlodarczyk, Katarzyna; Vandenheuvel, Dieter; Jang, Ho Bin; Briers, Yves; Olszak, Tomasz; Arabski, Michal; Wasik, Slawomir; Drabik, Marcin; Higgins, Gerard; Tyrrell, Jean; Harvey, Brian J.; Noben, Jean-Paul; Lavigne, Rob; Drulis-Kawa, Zuzanna

    2016-01-01

    Bacteriophage therapy is currently resurging as a potential complement/alternative to antibiotic treatment. However, preclinical evaluation lacks streamlined approaches. We here focus on preclinical approaches which have been implemented to assess bacteriophage efficacy against Pseudomonas biofilms and infections. Laser interferometry and profilometry were applied to measure biofilm matrix permeability and surface geometry changes, respectively. These biophysical approaches were combined with an advanced Airway Surface Liquid infection model, which mimics in vitro the normal and CF lung environments, and an in vivo Galleria larvae model. These assays have been implemented to analyze KTN4 (279,593 bp dsDNA genome), a type-IV pili dependent, giant phage resembling phiKZ. Upon contact, KTN4 immediately disrupts the P. aeruginosa PAO1 biofilm and reduces pyocyanin and siderophore production. The gentamicin exclusion assay on NuLi-1 and CuFi-1 cell lines revealed the decrease of extracellular bacterial load between 4 and 7 logs and successfully prevents wild-type Pseudomonas internalization into CF epithelial cells. These properties and the significant rescue of Galleria larvae indicate that giant KTN4 phage is a suitable candidate for in vivo phage therapy evaluation for lung infection applications. PMID:27301427

  2. Assessing Adverse Events of Postprostatectomy Radiation Therapy for Prostate Cancer: Evaluation of Outcomes in the Regione Emilia-Romagna, Italy

    SciTech Connect

    Showalter, Timothy N.; Hegarty, Sarah E.; Rabinowitz, Carol; Maio, Vittorio; Hyslop, Terry; Dicker, Adam P.; Louis, Daniel Z.

    2015-03-15

    Purpose: Although the likelihood of radiation-related adverse events influences treatment decisions regarding radiation therapy after prostatectomy for eligible patients, the data available to inform decisions are limited. This study was designed to evaluate the genitourinary, gastrointestinal, and sexual adverse events associated with postprostatectomy radiation therapy and to assess the influence of radiation timing on the risk of adverse events. Methods: The Regione Emilia-Romagna Italian Longitudinal Health Care Utilization Database was queried to identify a cohort of men who received radical prostatectomy for prostate cancer during 2003 to 2009, including patients who received postprostatectomy radiation therapy. Patients with prior radiation therapy were excluded. Outcome measures were genitourinary, gastrointestinal, and sexual adverse events after prostatectomy. Rates of adverse events were compared between the cohorts who did and did not receive postoperative radiation therapy. Multivariable Cox proportional hazards models were developed for each class of adverse events, including models with radiation therapy as a time-varying covariate. Results: A total of 9876 men were included in the analyses: 2176 (22%) who received radiation therapy and 7700 (78%) treated with prostatectomy alone. In multivariable Cox proportional hazards models, the additional exposure to radiation therapy after prostatectomy was associated with increased rates of gastrointestinal (rate ratio [RR] 1.81; 95% confidence interval [CI] 1.44-2.27; P<.001) and urinary nonincontinence events (RR 1.83; 95% CI 1.83-2.80; P<.001) but not urinary incontinence events or erectile dysfunction. The addition of the time from prostatectomy to radiation therapy interaction term was not significant for any of the adverse event outcomes (P>.1 for all outcomes). Conclusion: Radiation therapy after prostatectomy is associated with an increase in gastrointestinal and genitourinary adverse events. However

  3. Evaluating the Quality of Website Information of Private-Practice Clinics Offering Cell Therapies in Japan

    PubMed Central

    Nakayama, Takeo; Hatta, Taichi; Takahashi, Naomi; Fujita, Misao

    2016-01-01

    Background Although the safety and effectiveness of stem cell therapies are yet to be proven, recent studies show that such therapies are being advertised with some questionable marketing techniques to effect positive portrayal of the therapies on the webpages of private-practice clinics to sell their therapies worldwide. In such context, those clinics communicate directly with consumers (patients and their family members) via the clinics’ websites. Meanwhile, the Health Science Council at the Ministry of Health, Labour, and Welfare (MHLW) in Japan has pointed out noncompliance of some local clinics with the provisions concerning medical advertising in the Medical Care Act in the past. However, locally little is known about the current status of those clinics including the quality of their webpage information disseminated. Objective To evaluate the quality of website information of private-practice clinics offering cell therapies in Japan. Methods Twenty-four websites with 77 treatments from the Google search were identified for evaluation. The following three exploratory analyses were performed: first in order to ascertain web-based portrayal of private-practice clinics offering cell therapies, a descriptive analysis was conducted using a coding frame; second we evaluated the quality of the target website information from the viewpoint of the level of consideration taken for patients and their family members, using 10 quality criteria (“the Minimum Standard”) from the e-Health Code of Ethics 2.0; third we counted and coded expressions that matched set categories for “name-dropping” and “personalized medicine” in the information posted on these websites. Results Analysis on the treatments (N=77) revealed 126 indications (multiple response): the top three indications were “cancer,” “skin-rejuvenation/antiaging/anti–skin aging,” and “breast augmentation/buttock augmentation.” As for the portrayal of treatment risks and benefits, 78% (60

  4. Automated evaluation of setup errors in carbon ion therapy using PET: Feasibility study

    SciTech Connect

    Kuess, Peter Hopfgartner, Johannes; Georg, Dietmar; Helmbrecht, Stephan; Fiedler, Fine; Birkfellner, Wolfgang; Enghardt, Wolfgang

    2013-12-15

    particle therapy PET verification techniques in four indications. The automated detection of patients' setup errors was investigated in a broad accumulation of data sets. The evaluation of introduced setup errors is performed automatically, which is of utmost importance to introduce highly required particle therapy monitoring devices into the clinical routine.

  5. An Evaluation of Non-Surgical Periodontal Therapy in Patients with Rheumatoid Arthritis

    PubMed Central

    Roman-Torres, Caio V.G; Neto, José S; Souza, Marcio A; Schwartz-Filho, Humberto O; Brandt, William C; Diniz, Ricardo E.A.S

    2015-01-01

    aim of this study was to evaluate the efficacy of periodontal scaling and oral hygiene instruction for patients with mild chronic periodontitis and rheumatoid arthritis through clinical periodontal parameters and laboratory tests for CRP (C- reactive protein) and ESR (erythrocyte sedimentation rate). Twelve individuals with rheumatoid arthritis and 12 healthy individuals were evaluated, with a mean age of 45.38 and 46.75 respectively, all female and with mild, chronic periodontitis. The participants were evaluated clinically and periapical radiographs were taken (T1), after which periodontal treatment was instituted. After ninety days (T2), new clinical and laboratory data were obtained. Probing depth, bleeding index, and plaque indexes were observed in both groups, and the results demonstrated reductions but no statistical differences. Laboratory tests for CRP and ESR produced higher values for the rheumatoid arthritis group with T1- T2 reductions on the average, but the values were still higher than in the health group. We conclude that periodontal therapy in patients with rheumatoid arthritis and mild chronic periodontitis showed a improvement in the periodontal clinical parameters and laboratory tests that were evaluated. PMID:26140059

  6. Monitoring the autonomic nervous activity as the objective evaluation of music therapy for severely and multiply disabled children.

    PubMed

    Orita, Makiko; Hayashida, Naomi; Shinkawa, Tetsuko; Kudo, Takashi; Koga, Mikitoshi; Togo, Michita; Katayama, Sotetsu; Hiramatsu, Kozaburo; Mori, Shunsuke; Takamura, Noboru

    2012-01-01

    Severely and multiply disabled children (SMDC) are frequently affected in more than one area of development, resulting in multiple disabilities. The aim of the study was to evaluate the efficacy of music therapy in SMDC using monitoring changes in the autonomic nervous system, by the frequency domain analysis of heart rate variability. We studied six patients with SMDC (3 patients with cerebral palsy, 1 patient with posttraumatic syndrome after head injury, 1 patient with herpes encephalitis sequelae, and 1 patient with Lennox-Gastaut syndrome characterized by frequent seizures, developmental delay and psychological and behavioral problems), aged 18-26 (mean 22.5 ± 3.5). By frequency domain method using electrocardiography, we measured the high frequency (HF; with a frequency ranging from 0.15 to 0.4 Hz), which represents parasympathetic activity, the low frequency/high frequency ratio, which represents sympathetic activity between the sympathetic and parasympathetic activities, and heart rate. A music therapist performed therapy to all patients through the piano playing for 50 min. We monitored each study participant for 150 min before therapy, 50 min during therapy, and 10 min after therapy. Interestingly, four of 6 patients showed significantly lower HF components during music therapy than before therapy, suggesting that these four patients might react to music therapy through the suppression of parasympathetic nervous activities. Thus, music therapy can suppress parasympathetic nervous activities in some patients with SMDC. The monitoring changes in the autonomic nervous activities could be a powerful tool for the objective evaluation of music therapy in patients with SMDC.

  7. Development and evaluation of polycrystalline cadmium telluride dosimeters for accurate quality assurance in radiation therapy

    NASA Astrophysics Data System (ADS)

    Oh, K.; Han, M.; Kim, K.; Heo, Y.; Moon, C.; Park, S.; Nam, S.

    2016-02-01

    For quality assurance in radiation therapy, several types of dosimeters are used such as ionization chambers, radiographic films, thermo-luminescent dosimeter (TLD), and semiconductor dosimeters. Among them, semiconductor dosimeters are particularly useful for in vivo dosimeters or high dose gradient area such as the penumbra region because they are more sensitive and smaller in size compared to typical dosimeters. In this study, we developed and evaluated Cadmium Telluride (CdTe) dosimeters, one of the most promising semiconductor dosimeters due to their high quantum efficiency and charge collection efficiency. Such CdTe dosimeters include single crystal form and polycrystalline form depending upon the fabrication process. Both types of CdTe dosimeters are commercially available, but only the polycrystalline form is suitable for radiation dosimeters, since it is less affected by volumetric effect and energy dependence. To develop and evaluate polycrystalline CdTe dosimeters, polycrystalline CdTe films were prepared by thermal evaporation. After that, CdTeO3 layer, thin oxide layer, was deposited on top of the CdTe film by RF sputtering to improve charge carrier transport properties and to reduce leakage current. Also, the CdTeO3 layer which acts as a passivation layer help the dosimeter to reduce their sensitivity changes with repeated use due to radiation damage. Finally, the top and bottom electrodes, In/Ti and Pt, were used to have Schottky contact. Subsequently, the electrical properties under high energy photon beams from linear accelerator (LINAC), such as response coincidence, dose linearity, dose rate dependence, reproducibility, and percentage depth dose, were measured to evaluate polycrystalline CdTe dosimeters. In addition, we compared the experimental data of the dosimeter fabricated in this study with those of the silicon diode dosimeter and Thimble ionization chamber which widely used in routine dosimetry system and dose measurements for radiation

  8. Combined molecular docking, molecular dynamics simulation and quantitative structure-activity relationship study of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives as potent anti-HIV drugs

    NASA Astrophysics Data System (ADS)

    Deng, Fangfang; Xie, Meihong; Zhang, Xiaoyun; Li, Peizhen; Tian, Yueli; Zhai, Honglin; Li, Yang

    2014-06-01

    3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine is an antiretroviral agent, which can act against human immunodeficiency virus (HIV) infection, but the mechanism of action of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives remained ambiguous. In this study, multiple linear regression (MLR) was applied to establish a quite reliable model with the squared correlation coefficient (R2) of 0.8079. We also used chemical information descriptors based on the simplified molecular input line entry system (SMILES) to get a better model with R2 of 0.9086 for the training set, and R2 of 0.8031 for the test set. Molecular docking was utilized to provide more useful information between pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives and HIV-1 protease, such as active site, binding mode and important residues. Molecular dynamics simulation was employed to further validate the docking results. This work may lead to a better understanding of the mechanism of action and aid to design novel and more potent anti-HIV drugs.

  9. Antiretroviral Drug-Related Liver Mortality Among HIV-Positive Persons in the Absence of Hepatitis B or C Virus Coinfection: The Data Collection on Adverse Events of Anti-HIV Drugs Study

    PubMed Central

    Kovari, Helen; Sabin, Caroline A.; Ledergerber, Bruno; Ryom, Lene; Worm, Signe W.; Smith, Colette; Phillips, Andrew; Reiss, Peter; Fontas, Eric; Petoumenos, Kathy; De Wit, Stéphane; Morlat, Philippe; Lundgren, Jens D.; Weber, Rainer

    2013-01-01

    Background. Liver diseases are the leading causes of death in human immunodeficiency virus (HIV)–positive persons since the widespread use of combination antiretroviral treatment (cART). Most of these deaths are due to hepatitis C (HCV) or B (HBV) virus coinfections. Little is known about other causes. Prolonged exposure to some antiretroviral drugs might increase hepatic mortality. Methods. All patients in the Data Collection on Adverse Events of Anti-HIV Drugs study without HCV or HBV coinfection were prospectively followed from date of entry until death or last follow-up. In patients with liver-related death, clinical charts were reviewed using a structured questionnaire. Results. We followed 22 910 participants without hepatitis virus coinfection for 114 478 person-years. There were 12 liver-related deaths (incidence, 0.10/1000 person-years); 7 due to severe alcohol use and 5 due to established ART-related toxicity. The rate of ART-related deaths in treatment-experienced persons was 0.04/1000 person-years (95% confidence interval, .01, .10). Conclusions. We found a low incidence of liver-related deaths in HIV-infected persons without HCV or HBV coinfection. Liver-related mortality because of ART-related toxicity was rare. PMID:23090925

  10. Pharmacophore determination of a gp120 C terminal-derived anti-HIV peptide construct interfering with membrane fusion suggesting that processing of the gp120 C terminus is a prelude to fusion.

    PubMed

    Barbouche, R; Feyfant, E; Belhaj, B; Fenouillet, E

    2002-02-10

    A multiple antigen peptide [CLIV; (PTKAKRR1VVQREKR2)4-K2-K-betaA] from the C terminus of the gp120 subunit of HIV Env inhibits Env-mediated cell-to-cell fusion through direct interference with the process (Virology 2000;273:169). We have examined various CLIV analogs using a cell-to-cell fusion assay, receptor binding assays, and molecular modeling to further address the characteristics of the peptide responsible for its anti-HIV activity. We show that (1) CLIV does not interfere with Env binding to CD4 and does not interact with the binding site of Env on CXCR4; (2) CLIV does not inhibit protease activities already reported to play a role in fusion; and (3) the pharmacophore is composed of cleavage site1 with amino acid residues at its C terminal end. Based on our data and on the literature, we propose that CLIV interferes with processing of the gp120 C terminus at site1 by the lymphocyte surface after CD4 binding. Our hypothesis implies that the cleavage region of Env is submitted to a stepwise processing including the known intracellular cleavage of gp160 at site2 in order to set the activation of the fusion peptide and a yet unexplored cleavage at site1 by the target cell surface that triggers fusion.

  11. Technology evaluation: PRO-542, Progenics Pharmaceuticals inc.

    PubMed

    Mukhtar, M; Parveen, Z; Pomerantz, R J

    2000-12-01

    Progenics's rCD4-IgG2 (PRO-542) is a recombinant fusion protein, which has been developed using the company's Universal Antiviral Binding (UnAB) technology, and is in phase I/II clinical trials for the treatment of human immunodeficiency virus type I (HIV-1) infection [273391]. At the beginning of 1997, Progenics received a Phase II Small Business Innovation Research Program (SBIR) grant from the National Institute of Allergy and Infectious diseases (NIAID) to fund the development of PRO-542 [236048]. A further grant of $2.7 million was awarded in August 1998 for the clinical evaluation of PRO-542 and other anti-HIV therapies [294200]. Progenics is collaborating with the Aaron Diamond AIDS Research Center (ADARC) in New York and the Center for Disease Control and Prevention in Atlanta [178410]. In February 2000, Progenics and Genzyme Transgenics Corp signed an agreement to continue the development of a transgenic source of PRO-542. Genzyme will develop transgenic goats that produce PRO-542 in their milk in exchange for undisclosed fees and milestone payments. Genzyme will supply PRO-542 to Progenics for clinical trials with a possibility for eventual commercial supply [357291]. Following on from this, in October 2000, Progenics received an SBIR grant to fund a two-year project with Genzyme Transgenics into the development of cost-effective methods for the manufacture of PRO-542, by optimization of the production of the drug in the milk of transgenic dairy animals [385982]. In August 2000, Punk, Ziegel & Company predicted that Progenics Pharmaceuticals will become sustainably profitable in 2003 following the launch of PRO-542 and GMK (Progenics Pharmaceuticals) in 2002 [390063]. PMID:11249748

  12. Evaluation of the Effect of Low Level Laser Therapy Toothbrush in Treatment of Dentin Hypersensitivity

    PubMed Central

    Yaghini, Jaber; Mogharehabed, Ahmad; Safavi, Nassimeh; Mohamadi, Mehrnush; Ashtiju, Fahime

    2015-01-01

    Introduction: Dentin hypersensitivity is one of the most common complications that affect patients after periodontal therapy. Recently low level laser therapy has been introduced as a new treatment modality and has produced beneficial results. The purpose of this study is to evaluate the effect of low level laser therapy toothbrushes in reduction of dentin hypersensitivity. Methods: In this pilot interventional controlled clinical trial, 40 patients suffering from dentin hypersensitivity were selected using simple randomization. Half of the patients were given laser toothbrushes and the other half was given non-laser sensodyne toothbrushes. Primary dentin hypersensitivity was recorded by visual analogue scale (VAS) score and ice spray. Then dentin hypersensitivity was measured right after the treatment as well az in the intervals of 1 month and 2 months after initiation of the study. Data were compared using Statistical Package for the Social Sciences (SPSS) software and Analysis of variance (ANOVA) paired T test. Results: The results of this study showed that there was a significant difference in each of the two kinds of tooth brushes separately for all time intervals (P < 0.001). Also the effect of the type of toothbrush was investigated using before treatment VAS with covariance analyses. P values for immediately, 1 month and 2 months after treatment were calculated to be 0.078, 0.02, 0.01 respectfully. Also the effect of the toothbrush type was significant in the manner that laser toothbrushes reduce dentin hypersensitivity more than ordinary toothbrushes (P< 0.05). Conclusion: Both sensodyne and laser tooth brushes improve dentin hypersensitivity, although the laser toothbrush led to better results in short. PMID:25987974

  13. Optimum scratch assay condition to evaluate connective tissue growth factor expression for anti-scar therapy.

    PubMed

    Moon, Heekyung; Yong, Hyeyoung; Lee, Ae-Ri Cho

    2012-02-01

    To evaluate a potential anti-scar therapy, we first need to have a reliable in vitro wound model to understand dermal fibroblast response upon cell injury and how cytokine levels are changed upon different wound heal phases. An in vitro wound model with different scratch assay conditions on primary human foreskin fibroblast monolayer cultures was prepared and cytokine levels and growth properties were evaluated with the aim of determining optimum injury conditions and observation time. Morphological characteristics of differently scratched fibroblasts from 0 to 36 h post injury (1 line, 2 lines and 3 lines) were investigated. The expression of connective tissue growth factor, CTGF, which is a key mediator in hyper-tropic scarring, and relative intensity of CTGF as a function of time were determined by western blot and gelatin Zymography. After injury (1 line), CTGF level was increased more than 2-fold within 1 h and continuously increased up to 3-fold at 6 h and was leveled down to reach normal value at 36 h, at which cell migration was complete. In more serious injury (2 lines), higher expression of CTGF was observed. The down regulation of CTGF expression after CTGF siRNA/lipofectamine transfection in control, 1 line and 2 lines scratch conditions were 40%, 75% and 55%, respectively. As a model anti-CTGF based therapy, CTGF siRNA with different ratios of linear polyethyleneimine (PEI) complexes (1:1, 1:5, 1:10, 1:20 and 1:30) were prepared and down-regulation efficacy of CTGF was evaluated with our optimized scratch assay, which is 1 line injury at 6 h post injury observation time. As the cationic linear PEI ratio increased, the down regulation efficacy was increased from 20% (1:20) to 55% (1:30). As CTGF level was increased to the highest at 6 h and leveled down afterwards, CTGF level at 6 h could provide the most sensitive response upon CTGF siRNA transfection. The scratch assay in the present study can be employed as a useful experimental tool to differentiate

  14. Dosimetric evaluation of new approaches in GRID therapy using nonconventional radiation sources

    SciTech Connect

    Martínez-Rovira, I. Prezado, Y.; Fois, G.

    2015-02-15

    Purpose: Spatial fractionation of the dose has proven to be a promising approach to increase the tolerance of healthy tissue, which is the main limitation of radiotherapy. A good example of that is GRID therapy, which has been successfully used in the management of large tumors with low toxicity. The aim of this work is to explore new avenues using nonconventional sources: GRID therapy by using kilovoltage (synchrotron) x-rays, the use of very high-energy electrons, and proton GRID therapy. They share in common the use of the smallest possible grid sizes in order to exploit the dose–volume effects. Methods: Monte Carlo simulations (PENELOPE/PENEASY and GEANT4/GATE codes) were used as a method to study dose distributions resulting from irradiations in different configurations of the three proposed techniques. As figure of merit, percentage (peak and valley) depth dose curves, penumbras, and central peak-to-valley dose ratios (PVDR) were evaluated. As shown in previous biological experiments, high PVDR values are requested for healthy tissue sparing. A superior tumor control may benefit from a lower PVDR. Results: High PVDR values were obtained in the healthy tissue for the three cases studied. When low energy photons are used, the treatment of deep-seated tumors can still be performed with submillimetric grid sizes. Superior PVDR values were reached with the other two approaches in the first centimeters along the beam path. The use of protons has the advantage of delivering a uniform dose distribution in the tumor, while healthy tissue benefits from the spatial fractionation of the dose. In the three evaluated techniques, there is a net reduction in penumbra with respect to radiosurgery. Conclusions: The high PVDR values in the healthy tissue and the use of small grid sizes in the three presented approaches might constitute a promising alternative to treat tumors with such spatially fractionated radiotherapy techniques. The dosimetric results presented here

  15. Evaluation and art therapy treatment of the burnout syndrome in oncology units.

    PubMed

    Italia, Simona; Favara-Scacco, Cinzia; Di Cataldo, Andrea; Russo, Giovanna

    2008-07-01

    We undertook a pilot study to evaluate and potentially reduce the level of burnout in the operators of two oncology centers. The study included 65 doctors and nurses of an adult (Group A) and a pediatric oncology unit (Group B). We used the Maslach Burnout Inventory to estimate the level of burnout obtained in three dimensions: emotional exhaustion, distancing (cognitive and emotional) and reduced personal achievement. Data showed a medium-high level of burnout in Group A and a medium-low level in Group B. In the second part of the study, Group B underwent a program of art therapy interventions with the aim of reducing the level of burnout. Comparing the responses from Group B participants before and after the intervention indicated a statistically significant decreased level of burnout. In conclusion, burnout syndrome exists among oncology unit personnel and can be effectively treated with art therapies. Attention devoted to this aspect is required in order to improve the workers' well-being, thus enhancing attention and dedication to patients.

  16. [Evaluation of cancer therapy from the perspective of a statutory health insurance].

    PubMed

    Rebscher, H; Schellhammer, S; Kopp, T; Scharnetzky, E

    2011-12-01

    Increasing life expectancy, the introduction of costly new drugs and contributions from the health fund which do not cover overall costs, all contribute to financial problems for statutory health insurances (SHI) in oncology. Only an evidence-based approach can help to address these problems. In a first step patient-relevant benefits have to be substantiated as a necessary prerequisite for coverage of any treatment by SHIs. For products with no additional benefit compared to established forms of therapy the price will be limited by the established cost-benefit ratio. For products with additional benefits pricing is more difficult. For this situation the Institute for Quality and Efficiency in Healthcare (IQWiG) has developed general methods for the assessment of the relation of benefits to costs. Pricing based on this health economic evaluation is developed using efficiency frontier plots. However, this method is prone to manipulation and needs to be refined. Therapies without comparators, so-called soloists, cannot be priced in this way. New approaches to increase cost efficiency need to be developed in order to ensure the availability of high quality care in the future.

  17. Evaluation of Antimicrobial Therapy of Blood Culture Positive Healthcare-Associated Infections in Children

    PubMed Central

    Vaara, Martti; Anttila, Veli-Jukka; Hoppu, Kalle; Laaksonen, Raisa; Airaksinen, Marja

    2015-01-01

    Aim Knowledge of the quality of antimicrobial therapy (AMT) used for invasive healthcare-associated infections (HAIs) in paediatrics is scarce. Influence of the final information about the isolated pathogen on the subsequent targeted AMT was investigated in our study. Methods Data on 149 children (0–17 years) with blood culture positive HAIs were collected. The causative microbes under investigation were Staphylococcus aureus, Staphylococcus epidermidis, streptococci, Gram negative rods, and mixed infections were likewise included. For adjusting the antimicrobial regimen, an expert panel evaluated the quality of the targeted AMT and the delay of 72 hours after final microbiology results. AMT was regarded as inappropriate if the pathogen was totally resistant to the used antimicrobials (i) or if the chosen therapy was of not optimal efficacy against the pathogen (ii). Results 17% of the patients received inappropriate AMT. Half of these infections 13/26 (50%) were treated with an antimicrobial to which the isolate was resistant. Three (3/13, 23%) of these patients received antimicrobials which were totally ineffective according to in vitro data. Suboptimal or too broad spectrum AMT was administered to 13/26 (50%) patients. The most common causes of inappropriate use were the use of beta-lactams in oxacillin-resistant Staphylococcus epidermidis infections and vancomycin given in oxacillin-sensitive Staphylococcus aureus infections. Conclusion Approximately 17% of the selected cohort received inappropriate AMT. More attention should be paid to the appropriate use of antimicrobials, and training of prescribers should be urgently provided. PMID:26539831

  18. Pleiotrophin Gene Therapy for Peripheral Ischemia: Evaluation of Full-Length and Truncated Gene Variants

    PubMed Central

    Fang, Qizhi; Mok, Pamela Y.; Thomas, Anila E.; Haddad, Daniel J.; Saini, Shereen A.; Clifford, Brian T.; Kapasi, Neel K.; Danforth, Olivia M.; Usui, Minako; Ye, Weisheng; Luu, Emmy; Sharma, Rikki; Bartel, Maya J.; Pathmanabhan, Jeremy A.; Ang, Andrew A. S.; Sievers, Richard E.; Lee, Randall J.; Springer, Matthew L.

    2013-01-01

    Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model. PMID:23630585

  19. An evaluation of combination second molar extraction and functional appliance therapy.

    PubMed

    Whitney, E F; Sinclair, P M

    1987-03-01

    The purpose of this study was to examine the results of a treatment regimen involving the extraction of four second molars followed by a combination of sagittal, Bionator, and fixed appliance therapy. The pretreatment and posttreatment cephalometric and dental cast records of 30 consecutively treated Class II, Division 1 cases were evaluated. Results showed that the Class II skeletal correction was achieved by a "headgear" effect inhibiting maxillary growth in conjunction with normal forward mandibular growth. No significant distal bodily movement or tipping of either maxillary or mandibular first molars was found. Significant increases were seen in maxillary arch length, maxillary intercanine and intermolar width, and mandibular intermolar width as a result of treatment. Maxillary third molar position tended to improve following second molar extraction; mandibular third molar changes were more variable.

  20. Magnetic resonance imaging evaluation of lipodystrophy in HIV-positive patients receiving highly active antiretroviral therapy.

    PubMed

    Eichler, K; Bickel, T M; Klauke, S; Eisen, J; Vogl, T J; Zangos, S

    2015-07-01

    We evaluated retrospectively an automated method for the separate detection of subcutaneous and visceral fat in the abdominal region by magnetic resonance studies in HIV-positive patients on highly active antiretroviral therapy. The patients were divided into four different groups: lipoatrophy, lipohypertrophy, mixed and the control group. The use of software for the automated detection of abdominal compartment visceral adipose tissue (VAT), total adipose tissue (TAT) and subcutaneous adipose tissue (SAT) was compared to manual evaluation methods (fuzzy C-mean). The results of ROC analysis showed that the parameters, particularly the VAT, are better than the VAT/TAT and at identifying patients with the symptoms of abdominal fat accumulation. A sensitivity of 80.3% and a specificity of 79.5% resulted from a threshold VAT value of >87 cm(2). Moreover, the manual evaluation method was shown to provide greater values for VAT and the VAT/TAT ratio than those given by the automated method. In the present study, a rapid MRI protocol for the detection and assessment of the course of lipodystrophy was presented and tested on a group of patients with signs of HALS, as well as on an antiretroviral naïve control group.

  1. A CT-based software tool for evaluating compensator quality in passively scattered proton therapy

    NASA Astrophysics Data System (ADS)

    Li, Heng; Zhang, Lifei; Dong, Lei; Sahoo, Narayan; Gillin, Michael T.; Zhu, X. Ronald

    2010-11-01

    We have developed a quantitative computed tomography (CT)-based quality assurance (QA) tool for evaluating the accuracy of manufactured compensators used in passively scattered proton therapy. The thickness of a manufactured compensator was measured from its CT images and compared with the planned thickness defined by the treatment planning system. The difference between the measured and planned thicknesses was calculated with use of the Euclidean distance transformation and the kd-tree search method. Compensator accuracy was evaluated by examining several parameters including mean distance, maximum distance, global thickness error and central axis shifts. Two rectangular phantoms were used to validate the performance of the QA tool. Nine patients and 20 compensators were included in this study. We found that mean distances, global thickness errors and central axis shifts were all within 1 mm for all compensators studied, with maximum distances ranging from 1.1 to 3.8 mm. Although all compensators passed manual verification at selected points, about 5% of the pixels still had maximum distances of >2 mm, most of which correlated with large depth gradients. The correlation between the mean depth gradient of the compensator and the percentage of pixels with mean distance <1 mm is -0.93 with p < 0.001, which suggests that the mean depth gradient is a good indicator of compensator complexity. These results demonstrate that the CT-based compensator QA tool can be used to quantitatively evaluate manufactured compensators.

  2. A model evaluation study for treatment planning of laser-induced thermal therapy.

    PubMed

    Fahrenholtz, Samuel J; Moon, Tim Y; Franco, Michael; Medina, David; Danish, Shabbar; Gowda, Ashok; Shetty, Anil; Maier, Florian; Hazle, John D; Stafford, Roger J; Warburton, Tim; Fuentes, David

    2015-01-01

    A cross-validation analysis evaluating computer model prediction accuracy for a priori planning magnetic resonance-guided laser-induced thermal therapy (MRgLITT) procedures in treating focal diseased brain tissue is presented. Two mathematical models are considered. (1) A spectral element discretisation of the transient Pennes bioheat transfer equation is implemented to predict the laser-induced heating in perfused tissue. (2) A closed-form algorithm for predicting the steady-state heat transfer from a linear superposition of analytic point source heating functions is also considered. Prediction accuracy is retrospectively evaluated via leave-one-out cross-validation (LOOCV). Modelling predictions are quantitatively evaluated in terms of a Dice similarity coefficient (DSC) between the simulated thermal dose and thermal dose information contained within N = 22 MR thermometry datasets. During LOOCV analysis, the transient model's DSC mean and median are 0.7323 and 0.8001 respectively, with 15 of 22 DSC values exceeding the success criterion of DSC ≥ 0.7. The steady-state model's DSC mean and median are 0.6431 and 0.6770 respectively, with 10 of 22 passing. A one-sample, one-sided Wilcoxon signed-rank test indicates that the transient finite element method model achieves the prediction success criteria, DSC ≥ 0.7, at a statistically significant level.

  3. A Model Evaluation Study for Treatment Planning of Laser Induced Thermal Therapy

    PubMed Central

    Fahrenholtz, S.; Moon, T.; Franco, M.; Medina, D.; Danish, S.; Gowda, A.; Shetty, A.; Maier, F.; Hazle, J. D.; Stafford, R. J.; Warburton, T.; Fuentes, D.

    2016-01-01

    A cross validation analysis evaluating computer model prediction accuracy for a priori planning magnetic resonance-guided laser induced thermal therapy (MRgLITT) procedures in treating focal diseased brain tissue is presented. Two mathematical models are considered. (1) A spectral element discretization of the transient Pennes bioheat transfer equation is implemented to predict the laser induced heating in perfused tissue. (2) A closed-form algorithm for predicting the steady state heat transfer from a linear superposition of analytic point source heating functions is also considered. Prediction accuracy is retrospectively evaluated via leave-one-out cross validation (LOOCV). Modeling predictions are quantitatively evaluated in terms of a Dice similarity coefficient (DSC) between the simulated thermal dose and thermal dose information contained within N = 22 MR thermometry datasets. During LOOCV analysis, the transient model’s DSC mean and median is 0.7323 and 0.8001, respectively, with 15 of 22 DSC values exceeding the success criterion of DSC ≥ 0.7. The steady state model’s DSC mean and median is 0.6431 and 0.6770, respectively, with 10 of 22 passing. A one-sample, one-sided Wilcoxon signed rank test indicates that the transient FEM model achieves the prediction success critera, DSC ≥ 0.7, at a statistically significant level. PMID:26368014

  4. Evaluation of polyelectrolyte complex-based scaffolds for mesenchymal stem cell therapy in cardiac ischemia treatment.

    PubMed

    Ceccaldi, Caroline; Bushkalova, Raya; Alfarano, Chiara; Lairez, Olivier; Calise, Denis; Bourin, Philippe; Frugier, Celine; Rouzaud-Laborde, Charlotte; Cussac, Daniel; Parini, Angelo; Sallerin, Brigitte; Fullana, Sophie Girod

    2014-02-01

    Three-dimensional (3D) scaffolds hold great potential for stem cell-based therapies. Indeed, recent results have shown that biomimetic scaffolds may enhance cell survival and promote an increase in the concentration of therapeutic cells at the injury site. The aim of this work was to engineer an original polymeric scaffold based on the respective beneficial effects of alginate and chitosan. Formulations were made from various alginate/chitosan ratios to form opposite-charge polyelectrolyte complexes (PECs). After freeze-drying, the resultant matrices presented a highly interconnected porous microstructure and mechanical properties suitable for cell culture. In vitro evaluation demonstrated their compatibility with mesenchymal stell cell (MSC) proliferation and their ability to maintain paracrine activity. Finally, the in vivo performance of seeded 3D PEC scaffolds with a polymeric ratio of 40/60 was evaluated after an acute myocardial infarction provoked in a rat model. Evaluation of cardiac function showed a significant increase in the ejection fraction, improved neovascularization, attenuated fibrosis as well as less left ventricular dilatation as compared to an animal control group. These results provide evidence that 3D PEC scaffolds prepared from alginate and chitosan offer an efficient environment for 3D culturing of MSCs and represent an innovative solution for tissue engineering.

  5. Preclinical evaluation of dual action intranasal formulation intended for postoperative/cancer associated therapies.

    PubMed

    El-Setouhy, Doaa Ahmed; Ahmed, Sami; Badawi, Alia Abd El-Latif; El-Nabarawi, Mohamed Ahmed; Sallam, Nada

    2015-08-30

    Granisetron hydrochloride is a potent antiemetic yet experiencing first pass metabolism. Ketorolac tromethamine is a potent analgesic NSAID that is known to cause gastrointestinal complications. The purpose of this study is to prepare combined in situ nasal copolymer thermal gel combining both drugs for the management of postoperative and cancer associated nausea, vomiting and pain while avoiding the problems associated with their therapy. In situ gelling nasal formulations with/without different mucoadhesive polymers were prepared and evaluated. Viscosity of different formulations was measured and correlated to in-vitro drug release. Selected formulae were evaluated for in-vivo mucociliary transit time. Based on in-vitro release pattern and mucociliary transit time, the selected formula F4 was evaluated for chemical and thermal anti-nociception activity in rats following intranasal or intraperitoneal administration. Only the intra-nasal administration of the selected formulation F4 showed significant analgesia against chemical nociception during both the early and late phases. Also, intranasal administration of the selected formulation F4 showed significant analgesia against thermal nociception. F4 intranasal formulation may offer higher therapeutic value than oral administration as it may not only avoid granisetron first pass metabolism but may also minimize ketorolac gastrointestinal adverse effects as well. PMID:25917526

  6. Gold-nanobeacons for gene therapy: evaluation of genotoxicity, cell toxicity and proteome profiling analysis.

    PubMed

    Conde, João; Larguinho, Miguel; Cordeiro, Ana; Raposo, Luís R; Costa, Pedro M; Santos, Susana; Diniz, Mário S; Fernandes, Alexandra R; Baptista, Pedro V

    2014-08-01

    Antisense therapy is a powerful tool for post-transcriptional gene silencing suitable for down-regulating target genes associated to disease. Gold nanoparticles have been described as effective intracellular delivery vehicles for antisense oligonucleotides providing increased protection against nucleases and targeting capability via simple surface modification. We constructed an antisense gold-nanobeacon consisting of a stem-looped oligonucleotide double-labelled with 3'-Cy3 and 5'-Thiol-C6 and tested for the effective blocking of gene expression in colorectal cancer cells. Due to the beacon conformation, gene silencing was directly detected as fluorescence increases with hybridisation to target, which can be used to assess the level of silencing. Moreover, this system was extensively evaluated for the genotoxic, cytotoxic and proteomic effects of gold-nanobeacon exposure to cancer cells. The exposure was evaluated by two-dimensional protein electrophoresis followed by mass spectrometry to perform a proteomic profile and 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay, glutathione-S-transferase assay, micronucleus test and comet assay to assess the genotoxicity. This integrated toxicology evaluation showed that the proposed nanotheranostics strategy does not exhibit significant toxicity, which is extremely relevant when translating into in vivo systems.

  7. Optimization of Collimator Trajectory in Volumetric Modulated Arc Therapy: Development and Evaluation for Paraspinal SBRT

    SciTech Connect

    Zhang Pengpeng; Happersett, Laura; Yang Yingli; Yamada, Yoshiya; Mageras, Gig; Hunt, Margie

    2010-06-01

    Purpose: To develop a collimator trajectory optimization paradigm for volumetric modulated arc therapy (VMAT) and evaluate this technique in paraspinal stereotactic body radiation therapy (SBRT). Method and Materials: We propose a novel VMAT paradigm, Coll-VMAT, which integrates collimator rotation with synchronized gantry rotation, multileaf collimator (MLC) motion, and dose-rate modulation. At each gantry angle a principal component analysis (PCA) is applied to calculate the primary cord orientation. The collimator angle is then aligned so that MLC travel is parallel to the PCA-derived direction. An in-house VMAT optimization follows the geometry-based collimator trajectory optimization to obtain the optimal MLC position and monitor units (MU) at each gantry angle. A treatment planning study of five paraspinal SBRT patients compared Coll-VMAT to standard VMAT (fixed collimator angle) and static field IMRT plans. Plan evaluation statistics included planning target volume (PTV) V95%, PTV-D95%, cord-D05%, and total beam-on time. Results: Variation of collimator angle in Coll-VMAT plans ranges from 26 deg. to 54 deg., with a median of 40 deg. Patient-averaged PTV V95% (94.6% Coll-VMAT vs. 92.1% VMAT and 93.3% IMRT) and D95% (22.5 Gy vs. 21.4 Gy and 22.0 Gy, respectively) are highest with Coll-VMAT, and cord D05% (9.8 Gy vs. 10.0 Gy and 11.7 Gy) is lowest. Total beam-on time with Coll-VMAT (5,164 MU) is comparable to standard VMAT (4,868 MU) and substantially lower than IMRT (13,283 MU). Conclusion: Collimator trajectory optimization-based VMAT provides an additional degree of freedom that can improve target coverage and cord sparing of paraspinal SBRT plans compared with standard VMAT and IMRT approaches.

  8. Monte Carlo fluence simulation for prospective evaluation of interstitial photodynamic therapy treatment plans

    NASA Astrophysics Data System (ADS)

    Cassidy, Jeffrey; Betz, Vaughn; Lilge, Lothar

    2015-03-01

    Photodynamic therapy (PDT) delivers a localized cytotoxic dose that is a function of tissue oxygen availability, photosensitive drug concentration, and light fluence. Providing safe and effective PDT requires an understanding of all three elements and the physiological response to the radicals generated. Interstitial PDT (IPDT) for solid tumours poses particular challenges due to complex organ geometries and the associated limitations for diffusion theory based fluence rate prediction, in addition to restricted access for light delivery and dose monitoring. As a first step towards enabling a complete prospective IPDT treatment-planning platform, we demonstrate use of our previously developed FullMonte tetrahedral Monte Carlo simulation engine for modeling of the interstitial fluence field due to intravesicular insertion of brief light sources. The goal is to enable a complete treatment planning and monitoring work flow analogous to that used in ionizing radiation therapy, including plan evaluation through dose-volume histograms and algorithmic treatment plan optimization. FullMonte is to our knowledge the fastest open-source tetrahedral MC light propagation software. Using custom hardware acceleration, we achieve 4x faster computing with 67x better power efficiency for limited-size meshes compared to the software. Ongoing work will improve the performance advantage to 16x with unlimited mesh size, enabling algorithmic plan optimization in reasonable time. Using FullMonte, we demonstrate significant new plan-evaluation capabilities including fluence field visualization, generation of organ dose-volume histograms, and rendering of isofluence surfaces for a representative bladder cancer mesh from a real patient. We also discuss the advantages of MC simulations for dose-volume histogram generation and the need for online personalized fluence-rate monitoring.

  9. Efficacy of combination therapy for systolic blood pressure in patients with severe systolic hypertension: the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study.

    PubMed

    Neutel, Joel M; Smith, David H G; Weber, Michael A; Schofield, Lesley; Purkayastha, Das; Gatlin, Marjorie

    2005-11-01

    Systolic hypertension is predominant among patients over 50 years of age, is a more important cardiovascular risk factor than diastolic blood pressure, and is more difficult to control than diastolic blood pressure. Consequently, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends combination therapy as first-line treatment for patients with stage 2 hypertension. In the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study, 24-hour ambulatory blood pressure monitoring was used to identify patients with systolic hypertension and to determine the impact of 8 weeks of treatment with either amlodipine besylate/benazepril HCl 5/20 mg combination therapy (n=149), amlodipine besylate 5 mg (n=146), or benazepril HCl 20 mg (n=148). Combination therapy was significantly more effective in reducing systolic blood pressure and pulse pressure than either monotherapy (p<0.0001). Significantly greater percentages of patients in the combination group compared with either monotherapy achieved blood pressure control (p<0.0001). Adverse events were low in all three treatment arms, with less peripheral edema in the combination group than in the amlodipine-treated group. The combination of amlodipine besylate/benazepril HCl given to patients with stage 2 systolic hypertension resulted in significantly greater reductions in blood pressure and pulse pressure than those seen with monotherapy and was at least as well tolerated as the separate components. This data supports the recommendation of the JNC 7 for the use of combination therapy in patients with stage 2 hypertension. PMID:16278521

  10. Strategies for inhibiting function of HIV-1 accessory proteins: a necessary route to AIDS therapy?

    PubMed

    Richter, S N; Frasson, I; Palù, G

    2009-01-01

    The Human Immunodeficiency Virus (HIV) genome encodes three major structural proteins common to all retroviruses (Gag, Pol and Env), two regulatory proteins (Tat and Rev) that are essential for viral replication, and four accessory proteins (Nef, Vif, Vpu, Vpr). While accessory proteins were initially reported to be unnecessary for viral growth, their importance as virulence factors is now being more and more appreciated: they can dramatically alter the course and severity of viral infection, replication and disease progression. None of the HIV accessory proteins display enzymatic activity: they rather act altering cellular pathways via multiple protein-protein interactions with a number of host cell factors. All currently approved anti-HIV drugs target pol and env encoded proteins. Therefore, widening the molecular targets of HIV therapy by additionally targeting accessory proteins may expand treatment options, resulting in high impact effective new therapy. In this review we present the state of the art of compounds that target HIV accessory proteins. Most of the research has focused on the inhibition of specific accessory proteins/host cell partner interactions. Promising compounds have been found within different classes of molecules: small natural and synthetic molecules, peptides and proteins, oligonucleotides, in particular those used as RNA interference (RNAi) tools. With the assortment of compounds available, especially against Nef and Vif functions, the demonstration of the clinical efficacy of the new anti-HIV-1 drugs targeting accessory proteins is next challenge.

  11. Highly active antiretroviral therapy potently suppresses HIV infection in humanized Rag2-/-gammac-/- mice.

    PubMed

    Sango, Kaori; Joseph, Aviva; Patel, Mahesh; Osiecki, Kristin; Dutta, Monica; Goldstein, Harris

    2010-07-01

    Humanized Rag2(-/-)gamma(c)(-/-) mice (Hu-DKO mice) become populated with functional human T cells, B cells, and dendritic cells following transplantation with human hematopoietic stem cells (HSC) and represent an improved model for studying HIV infection in vivo. In the current study we demonstrated that intrasplenic inoculation of hu-DKO mice with HIV-1 initiated a higher level of HIV infection than intravenous or intraperitoneal inoculation, associated with a reciprocal decrease in peripheral CD4(+) T cells and increase in peripheral CD8(+) T cells. HIV infection by intrasplenic injection increased serum levels of human IgG and IgM including human IgM and IgG specific for HIV-1 gp120. There was a significant inverse correlation between the level of HIV-1 infection and the extent of CD4(+) T cell depletion. Highly active antiretroviral therapy (HAART) initiated 1 week after HIV-1 inoculation markedly suppressed HIV-1 infection and prevented CD4(+) T cell depletion. Taken together, these findings demonstrate that intrasplenic injection of hu-DKO mice with HIV is a more efficient route of HIV infection than intravenous or intraperitoneal injection and generates increased infection associated with an increased anti-HIV humoral response. This animal model can serve as a valuable in vivo model to study the efficacy of anti-HIV therapies.

  12. Development of a Novel Anti-HIV-1 Agent from within: Effect of Chimeric Vpr-Containing Protease Cleavage Site Residues on Virus Replication

    NASA Astrophysics Data System (ADS)

    Serio, D.; Rizvi, T. A.; Cartas, M.; Kalyanaraman, V. S.; Weber, I. T.; Koprowski, H.; Srinivasan, A.

    1997-04-01

    Effective antiviral agents will be of great value in controlling virus replication and delaying the onset of HIV-1-related disease symptoms. Current therapy involves the use of antiviral agents that target the enzymatic functions of the virus, resulting in the emergence of resistant viruses to these agents, thus lowering their effectiveness. To overcome this problem, we have considered the idea of developing novel agents from within HIV-1 as inhibitors of virus replication. The specificity of the Vpr protein for the HIV-1 virus particle makes it an attractive molecule for the development of antiviral agents targeting the events associated with virus maturation. We have generated chimeric Vpr proteins containing HIV-1-specific sequences added to the C terminus of Vpr. These sequences correspond to nine cleavage sites of the Gag and Gag-Pol precursors of HIV-1. The chimeric Vpr constructs were introduced into HIV-1 proviral DNA to assess their effect on virus infectivity using single- and multiple-round replication assays. The virus particles generated exhibited a variable replication pattern depending on the protease cleavage site used as a fusion partner. Interestingly, the chimeric Vpr containing the cleavage sequences from the junction of p24 and p2, 24/2, completely abolished virus infectivity. These results show that chimeric proteins generated from within HIV-1 have the ability to suppress HIV-1 replication and make ideal agents for gene therapy or intracellular immunization to treat HIV-1 infection.

  13. Development of a novel anti-HIV-1 agent from within: effect of chimeric Vpr-containing protease cleavage site residues on virus replication.

    PubMed

    Serio, D; Rizvi, T A; Cartas, M; Kalyanaraman, V S; Weber, I T; Koprowski, H; Srinivasan, A

    1997-04-01

    Effective antiviral agents will be of great value in controlling virus replication and delaying the onset of HIV-1-related disease symptoms. Current therapy involves the use of antiviral agents that target the enzymatic functions of the virus, resulting in the emergence of resistant viruses to these agents, thus lowering their effectiveness. To overcome this problem, we have considered the idea of developing novel agents from within HIV-1 as inhibitors of virus replication. The specificity of the Vpr protein for the HIV-1 virus particle makes it an attractive molecule for the development of antiviral agents targeting the events associated with virus maturation. We have generated chimeric Vpr proteins containing HIV-1-specific sequences added to the C terminus of Vpr. These sequences correspond to nine cleavage sites of the Gag and Gag-Pol precursors of HIV-1. The chimeric Vpr constructs were introduced into HIV-1 proviral DNA to assess their effect on virus infectivity using single- and multiple-round replication assays. The virus particles generated exhibited a variable replication pattern depending on the protease cleavage site used as a fusion partner. Interestingly, the chimeric Vpr containing the cleavage sequences from the junction of p24 and p2, 24/2, completely abolished virus infectivity. These results show that chimeric proteins generated from within HIV-1 have the ability to suppress HIV-1 replication and make ideal agents for gene therapy or intracellular immunization to treat HIV-1 infection.

  14. Development of a novel anti-HIV-1 agent from within: Effect of chimeric Vpr-containing protease cleavage site residues on virus replication

    PubMed Central

    Serio, D.; Rizvi, T. A.; Cartas, M.; Kalyanaraman, V. S.; Weber, I. T.; Koprowski, H.; Srinivasan, A.

    1997-01-01

    Effective antiviral agents will be of great value in controlling virus replication and delaying the onset of HIV-1-related disease symptoms. Current therapy involves the use of antiviral agents that target the enzymatic functions of the virus, resulting in the emergence of resistant viruses to these agents, thus lowering their effectiveness. To overcome this problem, we have considered the idea of developing novel agents from within HIV-1 as inhibitors of virus replication. The specificity of the Vpr protein for the HIV-1 virus particle makes it an attractive molecule for the development of antiviral agents targeting the events associated with virus maturation. We have generated chimeric Vpr proteins containing HIV-1-specific sequences added to the C terminus of Vpr. These sequences correspond to nine cleavage sites of the Gag and Gag–Pol precursors of HIV-1. The chimeric Vpr constructs were introduced into HIV-1 proviral DNA to assess their effect on virus infectivity using single- and multiple-round replication assays. The virus particles generated exhibited a variable replication pattern depending on the protease cleavage site used as a fusion partner. Interestingly, the chimeric Vpr containing the cleavage sequences from the junction of p24 and p2, 24/2, completely abolished virus infectivity. These results show that chimeric proteins generated from within HIV-1 have the ability to suppress HIV-1 replication and make ideal agents for gene therapy or intracellular immunization to treat HIV-1 infection. PMID:9096396

  15. Dyslipidemias and Elevated Cardiovascular Risk on Lopinavir-Based Antiretroviral Therapy in Cambodia

    PubMed Central

    Ly, Sowath; Ouk, Vara; Chanroeurn, Hak; Thavary, Saem; Boroath, Ban; Canestri, Ana; Viretto, Gérald; Delfraissy, Jean-François; Ségéral, Olivier

    2016-01-01

    Background Lopinavir/ritonavir (LPV/r) is widely used in Cambodia with high efficacy but scarce data exist on long-term metabolic toxicity. Methods We carried out a cross-sectional and retrospective study evaluating metabolic disorders and cardiovascular risk in Cambodian patients on LPV/r-based antiretroviral therapy (ART) for > 1 year followed in Calmette Hospital, Phnom Penh. Data collected included cardiovascular risk factors, fasting blood lipids and glucose, and retrospective collection of bioclinical data. We estimated the 10-year risks of coronary heart disease with the Framingham, Ramathibodi-Electricity Generating Authority of Thailand (Rama-EGAT), and the Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) risk equations. We identified patients with LDL above targets defined by the French expert group on HIV and by the HIV Medicine Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group (IDSA-AACTG). Results Of 115 patients enrolled—mean age 40.9 years, 69.2% male, mean time on LPV/r 3.8 years—40 (34.8%) had hypercholesterolemia (> 2.40 g/L), and 69 (60.0%) had low HDL cholesterol (< 0.40 g/L). Twelve (10.5%), 28 (24%) and 9 (7.7%) patients had a 10-year risk of coronary heart disease ≥ 10% according to the Framingham, D:A:D, and Rama-EGAT score, respectively. Fifty one (44.4%) and 36 (31.3%) patients had not reached their LDL target according to IDSA-AACTG and French recommendations, respectively. Conclusion Prevalence of dyslipidemia was high in this cohort of HIV-infected Cambodian patients on LPV/r. Roughly one third had high LDL levels requiring specific intervention. PMID:27579612

  16. Predictive parameters for medical expulsive therapy in ureteral stones: a critical evaluation.

    PubMed

    Sahin, Cahit; Eryildirim, Bilal; Kafkasli, Alper; Coskun, Alper; Tarhan, Fatih; Faydaci, Gokhan; Sarica, Kemal

    2015-06-01

    To evaluate the predictive value of some certain radiological as well as stone-related parameters for medical expulsive therapy (MET) success with an alpha blocker in ureteral stones. A total 129 patients receiving MET for 5 to 10 mm ureteral stones were evaluated. Patients were divided into two subgroups where MET was successful in 64 cases (49.61%) and unsuccessful in 65 cases (50.39%). Prior to management, stone size, location, position in the ureter, degree of hydronephrosis, diameter of ureteral lumen proximal to the stone, ureteral wall thickness along with patient's demographics including body mass index (BMI) values were evaluated and recorded. The possible predictive values of these parameters for stone expulsion (and stone expulsion time) were evaluated in a comparative manner between two groups. The overall mean patient age and stone size values were 38.02 ± 0.94 years and 40.31 ± 1.13 mm(2), respectively. Regarding the predictive values of these parameters for MET-success, while stone size and localization, degree of hydronephrosis, proximal ureteral diameter and ureteral wall thickness were found to be highly predictive for MET-success, patients age, BMI values and stone density had no predictive value on this aspect. Our findings indicated that some stone and anatomical factors may be used to predict the success of MET in an effective manner. With this approach unnecessary use of these drugs that may cause a delay for stone removal will be avoided and the possible adverse effects of obstruction as well as stone-related clinical symptoms could be minimized.

  17. [Clinical evaluation of the efficacy of external therapies of traditional Chinese medicine in treatment of cancer pain].

    PubMed

    Zhu, Shi-jie; Jia, Li-qun; Li, Pei-wen

    2011-01-01

    There lack scientific methods for evaluating the treatment of cancer pain with external therapies of traditional Chinese medicine (TCM). The level of clinical study in this field needs to be improved. The authors assert that when external therapies of TCM are applied to treat cancer pain, different types of cancer pain should be distinguished and treatment should be applied according to such a differentiation. Under this framework scientific evaluation can be conducted. The authors also assert that the findings of randomized, blinded and controlled trials should be given particular attention, and it is necessary to include titration of morphine into clinical trails of external therapies for the treatment of cancer pain, not only complying with the three-ladder principle for treating cancer pain suggested by the World Health Organization, but also not influencing the effect evaluation of external therapies of TCM on cancer pain. Patient diaries recording pain were revised as observation indexes. The primary indicator of efficacy was the pain intensity score and the secondary indicators were the equivalent of morphine and the remission rate of pain. The time to onset, remission duration and comparison of assessment of pain influence can mirror the characteristics of external therapies of TCM on cancer pain.

  18. Formulation Design and Development of a Unani Transdermal Patch for Antiemetic Therapy and Its Pharmaceutical Evaluation

    PubMed Central

    Idris, Mohammad

    2016-01-01

    The Transdermal Drug Delivery System (TDDS) is one of the novel routes for systemic delivery of drugs through intact skin. A transdermal patch (TP) is a medicated patch that is placed on skin for delivery of medication through skin into the blood stream. The aim of present study was to formulate and evaluate a Unani transdermal patch that could be used for antiemetic therapy. The incorporation of Unani ingredients, namely, Khardal (Brassica nigra), Zanjabeel (Zingiber officinale), Podina (Mentha arvensis), and Sirka (Vinegar) were envisaged. The TP was prepared by solvent evaporation technique and was evaluated for organoleptic characteristics and other physicochemical properties, such as thickness, weight uniformity, folding endurance, moisture content, drug content, and tolerability and acceptability of patch. The in vitro permeation study of the patch was carried out through Franz diffusion cell using egg shell membrane as barrier membrane. Phosphate buffer pH 7.4 was used as dissolution medium and the temperature was maintained at 37 ± 1°C. The in vitro permeation study of the prepared TP indicated a time dependent increase in drug release throughout the study. The percentage of cumulative drug release was found to be 77.38% in 24 hours. The study shows a new approach to work in Unani pharmaceutics. PMID:27403377

  19. Formulation Design and Development of a Unani Transdermal Patch for Antiemetic Therapy and Its Pharmaceutical Evaluation.

    PubMed

    Saleem, Mohd Nauman; Idris, Mohammad

    2016-01-01

    The Transdermal Drug Delivery System (TDDS) is one of the novel routes for systemic delivery of drugs through intact skin. A transdermal patch (TP) is a medicated patch that is placed on skin for delivery of medication through skin into the blood stream. The aim of present study was to formulate and evaluate a Unani transdermal patch that could be used for antiemetic therapy. The incorporation of Unani ingredients, namely, Khardal (Brassica nigra), Zanjabeel (Zingiber officinale), Podina (Mentha arvensis), and Sirka (Vinegar) were envisaged. The TP was prepared by solvent evaporation technique and was evaluated for organoleptic characteristics and other physicochemical properties, such as thickness, weight uniformity, folding endurance, moisture content, drug content, and tolerability and acceptability of patch. The in vitro permeation study of the patch was carried out through Franz diffusion cell using egg shell membrane as barrier membrane. Phosphate buffer pH 7.4 was used as dissolution medium and the temperature was maintained at 37 ± 1°C. The in vitro permeation study of the prepared TP indicated a time dependent increase in drug release throughout the study. The percentage of cumulative drug release was found to be 77.38% in 24 hours. The study shows a new approach to work in Unani pharmaceutics. PMID:27403377

  20. An Evaluation of Trauma Focused Cognitive Behavioral Therapy for Children in Zambia

    PubMed Central

    Murray, Laura K; Familiar, Itziar; Skavenski, Stephanie; Jere, Elizabeth; Cohen, Judy; Imasiku, Mwiya; Mayeya, John; Bass, Judith K; Bolton, Paul

    2013-01-01

    Objectives To monitor and evaluate the feasibility of implementing Trauma Focused-Cognitive Behavioral Therapy (TF-CBT) to address trauma and stress-related symptoms in orphans and vulnerable children (OVC) in Zambia as part of ongoing programming within a non-governmental organization (NGO). Methods As part of ongoing programming, voluntary care-workers administered locally validated assessments to identify children who met criteria for moderate to severe trauma symptomatology. Local lay counselors implemented TF-CBT with identified families, while participating in ongoing supervision. Fifty-eight children and adolescents aged 5–18 completed the TF-CBT treatment, with pre- and post-assessments. Results The mean number of traumas reported by the treatment completers (N=58) was 4.11. Post assessments showed significant reductions in severity of trauma symptoms (p<0.0001), and severity of shame symptoms (p<0.0001). Conclusions Our results suggest that TF-CBT is a feasible treatment option in Zambia for OVC. A decrease in symptoms suggests that a controlled trial is warranted. Implementation factors monitored suggest that it is feasible to integrate and evaluate evidence-based mental health assessments and intervention into programmatic services run by an NGO in low/middle resource countries. Results also support the effectiveness of implementation strategies such as task shifting, and the apprenticeship model of training and supervision. PMID:23768939

  1. Steps and Time to Process Clinical Trials at the Cancer Therapy Evaluation Program

    PubMed Central

    Dilts, David M.; Sandler, Alan B.; Cheng, Steven K.; Crites, Joshua S.; Ferranti, Lori B.; Wu, Amy Y.; Finnigan, Shanda; Friedman, Steven; Mooney, Margaret; Abrams, Jeffrey

    2009-01-01

    Purpose To examine the processes and document the calendar time required for the National Cancer Institute's Cancer Therapy Evaluation Program (CTEP) and Central Institutional Review Board (CIRB) to evaluate and approve phase III clinical trials. Methods Process steps were documented by (1) interviewing CTEP and CIRB staff regarding the steps required to activate a trial from initial concept submission to trial activation by a cooperative group, (2) reviewing standard operating procedures, and (3) inspecting trial records and documents for selected trials to identify any additional steps. Calendar time was collected from initial concept submission to activation using retrospective data from the CTEP Protocol and Information Office. Results At least 296 distinct processes are required for phase III trial activation: at least 239 working steps, 52 major decision points, 20 processing loops, and 11 stopping points. Of the 195 trials activated during the January 1, 2000, to December 31, 2007, study period, a sample of 167 (85.6%) was used for gathering timing data. Median calendar days from initial formal concept submission to CTEP to trial activation by a cooperative group was 602 days (interquartile range, 454 to 861 days). This time has not significantly changed over the past 8 years. There is a high variation in the time required to activate a clinical trial. Conclusion Because of their complexity, the overall development time for phase III clinical trials is lengthy, process laden, and highly variable. To streamline the process, a solution must be sought that includes all parties involved in developing trials. PMID:19255315

  2. The evaluation of extracorporeal shockwave therapy in naturally occurring osteoarthritis of the stifle joint in dogs.

    PubMed

    Dahlberg, J; Fitch, G; Evans, R B; McClure, S R; Conzemius, M

    2005-01-01

    Extracorporeal shockwave therapy (ESWT) has expanded from the original uses of human urinary calculi treatment to veterinary orthopaedic applications. This paper investigates the feasibility and efficacy of treating dogs with osteoarthritis of the stifle joint with ESWT. In this study, dogs with persistent stifle lameness despite previous surgical or medical treatment were either treated with ESWT or served as untreated controls. The more lame rear limb of each dog was determined by force platform analysis. The range of motion (ROM) of the stifle joints was assessed by goniometry. Force platform gait analysis and goniometry were performed on both groups for four visits at three-week intervals and a final examination four weeks later. Shock wave therapy was performed three times on the treated dogs, once at each of the first three examinations. A placebo treatment consisting of clipping and wetting the hair was performed on the control dogs. The vertical forces were evaluated for objective analysis of treatment response. For peak vertical force (PVF), four of seven treated dogs improved, while only one of five of control dogs improved. The PVF for the within group analysis did not show any significant change for the treated group, however, the control group has a significant decrease (p = 0.05) in PVF consistent with an increase in lameness. The range of motion (ROM) of the stifle joint improved in five of seven treated dogs and three of five controls. Dogs in the treated group had a trend toward increased ROM (p = 0.07) and a 'positive slope' when compared to dogs in the control group which did not have a significant change (p = 0.78) and had a negative slope indicating the dogs were developing a decrease in ROM. The subjective data provided by client questionnaire did not show significant difference between groups.

  3. Fabrication, characterization, and evaluation of microsponge delivery system for facilitated fungal therapy

    PubMed Central

    Moin, Afrasim; Deb, Tamal K.; Osmani, Riyaz Ali M.; Bhosale, Rohit R.; Hani, Umme

    2016-01-01

    Objective: The rationale behind present research vocation was to develop and investigate a novel microsponge based gel as a topical carrier for the prolonged release and cutaneous drug deposition of fluconazole (FLZ); destined for facilitated fungal therapy. Materials and Methods: Microsponges were prepared using quasi-emulsion solvent diffusion method using Eudragit S-100. In the direction of optimization, the effect of formulation variables (drug-polymer ratio and amount of emulsifier) and diverse factors affecting physical characteristics of microsponge were investigated as well. Fabricated microsponges were characterized by differential scanning calorimetry, Fourier transform-infrared, scanning electron microscopy (SEM), particle size analysis, and also evaluated for drug content, encapsulation efficiency, in vitro drug release and in vitro antifungal activity. Results: Compatibility studies results reflected no sign of any chemical interaction between the drug and polymers used. Whereas, varied drug-polymer ratios and emulsifier concentration indicated significant effect on production yield, drug content, encapsulation efficiency, particle size and drug release. Spherical microsponges with a porous surface and 29.327 ± 0.31 μm mean particle size were evident from SEM micrographs. In vitro release outcomes, from microsponge loaded gels depicted that F1 formulation was more efficient to give extended drug release of 85.38% at the end of 8 h, while conventional formulation by releasing 83.17% of drug got exhausted incredibly earlier at the end of 4 h merely. Moreover, microsponge gels demonstrated substantial spreadability and extrudability along with promising antifungal activity. Conclusions: Fabricated microsponges would be impending pharmaceutical topical carriers of FLZ and a leading alternative to conventional therapy for efficient, safe and facilitated eradication of fungal infections. PMID:27057125

  4. Development and evaluation of oxaliplatin and irinotecan co-loaded liposomes for enhanced colorectal cancer therapy.

    PubMed

    Zhang, Bo; Wang, Tianqi; Yang, Shaomei; Xiao, Yanan; Song, Yunmei; Zhang, Na; Garg, Sanjay

    2016-09-28

    Drug combinations are widely employed in chemotherapy for colorectal cancer treatment. However, traditional cocktail combination in clinic causes the uncertainty of the treatment, owing to varying pharmacokinetics of different drugs. The aim of this study was to design co-loaded liposomes to achieve the synchronised delivery and release. Oxaliplatin and irinotecan hydrochloride, as one of recommended combination schemes for the treatment of colorectal cancer in clinic, were co-loaded into the liposomes. The particle sizes of the liposomes were <200nm with uniform size distribution. In vitro release study showed that both drugs could be synchronously released from the liposomes, which means the optimized synergistic ratio of two drugs could be achieved. In vitro cellular uptake revealed that co-loaded liposomes could efficiently deliver different drugs into the same cells, indicating their potential as carriers for enhancing the cancer therapy. CLSM images of cryo-sections for in vivo co-delivery study also revealed that co-loaded liposomes had superior ability to co-deliver both the cargoes into the same tumor cells. Besides, in vivo NIRF imaging indicated that the liposomes could increase the drug accumulation in tumor compared with free drug. In vitro cytotoxicity evaluation demonstrated that co-loaded liposomes exhibited higher cytotoxicity than the mixture of single loaded liposomes in both CT-26 and HCT-116 cells. Furthermore, co-loaded liposomes also presented superior anti-tumor activity in CT-26 bearing BALB/c mice. In vivo safety assessment demonstrated that liposomes had lower toxicities than their solution formulations. These results indicated that oxaliplatin and irinotecan hydrochloride co-loaded liposomes would be an efficient formulation for improving colorectal cancer therapy with potential clinical applications. PMID:27432750

  5. Evaluation of the potential role of chelation therapy in treatment of low to moderate lead exposures

    SciTech Connect

    Chisolm, J.J. Jr. )

    1990-11-01

    In the overall long-term management of lead poisoning, chelation therapy can have short-term benefits; however, these benefits must be accompanied by drastic reduction in environmental exposure to lead if therapy is to have any long-term benefit. This discussion is limited to calcium disodium ethylenediaminetetraacetate (CaNa{sub 2}EDTA), the chelating agent that has been the mainstay of treatment of lead poisoning for the past 38 years, and to meso-2,3-dimercaptosuccinic acid (DMSA), a new and promising oral chelating agent, which is an orphan drug and is currently classified as an investigational new drug by the US Food and Drug Administration. With both drugs, multiple courses of treatment will be needed if any substantial reduction in body lead burden is to be achieved. A major limitation of CaNa{sub 2}EDTA is the enormous diuresis of zinc that it produces. DMSA produces a comparable diuresis of lead, a greater decrease in blood lead, and has negligible influence on the urinary losses of zinc, copper, iron, and calcium. Limited experience to date in man has revealed no significant adverse side effects of DMSA. In animals, DMSA will promptly reduce the concentration of lead in brain and kidney, in particular. By contrast, similar 5-day courses of CaNa{sub 2}EDTA do not produce any net reduction in brain lead. This is important, as the brain is the critical organ of the adverse effects of lead in children. If the efficacy of DMSA is to be comprehensively evaluated ethically in children, new and more sensitive neurochemical, electrophysiologic, or other markers must be developed.

  6. Four-week histologic evaluation of grafted calvarial defects with adjunctive hyperbaric oxygen therapy in rats

    PubMed Central

    2016-01-01

    Purpose The aim of this study was to characterize the healing in the grafted calvarial defects of rats after adjunctive hyperbaric oxygen therapy. Methods Twenty-eight male Sprague-Dawley rats (body weight, 250–300 g) were randomly divided into two treatment groups: with hyperbaric oxygen therapy (HBO; n=14) and without HBO (NHBO; n=14). Each group was further subdivided according to the bone substitute applied: biphasic calcium phosphate (BCP; n=7) and surface-modified BCP (mBCP; n=7). The mBCP comprised BCP coated with Escherichia-coli-derived recombinant human bone morphogenetic protein-2 (ErhBMP-2) and epigallocatechin-3-gallate (EGCG). Two symmetrical circular defects (6-mm diameter) were created in the right and left parietal bones of each animal. One defect was assigned as a control defect and received no bone substitute, while the other defect was filled with either BCP or mBCP. The animals were allowed to heal for 4 weeks, during which those in the HBO group underwent 5 sessions of HBO. At 4 weeks, the animals were sacrificed, and the defects were harvested for histologic and histomorphometric analysis. Results Well-maintained space was found in the grafted groups. Woven bone connected to and away from the defect margin was formed. More angiogenesis was found with HBO and EGCG/BMP-2 (P<0.05). None of the defects achieved complete defect closure. Increased new bone formation with HBO or EGCG/BMP-2 was evident in histologic evaluation, but it did not reach statistical significance in histometric analysis. A synergic effect between HBO and EGCG/BMP-2 was not found. Conclusions Within the limitations of this study, the present findings indicate that adjunctive HBO and EGCG/BMP-2 could be beneficial for new bone formation in rat calvarial defects. PMID:27588214

  7. Development of a patient-specific 3D dose evaluation program for QA in radiation therapy

    NASA Astrophysics Data System (ADS)

    Lee, Suk; Chang, Kyung Hwan; Cao, Yuan Jie; Shim, Jang Bo; Yang, Dae Sik; Park, Young Je; Yoon, Won Sup; Kim, Chul Yong

    2015-03-01

    We present preliminary results for a 3-dimensional dose evaluation software system ( P DRESS, patient-specific 3-dimensional dose real evaluation system). Scanned computed tomography (CT) images obtained by using dosimetry were transferred to the radiation treatment planning system (ECLIPSE, VARIAN, Palo Alto, CA) where the intensity modulated radiation therapy (IMRT) nasopharynx plan was designed. We used a 10 MV photon beam (CLiX, VARIAN, Palo Alto, CA) to deliver the nasopharynx treatment plan. After irradiation, the TENOMAG dosimeter was scanned using a VISTA ™ scanner. The scanned data were reconstructed using VistaRecon software to obtain a 3D dose distribution of the optical density. An optical-CT scanner was used to readout the dose distribution in the gel dosimeter. Moreover, we developed the P DRESS by using Flatform, which were developed by our group, to display the 3D dose distribution by loading the DICOM RT data which are exported from the radiotherapy treatment plan (RTP) and the optical-CT reconstructed VFF file, into the independent P DRESS with an ioniz ation chamber and EBT film was used to compare the dose distribution calculated from the RTP with that measured by using a gel dosimeter. The agreement between the normalized EBT, the gel dosimeter and RTP data was evaluated using both qualitative and quantitative methods, such as the isodose distribution, dose difference, point value, and profile. The profiles showed good agreement between the RTP data and the gel dosimeter data, and the precision of the dose distribution was within ±3%. The results from this study showed significantly discrepancies between the dose distribution calculated from the treatment plan and the dose distribution measured by a TENOMAG gel and by scanning with an optical CT scanner. The 3D dose evaluation software system ( P DRESS, patient specific dose real evaluation system), which were developed in this study evaluates the accuracies of the three-dimensional dose

  8. Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles

    SciTech Connect

    Martínez-Rovira, I. Prezado, Y.

    2015-11-15

    Purpose: The outcome of radiotherapy can be further improved by combining irradiation with dose enhancers such as high-Z nanoparticles. Since 2004, spectacular results have been obtained when low-energy x-ray irradiations have been combined with nanoparticles. Recently, the same combination has been explored in hadron therapy. In vitro studies have shown a significant amplification of the biological damage in tumor cells charged with nanoparticles and irradiated with fast ions. This has been attributed to the increase in the ionizations and electron emissions induced by the incident ions or the electrons in the secondary tracks on the high-Z atoms, resulting in a local energy deposition enhancement. However, this subject is still a matter of controversy. Within this context, the main goal of the authors’ work was to provide new insights into the dose enhancement effects of nanoparticles in proton therapy. Methods: For this purpose, Monte Carlo calculations (GATE/GEANT4 code) were performed. In particular, the GEANT4-DNA toolkit, which allows the modeling of early biological damages induced by ionizing radiation at the DNA scale, was used. The nanometric radial energy distributions around the nanoparticle were studied, and the processes (such as Auger deexcitation or dissociative electron attachment) participating in the dose deposition of proton therapy treatments in the presence of nanoparticles were evaluated. It has been reported that the architecture of Monte Carlo calculations plays a crucial role in the assessment of nanoparticle dose enhancement and that it may introduce a bias in the results or amplify the possible final dose enhancement. Thus, a dosimetric study of different cases was performed, considering Au and Gd nanoparticles, several nanoparticle sizes (from 4 to 50 nm), and several beam configurations (source-nanoparticle distances and source sizes). Results: This Monte Carlo study shows the influence of the simulations’ parameters on the local

  9. The Relation Between Mindfulness and Fear of Negative Evaluation Over the Course of Cognitive Behavioral Therapy for Social Anxiety Disorder

    PubMed Central

    Burton, Mark; Schmertz, Stefan K.; Price, Matthew; Masuda, Akihiko; Anderson, Page L.

    2015-01-01

    Objectives This study examined the relation between mindfulness and fear of negative evaluation over the course of nonmindfulness based cognitive-behavioral therapy (CBT) for social anxiety disorder (SAD). We expected that higher levels of mindfulness would be associated with a more positive response to treatment. Method This study is a secondary report from a randomized controlled trial in which participants (N = 65) diagnosed with SAD were randomly assigned to receive 8 weeks of 1 of 2 manualized treatments (exposure group therapy, n = 33; or virtual reality exposure therapy, n = 32) either immediately or following an 8 week waiting period. Results Fear of negative evaluation decreased following treatment and was negatively related to mindfulness throughout treatment and follow-up. Mindfulness did not moderate treatment outcome. Conclusions These findings indicate that while mindfulness is related to fear, it is not a moderator of symptom reduction in nonmindfulness-based treatment. Implications for treatment and future research are discussed. PMID:23124529

  10. Synthesis and biological evaluation of new boron-containing chlorin derivatives as agents for both photodynamic therapy and boron neutron capture therapy of cancer.

    PubMed

    Asano, Ryuji; Nagami, Amon; Fukumoto, Yuki; Miura, Kaori; Yazama, Futoshi; Ito, Hideyuki; Sakata, Isao; Tai, Akihiro

    2014-03-01

    New boron-containing chlorin derivatives 9 and 13 as agents for both photodynamic therapy (PDT) and boron neutron capture therapy (BNCT) of cancer were synthesized from photoprotoporphyrin IX dimethyl ester (2) and L-4-boronophenylalanine-related compounds. The in vivo biodistribution and clearance of 9 and 13 were investigated in tumor-bearing mice. The time to maximum accumulation of compound 13 in tumor tissue was one-fourth of that of compound 9, and compound 13 showed rapid clearance from normal tissues within 24h after injection. The in vivo therapeutic efficacy of PDT using 13 was evaluated by measuring tumor growth rates in tumor-bearing mice with 660 nm light-emitting diode irradiation at 3h after injection of 13. Tumor growth was significantly inhibited by PDT using 13. These results suggested that 13 might be a good candidate for both PDT and BNCT of cancer.

  11. Clinical, Radiographic and Microbiological Evaluation of High Level Laser Therapy, a New Photodynamic Therapy Protocol, in Peri-Implantitis Treatment; a Pilot Experience

    PubMed Central

    Caccianiga, Gianluigi; Rey, Gerard; Baldoni, Marco; Paiusco, Alessio

    2016-01-01

    Aim. Endosseous implants are widely used to replace missing teeth but mucositis and peri-implantitis are the most frequent long-term complications related with dental implants. Removing all bacterial deposits on contaminated implant surface is very difficult due to implant surface morphology. The aim of this study was to evaluate the bactericidal potential of photodynamic therapy by using a new high level laser irradiation protocol associated with hydrogen peroxide in peri-implantitis. Materials and Methods. 10 patients affected by peri-implantitis were selected for this study. Medical history, photographic documentation, periodontal examination, and periapical radiographs were collected at baseline and 6 months after surgery. Microbiological analysis was performed with PCR Real Time. Each patient underwent nonsurgical periodontal therapy and surgery combined with photodynamic therapy according to High Level Laser Therapy protocol. Results. All peri-implant pockets were treated successfully, without having any complication and not showing significant differences in results. All clinical parameters showed an improvement, with a decrease of Plaque Index (average decrease of 65%, range 23–86%), bleeding on probing (average decrease of 66%, range 26–80%), and probing depth (average decrease of 1,6 mm, range 0,46–2,6 mm). Periapical radiographs at 6 months after surgery showed a complete radiographic filling of peri-implant defect around implants treated. Results showed a decrease of total bacterial count and of all bacterial species, except for Eikenella corrodens, 6 months after surgery. Conclusion. Photodynamic therapy using HLLT appears to be a good adjunct to surgical treatment of peri-implantitis. PMID:27379251

  12. Evaluation of miglustat as maintenance therapy after enzyme therapy in adults with stable type 1 Gaucher disease: a prospective, open-label non-inferiority study

    PubMed Central

    2012-01-01

    Background Previous studies have provided equivocal data on the use of miglustat as maintenance therapy in Gaucher disease type 1. We report findings from a clinical trial evaluating the effects of miglustat treatment in patients with stable type 1 Gaucher disease after enzyme therapy. Methods Adult type 1 Gaucher disease patients stabilized during at least 3 years of previous enzyme therapy were included in this 2-year, prospective, open-label non-inferiority study. The primary endpoint was percent change from baseline in liver volume. Secondary endpoints included changes in spleen volume, hemoglobin concentration and platelet count. Results Forty-two patients were enrolled (mean±SD age, 45.1±12.7 years; previous enzyme therapy duration 9.5±4.0 years). Median (range) exposure to miglustat 100 mg t.i.d. was 658 (3–765) days. Twenty-one patients discontinued treatment prematurely; 13 due to adverse events, principally gastrointestinal. The upper 95% confidence limit of mean percent change in liver volume from baseline to end of treatment was below the non-inferiority margin of 10% (–1.1%; 95%CI −6.0, 3.9%). Mean (95%CI) changes in spleen volume, hemoglobin concentration and platelet count were 102 (24,180) mL, –0.95 (−1.38, –0.53) g/dL and −44.1 (–57.6, –30.7) ×109/L, respectively. Conclusions The primary efficacy endpoint was met; overall there was no change in liver volume during 24 months of miglustat therapy. Several patients showed a gradual deterioration in some disease manifestations, suggesting that miglustat could maintain clinical stability, but not in all patients. Miglustat demonstrated a predictable profile of safety and tolerability that was consistent with that reported in previous clinical trials and experience in clinical practice. Trial registration Clinicaltrials.gov identifier NCT00319046 PMID:23270487

  13. Structure of an anti-HIV-1 hammerhead ribozyme complex with a 17-mer DNA substrate analog of HIV-1 gag RNA and a mechanism for the cleavage reaction: 750 MHz NMR and computer experiments

    NASA Technical Reports Server (NTRS)

    Ojha, R. P.; Dhingra, M. M.; Sarma, M. H.; Myer, Y. P.; Setlik, R. F.; Shibata, M.; Kazim, A. L.; Ornstein, R. L.; Rein, R.; Turner, C. J.; Sarma, R. H.

    1997-01-01

    The structure of an anti-HIV-1 ribozyme-DNA abortive substrate complex was investigated by 750 MHz NMR and computer modeling experiments. The ribozyme was a chimeric molecule with 30 residues-18 DNA nucleotides, and 12 RNA residues in the conserved core. The DNA substrate analog had 17 residues. The chimeric ribozyme and the DNA substrate formed a shortened ribozyme-abortive substrate complex of 47 nucleotides with two DNA stems (stems I and III) and a loop consisting of the conserved core residues. Circular dichroism spectra showed that the DNA stems assume A-family conformation at the NMR concentration and a temperature of 15 degrees C, contrary to the conventional wisdom that DNA duplexes in aqueous solution populate entirely in the B-form. It is proposed that the A-family RNA residues at the core expand the A-family initiated at the core into the DNA stems because of the large free energy requirement for the formation of A/B junctions. Assignments of the base H8/H6 protons and H1' of the 47 residues were made by a NOESY walk. In addition to the methyl groups of all T's, the imino resonances of stems I and III and AH2's were assigned from appropriate NOESY walks. The extracted NMR data along with available crystallographic data, were used to derive a structural model of the complex. Stems I and III of the final model displayed a remarkable similarity to the A form of DNA; in stem III, a GC base pair was found to be moving into the floor of the minor groove defined by flanking AT pairs; data suggest the formation of a buckled rhombic structure with the adjacent pair; in addition, the base pair at the interface of stem III and the loop region displayed deformed geometry. The loop with the catalytic core, and the immediate region of the stems displayed conformational multiplicity within the NMR time scale. A catalytic mechanism for ribozyme action based on the derived structure, and consistent with biochemical data in the literature, is proposed. The complex

  14. Structure of an anti-HIV-1 hammerhead ribozyme complex with a 17-mer DNA substrate analog of HIV-1 gag RNA and a mechanism for the cleavage reaction: 750 MHz NMR and computer experiments.

    PubMed

    Ojha, R P; Dhingra, M M; Sarma, M H; Myer, Y P; Setlik, R F; Shibata, M; Kazim, A L; Ornstein, R L; Rein, R; Turner, C J; Sarma, R H

    1997-10-01

    The structure of an anti-HIV-1 ribozyme-DNA abortive substrate complex was investigated by 750 MHz NMR and computer modeling experiments. The ribozyme was a chimeric molecule with 30 residues-18 DNA nucleotides, and 12 RNA residues in the conserved core. The DNA substrate analog had 17 residues. The chimeric ribozyme and the DNA substrate formed a shortened ribozyme-abortive substrate complex of 47 nucleotides with two DNA stems (stems I and III) and a loop consisting of the conserved core residues. Circular dichroism spectra showed that the DNA stems assume A-family conformation at the NMR concentration and a temperature of 15 degrees C, contrary to the conventional wisdom that DNA duplexes in aqueous solution populate entirely in the B-form. It is proposed that the A-family RNA residues at the core expand the A-family initiated at the core into the DNA stems because of the large free energy requirement for the formation of A/B junctions. Assignments of the base H8/H6 protons and H1' of the 47 residues were made by a NOESY walk. In addition to the methyl groups of all T's, the imino resonances of stems I and III and AH2's were assigned from appropriate NOESY walks. The extracted NMR data along with available crystallographic data, were used to derive a structural model of the complex. Stems I and III of the final model displayed a remarkable similarity to the A form of DNA; in stem III, a GC base pair was found to be moving into the floor of the minor groove defined by flanking AT pairs; data suggest the formation of a buckled rhombic structure with the adjacent pair; in addition, the base pair at the interface of stem III and the loop region displayed deformed geometry. The loop with the catalytic core, and the immediate region of the stems displayed conformational multiplicity within the NMR time scale. A catalytic mechanism for ribozyme action based on the derived structure, and consistent with biochemical data in the literature, is proposed. The complex

  15. Novel CD4-Based Bispecific Chimeric Antigen Receptor Designed for Enhanced Anti-HIV Potency and Absence of HIV Entry Receptor Activity

    PubMed Central

    Liu, Li; Patel, Bhavik; Ghanem, Mustafa H.; Bundoc, Virgilio; Zheng, Zhili; Morgan, Richard A.; Rosenberg, Steven A.; Dey, Barna

    2015-01-01

    ABSTRACT Adoptive transfer of CD8 T cells genetically engineered to express “chimeric antigen receptors” (CARs) represents a potential approach toward an HIV infection “functional cure” whereby durable virologic suppression is sustained after discontinuation of antiretroviral therapy. We describe a novel bispecific CAR in which a CD4 segment is linked to a single-chain variable fragment of the 17b human monoclonal antibody recognizing a highly conserved CD4-induced epitope on gp120 involved in coreceptor binding. We compared a standard CD4 CAR with CD4-17b CARs where the polypeptide linker between the CD4 and 17b moieties is sufficiently long (CD4-35-17b CAR) versus too short (CD4-10-17b) to permit simultaneous binding of the two moieties to a single gp120 subunit. When transduced into a peripheral blood mononuclear cell (PBMC) or T cells thereof, all three CD4-based CARs displayed specific functional activities against HIV-1 Env-expressing target cells, including stimulation of gamma interferon (IFN-γ) release, specific target cell killing, and suppression of HIV-1 pseudovirus production. In assays of spreading infection of PBMCs with genetically diverse HIV-1 primary isolates, the CD4-10-17b CAR displayed enhanced potency compared to the CD4 CAR whereas the CD4-35-17b CAR displayed diminished potency. Importantly, both CD4-17b CARs were devoid of a major undesired activity observed with the CD4 CAR, namely, rendering the transduced CD8+ T cells susceptible to HIV-1 infection. Likely mechanisms for the superior potency of the CD4-10-17b CAR over the CD4-35-17b CAR include the greater potential of the former to engage in the serial antigen binding required for efficient T cell activation and the ability of two CD4-10-17b molecules to simultaneously bind a single gp120 subunit. IMPORTANCE HIV research has been energized by prospects for a cure for HIV infection or, at least, for a “functional cure” whereby antiretroviral therapy can be discontinued

  16. Heuristic Evaluation of Online COPD Respiratory Therapy and Education Video Resource Center

    PubMed Central

    Chaney, Beth; Chaney, Don

    2014-01-01

    Abstract Purpose: Because of limited accessibility to pulmonary rehabilitation programs, patients with chronic obstructive pulmonary disease (COPD) are infrequently provided with patient education resources. To help educate patients with COPD on how to live a better life with diminished breathing capacity, we developed a novel social media resource center containing COPD respiratory therapy and education videos called “COPDFlix.” Methodology: A heuristic evaluation of COPDFlix was conducted as part of a larger study to determine whether the prototype was successful in adhering to formal Web site usability guidelines for older adults. A purposive sample of three experts, with expertise in Web design and health communications technology, was recruited (a) to identify usability violations and (b) to propose solutions to improve the functionality of the COPDFlix prototype. Each expert evaluated 18 heuristics in four categories of task-based criteria (i.e., interaction and navigation, information architecture, presentation design, and information design). Seventy-six subcriteria across these four categories were assessed. Quantitative ratings and qualitative comments from each expert were compiled into a single master list, noting the violated heuristic and type/location of problem(s). Results: Sixty-one usability violations were identified across the 18 heuristics. Evaluators rated the majority of heuristic subcriteria as either a “minor hindrance” (n=32) or “no problem” (n=132). Moreover, only 2 of the 18 heuristic categories were noted as “major” violations, with mean severity scores of ≥3. Conclusions: Mixed-methods data analysis helped the multidisciplinary research team to categorize and prioritize usability problems and solutions, leading to 26 discrete design modifications within the COPDFlix prototype. PMID:24650318

  17. Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma

    SciTech Connect

    Mizumoto, Masashi; Okumura, Toshiyuki; Hashimoto, Takayuki; Fukuda, Kuniaki; Oshiro, Yoshiko; Fukumitsu, Nobuyoshi; Abei, Masato; Kawaguchi, Atsushi; Hayashi, Yasutaka; Ohkawa, Ayako; Hashii, Haruko; Kanemoto, Ayae; Moritake, Takashi; Tohno, Eriko; Tsuboi, Koji; Sakae, Takeji; Sakurai, Hideyuki

    2012-03-01

    Purpose: Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials: The subjects were 259 patients treated with PBT at University of Tsukuba between January 2001 and December 2007. We evaluated the Child-Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the Child-Pugh score of 1 or more was defined as an adverse event. Results: Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child-Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child-Pugh score, 15 had a 1-point increase, and 10 had an increase of {>=}2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion: Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.

  18. Evaluation of a lysostaphin-fusion protein as a dry-cow therapy for Staphylococcus aureus mastitis in dairy cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study evaluated the efficacy of a lysostaphin-fusion protein (Lyso-PTD) as a dry-cow therapy for the treatment of experimentally-induced chronic, subclinical Staphylococcus aureus mastitis. Twenty-two Holstein dairy cows were experimentally infected with Staph. aureus in a single pair of diago...

  19. A Bioecological Framework to Evaluate Communicative Participation Outcomes for Preschoolers Receiving Speech-Language Therapy Interventions in Ontario, Canada

    ERIC Educational Resources Information Center

    Cunningham, Barbara J.; Rosenbaum, Peter L.

    2015-01-01

    Background: The Preschool Speech and Language Program (PSLP) in Ontario, Canada, is a publicly funded intervention service for children from birth to 5 years with communication disorders. It has begun a population-level programme evaluation of children's communicative participation outcomes following therapy. Data are currently being collected for…

  20. A Cinnamon-Derived Procyanidin Compound Displays Anti-HIV-1 Activity by Blocking Heparan Sulfate- and Co-Receptor- Binding Sites on gp120 and Reverses T Cell Exhaustion via Impeding Tim-3 and PD-1 Upregulation

    PubMed Central

    Connell, Bridgette Janine; Chang, Sui-Yuan; Prakash, Ekambaranellore; Yousfi, Rahima; Mohan, Viswaraman; Posch, Wilfried; Wilflingseder, Doris; Moog, Christiane; Kodama, Eiichi N.; Clayette, Pascal; Lortat-Jacob, Hugues

    2016-01-01

    Amongst the many strategies aiming at inhibiting HIV-1 infection, blocking viral entry has been recently recognized as a very promising approach. Using diverse in vitro models and a broad range of HIV-1 primary patient isolates, we report here that IND02, a type A procyanidin polyphenol extracted from cinnamon, that features trimeric and pentameric forms displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses with 1–7 μM ED50 for the trimer. Competition experiments, using a surface plasmon resonance-based binding assay, revealed that IND02 inhibited envelope binding to CD4 and heparan sulphate (HS) as well as to an antibody (mAb 17b) directed against the gp120 co-receptor binding site with an IC50 in the low μM range. IND02 has thus the remarkable property of simultaneously blocking gp120 binding to its major host cell surface counterparts. Additionally, the IND02-trimer impeded up-regulation of the inhibitory receptors Tim-3 and PD-1 on CD4+ and CD8+ cells, thereby demonstrating its beneficial effect by limiting T cell exhaustion. Among naturally derived products significantly inhibiting HIV-1, the IND02-trimer is the first component demonstrating an entry inhibition property through binding to the viral envelope glycoprotein. These data suggest that cinnamon, a widely consumed spice, could represent a novel and promising candidate for a cost-effective, natural entry inhibitor for HIV-1 which can also down-modulate T cell exhaustion markers Tim-3 and PD-1. PMID:27788205

  1. Structure-activity and cross-resistance evaluations of a series of human immunodeficiency virus type-1-specific compounds related to oxathiin carboxanilide.

    PubMed Central

    Buckheit, R W; Kinjerski, T L; Fliakas-Boltz, V; Russell, J D; Stup, T L; Pallansch, L A; Brouwer, W G; Dao, D C; Harrison, W A; Schultz, R J

    1995-01-01

    A series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide (UC84) were evaluated for activity against the human immunodeficiency virus (HIV) to determine structural requirements for anti-HIV activity. Twenty-seven compounds representative of the more than 400 Uniroyal Chemical Company (UC) compounds were evaluated for structure-activity relationships. Several of the compounds evaluated were highly active, with 50% effective concentrations in the nanomolar range and therapeutic indices of > 1,000. Highly synergistic anti-HIV activity was observed for each compound when used in combination with 3'-azido-3'-deoxythymidine; additive to slightly synergistic interactions were observed with the compounds used in combination with dideoxycytidine. In combination with the NNRTI costatolide, only UC38 synergistically inhibited HIV type 1. Residues in the RT which, when mutated, impart resistance to the virus isolates selected in cell culture, against virus variants with site-directed mutations, and against RTs containing defined single amino acid changes. The mutations included changes in RT amino acids 100, 101, 103, 106, 108, and 181. The results with isolates selected in cell culture indicate that the carboxanilide compounds interact with the RT at two vulnerable sites, selecting UC-resistant virus isolates with the Y-to-C mutation at position 181 (Y181C) or the L100I substitution. A resistant virus isolate containing both Y181C combination with calanolide A, an NNRTI which retains activity against virus with the single Y181C mutation, UC10 rapidly selected a virus isolate with the K103N mutation. The merits of selecting potential candidate anti-HIV agents to be used in rational combination drugs design as part of an armamentarium of highly active anti-HIV compounds are discussed. PMID:8593008

  2. Selective Thrombolysis in Acute Deep Vein Thrombosis: Evaluation of Adjuvant Therapy In Vivo

    SciTech Connect

    Roy, Sumit; Brosstad, Frank; Sakariassen, Kjell S.

    1999-09-15

    Purpose: To evaluate in a porcine model of acute deep vein thrombosis (DVT) the efficacy of dalteparin and antithrombin with respect to heparin for local adjuvant therapy during selective thrombolysis, and the utility of nitroglycerin and iloprost as heparin supplements. Methods: DVT was induced in both hind limbs using a previously described technique (n = 20). Thirty minutes later, the animal was heparinized (2500 IU IV), and bilateral sequestrated thrombolysis was performed using 8 mg alteplase: both external iliac veins were endoluminally occluded with Swan-Ganz catheters, and a multi-sideport infusion wire coaxially introduced through each catheter and advanced into the ipsilateral popliteal vein. In the control limbs, tissue plasminogen activator (tPA) 8 mg was injected as 0.8-ml boluses at 3-min intervals for 2 hr as a 0.25-mg/ml solution containing heparin 50 IU/ml (n 20). On the contralateral side, heparin was substituted with either dalteparin 50 IU/ml (n = 5) or antithrombin 12.5 IU/ml (n = 5), or supplemented with either nitroglycerin 0.075 mg/ml (n = 5) or iloprost (150 ng/ml) (n = 5). Blood samples were taken at predetermined intervals to measure the activated partial thromboplastin time (aPTT), prothrombin time (PT), and fibrinogen concentration. At autopsy, the thrombus mass in the iliofemoral veins was measured, and the extent of residual thrombosis in the venous tributaries graded at four sites. Results: Bilateral thrombolysis was successfully completed in all animals. The median thrombus mass in the iliofemoral veins after thrombolysis was 0.48 g (range 0.06-1.58 g), 0.95 g (0.59-1.29 g), 0.74 g (0.52-0.96 g), and 0.29 g (0.0-0.77 g) for dalteparin, antithrombin, iloprost, and nitroglycerin respectively, as compared with 0.53 g (0.18-0.88 g) (p = 0.69), 0.97 g (0.46-1.15 g) (p = 0.69), 0.53 g (0.48-1.10 g) (p = 0.69), and 0.18 g (0.13-1.04 g) (p = 0.5) for the respective controls. Likewise, the severity of residual thrombosis in the venous

  3. Integration and evaluation of automated Monte Carlo simulations in the clinical practice of scanned proton and carbon ion beam therapy

    NASA Astrophysics Data System (ADS)

    Bauer, J.; Sommerer, F.; Mairani, A.; Unholtz, D.; Farook, R.; Handrack, J.; Frey, K.; Marcelos, T.; Tessonnier, T.; Ecker, S.; Ackermann, B.; Ellerbrock, M.; Debus, J.; Parodi, K.

    2014-08-01

    Monte Carlo (MC) simulations of beam interaction and transport in matter are increasingly considered as essential tools to support several aspects of radiation therapy. Despite the vast application of MC to photon therapy and scattered proton therapy, clinical experience in scanned ion beam therapy is still scarce. This is especially the case for ions heavier than protons, which pose additional issues like nuclear fragmentation and varying biological effectiveness. In this work, we present the evaluation of a dedicated framework which has been developed at the Heidelberg Ion Beam Therapy Center to provide automated FLUKA MC simulations of clinical patient treatments with scanned proton and carbon ion beams. Investigations on the number of transported primaries and the dimension of the geometry and scoring grids have been performed for a representative class of patient cases in order to provide recommendations on the simulation settings, showing that recommendations derived from the experience in proton therapy cannot be directly translated to the case of carbon ion beams. The MC results with the optimized settings have been compared to the calculations of the analytical treatment planning system (TPS), showing that regardless of the consistency of the two systems (in terms of beam model in water and range calculation in different materials) relevant differences can be found in dosimetric quantities and range, especially in the case of heterogeneous and deep seated treatment sites depending on the ion beam species and energies, homogeneity of the traversed tissue and size of the treated volume. The analysis of typical TPS speed-up approximations highlighted effects which deserve accurate treatment, in contrast to adequate beam model simplifications for scanned ion beam therapy. In terms of biological dose calculations, the investigation of the mixed field components in realistic anatomical situations confirmed the findings of previous groups so far reported only in

  4. Development of Lentiviral Vectors Simultaneously Expressing Multiple siRNAs Against CCR5, vif and tat/rev Genes for an HIV-1 Gene Therapy Approach

    PubMed Central

    Spanevello, Francesca; Calistri, Arianna; Del Vecchio, Claudia; Mantelli, Barbara; Frasson, Chiara; Basso, Giuseppe; Palù, Giorgio; Cavazzana, Marina; Parolin, Cristina

    2016-01-01

    Gene therapy holds considerable promise for the functional cure of HIV-1 infection and, in this context, RNA interference (RNAi)-based approaches represent powerful strategies. Stable expression of small interfering RNAs (siRNAs) targeting HIV genes or cellular cofactors has the potential to render HIV-1 susceptible cells resistant to infection. To inhibit different steps of virus life cycle, self-inactivating lentiviral vectors expressing multiple siRNAs targeting the CCR5 cellular gene as well as vif and tat/rev viral transcripts, under the control of different RNA polymerase III promoters (U6, 7SK, H1) were developed. The use of a single RNA polymerase III promoter driving the expression of a sequence giving rise to three siRNAs directed against the selected targets (e-shRNA) was also investigated. Luciferase assay and inhibition of HIV-1 replication in human Jurkat T-cell line were adopted to select the best combination of promoter/siRNA. The efficacy of selected developed combinatorial vectors in interfering with viral replication was evaluated in human primary CD4+ T lymphocytes. We identified two effective anti-HIV combinatorial vectors that conferred protection against R5- and X4- tropic viruses. Overall, our results showed that the antiviral effect is influenced by different factors, including the promoter used to express the RNAi molecules and the selected cassette combination. These findings contribute to gain further insights in the design of RNAi-based gene therapy approaches against HIV-1 for clinical application. PMID:27093170

  5. Clinical evaluation of a commercial orthopedic metal artifact reduction tool for CT simulations in radiation therapy

    SciTech Connect

    Li Hua; Noel, Camille; Chen, Haijian; Harold Li, H.; Low, Daniel; Moore, Kevin; Klahr, Paul; Michalski, Jeff; Gay, Hiram A.; Thorstad, Wade; Mutic, Sasa

    2012-12-15

    Purpose: Severe artifacts in kilovoltage-CT simulation images caused by large metallic implants can significantly degrade the conspicuity and apparent CT Hounsfield number of targets and anatomic structures, jeopardize the confidence of anatomical segmentation, and introduce inaccuracies into the radiation therapy treatment planning process. This study evaluated the performance of the first commercial orthopedic metal artifact reduction function (O-MAR) for radiation therapy, and investigated its clinical applications in treatment planning. Methods: Both phantom and clinical data were used for the evaluation. The CIRS electron density phantom with known physical (and electron) density plugs and removable titanium implants was scanned on a Philips Brilliance Big Bore 16-slice CT simulator. The CT Hounsfield numbers of density plugs on both uncorrected and O-MAR corrected images were compared. Treatment planning accuracy was evaluated by comparing simulated dose distributions computed using the true density images, uncorrected images, and O-MAR corrected images. Ten CT image sets of patients with large hip implants were processed with the O-MAR function and evaluated by two radiation oncologists using a five-point score for overall image quality, anatomical conspicuity, and CT Hounsfield number accuracy. By utilizing the same structure contours delineated from the O-MAR corrected images, clinical IMRT treatment plans for five patients were computed on the uncorrected and O-MAR corrected images, respectively, and compared. Results: Results of the phantom study indicated that CT Hounsfield number accuracy and noise were improved on the O-MAR corrected images, especially for images with bilateral metal implants. The {gamma} pass rates of the simulated dose distributions computed on the uncorrected and O-MAR corrected images referenced to those of the true densities were higher than 99.9% (even when using 1% and 3 mm distance-to-agreement criterion), suggesting that dose

  6. Using patient-specific phantoms to evaluate deformable image registration algorithms for adaptive radiation therapy.

    PubMed

    Stanley, Nick; Glide-Hurst, Carri; Kim, Jinkoo; Adams, Jeffrey; Li, Shunshan; Wen, Ning; Chetty, Indrin J; Zhong, Hualiang

    2013-11-04

    The quality of adaptive treatment planning depends on the accuracy of its underlying deformable image registration (DIR). The purpose of this study is to evaluate the performance of two DIR algorithms, B-spline-based deformable multipass (DMP) and deformable demons (Demons), implemented in a commercial software package. Evaluations were conducted using both computational and physical deformable phantoms. Based on a finite element method (FEM), a total of 11 computational models were developed from a set of CT images acquired from four lung and one prostate cancer patients. FEM generated displacement vector fields (DVF) were used to construct the lung and prostate image phantoms. Based on a fast-Fourier transform technique, image noise power spectrum was incorporated into the prostate image phantoms to create simulated CBCT images. The FEM-DVF served as a gold standard for verification of the two registration algorithms performed on these phantoms. The registration algorithms were also evaluated at the homologous points quantified in the CT images of a physical lung phantom. The results indicated that the mean errors of the DMP algorithm were in the range of 1.0 ~ 3.1 mm for the computational phantoms and 1.9 mm for the physical lung phantom. For the computational prostate phantoms, the corresponding mean error was 1.0-1.9 mm in the prostate, 1.9-2.4mm in the rectum, and 1.8-2.1 mm over the entire patient body. Sinusoidal errors induced by B-spline interpolations were observed in all the displacement profiles of the DMP registrations. Regions of large displacements were observed to have more registration errors. Patient-specific FEM models have been developed to evaluate the DIR algorithms implemented in the commercial software package. It has been found that the accuracy of these algorithms is patient dependent and related to various factors including tissue deformation magnitudes and image intensity gradients across the regions of interest. This may suggest that

  7. Variation in inpatient therapy and diagnostic evaluation of children with Henoch Schönlein purpura

    PubMed Central

    Weiss, Pamela F.; Klink, Andrew J.; Hexem, Kari; Burnham, Jon M.; Leonard, Mary B.; Keren, Ron; Localio, Russell; Feudtner, Chris

    2009-01-01

    Objective To describe variation regarding inpatient therapy and evaluation of children with Henoch Schönlein purpura (HSP) admitted to children’s hospitals across the United States. Study design We conducted a retrospective cohort study of children discharged with a diagnosis of HSP between 2000 and 2007 using inpatient administrative data from 36 children’s hospitals. We examined variation among hospitals in the use of medications, diagnostic tests, and intensive care services using multivariate mixed effects logistic regression models. Results During the initial HSP hospitalization (N=1,988), corticosteroids were the most common medication (56% of cases), followed by opioids (36%), NSAIDs (35%), and anti-hypertensives (11%). After adjustment for patient characteristics, hospitals varied significantly in their use of corticosteroids, opioids, and NSAIDs; the use of diagnostic abdominal imaging, endoscopy, laboratory testing, and renal biopsy; and the utilization of intensive care services. By contrast, hospitals did not differ significantly regarding administration of anti-hypertensives or performance of skin biopsy. Conclusions The significant variation identified may contribute to varying HSP clinical outcomes between hospitals, warrants further investigation, and represents a potentially important opportunity to improve quality of care. PMID:19643437

  8. Multi-function microsystem for cells migration analysis and evaluation of photodynamic therapy procedure in coculture

    PubMed Central

    Jastrzebska (Jedrych), Elzbieta; Grabowska-Jadach, Ilona; Chudy, Michal; Dybko, Artur; Brzozka, Zbigniew

    2012-01-01

    Cell migration is an important physiological process, which is involved in cancer metastasis. Therefore, the investigation of cell migration may lead to the development of novel therapeutic approaches. In this study, we have successfully developed a microsystem for culture of two cell types (non-malignant and carcinoma) and for analysis of cell migration dependence on distance between them. Finally, we studied quantitatively the influence of photodynamic therapy (PDT) procedures on the viability of pairs of non-malignant (MRC5 or Balb/3T3) and carcinoma (A549) cells coculture. The proposed geometry of the microsystem allowed for separate introduction of two cell lines and analysis of cells migration dependence on distance between the cells. We found that a length of connecting microchannel has an influence on cell migration and viability of non-malignant cells after PDT procedure. Summarizing, the developed microsystem can constitute a new tool for carrying out experiments, which offers a few functions: cell migration analysis, carcinoma and non-malignant cells coculture, and evaluation of PDT procedure in the various steps of cell migration. PMID:24339849

  9. Phantom evaluation of a commercially available three modality image guided radiation therapy system

    SciTech Connect

    Ploquin, Nicolas; Rangel, Alejandra; Dunscombe, Peter

    2008-12-15

    The authors describe a detailed evaluation of the capabilities of imaging and image registration systems available with Varian linear accelerators for image guided radiation therapy (IGRT). Specifically, they present modulation transfer function curves for megavoltage planar, kilovoltage (kV) planar, and cone beam computed tomography imaging systems and compare these with conventional computed tomography. While kV planar imaging displayed the highest spatial resolution, all IGRT imaging techniques were assessed as adequate for their intended purpose. They have also characterized the image registration software available for use in conjunction with these imaging systems through a comprehensive phantom study involving translations in three orthogonal directions. All combinations of imaging systems and image registration software were found to be accurate, although the planar kV imaging system with automatic registration was generally superior, with both accuracy and precision of the order of 1 mm, under the conditions tested. Based on their phantom study, the attainable accuracy for rigid body translations using any of the features available with Varian equipment will more likely be limited by the resolution of the couch readouts than by inherent limitations in the imaging systems and image registration software. Overall, the accuracy and precision of currently available IGRT technology exceed published experience with the accuracy and precision of contouring for planning.

  10. [The evaluation of medicinal therapy under treatment of arterial hypertension in hospital].

    PubMed

    Maksimova, T M; Lushkina, N P; Alekseeva, N Yu; Lomakina, E A; Saurina, O S; Telnova, E A

    2015-01-01

    The article presents the analysis of data of "Study on Global AGEing and Adult Health, 2007-2010" (SAGE) concerning subjective judging of health, prevalence of ischemic heart disease under different levels of arterial pressure in similar age groups. An attempt is made to evaluate spectrum of pharmaceuticals applied in treatment of patients with arterial pressure in hospital at the level of oblast hospital. According official statistics of Minzdrav of Russia, in 20102 prevalence of diseases characterized by higher arterial pressure amounted to 10.5% in adult population and to 22.3% in population older than able-bodied age. At the same time, according SAGE data, prevalence of various forms of hypertension disease in population older than 50 years amounted to 52.8%. That is, this pathology is often missed in conditions of mass medical network. Thereafter, patients receive no necessary medicinal therapy. The one or another treatment was provided to almost 94% of patients with hypertension disease diagnosed by physician. At that, among patients received treatment the normal levels of both systolic and diastolic pressure were established in less than 20% of patients with hypertension. Therefore, the issue of effectiveness of applied methods of correction of arterial hypertension become a matter of interest. The appropriate treatment of hypertension is a mean to decrease complications and as a result to diminish mortality of diseases of circulatory system.

  11. Economic evaluation of drug therapy: a review of the contingent valuation method.

    PubMed

    Johannesson, M; Johansson, P O; Jönsson, B

    1992-05-01

    The aim of this paper is to review the use of the contingent valuation (CV) method in economic evaluation of drug therapy. With the CV method, willingness to pay for a project 'treatment' is measured with survey methods, which makes it possible to carry out traditional cost-benefit analysis. The CV method has been developed in environmental economics and is now the most commonly used method of measuring environmental benefits. Due to the limitations of existing methods, empirical applications are starting to appear in the health field as well. From the empirical applications with respect to drug treatment it is evident that it is possible to achieve acceptable response rates. The methodological problems encountered when measuring willingness to pay with survey methods are similar to the problems encountered when measuring utility and quality of life in cost-utility analysis. It is concluded that further studies with the CV method are necessary to further explore questions concerning the reliability and validity of the method in this field.

  12. In vivo evaluating skin doses for lung cancer patients undergoing volumetric modulated arc therapy treatment.

    PubMed

    Tseng, Hsien-Chun; Pan, Lung-Kang; Chen, Hsin-Yu; Liu, Wen-Shan; Hsu, Chang-Chieh; Chen, Chien-Yi

    2015-01-01

    This study is the first to use 10- to 90-kg tissue-equivalent phantoms as patient surrogates to measure peripheral skin doses (Dskin) in lung cancer treatment through Volumetric Modulated Arc Therapy of the Axesse linac. Five tissue-equivalent and Rando phantoms were used to simulate lung cancer patients using the thermoluminescent dosimetry (TLD-100H) approach. TLD-100H was calibrated using 6 MV photons coming from the Axesse linac. Then it was inserted into phantom positions that closely corresponded with the position of the represented organs and tissues. TLDs were measured using the Harshaw 3500 TLD reader. The ICRP 60 evaluated the mean Dskin to the lung cancer for 1 fraction (7 Gy) undergoing VMAT. The Dskin of these phantoms ranged from 0.51±0.08 (10-kg) to 0.22±0.03 (90-kg) mSv/Gy. Each experiment examined the relationship between the Dskin and the distance from the treatment field. These revealed strong variations in positions close to the tumor center. The correlation between Dskin and body weight was Dskin (mSv) = -0.0034x + 0.5296, where x was phantom's weight in kg. R2 is equal to 0.9788. This equation can be used to derive an equation for lung cancer in males. Finally, the results are compared to other published research. These findings are pertinent to patients, physicians, radiologists, and the public.

  13. Low-level laser therapy on skeletal muscle inflammation: evaluation of irradiation parameters

    NASA Astrophysics Data System (ADS)

    Mantineo, Matías; Pinheiro, João P.; Morgado, António M.

    2014-09-01

    We evaluated the effect of different irradiation parameters in low-level laser therapy (LLLT) for treating inflammation induced in the gastrocnemius muscle of rats through cytokines concentration in systemic blood and analysis of muscle tissue. We used continuous (830 and 980 nm) and pulsed illuminations (830 nm). Animals were divided into five groups per wavelength (10, 20, 30, 40, and 50 mW), and a control group. LLLT was applied during 5 days with a constant irradiation time and area. TNF-α, IL-1β, IL-2, and IL-6 cytokines were quantified by ELISA. Inflammatory cells were counted using microscopy. Identical methodology was used with pulsed illumination. Average power (40 mW) and duty cycle were kept constant (80%) at five frequencies (5, 25, 50, 100, and 200 Hz). For continuous irradiation, treatment effects occurred for all doses, with a reduction of TNF-α, IL-1β, and IL-6 cytokines and inflammatory cells. Continuous irradiation at 830 nm was more effective, a result explained by the action spectrum of cytochrome c oxidase (CCO). Best results were obtained for 40 mW, with data suggesting a biphasic dose response. Pulsed wave irradiation was only effective for higher frequencies, a result that might be related to the rate constants of the CCO internal electron transfer process.

  14. Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy

    PubMed Central

    Hulin-Curtis, S L; Uusi-Kerttula, H; Jones, R; Hanna, L; Chester, J D; Parker, A L

    2016-01-01

    Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cancer. PMID:27229159

  15. Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy.

    PubMed

    Hulin-Curtis, S L; Uusi-Kerttula, H; Jones, R; Hanna, L; Chester, J D; Parker, A L

    2016-07-01

    Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cancer.

  16. Evaluation of flexible and rigid (class solution) radiation therapy conformal prostate planning protocols

    SciTech Connect

    Coburn, Natalie; Beldham-Collins, Rachael; Westling, Jelene; Trovato, Jenny; Gebski, Val

    2012-04-01

    Protocols commonly implemented in radiotherapy work areas may be classified as being either rigid (class solution) or flexible. Because formal evaluation of these protocol types has not occurred within the literature, we evaluated the efficiency of a rigid compared with flexible prostate planning protocol by assessing a series of completed 3D conformal prostate plans. Twenty prostate cancer patients with an average age of 70 years (range, 52-77) and sizes comprising 8 small, 10 medium, and 2 large were planned on the Phillips Pinnacle treatment planning system 6 times by radiation therapists with <2 years, 2-5 years, and >5 years of experience using a rigid and flexible protocol. Plans were critiqued using critical organ doses, confirmation numbers, and conformity index. Plans were then classified as being acceptable or not. Plans produced with the flexible protocol were 53% less likely to require modification (OR 0.47, 95% CI: 0.26, 0.84, p = 0.01). Planners with >5 years of experience were 78% more likely to produce plans requiring modification (OR 1.78, 95% CI: 1.12, 2.83, P = 0.02). Plans according to the flexible protocol took longer (112 min) compared with the time taken using a rigid protocol (68 min) (p < 0.001). The results suggest that further studies are needed; however, we propose that all radiation therapy planners should start with the same limitations, and if an acceptable plan is not reached, then flexibility should be given to improve the plan to meet the desired results.

  17. Long term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma

    PubMed Central

    Trzil, Julie E; Masseau, Isabelle; Webb, Tracy L; Chang, Chee-hoon; Dodam, John R; Cohn, Leah A; Liu, Hong; Quimby, Jessica M; Dow, Steven W; Reinero, Carol R

    2014-01-01

    Background Mesenchymal stem cells (MSCs) decrease airway eosinophilia, airway hyperresponsiveness (AHR), and remodeling in murine models of acutely induced asthma. We hypothesized that MSCs would diminish these hallmark features in a chronic feline asthma model. Objective To document effects of allogeneic, adipose-derived MSCs on airway inflammation, airway hyperresponsiveness (AHR), and remodeling over time and investigate mechanisms by which MSCs alter local and systemic immunologic responses in chronic experimental feline allergic asthma. Methods Cats with chronic, experimentally-induced asthma received six intravenous infusions of MSCs (0.36–2.5X10E7 MSCs/infusion) or placebo bimonthly at the time of study enrollment. Cats were evaluated at baseline and longitudinally for one year. Outcome measures included: bronchoalveolar lavage fluid cytology to assess airway eosinophilia; pulmonary mechanics and clinical scoring to assess AHR; and thoracic computed tomographic (CT) scans to assess structural changes (airway remodeling). CT scans were evaluated using a scoring system for lung attenuation (LA) and bronchial wall thickening (BWT). To assess mechanisms of MSC action, immunologic assays including allergen-specific IgE, cellular IL-10 production, and allergen-specific lymphocyte proliferation were performed. Results There were no differences between treatment groups or over time with respect to airway eosinophilia or AHR. However, significantly lower LA and BWT scores were noted in CT images of MSC-treated animals compared to placebo-treated cats at month 8 of the study (LA p=0.0311; BWT p=0.0489). No differences were noted between groups in the immunologic assays. Conclusions and Clinical Relevance When administered after development of chronic allergic feline asthma, MSCs failed to reduce airway inflammation and AHR. However, repeated administration of MSCs at the start of study did reduce computed tomographic measures of airway remodeling by month 8, though

  18. Volumetric Modulated Arc Therapy: Planning and Evaluation for Prostate Cancer Cases

    SciTech Connect

    Zhang, Pengpeng; Happersett, Laura; Hunt, Margie; Jackson, Andrew; Zelefsky, Michael; Mageras, Gig

    2010-04-15

    Purpose: To develop an optimization method using volumetric modulated arc therapy (VMAT) and evaluate VMAT plans relative to the standard intensity-modulated radiotherapy (IMRT) approach in prostate cancer. Methods and Materials: A single gantry rotation was modeled using 177 equispaced beams. Multileaf collimator apertures and dose rates were optimized with respect to gantry angle subject to dose-volume-based objectives. Our VMAT implementation used conjugate gradient descent to optimize dose rate, and stochastic sampling to find optimal multileaf collimator leaf positions. A treatment planning study of 11 prostate cancer patients with a prescription dose of 86.4 Gy was performed to compare VMAT with a standard five-field IMRT approach. Plan evaluation statistics included the percentage of planning target volume (PTV) receiving 95% of prescribed dose (V95), dose to 95% of PTV (D95), mean PTV dose, tumor control probability, and dosimetric endpoints of normal organs, whereas monitor unit (MU) and delivery time were used to assess delivery efficiency. Results: Patient-averaged PTV V95, D95, mean dose, and tumor control probability in VMAT plans were 96%, 82.6 Gy, 88.5 Gy, and 0.920, respectively, vs. 97%, 84.0 Gy, 88.9 Gy, and 0.929 in IMRT plans. All critical structure dose requirements were met. The VMAT plans presented better rectal wall sparing, with a reduction of 1.5% in normal tissue complication probability. An advantage of VMAT plans was that the average number of MUs (290 MU) was less than for IMRT plans (642 MU). Conclusion: The VMAT technique can reduce beam on time by up to 55% while maintaining dosimetric quality comparable to that of the standard IMRT approach.

  19. Evaluation of Parotid Gland Function following Intensity Modulated Radiation Therapy for Head and Neck Cancer

    PubMed Central

    Lee, Seok Ho; Kim, Tae Hyun; Kim, Joo Young; Park, Sung Yong; Pyo, Hong Ryull; Shin, Kyung Hwan; Kim, Dae Yong; Kim, Joo Young

    2006-01-01

    Purpose This study was undertaken to determine the parotid gland tolerance dose levels following intensity modulated radiation therapy (IMRT) for treating patients who suffered with head and neck cancer. Materials and Methods From February 2003 through June 2004, 34 head and neck patients with 6 months of follow-up were evaluated for xerostomia after being treated by IMRT. Their median age was 59 years (range: 29~78). Xerostomia was assessed using a 4-question xerostomia questionnaire score (XQS) and a test for the salivary flow rates (unstimulated and stimulated: USFR and SSFR, respectively). The patients were also given a validated LENT SOMA scale (LSS) questionnaire. Evaluations were performed before IMRT and at 1, 3 and 6 months after IMRT. Results All 34 patients showed significant changes in the XQS, LSS and Salivary Flow rates (USFR and SSFR) after IMRT. No significant changes in the XQS or LSS were noted in 12 patients who received a total parotid mean dose of ≤3,100 cGy at 1, 3 and 6 months post-IMRT relative to the baseline values. However, for the 22 patients who received >3,100 cGy, significant increases in the XQS and LSS were observed. The USFR and SSFR from the parotid glands in 7 patients who received ≤2,750 cGy were significantly preserved at up to 6 months after IMRT. However, the USFR and SSFR in 27 patients who were treated with >2,750 cGy were significantly lower than the baseline values at all times after IMRT. Conclusion We suggest that the total parotid mean dose should be limited to ≤2,750 cGy to preserve the USFR and SSFR and so improve the subsequent quality of life. PMID:19771265

  20. Calibration and evaluation of a magnetically tracked ICE probe for guidance of left atrial ablation therapy

    NASA Astrophysics Data System (ADS)

    Linte, Cristian A.; Rettmann, Maryam E.; Dilger, Ben; Gunawan, Mia S.; Arunachalam, Shivaram P.; Holmes, David R., III; Packer, Douglas L.; Robb, Richard A.

    2012-02-01

    The novel prototype system for advanced visualization for image-guided left atrial ablation therapy developed in our laboratory permits ready integration of multiple imaging modalities, surgical instrument tracking, interventional devices and electro-physiologic data. This technology allows subject-specific procedure planning and guidance using 3D dynamic, patient-specific models of the patient's heart, augmented with real-time intracardiac echocardiography (ICE). In order for the 2D ICE images to provide intuitive visualization for accurate catheter to surgical target navigation, the transducer must be tracked, so that the acquired images can be appropriately presented with respect to the patient-specific anatomy. Here we present the implementation of a previously developed ultrasound calibration technique for a magnetically tracked ICE transducer, along with a series of evaluation methods to ensure accurate imaging and faithful representation of the imaged structures. Using an engineering-designed phantom, target localization accuracy is assessed by comparing known target locations with their transformed locations inferred from the tracked US images. In addition, the 3D volume reconstruction accuracy is also estimated by comparing a truth volume to that reconstructed from sequential 2D US images. Clinically emulating validation studies are conducted using a patient-specific left atrial phantom. Target localization error of clinically-relevant surgical targets represented by nylon fiducials implanted within the endocardial wall of the phantom was assessed. Our studies have demonstrated 2.4 +/- 0.8 mm target localization error in the engineering-designed evaluation phantoms, 94.8 +/- 4.6 % volume reconstruction accuracy, and 3.1 +/- 1.2 mm target localization error in the left atrial-mimicking phantom. These results are consistent with those disseminated in the literature and also with the accuracy constraints imposed by the employed technology and the clinical

  1. Could the FDA-approved anti-HIV PR inhibitors be promising anticancer agents? An answer from enhanced docking approach and molecular dynamics analyses.

    PubMed

    Arodola, Olayide A; Soliman, Mahmoud E S

    2015-01-01

    Based on experimental data, the anticancer activity of nelfinavir (NFV), a US Food and Drug Administration (FDA)-approved HIV-1 protease inhibitor (PI), was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized that the anticancer activity of NFV is due to its inhibitory effect on heat shock protein 90 (Hsp90), a promising target for anticancer therapy. Such findings prompted us to investigate the potential anticancer activity of all other FDA-approved HIV-1 PIs against human Hsp90. To accomplish this, "loop docking" - an enhanced in-house developed molecular docking approach - followed by molecular dynamic simulations and postdynamic analyses were performed to elaborate on the binding mechanism and relative binding affinities of nine FDA-approved HIV-1 PIs against human Hsp90. Due to the lack of the X-ray crystal structure of human Hsp90, homology modeling was performed to create its 3D structure for subsequent simulations. Results showed that NFV has better binding affinity (ΔG =-9.2 kcal/mol) when compared with other PIs: this is in a reasonable accordance with the experimental data (IC50 3.1 μM). Indinavir, saquinavir, and ritonavir have close binding affinity to NFV (ΔG =-9.0, -8.6, and -8.5 kcal/mol, respectively). Per-residue interaction energy decomposition analysis showed that hydrophobic interaction (most importantly with Val534 and Met602) played the most predominant role in drug binding. To further validate the docking outcome, 5 ns molecular dynamic simulations were performed in order to assess the stability of the docked complexes. To our knowledge, this is the first account of detailed computational investigations aimed to investigate the potential anticancer activity and the binding mechanism of the FDA-approved HIV PIs binding to human Hsp90. Information gained from this study should also provide a route map toward the design, optimization, and further experimental investigation of potential

  2. Could the FDA-approved anti-HIV PR inhibitors be promising anticancer agents? An answer from enhanced docking approach and molecular dynamics analyses

    PubMed Central

    Arodola, Olayide A; Soliman, Mahmoud ES

    2015-01-01

    Based on experimental data, the anticancer activity of nelfinavir (NFV), a US Food and Drug Administration (FDA)-approved HIV-1 protease inhibitor (PI), was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized that the anticancer activity of NFV is due to its inhibitory effect on heat shock protein 90 (Hsp90), a promising target for anticancer therapy. Such findings prompted us to investigate the potential anticancer activity of all other FDA-approved HIV-1 PIs against human Hsp90. To accomplish this, “loop docking” – an enhanced in-house developed molecular docking approach – followed by molecular dynamic simulations and postdynamic analyses were performed to elaborate on the binding mechanism and relative binding affinities of nine FDA-approved HIV-1 PIs against human Hsp90. Due to the lack of the X-ray crystal structure of human Hsp90, homology modeling was performed to create its 3D structure for subsequent simulations. Results showed that NFV has better binding affinity (ΔG =−9.2 kcal/mol) when compared with other PIs: this is in a reasonable accordance with the experimental data (IC50 3.1 μM). Indinavir, saquinavir, and ritonavir have close binding affinity to NFV (ΔG =−9.0, −8.6, and −8.5 kcal/mol, respectively). Per-residue interaction energy decomposition analysis showed that hydrophobic interaction (most importantly with Val534 and Met602) played the most predominant role in drug binding. To further validate the docking outcome, 5 ns molecular dynamic simulations were performed in order to assess the stability of the docked complexes. To our knowledge, this is the first account of detailed computational investigations aimed to investigate the potential anticancer activity and the binding mechanism of the FDA-approved HIV PIs binding to human Hsp90. Information gained from this study should also provide a route map toward the design, optimization, and further experimental investigation of

  3. Could the FDA-approved anti-HIV PR inhibitors be promising anticancer agents? An answer from enhanced docking approach and molecular dynamics analyses.

    PubMed

    Arodola, Olayide A; Soliman, Mahmoud E S

    2015-01-01

    Based on experimental data, the anticancer activity of nelfinavir (NFV), a US Food and Drug Administration (FDA)-approved HIV-1 protease inhibitor (PI), was reported. Nevertheless, the mechanism of action of NFV is yet to be verified. It was hypothesized that the anticancer activity of NFV is due to its inhibitory effect on heat shock protein 90 (Hsp90), a promising target for anticancer therapy. Such findings prompted us to investigate the potential anticancer activity of all other FDA-approved HIV-1 PIs against human Hsp90. To accomplish this, "loop docking" - an enhanced in-house developed molecular docking approach - followed by molecular dynamic simulations and postdynamic analyses were performed to elaborate on the binding mechanism and relative binding affinities of nine FDA-approved HIV-1 PIs against human Hsp90. Due to the lack of the X-ray crystal structure of human Hsp90, homology modeling was performed to create its 3D structure for subsequent simulations. Results showed that NFV has better binding affinity (ΔG =-9.2 kcal/mol) when compared with other PIs: this is in a reasonable accordance with the experimental data (IC50 3.1 μM). Indinavir, saquinavir, and ritonavir have close binding affinity to NFV (ΔG =-9.0, -8.6, and -8.5 kcal/mol, respectively). Per-residue interaction energy decomposition analysis showed that hydrophobic interaction (most importantly with Val534 and Met602) played the most predominant role in drug binding. To further validate the docking outcome, 5 ns molecular dynamic simulations were performed in order to assess the stability of the docked complexes. To our knowledge, this is the first account of detailed computational investigations aimed to investigate the potential anticancer activity and the binding mechanism of the FDA-approved HIV PIs binding to human Hsp90. Information gained from this study should also provide a route map toward the design, optimization, and further experimental investigation of potential

  4. Evaluation of multisystemic therapy pilot services in the Systemic Therapy for At Risk Teens (START) trial: study protocol for a randomised controlled trial

    PubMed Central

    2013-01-01

    depending on whether the outcome is time-to-event or continuous. Discussion The START trial is a pragmatic national trial of sufficient size to evaluate multisystemic therapy, to inform policymakers, service commissioners, professionals, service users and their families about its potential in the UK. It will also provide data on the clinical and cost-effectiveness of usual services provided to youth with serious antisocial behaviour problems. Trial registration ISRCTN77132214 PMID:23962220

  5. Clinical evaluations of an amplitude-based binning algorithm for 4DCT reconstruction in radiation therapy

    SciTech Connect

    Li Hua; Noel, Camille; Garcia-Ramirez, Jose; Low, Daniel; Bradley, Jeffrey; Robinson, Clifford; Mutic, Sasa; Parikh, Parag

    2012-02-15

    Purpose: Phase-binning algorithms are commonly utilized in 4DCT image reconstruction for characterization of tumor or organ shape and respiration motion, but breathing irregularities occurring during 4DCT acquisition can cause considerable image distortions. Recently, amplitude-binning algorithms have been evaluated as a potential improvement to phase-binning algorithms for 4DCT image reconstruction. The purpose of this study was to evaluate the performance of the first commercially available on-line retrospective amplitude-binning algorithm for comparison to the traditional phase-binning algorithm. Methods: Both phantom and clinical data were used for evaluation. A phantom of known geometry was mounted on a 4D motion platform programmed with seven respiratory waves (two computer generated and five patient trajectories) and scanned with a Philips Brilliance Big bore 16-slice CT simulator. 4DCT images were reconstructed using commercial amplitude- and phase-binning algorithms. Image quality of the amplitude- and phase-binned image sets was compared by evaluation of shape and volume distortions in reconstructed images. Clinical evaluations were performed on 64 4DCT patient image sets in a blinded review process. The amplitude- and phase-binned 4DCT maximum intensity projection (MIP) images were further evaluated for 28 stereotactic body radiation therapy (SBRT) cases of total 64 cases. A preliminary investigation of the effects of respiratory amplitude and pattern irregularities on motion artifact severity was conducted. Results: The phantom experiments illustrated that, as expected, maximum inhalation occurred at the 0% amplitude and maximum exhalation occurred at the 50% amplitude of the amplitude-binned 4DCT image sets. The phantom shape distortions were more severe in the images reconstructed from the phase-binning algorithm. In the clinical study, compared to the phase-binning algorithm, the amplitude-binning algorithm yielded fewer or less severe motion

  6. Evaluation of an Optimized Injection System for Retinal Gene Therapy in Human Patients.

    PubMed

    Fischer, M Dominik; Hickey, Doron G; Singh, Mandeep S; MacLaren, Robert E

    2016-08-01

    Many retinal gene therapy clinical trials require subretinal injections of small volumes of adeno-associated viral (AAV) vector solutions in patients with retinal dystrophies, using equipment not specifically designed for this purpose. We therefore evaluated an optimized injection system in order to identify variables that might influence the rate of injection and final dose of vector delivered. An optimized injection system was assembled with a 41G polytetrafluoroethylene tip for retinal gene therapy. Flow rate was recorded at relevant infusion pressures (2-22 psi [14-152 kPa]), different target pressures (0.02-30 mm Hg [0.003-4 kPa]) and temperatures (18°C vs. 36°C) using a semiautomated Accurus(®) Surgical System. Retention of AAV2/8 and AAV2/8(Y733F) vector was quantified after simulating loading/injection with or without 0.001% Pluronic(®) F-68 (PF-68). The optimized injection system provided a linear flow rate (μl/s)-to-infusion pressure (psi) relationship (y = 0.62x; r(2) = 0.99), independent of temperature and pressure changes relevant for intraocular surgery (18-36°C, 0.02-30 mm Hg). Differences in length of 41G polytetrafluoroethylene tips caused significant variation in flow rate (p < 0.001). Use of PF-68 significantly (p < 0.001) reduced loss of vector genomes in the injection system by 55% (AAV2/8) and 52% (AAV2/8(Y733F)). A customized subretinal injection system assembled using equipment currently available in the operating room can deliver a controlled volume of vector at a fixed rate across a range of possible clinical parameters encountered in vitreoretinal surgery. The inclusion of 0.001% PF-68 had a significant effect on the final dose of vector genomes delivered. The described technique is currently used successfully in a clinical trial. PMID:27480111

  7. A Controlled Evaluation of Family Behavior Therapy in Concurrent Child Neglect and Drug Abuse

    PubMed Central

    Donohue, Brad; Azrin, Nathan H.; Bradshaw, Kelsey; Van Hasselt, Vincent B.; Cross, Chad L.; Urgelles, Jessica; Romero, Valerie; Hill, Heather H.; Allen, Daniel N.

    2015-01-01

    Objective Approximately 50% of Child Protective Service (CPS) referrals abuse drugs; yet, existing treatment studies in this population have been limited to case examinations. Therefore, a family-based behavioral therapy was evaluated in mothers referred from CPS for child neglect and drug abuse utilizing a controlled experimental design. Method 72 mothers evidencing drug abuse or dependence and child neglect were randomly assigned to Family Behavior Therapy (FBT) or Treatment as Usual (TAU). Participants were assessed at baseline, 6- month-, and 10-month post-randomization. Results As hypothesized, intent-to-treat repeated measures analyses revealed mothers referred for child neglect not due to their children being exposed to illicit drugs demonstrated better outcomes in child maltreatment potential from baseline to 6- and 10-month post-randomization assessments when assigned to FBT, as compared with TAU mothers and FBT mothers who were referred due to child drug exposure. Similar results occurred for hard drug use from baseline to 6- and 10-month post-randomization. However, TAU mothers referred due to child drug exposure were also found to decrease their hard drug use more than TAU mothers of non-drug exposed children and FBT mothers of drug exposed children at 6- and 10-month post-randomization. Although effect sizes for mothers assigned to FBT were slightly larger for marijuana use than TAU (medium vs. large), these differences were not statistically significant. Specific to secondary outcomes, mothers in FBT, relative to TAU, increased time employed from baseline to 6- and 10-month post-randomization. Mothers in FBT, compared to TAU, also decreased HIV risk from baseline to 6-month post-randomization. There were no differences in outcome between FBT and TAU for number of days children were in CPS custody and alcohol intoxication, although FBT mothers demonstrated marginal decreases (p = .058) in incarceration from baseline to 6-month post

  8. Antiretroviral Therapy in the Clinic▿

    PubMed Central

    Tsibris, Athe M. N.; Hirsch, Martin S.

    2010-01-01

    Antiretroviral therapy in the developed world has resulted in substantial reductions in HIV-associated morbidity and mortality, changing an HIV diagnosis from a likely death sentence into a manageable chronic infection (F. J. Palella, Jr., K. M. Delaney, A. C. Moorman, M. O. Loveless, J. Fuhrer, G. A. Satten, D. J. Aschman, and S. D. Holmberg, N. Engl. J. Med. 338:853-860, 1998). Several million years of life have been saved by effective anti-HIV treatment, although these successes should not obscure the magnitude of the ongoing worldwide HIV epidemic (R. P. Walensky, A. D. Paltiel, E. Losina, L. M. Mercincavage, B. R. Schackman, P. E. Sax, M. C. Weinstein, and K. A. Freedberg, J. Infect. Dis. 194:11-19, 2006). Readers of the Journal of Virology are doubtless aware of the fundamental advances in retrovirology that have made possible the development of potent inhibitors of HIV replication. In this review, we focus on the issues surrounding how these drugs and drug regimens are actually used in clinical settings. Their proper use requires detailed knowledge of the natural history of HIV infection, the pharmacology of the individual drugs, the complexities of drug-drug interactions, and the use of sophisticated molecular tests for monitoring of viral load, immunologic response, and drug resistance. PMID:20181709

  9. siRNA-loaded cationic liposomes for cancer therapy: Development, characterization and efficacy evaluation

    NASA Astrophysics Data System (ADS)

    Ying, Bo

    Cancer is a major health problem in the United States and many other parts of the world. However, cancer treatment is severely limited by the lack of highly effective cytotoxic agents and selective delivery methods which can serve as the "magic bullet" (first raised by Dr. Paul Ehrlich, the goal of targeting a specific location without causing harm to surrounding tissues or to more distant regions in the body). The revolutionary finding that tumors cannot grow beyond a microscopic size without dedicated blood supply provided a highly effective alternative for the treatment of cancer. Currently, anti-angiogenic therapy and the discovery of RNA interference makes it possible to treat some conditions by silencing disorder-causing genes of targeting cells which are otherwise difficult to eradicate with more conventional therapies. However, before siRNA technology could be widely used as a therapeutic approach, the construct must be efficiently and safely delivered to target cells. Strategies used for siRNA delivery should minimize uptake by phagocytes, enzymatic degradation by nucleases and should be taken up preferentially, if not specifically, by the intended cell population. Kinesin spindle proteins (KSP) are the motor proteins which play critical roles during mitosis. Different from tubulins which are also present in post-mitotic cells, such as axons, KSP is exclusively expressed in mitotic cells, which makes them the ideal target for anti-mitotics. In the present study, we intend to develop, characterize and evaluate a liposome-based delivery system which can deliver KSP siRNA selectively to the tumor vasculature (thus inhibiting angiogenesis, destroying tumor vasculature and eventually, eradicating tumor growth). We first developed ten different liposome preparation types with different compositions of lipids. Next, the capacity for loading siRNA and efficiency of targeting the tumor vascular supply was evaluated using relevant cellular and tumor models

  10. Evaluation of different fiducial markers for image-guided radiotherapy and particle therapy

    PubMed Central

    Habermehl, Daniel; Henkner, Katrin; Ecker, Swantje; Jäkel, Oliver; Debus, Jürgen; Combs, Stephanie E.

    2013-01-01

    Modern radiotherapy (RT) techniques are widely used in the irradiation of moving organs. A crucial step in ensuring the correct position of a target structure directly before or during treatment is daily image guidance by computed tomography (CT) or X-ray radiography (image-guided radiotherapy, IGRT). Therefore, combinations of modern irradiation devices and imaging, such as on-board imaging (OBI) with X-rays, or in-room CT such as the tomotherapy system, have been developed. Moreover, combinations of linear accelerators and in-room CT-scanners have been designed. IGRT is of special interest in hypofractionated and radiosurgical treatments where high single doses are applied in the proximity of critical organs at risk. Radiographically visible markers in or in close proximity to the target structure may help to reproduce the position during RT and could therefore be used as external surrogates for motion monitoring. Criteria sought for fiducial markers are (i) visibility in the radiologic modalities involved in radiotherapeutic treatment planning and image guidance, such as CT and kilovoltage (kV) OBI), (ii) low production of imaging artifacts, and (iii) low perturbation of the therapeutic dose to the target volume. Photon interaction with interstitial markers has been shown to be not as important as in particle therapy, where interaction of the particle beam, especially with metal markers, can have a significant impact on treatment. This applies especially with a scanned ion beam. Recently we commenced patient recruitment at our institution within the PROMETHEUS trial, which evaluates a hypofractionation regime, starting with 4 x 10 Gy (RBE), for patients with hepatocellular carcinoma. The aim of this work is, therefore, to evaluate potential implantable fiducial markers for enabling precise patient and thus organ positioning in scanned ion beams. To transfer existing knowledge of marker application from photon to particle therapy, we used a range of commercially

  11. Evaluation of different fiducial markers for image-guided radiotherapy and particle therapy.

    PubMed

    Habermehl, Daniel; Henkner, Katrin; Ecker, Swantje; Jäkel, Oliver; Debus, Jürgen; Combs, Stephanie E

    2013-07-01

    Modern radiotherapy (RT) techniques are widely used in the irradiation of moving organs. A crucial step in ensuring the correct position of a target structure directly before or during treatment is daily image guidance by computed tomography (CT) or X-ray radiography (image-guided radiotherapy, IGRT). Therefore, combinations of modern irradiation devices and imaging, such as on-board imaging (OBI) with X-rays, or in-room CT such as the tomotherapy system, have been developed. Moreover, combinations of linear accelerators and in-room CT-scanners have been designed. IGRT is of special interest in hypofractionated and radiosurgical treatments where high single doses are applied in the proximity of critical organs at risk. Radiographically visible markers in or in close proximity to the target structure may help to reproduce the position during RT and could therefore be used as external surrogates for motion monitoring. Criteria sought for fiducial markers are (i) visibility in the radiologic modalities involved in radiotherapeutic treatment planning and image guidance, such as CT and kilovoltage (kV) OBI), (ii) low production of imaging artifacts, and (iii) low perturbation of the therapeutic dose to the target volume. Photon interaction with interstitial markers has been shown to be not as important as in particle therapy, where interaction of the particle beam, especially with metal markers, can have a significant impact on treatment. This applies especially with a scanned ion beam. Recently we commenced patient recruitment at our institution within the PROMETHEUS trial, which evaluates a hypofractionation regime, starting with 4 x 10 Gy (RBE), for patients with hepatocellular carcinoma. The aim of this work is, therefore, to evaluate potential implantable fiducial markers for enabling precise patient and thus organ positioning in scanned ion beams. To transfer existing knowledge of marker application from photon to particle therapy, we used a range of commercially

  12. Evaluating Acceptance and Commitment Therapy: An Analysis of a Recent Critique

    ERIC Educational Resources Information Center

    Gaudiano, Brandon A.

    2011-01-01

    Acceptance and commitment therapy (ACT) is a newer psychotherapy that has generated much clinical and research interest in recent years. However, the approach has begun to receive strong criticism from proponents of traditional cognitive-behavioral therapy (CBT). Hofmann and Asmundson (2008) recently compared and contrasted ACT and traditional…

  13. Evaluating Acceptance and Commitment Therapy: An Analysis of a Recent Critique

    ERIC Educational Resources Information Center

    Gaudiano, Brandon A.

    2009-01-01

    Acceptance and commitment therapy (ACT) is a newer psychotherapy that has generated much clinical and research interest in recent years. However, the approach has begun to receive strong criticism from proponents of traditional cognitive-behavioral therapy (CBT). Hofmann and Asmundson (2008) recently compared and contrasted ACT and traditional…

  14. Evaluation of a Reality Therapy Stratification System in a Residential Drug Rehabilitation Center

    ERIC Educational Resources Information Center

    Schuster, Richard

    1978-01-01

    A stratification system was designed and implemented based on the principles of reality therapy for use in a male adolescent drug rehabilitation center. The program involved four levels in an ascending order of responsibility and privileges. Problems are discussed as well as requirements for successfully implementing reality therapy in…

  15. Evaluating the first-in-human clinical trial of a human embryonic stem cell-based therapy.

    PubMed

    Chapman, Audrey R; Scala, Courtney C

    2012-09-01

    Phase I clinical trials generally raise greater ethical and human protection challenges than later stage clinical trials, suggesting a need to proceed cautiously. This is particularly the case for Phase I trials with a novel therapy being tested in humans for the first time, usually termed first-in-human (FIH) trials. In January 2009, the Food and Drug Administration approved the Investigational New Drug application of Geron Corporation, a small California-based biopharmaceutical company, to initiate a clinical trial to assess GRNOPC1, a human embryonic stem cell-derived candidate therapy for severe spinal cord injuries. This article evaluates the ethical and human subject protection issues raised by the Geron FIH trial. It identifies problems with the approval process and with the conduct of the trial, and then recommends ways to improve review of future proposed trials with novel and high-risk therapies.

  16. Phantom based evaluation of CT to CBCT image registration for proton therapy dose recalculation

    NASA Astrophysics Data System (ADS)

    Landry, Guillaume; Dedes, George; Zöllner, Christoph; Handrack, Josefine; Janssens, Guillaume; Orban de Xivry, Jonathan; Reiner, Michael; Paganelli, Chiara; Riboldi, Marco; Kamp, Florian; Söhn, Matthias; Wilkens, Jan J.; Baroni, Guido; Belka, Claus; Parodi, Katia

    2015-01-01

    The ability to perform dose recalculation on the anatomy of the day is important in the context of adaptive proton therapy. The objective of this study was to investigate the use of deformable image registration (DIR) and cone beam CT (CBCT) imaging to generate the daily stopping power distribution of the patient. We investigated the deformation of the planning CT scan (pCT) onto daily CBCT images to generate a virtual CT (vCT) using a deformable phantom designed for the head and neck (H & N) region. The phantom was imaged at a planning CT scanner in planning configuration, yielding a pCT and in deformed, treatment day configuration, yielding a reference CT (refCT). The treatment day configuration was additionally scanned at a CBCT scanner. A Morphons DIR algorithm was used to generate a vCT. The accuracy of the vCT was evaluated by comparison to the refCT in terms of corresponding features as identified by an adaptive scale invariant feature transform (aSIFT) algorithm. Additionally, the vCT CT numbers were compared to those of the refCT using both profiles and regions of interest and the volumes and overlap (DICE coefficients) of various phantom structures were compared. The water equivalent thickness (WET) of the vCT, refCT and pCT were also compared to evaluate proton range differences. Proton dose distributions from the same initial fluence were calculated on the refCT, vCT and pCT and compared in terms of proton range. The method was tested on a clinical dataset using a replanning CT scan acquired close in time to a CBCT scan as reference using the WET evaluation. Results from the aSIFT investigation suggest a deformation accuracy of 2-3 mm. The use of the Morphon algorithm did not distort CT number intensity in uniform regions and WET differences between vCT and refCT were of the order of 2% of the proton range. This result was confirmed by proton dose calculations. The patient results were consistent with phantom observations. In conclusion, our phantom

  17. In Search of a Gold Standard Scoring System for the Subjective Evaluation of Cosmetic Outcomes Following Breast-Conserving Therapy.

    PubMed

    Racz, Jennifer M; Hong, Nicole Look; Latosinsky, Steven

    2015-01-01

    The absence of a widely accepted method for aesthetic evaluation following breast-conserving surgery for breast cancer limits the ability to evaluate cosmetic outcomes. In this study, two different panel scoring approaches were compared in an attempt to identify a gold standard scoring system for subjectively assessing cosmetic outcomes following breast-conserving therapy. Standardized photographs of each participant were evaluated independently by twelve health care professionals involved in breast cancer diagnosis and treatment using the Danoff four-point scale. Individual Danoff scores were combined using two methods, a random sample "three-panel" score and an iterative "Delphi-panel" score, in order to create a final cosmetic score for each patient. Agreement between these two aggregative approaches was assessed with a weighted kappa (wk) statistic. Patient and professional recruitment occurred at two separate tertiary care multi-disciplinary breast health centers. Women with unilateral breast cancer who underwent breast-conserving therapy (segmental mastectomy or lumpectomy and radiotherapy) and were at least 2 years after radiotherapy were asked to participate. Ninety-seven women were evaluated. The Delphi approach required three rounds of evaluation to obtain greater than 50% agreement in all photographs. The wk statistic between scores generated from the "three-panel" and "Delphi-panel" approaches was 0.80 (95% CI: 0.71-0.89), thus demonstrating substantial agreement. Evaluation of cosmetic outcomes following breast-conserving therapy using a "three-panel" and "Delphi-panel" score provide similar results, confirming the reliability of either approach for subjective evaluation. Simplicity of use and interpretation favors the "three-panel" score. Future work should concentrate on the integration of the three-panel score with objective and patient-reported scales to generate a comprehensive cosmetic evaluation platform. PMID:25940058

  18. A Multiple siRNA-Based Anti-HIV/SHIV Microbicide Shows Protection in Both In Vitro and In Vivo Models.

    PubMed

    Boyapalle, Sandhya; Xu, Weidong; Raulji, Payal; Mohapatra, Subhra; Mohapatra, Shyam S

    2015-01-01

    Human immunodeficiency virus (HIV) types 1 and 2 (HIV-1 and HIV-2) are the etiologic agents of AIDS. Most HIV-1 infected individuals worldwide are women, who acquire HIV infections during sexual contact. Blocking HIV mucosal transmission and local spread in the female lower genital tract is important in preventing infection and ultimately eliminating the pandemic. Microbicides work by destroying the microbes or preventing them from establishing an infection. Thus, a number of different types of microbicides are under investigation, however, the lack of their solubility and bioavailability, and toxicity has been major hurdles. Herein, we report the development of multifunctional chitosan-lipid nanocomplexes that can effectively deliver plasmids encoding siRNA(s) as microbicides without adverse effects and provide significant protection against HIV in both in vitro and in vivo models. Chitosan or chitosan-lipid (chlipid) was complexed with a cocktail of plasmids encoding HIV-1-specific siRNAs (psiRNAs) and evaluated for their efficacy in HEK-293 cells, PBMCs derived from nonhuman primates, 3-dimensional human vaginal ectocervical tissue (3D-VEC) model and also in non-human primate model. Moreover, prophylactic administration of the chlipid to deliver a psiRNA cocktail intravaginally with a cream formulation in a non-human primate model showed substantial reduction of SHIV (simian/human immunodeficiency virus SF162) viral titers. Taken together, these studies demonstrate the potential of chlipid-siRNA nanocomplexes as a potential genetic microbicide against HIV infections. PMID:26407080

  19. A Multiple siRNA-Based Anti-HIV/SHIV Microbicide Shows Protection in Both In Vitro and In Vivo Models

    PubMed Central

    Raulji, Payal; Mohapatra, Subhra; Mohapatra, Shyam S

    2015-01-01

    Human immunodeficiency virus (HIV) types 1 and 2 (HIV-1 and HIV-2) are the etiologic agents of AIDS. Most HIV-1 infected individuals worldwide are women, who acquire HIV infections during sexual contact. Blocking HIV mucosal transmission and local spread in the female lower genital tract is important in preventing infection and ultimately eliminating the pandemic. Microbicides work by destroying the microbes or preventing them from establishing an infection. Thus, a number of different types of microbicides are under investigation, however, the lack of their solubility and bioavailability, and toxicity has been major hurdles. Herein, we report the development of multifunctional chitosan-lipid nanocomplexes that can effectively deliver plasmids encoding siRNA(s) as microbicides without adverse effects and provide significant protection against HIV in both in vitro and in vivo models. Chitosan or chitosan-lipid (chlipid) was complexed with a cocktail of plasmids encoding HIV-1-specific siRNAs (psiRNAs) and evaluated for their efficacy in HEK-293 cells, PBMCs derived from nonhuman primates, 3-dimensional human vaginal ectocervical tissue (3D-VEC) model and also in non-human primate model. Moreover, prophylactic administration of the chlipid to deliver a psiRNA cocktail intravaginally with a cream formulation in a non-human primate model showed substantial reduction of SHIV (simian/human immunodeficiency virus SF162) viral titers. Taken together, these studies demonstrate the potential of chlipid-siRNA nanocomplexes as a potential genetic microbicide against HIV infections. PMID:26407080

  20. Evaluation of the effect of photodynamic antimicrobial therapy in dentin caries: a pilot in vivo study

    NASA Astrophysics Data System (ADS)

    Borges, F. M. C.; de-Melo, M. A. S.; Lima, J. M. P.; Zanin, I. C. J.; Rodrigues, L. K. A.; Nobre-dos-Santos, M.

    2010-02-01

    In vitro and in situ studies have demonstrated that the photodynamic antimicrobial therapy (PACT) is effective in reducing Streptococcus mutans population in artificially carious dentin. This pilot in vivo study evaluated the antimicrobial effect of PACT using toluidine blue O (TBO) and a light-emitting diode (LED) in carious dentin lesions. Five healthy adult volunteers (19-36 yr), with at least 4 active carious cavities each, participated in this study. Teeth of each volunteer were randomly divided into four groups: (1) without TBO and without light (Control); (2) with TBO alone (TBO); (3) with LED at 94/J cm2 alone (LED); and (4) with TBO plus LED at 94 J/cm2 (PACT). Each cavity was divided into two halves. The baseline carious dentin sample was collected from half of each cavity. Following, the treatments were performed using a random distribution of tooth into treatments. Then, the second collection of carious dentin samples was performed. Before and after treatments, dentin samples were analyzed with regard to the counts of total viable microorganisms, total streptococci, mutans streptococci, and lactobacilli. The data were statistically analyzed by Kruskal-Wallis and Student-Newman-Keuls tests (α=5%). Log reductions ranged from -0.12 to 2.68 and significant reductions were observed for PACT (group 4) when compared to the other groups (1, 2, and 3) for total streptococci and mutans streptococci. Concluding, PACT was effective in killing oral microorganisms present in in vivo carious dentin lesions and may be a promising technique for eliminating bacteria from dentin before restoration.

  1. DICOM-based computer-aided evaluation of intensity modulated radiation therapy (IMRT) treatment plans

    NASA Astrophysics Data System (ADS)

    Cheung, Fion W. K.; Law, Maria Y. Y.

    2011-03-01

    Intensity-modulated radiation therapy (IMRT) has gained popularity in the treatment of cancers because of its excellent local control with decreased normal tissue complications. Yet, computer planning for the treatment relies heavily on human inspection of resultant radiation dose distribution within the irradiated region of the body. Even for experienced planners, comparison of IMRT plans is definitely cumbersome and not error-free. To solve this problem, a computer-aided decision-support system was built for automatic evaluation of IMRT plans based on the DICOM standard. A DICOM based IMRT plan with DICOM and DICOM-RT objects including CT images, RT Structure Set, RT Dose and RT Plan were retrieved from the Treatment Planning System for programming. Utilizing the MATLAB program language, the decoding-encoding software applications were developed on the basis of the DICOM information object definitions. After tracing the clinical workflow and understanding the needs and expectations from radiation oncologists, a set of routines were written to parse key data items such as isodose curves, region of interests, dose-volume histogram from the DICOM-RT objects. Then graphical user interfaces (GUIs) were created to allow planners to query for parameters such as overdose or underdose areas. A total of 30 IMRT plans were collected in a Department of Clinical Oncology for systematic testing of the DICOM-based decision-support system. Both structural and functional tests were implemented as a major step on the road to software maturity. With promising test results, this decision-support system could represent a major breakthrough in the routine IMRT planning workflow.

  2. Evaluation of Health Plan Interventions to Influence Chronic Opioid Therapy Prescribing

    PubMed Central

    Saunders, Kathleen; Shortreed, Susan; Thielke, Stephen; Turner, Judith A.; LeResche, Linda; Beck, Randi; Von Korff, Michael

    2015-01-01

    Objectives Evaluate health plan interventions targeting physician chronic opioid therapy (COT) prescribing. Methods In 2006, Group Health’s (GH) integrated group practice (IGP) initiated diverse interventions targeting COT prescriber norms and practices. In 2010, the IGP implemented a COT guideline, including a mandated online course for physicians managing COT. These interventions were not implemented in GH’s network practices. We compared trends in GH-IGP and network practices for 2006–12 in the percent of patients receiving COT and their opioid dose. We compared physician beliefs before versus after the mandated course and pre- to post-course changes in COT dosing for IGP physicians who took the course. Results From 2006 to 2012, mean (SE) daily opioid dose among IGP COT patients (intervention setting) declined from 74.1 (1.9) mg. morphine equivalent dose (MED) to 48.3 (1.0) mg. MED. Dose changes among GH network COT patients (control setting) were modest—88.2 (5.0) mg. MED in 2006 to 75.7 (2.3) mg. MED in 2012. Among physicians taking the mandated course in 2011, we observed pre- to post-course changes toward more conservative opioid prescribing beliefs. However, COT dosing trends did not change pre- to post-course. Discussion Following initiatives implemented to alter physician prescribing practices and norms, mean opioid dose prescribed to COT patients declined more in intervention than control practices. Physicians reported more conservative beliefs regarding opioid prescribing immediately after completing an online course in 2011, but the course was not associated with additional reductions in mean daily opioid dose prescribed by physicians completing the course. PMID:25621426

  3. Evaluation of low level laser therapy irradiation parameters on rat muscle inflammation through systemic blood cytokines

    NASA Astrophysics Data System (ADS)

    Mantineo, Matias; Pinheiro, João. P.; Morgado, António M.

    2014-02-01

    Low level laser therapy (LLLT) has been used for inflammation treatment. Here, we evaluate the effect of different doses, using continuous (830 and 980 nm) and pulsed illumination (830 nm), in the treatment of inflammation induced in the gastrocnemius muscle of Wistar rats, through cytokines concentration in systemic blood and histological analysis of muscle tissue. Animals were randomly divided into five groups per wavelength (5 animals per group: 10, 20, 30, 40 and 50 mW) plus a control group. LLLT was applied during five days, with constant exposure time and irradiated area (3 minutes; 0.5026 cm2). Blood was collected on days 0, 3 and 6. TNF-α, IL-1β, IL-2 and IL-6 cytokines were quantified by ELISA. Rats were killed on day 6. Muscle inflammatory cells were counted using optical microscopy. Treatment effects occurred for all applied doses (largest effect at 40 mW: 7.2 J, 14 J/cm2 per irradiation), with reduction of proinflammatory TNF-α, IL-1β and IL-6 cytokines and lower number of inflammatory cells. Results were better for 830 nm. Identical methodology was used with pulsed illumination. Average power (40 mW) and duty cycle were kept constant (80%) at five frequencies (5, 25, 50, 100 and 200 Hz). Treatment effects were observed at higher frequencies, with no significant differences between them. However, the treatment effect was lower than for continuous illumination. LLLT effect on inflammation treatment can be monitored by measuring systemic blood cytokines. A larger treatment effect was observed with continuous illumination, where results seem to be compatible with a biphasic dose response.

  4. A cephalometric evaluation of high-pull molar headgear and face-bow neck strap therapy.

    PubMed

    Brown, P

    1978-12-01

    The effects of two different extraoral appliances were evaluated over a 1-year period. Of the thirty-seven cases selected for study, twenty were treated with a face-bow neck strap and seventeen were treated with a high-pull molar headgear. Patients ranged in age from 10.10 to 16.6 years and averaged 13.4 years. The appliances exerted less than 600 Gm. of force per side and were worn for 12 to 16 hours per day. All cases were fully banded, and extraction and nonextraction treatment were included. An analysis of pretreatment data revealed a high degree of selection. Patients selected for high-pull treatment generally exhibited larger anterior face heights, steeper mandibular plane angles, and a greater amount of tooth eruption of the upper first molars than the patients selected for neck strap therapy. A control group of ten untreated subjects was matched to each treatment group to permit assessment of the impact of treatment on growth. Relative to normal growth, treatment with face-bow neck strap traction tended to direct the maxilla and mandible downward and backward. The palatal plane was lowered anteriorly and point A was retracted. The maxillary molars were extruded, and concomitantly an increase in anterior face height and mandibular plane angle was observed. On the other hand, the high-pull molar headgear traction resulted only in increased mandibular molar eruption. However, there was also a nonsignificant tendency for point A to be held back and for lower anterior face height to increase. The comparison of the two treatment samples revealed that the functional occlusal plane was tipped down at the back as the maxillary molars were more extruded in the neck strap sample. In the high-pull sample, the functional occlusal plane was unchanged and the mandibular molars were more extruded than they were in the neck strap group.

  5. Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.

    PubMed Central

    Haasova, Marcela; Snowsill, Tristan; Jones-Hughes, Tracey; Crathorne, Louise; Cooper, Chris; Varley-Campbell, Jo; Mujica-Mota, Ruben; Coelho, Helen; Huxley, Nicola; Lowe, Jenny; Dudley, Jan; Marks, Stephen; Hyde, Chris; Bond, Mary; Anderson, Rob

    2016-01-01

    BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE

  6. MABGEL 1: First Phase 1 Trial of the Anti-HIV-1 Monoclonal Antibodies 2F5, 4E10 and 2G12 as a Vaginal Microbicide

    PubMed Central

    Morris, Georgina C.; Wiggins, Rebecca C.; Woodhall, Sarah C.; Bland, J. Martin; Taylor, Carol R.; Jespers, Vicky; Vcelar, Brigitta A.; Lacey, Charles J.

    2014-01-01

    Background Monoclonal antibodies (mAbs) which potently neutralize a broad range of HIV isolates are potential microbicide candidates. To date, topical application of mAbs in humans and their stability in vaginal secretions has not been studied. Objectives To assess the pharmacokinetics and safety of the mAbs 2F5, 4E10 and 2G12 when applied vaginally in women. Design A randomized, double-blind, placebo-controlled phase 1 trial. Methods Twenty-eight healthy, sexually abstinent women administered 2.5 g of gel daily for 12 days containing either 10 or 20 mg/g of each mAb (MABGEL) or placebo. Main clinical evaluations and sampling occurred at baseline, 1, 8, and 24 hours post-1st dose and 12 and 36 hours post-12th dose. Results After adjustment for dilution factors, median levels of 2F5, 4E10 and 2G12 in vaginal secretions at 1 hour post high-dose MABGEL were 7.74, 5.28 and 7.48 mg/ml respectively. Levels of 2F5 and 4E10 declined exponentially thereafter with similar estimated half-lives (4.6 and 4.3 hours). In contrast, 2G12 levels declined more rapidly in the first 8 hours, with an estimated half-life of 1.4 hours during this period. There was no evidence of systemic absorption. There were no significant differences in local or systemic adverse event rates or vaginal flora changes (by qPCR) between active and placebo gel arms. Whilst at least 1 adverse event was recorded in 96% of participants, 95% were mild and none were serious. Conclusions Vaginal application of 50 mg of each mAb daily was safe over a 12 day period. Median mAb concentrations detected at 8 hours post dose were potentially sufficient to block HIV transmission.2G12 exhibited more rapid elimination from the human vagina than 4E10 and 2F5, likely due to poor stability of 2G12 in acidic human vaginal secretions. Further research is needed to develop mAb-based vaginal microbicides and delivery systems. Trial Registration ISRCTN 64808733 UK CRN Portfolio 6470 PMID:25546420

  7. MAL Daylight Photodynamic Therapy for Actinic Keratosis: Clinical and Imaging Evaluation by 3D Camera.

    PubMed

    Cantisani, Carmen; Paolino, Giovanni; Pellacani, Giovanni; Didona, Dario; Scarno, Marco; Faina, Valentina; Gobello, Tommaso; Calvieri, Stefano

    2016-07-11

    Non-melanoma skin cancer is the most common skin cancer with an incidence that varies widely worldwide. Among them, actinic keratosis (AK), considered by some authors as in situ squamous cell carcinoma (SCC), are the most common and reflect an abnormal multistep skin cell development due to the chronic ultraviolet (UV) light exposure. No ideal treatment exists, but the potential risk of their development in a more invasive form requires prompt treatment. As patients usually present with multiple AK on fields of actinic damage, there is a need for effective, safe, simple and short treatments which allow the treatment of large areas. To achieve this, daylight photodynamic therapy (DL-PDT) is an innovative treatment for multiple mild actinic keratosis, well tolerated by patients. Patients allocated to the PDT unit, affected by multiple mild-moderate and severe actinic keratosis on sun-exposed areas treated with DL-PDT, were clinically evaluated at baseline and every three months with an Antera 3D, Miravex(©) camera. Clinical and 3D images were performed at each clinical check almost every three months. In this retrospective study, 331 patients (56.7% male, 43.3% female) were treated with DL-PDT. We observed a full clearance in more than two-thirds of patients with one or two treatments. Different responses depend on the number of lesions and on their severity; for patients with 1-3 lesions and with grade I or II AK, a full clearance was reached in 85% of cases with a maximum of two treatments. DL-PDT in general improved skin tone and erased sun damage. Evaluating each Antera 3D images, hemoglobin concentration and pigmentation, a skin color and tone improvement in 310 patients was observed. DL-PDT appears as a promising, effective, simple, tolerable and practical treatment for actinic damage associated with AK, and even treatment of large areas can be with little or no pain. The 3D imaging allowed for quantifying in real time the aesthetic benefits of DL

  8. MAL Daylight Photodynamic Therapy for Actinic Keratosis: Clinical and Imaging Evaluation by 3D Camera

    PubMed Central

    Cantisani, Carmen; Paolino, Giovanni; Pellacani, Giovanni; Didona, Dario; Scarno, Marco; Faina, Valentina; Gobello, Tommaso; Calvieri, Stefano

    2016-01-01

    Non-melanoma skin cancer is the most common skin cancer with an incidence that varies widely worldwide. Among them, actinic keratosis (AK), considered by some authors as in situ squamous cell carcinoma (SCC), are the most common and reflect an abnormal multistep skin cell development due to the chronic ultraviolet (UV) light exposure. No ideal treatment exists, but the potential risk of their development in a more invasive form requires prompt treatment. As patients usually present with multiple AK on fields of actinic damage, there is a need for effective, safe, simple and short treatments which allow the treatment of large areas. To achieve this, daylight photodynamic therapy (DL-PDT) is an innovative treatment for multiple mild actinic keratosis, well tolerated by patients. Patients allocated to the PDT unit, affected by multiple mild−moderate and severe actinic keratosis on sun-exposed areas treated with DL-PDT, were clinically evaluated at baseline and every three months with an Antera 3D, Miravex© camera. Clinical and 3D images were performed at each clinical check almost every three months. In this retrospective study, 331 patients (56.7% male, 43.3% female) were treated with DL-PDT. We observed a full clearance in more than two-thirds of patients with one or two treatments. Different responses depend on the number of lesions and on their severity; for patients with 1–3 lesions and with grade I or II AK, a full clearance was reached in 85% of cases with a maximum of two treatments. DL-PDT in general improved skin tone and erased sun damage. Evaluating each Antera 3D images, hemoglobin concentration and pigmentation, a skin color and tone improvement in 310 patients was observed. DL-PDT appears as a promising, effective, simple, tolerable and practical treatment for actinic damage associated with AK, and even treatment of large areas can be with little or no pain. The 3D imaging allowed for quantifying in real time the aesthetic benefits of DL

  9. An in vitro evaluation of drugs used in the Kenyan ART program.

    PubMed

    Muriuki, Joseph; Ng'ang'a, Zipporah; Lihana, Raphael; Lwembe, Raphael; Mwangi, Joseph; Mwau, Matilu

    2016-01-01

    The majority of anti-HIV drug susceptibility tests have been performed on subtype B HIV-1 strains, since these are the most prevalent in countries designing, testing, and manufacturing the current anti-HIV agents. The increasing global spread of HIV subtype highlights the need to determine the activity of anti-HIV drugs against subtypes of HIV other than subtype B. Furthermore an increasing number of individuals infected with many of the non subtype B virus strains now receive antiretroviral therapy because of rollout programs in developing countries as well as increasing migration to the developed world. The phenotypic susceptibility of two laboratory strains HIV-1JFRL and HIV-1IIIB (representing subtype B) and two clinical isolates HIV-104RTA and HIV-1025RTA (representing subtypes A and D respectively) was determined. The in vitro drug susceptibility testing of the isolates was carried out in C8166 cell line and in peripheral blood mononuclear cells (PBMCs). The study revealed that the drugs used in the Kenyan national ART program inhibited HIV-1 replication in-vitro as their inhibitory concentrations (IC50) compared well with the standard Inhibitory concentration values. The results also suggest a biochemical similarity of the reverse transcriptase (RT) and protease enzymes from these subtypes despite the divergence at the genetic level. The findings suggest that similar clinical benefits of antiviral therapy obtain in persons infected with other subtypes of HIV-1other than subtype B and that the generic drugs used in the national ART program in Kenya are as efficacious as branded drugs in inhibiting HIV replication in vitro despite the limited number of the viruses studied. PMID:27313820

  10. Bone Marrow Gene Therapy for HIV/AIDS.

    PubMed

    Herrera-Carrillo, Elena; Berkhout, Ben

    2015-07-01

    Bone marrow gene therapy remains an attractive option for treating chronic immunological diseases, including acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV). This technology combines the differentiation and expansion capacity of hematopoietic stem cells (HSCs) with long-term expression of therapeutic transgenes using integrating vectors. In this review we summarize the potential of bone marrow gene therapy for the treatment of HIV/AIDS. A broad range of antiviral strategies are discussed, with a particular focus on RNA-based therapies. The idea is to develop a durable gene therapy that lasts the life span of the infected individual, thus contrasting with daily drug regimens to suppress the virus. Different approaches have been proposed to target either the virus or cellular genes encoding co-factors that support virus replication. Some of these therapies have been tested in clinical trials, providing proof of principle that gene therapy is a safe option for treating HIV/AIDS. In this review several topics are discussed, ranging from the selection of the antiviral molecule and the viral target to the optimal vector system for gene delivery and the setup of appropriate preclinical test systems. The molecular mechanisms used to formulate a cure for HIV infection are described, including the latest antiviral strategies and their therapeutic applications. Finally, a potent combination of anti-HIV genes based on our own research program is described.

  11. Bone Marrow Gene Therapy for HIV/AIDS.

    PubMed

    Herrera-Carrillo, Elena; Berkhout, Ben

    2015-07-01

    Bone marrow gene therapy remains an attractive option for treating chronic immunological diseases, including acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV). This technology combines the differentiation and expansion capacity of hematopoietic stem cells (HSCs) with long-term expression of therapeutic transgenes using integrating vectors. In this review we summarize the potential of bone marrow gene therapy for the treatment of HIV/AIDS. A broad range of antiviral strategies are discussed, with a particular focus on RNA-based therapies. The idea is to develop a durable gene therapy that lasts the life span of the infected individual, thus contrasting with daily drug regimens to suppress the virus. Different approaches have been proposed to target either the virus or cellular genes encoding co-factors that support virus replication. Some of these therapies have been tested in clinical trials, providing proof of principle that gene therapy is a safe option for treating HIV/AIDS. In this review several topics are discussed, ranging from the selection of the antiviral molecule and the viral target to the optimal vector system for gene delivery and the setup of appropriate preclinical test systems. The molecular mechanisms used to formulate a cure for HIV infection are described, including the latest antiviral strategies and their therapeutic applications. Finally, a potent combination of anti-HIV genes based on our own research program is described. PMID:26193303

  12. Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: complete protection of rhesus monkeys from mucosal SHIV challenge.

    PubMed

    Sholukh, Anton M; Watkins, Jennifer D; Vyas, Hemant K; Gupta, Sandeep; Lakhashe, Samir K; Thorat, Swati; Zhou, Mingkui; Hemashettar, Girish; Bachler, Barbara C; Forthal, Donald N; Villinger, Francois; Sattentau, Quentin J; Weiss, Robin A; Agatic, Gloria; Corti, Davide; Lanzavecchia, Antonio; Heeney, Jonathan L; Ruprecht, Ruth M

    2015-04-21

    Although IgA is the most abundantly produced immunoglobulin in humans, its role in preventing HIV-1 acquisition, which occurs mostly via mucosal routes, remains unclear. In our passive mucosal immunizations of rhesus macaques (RMs), the anti-HIV-1 neutralizing monoclonal antibody (nmAb) HGN194, given either as dimeric IgA1 (dIgA1) or dIgA2 intrarectally (i.r.), protected 83% or 17% of the RMs against i.r. simian-human immunodeficiency virus (SHIV) challenge, respectively. Data from the RV144 trial implied that vaccine-induced plasma IgA counteracted the protective effector mechanisms of IgG1 with the same epitope specificity. We thus hypothesized that mucosal dIgA2 might diminish the protection provided by IgG1 mAbs targeting the same epitope. To test our hypothesis, we administered HGN194 IgG1 intravenously (i.v.) either alone or combined with i.r. HGN194 dIgA2. We enrolled SHIV-exposed, persistently aviremic RMs protected by previously administered nmAbs; RM anti-human IgG responses were undetectable. However, low-level SIV Gag-specific proliferative T-cell responses were found. These animals resemble HIV-exposed, uninfected humans, in which local and systemic cellular immune responses have been observed. HGN194 IgG1 and dIgA2 used alone and the combination of the two neutralized the challenge virus equally well in vitro. All RMs given only i.v. HGN194 IgG1 became infected. In contrast, all RMs given HGN194 IgG1+dIgA2 were completely protected against high-dose i.r. SHIV-1157ipEL-p challenge. These data imply that combining suboptimal defenses at the mucosal and systemic levels can completely prevent virus acquisition. Consequently, active vaccination should focus on defense-in-depth, a strategy that seeks to build up defensive fall-back positions well behind the fortified frontline.

  13. Evaluation of volumetric modulated arc therapy for cranial radiosurgery using multiple noncoplanar arcs

    SciTech Connect

    Audet, Chantal; Poffenbarger, Brett A.; Chang, Pauling; Jackson, Paul S.; Lundahl, Robert E.; Ryu, Stephen I.; Ray, Gordon R.

    2011-11-15

    Purpose: To evaluate a commercial volumetric modulated arc therapy (VMAT), using multiple noncoplanar arcs, for linac-based cranial radiosurgery, as well as evaluate the combined accuracy of the VMAT dose calculations and delivery. Methods: Twelve patients with cranial lesions of variable size (0.1-29 cc) and two multiple metastases patients were planned (Eclipse RapidArc AAA algorithm, v8.6.15) using VMAT (1-6 noncoplanar arcs), dynamic conformal arc (DCA, {approx}4 arcs), and IMRT (nine static fields). All plans were evaluated according to a conformity index (CI), healthy brain tissue doses and volumes, and the dose to organs at risk. A 2D dose distribution was measured (Varian Novalis Tx, HD120 MLC, 1000 MU/min, 6 MV beam) for the {approx}4 arc VMAT treatment plans using calibrated film dosimetry. Results: The CI (0-1 best) average for all plans was best for {approx}4 noncoplanar arc VMAT at 0.86 compared with {approx}0.78 for IMRT and a single arc VMAT and 0.68 for DCA. The volumes of healthy brain receiving 50% of the prescribed target coverage dose or more (V{sub 50%}) were lowest for the four arc VMAT [RA(4)] and DCA plans. The average ratio of the V{sub 50%} for the other plans to the RA(4) V{sub 50%} were 1.9 for a single noncoplanar arc VMAT [RA(1nc)], 1.4 for single full coplanar arc VMAT [RA(1f)] and 1.3 for IMRT. The V{sub 50%} improved significantly for single isocenter multiple metastases plan when two noncoplanar VMAT arcs were added to a full single coplanar one. The maximum dose to 5 cc of the outer 1 cm rim of healthy brain which one may want to keep below nonconsequential doses of 300-400 cGy, was 2-3 times greater for IMRT, RA(1nc) and RA(1f) plans compared with the multiple noncoplanar arc DCA and RA(4) techniques. Organs at risk near (0-4 mm) to targets were best spared by (i) single noncoplanar arcs when the targets are lateral to the organ at risk and (ii) by skewed nonvertical planes of IMRT fields when the targets are not lateral to the

  14. A novel conformity index for intensity modulated radiation therapy plan evaluation

    SciTech Connect

    Cheung, Fion W. K.; Law, Maria Y. Y.

    2012-09-15

    Purpose: Intensity modulated radiation therapy (IMRT) has gained popularity in the treatment of cancers. Manual evaluation of IMRT plans for head-and-neck cancers has been especially challenging necessitating efficient and objective assessment tools. In this work, the authors address this issue by developing a personalized conformity index (CI) for comparison of IMRT plans for head-and-neck cancers and evaluating its plan quality discerning power in comparison with other widely used CIs. Methods: A two-dimensional CI with dose and distance incorporated (CI{sub DD}) was developed using the MATLAB program language, to quantify the planning target volume (PTV) coverage. Valuable information contained in the digital imaging and communication in medicine (DICOM) RT objects were harvested for computation of each of the CI{sub DD} components. Apart from the dose penalty factor, a distance-based exponential function was employed by varying the penalty weight associated with the location of cold spots within the PTV. With the goal of deriving a customized penalty factor, the distances between individual pixel and its nearest PTV boundary was found. Using the exponential function, the impact of distance penalty was substantially larger for cold spots closer to the PTV centroid but petered out quickly wherever they were situated in the vicinity of PTV border. In order to evaluate the CI{sub DD} scoring system, three CT image data sets of nasopharyngeal carcinoma (NPC) patients were collected. Ten IMRT plans with degrading qualities were generated from each dataset and were ranked based on CI{sub DD} and other existing indices. The coefficient of variance was calculated for each dataset to compare the degree of variation. Results: The CI{sub DD} scoring system that considered spatial importance of each voxel within the PTV was successfully developed. The results demonstrated that the CI{sub DD} including four discrete factors could provide accurate rankings of plan quality by

  15. Evaluation of the Effects of Photodynamic Therapy Alone and Combined with Standard Antifungal Therapy on Planktonic Cells and Biofilms of Fusarium spp. and Exophiala spp.

    PubMed

    Gao, Lujuan; Jiang, Shaojie; Sun, Yi; Deng, Meiqi; Wu, Qingzhi; Li, Ming; Zeng, Tongxiang

    2016-01-01

    Infections of Fusarium spp. and Exophiala spp. are often chronic, recalcitrant, resulting in significant morbidity, causing discomfort, disfigurement, social isolation. Systemic disseminations happen in compromised patients, which are often refractory to available antifungal therapies and thereby lead to death. The antimicrobial photodynamic therapy (aPDT) has been demonstrated to effectively inactivate multiple pathogenic fungi and is considered as a promising alternative treatment for mycoses. In the present study, we applied methylene blue (8, 16, and 32 μg/ml) as a photosensitizing agent and light emitting diode (635 ± 10 nm, 12 and 24 J/cm(2)), and evaluated the effects of photodynamic inactivation on five strains of Fusarium spp. and five strains of Exophiala spp., as well as photodynamic effects on in vitro susceptibility to itraconazole, voriconazole, posaconazole and amphotericin B, both planktonic and biofilm forms. Photodynamic therapy was efficient in reducing the growth of all strains tested, exhibiting colony forming unit-reductions of up to 6.4 log10 and 5.6 log10 against planktonic cultures and biofilms, respectively. However, biofilms were less sensitive since the irradiation time was twice longer than that of planktonic cultures. Notably, the photodynamic effects against Fusarium strains with high minimal inhibitory concentration (MIC) values of ≥16, 4-8, 4-8, and 2-4 μg/ml for itraconazole, voriconazole, posaconazole and amphotericin B, respectively, were comparable or even superior to Exophiala spp., despite Exophiala spp. showed relatively better antifungal susceptibility profile. MIC ranges against planktonic cells of both species were up to 64 times lower after aPDT treatment. Biofilms of both species showed high sessile MIC50 (SMIC50) and SMIC80 of ≥16 μg/ml for all azoles tested and variable susceptibilities to amphotericin B, with SMIC ranging between 1 and 16 μg/ml. Biofilms subjected to aPDT exhibited a distinct reduction in

  16. Evaluation of the Effects of Photodynamic Therapy Alone and Combined with Standard Antifungal Therapy on Planktonic Cells and Biofilms of Fusarium spp. and Exophiala spp.

    PubMed Central

    Gao, Lujuan; Jiang, Shaojie; Sun, Yi; Deng, Meiqi; Wu, Qingzhi; Li, Ming; Zeng, Tongxiang

    2016-01-01

    Infections of Fusarium spp. and Exophiala spp. are often chronic, recalcitrant, resulting in significant morbidity, causing discomfort, disfigurement, social isolation. Systemic disseminations happen in compromised patients, which are often refractory to available antifungal therapies and thereby lead to death. The antimicrobial photodynamic therapy (aPDT) has been demonstrated to effectively inactivate multiple pathogenic fungi and is considered as a promising alternative treatment for mycoses. In the present study, we applied methylene blue (8, 16, and 32 μg/ml) as a photosensitizing agent and light emitting diode (635 ± 10 nm, 12 and 24 J/cm2), and evaluated the effects of photodynamic inactivation on five strains of Fusarium spp. and five strains of Exophiala spp., as well as photodynamic effects on in vitro susceptibility to itraconazole, voriconazole, posaconazole and amphotericin B, both planktonic and biofilm forms. Photodynamic therapy was efficient in reducing the growth of all strains tested, exhibiting colony forming unit-reductions of up to 6.4 log10 and 5.6 log10 against planktonic cultures and biofilms, respectively. However, biofilms were less sensitive since the irradiation time was twice longer than that of planktonic cultures. Notably, the photodynamic effects against Fusarium strains with high minimal inhibit