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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. Lentiviral vector engineering for anti-HIV RNAi gene therapy.

    PubMed

    ter Brake, Olivier; Westerink, Jan-Tinus; Berkhout, Ben

    2010-01-01

    RNA interference or RNAi-based gene therapy for the treatment of HIV-1 infection has recently emerged as a highly effective antiviral approach. The lentiviral vector system is a good candidate for the expression of antiviral short hairpin RNAs (shRNA) in HIV-susceptible cells. However, this strategy can give rise to vector problems because the anti-HIV shRNAs can also target the HIV-based lentiviral vector system. In addition, there may be self-targeting of the shRNA-encoding sequences within the vector RNA genome in the producer cell. The insertion of microRNA (miRNA) cassettes in the vector may introduce Drosha cleavage sites that will also result in the destruction of the vector genome during the production and/or the transduction process. Here, we describe possible solutions to these lentiviral-RNAi problems. We also describe a strategy for multiple shRNA expression to establish a combinatorial RNAi therapy.

  3. CD25 preselective anti-HIV vectors for improved HIV gene therapy.

    PubMed

    Kalomoiris, Stefanos; Lawson, Je'tai; Chen, Rachel X; Bauer, Gerhard; Nolta, Jan A; Anderson, Joseph S

    2012-12-01

    As HIV continues to be a global public health problem with no effective vaccine available, new and innovative therapies, including HIV gene therapies, need to be developed. Due to low transduction efficiencies that lead to low in vivo gene marking, therapeutically relevant efficacy of HIV gene therapy has been difficult to achieve in a clinical setting. Methods to improve the transplantation of enriched populations of anti-HIV vector-transduced cells may greatly increase the in vivo efficacy of HIV gene therapies. Here we describe the development of preselective anti-HIV lentiviral vectors that allow for the purification of vector-transduced cells to achieve an enriched population of HIV-resistant cells. A selectable protein, human CD25, not normally found on CD34+ hematopoietic progenitor cells (HPCs), was incorporated into a triple combination anti-HIV lentiviral vector. Upon purification of cells transduced with the preselective anti-HIV vector, safety was demonstrated in CD34+ HPCs and in HPC-derived macrophages in vitro. Upon challenge with HIV-1, improved efficacy was observed in purified preselective anti-HIV vector-transduced macrophages compared to unpurified cells. These proof-of-concept results highlight the potential use of this method to improve HIV stem cell gene therapy for future clinical applications.

  4. 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

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

    PubMed Central

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

    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. PMID:26598461

  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. Current developments in anti-HIV/AIDS gene therapy.

    PubMed

    Tsygankov, Alexander Y

    2009-02-01

    Since the introduction of highly active retroviral therapy (HAART) in 1996, dramatic improvements in therapeutic treatment modalities for HIV type 1 (HIV-1) infection have occurred. Potent drug combinations in HAART regimens efficiently block HIV-1 replication in most patients; however, multiple shortcomings of HAART are apparent and require novel treatments that can be utilized in combination with HAART or as stand-alone therapies. Gene therapy of HIV-1 represents one such treatment and several strategies are currently under development. This review focuses on advancements in the gene therapy of HIV/AIDS by highlighting the progress made in selecting new therapeutic targets and developing novel tools to exert an effect on these targets. In addition, new trends emerging from this progress are summarized. This review is based primarily on literature published between 2006 and 2008.

  8. 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

  9. Combinatorial anti-HIV gene therapy: using a multipronged approach to reach beyond HAART.

    PubMed

    Peterson, C W; Younan, P; Jerome, K R; Kiem, H-P

    2013-07-01

    The 'Berlin Patient', who maintains suppressed levels of HIV viremia in the absence of antiretroviral therapy, continues to be a standard bearer in HIV eradication research. However, the unique circumstances surrounding his functional cure are not applicable to most HIV(+) patients. To achieve a functional or sterilizing cure in a greater number of infected individuals worldwide, combinatorial treatments, targeting multiple stages of the viral life cycle, will be essential. Several anti-HIV gene therapy approaches have been explored recently, including disruption of the C-C chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4) coreceptor loci in CD4(+) T cells and CD34(+) hematopoietic stem cells. However, less is known about the efficacy of these strategies in patients and more relevant HIV model systems such as non-human primates (NHPs). Combinatorial approaches, including genetic disruption of integrated provirus, functional enhancement of endogenous restriction factors and/or the use of pharmacological adjuvants, could amplify the anti-HIV effects of CCR5/CXCR4 gene disruption. Importantly, delivering gene disruption molecules to genetic sites of interest will likely require optimization on a cell type-by-cell type basis. In this review, we highlight the most promising gene therapy approaches to combat HIV infection, methods to deliver these therapies to hematopoietic cells and emphasize the need to target viral replication pre- and post-entry to mount a suitably robust defense against spreading infection.

  10. Evaluation of needle exchange in central London: behaviour change and anti-HIV status over one year.

    PubMed

    Hart, G J; Carvell, A L; Woodward, N; Johnson, A M; Williams, P; Parry, J V

    1989-05-01

    From November 1987 to October 1988, numbers of clients, visits made and syringes dispensed and returned were monitored at the needle exchange of the Middlesex Hospital, London, UK. A sample of clients were interviewed 1 month after entry to the scheme and again 3 months later to evaluate changes in injecting and sexual risk behaviours for HIV infection. Clients were asked to donate saliva for anti-HIV immunoglobulin G (IgG) antibody capture radioimmunoassay (GACRIA). The rate of lending and borrowing used injecting equipment fell, both compared with rates prior to entry to the scheme and during the period of study. Frequency of injecting did not increase and there was reduced incidence of abscesses. There was a highly significant correlation between multiple sexual partners and condom use and a reduction in the proportion of clients with multiple partners. On entry to the study, seven out of 121 (6%) clients were anti-HIV positive; after 3 months, a further two clients tested were found to be anti-HIV positive. Anti-HIV positivity prevalence for the year of study was nine out of 121 (7%). The scheme attracts clients, reduces injecting-related risk for HIV infection and has high equipment return rates. Saliva testing is acceptable to clients. Continued monitoring of anti-HIV in saliva is indicated.

  11. [Retrospective evaluation of HBsAg, anti-HCV, anti-HIV and syphilis reagin antibody seropositivity in blood donors at the Trabzon Farabi Hospital].

    PubMed

    Aydin, Faruk; Cubukçu, Kivanç; Yetişkul, Serpil; Yazici, Yelda; Kaklikkaya, Neşe

    2002-01-01

    Transfusion of blood and blood products is a widely used method for therapy in medicine, however it may result with the transmission of infectious agents from donor to recipient. In order to achieve safe blood transfusions and to minimize post-transfusion infections, several screening tests for infectious agents are routinely done all around the world as well as in our country. In this study, HBsAg, anti-HCV, anti-HIV and syphilis reagin antibody tests results have been retrospectively evaluated for 33.766 blood donors during January 1, 1997 to December 31, 2000 in Blood Center of Farabi Hospital, Black Sea Technical University. Testing for HBsAg, anti-HIV and anti-HCV has been done by using commercially available micro and/or macro enzyme immunoassays, and syphilis reagin antibody test by latex agglutination (RPR) method. The indeterminate results were confirmed by retesting of sera with microparticle enzyme immunoassay and Western blot methods. As a result, in 1331 (3.94%) subjects HBsAg, in 250 (0.74%) subjects anti-HCV, and in 161 (0.47%) subjects RPR were found positive. Twenty samples which have had the results in gray-zone for anti-HIV, have been found negative with the confirmation tests.

  12. Preclinical evaluation of anti-HIV microbicide products: New models and biomarkers.

    PubMed

    Doncel, Gustavo F; Clark, Meredith R

    2010-12-01

    A safe and effective microbicide product designed to prevent sexual transmission of HIV-1 rests on a solid foundation provided by the proper selection and preclinical characterization of both its active pharmaceutical ingredient (API) and formulation. The evaluation of API and formulation physicochemical properties, drug release, specific antiviral activity, cell and tissue toxicity, organ toxicity, pharmacokinetics, and pharmacodynamics and efficacy provides information to understand the product, make go/no go decisions in the critical path of product development and complete a regulatory dossier to file an investigational new drug (IND) with the US Food and Drug Administration. Incorporation of new models, assays and biomarkers has expanded our ability to understand the mechanisms of action underlying microbicide toxicity and efficacy, enabling a more rational selection of drug and formulation candidates. This review presents an overview of the models and endpoints used to comprehensively evaluate an anti-HIV microbicide in preclinical development. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA.

  13. 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.

  14. 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

  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. Evaluation of LIAISON® XL system for HBsAg, and anti-HCV and anti-HIV/Ag p24.

    PubMed

    De Paschale, Massimo; Manco, Maria Teresa; Belvisi, Luisa; Cagnin, Debora; Cerulli, Teresa; Paganini, Alessia; Arpino, Olivia; Cianflone, Annalisa; Agrappi, Carlo; Mirri, Paola; Clerici, Pierangelo

    2017-03-01

    The aim of this study was to compare the data obtained using the new LIAISON® XL chemiluminescence system to search for HBsAg, anti-HCV, and anti-HIV1-2/p24 Ag with those obtained using the VITROS system currently adopted by the Microbiology Unit of the Hospital of Legnano. Routine samples of patients who were referred by practitioners for the determination of HBsAg (1,000 samples) and/or anti-HCV (1,002 samples) and/or anti-HIV1-2 (995 samples) were simultaneously analyzed using both systems. The concordant positive and discordant samples were re-examined for confirmation by means of an HBsAg neutralization assay, anti-HCV immunoblot, or anti-HIV1-2 Western blot; HBV-DNA, or HCV-RNA or HIV-RNA was also sought in the discordant samples. Samples of patients known to be positive were tested (100 HBsAg positive, 100 anti-HCV positive, and 100 HIV 1-2 positive) as well throughout treatment, with viremia levels becoming undetectable after treatment. The HBsAg, anti-HCV, and anti-HIV1-2 concordance between the two systems in routine series was respectively 99.8%, 98.5% and 99.7%, and 100% for all markers in samples known positive. The various molecular biology and confirmatory tests of the discordant samples were all negative (except for one anti-HCV positive sample). Measure of Cohen's kappa coefficient for HBsAg, anti-HCV, and anti-HIV gave K values of respectively 0.992, 0.946, and 0.980. In conclusion, the performance of the LIAISON® XL system in the routine laboratory determination for all three markers was comparable with that of the VITROS system. J. Med. Virol. 89:489-496, 2017. © 2016 Wiley Periodicals, Inc.

  17. A novel gene therapy strategy using secreted multifunctional anti-HIV proteins to confer protection to gene-modified and unmodified target cells.

    PubMed

    Falkenhagen, A; Ameli, M; Asad, S; Read, S E; Joshi, S

    2014-02-01

    Current human immunodeficiency virus type I (HIV) gene therapy strategies focus on rendering HIV target cells non-permissive to viral replication. However, gene-modified cells fail to accumulate in patients and the virus continues to replicate in the unmodified target cell population. We have designed lentiviral vectors encoding secreted anti-HIV proteins to protect both gene-modified and unmodified cells from infection. Soluble CD4 (sCD4), a secreted single chain variable fragment (sscFv(17b)) and a secreted fusion inhibitor (sFI(T45)) were used to target receptor binding, co-receptor binding and membrane fusion, respectively. Additionally, we designed bi- and tri-functional fusion proteins to exploit the multistep nature of HIV entry. Of the seven antiviral proteins tested, sCD4, sCD4-scFv(17b), sCD4-FI(T45) and sCD4-scFv(17b)-FI(T45) efficiently inhibited HIV entry. The neutralization potency of the bi-functional fusion proteins sCD4-scFv(17b) and sCD4-FI(T45) was superior to that of sCD4 and the Food and Drug Administration-approved fusion inhibitor T-20. In co-culture experiments, sCD4, sCD4-scFv(17b) and sCD4-FI(T45) secreted from gene-modified producer cells conferred substantial protection to unmodified peripheral blood mononuclear cells. In conclusion, continuous delivery of secreted anti-HIV proteins via gene therapy may be a promising strategy to overcome the limitations of the current treatment.

  18. Anti-HIV-1 Activity of Eight Monofloral Iranian Honey Types

    PubMed Central

    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

  19. Anti-HIV activity of some synthetic lignanolides and intermediates.

    PubMed

    Sancho, Rocío; Medarde, Manuel; Sánchez-Palomino, Sonsoles; Madrigal, Blanca M; Alcamí, José; Muñoz, Eduardo; San Feliciano, Arturo

    2004-09-06

    The evaluation of the anti-HIV-1 activity of synthetic lignanolides and their intermediates is reported. The antiviral activity was studied through luciferase-based assays targeting the HIV-1 promoter activation induced by either, the HIV-1 Tat protein or the cellular transcription factor NF-kappaB, both known as crucial factors in HIV-1 replication. Among the compounds tested, three of them 2, 4 and 13 were further analysed for their anti-HIV-1 activity by recombinant virus assays, showing a suitable profile for development of novel anti-HIV-1 drugs.

  20. 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

  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.

  3. Learning from past treatments and their outcome improves prediction of in vivo response to anti-HIV therapy.

    PubMed

    Saigo, Hiroto; Altmann, Andre; Bogojeska, Jasmina; Müller, Fabian; Nowozin, Sebastian; Lengauer, Thomas

    2011-01-01

    Infections with the human immunodeficiency virus type 1 (HIV-1) are treated with combinations of drugs. Unfortunately, HIV responds to the treatment by developing resistance mutations. Consequently, the genome of the viral target proteins is sequenced and inspected for resistance mutations as part of routine diagnostic procedures for ensuring an effective treatment. For predicting response to a combination therapy, currently available computer-based methods rely on the genotype of the virus and the composition of the regimen as input. However, no available tool takes full advantage of the knowledge about the order of and the response to previously prescribed regimens. The resulting high-dimensional feature space makes existing methods difficult to apply in a straightforward fashion. The machine learning system proposed in this work, sequence boosting, is tailored to exploiting such high-dimensional information, i.e. the extraction of longitudinal features, by utilizing the recent advancements in data mining and boosting. When applied to predicting the latest treatment outcome for 3,759 treatment-experienced patients from the EuResist integrated database, sequence boosting achieved superior performance compared to SVMs with RBF kernels. Moreover, sequence boosting allows an easy access to the discriminative treatment information. Analysis of feature importance values provided by our model confirmed known facts regarding HIV treatment. For instance, application of potent and recently licensed drugs was beneficial for patients, and, conversely, the patient group that was subject to NRTI mono-therapies in the past had poor treatment perspectives today. Furthermore, our model revealed novel biological insights. More precisely, the combination of previously used drugs with their in vivo response is more informative than the information of previously used drugs alone. Using this information improves the performance of systems for predicting therapy outcome.

  4. Polymeric anti-HIV therapeutics.

    PubMed

    Danial, Maarten; Klok, Harm-Anton

    2015-01-01

    The scope of this review is to highlight the application of polymer therapeutics in an effort to curb the transmission and infection of the human immunodeficiency virus (HIV). Following a description of the HIV life cycle, the use of approved antiretroviral drugs that inhibit critical steps in the HIV infection process is highlighted. After that, a comprehensive overview of the structure and inhibitory properties of polymeric anti-HIV therapeutic agents is presented. This overview will include inhibitors based on polysaccharides, synthetic polymers, dendritic polymers, polymer conjugates as well as polymeric DC-SIGN antagonists. The review will conclude with a section that discusses the applications of polymers and polymer conjugates as systemic and topical anti-HIV therapeutics.

  5. 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

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

    PubMed

    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.

  7. 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.

  8. Quantitative evaluation and optimization of co-drugging to improve anti-HIV latency therapy

    PubMed Central

    Wong, Victor C.; Fong, Linda E.; Adams, Nicholas M.; Xue, Qiong; Dey, Siddharth S.; Miller-Jensen, Kathryn

    2014-01-01

    Human immunodeficiency virus 1 (HIV) latency remains a significant obstacle to curing infected patients. One promising therapeutic strategy is to purge the latent cellular reservoir by activating latent HIV with latency-reversing agents (LRAs). In some cases, co-drugging with multiple LRAs is necessary to activate latent infections, but few studies have established quantitative criteria for determining when co-drugging is required. Here we systematically quantified drug interactions between histone deacetylase inhibitors and transcriptional activators of HIV and found that the need for co-drugging is determined by the proximity of latent infections to the chromatin-regulated viral gene activation threshold at the viral promoter. Our results suggest two classes of latent viral integrations: those far from the activation threshold that benefit from co-drugging, and those close to the threshold that are efficiently activated by a single drug. Using a primary T cell model of latency, we further demonstrated that the requirement for co-drugging was donor dependent, suggesting that the host may set the level of repression of latent infections. Finally, we showed that single drug or co-drugging doses could be optimized, via repeat stimulations, to minimize unwanted side effects while maintaining robust viral activation. Our results motivate further study of patient-specific latency-reversing strategies. PMID:26191086

  9. 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.

  10. Peltophorum africanum, a traditional South African medicinal plant, contains an anti HIV-1 constituent, betulinic acid.

    PubMed

    Theo, Andros; Masebe, Tracy; Suzuki, Yasuhiro; Kikuchi, Haruhisa; Wada, Shoko; Obi, Chikwelu Larry; Bessong, Pascal Obong; Usuzawa, Motoki; Oshima, Yoshiteru; Hattori, Toshio

    2009-02-01

    The biodiversity of medicinal plants in South Africa makes them rich sources of leading compounds for the development of novel drugs. Peltophorum africanum (Fabaceae) is a deciduous tree widespread in South Africa. The stem bark has been traditionally employed to treat diarrhoea, dysentery, sore throat, wounds, human immunodeficiency virus/ acquired immune deficiency syndrome (HIV/AIDS), venereal diseases and infertility. To evaluate these ethnobotanical clues and isolate lead compounds, butanol and ethyl acetate extracts of the stem bark were screened for their inhibitory activities against HIV-1 using MAGI CCR5+ cells, which are derived from HeLa cervical cancer cells and express HIV receptor CD4, a chemokine receptor CCR5 and HIV-LTR-beta- galactosidase. Bioassay-guided fractionation using silica gel chromatography was also conducted. The ethyl acetate and butanol extracts of the stem bark of Peltophorum africanum showed inhibitory activity against HIV-1, CXCR4 (X4) and CCR5 (R5) tropic viruses. The ethyl acetate and butanol extracts yielded previously reported anti-HIV compounds, (+)-catechin, a flavonoid, and bergenin, a C-galloylglycoside, respectively. Furthermore, we identified betulinic acid from the ethyl acetate fraction for the first time. The fractions, which contained betulinic acid, showed the highest selective index. We therefore describe the presence of betulinic acid, a not well-known anti-HIV compound, in an African medicinal herb, which has been used for therapy, and claim that betulinic acid is the predominant anti-HIV-1 constituent of Peltophorum africanum. These data suggest that betulinic acid and its analogues could be used as potential therapeutics for HIV-1 infection.

  11. Anti-HIV-1 activities of extracts and phenolics from Smilax china L.

    PubMed

    Wang, Wei-Xin; Qian, Jing-Yi; Wang, Xiao-Jing; Jiang, Ai-Ping; Jia, Ai-Qun

    2014-01-01

    Four extracts (EtOH, CHCl3, EtOAc, and BuOH) and five phenolics (dihydrokaempferol (1), resveratrol (2), kaempferol-7-O-β-D-glucoside (3), dihydrokaempferol-3-O-α-L-rhamnoside (4), oxyresveratrol (5)) from Smilax china L. was evaluated for anti-HIV-1 activities and cytotoxicity activities in vitro. All these extracts and phenolics showed lower or no cytotoxicity at a concentration ranged from 0.8 μg/mL to 100 μg/mL, but some showed potential anti-HIV-1 activities, that is, BuOH extract and compound 2 showed higher anti-HIV-1 activities than other extracts and compounds in the tested concentrations. EtOAc extract and compound 1 and 3 showed moderate anti-HIV-1 activities at a concentration higher than 4 μg/mL. In the end, the structure-activity relationship of four extracts and five phenolics was discussed.

  12. 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

    2015-01-06

    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.

  13. Setting the stage for bench-to-bedside movement of anti-HIV RNA inhibitors-gene therapy for AIDS in macaques.

    PubMed

    Braun, Stephen E; Johnson, R Paul

    2006-01-01

    Despite significant progress over the last two decades, treatment of HIV infection remains a tremendous challenge. Although antiretroviral therapy has proved quite effective in most HIV-infected patients, increasing recognition of toxicity and the emergence of multidrug resistant HIV strains has fueled the development of alternative therapeutic approaches. Introduction of genes to inhibit HIV replication into CD4+ T lymphocytes or hematopoietic stem cells represents a potentially attractive but still unproven strategy. Despite the availability of a diverse range of molecular strategies that are able to provide potent inhibition of HIV replication in the laboratory, translation of these in vitro successes to in vivo therapies has been difficult. Fundamental challenges facing AIDS gene therapy at the present time includes the need to increase the efficiency of gene transfer in vivo, to confer upon genetically-modified T cells the ability to have a selective growth advantage in vivo, and the development of additional techniques to decrease the probability of emergence of resistant viruses. As one of the leading animal models for AIDS and for hematopoietic stem cell gene therapy, nonhuman primates are ideally suited to help address many of these basic questions. This review will provide a general overview of RNA-based genetic strategies for inhibition of HIV and SIV replication, criteria to be considered in the selection of promising inhibitory strategies for in vivo use, and key questions that can be addressed in the macaque model.

  14. 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

  15. Thiazoline Peptides and a Tris-Phenethyl Urea from Didemnum molle with Anti-HIV Activity

    PubMed Central

    Lu, Zhenyu; Harper, Mary Kay; Pond, Christopher D.; Barrows, Louis R.; Ireland, Chris M.; Wagoner, Ryan M. Van

    2012-01-01

    Summary As part of our screening for anti-HIV agents from marine invertebrates, the MeOH extract of Didemnum molle was tested and showed moderate in vitro anti-HIV activity. Bioassay-guided fractionation of a large scale extract allowed the identification of two new cyclopeptides, mollamides E and F (1 and 2), and one new tris-phenethyl urea, molleurea A (3). The absolute configurations were established using the advanced Marfey’s method. The three compounds were evaluated for anti-HIV activity in both an HIV integrase inhibition assay and a cytoprotective cell-based assay. Compound 2 was active in both assays with IC50 values of 39 and 78 µM, respectively. Compound 3 was only active in the cytoprotective cell-based assay with an IC50 value of 60 µM. PMID:22845329

  16. Thiazoline peptides and a tris-phenethyl urea from Didemnum molle with anti-HIV activity.

    PubMed

    Lu, Zhenyu; Harper, Mary Kay; Pond, Christopher D; Barrows, Louis R; Ireland, Chris M; Van Wagoner, Ryan M

    2012-08-24

    As part of our screening for anti-HIV agents from marine invertebrates, the MeOH extract of Didemnum molle was tested and showed moderate in vitro anti-HIV activity. Bioassay-guided fractionation of a large-scale extract allowed the identification of two new cyclopeptides, mollamides E and F (1 and 2), and one new tris-phenethyl urea, molleurea A (3). The absolute configurations were established using the advanced Marfey's method. The three compounds were evaluated for anti-HIV activity in both an HIV integrase inhibition assay and a cytoprotective cell-based assay. Compound 2 was active in both assays with IC(50) values of 39 and 78 μM, respectively. Compound 3 was active only in the cytoprotective cell-based assay, with an IC(50) value of 60 μM.

  17. Synthesis of 3' '-substituted TSAO derivatives with anti-HIV-1 and anti-HIV-2 activity through an efficient palladium-catalyzed cross-coupling approach.

    PubMed

    Lobatón, Esther; Rodríguez-Barrios, Fátima; Gago, Federico; Pérez-Pérez, María-Jesús; De Clercq, Erik; Balzarini, Jan; Camarasa, María-José; Velázquez, Sonsoles

    2002-08-29

    Various synthetic studies for the introduction of several functional groups at position 3' ' of the spiro moiety of TSAO derivatives have been explored. Among them, Stille cross-coupling of 3' '-iodo-TSAO derivatives with different stannanes provided an efficient and straightforward route for the direct and selective functionalization of the 3' '-position of the sultone spiro moiety via carbon-carbon bond formation. The compounds synthesized were evaluated for their inhibitory effect on HIV-1 and HIV-2 replication in cell culture. The introduction of a bromine and particularly an iodine at the 3' '-position conferred the highest anti-HIV-1 activity. In contrast, the presence at this position of (un)substituted vinyl, alkynyl, phenyl, or thienyl groups markedly diminished the anti-HIV-1 activity. Surprisingly, several of the 3' '-alkenyl-substituted TSAO derivatives also gained anti-HIV-2 activity at subtoxic concentrations, an observation that is very unusual for NNRTIs and never observed before for TSAO derivatives. Finally, the anti-HIV-1 activity of some of the 3' '-substituted TSAO derivatives is discussed in light of our recently proposed molecular model of interaction of TSAO derivatives with the interphase between the two subunits of HIV-1 reverse transcriptase.

  18. Anti-HIV activities of natural antioxidant caffeic acid derivatives: toward an antiviral supplementation diet.

    PubMed

    Bailly, Fabrice; Cotelle, Philippe

    2005-01-01

    Since 1996, highly active antiretroviral therapy (HAART) was designed to rapidly control HIV replication. It has had a significant impact on patient health and progression of AIDS in developed countries, but its success has not been complete. HAART strategy still suffers from issues of patient compliance, cost, deleterious side effects and emerging drug resistance. Therefore, expansion of novel anti-HIV drugs and targets will be critical in the coming years. In this context, discovering anti-HIV agents from natural sources and particularly from plants, may highlight the principle of a nutritional antioxidant antiretroviral diet. In this paper, we review the putative anti-HIV activity of simple caffeic acid derivatives, together with their antioxidant properties. Toxicity, metabolism and bioavailability, when known, will also be detailed. Well-known caffeic acid derivatives, such as chicoric, rosmarinic and lithospermic acids, may be designed as future leads multi-target anti-HIV compounds and the plants and vegetables containing them as potent nutritional therapeutic supplementation source. They are not expected to replace the actual antiretroviral therapy, but more likely, to complete and perhaps lighten it by adapted diet.

  19. The anti-HIV activities of photoactive terthiophenes.

    PubMed

    Hudson, J B; Harris, L; Marles, R J; Arnason, J T

    1993-08-01

    Various synthetic analogues of the naturally occurring terthiophene, alpha-terthienyl (alpha T), were evaluated for anti-human immunodeficiency virus (HIV) activity. The compounds were incubated individually with a known amount of the virus, with or without UVA radiation (long-wavelength ultraviolet) and residual virus was monitored for its ability to produce cytopathic effects in cell culture and the production of virus-specific protein (p24). The basic terthiophene structure was essential for good anti-HIV activity, although various side chains, such as alcohols, bromo, methyl, thiomethyl and trimethylsilyl groups, permitted retention of maximum activity. Under optimum conditions, as little as 12 ng/mL of these compounds (i.e. approximately 3 x 10(-8) M) could inactivate 10(3) infectious virions. None of the compounds however were more active than alpha T itself. In all cases, UVA radiation was essential. Several side chains decreased the antiviral efficacy, and some side chains abrogated the activity.

  20. 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.

  1. Triterpene Constituents of Euphorbia Erythradenia Bioss. and their Anti-HIV Activity

    PubMed Central

    Ayatollahi, Abdul Majid; Zarei, Seyed Mohammad; Memarnejadian, Arash; Ghanadian, Mustafa; Heydarian Moghadam, Mohammad; Kobarfard, Farzad

    2016-01-01

    Phytochemical investigation of the aerial parts of Euphorbia erythradenia Bioss. (Euphorbiaceae), one of Iranian endemic Euphorbias, with particular attention to triterpene constituents, using methanol solvent extraction was carried out. Five known triterpenes, including four cycloartanes and oleanolic acid, were isolated for the first time and identified using NMR and Mass techniques. Anti HIV activity of the isolated triterpenes and ingenoid diterpenes was evaluated using single cycle replicable HIV-1 (SCR HIV-1) virions. Molecular features of the most active compound (IC50 = 0.008 μM, CC50 = 3.264 μM, TI = 380.64), which showed higher therapeutic index than nevirapine, was assessed using molecular docking. Docking studies demonstrated three hydrogen bonds between HIV-1 virion protease active site and this compound with a distance less than 3 A° which can be responsible for the observed anti HIV-1 activity. PMID:28228800

  2. Zinc coupling potentiates anti-HIV-1 activity of baicalin.

    PubMed

    Wang, Qian; Wang, Yu-Tian; Pu, Shao-Ping; Zheng, Yong-Tang

    2004-11-12

    Baicalin (BA) has been shown with anti-HIV-1 activity. Zinc is a nutrient element. The anti-HIV-1 activity of zinc complex of baicalin (BA-Zn) in vitro was studied and compared with the anti-HIV-1 activities between BA and BA-Zn in the present study. Our results suggested that BA-Zn has lower cytotoxicity and higher anti-HIV-1 activity compared with those of BA in vitro. The CC50s of BA-Zn and BA were 221.52 and 101.73 microM, respectively. The cytotoxicity of BA-Zn was about 1.2-fold lower than that of BA. The BA and BA-Zn inhibited HIV-1 induced syncytium formation, HIV-1 p24 antigen and HIV-1 RT production. The EC50s of BA-Zn on inhibiting HIV-1 induced syncytium formation (29.08 microM) and RT production (31.17 microM) were lower than those of BA (43.27 and 47.34 microM, respectively). BA-Zn was more effective than BA in inhibiting the activities of recombinant RT and HIV-1 entry into host cells. Zinc coupling enhanced the anti-HIV-1 activity of baicalin.

  3. Designed multiple ligands: an emerging anti-HIV drug discovery paradigm.

    PubMed

    Zhan, Peng; Liu, Xinyong

    2009-01-01

    Currently, the effect of AIDS single-target chemotherapy is severely compromised by the quick emergence of resistant HIV strains. Highly active antiretroviral therapy (HAART) combines HIV reverse transcriptase inhibitors with protease inhibitors or integrase inhibitors, and successfully suppresses HIV viral load to an undetectable level, dramatically improving the life quality of AIDS patients. However, the benefits of this approach are often compromised by poor patient compliance. Recently, there has been a move toward multicomponent drugs whereby two or more agents are coformulated in a single tablet to make dosing regimes simpler and thereby to improve patient compliance, but there are significant risks involved in the development of multicomponent drugs. Designed multiple ligands (DMLs) therapy as an emerging anti-HIV drug discovery paradigm, using a single entity to inhibit multitargets could yield improved patient compliance, thus reducing the likelihood of drug resistance. The exploration of such multifunctional ligands has proven valuable for anti-HIV leads discovery. However, presently many multifunctional scaffolds were first discovered by serendipity or screening; rational design by combining existing monofunctional scaffolds remains an enormous challenge. A key issue in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. This review of literature examples introduce numerous attractive lead compounds, capable of interfering with different stages of HIV infection and AIDS pathogenesis, which reveals trends and insights that might provide valuable clues for novel anti-HIV drug design and help medicinal chemists discover the next generation of multiple ligands.

  4. Hydroxytyrosol: a new class of microbicide displaying broad anti-HIV-1 activity

    PubMed Central

    Bedoya, Luis M.; Beltrán, Manuela; Obregón-Calderón, Patricia; García-Pérez, Javier; de la Torre, Humberto E.; González, Nuria; Pérez-Olmeda, Mayte; Auñón, David; Capa, Laura; Gómez-Acebo, Eduardo; Alcamí, José

    2016-01-01

    Objective: To investigate the toxicity and activity against HIV of 5-hydroxytyrosol as a potential microbicide. Design: The anti-HIV-1 activity of 5-hydroxytyrosol, a polyphenolic compound, was tested against wild-type HIV-1 and viral clones resistant to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and integrase inhibitors. In addition to its activity against founder viruses, different viral subtypes and potential synergy with tenofovir disoproxil fumarate, lamivudine and emtricitabine was also tested. 5-Hydroxytyrosol toxicity was evaluated in vivo in rabbit vaginal mucosa. Methods: We have cloned pol gene from drug-resistant HIV-1 isolated from infected patients and env gene from Fiebeg III/IV patients or A, C, D, E, F and G subtypes in the NL4.3-Ren backbone. 5-Hydroxytyrosol anti-HIV-1 activity was evaluated in infections of MT-2, U87-CCR5 or peripheral blood mononuclear cells preactivated with phytohemagglutinin + interleukin-2 with viruses obtained through 293T transfections. Inhibitory concentration 50% and cytotoxic concentration 50% were calculated. Synergy was analysed according to Chou and Talalay method. In-vivo toxicity was evaluated for 14 days in rabbit vaginal mucosa. Results: 5-Hydroxytyrosol inhibited HIV-1 infections of recombinant or wild-type viruses in all the target cells tested. Moreover, 5-hydroxytyrosol showed similar inhibitory concentration 50% values for infections with NRTIs, NNRTIs, protease inhibitors and INIs resistant viruses; founder viruses and all the subtypes tested. Combination of 5-hydroxytyrosol with tenofovir was found to be synergistic, whereas it was additive with lamivudine and emtricitabine. In-vivo toxicity of 5-hydroxytyrosol was very low even at the highest tested doses. Conclusion: 5-Hydroxytyrosol displayed a broad anti-HIV-1 activity in different cells systems in the absent of in-vivo toxicity, therefore supporting its

  5. 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

  6. Anti-HIV diphyllin glycosides from Justicia gendarussa.

    PubMed

    Zhang, Hong-Jie; Rumschlag-Booms, Emily; Guan, Yi-Fu; Liu, Kang-Lun; Wang, Dong-Ying; Li, Wan-Fei; Nguyen, Van Hung; Cuong, Nguyen Manh; Soejarto, Djaja Doel; Fong, Harry H S; Rong, Lijun

    2017-04-01

    In a search for new anti-HIV active leads from over several thousands of plant extracts, we have identified a potent plant lead. The active plant is determined as Justicia gendarussa (Acanthaceae), a medicinal plant that has been used for the treatment of injury, arthritis and rheumatism in Asia including China. Our bioassay-guided fractionation of the methanol extract of the stems and barks of the plant led to the isolation of two anti-HIV compounds, justiprocumins A and B. The compounds are identified as new arylnaphthalide lignans (ANL) glycosides. We further determined that the ANL glycosides are the chemical constituents that contribute to the anti-HIV activity of this plant. Justiprocumin B displayed potent activity against a broad spectrum of HIV strains with IC50 values in the range of 15-21 nM (AZT, IC50 77-95 nM). The compound also displayed potent inhibitory activity against the NRTI (nucleoside reverse transcriptase inhibitor)-resistant isolate (HIV-11617-1) of the analogue (AZT) as well as the NNRTI (non-nucleoside reverse transcriptase inhibitor)-resistant isolate (HIV-1N119) of the analogue (nevaripine).

  7. Synthetic galactomannans with potent anti-HIV activity.

    PubMed

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

    2015-10-05

    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.

  8. Stimuli-sensitive nanoparticles for multiple anti-HIV microbicides

    NASA Astrophysics Data System (ADS)

    Giri, Namita; Oh, Byeongtaek; Lee, Chi H.

    2016-05-01

    This study is aimed to develop and evaluate an advanced intravaginal formulation for the delivery of multiple anti-HIV microbicides. Novel stimuli-sensitive nanoparticles (NPs) which protected the encapsulated drugs from being degraded in acidic pH conditions were made of Eudragit S-100® (ES100®), a pH-sensitive polymer. ES100® NPs were prepared using the quasi-emulsion solvent diffusion technique and loaded with two microbicides namely Tenofovir (TNF) and Etravirine (ETV). The effects of various fabrication parameters on the formulation properties were evaluated for the optimization of ES100® NPs. The morphology of the ES100® NPs was examined by scanning electron microscopy. The cytotoxicity of NPs containing microbicides individually or in a combination was assessed using cell viability and trans-epithelial electrical resistance (TEER) measurements. The cellular uptake rates of the model microbicides by human vaginal epithelial cells, VK2 E6/E7 cells, were evaluated using confocal microscopy and florescence-assisted cell sorting technique. ES100® NPs had a spherical shape, smooth surface, and uniform texture with a little aggregation. The average particle size for NPs loaded with TNF ranged from 125 to 230 nm, whereas those for ETV-loaded NPs ranged from 160 to 280 nm. ES100® NPs had zeta potential in the range of -5 to -10 mV. In-vitro release studies displayed the potential benefits of ES100® NPs in retaining and protecting the loaded microbicides at vaginal pH (acidic), but immediately releasing them as the pH changes to neutral or 7.4 (physiological pH). Cell viability studies demonstrated that ES100® NPs did not exert any cytotoxicity individually or in a combination of both microbicides. TEER measurements confirmed that ES100® NPs loaded with TNF and ETV did not cause any changes in the barrier integrity of VK2 E6/E7 cell monolayer. The cellular uptake study revealed that ES100® NPs were taken by vaginal epithelial cells through the endocytosis

  9. 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.

  10. The rate of anti-HIV seropositivity among donated cadavers: experience in a cadaver donation center.

    PubMed

    Wiwanitkit, Viroj; Agthong, Sithiporn

    2002-01-01

    Cadavers are crucial for the medical education provided by medical schools. However, currently, donation is the only way to obtain cadavers for education in Thailand. Moreover, some traditional beliefs result in insufficient numbers of cadavers. Apart from finding donors, the occupational health of the workers in the cadaver donation center and the users, the medical students, residents, and staffs should be addressed. Screening for anti-HIV in donated organs is the current trend in transplantation medicine. Therefore, screening for anti-HIV in donated cadavers is useful. Here, we report the rate of anti-HIV seropositivity in cadavers in a 1-year period in our setting, the largest Thai Red Cross Society hospital. Of the total 84 cadavers received, two cadavers (2.4%) were anti-HIV seropositive. With the increasing rate of anti-HIV, screening for anti-HIV serology in donated cadavers for medical teaching is of great benefit.

  11. Anti-Tat and anti-HIV activities of trimers of n-alkylglycines.

    PubMed

    Márquez, Nieves; Sancho, Rocío; Macho, Antonio; Moure, Alejandra; Masip, Isabel; Messeguer, Angel; Muñoz, Eduardo

    2006-02-28

    Transcription of human immunodeficiency virus (HIV-1) is activated by viral Tat protein which regulates HIV-LTR transcription and elongation. In the present report, the evaluation of the anti-Tat activity of a combinatorial library composed of 5120 N-trialkylglycines is reported. The antiviral activity was studied through luciferase-based assays targeting the HIV-1 promoter activation induced by the HIV-1 Tat protein. We identified five peptoids with specific anti-HIV-1 Tat activity; none of these peptoids affected the binding of HIV-1 Tat protein to the viral TAR RNA. Using a recombinant-virus assay in which luciferase activity correlates with the rate of HIV-1 transcription we have detected that one of the five selected peptoids, NC37-37-15C, is a potent inhibitor of HIV-1-LTR transcription in both primary T lymphocytes and transformed cell lines. The inhibitory effect of NC37-37-15C, which is additive with azidothymidine (AZT), correlates with its ability to inhibit CTD phosphorylation and shows a suitable profile for development of novel anti-HIV-1 drugs. Likewise, the structural simplicity of N-alkylglycine oligomers makes these peptidomimetics amenable to structural manipulation, thus facilitating the optimisation of lead molecules for drug-like properties.

  12. 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.

  13. Anti-HIV-1 potency of the CRISPR/Cas9 system insufficient to fully inhibit viral replication.

    PubMed

    Ueda, Shuhei; Ebina, Hirotaka; Kanemura, Yuka; Misawa, Naoko; Koyanagi, Yoshio

    2016-07-01

    The range of genome-editing tools has recently been expanded. In particular, an RNA-guided genome-editing tool, the clustered regularly interspaced short palindromic repeat (CRISPR)-associated 9 (Cas9) system, has many applications for human diseases. In this study, guide RNA (gRNA) to target gag, pol and a long terminal repeat of HIV-1 was designed and used to generate gRNA-expressing lentiviral vectors. An HIV-1-specific gRNA and Cas9 were stably dually transduced into a highly HIV-1-susceptible human T-cell line and the inhibitory ability of the anti-HIV-1 CRISPR/Cas9 lentiviral vector assessed. Although clear inhibition of the early phase of HIV-1 infection was observed, as evaluated by a VSV-G-pseudotyped HIV-1 reporter system, the anti-HIV-1 potency in multiple rounds of wild type (WT) viral replication was insufficient, either because of generation of resistant viruses or overcoming of the activity of the WT virus. Thus, there are potential difficulties that must be addressed when considering anti-HIV-1 treatment with the CRISPR/Cas9 system alone.

  14. Developments of indoles as anti-HIV-1 inhibitors.

    PubMed

    Xu, Hui; Lv, Min

    2009-01-01

    Since the first case of acquired immunodeficiency syndrome (AIDS) was reported in 1981, AIDS has always been a global health threat and the leading cause of deaths due to the rapid emergence of drug-resistance and unwanted metabolic side effects. Every day in 2007 an estimated 6850 people were newly infected with human immunodeficiency virus (HIV). Over the past 28 years the rapid worldwide spread of AIDS has prompted an intense research effort to discover compounds that could effectively inhibit HIV. The development of new, selective and safe inhibitors for the treatment of HIV, therefore, still remains a high priority for medical research. To the best of our knowledge, the indole derivatives have been considered as one class of promising HIV-1 inhibitors, such as delavirdine approved by the Food and Drug Administration (FDA) in 1997 for use in combination with other antiretrovirals in adults with HIV infection. In this review we focus on the synthesis and anti-HIV-1 activity of indole derivatives, in the meantime, the structure-activity relationship (SAR) for some derivatives are also surveyed. It will pave the way for the design of indole derivatives as anti-HIV-1 drugs in the future.

  15. AIDS: Anti-HIV Agents, Therapies, and Vaccines

    DTIC Science & Technology

    1990-12-26

    hammerhead ribozyme , to design and test RNAs that can specifically cleave HIV-I genomic and messenger RNAs at predetermined sites. The cleavage reactions...that cleavage is specific. Hairpin catalytic RNA is a newly identified ribozyme that differs from hammerhead catalytic RNA in having distinct primary... hammerhead ribozymes , specifically the ability to cleave substrate RNA in trans in a catalytic fashion (Fic. 2). During the course of the reaction there is a

  16. Characterization of the third generation enzyme immunoassay IEA-HIV1/2-III for the detection of anti-HIV specific antibodies in human sera.

    PubMed

    Rayevskaya, G; Pilipenko, V G; Tkáciková, L; Spivak, N Y; Mikula, I; Chumak, R M

    2000-01-01

    The sensitivity and specificity of the developed anti-HIV1/2 third generation enzyme immunoassay, the IEA-HIV1/2-III, was examined. The test system for the detection of anti-HIV antibodies included peroxidase-conjugated HIV-specific recombinant Gag protein fragments (epitopes of p24 and p17 proteins), Env-1 (epitopes of p41 and p120 proteins), and Env-2 (p36 epitopes). Sensitivity was evaluated with 346 sera from HIV1-seropositive subjects, Anti-HIV1 Low Titer panels no. 10 and PRB-106 and seropositive panel PRB-931 in comparison with other third- and second-generation assays. The IEA-HIV1/2-III assays are characterized with high sensitivity comparable to the other third generation assays and the better sensitivity with respect to the second generation test-kit to determine HIV-specific antibodies in human sera. The specificity was determined using three hundred sixty-seven potentially cross-reactive samples (but negative for anti-HIV1/2). Only one specimen among them was reactive by IEA-HIV1/2-III.

  17. 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

  18. The anti-HIV activity of the phytochemical alpha-terthienyl.

    PubMed

    Hudson, J B; Harris, L; Teeple, A; Towers, G H

    1993-01-01

    The plant trithiophene, alpha-terthienyl (alpha T), was evaluated for activity against the human immunodeficiency virus (HIV-1). Antiviral activity specifically required long wavelength light (UVA, 320-400 nm). The compound had little or no activity in visible light or in the dark. The anti-HIV effect was UVA-dose dependent and was proportional to the concentration of alpha T, according to several parameters of virus infectivity and replication. The efficacy was decreased to some extent by the presence of bovine serum in the reactions; but under optimal conditions 0.1 microgram/ml. alpha T (3 x 10(-7) M) could inactivate 10(4)-10(5) infectious particles. In contrast poliovirus and Coxsackievirus infectivity were relatively resistant to alpha T + UVA.

  19. Inhibition of clinical human immunodeficiency virus (HIV) type 1 isolates in primary CD4+ T lymphocytes by retroviral vectors expressing anti-HIV genes.

    PubMed Central

    Vandendriessche, T; Chuah, M K; Chiang, L; Chang, H K; Ensoli, B; Morgan, R A

    1995-01-01

    Gene therapy may be of benefit in human immunodeficiency virus type 1 (HIV-1)-infected individuals by virtue of its ability to inhibit virus replication and prevent viral gene expression. It is not known whether anti-HIV-1 gene therapy strategies based on antisense or transdominant HIV-1 mutant proteins can inhibit the replication and expression of clinical HIV-1 isolates in primary CD4+ T lymphocytes. We therefore transduced CD4+ T lymphocytes from uninfected individuals with retroviral vectors expressing either HIV-1-specific antisense-TAR or antisense-Tat/Rev RNA, transdominant HIV-1 Rev protein, and a combination of antisense-TAR and transdominant Rev. The engineered CD4+ T lymphocytes were then infected with four different clinical HIV-1 isolates. We found that replication of all HIV-1 isolates was inhibited by all the anti-HIV vectors tested. Greater inhibition of HIV-1 was observed with transdominant Rev than with antisense RNA. We hereby demonstrated effective protection by antisense RNA or transdominant mutant proteins against HIV-1 infection in primary CD4+ T lymphocytes using clinical HIV-1 isolates, and this represents an essential step toward clinical anti-HIV-1 gene therapy. PMID:7769662

  20. Anti-HIV-1 activity of Trim 37.

    PubMed

    Tabah, Azah A; Tardif, Keith; Mansky, Louis M

    2014-04-01

    Trim 5α was the first member of the tripartite motif (TRIM) family of proteins that was identified to potently restrict human immunodeficiency virus type 1 (HIV-1) replication. The breadth of antiretroviral activity of TRIM family members is an active area of investigation. In this study, we demonstrate that human Trim 37 possesses anti-HIV-1 activity. This antiretroviral activity and the manner in which it was displayed were implicated by (1) decreased viral replication upon Trim 37 transient overexpression in virus-producing cells, (2) correlation of the reduction of viral infectivity with Trim 37 virion incorporation, (3) increased HIV-1 replication during siRNA depletion of Trim 37 expression, and (4) reduction in viral DNA synthesis upon Trim 37 transient overexpression. Our findings provide the first demonstration, to our knowledge, of the potent antiviral activity of human Trim 37, and implicate an antiviral mechanism whereby Trim 37 interferes with viral DNA synthesis.

  1. International award received recognizing anti-HIV spermicide.

    PubMed

    1998-10-19

    Until recently, the only topical microbicide being considered for protection against sexually transmitted HIV infection contains nonoxynol-9 (N-9), a detergent ingredient widely used for more than 30 years in the form of gels, foams, aerosols, creams, sponges, suppositories, films, and foaming tablets. While N-9 has both spermicidal and antibacterial/antiviral properties against pathogens responsible for STDs, including HIV, recent clinical studies have found it to be ineffective in protecting against HIV and other STDs. Moreover, N-9 disrupts cell membranes, damages cervicovaginal epithelia, and causes an acute tissue inflammatory response, thus enhancing the likelihood of HIV infection. There is therefore an urgent need for new, effective, safe, and easy-to-use microbicides with anti-HIV activity lacking detergent-type membrane toxicity. Dr. Osmond D'Cruz et al. of the Hughes Institute in St. Paul, Minnesota, have developed an anti-HIV spermicide with the potential of becoming the active ingredient in many beneficial products. Its lead compound is 400 times more potent than N-9 against HIV and at least 10 times more potent than N-9 as a spermicide. These dual-function compounds are non-inflammatory by their nature. Hughes et al.'s discovery is expected to enter human clinical trials within 12 months. A clinical paper describing their achievement won the prestigious Prize Paper Award for the Plenary Session of the Conjoint 16th World Congress on Fertility and Sterility at the 54th Annual Meeting of the American Society of Reproductive Medicine, held in San Francisco, California, during October 4-9, 1998.

  2. Stimulation of the primary anti-HIV antibody response by IFN-{alpha} in patients with acute HIV-1 infection

    PubMed Central

    Adalid-Peralta, Laura; Godot, Véronique; Colin, Céline; Krzysiek, Roman; Tran, Thi; Poignard, Pascal; Venet, Alain; Hosmalin, Anne; Lebon, Pierre; Rouzioux, Christine; Chêne, Geneviève; Emilie, Dominique

    2008-01-01

    Type I IFNs are needed for the production of antiviral antibodies in mice; whether they also stimulate primary antibody responses in vivo during human viral infections is unknown. This was assessed in patients acutely infected with HIV-1 and treated with IFN-α2b. Patients with acute HIV-1 infection were randomized to receive anti-retroviral therapy alone (Group A, n=60) or combined for 14 weeks with pegylated-IFN-α2b (Group B, n=30). Emergence of anti-HIV antibodies was monitored during 32 weeks by Western blot (WB) analyses of serum samples. IFN-α2b treatment stimulated the production of anti-HIV antibodies. On Week 32, 19 weeks after the last IFN-α2b administration, there were 8.5 (6.5–10.0) HIV WB bands (median, interquartile range) in Group B and 7.0 (5.0–10.0) bands in Group A (P=0.054), and band intensities were stronger in Group B (P<0.05 for p18, p24, p34, p40, and p55 HIV antigens). IFN-α2b treatment also increased circulating concentrations of the B cell-activating factor of the TNF family (P<0.001) and ex vivo production of IL-12 (P<0.05), reflecting its effect on innate immune cells. Withdrawal of antiretroviral treatment on Week 36 resulted in a lower rebound of HIV replication in Group B than in Group A (P<0.05). Therefore, type I IFNs stimulate the emerging anti-HIV immune response in patients with acute HIV-1 infection, resulting in an improved control of HIV replication. Type I IFNs are thus critical in the development of efficient antiviral immune responses in humans, including the production of antiviral antibodies. PMID:18182457

  3. Stimulation of the primary anti-HIV antibody response by IFN-alpha in patients with acute HIV-1 infection.

    PubMed

    Adalid-Peralta, Laura; Godot, Véronique; Colin, Céline; Krzysiek, Roman; Tran, Thi; Poignard, Pascal; Venet, Alain; Hosmalin, Anne; Lebon, Pierre; Rouzioux, Christine; Chene, Genevieve; Emilie, Dominique

    2008-04-01

    Type I IFNs are needed for the production of antiviral antibodies in mice; whether they also stimulate primary antibody responses in vivo during human viral infections is unknown. This was assessed in patients acutely infected with HIV-1 and treated with IFN-alpha2b. Patients with acute HIV-1 infection were randomized to receive antiretroviral therapy alone (Group A, n=60) or combined for 14 weeks with pegylated-IFN-alpha2b (Group B, n=30). Emergence of anti-HIV antibodies was monitored during 32 weeks by Western blot (WB) analyses of serum samples. IFN-alpha2b treatment stimulated the production of anti-HIV antibodies. On Week 32, 19 weeks after the last IFN-alpha2b administration, there were 8.5 (6.5-10.0) HIV WB bands (median, interquartile range) in Group B and 7.0 (5.0-10.0) bands in Group A (P=0.054), and band intensities were stronger in Group B (P<0.05 for p18, p24, p34, p40, and p55 HIV antigens). IFN-alpha2b treatment also increased circulating concentrations of the B cell-activating factor of the TNF family (P<0.001) and ex vivo production of IL-12 (P<0.05), reflecting its effect on innate immune cells. Withdrawal of antiretroviral treatment on Week 36 resulted in a lower rebound of HIV replication in Group B than in Group A (P<0.05). Therefore, type I IFNs stimulate the emerging anti-HIV immune response in patients with acute HIV-1 infection, resulting in an improved control of HIV replication. Type I IFNs are thus critical in the development of efficient antiviral immune responses in humans, including the production of antiviral antibodies.

  4. 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.

  5. 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.

  6. Novel anti-HIV therapeutics targeting chemokine receptors and actin regulatory pathways.

    PubMed

    Spear, Mark; Guo, Jia; Wu, Yuntao

    2013-11-01

    The human immunodeficiency virus-1 (HIV-1) infects helper CD4(+) T cells, and causes CD4(+) T-cell depletion and immunodeficiency. In the past 30 years, significant progress has been made in antiretroviral therapy, and the disease has become manageable. Nevertheless, an effective vaccine is still nowhere in sight, and a cure or a functional cure awaits discovery. Among possible curative therapies, traditional antiretroviral therapy, mostly targeting viral proteins, has been proven ineffective. It is possible that targeting HIV-dependent host cofactors may offer alternatives, both for preventing HIV transmission and for forestalling disease progression. Recently, the actin cytoskeleton and its regulators in blood CD4(+) T cells have emerged as major host cofactors that could be targeted. The novel concept that the cortical actin is a barrier to viral entry and early post-entry migration has led to the nascent model of virus-host interaction at the cortical actin layer. Deciphering the cellular regulatory pathways has manifested exciting prospects for future therapeutics. In this review, we describe the study of HIV interactions with actin cytoskeleton. We also examine potential pharmacological targets that emerge from this interaction. In addition, we briefly discuss several actin pathway-based anti-HIV drugs that are currently in development or testing.

  7. Novel anti-HIV therapeutics targeting chemokine receptors and actin regulatory pathways

    PubMed Central

    Spear, Mark; Guo, Jia; Wu, Yuntao

    2013-01-01

    Summary The human immunodeficiency virus-1 (HIV-1) infects helper CD4+ T cells, and causes CD4+ T-cell depletion and immunodeficiency. In the past 30 years, significant progress has been made in antiretroviral therapy, and the disease has become manageable. Nevertheless, an effective vaccine is still nowhere in sight, and a cure or a functional cure awaits discovery. Among possible curative therapies, traditional antiretroviral therapy, mostly targeting viral proteins, has been proven ineffective. It is possible that targeting HIV-dependent host cofactors may offer alternatives, both for preventing HIV transmission and for forestalling disease progression. Recently, the actin cytoskeleton and its regulators in blood CD4+ T cells have emerged as major host cofactors that could be targeted. The novel concept that the cortical actin is a barrier to viral entry and early post-entry migration has led to the nascent model of virus-host interaction at the cortical actin layer. Deciphering the cellular regulatory pathways has manifested exciting prospects for future therapeutics. In this review, we describe the study of HIV interactions with actin cytoskeleton. We also examine potential pharmacological targets that emerge from this interaction. In addition, we briefly discuss several actin pathway-based anti-HIV drugs that are currently in development or testing. PMID:24117829

  8. L-chicoric acid, an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase, improves on the in vitro anti-HIV-1 effect of Zidovudine plus a protease inhibitor (AG1350).

    PubMed

    Robinson, W E

    1998-08-01

    Combinations of anti-human immunodeficiency virus (HIV) drugs, including reverse transcriptase inhibitors and protease inhibitors, have proven immensely potent in the therapy of acquired immune deficiency syndrome (AIDS). To determine whether HIV integrase is a suitable target for combination therapy, the ability of an HIV integrase inhibitor, L-chicoric acid, to work in combination with a protease inhibitor and Zidovudine was tested in vitro. The addition of L-chicoric acid to either Zidovudine or protease inhibitor improved upon the observed anti-HIV activity of either compound alone. When all three drugs were combined, the anti-HIV activity was substantially better than either of the three compounds alone or any combination of two inhibitors. Doses of both Zidovudine and protease inhibitor could be reduced by more than 33% for an equivalent anti-HIV effect if L-chicoric acid was added. The improved anti-HIV activity was observed with a tissue culture adapted strain of HIV (HIV(LAI)) and with limited passage clinical isolates of HIV (HIV(R19) and HIV(R45)). These data demonstrate that a first generation HIV integrase inhibitor, L-chicoric acid, is at least additive in combination with existing multi-drug regimens and suggest that HIV integrase will be an excellent target for combination therapy of HIV infection.

  9. Synthesis of single- and double-chain fluorocarbon and hydrocarbon galactosyl amphiphiles and their anti-HIV-1 activity.

    PubMed

    Faroux-Corlay, B; Clary, L; Gadras, C; Hammache, D; Greiner, J; Santaella, C; Aubertin, A M; Vierling, P; Fantini, J

    2000-07-24

    Galactosylceramide (GalCer) is an alternative receptor allowing HIV-1 entry into CD4(-)/GalCer(+) cells. This glycosphingolipid recognizes the V3 loop of HIV gp120, which plays a key role in the fusion of the HIV envelope and cellular membrane. To inhibit HIV uptake and infection, we designed and synthesized analogs of GalCer. These amphiphiles and bolaamphiphiles consist of single and double hydrocarbon and/or fluorocarbon chain beta-linked to galactose and galactosamine. They derive from serine (GalSer), cysteine (GalCys), and ethanolamine (GalAE). The anti-HIV activity and cytotoxicity of these galactolipids were evaluated in vitro on CEM-SS (a CD4(+) cell line), HT-29, a CD4(-) cell line expressing high levels of GalCer receptor, and/or HT29 genetically modified to express CD4. GalSer and GalAE derivatives, tested in aqueous medium or as part of liposome preparation, showed moderate anti-HIV-1 activities (IC50 in the 20-220 microM range), whereas none of the GalCys derivatives was found to be active. Moreover, only some of these anti-HIV active analogs inhibited the binding of [3H]suramin (a polysulfonyl compound which displays a high affinity for the V3 loop) to SPC3, a synthetic peptide which contains the conserved GPGRAF region of the V3 loop. Our results most likely indicate that the neutralization of the virion through masking of this conserved V3 loop region is not the only mechanism involved in the HIV-1 antiviral activity of our GalCer analogs.

  10. Mechanisms and Modifications of Naturally Occurring Host Defense Peptides for Anti-HIV Microbicide Development

    PubMed Central

    Eade, Colleen R.; Wood, Matthew P.; Cole, Alexander M.

    2014-01-01

    Despite advances in the treatment of HIV infection, heterosexual transmission of HIV remains high, and vaccines to prevent HIV acquisition have been unfruitful. Vaginal microbicides, on the other hand, have demonstrated considerable potential for HIV prevention, and a variety of compounds have been screened for their activity and safety as anti-HIV microbicides. Among these are the naturally occurring host defense peptides, small peptides from diverse lineages with intrinsic antiviral activity. Naturally occurring host defense peptides with anti-HIV activity are promising candidates for vaginal microbicide development. Their structural variance and accompanying mechanistic diversity provide a wide range of inhibitors whose antiviral activity can be exerted at nearly every stage of the HIV lifecycle. Additionally, peptide modification has been explored as a method for improving the anti-HIV activity of host defense peptides. Structure- and sequence-based alterations have achieved varying success in improving the potency and specificity of anti-HIV peptides. Overall, peptides have been discovered or engineered to inhibit HIV with therapeutic indices of >1000, encouraging their advancement toward clinical trials. Here we review the naturally occurring anti-HIV host defense peptides, demonstrating their breadth of mechanistic diversity, and exploring approaches to enhance and optimize their activity in order to expedite their development as safe and effective anti-HIV vaginal microbicides. PMID:22264047

  11. Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of β-Diketo Acids.

    PubMed

    Nair, Vasu; Okello, Maurice

    2015-07-13

    HIV integrase, encoded at the 3'-end of the HIV pol gene, is essential for HIV replication. This enzyme catalyzes the incorporation of HIV DNA into human DNA, which represents the point of "no-return" in HIV infection. Integrase is a significant target in anti-HIV drug discovery. This review article focuses largely on the design of integrase inhibitors that are β-diketo acids constructed on pyridinone scaffolds. Methodologies for synthesis of these compounds are discussed. Integrase inhibition data for the strand transfer (ST) step are compared with in vitro anti-HIV data. The review also examines the issue of the lack of correlation between the ST enzymology data and anti-HIV assay results. Because this disconnect appeared to be a problem associated with permeability, prodrugs of these inhibitors were designed and synthesized. Prodrugs dramatically improved the anti-HIV activity data. For example, for compound, 96, the anti-HIV activity (EC50) improved from 500 nM for this diketo acid to 9 nM for its prodrug 116. In addition, there was excellent correlation between the IC50 and IC90 ST enzymology data for 96 (6 nM and 97 nM, respectively) and the EC50 and EC90 anti-HIV data for its prodrug 116 (9 nM and 94 nM, respectively). Finally, it was confirmed that the prodrug 116 was rapidly hydrolyzed in cells to the active compound 96.

  12. 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

  13. Differential in vitro anti-HIV activity of natural lignans.

    PubMed

    Schröder, H C; Merz, H; Steffen, R; Müller, W E; Sarin, P S; Trumm, S; Schulz, J; Eich, E

    1990-01-01

    Two naturally occurring lignanolides, isolated from the tropical climbing shrub Ipomoea cairica, (-)-arctigenin and (-)-trachelogenin, were found to inhibit strongly replication of human immunodeficiency virus type 1 (HIV-1; strain HTLV-III B) in vitro. At a concentration of 0.5 microM, (-)-arctigenin and (-)-trachelogenin inhibited the expression of HIV-1 proteins p17 and p24 by 80-90% and 60-70%, respectively. The reverse transcriptase activity in the culture fluids was reduced by 80-90% when the cells (HTLV-III B/H9) were cultivated in the presence of 0.5 microM (-)-arctigenin or 1 microM (-)-trachelogenin. At the same concentrations, the formation of syncytia in the HTLV-III B/H9-Jurkat cell system was inhibited by the compounds by more than 80%. A series of other lignan type compounds displayed no anti-HIV activity. Studying the molecular mechanism of action of (-)-arctigenin and (-)-trachelogenin we found that both compounds are efficient inhibitors of the nuclear matrix-associated DNA topoisomerase II activity, particularly of the enzyme from HIV-1-infected cells. Our results suggest that both compounds prevent the increase of topoisomerase II activity, involved in virus replication, after infection of cells with HIV-1.

  14. Combinatorial synthesis of anti-HIV agents--a review.

    PubMed

    Sriram, Dharmarajan; Yogeeswari, Perumal; Nagappa, Ananantha Naik

    2005-08-01

    Combinatorial chemistry has been well recognized as an important tool of drug discovery. An ongoing hand is to integrate the combinatorial approach with fundamentals of medicinal chemistry and rational drug design. The last five years has seen an explosion in the exploration and adoption of combinatorial techniques. Indeed, it is difficult to identify any other topic in chemistry that has ever caught the imagination of chemists with such fervor and with the continuous development of high throughput screening methods. There is a growing need for the synthesis of a large number of molecules. Compound libraries designed to produce specific inhibitors of therapeutic target proteins have generated significant interest in drug discovery research. Combinatorial chemistry provides the opportunity to generate large libraries of compounds for biological testing. A literature search revealed that many lead compounds have indeed been discovered from libraries and this review presents a survey of combinatorial synthesis of HIV-1 reverse transcriptase inhibitors, protease inhibitors, HIV-1 function inhibitors such as adsorption inhibitors, CCR5 antagonists and HIV-1 Tat-tar inhibitors that can be developed as potential anti-HIV drugs.

  15. 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.

  16. 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

  17. Synthesis, anti-HIV activity, integrase enzyme inhibition and molecular modeling of catechol, hydroquinone and quinol labdane analogs.

    PubMed

    Pawar, Rohan; Das, Tiyasa; Mishra, Sanjay; Nutan; Pancholi, Boskey; Gupta, Satish K; Bhat, Sujata V

    2014-01-01

    Labdane analogs with o-quinol, catechol and hydroquinone moiety have been synthesized using Diels-Alder reaction of methyl 3,4-dioxocyclohexa-1,5-diene-carboxylate, 3,4-dioxocyclohexa-1,5-diene-carboxylic acid and 3,6-dioxocyclohexa-1,4-dienecarboxylic acid with mono terpene 1,3-dienes, namely ocimene and myrcene. The resulting molecules and their derivatives were evaluated for their anti-HIV-1 activity using TZM-bl cell based virus infectivity assay. Two molecules 13 and 18 showed anti-HIV activity with IC50 values 5.0 (TI=11) and 4.6 (TI=46)μM, respectively. The compounds 17, 18 and 20 showed efficacy against HIV-1 integrase activity and showed inhibition with IC50 13.4, 11.1 and 11.5μM, respectively. The HIV-1 integrase inhibition activity of these synthetic molecules was comparable with integric acid, the natural fungal metabolite. Molecular modeling studies for the HIV-1 integrase inhibition of these active synthetic molecules indicated the binding to the active site residues of the enzyme.

  18. 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.

  19. [Sensitivity of screening kits for anti-HIV antibodies. 1999 update. Retrovirus Working Group of the French Society for Blood Transfusion].

    PubMed

    Couroucé, A M

    1999-12-01

    A comparative evaluation of the sensitivity of anti-HIV screening assays has been recently performed with a selected panel of 65 samples which included HIV1 group M (per-seroconversions, seroconversions and seropositives infected with genotypes A, B, C, D, E), HIV1 group O and HIV2. The results obtained with the 21 ELISA HIV1 + HIV2 screening assays are presented. Among these 21 assays, four are combined anti-HIV and p24 Ag assays. All the assays except four fulfilled the criteria defined at the beginning of the study, i.e., positive results on all the seropositives including seroconversions and positive results on at least 50% of the per-seroconversions. The main differences were observed with the ten per-seroconversion samples, the number of positive results on such samples varying from three to ten. The constant improvement of anti-HIV screening tests which leads one to shorten the 'window' period permits and earlier diagnosis of HIV infection and a progressive decrease of the transfusional risk.

  20. Anti-HIV cyclotides from the Chinese medicinal herb Viola yedoensis.

    PubMed

    Wang, Conan K L; Colgrave, Michelle L; Gustafson, Kirk R; Ireland, David C; Goransson, Ulf; Craik, David J

    2008-01-01

    Cyclotides are macrocyclic plant peptides characterized by a knotted arrangement of three disulfide bonds. They display a range of interesting bioactivities, including anti-HIV and insecticidal activities. More than 100 different cyclotides have been isolated from two phylogenetically distant plant families, the Rubiaceae and Violaceae. In this study we have characterized the cyclotides from Viola yedoensis, an important Chinese herb from the Violaceae family that has been reported to contain potential anti-HIV agents. From V. yedoensis five new and three known cyclotides were identified and shown to have anti-HIV activity. The most active of these is cycloviolacin Y5, which is one of the most potent of all cyclotides tested so far using in vitro XTT-based anti-HIV assays. Cycloviolacin Y5 is the most hydrophobic of the cyclotides from V. yedoensis. We show that there is a positive correlation between the hydrophobicity and the anti-HIV activity of the new cyclotides and that this trend tracks with their ability to disrupt membranes, as judged from hemolytic assays on human erythrocytes.

  1. Role of nucleoside diphosphate kinase in the activation of anti-HIV nucleoside analogs.

    PubMed

    Schneider, B; Sarfati, R; Deville-Bonne, D; Véron, M

    2000-06-01

    Nucleoside analogs are currently used in antiretrovirus therapies. The best known example is AZT one of the first drug to be used for the treatment of AIDS. However, only the triphosphate derivatives of these compounds act as substrates of the viral reverse transcriptase. Since they do not enter cells, nucleoside analogs are administered and phosphorylated by cellular kinases. The last step in this phosphorylation pathway is catalyzed by nucleoside diphosphate (NDP) kinase. The incorporation of the nucleoside triphosphates into nascent viral DNA chain results in termination of the elongation process. We have performed kinetics studies of the phosphorylation reaction by NDP kinase of dideoxynucleoside diphosphates such as 2',3'-dideoxy-3'-azidothymidine diphosphate (AZT-DP) and 2',3'-dideoxy-2',3'-didehydrothymidine diphosphate (d4T-DP). We show that the catalytic efficiency is strongly decreased and, therefore, that the reaction step catalyzed by NDP kinase constitutes a bottleneck in the processing pathway of anti-HIV compounds. In addition, the affinity of the analogs in the absence of catalysis was determined using a catalytically inactive NDP kinase mutant, showing a reduction of affinity by a factor of 2 to 30, depending on the analog. The structure of NDP kinase provides a structural explanation for these results. Indeed, all nucleoside analogs acting as chain terminators must lack a 3'-OH in the nucleotide deoxyribose. Unfortunately, this same substitution is detrimental for their capacity to be phosphorylated by NDP kinase. This defines the framework for the design of new nucleoside analogs with increased efficiency in antiretroviral therapies.

  2. 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.

  3. 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.

  4. New anti-HIV aptamers based on tetra-end-linked DNA G-quadruplexes: effect of the base sequence on anti-HIV activity.

    PubMed

    D'Atri, Valentina; Oliviero, Giorgia; Amato, Jussara; Borbone, Nicola; D'Errico, Stefano; Mayol, Luciano; Piccialli, Vincenzo; Haider, Shozeb; Hoorelbeke, Bart; Balzarini, Jan; Piccialli, Gennaro

    2012-10-04

    This communication reports on the synthesis and biophysical, biological and SAR studies of a small library of new anti-HIV aptamers based on the tetra-end-linked G-quadruplex structure. The new aptamers showed EC(50) values against HIV-1 in the range of 0.04-0.15 μM as well as affinities for the HIV-1 gp120 envelope in the same order of magnitude.

  5. 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

  6. Gene therapy strategies for HIV/AIDS: preclinical modeling in humanized mice.

    PubMed

    Bennett, Michael S; Akkina, Ramesh

    2013-12-12

    In the absence of an effective vaccine and lack of a complete cure, gene therapy approaches to control HIV infection offer feasible alternatives. Due to the chronic nature of infection, a wide window of opportunity exists to gene modify the HIV susceptible cells that continuously arise from the bone marrow source. To evaluate promising gene therapy approaches that employ various anti-HIV therapeutic molecules, an ideal animal model is necessary to generate important efficacy and preclinical data. In this regard, the humanized mouse models that harbor human hematopoietic cells susceptible to HIV infection provide a suitable in vivo system. This review summarizes the currently used humanized mouse models and different anti-HIV molecules utilized for conferring HIV resistance. Humanized mouse models are compared for their utility in this context and provide perspectives for new directions.

  7. 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).

  8. 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.

  9. 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

  10. 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

  11. Anti-HIV-1 activity of propolis in CD4(+) lymphocyte and microglial cell cultures.

    PubMed

    Gekker, Genya; Hu, Shuxian; Spivak, Marla; Lokensgard, James R; Peterson, Phillip K

    2005-11-14

    An urgent need for additional agents to treat human immunodeficiency virus type 1 (HIV-1) infection led us to assess the anti-HIV-1 activity of the natural product propolis in CD4(+) lymphocytes and microglial cell cultures. Propolis inhibited viral expression in a concentration-dependent manner (maximal suppression of 85 and 98% was observed at 66.6 microg/ml propolis in CD4(+) and microglial cell cultures, respectively). Similar anti-HIV-1 activity was observed with propolis samples from several geographic regions. The mechanism of propolis antiviral property in CD4(+) lymphocytes appeared to involve, in part, inhibition of viral entry. While propolis had an additive antiviral effect on the reverse transcriptase inhibitor zidovudine, it had no noticeable effect on the protease inhibitor indinavir. The results of this in vitro study support the need for clinical trials of propolis or one or more of its components in the treatment of HIV-1 infection.

  12. [Anti-HIV chemical constituents of aerial parts of Caragana rosea].

    PubMed

    Yang, Guo-xun; Qi, Jian-bin; Cheng, Ke-jun; Hu, Chang-qi

    2007-02-01

    This study was intended to look for anti-HIV chemical constituents of aerial parts of Caragana rosea Turcz. Column chromatographic technique was used for the isolation and purification of constituents of Caragana rosea under the guide of anti-HIV assay. The structures were established on the basis of physical and chemical properties and spectroscopic data. Five compounds were obtained from the EtOAc fraction of aerial parts of Caragana rosea and identified as myricetin (1), mearnsetin (2), p-hydroxy cinnamic acid (3), cararosinol A (4) and cararosinol B (5). At the same time, one possible transformation route between cararosinol B and kobophenol A, another resveratrol tetramer isolated from this plant previously, was proposed. Compounds 4, 5 are new resveratrol tetramers, compounds 1 -3 were isolated from this plant for the first time. All compounds showed no activities in an in vitro assay against HIV-1.

  13. Anti-HIV-1 Activity of a New Scorpion Venom Peptide Derivative Kn2-7

    PubMed Central

    Chen, Yaoqing; Cao, Luyang; Zhong, Maohua; Zhang, Yan; Han, Chen; Li, Qiaoli; Yang, Jingyi; Zhou, Dihan; Shi, Wei; He, Benxia; Liu, Fang; Yu, Jie; Sun, Ying; Cao, Yuan; Li, Yaoming; Li, Wenxin; Guo, Deying; Cao, Zhijian; Yan, Huimin

    2012-01-01

    For over 30 years, HIV/AIDS has wreaked havoc in the world. In the absence of an effective vaccine for HIV, development of new anti-HIV agents is urgently needed. We previously identified the antiviral activities of the scorpion-venom-peptide-derived mucroporin-M1 for three RNA viruses (measles viruses, SARS-CoV, and H5N1). In this investigation, a panel of scorpion venom peptides and their derivatives were designed and chosen for assessment of their anti-HIV activities. A new scorpion venom peptide derivative Kn2-7 was identified as the most potent anti-HIV-1 peptide by screening assays with an EC50 value of 2.76 µg/ml (1.65 µM) and showed low cytotoxicity to host cells with a selective index (SI) of 13.93. Kn2-7 could inhibit all members of a standard reference panel of HIV-1 subtype B pseudotyped virus (PV) with CCR5-tropic and CXCR4-tropic NL4-3 PV strain. Furthermore, it also inhibited a CXCR4-tropic replication-competent strain of HIV-1 subtype B virus. Binding assay of Kn2-7 to HIV-1 PV by Octet Red system suggested the anti-HIV-1 activity was correlated with a direct interaction between Kn2-7 and HIV-1 envelope. These results demonstrated that peptide Kn2-7 could inhibit HIV-1 by direct interaction with viral particle and may become a promising candidate compound for further development of microbicide against HIV-1. PMID:22536342

  14. 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

  15. Latino Families in Therapy: Engagement and Evaluation.

    ERIC Educational Resources Information Center

    Bernal, Guillermo; Flores-Ortiz, Yvette

    1982-01-01

    Suggests that a therapist's involvement of Latinos in therapy requires both skills in family therapy and sensitivity to cultural issues. Presents factors found to be useful in the family assessment. Discusses issues in the engagement and evaluation phases of family therapy with Latino families. (Author)

  16. Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs.

    PubMed

    Shen, Lin; Peterson, Susan; Sedaghat, Ahmad R; McMahon, Moira A; Callender, Marc; Zhang, Haili; Zhou, Yan; Pitt, Eleanor; Anderson, Karen S; Acosta, Edward P; Siliciano, Robert F

    2008-07-01

    Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but suboptimal treatment allows for the evolution of resistance and rebound viremia. A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and the selection of regimens that maximally suppress replication. Here we show that current measures of antiviral activity, including IC(50) and inhibitory quotient, neglect a key dimension, the dose-response curve slope. Using infectivity assays with wide dynamic range, we show that this slope has noteworthy effects on antiviral activity. Slope values are class specific for antiviral drugs and define intrinsic limitations on antiviral activity for some classes. Nucleoside reverse transcriptase inhibitors and integrase inhibitors have slopes of approximately 1, characteristic of noncooperative reactions, whereas non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors unexpectedly show slopes >1. Instantaneous inhibitory potential (IIP), the log reduction in single-round infectivity at clinical drug concentrations, is strongly influenced by slope and varies by >8 logs for anti-HIV drugs. IIP provides a more accurate measure of antiviral activity and in general correlates with clinical outcomes. Only agents with slopes >1 achieve high-level inhibition of single-round infectivity, a finding with profound implications for drug and vaccine development.

  17. Improved specificity of in vitro anti-HIV antibody production: implications for diagnosis and timing of transmission in infants born to HIV-seropositive mothers.

    PubMed

    Wang, X P; Paul, M; Tetali, S; Abrams, E; Bamji, M; Gulick, L; Chirmule, N; Oyaizu, N; Bakshi, S; Pahwa, S

    1994-06-01

    In vitro anti-HIV antibody production (IVAP), initially introduced as a method for diagnosis of human immunodeficiency virus type 1 (HIV-1) infection in infants, has been limited in its application because of poor specificity and sensitivity early in life. The aims of this study were to improve the specificity of the IVAP assay and to evaluate its sensitivity in conjunction with assays of HIV culture, polymerase chain reaction (PCR), and p24 antigen. To prevent false-positive reactions resulting from maternal serum-derived cytophilic anti-HIV IgG, additional preculture and washing steps for peripheral blood mononuclear cells (PBMCs) were introduced that resulted in dramatic improvement in specificity of IVAP. The sensitivity of the revised IVAP at age < 3 months in 20 infected infants was, however, only 25%; of 15 infected infants initially negative in IVAP, 13 became positive at a mean estimated age of 4.4 +/- 1.8 months. When correlated with virological assays, a failure to respond in IVAP at age < 1 month was often associated with negative virological identification, whereas a positive IVAP response at age < 3 months was always associated with positive results in all virological assays. Moreover, conversion from negative IVAP to positive responses occurred subsequent to, and not concurrently with, a positive virological identification of infected infants. The revised IVAP methodology renders this assay potentially useful as an additional tool not only for the diagnosis of HIV infection, but for estimating timing of maternal-infant HIV transmission as well.

  18. A novel family of diarylpyrimidines (DAPYs) featuring a diatomic linker: Design, synthesis and anti-HIV activities.

    PubMed

    Gu, Shuang-Xi; Qiao, Heng; Zhu, Yuan-Yuan; Shu, Qi-Chao; Liu, Hui; Ju, Xiu-Lian; De Clercq, Erik; Balzarini, Jan; Pannecouque, Christophe

    2015-10-15

    To improve the conformational flexibility and positional adaptability of the traditional diarylpyrimidines (DAPYs), a family of diarylpyrimidines featuring a C-N diatomic linker between the left wing benzene ring and the central pyrimidine was firstly designed, synthesized, and evaluated for in vitro anti-HIV activity. Most of target molecules showed excellent activities against wild-type (WT) HIV-1. Among them the most potent two compounds 12h and 12r displayed extremely potent WT HIV-1 inhibitory activities with an EC50 of 2.6 nM and 3.0 nM, respectively, while their selective index (CC50/EC50) values were both over 1000. Another compound 12b (EC50 14.9 nM) was also noteworthy due to its high SI of 18,614. Moreover, all of compounds were evaluated for their WT HIV-1 reverse transcriptase activities, which shown that the newly synthesized CH2NH-DAPYs bind to HIV-1 RT and belong to the genuine NNRTIs. However, the synthesized compounds lack the activities against HIV-1 double mutant (RES056) and HIV-2 (ROD). Thus it is an upcoming objective to improve the activities against HIV-1 double mutants.

  19. Novel [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]- 3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2" -dioxide) derivatives with anti-HIV-1 and anti-human-cytomegalovirus activity.

    PubMed

    de Castro, Sonia; Lobatón, Esther; Pérez-Pérez, María-Jesús; San-Félix, Ana; Cordeiro, Alessandra; Andrei, Graciela; Snoeck, Robert; De Clercq, Erik; Balzarini, Jan; Camarasa, María-José; Velázquez, Sonsoles

    2005-02-24

    New [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-d-ribofuranosyl]-3'-spiro-5' '-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) (TSAO) derivatives substituted at the 4' '-amino group of the spiro moiety with different carbonyl functionalities have been designed and synthesized. Various synthetic procedures, on the scarcely studied reactivity of the 3'-spiroaminooxathioledioxide moiety, have been explored. The compounds were evaluated for their inhibitory effect on both wild-type and TSAO-resistant HIV-1 strains, in cell culture. The presence of a methyl ester (10) or amide groups (12) at the 4''-position conferred the highest anti-HIV-1 activity, while the free oxalyl acid derivative (11) was 10- to 20-fold less active against the virus. In contrast, the presence at this position of (un)substituted ureido or acyl groups markedly diminished or annihilated the anti-HIV-1 activity. Surprisingly, some of the target compounds also showed inhibition of human cytomegalovirus (HCMV) replication at subtoxic concentrations. This has never been observed previously for TSAO derivatives. In particular, compound 26 represents the first TSAO derivative with dual anti-HIV-1 and -HCMV activity.

  20. Bioactivation to an aldehyde metabolite--possible role in the onset of toxicity induced by the anti-HIV drug abacavir.

    PubMed

    Grilo, Nádia M; Charneira, Catarina; Pereira, Sofia A; Monteiro, Emília C; Marques, M Matilde; Antunes, Alexandra M M

    2014-01-30

    Aldehydes are highly reactive molecules, which can be generated during numerous physiological processes, including the biotransformation of drugs. Several non-P450 enzymes participate in their metabolism albeit alcohol dehydrogenase and aldehyde dehydrogenase are the ones most frequently involved in this process. Endogenous and exogenous aldehydes have been strongly implicated in multiple human pathologies. Their ability to react with biomacromolecules (e.g. proteins) yielding covalent adducts is suggested to be the common primary mechanism underlying the toxicity of these reactive species. Abacavir is one of the options for combined anti-HIV therapy. Although individual susceptibilities to adverse effects differ among patients, abacavir is associated with idiosyncratic hypersensitivity drug reactions and an increased risk of cardiac dysfunction. This review highlights the current knowledge on abacavir metabolism and discusses the potential role of bioactivation to an aldehyde metabolite, capable of forming protein adducts, in the onset of abacavir-induced toxic outcomes.

  1. QSAR study and VolSurf characterization of anti-HIV quinolone library

    NASA Astrophysics Data System (ADS)

    Filipponi, Enrica; Cruciani, Gabriele; Tabarrini, Oriana; Cecchetti, Violetta; Fravolini, Arnaldo

    2001-03-01

    Antiviral quinolones are promising compounds in the search for new therapeutically effective agents for the treatment of AIDS. To rationalize the SAR for this new interesting class of anti-HIV derivatives, we performed a 3D-QSAR study on a library of 101 6-fluoro and 6-desfluoroquinolones, taken either from the literature or synthesized by us. The chemometric procedure involved a fully semiempirical minimization of the molecular structures by the AMSOL program, which takes into account the solvatation effect, and their 3D characterization by the VolSurf/GRID program. The QSAR analysis, based on PCA and PLS methods, shows the key structural features responsible for the antiviral activity.

  2. HIV Integrase Inhibitors with Nucleobase Scaffolds: Discovery of a Highly Potent anti-HIV Agent

    PubMed Central

    Nair, Vasu; Chi, Guochen; Ptak, Roger; Neamati, Nouri

    2008-01-01

    HIV integrase is essential for HIV replication. However, there are currently no integrase inhibitors in clinical use for AIDS. We have discovered a conceptually new β-diketo acid that is a powerful inhibitor of both the 3′-processing and strand transfer steps of HIV-1 integrase. The in vitro anti-HIV data of this inhibitor were remarkable as exemplified by its highly potent antiviral therapeutic efficacy against HIVTEKI and HIV-1NL4-3 replication in PBMC (TI >4,000 and >10,000, respectively). PMID:16420027

  3. Development and characterization of a solid dispersion film for the vaginal application of the anti-HIV microbicide UAMC01398.

    PubMed

    Grammen, Carolien; Van den Mooter, Guy; Appeltans, Bernard; Michiels, Johan; Crucitti, Tania; Ariën, Kevin K; Augustyns, Koen; Augustijns, Patrick; Brouwers, Joachim

    2014-11-20

    The purpose of this work was to design and evaluate a vaginal film delivery system for UAMC01398, a novel non-nucleoside reverse transcriptase inhibitor currently under investigation for use as an anti-HIV microbicide. UAMC01398 (1mg) films consisting of hydroxypropylmethylcellulose (HPMC) and polyethylene glycol 400 (PEG400) in different ratios were prepared by solvent evaporation. Based on its flexibility, softness and translucent appearance, the 30% PEG400 and 70% HPMC containing film was selected for further assessment. The vaginal film formulation was fast-dissolving (<10 min in 1 mL of vaginal fluid simulant), stable up to at least one month and safe toward epithelial cells and lactobacilli. Furthermore, formulating UAMC01398 into the film dosage form did not influence its antiviral activity. Powder X-ray diffraction revealed the amorphous nature of the UAMC01398 film, resulting in enhanced compound permeation across the epithelial HEC-1A cell layer, presumably owing to the induction of supersaturation. The in vivo vaginal tissue uptake of UAMC01398 in rabbits, as measured by systemic concentrations, was increased compared to the previously established non-solubilizing gel (significant difference) and sulfobutyl ether-β-cyclodextrin (5%) containing gel. To conclude, we identified a film formulation suitable for the vaginal delivery of UAMC01398.

  4. Notable Difference in anti-HIV Activity of Integrase Inhibitors as a Consequence of Geometric and Enantiomeric Configurations

    PubMed Central

    Okello, Maurice; Mishra, Sanjay; Nishonov, Malik; Nair, Vasu

    2013-01-01

    While some examples are known of integrase inhibitors that exhibit potent anti-HIV activity, there are very few cases reported of integrase inhibitors that show significant differences in anti-HIV activity that result from distinctions in cis-and trans-configurations as well as enantiomeric stereostructure. We describe here the design and synthesis of two enantiomeric trans-hydroxycyclopentyl carboxamides which exhibit notable difference in anti-HIV activity. This difference is explained through their binding interactions within the active site of the HIV-1 integrase intasome. The more active enantiomer 3 (EC50 25 nM) was relatively stable in human liver microsomes. Kinetic data revealed that its impact on key cytochrome P450 isozymes, as either an inhibitor or an activator, was minor, suggesting a favorable CYP profile. PMID:23746474

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

    PubMed

    Li, Shen; Ma, Jun-An

    2015-11-07

    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.

  6. 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

  7. Anti-HIV activity in vitro of MGN-3, an activated arabinoxylane from rice bran.

    PubMed

    Ghoneum, M

    1998-02-04

    MGN-3 an arabinoxylane from rice bran that has been enzymatically modified with extract from Hyphomycetes mycelia, was tested for anti-HIV activity in vitro. MGN-3 activity against HIV-1 (SF strain) was examined in primary cultures of peripheral blood mononuclear cells. MGN-3 inhibited HIV-1 replication by: (1) inhibition of HIV-1 p24 antigen production in a dose dependent manner--MGN-3 concentrations of 12.5, 25, 50, and 100 micrograms/ml showed 18.3, 42.8, 59, and 75% reduction in p24 antigen, respectively; and (2) inhibition of syncytia formation maximized (75%) at concentrations of 100 micrograms/ml. Further studies showed that ingestion of MGN-3 at concentration of 15 mg/kg/day resulted in a significant increase in T and B cell mitogen response at 2 months after treatment: 146% for PHA, 140% for Con A, and 136.6% for PWM mitogen. We conclude that MGN-3 possesses potent anti-HIV activity and in the absence of any notable side effects, MGN-3 shows promise as an agent for treating patients with AIDS.

  8. From Docking False-Positive to Active Anti-HIV Agent

    PubMed Central

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

    2008-01-01

    Virtual screening of the Maybridge library of ca. 70,000 compounds was performed using a similarity filter, docking, and MM-GB/SA post-processing to seek potential non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). Though 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 evolve efficiently a false positive into a true active. In addition, the need for adequate structure validation was confirmed by the apparent misrepresentation of a purchased compound elsewhere as the present oxadiazole core compound, 16. PMID:17918923

  9. Evaluating Complementary and Alternative Therapies

    MedlinePlus

    ... herbal therapies and dietary products often act like drugs in your body and cause side effects. Before giving a dietary or herbal product to a child, talk with his or her pediatric oncologist. A child's body uses drugs and nutrients differently and needs different doses than ...

  10. In Vitro Drug Combination Studies of Letermovir (AIC246, MK-8228) with Approved Anti-Human Cytomegalovirus (HCMV) and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication

    PubMed Central

    Wildum, Steffen; Zimmermann, Holger

    2015-01-01

    Despite modern prevention and treatment strategies, human cytomegalovirus (HCMV) remains a common opportunistic pathogen associated with serious morbidity and mortality in immunocompromised individuals, such as transplant recipients and AIDS patients. All drugs currently licensed for the treatment of HCMV infection target the viral DNA polymerase and are associated with severe toxicity issues and the emergence of drug resistance. Letermovir (AIC246, MK-8228) is a new anti-HCMV agent in clinical development that acts via a novel mode of action and has demonstrated anti-HCMV activity in vitro and in vivo. For the future, drug combination therapies, including letermovir, might be indicated under special medical conditions, such as the emergence of multidrug-resistant virus strains in transplant recipients or in HCMV-HIV-coinfected patients. Accordingly, knowledge of the compatibility of letermovir with other HCMV or HIV antivirals is of medical importance. Here, we evaluated the inhibition of HCMV replication by letermovir in combination with all currently approved HCMV antivirals using cell culture checkerboard assays. In addition, the effects of letermovir on the antiviral activities of selected HIV drugs, and vice versa, were analyzed. Using two different mathematical techniques to analyze the experimental data, (i) additive effects were observed for the combination of letermovir with anti-HCMV drugs and (ii) no interaction was found between letermovir and anti-HIV drugs. Since none of the tested drug combinations significantly antagonized letermovir efficacy (or vice versa), our findings suggest that letermovir may offer the potential for combination therapy with the tested HCMV and HIV drugs. PMID:25779572

  11. Identification of anti-HIV active dicaffeoylquinic- and tricaffeoylquinic acids in Helichrysum populifolium by NMR-based metabolomic guided fractionation.

    PubMed

    Heyman, Heino Martin; Senejoux, François; Seibert, Isabell; Klimkait, Thomas; Maharaj, Vinesh Jaichand; Meyer, Jacobus Johannes Marion

    2015-06-01

    South Africa being home to more than 35% of the world's Helichrysum species (c.a. 244) of which many are used in traditional medicine, is seen potentially as a significant resource in the search of new anti-HIV chemical entities. It was established that five of the 30 Helichrysum species selected for this study had significant anti-HIV activity ranging between 12 and 21 μg/mL (IC50) by using an in-house developed DeCIPhR method on a full virus model. Subsequent toxicity tests also revealed little or no toxicity for these active extracts. With the use of NMR-based metabolomics, the search for common chemical characteristics within the plant extract was conducted, which resulted in specific chemical shift areas identified that could be linked to the anti-HIV activity of the extracts. The NMR chemical shifts associated with the activity were identified to be 2.56-3.08 ppm, 5.24-6.28 ppm, 6.44-7.04 ppm and 7.24-8.04 ppm. This activity profile was then used to guide the fractionation process by narrowing down and focusing the fractionation and purification processes to speed up the putative identification of five compounds with anti-HIV activity in the most active species, Helichrysum populifolium. The anti-HIV compounds identified for the first time from H. populifolium were three dicaffeoylquinic acid derivatives, i.e. 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid as well as two tricaffeoylquinic acid derivatives i.e. 1,3,5-tricaffeoylquinic acid and either 5-malonyl-1,3,4-tricaffeoylquinic or 3-malonyl-1,4,5-tricaffeoylquinic acid, with the latter being identified for the first time in the genus.

  12. Chemoenzymatic Syntheses and Anti-HIV-1 Activity of Glucose-Nucleoside Conjugates as Prodrugs

    PubMed Central

    Rodríguez-Pérez, Tatiana; Fernández, Susana; Sanghvi, Yogesh S.; Detorio, Mervi; Schinazi, Raymond F.; Gotor, Vicente; Ferrero, Miguel

    2010-01-01

    Phosphodiester linked conjugates of various nucleosides such as d4U, d4T, IdUrd, ddI, ddA, virazole, ara-A and ara-C containing a glucosyl moiety have been described. These compounds were designed to act as prodrugs, where the corresponding 5′-monophosphates may be generated intracellularly. The synthesis of the glycoconjugates was achieved in good yields by condensation of a glucosyl phosphoramidite 7 with nucleosides in the presence of an activating agent. It was demonstrated that the glucose-conjugates improve water solubility of the nucleoside analogues, for example up to 31-fold for ara-A conjugate compared to ara-A alone. The new conjugates were tested for their anti-HIV-1 activity in human lymphocytes. These derivatives offer a convenient design for potential prodrug candidates with the possibility to improve the physicochemical properties and therapeutic activity of nucleoside analogues. PMID:21077659

  13. [Asymmetry in international relations, industrial property rights and anti-HIV medication].

    PubMed

    Costa-Couto, Maria Helena; Nascimento, Alvaro César

    2008-01-01

    This paper analyzes the asymmetry in the international relations as refers to the recognition of industrial property rights in the pharmaceutical industry. It focuses on the impact of such relations upon the access to ARV medication, an issue of worldwide interest due to its connection with the development of the nations. Clashing interests and the position taken by some countries in their patent laws point to a scenario less favorable for the access of peripheral countries to anti-HIV/AIDS medication. On the other hand, it seems that the success of the Brazilian STD/AIDS program in negotiating ARV prices will open new possibilities. The solution may be the internal strengthening of the National States and the active role played by the Agencies of the United Nations System in defense of the collective human interests.

  14. 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.

  15. A SINGLE INJECTION OF ANTI-HIV-1 ANTIBODIES PROTECTS AGAINST REPEATED SHIV CHALLENGES

    PubMed Central

    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.

    2016-01-01

    Despite the success of potent anti-retroviral drugs in controlling HIV-1 infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 bNAbs can protect mice or macaques against a single high dose challenge with HIV or SIV/HIV chimeric viruses respectively1-8, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Based on the relatively long term protection conferred by Hepatitis A immune globulin, we tested the efficacy of a single injection (20mg/kg) of four anti-HIV-1 neutralizing monoclonal antibodies (MAbs) (VRC01, VRC01-LS, 3BNC117, and 10-10749-12) in blocking repeated weekly low dose virus challenges of the clade B SHIVAD8. Compared to control animals, which required 2 to 6 challenges (median=3 weeks) for infection, a single bNAb infusion prevented virus acquisition for up to 23 weeks. 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 Fc domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered in to populations at high risk for HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission. PMID:27120156

  16. Nanoparticles-in-film for the combined vaginal delivery of anti-HIV microbicide drugs.

    PubMed

    Cunha-Reis, Cassilda; Machado, Alexandra; Barreiros, Luísa; Araújo, Francisca; Nunes, Rute; Seabra, Vítor; Ferreira, Domingos; Segundo, Marcela A; Sarmento, Bruno; das Neves, José

    2016-12-10

    Combining two or more antiretroviral drugs in one medical product is an interesting but challenging strategy for developing topical anti-HIV microbicides. We developed a new vaginal delivery system comprising the incorporation of nanoparticles (NPs) into a polymeric film base - NPs-in-film - and tested its ability to deliver tenofovir (TFV) and efavirenz (EFV). EFV-loaded poly(lactic-co-glycolic acid) NPs were incorporated alongside free TFV into fast dissolving films during film manufacturing. The delivery system was characterized for physicochemical properties, as well as genital distribution, local and systemic 24h pharmacokinetics (PK), and safety upon intravaginal administration to mice. NPs-in-film presented suitable technological, mechanical and cytotoxicity features for vaginal use. Retention of NPs in vivo was enhanced both in vaginal lavages and tissue when associated to film. PK data evidenced that vaginal drug levels rapidly decreased after administration but NPs-in-film were still able to enhance drug concentrations of EFV. Obtained values for area-under-the-curve for EFV were around one log10 higher than those for the free drugs in aqueous vehicle (phosphate buffered saline). Film alone also contributed to higher and more prolonged local drug levels as compared to the administration of TFV and EFV in aqueous vehicle. Systemic exposure to both drugs was low. NPs-in-film was found to be safe upon once daily vaginal administration to mice, with no significant genital histological changes or major alterations in cytokine/chemokine profiles being observed. Overall, the proposed NPs-in-film system seems to be an interesting delivery platform for developing combination vaginal anti-HIV microbicides.

  17. The in vitro ejection of zinc from human immunodeficiency virus (HIV) type 1 nucleocapsid protein by disulfide benzamides with cellular anti-HIV activity.

    PubMed Central

    Tummino, P J; Scholten, J D; Harvey, P J; Holler, T P; Maloney, L; Gogliotti, R; Domagala, J; Hupe, D

    1996-01-01

    Several disulfide benzamides have been shown to possess wide-spectrum antiretroviral activity in cell culture at low micromolar to submicromolar concentrations, inhibiting human immunodeficiency virus (HIV) type 1 (HIV-1) clinical and drug-resistant strains along with HIV-2 and simian immunodeficiency virus [Rice, W. G., Supko, J. G., Malspeis, L., Buckheit, R. W., Jr., Clanton, D., Bu, M., Graham, L., Schaeffer, C. A., Turpin, J. A., Domagala, J., Gogliotti, R., Bader, J. P., Halliday, S. M., Coren, L., Sowder, R. C., II, Arthur, L. O. & Henderson, L. E. (1995) Science 270, 1194-1197]. Rice and coworkers have proposed that the compounds act by "attacking" the two zinc fingers of HIV nucleocapsid protein. Shown here is evidence that low micromolar concentrations of the anti-HIV disulfide benzamides eject zinc from HIV nucleocapsid protein (NCp7) in vitro, as monitored by the zinc-specific fluorescent probe N-(6-methoxy-8-quinoyl)-p-toluenesulfonamide (TSQ). Structurally similar disulfide benzamides that do not inhibit HIV-1 in culture do not eject zinc, nor do analogs of the antiviral compounds with the disulfide replaced with a methylene sulfide. The kinetics of NCp7 zinc ejection by disulfide benzamides were found to be nonsaturable and biexponential, with the rate of ejection from the C-terminal zinc finger 7-fold faster than that from the N-terminal. The antiviral compounds were found to inhibit the zinc-dependent binding of NCp7 to HIV psi RNA, as studied by gel-shift assays, and the data correlated well with the zinc ejection data. Anti-HIV disulfide benzamides specifically eject NCp7 zinc and abolish the protein's ability to bind psi RNA in vitro, providing evidence for a possible antiretroviral mechanism of action of these compounds. Congeners of this class are under advanced preclinical evaluation as a potential chemotherapy for acquired immunodeficiency syndrome. Images Fig. 7 PMID:8577770

  18. Expressing anti-HIV VRC01 antibody using the murine IgG1 secretion signal in Pichia pastoris.

    PubMed

    Aw, Rochelle; McKay, Paul F; Shattock, Robin J; Polizzi, Karen M

    2017-12-01

    The use of the recombinant expression platform Pichia pastoris to produce pharmaceutically important proteins has been investigated over the past 30 years. Compared to mammalian cultures, expression in P. pastoris is cheaper and faster, potentially leading to decreased costs and process development times. Product yields depend on a number of factors including the secretion signal chosen for expression, which can influence the host cell response to recombinant protein production. VRC01, a broadly neutralising anti-HIV antibody, was expressed in P. pastoris, using the methanol inducible AOX1 promoter for both the heavy and light chains. Titre reached up to 3.05 μg mL(-1) in small scale expression. VRC01 was expressed using both the α-mating factor signal peptide from Saccharomyces cerevisiae and the murine IgG1 signal peptide. Surprisingly, using the murine IgG1 signal peptide resulted in higher yield of antibody capable of binding gp140 antigen. Furthermore, we evaluated levels of secretory stress compared to the untransformed wild-type strain and show a reduced level of secretory stress in the murine IgG1 signal peptide strains versus those containing the α-MF signal peptide. As bottlenecks in the secretory pathway are often the limiting factor in protein secretion, reduced levels of secretory stress and the higher yield of functional antibody suggest the murine IgG1 signal peptide may lead to better protein folding and secretion. This work indicates the possibilities for utilising the murine IgG1 signal peptide for a range of antibodies, resulting in high yields and reduced cellular stress.

  19. 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.

  20. Density functional theory study of the local molecular properties of acetamide derivatives as anti-HIV drugs

    PubMed Central

    Oftadeh, M.; Mahani, N. Madadi; Hamadanian, M.

    2013-01-01

    Accurate quantum chemical computations based on density functional theory (DFT) were performed on the series of 2-(4-(naphthalen-2-yl)-1,2,3-thiadiazol-5-ylthio)-N-acetamide (TTA) derivatives. The local reactivity of the acetamide derivatives as anti-HIV drugs were studied in terms of Fukui functions in the framework of DFT. The results based on the basis set superposition error (BSSE) corrections showed that the mechanism of bond formation between the acetamide derivatives and tyrosine as a biological molecule occurs mainly through nitrogen atoms. The intramolecular interaction energies between the acetamide derivatives and tyrosine were calculated and the nature of the intermolecular interaction was revealed by natural bond orbital charge (NBO) analysis. The results suggest that acetamide derivatives with bromophenyl and nitrophenyl substitutions are the most potent as anti-HIV drugs. PMID:24082898

  1. High titer anti-HIV antibody reactivity associated with a paraprotein spike in a homosexual male with AIDS related complex.

    PubMed

    Ng, V L; Hwang, K M; Reyes, G R; Kaplan, L D; Khayam-Bashi, H; Hadley, W K; McGrath, M S

    1988-05-01

    We observed a human immunodeficiency virus (HIV)-infected homosexual male with AIDS related complex (ARC) who had a serum globulin level of 80 g/L. Serum protein electrophoresis revealed a gamma globulin fraction of 40 g/L, of which 50% (20 g/L) was contained within a paraprotein spike, comprised predominantly of IgG kappa. This patient also had high titer anti-HIV antibodies in his serum, which were Western blot reactive at a final dilution of 1:500,000, and recognized gp120env, p66pol, p55gag, p53pol, p41gag, and p24gag. Because paraproteins in the past have been shown to be directed against specific antigens, we purified this patient's paraprotein using a modified high performance liquid chromatography (HPLC)-hydroxylapatite procedure and tested the purified paraprotein for anti-HIV antibody activity. The purified paraprotein retained anti-HIV antibody activity to a final dilution of 1:100,000, and recognized p66pol, p55gag, p53pol, p41gag, and p24gag. The recognition of both "gag" and "pol" gene products suggested that the purified paraprotein might not be monoclonal in origin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that the purified paraprotein contained at least two immunoglobulin light chain species (Mol wt 30 to 33 Kd). Affinity chromatography of the purified paraprotein using a p24-Sepharose 4B matrix separated the "gag" and "pol" antibody activities. Immunoglobulin gene rearrangement analysis of a bone marrow aspirate (which contained 15% plasma cells) failed to reveal a clonal population of immunoglobulin producing cells. We conclude that this patient's paraprotein accounted for most of the anti-HIV activity present in whole serum, and that this paraprotein was not monoclonal in origin.

  2. Anti-HIV seropositivity was related to HBsAg seropositivity among injecting drug users in Taiwan.

    PubMed

    Hsieh, Meng-Hsuan; Hsieh, Ming-Yen; Huang, Chung-Feng; Yeh, Ming-Lun; Wang, Shu-Chi; Yang, Jeng-Fu; Chang, Ko; Lin, Wei-Ru; Lin, Chun-Yu; Chen, Tun-Chieh; Huang, Jee-Fu; Dai, Chia-Yen; Tsai, Jih-Jin; Chuang, Wan-Long; Yu, Ming-Lung

    2016-02-01

    In Taiwan, the number of new cases of human immunodeficiency virus (HIV) infection via drug injection has been increasing since 2003. Due to HIV and hepatitis B virus (HBV) having similar transmission routes, HBV and HIV infections among injecting drug users (IDUs) has become an important public health issue. The aim of this study was explore the prevalence of HBV infection among IDUs with and without HIV infection, and examine whether HIV infection is associated with HBV infection among IDUs in Southern Taiwan. We enrolled 566 IDUs, including 87 anti-HBV positive IDUs and 479 anti-HBV negative IDUs, and also analyzed the results of liver function tests, HBV DNA, anti-HIV, HIV RNA, and CD4 cell count. The results showed that the prevalence of HBV infection among IDUs was 15.4%. The prevalence of hepatitis B surface antigen (HBsAg) was higher among individuals born before 1985 (15.9% vs. 4.0%), but this was not significant. Anti-HIV seropositivity was related to HBsAg seropositivity [odds ratio (OR) = 2.47, 95% confidence interval = 1.26-4.82, p = 0.008). Anti-HCV and anti-HIV were risk factors for abnormal alanine aminotransferase (ALT; OR = 2.11, 95% confidence interval = 1.005-4.42, p = 0.048 and OR = 1.47, 95% confidence interval = 1.02-2.10, p = 0.04, respectively), and HBsAg was not a factor related to abnormal ALT. In conclusion, the prevalence of HBV infection was similar in the general population and in IDUs, and due to anti-HIV seropositivity being significantly related to HBsAg seropositivity, HBV infection among IDUs is still important. We suggest that for IDUs, HBsAg should be monitored closely.

  3. Structure and conformational analysis of the anti-HIV AZT 5‧-aminocarbonylphosphonate prodrug using DFT methods

    NASA Astrophysics Data System (ADS)

    Tamara Molina, A.; Alcolea Palafox, M.

    2011-08-01

    A comprehensive theoretical conformational analysis of the anti-HIV AZT 5'-aminocarbonylphosphonate prodrug was carried out, due to this prodrug has noticeable advantage over approved drugs AZT and Nikavir. The whole conformational parameters ( χ, γ, β, α, δ, ɛ, τ, P, νmax) were analysed as well as the NBO Natural atomic charges. The calculations were carried out by means of B3LYP/6-31G ∗∗ and B3LYP/6-311++G(3df,pd) DFT levels of theory with full relaxation of all geometrical parameters. The search located at least 86 stable structures, 6 of which are within a 1 kcal/mol electronic energy range of the global minimum and 11 conformers are within a 1 kcal/mol Gibbs energy range. The global minimum with the 6-311++G(3df,pd) basis set corresponds to the calculated values of the exocyclic torsional angles χ = -121.6°, β = 153.0°, γ = -152.0° and α = -74.1°. The results obtained are in accordance to those found in related anti-HIV nucleoside Analogs. Comparisons of the conformers with those determined in the common anti-HIV drug AZT were carried out. Several correlations and general conclusions were emphasized.

  4. Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells.

    PubMed

    Hong, Bangxing; Song, Xiao-Tong; Rollins, Lisa; Berry, Lindsey; Huang, Xue F; Chen, Si-Yi

    2011-02-01

    Both mucosal and systemic immune responses are required for preventing or containing HIV transmission and chronic infection. However, currently described vaccination approaches are largely ineffective in inducing both mucosal and systemic responses. In this study, we found that the ubiquitin-editing enzyme A20--an inducible feedback inhibitor of the TNFR, RIG-I, and TLR signaling pathways that broadly controls the maturation, cytokine production, and immunostimulatory potency of DCs--restricted systemically immunized DCs to induce both robust mucosal and systemic HIV-specific cellular and humoral responses. Mechanistic studies revealed that A20 regulated DC production of retinoic acid and proinflammatory cytokines, inhibiting the expression of gut-homing receptors on T and B cells. Furthermore, A20-silenced, hyperactivated DCs exhibited an enhanced homing capacity to draining and gut-associated lymphoid tissues (GALTs) after systemic administration. Thus, this study provides insights into the role of A20 in innate immunity. This work may allow the development of an efficient HIV vaccination strategy that is capable of inducing both robust systemic and mucosal anti-HIV cellular and humoral responses.

  5. Mucosal and systemic anti-HIV immunity controlled by A20 in mouse dendritic cells

    PubMed Central

    Hong, Bangxing; Song, Xiao-Tong; Rollins, Lisa; Berry, Lindsey; Huang, Xue F.; Chen, Si-Yi

    2011-01-01

    Both mucosal and systemic immune responses are required for preventing or containing HIV transmission and chronic infection. However, currently described vaccination approaches are largely ineffective in inducing both mucosal and systemic responses. In this study, we found that the ubiquitin-editing enzyme A20 — an inducible feedback inhibitor of the TNFR, RIG-I, and TLR signaling pathways that broadly controls the maturation, cytokine production, and immunostimulatory potency of DCs — restricted systemically immunized DCs to induce both robust mucosal and systemic HIV-specific cellular and humoral responses. Mechanistic studies revealed that A20 regulated DC production of retinoic acid and proinflammatory cytokines, inhibiting the expression of gut-homing receptors on T and B cells. Furthermore, A20-silenced, hyperactivated DCs exhibited an enhanced homing capacity to draining and gut-associated lymphoid tissues (GALTs) after systemic administration. Thus, this study provides insights into the role of A20 in innate immunity. This work may allow the development of an efficient HIV vaccination strategy that is capable of inducing both robust systemic and mucosal anti-HIV cellular and humoral responses. PMID:21206085

  6. Role for plasmacytoid dendritic cells in anti-HIV innate immunity.

    PubMed

    Müller-Trutwin, Michaela; Hosmalin, Anne

    2005-10-01

    The role of plasmacytoid dendritic cells (pDC) in anti-HIV immunity is mostly represented by the production of type I IFN in response to HIV infection in vitro and in vivo. This production is decreased in HIV-1 infected patients at the time of primary infection and during chronic disease in association with progression of disease. Circulating pDC counts are decreased concomitantly with type I IFN, and both factors correlate inversely overall with viral loads and positively with CD4+ T-cell counts. These parameters might be used in clinical immunology to monitor treatment and as predictive factors of immune control of HIV-1 replication to help decide whether to interrupt antiretroviral treatment. They may be related to control of HIV replication as well as to pathogenesis of infection, perhaps in setting the balance between immunity or tolerance to the virus. A better understanding of these parameters is required while attempts to use IFN-alpha or ligands of Toll-like receptors found on pDC are being made.

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. Precise engineering of dapivirine-loaded nanoparticles for the development of anti-HIV vaginal microbicides.

    PubMed

    das Neves, José; Sarmento, Bruno

    2015-05-01

    Polymeric nanoparticles (NPs) have the potential to provide effective and safe delivery of antiretroviral drugs in the context of prophylactic anti-HIV vaginal microbicides. Dapivirine-loaded poly(d,l-lactic-co-glycolic acid) (PLGA) NPs were produced by an emulsion-solvent evaporation method, optimized for colloidal properties using a 3-factor, 3-level Box-Behnken experimental design, and characterized for drug loading, production yield, morphology, thermal behavior, drug release, in vitro cellular uptake, cytotoxicity and pro-inflammatory potential. Also, drug permeability/membrane retention in well-established HEC-1-A and CaSki cell monolayer models as mediated by NPs was assessed in the absence or presence of mucin. Box-Behnken design allowed optimizing monodisperse 170nm drug-loaded NPs. Drug release experiments showed an initial burst effect up to 4h, followed by sustained 24h release at pH 4.2 and 7.4. NPs were readily taken up by different genital and macrophage cell lines as assessed by fluorescence microscopy. Drug-loaded NPs presented lower or at least similar cytotoxicity as compared to the free drug, with up to around one-log increase in half-maximal cytotoxic concentration values. In all cases, no relevant changes in cell pro-inflammatory cytokine/chemokine production were observed. Dapivirine transport across cell monolayers was significantly decreased when mucin was present at the donor side with either NPs or the free drug, thus evidencing the influence of this natural glycoprotein in membrane permeability. Moreover, drug retention in cell monolayers was significantly higher for NPs in comparison with the free drug. Overall, obtained dapivirine-loaded PLGA NPs possess interesting technological and biological features that may contribute to their use as novel safe and effective vaginal microbicides.

  14. Evaluation and therapy of polycystic ovarian syndrome.

    PubMed

    Loy, R; Seibel, M M

    1988-12-01

    The amenorrhea associated with bilateral polycystic ovaries, described by Stein and Leventhal, actually represents a syndrome involving various organs and systems. Clinically, this symptom complex commonly presents as menstrual disturbances, infertility, excessive body weight, and hirsutism. An understanding of the pathophysiology that underlies these symptoms provides a logical basis for evaluation and treatment of the syndrome. The diagnostic approach may involve biochemical determinations (baseline, stimulated, and suppressed) and radiologic testing. Therapy is directed at chronic anovulation, the hyperandrogenism responsible for hirsutism and acne, and the prophylaxis against endometrial and breast carcinomas. Ovulation can be induced with various agents, many of which have a risk of ovarian hyperstimulation in the PCOD patient. The use of GnRH agonists with HMG or FSH for ovulation induction will probably increase in the future. Although classic wedge resection has little place in modern management of PCOD, the recent laparoscopic ovarian cautery remains largely unstudied with respect to long-term postoperative plasma androgen levels and pelvic adhesions. It is too premature to evaluate this new surgical therapy. Hirsutism is effectively treated with estrogen-progestin combinations, medroxyprogesterone acetate, androgen receptor blockers (spironolactone, cimetidine, cyproterone acetate, and cyproheptadine), and glucocorticoids. To date, the available GnRH agonists have not been found selective enough to be used in the treatment of hirsutism, owing to possible long-term complications. Most medical approaches should include electrolysis for permanent hair removal. At present, gynecologic surgery seems to have little place in the management of hirsutism.

  15. 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

  16. 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.

  17. [Synthesis, properties and anti-HIV activity of novel lipophilic 3'-azido-3'-deoxythymidine conjugates containing functional phosphoric linkages].

    PubMed

    Shastina, N S; Mal'tseva, T Iu; D'iakova, L N; Lobach, O A; Chataeva, M S; Nosik, D N; Shvetz, V I

    2013-01-01

    One of the approaches to enhance bioavailability of nucleoside reverse transcriptase HIV inhibitors consists in design of their prodrugs based on 1,3-diacylglycerols, which may simulate nature lipids metabolic pathways promoting the improvement of drug delivery to the target cells. Glycerolipidic AZT conjugates with different functional phosphoric centers were synthesized by H-phosphonate technique in the present work. Study of prepared prodrugs sensibility to the chemical and enzymatic hydrolysis (in buffer solution and under the influence of pancreatic lipase) and also study of their anti-HIV activity on the T-lymphoid human MT-4 cells in regarding to virus HIV-1(899A) strain were carried out.

  18. 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.

  19. Application of 3D-QSAR techniques in anti-HIV-1 drug design--an overview.

    PubMed

    Debnath, Asim Kumar

    2005-01-01

    Despite the availability of several classes of drugs against acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus type 1(HIV-1), this deadly disease showing very little sign of containment, especially in Sub-Saharan Africa and South-East Asia. More than 20 million people died since the first diagnosis of AIDS more than twenty years ago and almost 40 million people are currently living with HIV/AIDS. Structure-based drug design effort was immensely successful in identifying several drugs that are currently available for the treatment of HIV-1. Many applications have been reported on the use of quantitative structure-activity relationship (QSAR) studies to understand the drug-receptor interactions and help in the design of more effective analogs. Extensive application was also reported on the application of 3D-QSAR techniques, such as, Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Analysis (CoMSIA), pharmacophore generation using Catalyst/HypoGen, free-energy binding analysis, GRID/GOLPE, HINT-based techniques, etc. in anti-HIV-1 drug discovery programs in academia and industry. We have attempted to put together a comprehensive overview on the 3D-QSAR applications in anti-HIV-1 drug design reported in the literature during the last decade.

  20. Discovery of a Potent HIV Integrase Inhibitor That Leads to a Prodrug with Significant anti-HIV Activity

    PubMed Central

    2011-01-01

    Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity, and drug–drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC50 70 nM), strategically assembled on a pyridinone scaffold. A focused structure–activity investigation of this parent compound led to a significantly more potent ST inhibitor, 2 (IC50 6 ± 3 nM). Compound 2 exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor 2, i.e., compound 10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC50 9 ± 4 nM, CC50 135 ± 7 μM, therapeutic index = 15 000). PMID:22328963

  1. Determining chemical reactivity driving biological activity from SMILES transformations: the bonding mechanism of anti-HIV pyrimidines.

    PubMed

    Putz, Mihai V; Dudaş, Nicoleta A

    2013-07-30

    Assessing the molecular mechanism of a chemical-biological interaction and bonding stands as the ultimate goal of any modern quantitative structure-activity relationship (QSAR) study. To this end the present work employs the main chemical reactivity structural descriptors (electronegativity, chemical hardness, chemical power, electrophilicity) to unfold the variational QSAR though their min-max correspondence principles as applied to the Simplified Molecular Input Line Entry System (SMILES) transformation of selected uracil derivatives with anti-HIV potential with the aim of establishing the main stages whereby the given compounds may inhibit HIV infection. The bonding can be completely described by explicitly considering by means of basic indices and chemical reactivity principles two forms of SMILES structures of the pyrimidines, the Longest SMILES Molecular Chain (LoSMoC) and the Branching SMILES (BraS), respectively, as the effective forms involved in the anti-HIV activity mechanism and according to the present work, also necessary intermediates in molecular pathways targeting/docking biological sites of interest.

  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.

  3. 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

  4. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques

    PubMed Central

    Shingai, Masashi; Donau, Olivia K.; Plishka, Ronald J.; Buckler-White, Alicia; Mascola, John R.; Nabel, Gary J.; Nason, Martha C.; Montefiori, David; Moldt, Brian; Poignard, Pascal; Diskin, Ron; Bjorkman, Pamela J.; Eckhaus, Michael A.; Klein, Florian; Mouquet, Hugo; Cetrulo Lorenzi, Julio Cesar; Gazumyan, Anna; Burton, Dennis R.; Nussenzweig, Michel C.

    2014-01-01

    It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). The passive transfer of anti–HIV-1 NAbs conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure, to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. We administered five recently isolated potent and broadly acting anti-HIV neutralizing monoclonal antibodies (mAbs) to rhesus macaques and challenged them intrarectally 24 h later with either of two different R5-tropic SHIVs. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus infection in 50% of the exposed monkeys was relatively modest (∼1:100) and potentially achievable by vaccination. PMID:25155019

  5. Methamphetamine inhibits HIV-1 replication in CD4+ T cells by modulating anti-HIV-1 miRNA expression.

    PubMed

    Mantri, Chinmay K; Mantri, Jyoti V; Pandhare, Jui; Dash, Chandravanu

    2014-01-01

    Methamphetamine is the second most frequently used illicit drug in the United States. Methamphetamine abuse is associated with increased risk of HIV-1 acquisition, higher viral loads, and enhanced HIV-1 pathogenesis. Although a direct link between methamphetamine abuse and HIV-1 pathogenesis remains to be established in patients, methamphetamine has been shown to increase HIV-1 replication in macrophages, dendritic cells, and cells of HIV transgenic mice. Intriguingly, the effects of methamphetamine on HIV-1 replication in human CD4(+) T cells that serve as the primary targets of infection in vivo are not clearly understood. Therefore, we examined HIV-1 replication in primary CD4(+) T cells in the presence of methamphetamine in a dose-dependent manner. Our results demonstrate that methamphetamine had a minimal effect on HIV-1 replication at concentrations of 1 to 50 μmol/L. However, at concentrations >100 μmol/L, it inhibited HIV-1 replication in a dose-dependent manner. We also discovered that methamphetamine up-regulated the cellular anti-HIV-1 microRNAs (miR-125b, miR-150, and miR-28-5p) in CD4(+) T cells. Knockdown experiments illustrated that up-regulation of the anti-HIV miRNAs inhibited HIV-1 replication. These results are contrary to the paradigm that methamphetamine accentuates HIV-1 pathogenesis by increasing HIV-1 replication. Therefore, our findings underline the complex interaction between drug use and HIV-1 and necessitate comprehensive understanding of the effects of methamphetamine on HIV-1 pathogenesis.

  6. Anti-Leu3a induces combining site-related anti-idiotypic antibody without inducing anti-HIV activity.

    PubMed

    Reeves, J P; Buck, D; Berkower, I; Murphy, D; Epstein, S L

    1991-01-01

    Development of a vaccine for acquired immunodeficiency syndrome (AIDS) has proven difficult, and so alternative approaches such as idiotypic manipulation have been suggested. As applied to AIDS, this approach could involve immunizing with an anti-CD4 antibody resembling gp120, to induce anti-idiotypic antibodies which would bind to gp120. The CD4 binding site on gp120 is conserved, and so, such an immune response should protect against all variants. Induction of anti-human immunodeficiency virus (HIV) immunity has been reported using anti-Leu3a, and this result has led to testing in humans. Negative results obtained by others have been attributed to differences in immunization protocols. Because of the importance of this question, we reinvestigated the potential of anti-Leu3a to induce anti-HIV antibodies, compared with control immunizations with OKT4A (another anti-CD4 antibody) and the irrelevant Ig MOPC-21. Responses to anti-Leu3a showed induction of high-titer anti-idiotypic activity, and included combining-site-related activity. Yet sera showed no binding to gp160 above controls and no detectable neutralizing activity in a sensitive HIV plaque assay, so the anti-idiotypes induced were not internal images of CD4. We conclude that the pronounced anti-HIV responses reported with anti-Leu3a cannot be generalized, and thus that anti-Leu3a does not offer promise as an HIV vaccine. However, these results do not negate the promise of the idiotypic approach, and a vaccine for AIDS based on idiotype manipulation remains a possibility.

  7. Phenotypic characterization of CD8+ T cell populations in HIV disease and in anti-HIV immunity.

    PubMed

    Watret, K C; Whitelaw, J A; Froebel, K S; Bird, A G

    1993-04-01

    The CD8+ T cell population is believed to play an important role in the control of viral infection, both for suppression of viral replication and for cytotoxic activity against viral infected cells. Elevated numbers of CD8+ T cells have been demonstrated in HIV infection, and CD8+ cytotoxic T cell (CTL) activity is associated with the early, asymptomatic stage of disease. We investigated the phenotypic characteristics of the CD8 population, in whole blood, in HIV disease and determined the predominant CD8+ subpopulation involved in anti-HIV CTL activity. We found that CD8+ T cells co-expressing markers of activation (HLA-DR), memory (CD45RO, CD29), and cytotoxic activity (S6F1) were significantly elevated in the early stages of disease, while the numbers of naive (CD45RA) cells remained unchanged. Progression to AIDS resulted in an overall loss of absolute CD8+ T cells, though the percentages of CD8+ HLA-DR+ and CD8+ S6F1+ remained elevated. In contrast to patients in the late stages of disease, anti-HIVgag CTL activity, following in vitro stimulation, was present in most HIV+ asymptomatic subjects and was associated with an expansion of CD8+ HLA-DR+ and CD8+ CD45RO+ cells. The absence of CTL activity was associated with a reduced ability of these populations to expand in vitro and with a significant loss of peripheral CD4+ T cells, independent of clinical stage. We suggest that CD8+ expressing HLA-DR+ CD45RO+ and S6F1+ play an important role in anti-HIV cytotoxicity.

  8. 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.

  9. 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

  10. Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12.

    PubMed

    Mascola, J R; Louder, M K; VanCott, T C; Sapan, C V; Lambert, J S; Muenz, L R; Bunow, B; Birx, D L; Robb, M L

    1997-10-01

    Three antibody reagents that neutralize primary human immunodeficiency virus type 1 (HIV-1) isolates were tested for magnitude and breadth of neutralization when used alone or in double or triple combinations. Hyperimmune anti-HIV immunoglobulin (HIVIG) is derived from the plasma of HIV-1-infected donors, and monoclonal antibodies (MAbs) 2F5 and 2G12 bind to distinct regions of the HIV-1 envelope glycoprotein. The antibodies were initially tested against a panel of 15 clade B HIV-1 isolates, using a single concentration that is achievable in vivo (HIVIG, 2,500 microg/ml; MAbs, 25 microg/ml). Individual antibody reagents neutralized many of the viruses tested, but antibody potency varied substantially among the viruses. The virus neutralization produced by double combinations of HIVIG plus 2F5 or 2G12, the two MAbs together, or the triple combination of HIVIG, 2F5, and 2G12 was generally equal to or greater than that predicted by the effect of individual antibodies. Overall, the triple combination displayed the greatest magnitude and breadth of neutralization. Synergistic neutralization was evaluated by analyzing data from dose-response curves of each individual antibody reagent compared to the triple combination and was demonstrated against each of four viruses tested. Therefore, combinations of polyclonal and monoclonal anti-HIV antibodies can produce additive or synergistic neutralization of primary HIV-1 isolates. Passive immunotherapy for treatment or prophylaxis of HIV-1 should consider mixtures of potent neutralizing antibody reagents to expand the magnitude and breadth of virus neutralization.

  11. Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12.

    PubMed Central

    Mascola, J R; Louder, M K; VanCott, T C; Sapan, C V; Lambert, J S; Muenz, L R; Bunow, B; Birx, D L; Robb, M L

    1997-01-01

    Three antibody reagents that neutralize primary human immunodeficiency virus type 1 (HIV-1) isolates were tested for magnitude and breadth of neutralization when used alone or in double or triple combinations. Hyperimmune anti-HIV immunoglobulin (HIVIG) is derived from the plasma of HIV-1-infected donors, and monoclonal antibodies (MAbs) 2F5 and 2G12 bind to distinct regions of the HIV-1 envelope glycoprotein. The antibodies were initially tested against a panel of 15 clade B HIV-1 isolates, using a single concentration that is achievable in vivo (HIVIG, 2,500 microg/ml; MAbs, 25 microg/ml). Individual antibody reagents neutralized many of the viruses tested, but antibody potency varied substantially among the viruses. The virus neutralization produced by double combinations of HIVIG plus 2F5 or 2G12, the two MAbs together, or the triple combination of HIVIG, 2F5, and 2G12 was generally equal to or greater than that predicted by the effect of individual antibodies. Overall, the triple combination displayed the greatest magnitude and breadth of neutralization. Synergistic neutralization was evaluated by analyzing data from dose-response curves of each individual antibody reagent compared to the triple combination and was demonstrated against each of four viruses tested. Therefore, combinations of polyclonal and monoclonal anti-HIV antibodies can produce additive or synergistic neutralization of primary HIV-1 isolates. Passive immunotherapy for treatment or prophylaxis of HIV-1 should consider mixtures of potent neutralizing antibody reagents to expand the magnitude and breadth of virus neutralization. PMID:9311792

  12. 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…

  13. 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…

  14. 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

  15. 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.

  16. Structure-activity relationship study of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives for potent anti-HIV agents.

    PubMed

    Mizuhara, Tsukasa; Oishi, Shinya; Ohno, Hiroaki; Shimura, Kazuya; Matsuoka, Masao; Fujii, Nobutaka

    2012-11-01

    3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is an antiretroviral agent with submicromolar inhibitory activity against human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. In the current study, the structure-activity relationships of accessory groups at the 3- and 9-positions of pyrimido[1,2-c][1,3]benzothiazin-6-imine were investigated for the development of more potent anti-HIV agents. Several different derivatives containing a 9-aryl group were designed and synthesized using Suzuki-Miyaura cross-coupling and Ullmann coupling reactions. Modification of the m-methoxyphenyl or benzo[d][1,3]dioxol-5-yl group resulted in improved anti-HIV activity. In addition, the 2,4-diazaspiro[5.5]undec-2-ene-fused benzo[e][1,3]thiazine derivatives were designed and tested for their anti-HIV activities. The most potent 9-(benzo[d][1,3]dioxol-5-yl) derivative was two-threefold more effective against several strains of HIV-1 and HIV-2 than the parent compound, PD 404182.

  17. Design, synthesis and activity evaluation of novel peptide fusion inhibitors targeting HIV-1 gp41.

    PubMed

    Tan, Jianjun; Su, Min; Zeng, Yi; Wang, Cunxin

    2016-01-15

    Human immunodeficiency virus type 1 (HIV-1), the pathogen of acquired immunodeficiency syndrome (AIDS), causes about 2 million people to death every year. Fusion inhibitors targeted the envelope protein (gp41) represent a novel and alternative approach for anti-AIDS therapy, which terminates the HIV-1 life cycle at an early stage. Using CP621-652 as a template, a series of peptides were designed, synthesized and evaluated in vitro assays. An interesting phenomenon was found that the substitution of hydrophobic residues at solvent accessible sites could increase the anti-HIV activity when the C-terminal sequence was extended with an enough numbers of amino acids. After the active peptides was synthesized and evaluated, peptide 8 showed the best anti-HIV-1 IIIB whole cell activity (MAGI IC50=53.02 nM). Further study indicated that peptide 8 bound with the gp41 NHR helix, and then blocked the conformation of 6-helix, thus inhibited virus-cell membrane fusion. The results would be helpful for the design of peptide fusion inhibitors against HIV-1 infection.

  18. Bicyclams, a class of potent anti-HIV agents, are targeted at the HIV coreceptor fusin/CXCR-4.

    PubMed

    Schols, D; Esté, J A; Henson, G; De Clercq, E

    1997-08-01

    Bicyclams are a novel class of antiviral compounds which are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. The prototype compound, AMD3100, has an IC50 of 1-10 ng/ml, which is a least 100,000 fold lower than the cytotoxic concentration. AMD3100 does not inhibit virus binding to the CD4 receptor and based on time-of-addition experiments, has been assumed to interact with the HIV fusion-uncoating process. Resistance of HIV-1 strains to AMD3100 is associated with the accumulation of several mutations in the viral envelope glycoprotein gp120. Here, we demonstrate that AMD3100 interacts with fusin (CXCR-4), the coreceptor used by T-tropic viruses to infect the target cells. The replication of NL4-3 wild type virus and NL4-3 dextran sulfate-resistant virus was inhibited by the CXC-chemokine, stromal cell-derived factor 1 (SDF-1), the natural ligand for CXCR-4. In contrast, the replication of the HIV-1 NL4-3 AMD3100-resistant virus was no longer inhibited by SDF-1. The bicyclams are the first low-molecular-weight anti-HIV agents shown to interact with the coreceptor for T-tropic viruses.

  19. [Anti-HIV effects of IFN-tau in human macrophages: role of cellular antiviral factors and interleukin-6].

    PubMed

    Maneglier, B; Rogez-Kreuz, C; Dereuddre-Bosquet, N; Martal, J; Devillier, P; Dormont, D; Clayette, P

    2008-01-01

    Tau interferon (IFN-tau) was shown to inhibit human immunodeficiency virus (HIV) replication in vitro more strongly than human IFN-alpha, particularly in human macrophages. IFN-tau efficiently inhibited the early steps of HIV biological cycle, decreasing intracellular HIV RNA and inhibiting the initiation of the reverse transcription of viral RNA into proviral DNA. In this study, the in vitro immunomodulatory effects of IFN-tau were explored in human macrophages. We found that IFN-tau increased the synthesis of the cellular antiviral factors, such as 2',5'-oligoadenylate synthetase/RNase L and MxA protein. These results suggested that IFN-tau induces the same antiviral pathways in macrophages as other type I IFNs. We found that IFN-tau increased the production of interleukins (IL)-10 and IL-6, but not of IL-1ss or TNF-alpha, in not infected and in in vitro HIV-1/Ba-L-infected macrophages. We also found that the neutralization of IL-6 biological activity in the cell culture supernatants of IFN-tau-treated macrophages led to a decrease in the antiretroviral effects of IFN-tau towards HIV RNA. In conclusion, anti-HIV effects of IFN-tau are mediated by several modes of action, mediated either directly by IFN-tau or via other cytokines, such as IL-6, also known to be induced by IFN-alpha.

  20. 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.

  1. 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.

  2. Exosomes contribute to the transmission of anti-HIV activity from TLR3-activated brain microvascular endothelial cells to macrophages

    PubMed Central

    Sun, Li; Wang, Xu; Zhou, Yu; Zhou, Run-Hong; Ho, Wen-Zhe; Li, Jie-Liang

    2017-01-01

    Human brain microvascular endothelial cells (HBMECs), the major cell type in the blood-brain barrier (BBB), play a key role in maintaining brain homeostasis. However, their role in the BBB innate immunity against HIV invasion of the central nervous system (CNS) remains to be determined. Our early work showed that TLR3 signaling of HBMECs could produce the antiviral factors that inhibit HIV replication in macrophages. The present study examined whether exosomes from TLR3-activated HBMECs mediate the intercellular transfer of antiviral factors to macrophages. Primary human macrophages could take up exosomes from TLR3-activated HBMECs. HBMECs-derived exosomes contained multiple antiviral factors, including several key IFN-stimulated genes (ISGs; ISG15, ISG56, and Mx2) at mRNA and protein levels. The depletion of exosomes from TLR3-activated HBMECs culture supernatant diminished HBMECs-mediated anti-HIV activity in macrophages. In conclusion, we demonstrate that exosomes shed by HBMECs are able to transport the antiviral molecules to macrophages. This finding suggests the possibility that HIV nonpermissive BBB cells (HBMECs) can help to restore the antiviral state in HIV-infected macrophages, which may be a defense mechanism against HIV neuroinvasion. PMID:27496004

  3. Phosphorylation of anti-HIV nucleoside analogs by nucleoside diphosphate kinase.

    PubMed

    Schneider, B; Xu, Y; Sellam, O; Sarfati, R; Janin, J; Véron, M; Deville-Bonne, D

    1999-01-01

    The reaction of NDP kinase with antiviral nucleoside triphosphates used in antiviral therapies was studied at the presteady state by fluorescence stopped-flow and compared with the steady-state parameters. The affinity of the analogs was determined by fluorescence titration of a mutated enzyme with an inserted Trp in the binding site. The lack of the 3' hydroxyl in analogs is shown to decrease the kcat more than the KD.

  4. WHI-05, a novel bromo-methoxy substituted phenyl phosphate derivative of zidovudine, is a dual-action spermicide with potent anti-HIV activity.

    PubMed

    D'Cruz, O J; Zhu, Z; Yiv, S H; Chen, C L; Waurzyniak, B; Uckun, F M

    1999-05-01

    Heterosexual transmission of HIV to women is the fastest-growing mode of transmission. In a systematic effort to develop a microbicide capable of preventing HIV transmission as well as providing fertility control, novel phenyl phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine, ZDV) have been identified that exhibit potent anti-HIV and spermicidal activities. This study reports the synthesis, characterization, and preclinical formulation of compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl) methoxyalaninyl phosphate. The anti-HIV activities of WHI-05 and ZDV were compared by measuring p24 antigen production and reverse transcriptase activity as markers of viral replication using human peripheral blood mononuclear cells (PBMC) infected with both ZDV-sensitive and ZDV-resistant strains of HIV. The sperm immobilizing activity (SIA) of WHI-05 was compared with that of ZDV and nonoxynol-9 (N-9) by computer-assisted sperm analysis (CASA). The effect of WHI-05 on sperm membrane integrity was examined by high resolution, low voltage scanning electron microscopy (HR-LVSEM). The in vitro cytotoxicity profile of WHI-05 versus N-9 were compared using normal human vaginal, ectocervical, and endocervical epithelial cells. The in vivo vaginal tolerance, absorption, and toxicity of a 2% WHI-05 gel-microemulsion was tested in the rabbit. Whereas ZDV displayed potent anti-HIV activity but lacked SIA, WHI-05 elicited both potent anti-HIV activity and SIA. WHI-05 inhibited the replication of ZDV-sensitive as well as ZDV-resistant strains of HIV in PBMC. CASA combined with HR-LVSEM demonstrated that WHI-05-induced SIA was not associated with membrane damage. Unlike, N-9, the spermicidal activity of WHI-05 was not associated with cytotoxicity to reproductive tract epithelial cells. Repetitive intravaginal application of a 2% WHI-05 gel-microemulsion did not damage the vaginal epithelium or cause local inflammation in the rabbit model. As a

  5. A mixed-methods evaluation of complementary therapy services in palliative care: yoga and dance therapy.

    PubMed

    Selman, L E; Williams, J; Simms, V

    2012-01-01

    To inform service provision and future research, we evaluated two complementary therapy services: yoga classes and dance therapy [The Lebed Method (TLM)]. Both were run as 6-week group courses. Patients completed the Measure Yourself Concerns and Wellbeing questionnaire pre- and post-course. Mean change over time was calculated for patient-nominated concern and well-being scores. Qualitative data regarding factors affecting health other than the therapy and benefits of the service were analysed using content analysis. Eighteen patients participated (mean age 63.8 years; 16 female; 14 cancer diagnoses); 10 were doing yoga, five TLM, and three both yoga and TLM; 14 completed more than one assessed course. Patients' most prevalent concerns were: mobility/fitness (n= 20), breathing problems (n= 20), arm, shoulder and neck problems (n= 18), difficulty relaxing (n= 8), back/postural problems (n= 8), fear/anxiety (n= 5). Factors affecting patients' health other than the therapy were prevalent and predominantly negative (e.g. treatment side effects). Patients reported psycho-spiritual, physical and social benefits. Concern scores improved significantly (P < 0.001) for both therapies; improved well-being was clinically significant for yoga. Evaluations of group complementary therapy services are feasible, can be conducted effectively and have implications for future research. Yoga and TLM may be of benefit in this population.

  6. 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.

  7. 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…

  8. Evaluation of patient satisfaction with physical therapy following primary THA.

    PubMed

    Issa, Kimona; Naziri, Qais; Johnson, Aaron J; Memon, Talha; Dattilo, Jonathan; Harwin, Steven F; Mont, Michael A

    2013-05-01

    Physical therapy following total hip arthroplasty (THA) is intended to maximize a patient's range of motion and function and improve the quality of life. No universally accepted standard of care exists for physical therapy among physicians or therapists. However, it may be crucial to enhance efforts to more fully elucidate contributing parameters that affect patient experiences. The purpose of this study was to evaluate various factors contributing to patient satisfaction with postoperative physical therapy. One hundred consecutive patients (110 hips) who underwent THA were prospectively surveyed for satisfaction with postoperative physical therapy. All surveys were filled out anonymously by the patients, and investigators were blinded to clinical outcomes and who was surveyed. Seventy-six percent of patients reported being satisfied with their rehabilitation experiences. Factors, including patient age and sex, duration of therapy, number of patients per session, continuity of care with the same therapist, amount of hands-on time spent with the therapist, number of patients per session, and total number of sessions completed, were significantly correlated with patient satisfaction. Co-pay amount did not significantly affect patient satisfaction. These factors may be underappreciated by physicians and physical therapists. To maximize patient satisfaction with physical therapy, physicians should identify institutions whose therapists are willing to spend adequate hands-on time during one-on-one or small-group sessions while maintaining the greatest possible continuity of care with a single provider.

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

    PubMed Central

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

    2015-01-01

    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. PMID:26126533

  10. Poly(ethylene glycol) enclatherated pectin-mucin submicron matrices for intravaginal anti-HIV-1 drug delivery.

    PubMed

    Mashingaidze, Felix; Choonara, Yahya E; Kumar, Pradeep; du Toit, Lisa C; Maharaj, Vinesh; Buchmann, Eckhart; Pillay, Viness

    2016-04-30

    This paper explores the potential of polyethylene glycol enclatherated pectin-mucin (PEG-encl-PEC:MUC) submicron matrices (SMMs) as an intravaginal drug delivery system capable of delivering an anti-HIV-1 agent (zidovudine; AZT) over a prolonged duration. A three factor and three level (3(3)) Box-Behnken statistical design was employed to optimize the SMMs. Optimized PEG-encl-PEC:MUC SMMs prepared as a stable W/O emulsion (determined by the degree of reversible colloidal phenomena) were spherical with a mean particle size of 270.6 ± 5.533 nm and mean zeta potential of -34.4 ± 0.539 mV. The microencapsulation of AZT and the hydrogen bonding mediated shielding of AZT by SMMs was confirmed by Fourier Transform Infrared (FTIR) analysis. The thermochemical (differential scanning calorimetry and thermogravimetric analysis) data proposed that Ca(2+)-based macromolecular ionic crosslinking as well as the intermolecular interactions may be responsible for the thermal stability of the delivery system. The partially amorphous nature of drug-loaded SMMs, as confirmed by X-ray diffraction patterns, further strengthened the matricization of AZT into the pectin-mucin matrix. In vitro drug release studies from the SMMs showed approximately 91% zidovudine release in simulated vaginal fluid (SVF) and 94% in phosphate buffered saline (PBS) in 24h. The mean dissolution time (MDT) of zidovudine from the SMMs was 5.974 h. The attainment of required dimensional structure and drug release profiles from SMMs highlights the potential of their inclusion into a secondary carrier system for extended and controlled intravaginal stay.

  11. Promise and problems associated with the use of recombinant AAV for the delivery of anti-HIV antibodies

    PubMed Central

    Fuchs, Sebastian P; Desrosiers, Ronald C

    2016-01-01

    Attempts to elicit antibodies with potent neutralizing activity against a broad range of human immunodeficiency virus (HIV) isolates have so far proven unsuccessful. Long-term delivery of monoclonal antibodies (mAbs) with such activity is a creative alternative that circumvents the need for an immune response and has the potential for creating a long-lasting sterilizing barrier against HIV. This approach is made possible by an incredible array of potent broadly neutralizing antibodies (bnAbs) that have been identified over the last several years. Recombinant adeno-associated virus (rAAV) vectors are ideally suited for long-term delivery for a variety of reasons. The only products made from rAAV are derived from the transgenes that are put into it; as long as those products are not viewed as foreign, expression from muscle tissue may continue for decades. Thus, use of rAAV to achieve long-term delivery of anti-HIV mAbs with potent neutralizing activity against a broad range of HIV-1 isolates is emerging as a promising concept for the prevention or treatment of HIV-1 infection in humans. Experiments in mice and monkeys that have demonstrated protective efficacy against AIDS virus infection have raised hopes for the promise of this approach. However, all published experiments in monkeys have encountered unwanted immune responses to the AAV-delivered antibody, and these immune responses appear to limit the levels of delivered antibody that can be achieved. In this review, we highlight the promise of rAAV-mediated antibody delivery for the prevention or treatment of HIV infection in humans, but we also discuss the obstacles that will need to be understood and solved in order for the promise of this approach to be realized. PMID:28197421

  12. 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.

  13. 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.

  14. Correlation between microstructure and bioequivalence in anti-HIV drug efavirenz.

    PubMed

    Fandaruff, Cinira; Segatto Silva, Marcos Antônio; Galindo Bedor, Danilo Cesar; de Santana, Davi Pereira; Rocha, Helvécio Vinícius Antunes; Rebuffi, Luca; Azanza Ricardo, Cristy Leonor; Scardi, Paolo; Cuffini, Silvia Lucia

    2015-04-01

    Polymorphism and particle size distribution can impact the dissolution behaviour and, as a consequence, bioavailability and bioequivalence of poorly soluble drugs, such as Efavirenz (EFV). Nevertheless, these characteristics do not explain some failures occurring in in vitro assays and in in vivo studies. EFV belongs to Class II and the High Activity Antiretroviral Therapy (HAART) is considered the best choice in the treatment of adults and children. EFV is a drug that needs bioequivalence studies for generic compounds. In this work, six raw materials were analyzed and two of them were utilized with human volunteers (in vivo assays or bioequivalence). All the routine pharmaceutical controls of raw materials were approved; however, the reasons for the failure of the bioequivalence assay could not be explained with current knowledge. The aim of this work was to study microstructure, a solid-state property of current interest in the pharmaceutical area, in order to find an explanation for the dissolution and bioequivalence behaviour. The microstructure of EFV raw materials was studied by Whole Powder Pattern Modelling (WPPM) of X-ray powder diffraction data. Results for different EFV batches showed the biorelevance of the crystalline domain size, and a clear correlation with in vitro (dissolution tests) and in vivo assays (bioequivalence).

  15. Evaluation of vancomycin for therapy of adult pneumococcal meningitis.

    PubMed Central

    Viladrich, P F; Gudiol, F; Liñares, J; Pallarés, R; Sabaté, I; Rufí, G; Ariza, J

    1991-01-01

    The emergence of pneumococci resistant to penicillin and other agents prompted us to evaluate intravenous vancomycin for the therapy of pneumococcal meningitis, which has an overall mortality of 30%. Eleven consecutive adult patients with cerebrospinal fluid (CSF)-culture-proven pneumococcal meningitis and positive initial CSF Gram stain were given intravenous vancomycin (usual dosage, 7.5 mg/kg every 6 h for 10 days). The MBCs of vancomycin ranged from 0.25 to 0.5 micrograms/ml. Early adjunctive therapy with intravenous dexamethasone, mannitol, and sodium phenytoin was also instituted. After 48 h of therapy, all 11 patients showed a satisfactory clinical response, although the CSF culture remained positive in one case; median trough CSF and serum vancomycin levels were 2 and 5.1 micrograms/ml, respectively, and trough CSF bactericidal titers ranged from less than 1:2 to 1:16. On day 3, one patient died of acute heart failure. Four patients had clinical failure at on days 4 (two patients), 7 (one), and 8 (one) of therapy; they all immediately responded to a change in antibiotic therapy. The remaining six patients were cured after 10 days of vancomycin therapy. At this point, median peak CSF and serum vancomycin levels were 1.9 and 18.5 micrograms/ml, respectively. A transient alteration of renal function occurred in two patients, and persistent slight hypoacusia occurred in three patients. In summary, 11 adults with pneumococcal meningitis were treated with vancomycin and early adjunctive therapy including dexamethasone. All patients initially improved, and 10 were ultimately cured of the infection. However, four patients experienced a therapeutic failure, which led to a change in vancomycin therapy. PMID:1810180

  16. Computational investigation of the anti-HIV activity of Chinese medicinal formula Three-Huang Powder.

    PubMed

    Hu, Jack Z; Bai, Li; Chen, Da-Gang; Xu, Qi-Tai; Southerland, William M

    2010-06-01

    An essential step in the life cycle of human immunodeficiency virus type 1 (HIV-1) is integration of the double-stranded retroviral DNA into the genome of the host cell. HIV-1 integrase, the enzyme that inserts the vital DNA into the host chromosome, is an attractive and rational target for anti-AIDS drug design because it is essential for HIV replication and there are no known counterparts in the host cell. Inhibitors of this enzyme have the great potential to complement the therapeutic use of HIV protease and reverse transcriptase inhibitors. Natural products have provided a source of new drug candidates for anti-AIDS therapy. Baicalein and baicalin, identified components of a Chinese herbal medicine Scutellaria baicalensis Georgi, have been shown to inhibit infectivity and replication of HIV. They are therefore promising lead compounds for developing new anti-AIDS drugs. To understand how the inhibitors work and therefore design more potent and specific inhibitors, we have used molecular modeling techniques to investigate the binding modes of these inhibitors. The three-dimensional structures of these inhibitors were first built. Then, computational binding studies of these inhibitors, based on the crystal structure of the HIV-1 integrase catalytic domain, were performed to study the complex structure. The preliminary results of our computational modeling study demonstrated that Baicalein binds to the active site region of the HIV-1 integrase. Our study will be of help to identify the pharmacophores of inhibitors binding to HIV-1 integrase and design new pharmaceuticals for the treatment of AIDS.

  17. Computational Investigation of the Anti-HIV Activity of Chinese Medicinal Formula Three-Huang Powder

    PubMed Central

    Hu, Jack Z.; Bai, Li; Chen, Da-Gang; Xu, Qi-Tai; Southerland, William M.

    2011-01-01

    An essential step in the life cycle of human immunodeficiency virus type 1 (HIV-1) is integration of the double-stranded retroviral DNA into the genome of the host cell. HIV-1 integrase, the enzyme that inserts the vital DNA into the host chromosome, is an attractive and rational target for anti-AIDS drug design because it is essential for HIV replication and there are no known counterparts in the host cell. Inhibitors of this enzyme have the great potential to complement the therapeutic use of HIV protease and reverse transcriptase inhibitors. Natural products have provided a source of new drug candidates for anti-AIDS therapy. Baicalein and baicalin, identified components of a Chinese herbal medicine Scutellaria baicalensis Georgi, have been shown to inhibit infectivity and replication of HIV. They are therefore promising lead compounds for developing new anti-AIDS drugs. To understand how the inhibitors work and therefore design more potent and specific inhibitors, we have used molecular modeling techniques to investigate the binding modes of these inhibitors. The three-dimensional structures of these inhibitors were first built. Then, computational binding studies of these inhibitors, based on the crystal structure of the HIV-1 integrase catalytic domain, were performed to study the complex structure. The preliminary results of our computational modeling study demonstrated that Baicalein binds to the active site region of the HIV-1 integrase. Our study will be of help to identify the pharmacophores of inhibitors binding to HIV-1 integrase and design new pharmaceuticals for the treatment of AIDS. PMID:20640783

  18. Trimethyl chitosan improves Anti-HIV effects of Atripla as a new nano-formulated drug.

    PubMed

    Shohani, Sepideh; Abdoli, Asghar; Khansarinejad, Behzad; Ardestani, Mehdi Shafiee; Salimi-Asl, Mohammad; Ghanbari, Maryam; Haj, Mehrdad Sadeghi; Zabihollahi, Rezvan; Mondanizadeh, Mahdieh

    2016-12-16

    Background; highly active antiretroviral therapy (HAART) has been commonly used for HIV treatment. Its main drawbacks like drug resistance and side effects raised researcher's interest to find new approaches for its treatment. Trimethyl chitosan is one of the drug carriers which was introduced recently. Materials and Methods; the conjugated atripla-trimethyl chitosan was designed and characterized by zetasizer, AFM and FTIR techniques. The drug conjugation with trimethyl chitosan and cellular uptake of nano-conjugate were determined by spectrophotometry. XTT test was used to measure the cytotoxicity. Anti-retroviral efficiency was studied by ELISA test. Results; Zetasizer Results proved that the average size of nano-conjugate particles agglomeration was 493.4±24.6 nm but the size of the majority of the particles was 177.2±7.8 nm with the intensity of 87.9%. AFM technique revealed that the size of nano-conjugate and trimethyl chitosan were 129 nm and 59.78 nm, respectively. Zeta potential was -1.35±0.04 mv for nano-conjugate and -7.69±0.3 mv for drug. Conjugation efficiency of atripla with trimethyl chitosan was 5.27%. Measured cellular uptake with spectrophotometry for nano-conjugate was about twice of the free drug in examined concentrations (P=0.007). Compared to atripla, the nano-conjugate showed a higher inhibitory effect on HIV replication (P=0.0001). Conclusion; The result showed that atripla-TMC conjugate does not have a significant cytotoxicity effect. Due to the higher inhibitory effect of nano-conjugate on viral replication, it can be used in lower concentration for antiviral treatment, which resulted in reduction of drug resistance and other side effects.

  19. Cerebral vascular accident: some characteristics of occupational therapy evaluation forms.

    PubMed

    Ottenbacher, K

    1980-04-01

    To determine areas most commonly evaluated by occupational therapists and to ascertain methods in which evaluative information is gathered, 35 evaluation forms currently employed by occupational therapists to assess dysfunction in patients with cerebral vascular accident were collected. Five general areas including motor function, sensory deficit, hadn function, activities of daily living, and visual perception were found to be most frequently listed on the forms. These areas were divided into sub areas to operationally define the information collected. Analysis revealed that the level of measurement most frequently employed by therapists to record evaluate findings was the descriptive level. There was a tendency to collect data at "higher" or more sophisticated levels of measurement in those areas evaluated most frequently. The findings are discussed in relation to professional competency concerns and the need to develop unique occupational therapy evaluative instruments for areas of practice such as cerebral vascular accident.

  20. 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.

  1. Latex bead immobilisation in PDMS matrix for the detection of p53 gene point mutation and anti-HIV-1 capsid protein antibodies.

    PubMed

    Marquette, Christophe A; Degiuli, Agnès; Imbert-Laurenceau, Emmanuelle; Mallet, Francois; Chaix, Carole; Mandrand, Bernard; Blum, Loïc J

    2005-03-01

    Two diagnostic chemiluminescent biochips were developed for either the detection of p53 gene point mutation or the serological detection of anti-HIV-1 p24 capsid protein. Both biochips were composed of 24 microarrays of latex beads spots (4x4) (150 microm in diameter, 800 microm spacing) entrapped in a poly(dimethylsiloxane) elastomer (PDMS). The latex beads, bearing oligonucleotide sequences or capsid protein, were spotted with a conventional piezoelectric spotter and subsequently transferred at the PDMS interface. The electron microscopy observation of the biochips showed how homogeneous and well distributed the spots could be. Point mutation detection on the codon 273 of the p53 gene was performed on the basis of the melting temperature difference between the perfect match sequence and the one base pair mismatch sequence. The hybridisation of a 20-mer oligonucleotide form the codon 273 including a one base pair mutation in its sequence on a biochip arrayed with non-muted and the muted complementary sequences, enabled a clear discrimination at 56 degrees C between muted and wild sequences. Moreover, the quantitative measurement of the amount of muted sequence in a sample was possible in the range 0.4-4 pmol. Serological measurement of anti-HIV-1 p24 capsid protein on the biochip, prepared with 1-microm-diameter latex beads, enabled the detection of monoclonal antibodies in the range 1.55-775 ng mL(-1). Such a range could be lowered to 0.775 ng mL(-1) when using 50-nm-diameter beads, which generated a higher specific surface. The validation of the biochip for the detection of anti-HIV-1 capsid protein antibodies was performed in human sera from seropositive and seronegative patients. The positivity of the sera was easily discriminated at serum dilutions below 1:1,000.

  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. Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer.

    PubMed

    Abdel-Motal, U M; Harbison, C; Han, T; Pudney, J; Anderson, D J; Zhu, Q; Westmoreland, S; Marasco, W A

    2014-09-01

    Topical microbicides are a leading strategy for prevention of HIV mucosal infection to women; however, numerous pharmacokinetic limitations associated with coitally related dosing strategy have contributed to their limited success. Here we test the hypothesis that adeno-associated virus (AAV) mediated delivery of the b12 human anti-HIV-1 gp120 minibody gene to the lower genital tract of female rhesus macaques (Rh) can provide prolonged expression of b12 minibodies in the cervical-vaginal secretions. Gene transfer studies demonstrated that, of various green fluorescent protein (GFP)-expressing AAV serotypes, AAV-6 most efficiently transduced freshly immortalized and primary genital epithelial cells (PGECs) of female Rh in vitro. In addition, AAV-6-b12 minibody transduction of Rh PGECs led to inhibition of SHIV162p4 transmigration and virus infectivity in vitro. AAV-6-GFP could also successfully transduce vaginal epithelial cells of Rh when applied intravaginally, including p63+ epithelial stem cells. Moreover, intravaginal application of AAV-6-b12 to female Rh resulted in prolonged minibody detection in their vaginal secretions throughout the 79-day study period. These data provide proof of principle that AAV-6-mediated delivery of anti-HIV broadly neutralizing antibody (BnAb) genes to the lower genital tract of female Rh results in persistent minibody detection for several months. This strategy offers promise that an anti-HIV-1 genetic microbicide strategy may be possible in which topical application of AAV vector, with periodic reapplication as needed, may provide sustained local BnAb expression and protection.

  4. Bitter gourd (Momordica charantia) is a cornucopia of health: a review of its credited antidiabetic, anti-HIV, and antitumor properties.

    PubMed

    Fang, E F; Ng, T B

    2011-07-01

    Bitter gourd (Momordica charantia, BG) is both a nutritious and healthy food with a distinctive bitter flavor, and it is also widely exploited in folklore medicine. This review focuses on the efficacies and molecular mechanisms of BG-induced anti-diabetic, anti-HIV, and antitumor activities contributed by over twenty active components. The intent of this review is to provide comprehensive and valuable information for medicinal researchers, drug investigators, clinicians, and even patients with an interest in BG. In conclusion, BG is a cornucopia of health and it deserves in-depth investigations for clinical application in the future.

  5. Inhibition of the integrase of human immunodeficiency virus (HIV) type 1 by anti-HIV plant proteins MAP30 and GAP31.

    PubMed Central

    Lee-Huang, S; Huang, P L; Huang, P L; Bourinbaiar, A S; Chen, H C; Kung, H F

    1995-01-01

    MAP30 (Momordica anti-HIV protein of 30 kDa) and GAP31 (Gelonium anti-HIV protein of 31 kDa) are anti-HIV plant proteins that we have identified, purified, and cloned from the medicinal plants Momordica charantia and Gelonium multiflorum. These antiviral agents are capable of inhibiting infection of HIV type 1 (HIV-1) in T lymphocytes and monocytes as well as replication of the virus in already-infected cells. They are not toxic to normal uninfected cells because they are unable to enter healthy cells. MAP30 and GAP31 also possess an N-glycosidase activity on 28S ribosomal RNA and a topological activity on plasmid and viral DNAs including HIV-1 long terminal repeats (LTRs). LTRs are essential sites for integration of viral DNA into the host genome by viral integrase. We therefore investigated the effect of MAP30 and GAP31 on HIV-1 integrase. We report that both of these antiviral agents exhibit dose-dependent inhibition of HIV-1 integrase. Inhibition was observed in all of the three specific reactions catalyzed by the integrase, namely, 3' processing (specific cleavage of the dinucleotide GT from the viral substrate), strand transfer (integration), and "disintegration" (the reversal of strand transfer). Inhibition was studied by using oligonucleotide substrates with sequences corresponding to the U3 and U5 regions of HIV LTR. In the presence of 20 ng of viral substrate, 50 ng of target substrate, and 4 microM integrase, total inhibition was achieved at equimolar concentrations of the integrase and the antiviral proteins, with EC50 values of about 1 microM. Integration of viral DNA into the host chromosome is a vital step in the replicative cycle of retroviruses, including the AIDS virus. The inhibition of HIV-1 integrase by MAP30 and GAP31 suggests that impediment of viral DNA integration may play a key role in the anti-HIV activity of these plant proteins. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:7568024

  6. Synthesis and anti-HIV activity of lupane and olean-18-ene derivatives. Absolute configuration of 19,20-epoxylupanes by VCD.

    PubMed

    Gutiérrez-Nicolás, Fátima; Gordillo-Román, Bárbara; Oberti, Juan C; Estévez-Braun, Ana; Ravelo, Angel G; Joseph-Nathan, Pedro

    2012-04-27

    Lupane triterpenoids 2 and 5-12 and oleanene derivatives 13 and 14 were prepared from lupeol (1), betulin (3), and germanicol (4). They were tested for anti-HIV activity, and some structure-activity relationships were outlined. The 20-(S) absolute configuration of epoxylupenone (8) was assessed by comparison of the observed and DFT-calculated vibrational circular dichroism spectra. The CompareVOA algorithm was employed to support the C-20 configuration assignment. The 20,29 double bond in lupenone (2) and 3-epilupeol (15) was stereoselectively epoxidized to produce 20-(S)-8 and 20-(S)-16, respectively, an assignment in agreement with their X-ray diffraction structures.

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

    PubMed

    Scott, Yanille M; Park, Seo Young; Dezzutti, Charlene S

    2016-02-01

    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.

  8. Surface Modifications of Nanocarriers for Effective Intracellular Delivery of Anti-HIV Drugs

    PubMed Central

    Gunaseelan, Simi; Gunaseelan, Krishnan; Deshmukh, Manjeet; Zhang, Xiaoping; Sinko, Patrick J.

    2010-01-01

    A variety of nanocarriers such as bioconjugates, dendrimers, liposomes, and nanoparticles have been widely evaluated as potential targeted drug delivery systems. Passive targeting of nanoscale carriers is based on a size-flow-filtration phenomenon that is usually limited to tumors, the reticular endothelial system, and possibly lymph nodes (LN). In fact, targeting the delivery of drugs to pivotal physiological sites such as the lymph nodes has emerged as a promising strategy in treating HIV disease. Ligands for specific cell surface receptors can be displayed on nanocarriers in order to achieve active targeting. The approach has been extensively used preclinically in cancer where certain receptors are over-expressed at various stages of the disease. Unfortunately, markers of HIV infection are lacking and latently infected cells do not show any signs of infection on their surface. However, the disease naturally targets only a few cell types. The HIV receptor CD4, coreceptors (CCR5 and CXCR4), and some receptors relatively specific for macrophages provide potentially valuable surface targets for drug delivery to all susceptible cells in patients infected by HIV. This review focuses on nanoscale targeting with an emphasis on surface modifications of drug delivery nanocarriers for active targeting. A number of related issues, including HIV biology, targets, pharmacokinetics, and intracellular fate as well as literature-cited examples of emerging surface-modified targeted carrier systems are discussed. PMID:19941919

  9. 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

  10. 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

  11. 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.

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

    PubMed

    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.

  13. Anti-HIV, anti-poxvirus, and anti-SARS activity of a nontoxic, acidic plant extract from the Trifollium species Secomet-V/anti-vac suggests that it contains a novel broad-spectrum antiviral.

    PubMed

    Kotwal, Girish J; Kaczmarek, Jennifer N; Leivers, Steven; Ghebremariam, Yohannes T; Kulkarni, Amod P; Bauer, Gabriele; De Beer, Corena; Preiser, Wolfgang; Mohamed, Abdu Rahman

    2005-11-01

    Enveloped animal viruses such as human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus, human papillomavirus, Marburg, and influenza are major public health concerns around the world. The prohibitive cost of antiretroviral (ARV) drugs for most HIV-infected patients in sub-Saharan Africa and the serious side effects in those who have access to ARV drugs make a compelling case for the study of complementary and alternative therapies. Such therapies should have scientifically proved antiviral activity and minimal toxic effects. A plant extract, Secomet-V, with an anecdotal indication in humans for promise as an anti-HIV treatment, was investigated. Using a previously described attenuated vaccinia virus vGK5, we established the antiviral activity of Secomet-V. Chemical analysis showed that it has an acidic pH, nontoxic traces of iron (<10 ppm), and almost undetectable levels of arsenic (<1.0 ppm). The color varies from colorless to pale yellow to dark brown. The active agent is heat stable at least up to sterilizing temperature of 121 degrees C. The crude plant extract is a mixture of several small molecules separable by high-pressure liquid chromatography. The HIV viral loads were significantly reduced over several months in a few patients monitored after treatment with Secomet-V. Secomet-V was also found to have antiviral activity against the SARS virus but not against the West Nile virus. Secomet-V, therefore, is a broad-spectrum antiviral, which possibly works by neutralizing viral infectivity, resulting in the prevention of viral attachment.

  14. 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.

  15. 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

  16. 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

  17. Optimized and enhanced DNA plasmid vector based in vivo construction of a neutralizing anti-HIV-1 envelope glycoprotein Fab.

    PubMed

    Muthumani, Kar; Flingai, Seleeke; Wise, Megan; Tingey, Colleen; Ugen, Kenneth E; Weiner, David B

    2013-10-01

    Monoclonal antibody preparations have demonstrated considerable clinical utility in the treatment of specific malignancies, as well as inflammatory and infectious diseases. Antibodies are conventionally delivered by passive administration, typically requiring costly large-scale laboratory development and production. Additional limitations include the necessity for repeat administrations, and the length of in vivo potency. Therefore, the development of methods to generate therapeutic antibodies and antibody like molecules in vivo, distinct from an active antigen-based immunization strategy, would have considerable clinical utility. In fact, adeno-associated viral (AAV) vector mediated delivery of immunoglobulin genes with subsequent generation of functional antibodies has recently been developed. As well, anon-viral vector mediated nucleic acid based delivery technology could permit the generation of therapeutic/prophylactic antibodies in vivo, obviating potential safety issues associated with viral vector based gene delivery. This delivery strategy has limitations as well, mainly due to very low in vivo production and expression of protein from the delivered gene. In the study reported here we have constructed an "enhanced and optimized" DNA plasmid technology to generate immunoglobulin heavy and light chains (i.e., Fab fragments) from an established neutralizing anti-HIV envelope glycoprotein monoclonal antibody (VRC01). This "enhanced" DNA (E-DNA) plasmid technology includes codon/RNA optimization, leader sequence utilization, as well as targeted potentiation of delivery and expression of the Fab immunoglobulin genes through use of "adaptive" in vivo electroporation. The results demonstrate that delivery by this method of a single administration of the optimized Fab expressing constructs resulted in generation of Fab molecules in mouse sera possessing high antigen specific binding and HIV neutralization activity for at least 7 d after injection, against diverse

  18. 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.

  19. Culture and its influence on occupational therapy evaluation.

    PubMed

    Paul, S

    1995-08-01

    In the increasingly multicultural society of north America, occupational therapists have a responsibility to develop awareness and knowledge concerning different cultural groups. By accepting and understanding clients' customs, values and beliefs, clinicians have a better chance of assessing and producing more effective outcomes. Since occupational therapy has incorporated western middle-class values into its theory and practice, many evaluation tools used are based on norms developed for a white middle-class population. Using these evaluations with minority groups brings the danger of improper interpretation of test results. Consequently, increasing emphasis is being placed on the importance of culture fairness and the development of culture-fair evaluation tools for usage across different cultural groups. This paper will present a discussion concerning the importance, advantages and disadvantages of both culture-fair and culture-specific tests and evaluation tools.

  20. Synthesis of new 2′-deoxy-2′-fluoro-4′-azido nucleoside analogues as potent anti-HIV agents

    PubMed Central

    Wang, Qiang; Hu, Weidong; Wang, Shuyang; Pan, Zhenliang; Tao, Le; Guo, Xiaohe; Qian, Keduo; Chen, Chin-Ho; Lee, Kuo-Hsiung; Chang, Junbiao

    2011-01-01

    We prepared 1-(4′-azido-2′-deoxy-2′-fluoro-β -D-arabinofuranosyl)cytosine (10) and its hydrochloride salt (11) as potential antiviral agents based on the favorable antiviral profiles of 4′-substituted nucleosides. Compounds 10 and 11 were synthesized from 1,3,5-O-tribenzoyl-2-deoxy-2-fluoro-D-arabinofuranoside in multiple steps, and their structures were unequivocally established by IR, 1H NMR, 13C NMR, and 19F NMR spectroscopy, HRMS, and X-ray crystallography. Compounds 10 and 11 exhibited potent anti-HIV-1 activity (EC50: 0.3 and 0.13 nM, respectively) without significant cytotoxicity in concentrations up to 100 μM. Compound 11 exhibited extremely potent anti-HIV activity against NL4-3 (wild-type), NL4-3 (K101E), and RTMDR viral strains, with EC50 values of 0.086, 0.15, and 0.11 nM, respectively. Due to the high potency of 11, it was also screened against an NIH Reagent Program NRTI-resistant virus panel containing eleven mutated viral strains and for cytotoxicity against six different human cell lines. The results of this screening indicated that 11 is a novel NRTI that could be developed as an anti-AIDS clinical trial candidate to overcome drug-resistance issues. PMID:21745701

  1. 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.

  2. Anti-HIV antibody in saliva: an assessment of the role of the components of saliva, testing methodologies and collection systems.

    PubMed

    Lamey, P J; Nolan, A; Follett, E A; Coote, I; MacFarlane, T W; Kennedy, D H; Connell, A; Parry, J V

    1996-03-01

    The various components of saliva, namely mixed saliva, parotid saliva, submandibular saliva, crevicular fluid and minor (labial) gland secretions, were collected from 63 known HIV antibody seropositive patients. A commercial test system, Wellcozyme HIV 1+2, and an antibody capture ELISA (GACELISA), were compared for sensitivity against all components. Sensitivity of the GACELISA system was 100% in 123 mixed saliva, 121 parotid saliva and 127 labial fluid samples, and 98% in 99 submandibular samples and 127 crevicular fluid samples. Respective figures for Wellcozyme 1+2 were 92%, 55%, 73%, 66% and 63%. Mixed saliva was most easily, conveniently and effectively collected using a plain Salivette. In 241 Salivette samples examined from the 63 patients, GACELISA proved 100% sensitive, and Wellcozyme 95% sensitive. Another form of Salivette impregnated with citric acid was unsuitable for GACELISA and gave a false negative value of 45%. In 197 samples from the gingival margin taken by a dry swab, GACELISA showed a sensitivity of 98% and Wellcozyme 81%. The most sensitive method for demonstrating anti-HIV antibody in saliva is to collect mixed saliva with the plain Salivette system and assay anti-HIV antibody levels by GACELISA.

  3. An Effective Vaccination Approach Augments anti-HIV Systemic and Vaginal Immunity in Mice with Decreased HIV-1 Susceptible α4β7high CD4+ T Cells

    PubMed Central

    Zhu, Wei; Shi, Guoping; Tang, Haijun; Lewis, Dorothy E; Song, Xiao-Tong

    2013-01-01

    HIV-1 preferentially infects activated CD4+ T cells expressing α4β7 integrin and conventional vaccination approaches non-selectively induce immune responses including α4β7high CD4+ T cells, suggesting that current candidate AIDS vaccines may produce more target cells for HIV-1 and paradoxically enhance HIV-1 infection. Thus it remains a challenge to selectively induce robust anti-HIV immunity without the unwanted HIV-1 susceptible α4β7high CD4+ T cells. Here we describe a vaccination strategy that targets ALDH1a2, a retinoic acid producing enzyme in dendritic cells (DCs). Silencing ALDH1a2 in DCs enhanced the maturation and production of proinflammatory cytokines of DCs and promoted Th1/Th2 differentiation while suppressing Treg. ALDH1a2-silenced DCs effectively downregulated the expression of guthoming receptors α4β7 and CCR9 on activated T and B lymphocytes. Consequently, intranasal immunization of a lentiviral vaccine encoding ALDH1a2 shRNA and HIV-1 gp140 redirected gp140-specific mucosal T cell and antibody responses from the gut to the vaginal tract, while dramatically enhancing systemic gp140-specific immune responses. We further demonstrated that silencing ALDH1a2 in human DCs resulted in downregulation of β7 expression on activated autologous CD4+ T cells. Hence this study provides a unique and effective strategy to induce α4β7low anti-HIV immune responses. PMID:23157585

  4. An effective vaccination approach augments anti-HIV systemic and vaginal immunity in mice with decreased HIV-1 susceptible α4β7high CD4+ T cells.

    PubMed

    Zhu, Wei; Shi, Guoping; Tang, Haijun; Lewis, Dorothy E; Song, Xiao-Tong

    2013-01-01

    HIV-1 preferentially infects activated CD4(+) T cells expressing α4β7 integrin and conventional vaccination approaches non-selectively induce immune responses including α4β7(high) CD4(+) T cells, suggesting that current candidate AIDS vaccines may produce more target cells for HIV-1 and paradoxically enhance HIV-1 infection. Thus it remains a challenge to selectively induce robust anti-HIV immunity without the unwanted HIV-1 susceptible α4β77(high) CD4(+)+ T cells. Here we describe a vaccination strategy that targets ALDH1a2, a retinoic acid producing enzyme in dendritic cells (DCs). Silencing ALDH1a2 in DCs enhanced the maturation and production of proinflammatory cytokines of DCs and promoted Th1/Th2 differentiation while suppressing Treg. ALDH1a2-silenced DCs effectively downregulated the expression of guthoming receptors α4β77 and CCR9 on activated T and B lymphocytes. Consequently, intranasal immunization of a lentiviral vaccine encoding ALDH1a2 shRNA and HIV-1 gp140 redirected gp140-specific mucosal T cell and antibody responses from the gut to the vaginal tract, while dramatically enhancing systemic gp140-specific immune responses. We further demonstrated that silencing ALDH1a2 in human DCs resulted in downregulation of β7 expression on activated autologous CD4(+) T cells. Hence this study provides a unique and effective strategy to induce α4β7(low) anti-HIV immune responses.

  5. Concise synthesis and anti-HIV activity of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic heterocycles.

    PubMed

    Mizuhara, Tsukasa; Oishi, Shinya; Ohno, Hiroaki; Shimura, Kazuya; Matsuoka, Masao; Fujii, Nobutaka

    2012-09-07

    3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is a virucidal heterocyclic compound active against various viruses, including HCV, HIV, and simian immunodeficiency virus. Using facile synthetic approaches that we developed for the synthesis of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic derivatives, the parallel structural optimizations of the central 1,3-thiazin-2-imine core, the benzene part, and the cyclic amidine part of PD 404182 were investigated. Replacement of the 6-6-6 pyrimido[1,2-c][1,3]benzothiazin-6-imine framework with 5-6-6 or 6-6-5 derivatives led to a significant loss of anti-HIV activity, and introduction of a hydrophobic group at the 9- or 10-positions improved the potency. In addition, we demonstrated that the PD 404182 derivative exerts anti-HIV effects at an early stage of viral infection.

  6. Medicinal attributes of Solanum xanthocarpum fruit consumed by several tribal communities as food: an in vitro antioxidant, anticancer and anti HIV perspective

    PubMed Central

    2014-01-01

    Background Solanum xanthocarpum (Solanaceae) has been used for treatment of many infectious and degenerative diseases in traditional medicine. Present study reports the medicinal efficacy of S. xanthocarpum fruit as antioxidant, anticancer and anti HIV agents. Methods Extracts were prepared using Soxhlet apparatus and partially characterized by thin layer chromatography (TLC). Total flavonoid content was determined spectrophotometrically. Reducing power, DPPH radical scavenging activity and lipid peroxidation inhibition assays were used for measurement of antioxidant potential. Cytotoxic (SRB assay) and anti-HIV RT inhibition (RT assay kit, Roche) activities were determined using ELISA. Results TLC revealed the diversity of phytoconstituents in various sequential extracts of S. xanthocarpum fruit. Total flavonoid contents in extracts ranged between 10.22–162.49 μg quercetin equivalent/mg. Spectroscopic scanning of water soluble phenolics showed maximum absorbance at 250 and 280 nm. Polar extracts displayed potent radical scavenging activity (>80%). Several sub-fractions (spots) of extracts separated on TLC plates also exhibited powerful radical scavenging activity. Considerable reducing power was observed in extracts. Hexane fraction provided 55% lipoprotection in rat kidney homogenate. Non-polar extracts exhibited appreciable cytotoxic activity (70-91%) against leukemia (THP-1) and lung cancer (HOP-62) cell lines. Lower inhibitory activity was observed in extracts against HIV Reverse Transcriptase enzyme. Conclusion The study demonstrated considerable antioxidant and anticancer activities in S. xanthocarpum fruit. PMID:24678980

  7. 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.

  8. [Safety evaluation of Chinese medicine on tumor therapy].

    PubMed

    Liu, Rui; Hua, Bao-Jin; Li, Jie

    2013-12-01

    As a characteristic tumor therapy in China, Chinese medicine (CM) plays an important position in comprehensive treatment of tumor. It's a critical issue of objective realization, analysis and evaluation of CM safety for scientific decision-making in tumor safe medication and it also is a pivotal issue which affects the international communication. The safety evaluation of CM includes three phases: pre-clinical safety evaluation, clinical trials (micro-dose studies and traditional clinical trials) and post-marketing CM safety assessment. The key point of evaluation should be distinguished among different stages and various types of CM (such as classic formulas, Chinese herbal extracts, etc). Emphasis should be given to chronic toxicity when evaluating oral Chinese herbal , microdose studies and quality control must be underlined while injection is evaluated and more attention should be pay to the dose-effect relationship and time-effect relationship when turned to toxic Chinese medicine , and so as for the toxicity grading study. Moreover, we should constantly improve CM safety assessment method in various stages of tumor treatment, such as introducing the concept of syndrome classification theory, bringing in metabonomics and real-world research method which are similar to the CM therapeutic concept. Most importantly, we must keep its own feature of CM theory when we learn the concept of safety evaluation from abroad. Actively exploring the anti-tumor medicine safety evaluation methods and strategies is of great significance for clinical and experimental research, and it can provide supportability platform to CM's international communication.

  9. 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.

  10. Evaluation of a continuous quality improvement program in anticoagulant therapy

    PubMed Central

    Cantin, Ariane; Lahaie, Alexandre; Odobasic, Bojan; Tremblay, Marie-Philip; Wazzan, Dana; Caron, Stéphanie; Leblanc, Caroline; Martineau, Josée; Lalonde, Lyne

    2016-01-01

    Background: The ACO Program (Programme ACO), a continuous quality improvement program (CQIP) in anticoagulation therapy, was offered in community pharmacies as a pilot project. Objective: To evaluate the participants’ appreciation for the various activities of the program. Methods: Participants had access to training activities, including an audit with feedback, online training activities (OTA), clinical tools and support from facilitators. Cognitive behavioural learning determinants were evaluated before and 5 months after the beginning of the program. Participants’ satisfaction and perception were documented via online questionnaires and a semistructured interview. Results: Of the 52 pharmacists in the ACO Program, 47 participated in this evaluation. Seventy-seven percent of the participants completed at least 1 OTA and 6% published on the forum. The feeling of personal effectiveness rose from 8.01 (7.67-8.35) to 8.62 (8.24-8.99). The audit and feedback, as well as the high-quality OTA and their lecturers, were the most appreciated elements. Discussion: There was a high OTA participation rate. The facilitators seemed to play a key role in the CQIP. The low level of participation in the forum reflects the known phenomenon of social loafing. Technical difficulties affecting the platform and data collection for the audit with feedback constituted limitations. Conclusion: The CQIP in anticoagulation therapy is appreciated by community pharmacists and is associated with an improved feeling of personal effectiveness. PMID:27829859

  11. 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.

  12. Convergence of voices: assimilation in linguistic therapy of evaluation.

    PubMed

    Gabalda, Isabel Caro

    2009-01-01

    This paper shows the convergence of voices in psychotherapy in the context of the assimilation model. Convergence is the link between patients' voices within the community of voices. The main aim of the paper was to explore (a) how convergence (and divergence) is shown during sessions and the usefulness of convergence for the process of assimilation; (b) if a well-structured patient is able to track the sociohistorical antecedents of his/her main voices; and (c) if, at the end of the therapy, the self becomes richer and with more resources.For this aim to be realized, a case study of a patient, María, treated with linguistic therapy of evaluation for 14 sessions, was analysed by using the Assimilation of Problematic Experiences Scale (APES). Three main problematic experiences or non-dominant voices were identified with the APES: inability to do things, dizziness and tiredness. María's main dominant voices were to cure, solve and overcome problems, to be always doing things and to cope.Results showed a convergence but no divergence of voices as early as session 3. Results also showed how continuity-benevolence assumptions were broken and that, at the end of therapy, the patient's self became richer due to assimilation through the dialogue between non-dominant and dominant voices.Discussion emphasized these results, which are especially representative of a well-integrated patient who showed a healthy multiplicity.

  13. 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…

  14. 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.

  15. Note on the formulation of thermosensitive and mucoadhesive vaginal hydrogels containing the miniCD4 M48U1 as anti-HIV-1 microbicide.

    PubMed

    Bouchemal, Kawthar; Frelichowska, Justyna; Martin, Loïc; Lievin-Le Moal, Vanessa; Le Grand, Roger; Dereuddre-Bosquet, Nathalie; Djabourov, Madeleine; Aka-Any-Grah, Armelle; Koffi, Armand; Ponchel, Gilles

    2013-10-01

    The miniCD4 M48U1 was formulated into thermosensitive and mucoadhesive pluronic(®) hydrogels as anti-HIV-1 microbicide. The release kinetics of M48U1 from F127/HPMC (20/1 wt%) and F127/F68/HPMC (22.5/2.5/1 wt%) studied during 24h by using Franz diffusion cells showed that HEC hydrogel (1.5 wt%) used as control released 93% of the peptide, while about 25% of M48U1 remained in pluronic(®) hydrogels. The formulation of M48U1 in pluronic(®) hydrogels ensures a local delivery because no diffusion of the peptide was detected through vaginal Cynomolgus macaque mucosa using Ussing chamber. Finally, toxicological studies showed no significant difference in the HeLa cell viability of the pluronic(®) hydrogels in comparison with HEC and phosphate buffer saline.

  16. [Significance of the control serum measurement in infectious disease tests--a case of lot-to-lot variation of anti-HIV antibody assay kit].

    PubMed

    Sasaki, Miho; Sasaki, Kenji

    2002-07-01

    We are using infectious disease test kits consisting of positive serum diluted with negative pooled serum (P-S) and positive control (P-C). In two anti-HIV antibody tests the results for both P-S and P-C fluctuated between positive and negative depending on the lot No. of the reagent. In Western blot tests carried out to confirm the tests, the P-C was found to be positive and the P-S tests were both inconclusive. We speculated that the P-S had very weak antibodies that reacted differently from patient samples. Manufacturers of such kits, however, must supply reagents with appropriate reactivity, so it is important that they be informed of inconsistencies that could invalidate cut-off values and lead to false-positives and false-negatives.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. Autoimmune anti-HIV-1gp120 antibody with antiidiotype-like activity in sera and immune complexes of HIV-1-related immunologic thrombocytopenia.

    PubMed Central

    Karpatkin, S; Nardi, M

    1992-01-01

    Autoimmune antiidiotype-like antibody (Ab2) directed against anti-HIV-1gp120 (Ab1) was found in high titer in the sera of 10 consecutive homosexual and 11 narcotic addict HIV-1-related immunologic thrombocytopenia (HIV-1-ITP) patients, was barely detectable in 10 nonthrombocytopenic HIV-1 sero-positive individuals, and was not detectable in 5 normal subjects by use of a solid-phase RIA. Reactivity of autologous Ab2 for Ab1 was 4-120-fold greater than Ab2 for homologous Ab1. Affinity-purified Ab2 did not block the binding of affinity-purified Ab1 to its HIV-1gp120 epitopes on immunoblot, indicating the absence of "internal image" antiidiotype. Both Ab1 and Ab2 are precipitable from sera with polyethylene glycol (PEG) and present in a macromolecular complex that is excluded by gel filtration on G200 and contains IgG, IgM, C3, and the anti-F(ab')2 antiidiotype-like complex. PEG-precipitable complexes bind to platelets in a saturation-dependent manner. Neither affinity-purified Ab1 nor Ab2 binds to platelets. However, the combination of Ab1 and Ab2 (preincubated for 2 h at 22 degrees C) binds to platelets in a saturation-dependent manner at an optimum ratio range of 10-20:1. Ab2 reactivity correlates with serum PEG-precipitable immune complex level (r = 0.91; P less than 0.001) and with thrombocytopenia (r = 0.89; P less than 0.001). We suggest that the anti-HIV-1gp120 antiidiotype-like complex contributes to the markedly elevated platelet Ig and C3 level of HIV-1-ITP patients and propose that this may contribute to their thrombocytopenia. Images PMID:1737832

  2. Reconstructive surgery in immunocompromised patients: evaluation and therapy

    PubMed Central

    Dunda, Sebastian E.; Bozkurt, Ahmet; Pallua, Norbert; Krapohl, Björn Dirk

    2015-01-01

    Background: An increasing number of patients undergoing reconstructive surgery are immunocompromised due to different reasons and different medical treatments. Some of the used immunosuppressive drugs may affect the process of wound healing and thereby, impair the long-term success of surgical treatment. Therefore, this retrospective analysis aimed at the evaluation of the perioperative treatment and surgical outcome of immunocompromised patients undergoing different reconstructive procedures. Methods: A retrospective review was performed of 8 immunocompromised patients with different primary diseases who needed reconstructive surgery: 2 patients with non-Hodgkin lymphoma, 1 patient with an acute myeloid leukemia, 1 patient with colitis ulcerosa, 1 patient with liver cirrhosis, 1 patient with chronic polyarthritis, and 2 patients with malignant melanoma. Results: In 7 of our 8 presented cases, multiple operations with wound debridements have been necessary to optimize the granulation of the wound bed before reconstructive surgery. 3 out of these 7 patients required further operations due to wound dehiscence or necrosis, with 2 of them as a result of increased immunosuppressive therapy. 5 out of 8 patients needed no further surgical treatment. Conclusions: Both the perioperative drug therapy and the reconstructive surgery concept need to be determined carefully in each individual case of the immunocompromised patients. Thus, the appropriate point in time of operation to achieve the best possible wound healing as well as the complexity of the procedure will require the consideration of a ‘less is more’ strategy in selected cases. PMID:26734539

  3. 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.

  4. 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

  5. Prospects for the therapeutic application of lentivirus-based gene therapy to HIV-1 infection.

    PubMed

    Yamamoto, Takuya; Tsunetsugu-Yokota, Yasuko

    2008-02-01

    Highly active antiretroviral therapy is not sufficient to fully control HIV replication and problems of side effects and escape mutation have emerged. Current prophylactic and therapeutic vaccine strategies appear to be unable to confer full protection. However, given the rapid recent progress made in RNA interference and lentivirus technologies, it may soon be possible to develop effective gene therapies against HIV infection. We describe here the recent progress made in the lentivirus-based HIV-1-targeting RNAi system and the possibility that this system can be used to generate an anti-HIV-1 gene therapy. We speculate that this system would be most useful if it would be used in a coordinated manner with vaccines that can initiate and maintain potent anti-HIV immunity.

  6. Evaluation of Oxidative Status in Patients Treated with Electroconvulsive Therapy

    PubMed Central

    Şenyurt, Mahmut; Aybek, Hulya; Herken, Hasan; Kaptanoglu, Bunyamin; Korkmaz, Ali

    2017-01-01

    Objective Electroconvulsive therapy (ECT) is used in the treatment of many psychiatric diseases and this therapy may be effective on antioxidant defence system. In this study, we aimed to evaluate the effects of ECT on oxidative stress. Methods Fourteen major depression, 11 schizophrenia and 8 bipolar affective disorder patients diagnosed and received ECT treatment, and 37 healthy volunteers enrolled in the study. ECT was applied to all patients. Before ECT, after the first and last ECTs, serum samples were obtained. Serum total antioxidant status (TAS), total oxidant status (TOS), and calculated oxidative stress index (OSI) were measured in patients before and after ECTs. Results TOS values before ECT were higher in major depression (p=0.005) and schizophrenia (p=0.001) groups compared to the control group. TAS values were lower in major depression (p=0.0001), schizophrenia (p=0.004), bipolar affective disorder (p=0.004) groups compared to the controls. Also OSI values were higher in major depression (p=0.0001), schizophrenia (p=0.001), bipolar affective disorder (p=0.009) groups compared to healthy group. After the last ECT, TOS values were significantly lower compared to TOS values before ECT in major depression (p=0.004) and schizophrenia patients (p=0.004). TAS values after the first ECT were higher compared to values before ECT in major depression patients (p=0.004). After last ECT, OSI values were significantly lower compared to before ECT in schizophrenia patients (p=0.006). Conclusion As a result, it can be said that ECT did not increase oxidative stress. However, further studies with more patients are needed. PMID:28138109

  7. A novel PET tracer for evaluation of gene therapy

    SciTech Connect

    Goldman, S.; Monclus, M.; Cool, V.

    1996-05-01

    A promising approach of gene therapy for cancer consist in the transduction of neoplastic cells with the herpes virus thymidine-kinase gene (HSV-tk) which renders transduced cells sensitive to the lethal effect of anti-viral agent such as ganciclovir (GCV). Pet with adapted radiotracers represents an adequate tool to determine in vivo the level of HSV-tk expression and to establish the optimal protocol of gene and GCV administrations in human. We have developed a new potential PET tracer, 9-((1-[F-18]fluoro-3-hydroxy-2-propoxy)methyl)guanine [F-18]FHPG should theoretically accumulate in cells expressing HSV-tk. [F-18]FHPG was obtained by nucleophilic substitution on a ditosylate precursor followed by hydrolysis. To determine the biological behavior of this compound, we synthetized the corresponding non radioactive fluorinated analog (FHPG) and tested its inhibitory activity on HSV-tk transduced 9L gliosarcoma cells maintained in culture. FHPG at 100 {mu}M suppress cell growth by 50% while GCV and acyclovir induced 100% suppression at 10 and 100 {mu}M, respectively. We then tested the in vitro uptake of n.c.a. [F-18]FHPG in cultured cells transduced with HSV-tk or a control gene (neomycin). Ratio of [F-18]FHPG uptake in HSV-tk versus control cells was 240 after 6 hours of incubation. In vivo uptake of [F-18]FHPG was tested in experimental tumors obtained by stereotactical implantion of transduced 9L cells in the brain of male Fischer 344 rats. Ratio of [F-18]FHPG uptake in HSV-tk versus control tumors was 2.5, 3 hours after intravenous tracer injection. Uptake in HSV-tk tumor was 19-fold higher than in the cortex. We concluded that [F-18]FHPG is a promising PET tracer for the evaluation of gene therapy involving viral thymidine kinase genes.

  8. Evaluating older patients with diabetes for insulin pump therapy.

    PubMed

    Stephens, Elizabeth A; Heffner, John

    2010-06-01

    The increasing prevalence of diabetes among elderly patients underscores the importance of matching the most effective therapy for diabetes self-management with patients' cognitive and motor skills, as these diminish with advancing age. Although many geriatric patients state interest in insulin pump therapy for tight glycemic control, few studies have examined the effectiveness, safety, and feasibility of insulin pumps compared to traditional injected insulin therapy in older age groups. It is important, therefore, for physicians to recognize the indications and the age-related barriers to insulin pump therapy in geriatric patients. Indications include glucose variability, hypoglycemia, and poor glycemic control with traditional insulin regimens. Common barriers include poor vision, dexterity, and cognitive status. Successful implementation of insulin pump therapy for older patients requires an experienced diabetes management team that can assess patient needs and tailor therapy in the context of age-related disabilities.

  9. 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.

  10. Evaluation of selection criteria for graduate students in radiation therapy.

    PubMed

    Schneider-Kolsky, Michal; Wright, Caroline; Baird, Marilyn

    2006-12-01

    Selection of suitable students into graduate medical and specialist health professional courses can be difficult. Historically, selection of students was primarily based on prior academic performance. Recently, however, more emphasis has been placed on considering broader academic backgrounds and personal characteristics and attitudes of students, but no reliable measurement tool is available to predict student success and satisfaction with their choice of profession. The aim of this study was to survey practising radiation therapists in Australia to seek their opinions regarding suitable selection criteria for graduate entry radiation therapy (RT) students in order to optimize selection procedures for future applicants. Four hundred questionnaires were sent to nine RT centres in three states within Australia. All nine clinics participated in the survey and 189 questionnaires were returned. Results show that the majority of radiation therapists place a high level of importance upon a sound knowledge of physics and mathematics, as well as life experience, and agree that a visit to an RT clinic plus an interview comprise important components of the selection process. Humanities, psychology and a psychometric test were not viewed as essential entry requirements. Experienced radiation therapists placed less value on academic performance in the primary degree and were more likely to include an interview as a selection criterion than junior practitioners. Empathy for patients was identified as the most important personal attribute. It is thus recommended that not only cognitive but also personal skills be evaluated during the selection of prospective radiation therapists.

  11. Porcine Neonatal Coccidiosis: Evaluation of Monensin as Preventive Therapy

    PubMed Central

    Doré, Monique; Morin, Michel

    1987-01-01

    In this study, we evaluated the efficacy of monensin as a preventive therapy for porcine neonatal coccidiosis. Fifteen three-day-old piglets were given 50,000 sporulated oocysts of Isospora suis and eight of them received 15 mg/kg of monensin orally every other day. Seven piglets served as normal controls. Fecal samples were collected and checked for oocyst shedding. At 18 days of age, piglets were euthanized and necropsied. The onset of clinical signs was delayed in the treated group, but all inoculated piglets displayed anorexia, soft stool, or diarrheic feces. Treated piglets shed large numbers of oocysts in their feces (up to 201,200 oocysts per gram of feces). All infected piglets had lesions of villous atrophy in the jejunum and most of them were in the late atrophic or villous regrowth stages. The results of this study suggest that monensin does not prevent clinical signs, oocyst shedding, and intestinal lesions caused by I. suis in neonatal piglets. PMID:17422909

  12. Stem-Cell-Based Gene Therapy for HIV Infection

    PubMed Central

    Zhen, Anjie; Kitchen, Scott

    2013-01-01

    Despite the enormous success of combined anti-retroviral therapy, HIV infection is still a lifelong disease and continues to spread rapidly worldwide. There is a pressing need to develop a treatment that will cure HIV infection. Recent progress in stem cell manipulation and advancements in humanized mouse models have allowed rapid developments of gene therapy for HIV treatment. In this review, we will discuss two aspects of HIV gene therapy using human hematopoietic stem cells. The first is to generate immune systems resistant to HIV infection while the second strategy involves enhancing anti-HIV immunity to eliminate HIV infected cells. PMID:24368413

  13. Stem-cell-based gene therapy for HIV infection.

    PubMed

    Zhen, Anjie; Kitchen, Scott

    2013-12-24

    Despite the enormous success of combined anti-retroviral therapy, HIV infection is still a lifelong disease and continues to spread rapidly worldwide. There is a pressing need to develop a treatment that will cure HIV infection. Recent progress in stem cell manipulation and advancements in humanized mouse models have allowed rapid developments of gene therapy for HIV treatment. In this review, we will discuss two aspects of HIV gene therapy using human hematopoietic stem cells. The first is to generate immune systems resistant to HIV infection while the second strategy involves enhancing anti-HIV immunity to eliminate HIV infected cells.

  14. 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…

  15. Broadening the use of antiretroviral therapy: the case for feline leukemia virus

    PubMed Central

    Greggs, Willie M; Clouser, Christine L; Patterson, Steven E; Mansky, Louis M

    2011-01-01

    Antiretroviral drugs have saved and extended the lives of millions of individuals infected with HIV. The major classes of anti-HIV drugs include reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and entry/fusion inhibitors. While antiretroviral drug regimens are not commonly used to treat other types of retroviral infections, there are instances where there is a perceived need for re-evaluation of the benefits of antiretroviral therapy. One case in point is that of feline leukemia virus (FeLV), an infection of companion felines. While vaccines exist to prevent FeLV infection and spread, they have not eliminated FeLV infection. For FeLV-infected felines and their human companions, antiretroviral therapy would be desirable and of practical importance if good options were available. Here, we discuss FeLV biology and current treatment options, and propose that there is a need for antiretroviral treatment options for FeLV infection. The comparative use and analysis of antiretroviral therapy can provide new insights into the mechanism of antiretroviral drug action. PMID:21479142

  16. 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

  17. Differences in the mannose oligomer specificities of the closely related lectins from Galanthus nivalis and Zea mays strongly determine their eventual anti-HIV activity

    PubMed Central

    2011-01-01

    Background In a recent report, the carbohydrate-binding specificities of the plant lectins Galanthus nivalis (GNA) and the closely related lectin from Zea mays (GNAmaize) were determined by glycan array analysis and indicated that GNAmaize recognizes complex-type N-glycans whereas GNA has specificity towards high-mannose-type glycans. Both lectins are tetrameric proteins sharing 64% sequence similarity. Results GNAmaize appeared to be ~20- to 100-fold less inhibitory than GNA against HIV infection, syncytia formation between persistently HIV-1-infected HuT-78 cells and uninfected CD4+ T-lymphocyte SupT1 cells, HIV-1 capture by DC-SIGN and subsequent transmission of DC-SIGN-captured virions to uninfected CD4+ T-lymphocyte cells. In contrast to GNA, which preferentially selects for virus strains with deleted high-mannose-type glycans on gp120, prolonged exposure of HIV-1 to dose-escalating concentrations of GNAmaize selected for mutant virus strains in which one complex-type glycan of gp120 was deleted. Surface Plasmon Resonance (SPR) analysis revealed that GNA and GNAmaize interact with HIV IIIB gp120 with affinity constants (KD) of 0.33 nM and 34 nM, respectively. Whereas immobilized GNA specifically binds mannose oligomers, GNAmaize selectively binds complex-type GlcNAcβ1,2Man oligomers. Also, epitope mapping experiments revealed that GNA and the mannose-specific mAb 2G12 can independently bind from GNAmaize to gp120, whereas GNAmaize cannot efficiently bind to gp120 that contained prebound PHA-E (GlcNAcβ1,2man specific) or SNA (NeuAcα2,6X specific). Conclusion The markedly reduced anti-HIV activity of GNAmaize compared to GNA can be explained by the profound shift in glycan recognition and the disappearance of carbohydrate-binding sites in GNAmaize that have high affinity for mannose oligomers. These findings underscore the need for mannose oligomer recognition of therapeutics to be endowed with anti-HIV activity and that mannose, but not complex-type glycan

  18. 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

  19. Dosimetric evaluation of whole-breast radiation therapy: Clinical experience

    SciTech Connect

    Osei, Ernest; Darko, Johnson; Fleck, Andre; White, Jana; Kiciak, Alexander; Redekop, Rachel; Gopaul, Darin

    2015-01-01

    Radiation therapy of the intact breast is the standard therapy for preventing local recurrence of early-stage breast cancer following breast conservation surgery. To improve patient standard of care, there is a need to define a consistent and transparent treatment path for all patients that reduces significance variations in the acceptability of treatment plans. There is lack of consistency among institutions or individuals about what is considered an acceptable treatment plan: target coverage vis-à-vis dose to organs at risk (OAR). Clinical trials usually resolve these issues, as the criteria for an acceptable plan within the trial (target coverage and doses to OAR) are well defined. We developed an institutional criterion for accepting breast treatment plans in 2006 after analyzing treatment data of approximately 200 patients. The purpose of this article is to report on the dosimetric review of 623 patients treated in the last 18 months to evaluate the effectiveness of the previously developed plan acceptability criteria and any possible changes necessary to further improve patient care. The mean patient age is 61.6 years (range: 25.2 to 93.0 years). The mean breast separation for all the patients is 21.0 cm (range: 12.4 to 34.9 cm), and the mean planning target volume (PTV-eval) (breast volume for evaluation) is 884.0 cm{sup 3} (range: 73.6 to 3684.6 cm{sup 3}). Overall, 314 (50.4%) patients had the disease in the left breast and 309 (49.6%) had it in the right breast. A total of 147 (23.6%) patients were treated using the deep inspiration breath-hold (DIBH) technique. The mean normalized PTV-eval receiving at least 92% (V{sub 92%} {sub PD}) and 95% (V{sub 95%} {sub PD}) of the prescribed dose (PD) are more than 99% and 97%, respectively, for all patients. The mean normalized PTV-eval receiving at least 105% (V{sub 105%} {sub PD}) of the PD is less than 1% for all groups. The mean homogeneity index (HI), uniformity index (UI), and conformity index (CI) for the

  20. Novel recombinant engineered gp41 N-terminal heptad repeat trimers and their potential as anti-HIV-1 therapeutics or microbicides.

    PubMed

    Chen, Xi; Lu, Lu; Qi, Zhi; Lu, Hong; Wang, Ji; Yu, Xiaoxia; Chen, Yinghua; Jiang, Shibo

    2010-08-13

    Peptides derived from N-terminal heptad repeat (NHR) of the HIV-1 gp41 are generally poor inhibitors of HIV-1 entry, because they tend to aggregate and do not form a trimeric coiled-coil. In this study, we have fused portions of gp41 NHR, e.g. N36 or N28, to the T4 fibritin trimerization domain, Foldon (Fd), thus constructing novel NHR trimers, designated N36Fd or N28Fd, which could be expressed in Escherichia coli cells. The purified N36Fd and N28Fd exhibited SDS-resistant trimeric coiled-coil conformation with improved alpha-helicity compared with the corresponding N-peptides. They could interact with a C-peptide (e.g. C34) to form stable six-helix bundle and possessed potent anti-HIV-1 activity against a broad spectrum of HIV-1 strains. N28Fd was effective against T20-resistant HIV-1 variants and more resistant to proteinase K compared with T20 (enfuvirtide), a C-peptide-based HIV fusion inhibitor. Therefore, N28Fd trimer has great potentials for further development as an affordable therapeutic or microbicide for treatment and prevention of HIV-1 infection.

  1. [Secreted phospholipases A2 (sPLA2): friends or foes? Are they actors in antibacterial and anti-HIV resistance?].

    PubMed

    Villarrubia, Vicente G; Costa, Luis A; Díez, Roberto A

    2004-11-27

    In this paper the authors update on the deletereous or beneficial roles of human and animal secretory phospholipases A2 (sPLA2). Although human sPLA2-IIA (inflammatory) was initially thought as a foe because its pathogenic implication in sepsis, multiorganic failure or other related syndromes, recent data indicates its role in in the antiinfectious host resistance. Thus, sPLA2-IIA exhibits potent bactericidal activities against gram-negative and gram-positive (in this case, together with other endogenous inflammatory factors) bacteria. Surprisingly, human sPLA-IIA does not show in vitro anti-human immunodeficiency virus (HIV) activity, whilst several sPLA2-IA isolated from bee and serpent venons do it: this is the case for crotoxin, a sPLA2-IA isolated from the venon of Crotalus durissus terrificus (sPLA2-Cdt). The mechanism for the in vitro anti-HIV activity of sPLA2-Cdt (inhibition of Gag p24) appears to be related to the ability of the drug to desestabilize ancorage (heparans) and fusion (cholesterol) receptors on HIV target cells.

  2. Medicinal chemistry discoveries among 1,3,5-triazines: recent advances (2000-2013) as antimicrobial, anti-TB, anti-HIV and antimalarials.

    PubMed

    Patel, Rahul V; Keum, Young-Soo; Park, Se Won

    2014-01-01

    The chemistry and an extensive spectrum of biological activities of s-triazines have been examined since several decades and this heterocyclic core has received emerging consensus. This article aims to summarize recent advances (2000-2013) made towards the discovery of antimicrobial, antituberculosis, anti-HIV and antimalarial agents holding 1,3,5-triazine ring as a nucleus with the substitution of several types of nucleophiles. Molecular patterns associated with particular potency have been identified targeting several Gram-positive and Gram-negative bacteria and some fungal species, mycobacterium tuberculosis H37Rv, HIV type I and HIV type II, particularly, HIV-1I IIB and HIV- 1ROD strains as well as a variety of P. falciparum malarial strains as chloroquine-resistant K1, chloroquine-susceptible NF54, chloroquine-sensitive 3D7, P. falciparum (D6 clone), P. falciparum (W2 clone), cycloguanil-resistant FCR-3, chloroquine sensitive RKL2. The report will be of considerable interest to gain useful information for the furtherance of drug discovery with extended 1,3,5-triazine designs.

  3. Correlation between digestion of the lipid phase of smedds and release of the anti-HIV drug UC 781 and the anti-mycotic drug enilconazole from smedds.

    PubMed

    Goddeeris, C; Coacci, J; Van den Mooter, G

    2007-05-01

    The present studies were conducted primarily to compare the drug release process of the anti-HIV drug UC781 from three different smedds to the smedds digestion profile. The influence of every formulation component on the digestion process, measured as the release of fatty acids, was determined. In addition, the release of the antimycotic drug enilconazole from a smedds was investigated as well in order to study the influence of the type of incorporated drug on oil digestion. Simulsol 1292, Tween 80, Cremophor RH40, ethanol and both drugs reduced the fatty acid release. C8, C10 and C12 fatty acids, originating from oil hydrolysis, were able to reverse the inhibitory effect of phospholipids present in the release medium. Similarly Cremophor RH40 lost its inhibitory capacities in combination with Captex 200P hydrolysis. In addition, UC781 did not decrease fatty acid release in combination with a Captex 200P-Tween 80-ethanol mixture. The release of UC781 from smedds significantly increased compared to the dissolution of the pure drug. The drug release profiles were characterized by rapid and complete release followed by precipitation. In order to detect possible correlations between drug release and oil digestion, release results were compared to those of vehicle digestion experiments. Contrary to what one would assume, a higher extent of fatty acid liberation did not enhance drug release. In other words, drug release does not seem to be driven by the extent of lipid digestion.

  4. 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.

  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. Tunable release of multiclass anti-HIV drugs that are water-soluble and loaded at high drug content in polyester blended electrospun fibers

    PubMed Central

    Carson, Daniel; Jiang, Yonghou; Woodrow, Kim

    2015-01-01

    Objectives Sustained release of small molecule hydrophilic drugs at high doses remains difficult to achieve from electrospun fibers and limits their use in clinical applications. Here we investigate tunable release of several water-soluble anti-HIV drugs from electrospun fibers fabricated with blends of two biodegradable polyesters. Methods Drug-loaded fibers were fabricated by electrospinning using ratios of PCL and PLGA. Fiber morphology was imaged using SEM, and DSC was used to measure thermal properties. HPLC was used to measure drug loading and release from fibers. Cytotoxicity and antiviral activity of drug-loaded fibers were measured in an in vitro cell culture assay. Results We show programmable release of hydrophilic antiretroviral drugs loaded up to 40 wt%. Incremental tuning of highly-loaded drug fibers within 24 hours or >30 days was achieved by controlling the ratio of PCL and PLGA. Fiber compositions containing higher PCL content yielded greater burst release whereas fibers with higher PLGA content resulted in greater sustained release kinetics. We also demonstrated that our drug-loaded fibers are safe and can sustain inhibition of HIV in vitro. Conclusions These data suggest that we were able to overcome current limitations associated with sustained release of small hydrophilic drugs at clinically relevant doses. We expect that our system represents an effective strategy to sustain delivery of water-soluble molecules that will benefit a variety of biomedical applications. PMID:26286184

  7. 3D-QSAR analysis of a series of S-DABO derivatives as anti-HIV agents by CoMFA and CoMSIA.

    PubMed

    Xu, H R; Fu, L; Zhan, P; Liu, X Y

    2016-12-01

    In this study, we retrieved a series of 59 dihydroalkylthio-benzyloxopyrimidine (S-DABO) derivatives, which is a class of highly potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) reported from published articles, and analysed them with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Statistically significant three-dimensional quantitative structure-activity relationship (3D-QSAR) models by CoMFA and CoMSIA were derived from a training set of 46 compounds on the basis of the rigid body alignment. Further, the predictive ability of the QSAR models was validated by a test set of 13 compounds. Based on the information derived from CoMFA and CoMSIA contour maps, we have identified some steric and electrostatic features for improving the activities of these inhibitors, and we validated the 3D-QSAR results by a molecular docking method. On the basis of the obtained results, we designed a new series of S-DABO derivatives with high activities. Therefore, this study could be utilized to design more potent S-DABO analogues as anti-HIV agents.

  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. 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…

  11. 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…

  12. Physical and hormonal evaluation of transsexual patients during hormonal therapy.

    PubMed

    Meyer, W J; Finkelstein, J W; Stuart, C A; Webb, A; Smith, E R; Payer, A F; Walker, P A

    1981-08-01

    The optimal hormonal therapy for transsexual patients is not known. The physical and hormonal characteristics of 38 noncastrate male-to-female transsexuals and 14 noncastrate female-to-male transsexuals have been measured before and/or during therapy with various forms and dosages of hormonal therapy. All patients were hormonally and physically normal prior to therapy. Ethinyl estradiol was superior to conjugated estrogen in suppression of testosterone and gonadotropins but equal in effecting breast growth. The changes in physical and hormonal characteristics were the same for 0.1 mg/d and 0.5 mg/d of ethinyl estradiol. The female-to-male transsexuals were well managed with a dose of intramuscular testosterone cypionate of 400 mg/month, usually given 200 mg every two weeks. The maximal clitoral length reached was usually 4 cm. Higher doses of testosterone did not further increase clitoral length or suppression of gonadotropins; lower doses did not suppress the gonadotropins. Based on the information found in this study, we recommend 0.1 mg/d of ethinyl estradiol for the noncastrate male-to-female transsexual and 200 mg of intramuscular testosterone cypionate every two weeks for the noncastrate female-to-male transsexual.

  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. 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.

  15. 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

  16. 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.

  17. A candidate anti-HIV reservoir compound, auranofin, exerts a selective 'anti-memory' effect by exploiting the baseline oxidative status of lymphocytes.

    PubMed

    Chirullo, B; Sgarbanti, R; Limongi, D; Shytaj, I L; Alvarez, D; Das, B; Boe, A; DaFonseca, S; Chomont, N; Liotta, L; Petricoin, E Iii; Norelli, S; Pelosi, E; Garaci, E; Savarino, A; Palamara, A T

    2013-12-05

    Central memory (T(CM)) and transitional memory (T(TM)) CD4(+) T cells are known to be the major cellular reservoirs for HIV, as these cells can harbor a transcriptionally silent form of viral DNA that is not targeted by either the immune system or current antiretroviral drug regimens. In the present study, we explored the molecular bases of the anti-HIV reservoir effects of auranofin (AF), a pro-oxidant gold-based drug and a candidate compound for a cure of AIDS. We here show that T(CM) and T(TM) lymphocytes have lower baseline antioxidant defenses as compared with their naive counterpart. These differences are mirrored by the effects exerted by AF on T-lymphocytes: AF was able to exert a pro-differentiating and pro-apoptotic effect, which was more pronounced in the memory subsets. AF induced an early activation of the p38 mitogen-activated protein kinase (p38 MAPK) followed by mitochondrial depolarization and a final burst in intracellular peroxides. The pro-differentiating effect was characterized by a downregulation of the CD27 marker expression. Interestingly, AF-induced apoptosis was inhibited by pyruvate, a well-known peroxide scavenger, but pyruvate did not inhibit the pro-differentiating effect of AF, indicating that the pro-apoptotic and pro-differentiating effects involve different pathways. In conclusion, our results demonstrate that AF selectively targets the T(CM)/T(TM) lymphocyte subsets, which encompass the HIV reservoir, by affecting redox-sensitive cell death pathways.

  18. Expression of deoxynucleotide carrier is not associated with the mitochondrial DNA depletion caused by anti-HIV dideoxynucleoside analogs and mitochondrial dNTP uptake.

    PubMed

    Lam, Wing; Chen, ChinShing; Ruan, Shuolun; Leung, Chung-Hang; Cheng, Yung-Chi

    2005-02-01

    Our previous studies suggested that the dNTP/dNDP transporter systems that exist in mitochondria for transporting dNTP/dNDP from the cytoplasm to the mitochondria for mitochondrial DNA (mtDNA) synthesis play a critical role in delayed cytotoxicity of anti-human immunodeficiency virus (HIV) dideoxynucleoside analogs in mitochondria. A protein, termed mitochondrial deoxynucleotide carrier (DNC), based on its ability to transport dNTPs in reconstituted proteoliposomes, was recently isolated. Lacking cellular information to substantiate DNC's involvement in the delayed cytotoxicity of dideoxynucleoside analogs, we expressed DNC and reconstituted it into proteoliposomes. The K(m) values for dNTPs uptake by reconstituted DNC were in the millimolar range, which is a thousandfold higher than that of the physiological level. Furthermore, we found that overexpressing DNC (wt and G177A-mutated DNC) in RKO cells did not sensitize the cells to the mtDNA depletion caused by beta-d-2',3'-dideoxycytidine (ddC), 2',3'-didehydro-2',3'-dideoxythymidine, and 2',3'-dideoxyinosine or affect the mtDNA recovery rate after ddC treatment. Mitochondria isolated from DNC-overexpressing cells did not significantly differ from that isolated from RKO cells in terms of the rate of uptake or the incorporation of dTTP into mitochondria DNA. Down-regulation of DNC expression by small interfering RNA was also ineffective in changing the action of dideoxynucleoside analogs on the mtDNA depletion and the rate of dTTP uptake into isolated mitochondria. Down-regulation of both DNC and thymidine kinase-2 also did not cause mtDNA depletion. We conclude that DNC does not play an important role in the delayed cytotoxicity (mtDNA depletion) of anti-HIV dideoxynucleoside analogs and dNTPs uptake into mitochondria.

  19. Identification of Effective Subdominant Anti-HIV-1 CD8+ T Cells Within Entire Post-infection and Post-vaccination Immune Responses

    PubMed Central

    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

    2015-01-01

    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

  20. A solution NMR study of the interactions of oligomannosides and the anti-HIV-1 2G12 antibody reveals distinct binding modes for branched ligands.

    PubMed

    Enríquez-Navas, Pedro M; Marradi, Marco; Padro, Daniel; Angulo, Jesús; Penadés, Soledad

    2011-02-01

    The structural and affinity details of the interactions of synthetic oligomannosides, linear (di-, tri-, and tetra-) and branched (penta- and hepta-), with the broadly neutralizing anti-HIV-1 antibody 2G12 (HIV=human immunodeficiency virus) have been investigated in solution by using ligand-based NMR techniques, specifically saturation transfer difference (STD) NMR spectroscopy and transferred NOE experiments. Linear oligomannosides show similar binding modes to the antibody, with the nonreducing terminal disaccharide Manα(1→2)Man (Man=mannose) making the closest protein/ligand contacts in the bound state. In contrast, the branched pentamannoside shows two alternate binding modes, involving both ligand arms (D2- and D3-like), a dual binding description of the molecular recognition of this ligand by 2G12 in solution that differs from the single binding mode deduced from X-ray studies. On the contrary, the antibody shows an unexpected selectivity for one arm (D1-like) of the other branched ligand (heptamannoside). This result explains the previously reported lack of affinity enhancement relative to that of the D1-like tetramannoside. Single-ligand STD NMR titration experiments revealed noticeable differences in binding affinities among the linear and branched ligands in solution, with the latter showing decreased affinity. Among the analyzed series of ligands, the strongest 2G12 binders were the linear tri- and tetramannosides because both show similar affinity for the antibody. These results demonstrate that NMR spectroscopic techniques can deliver abundant structural, dynamics, and affinity information for the characterization of oligomannose-2G12 binding in solution, thus complementing, and, as in the case of the pentamannoside, extending, the structural view from X-ray crystallography. This information is of key importance for the development of multivalent synthetic gp120 high-mannose glycoconjugate mimics in the context of vaccine development.

  1. Binary and ternary combinations of anti-HIV protease inhibitors: effect on gene expression and functional activity of CYP3A4 and efflux transporters

    PubMed Central

    Kwatra, Deep; Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Khurana, Varun; Pal, Dhananjay; Mitra, Ashim K.

    2015-01-01

    Background The purpose of this study is to identify the effect of binary and ternary combinations of anti-HIV protease inhibitors (PIs) on the expression of metabolizing enzyme (CYP3A4) and efflux transporters [multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)] in a model intestinal cell line (LS-180). Methods LS-180 cells were treated with various combinations of PIs (amprenavir, indinavir, saquinavir and lopinavir), and the mRNA expression levels of metabolizing enzyme and efflux transporters were measured using quantitative reverse transcription polymerase chain reaction. The alteration of gene expression was further correlated to the expression of nuclear hormone receptor PXR. Uptake of fluorescent and radioactive substrates was carried out to study the functional activity of these proteins. Cytotoxicity and adenosine triphosphate (ATP) assays were carried out to measure stress responses. Results Binary and ternary combinations of PIs appeared to modulate the expression of CYP3A4, MRP2, P-gp and BCRP in a considerable manner. Unlike the individual PIs, their binary combinations showed much greater induction of metabolizing enzyme and efflux proteins. However, such pronounced induction was not observed in the presence of ternary combinations. The observed trend of altered mRNA expression was found to correlate well with the change in expression levels of PXR. The gene expression was found to correlate with activity assays. Lack of cytotoxicity and ATP activity was observed in the treatment samples, suggesting that these alterations in expression levels were probably not stress responses. Conclusions In the present study, we demonstrated that combinations of drugs can have serious consequences toward the treatment of HIV infection by altering their bioavailability and disposition. PMID:24399676

  2. The mechanism of phosphorylation of natural nucleosides and anti-HIV analogues by nucleoside diphosphate kinase is independent of their sugar substituents.

    PubMed

    Hutter, Michael C; Helms, Volkhard

    2002-07-02

    The reaction mechanism of the phosphoryl transfer catalyzed by dinucleoside diphosphate kinase from Dictyostelium discoideum is investigated by semiempirical AM1 molecular orbital computation of an active site model system on the basis of various X-ray crystallographic structures. The computational results suggest that the phosphoryl transfer from adenosine triphosphate to the His122 residue is accompanied by the simultaneous shift of a proton from the histidine residue to one of the oxygen atoms of the gamma phosphate group. This involves a doubly protonated His122 residue whilst this residue is neutral in its ternary complex with ADP and the transition state analogue AlF(3). The proposed mechanism is thus analogous to that of phosphoryl transfer by cyclic adenosine monophosphate dependent protein kinase and uridine/cytidine monophosphate kinase as found in our earlier work and clarifies the role of the ribose 3'-OH group. Furthermore, the energetics of phosphoryl transfer onto other nucleoside analogues such as 3'-azido-3'-deoxythymidine-diphosphate and 2',3'-dideoxy-2',3'-didehydro-thymidine-diphosphate are investigated. The calculated reaction barriers for the phosphorylation of the diphosphates by the enzyme are all within a range of 13.1 kJ mol(-1), which suggests that variations in the activation energies alone cannot account for the experimentally observed differences in enzymatic activity. Consequences for the design of new anti-HIV nucleoside analogues are discussed. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2268/2002/f360_s.pdf or from the author.

  3. Anti-HIV-1 Activity Prediction of Novel Gp41 Inhibitors Using Structure-Based Virtual Screening and Molecular Dynamics Simulation.

    PubMed

    Sepehri, Saghi; Saghaie, Lotfollah; Fassihi, Afshin

    2017-03-01

    The fusion of viral and host cell membranes is mediated using gp41 subunit of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein. As the HIV-1 enters the host cells, the two helical regions (HR1 and HR2) in the ectodomain of gp41 form a six-helix bundle, which carries the target and viral cell membranes to close proximity. Steps of this process serve as attractive targets for developing HIV-1 fusion inhibitors. Identification of some novel HIV fusion inhibitors with the goal of blocking the formation of the six-helix bundle was accomplished by computer-aided drug design techniques. A virtual screening strategy was employed to recognize small molecules presumably able to bind the gp41 at the internal interface of the NHR helices at the core native viral six-helix. This study was carried out in two stages. In the first stage, a library of more than seven thousand compounds was collected from ZINC, PubChem and BindingDB databases and protein data bank. Key contacts of known inhibitors with gp41 binding site residues were considered as the collecting criteria. In the second stage series of filtering processes were performed on this library in subsequent steps to find the potential gp41 inhibitors. The filtering criteria included pharmacokinetic and ADMET properties as well as in silico anti-HIV-1 prediction. Molecular docking simulation was carried out to identify interactions of the filtered molecules with the key residues in the gp41 binding site. Finally, molecular dynamics simulation indicates the superior inhibitory ability of three selected compounds over the known gp41inhibitor, NB-64.

  4. Epitope Mapping of Ibalizumab, a Humanized Anti-CD4 Monoclonal Antibody with Anti-HIV-1 Activity in Infected Patients▿

    PubMed Central

    Song, Ruijiang; Franco, David; Kao, Chia-Ying; Yu, Faye; Huang, Yaoxing; Ho, David D.

    2010-01-01

    Ibalizumab is a humanized monoclonal antibody that binds human CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1). With its unique specificity for domain 2 of CD4, this antibody potently and broadly blocks HIV-1 infection in vitro by inhibiting a postbinding step required for viral entry but without interfering with major histocompatibility complex class II (MHC-II)-mediated immune function. In clinical trials, ibalizumab has demonstrated anti-HIV-1 activity in patients without causing immunosuppression. Thus, a characterization of the ibalizumab epitope was conducted in an attempt to gain insight into the underlying mechanism of its antiviral activity as well as its safety profile. By studying mouse/human chimeric CD4 molecules and site-directed point mutants of CD4, amino acids L96, P121, P122, and Q163 in domain 2 were found to be important for ibalizumab binding, with E77 and S79 in domain 1 also contributing. All these residues appear to cluster on the interface between domains 1 and 2 of human CD4 on a surface opposite the site where gp120 and the MHC-II molecule bind on domain 1. Separately, the epitope of M-T441, a weakly neutralizing mouse monoclonal antibody that competes with ibalizumab, was localized entirely within domain 2 on residues 123 to 125 and 138 to 140. The results reported herein not only provide an appreciation for why ibalizumab has not had significant adverse immunological consequences in infected patients to date but also raise possible steric hindrance mechanisms by which this antibody blocks HIV-1 entry into a CD4-positive cell. PMID:20463063

  5. Epitope mapping of ibalizumab, a humanized anti-CD4 monoclonal antibody with anti-HIV-1 activity in infected patients.

    PubMed

    Song, Ruijiang; Franco, David; Kao, Chia-Ying; Yu, Faye; Huang, Yaoxing; Ho, David D

    2010-07-01

    Ibalizumab is a humanized monoclonal antibody that binds human CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1). With its unique specificity for domain 2 of CD4, this antibody potently and broadly blocks HIV-1 infection in vitro by inhibiting a postbinding step required for viral entry but without interfering with major histocompatibility complex class II (MHC-II)-mediated immune function. In clinical trials, ibalizumab has demonstrated anti-HIV-1 activity in patients without causing immunosuppression. Thus, a characterization of the ibalizumab epitope was conducted in an attempt to gain insight into the underlying mechanism of its antiviral activity as well as its safety profile. By studying mouse/human chimeric CD4 molecules and site-directed point mutants of CD4, amino acids L96, P121, P122, and Q163 in domain 2 were found to be important for ibalizumab binding, with E77 and S79 in domain 1 also contributing. All these residues appear to cluster on the interface between domains 1 and 2 of human CD4 on a surface opposite the site where gp120 and the MHC-II molecule bind on domain 1. Separately, the epitope of M-T441, a weakly neutralizing mouse monoclonal antibody that competes with ibalizumab, was localized entirely within domain 2 on residues 123 to 125 and 138 to 140. The results reported herein not only provide an appreciation for why ibalizumab has not had significant adverse immunological consequences in infected patients to date but also raise possible steric hindrance mechanisms by which this antibody blocks HIV-1 entry into a CD4-positive cell.

  6. Developing a community-level anti-HIV/AIDS stigma and homophobia intervention in new York city: The project CHHANGE model.

    PubMed

    Frye, Victoria; Paige, Mark Q; Gordon, Steven; Matthews, David; Musgrave, Geneva; Kornegay, Mark; Greene, Emily; Phelan, Jo C; Koblin, Beryl A; Taylor-Akutagawa, Vaughn

    2017-03-19

    HIV/AIDS stigma and homophobia are associated with significant negative health and social outcomes among people living with HIV/AIDS (PLWHA) and those at risk of infection. Interventions to decrease HIV stigma have focused on providing information and education, changing attitudes and values, and increasing contact with people living with HIV/AIDS (PLWHA), activities that act to reduce stereotyped beliefs and prejudice, as well as acts of discrimination. Most anti-homophobia interventions have focused on bullying reduction and have been implemented at the secondary and post-secondary education levels. Few interventions address HIV stigma and homophobia and operate at the community level. Project CHHANGE, Challenge HIV Stigma and Homophobia and Gain Empowerment, was a community-level, multi-component anti-HIV/AIDS stigma and homophobia intervention designed to reduce HIV stigma and homophobia thus increasing access to HIV prevention and treatment access. The theory-based intervention included three primary components: workshops and trainings with local residents, businesses and community-based organizations (CBO); space-based events at a CBO-partner drop-in storefront and "pop-up" street-based events and outreach; and a bus shelter ad campaign. This paper describes the intervention design process, resultant intervention and the study team's experiences working with the community. We conclude that CHHANGE was feasible and acceptable to the community. Promoting the labeling of gay and/or HIV-related "space" as a non-stigmatized, community resource, as well as providing opportunities for residents to have contact with targeted groups and to understand how HIV stigma and homophobia relate to HIV/AIDS prevalence in their neighborhood may be crucial components of successful anti-stigma and discrimination programming.

  7. Combinatorial de novo design and application of a biomimetic affinity ligand for the purification of human anti-HIV mAb 4E10 from transgenic tobacco.

    PubMed

    Platis, Dimitris; Maltezos, Anastasios; Ma, Julian K-C; Labrou, Nikolaos E

    2009-01-01

    Monoclonal anti-HIV antibody 4E10 (mAb 4E10) is one of the most broadly neutralizing antibodies against HIV, directed against a specific epitope on envelope protein gp41. In the present study, a combinatorial de novo design approach was used for the development of a biomimetic ligand for the affinity purification of mAb 4E10 from tobacco transgenic extract in a single chromatographic step. The biomimetic ligand (4E10lig) was based on a L-Phe/beta-Ala bi-substituted 1,3,5-triazine (Trz) scaffold (beta-Ala-Trz-L-Phe, 4E10lig) which potentially mimics the more pronounced electrostatic and hydrophobic interactions of mAb 4E10-binding sequence determined by screening of a random peptide library. This library was comprised of Escherichia coli cells harboring a plasmid (pFlitrx) engineered to express a fusion protein containing random dodecapeptides that were inserted into the active loop of thioredoxin, which itself was inserted into the dispensable region of the flagellin gene. Adsorption equilibrium studies with this biomimetic ligand and mAb 4E10 determined a dissociation constant (K(D)) of 0.41 +/- 0.05 microM. Molecular modeling studies of the biomimetic ligand revealed that it can potentially occupy the same binding site as the natural binding core peptide epitope. The biomimetic affinity adsorbent was exploited in the development of a facile mAb 4E10 purification protocol, affording mAb 4E10 of high purity (approximately 95%) with good overall yield (60-80%). Analysis of the antibody preparation by SDS-PAGE, enzyme-linked immunosorbent assays (ELISA), and western blot showed that the mAb 4E10 was fully active and free of degraded variants, polyphenols, and alkaloids.

  8. Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma

    PubMed Central

    Kraft, John C.; McConnachie, Lisa A.; Koehn, Josefin; Kinman, Loren; Collins, Carol; Shen, Danny D.; Collier, Ann C.; Ho, Rodney J.Y.

    2017-01-01

    Objective: The aim of the present study was to determine whether a combination of anti-HIV drugs – tenofovir (TFV), lopinavir (LPV) and ritonavir (RTV) – in a lipid-stabilized nanosuspension (called TLC-ART101) could enhance and sustain intracellular drug levels and exposures in lymph node and blood cells above those in plasma. Design: Four macaques were given a single dose of TLC-ART101 subcutaneously. Drug concentrations in plasma and mononuclear cells of the blood (PBMCs) and lymph nodes (LNMCs) were analysed using a validated combination LC-MS/MS assay. Results: For the two active drugs (TFV, LPV), plasma and PBMC intracellular drug levels persisted for over 2 weeks; PBMC drug exposures were three- to four-fold higher than those in plasma. Apparent terminal half-lives (t1/2) of TFV and LPV were 65.3 and 476.9 h in plasma, and 169.1 and 151.2 h in PBMCs. At 24 and 192 h, TFV and LPV drug levels in LNMCs were up to 79-fold higher than those in PBMCs. Analysis of PBMC intracellular TFV and its active metabolite TFV-diphosphate (TFV-DP) indicated that intracellular exposures of total TFV and TFV-DP were markedly higher and persisted longer than in humans and macaques dosed with oral TFV prodrugs, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). Conclusions: A simple, scalable three-drug combination, lipid-stabilized nanosuspension exhibited persistent drug levels in cells of lymph nodes and the blood (HIV host cells) and in plasma. With appropriate dose adjustment, TLC-ART101 may be a useful HIV treatment with a potential to impact residual virus in lymph nodes. PMID:28099191

  9. Pharmacokinetic and Metabolic Characteristics of Herb-Derived Khellactone Derivatives, A Class of Anti-HIV and Anti-Hypertensive: A Review.

    PubMed

    Jing, Wanghui; Liu, Ruilin; Du, Wei; Luo, Zhimin; Guo, Pengqi; Zhang, Ting; Zeng, Aiguo; Chang, Chun; Fu, Qiang

    2016-03-08

    A vast number of structural modifications have been performed for khellactone derivatives (KDs) that have been widely concerned owing to their diverse biological properties, including anti-hypertension, anti-HIV, reversing P-glycoprotein (P-gp) mediated multidrug resistance, and anti-inflammation effects, to find the most active entity. However, extensive metabolism of KDs results in poor oral bioavailability, thus hindering the clinical trial performance of those components. The primary metabolic pathways have been revealed as hydrolysis, oxidation, acyl migration, and glucuronidation, while carboxylesterases and cytochrome P450 3A (CPY3A), as well as UDP-glucuronosyltransferases (UGTs) primarily mediate these metabolic pathways. Attention was mainly paid to the pharmacological features, therapeutic mechanisms and structure-activity relationships of KDs in previous reviews, whereas their pharmacokinetic and metabolic characteristics have seldom been discussed. In the present review, KDs' metabolism and their pharmacokinetic properties are summarized. In addition, the structure-metabolism relationships of KDs and the potential drug-drug interactions (DDIs) induced by KDs were also extensively discussed. The polarity, the acyl groups substituted at C-3' and C-4' positions, the configuration of C-3' and C-4', and the moieties substituted at C-3 and C-4 positions play the determinant roles for the metabolic profiles of KDs. Contributions from CYP3A4, UGT1A1, P-gp, and multidrug resistance-associated protein 2 have been disclosed to be primary for the potential DDIs. The review is expected to provide meaningful information and helpful guidelines for the further development of KDs.

  10. 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.

  11. Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine.

    PubMed

    Ghare, Smita S; Donde, Hridgandh; Chen, Wei-Yang; Barker, David F; Gobejishvilli, Leila; McClain, Craig J; Barve, Shirish S; Joshi-Barve, Swati

    2016-09-01

    Zidovudine (AZT) remains the mainstay of antiretroviral therapy against HIV in resource-poor countries; however, its use is frequently associated with hepatotoxicity. Not all HIV patients on AZT develop hepatotoxicity, and the determining factors are unclear. Alcohol consumption and cigarette smoking are known risk factors for HIV hepatotoxicity, and both are significant sources of acrolein, a highly reactive and toxic aldehyde. This study examines the potential hepatotoxic interactions between acrolein and AZT. Our data demonstrate that acrolein markedly enhanced AZT-induced transcriptionally permissive histone modifications (H3K9Ac and H3K9Me3) allowing the recruitment of transcription factor NF-kB and RNA polymerase II at the FasL gene promoter, resulting in FasL upregulation and apoptosis in hepatocytes. Notably, the acrolein scavenger, hydralazine prevented these promoter-associated epigenetic changes and inhibited FasL upregulation and apoptosis induced by the combination of AZT and acrolein, as well as AZT alone. Our data strongly suggest that acrolein enhancement of promoter histone modifications and FasL upregulation are major pathogenic mechanisms driving AZT-induced hepatotoxicity. Moreover, these data also indicate the therapeutic potential of hydralazine in mitigating AZT hepatotoxicity.

  12. 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.

  13. Breathing evaluation and retraining as an adjunct to manual therapy.

    PubMed

    McLaughlin, Laurie; Goldsmith, Charlie H; Coleman, Kimberly

    2011-02-01

    Back and neck pain are extremely common reasons for patients seeking manual therapy treatment. Epidemiological evidence supports a link between breathing difficulties and back pain. Since trunk muscles perform both postural and breathing functions, it is theorized that disruption in one function can negatively impact the other. Altered breathing mechanics can change respiratory chemistry and therefore pH causing smooth muscle constriction, altered electrolyte balance and decreased tissue oxygenation. These changes can profoundly impact any body system. Increased excitability in the muscular and nervous systems may be most relevant to a manual therapist. Respiratory function can be tested via capnography which measures CO₂ at the end of exhale known as End Tidal CO₂ (ETCO₂). ETCO₂ closely reflects arterial CO₂ in people with normal cardiopulmonary function. A case series of twenty nine outpatients with neck or back pain who had plateaued with manual therapy and exercise were identified all of whom were found to have low ETCO₂. Breathing retraining improved ETCO₂, pain and function in all patients with 93% achieving at least a clinically important change in either pain or function. Screening for breathing dysfunction using capnography may improve patient outcomes in those patients where manual therapy, exercise and education do not provide full resolution of symptoms.

  14. 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.

  15. Prediction and Early Evaluation of Anticancer Therapy Response: From Imaging of Drug Efflux Pumps to Targeted Therapy Response.

    PubMed

    Meng, Qingqing; Li, Zheng; Li, Shaoshun

    2016-01-01

    Multidrug resistance (MDR) describes the resistance of tumor cells to chemotherapy and has been ascribed to the overexpression of drug efflux pumps. Molecular imaging of drug efflux pumps is helpful to identify the patients who may be resistant to the chemotherapy and thus will avoid the unnecessary treatment and increase the therapeutic effectiveness. Imaging probes targeting drug efflux pumps can non-invasively evaluate the Pgp function and play an important role in identification of MDR, prediction of response, and monitoring MDR modulation. On the other hand, new anticancer agents based on molecular targets such as epidermal growth factor receptor (EGFR) and angiogenic factor receptor may potentially be combined with chemotherapeutic drugs to overcome the MDR. Imaging of molecular targets visualize treatment response of patients at molecular level vividly and help to select right patients for certain targeted anticancer therapy. Among all the imaging modalities, nuclear imaging including positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging has the greatest promise for rapid translation to the clinic and can realize quantitative visualization of biochemical processes in vivo. In this review, we will summarize the nuclear imaging probes utilized for predicting and evaluating the early anticancer therapy response.99mTc labeled agents and PET based radiopharmaceuticals like 18F-Paclitaxel, 11C-Verapamil for drug efflux pumps imaging will be discussed here. Moreover, molecular imaging probes used for targeted therapy response evaluation like 18F-Tamoxifen,89Zr-Trastuzumab will also be introduced in this review.

  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. A Method for Evaluating Quality Assurance Needs in Radiation Therapy

    SciTech Connect

    Huq, M. Saiful Fraass, Benedick A.; Dunscombe, Peter B.; Gibbons, John P.; Ibbott, Geoffrey S.; Medin, Paul M.; Mundt, Arno; Mutic, Sassa; Palta, Jatinder R.; Thomadsen, Bruce R.; Williamson, Jeffrey F.; Yorke, Ellen D.

    2008-05-01

    The increasing complexity of modern radiation therapy planning and delivery techniques challenges traditional prescriptive quality control and quality assurance programs that ensure safety and reliability of treatment planning and delivery systems under all clinical scenarios. Until now quality management (QM) guidelines published by concerned organizations (e.g., American Association of Physicists in Medicine [AAPM], European Society for Therapeutic Radiology and Oncology [ESTRO], International Atomic Energy Agency [IAEA]) have focused on monitoring functional performance of radiotherapy equipment by measurable parameters, with tolerances set at strict but achievable values. In the modern environment, however, the number and sophistication of possible tests and measurements have increased dramatically. There is a need to prioritize QM activities in a way that will strike a balance between being reasonably achievable and optimally beneficial to patients. A systematic understanding of possible errors over the course of a radiation therapy treatment and the potential clinical impact of each is needed to direct limited resources in such a way to produce maximal benefit to the quality of patient care. Task Group 100 of the AAPM has taken a broad view of these issues and is developing a framework for designing QM activities, and hence allocating resources, based on estimates of clinical outcome, risk assessment, and failure modes. The report will provide guidelines on risk assessment approaches with emphasis on failure mode and effect analysis (FMEA) and an achievable QM program based on risk analysis. Examples of FMEA to intensity-modulated radiation therapy and high-dose-rate brachytherapy are presented. Recommendations on how to apply this new approach to individual clinics and further research and development will also be discussed.

  18. A method for evaluating quality assurance needs in radiation therapy.

    PubMed

    Huq, M Saiful; Fraass, Benedick A; Dunscombe, Peter B; Gibbons, John P; Ibbott, Geoffrey S; Medin, Paul M; Mundt, Arno; Mutic, Sassa; Palta, Jatinder R; Thomadsen, Bruce R; Williamson, Jeffrey F; Yorke, Ellen D

    2008-01-01

    The increasing complexity of modern radiation therapy planning and delivery techniques challenges traditional prescriptive quality control and quality assurance programs that ensure safety and reliability of treatment planning and delivery systems under all clinical scenarios. Until now quality management (QM) guidelines published by concerned organizations (e.g., American Association of Physicists in Medicine [AAPM], European Society for Therapeutic Radiology and Oncology [ESTRO], International Atomic Energy Agency [IAEA]) have focused on monitoring functional performance of radiotherapy equipment by measurable parameters, with tolerances set at strict but achievable values. In the modern environment, however, the number and sophistication of possible tests and measurements have increased dramatically. There is a need to prioritize QM activities in a way that will strike a balance between being reasonably achievable and optimally beneficial to patients. A systematic understanding of possible errors over the course of a radiation therapy treatment and the potential clinical impact of each is needed to direct limited resources in such a way to produce maximal benefit to the quality of patient care. Task Group 100 of the AAPM has taken a broad view of these issues and is developing a framework for designing QM activities, and hence allocating resources, based on estimates of clinical outcome, risk assessment, and failure modes. The report will provide guidelines on risk assessment approaches with emphasis on failure mode and effect analysis (FMEA) and an achievable QM program based on risk analysis. Examples of FMEA to intensity-modulated radiation therapy and high-dose-rate brachytherapy are presented. Recommendations on how to apply this new approach to individual clinics and further research and development will also be discussed.

  19. 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.

  20. Spectroscopic evaluation of photodynamic therapy of the intraperitoneal cavity

    PubMed Central

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

    2015-01-01

    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 microlenstipped 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. PMID:26028798

  1. Evaluation of the Therac 6 linear accelerator for radiation therapy.

    PubMed

    Grant, W; Ames, J; Almond, P R

    1978-01-01

    The Therac 6 is new generation of low-energy linear accelerator. It incorporates a PDP-11/05 computer for beam control, treatment-factor input, and beam shutdown in the event of failure of the system. The performance of the unit has not been hindered by computer or software malfunction, and the computer has provided an excellent means for preventive maintenance and repair. Dosimetry parameters are similar to other 6 MV x-ray beams, and comparison to 60Co therapy beams shows that this unit may be more like 60Co units in penumbra and absence of off-axis peaking than other low-energy accelerators.

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

    PubMed

    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.

  3. 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

  4. 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…

  5. 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,…

  6. 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…

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. Hematopoietic bone marrow recovery after radiation therapy: MRI evaluation

    SciTech Connect

    Casamassima, F.; Ruggiero, C.; Caramella, D.; Tinacci, E.; Villari, N.; Ruggiero, M. )

    1989-05-01

    Magnetic resonance imaging (MRI) is able to detect the increase of adipocytes in the hematopoietic bone marrow that occurs as a consequence of radiotherapy and is indicative of the loss of myeloid tissue. By monitoring this process, it is also possible to determine the recovery of the bone marrow. The amount of viable hematopoietic tissue plays a fundamental role in determining whether the patient is able to undergo further antineoplastic therapy, particularly chemotherapy. We examined 35 patients who had been treated with radiotherapy for Hodgkin's lymphoma (12), uterine cervix carcinoma (nine), ovarian dysgerminoma (six), testicular seminoma (four), and non-Hodgkin's lymphoma (four). We observed that radiation-induced modifications of the MRI pattern in the bone marrow are tightly linked to two parameters; the administered radiation dose and the length of time passed after the treatment. Bone marrow recovery was observed only when patients were treated with doses lower than 50 Gy. The earlier radiation-induced modifications of the bone marrow MRI pattern occurred 6 to 12 months after irradiation, and they were most evident 5 to 6 years after the treatment. From 2 to 9 years after radiotherapy, we observed partial recovery. Complete recovery, when it occurred, was observed only 10 to 23 years after the treatment. Our results indicate that MRI studies are likely to be useful in the assessment of radiation-induced injuries.

  13. 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.

  14. 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.

  15. 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.

  16. Spontaneous secretion of immunoglobulins and anti-HIV-1 antibodies by in vivo activated B lymphocytes from HIV-1-infected subjects: monocyte and natural killer cell requirement for in vitro terminal differentiation into plasma cells.

    PubMed

    Fournier, Anne Marie; Fondere, Jean-Michel; Alix-Panabieres, Catherine; Merle, Corinne; Baillat, Vincent; Huguet, Marie-France; Taïb, Jacques; Ohayon, Viviane; Zembala, Marek; Reynes, Jacques; Vendrell, Jean Pierre

    2002-04-01

    Peripheral blood mononuclear cells from HIV-1-infected subjects secrete spontaneously in vitro immunoglobulins (Ig) and anti-HIV-1 antibodies (Ab). Purified B lymphocytes secrete only minute amounts of Ig and anti-HIV-1 Ab compared with unfractionated cells. Monocytes and natural killer cells enhanced both secretions by cell-to-cell contacts, involving adhesion and CD27, CD80 costimulatory molecules and IL-6. Cell interactions prolonged the survival and allowed the terminal maturation of in vivo activated B cells. The secreting cell precursors were highly differentiated B cells expressing a broad diversity of maturation markers (CD27(+), CD38(+), CD20(+/-), CD37(+/-), CD71(+/-), HLA-DQ(+/-), sIg(+/-)) but not sIgD, CD28, or CD40. This phenotype and the cytologic aspect of purified B cells suggest that these cells are early plasma cells originated from germinal center. Ex vivo secreting peripheral B cells had probably gone beyond the CD40/CD40 ligand interaction; then following CD28/CD80 and CD27/CD27 ligand (CD70) interactions in the presence of IL-6, they achieved in vitro their differentiation into plasma cells.

  17. Evaluation of lung tumor response to therapy: Current and emerging techniques.

    PubMed

    Coche, E

    2016-10-01

    Lung tumor response to therapy may be evaluated in most instances by morphological criteria such as RECIST 1.1 on computed tomography (CT) or magnetic resonance imaging (MRI). However, those criteria are limited because they are based on tumoral dimensional changes and do not take into account other morphologic criteria such as density evaluation, functional or metabolic changes that may occur following conventional or targeted chemotherapy. New techniques such as dual-energy CT, PET-CT, MRI including diffusion-weighted MRI has to be considered into the new technical armamentarium for tumor response evaluation. Integration of all informations provided by the different imaging modalities has to be integrated and represents probably the future goal of tumor response evaluation. The aim of the present paper is to review the current and emerging imaging criteria used to evaluate the response of therapy in the field of lung cancer.

  18. Predialysis versus postdialysis hematocrit evaluation during erythropoietin therapy.

    PubMed

    Movilli, Ezio; Pertica, Nicoletta; Camerini, Corrado; Cancarini, Giovanni C; Brunori, Giuliano; Scolari, Francesco; Maiorca, Rosario

    2002-04-01

    American guidelines for the management of renal anemia by recombinant human erythropoietin (rHuEPO) recommend collecting a predialysis blood sample to evaluate hemoglobin (Hb) and hematocrit (Hct) levels in hemodialysis patients. Although a predialysis blood sample is appropriate for evaluating when to start rHuEPO treatment, the same sample would not be appropriate for evaluating the target Hb/Hct to be maintained, particularly when normal or near-normal values are pursued. We measured the degree of intradialytic and extradialytic variation of Hb, Hct, and body weight in 68 stable hemodialysis patients on maintenance subcutaneous rHuEPO treatment. Hb and Hct concentrations were determined before and after dialysis. In 16 patients, Hb and Hct concentrations also were assessed 24 hours after the end of dialysis. Predialysis versus postdialysis Hb and Hct concentrations for all patients were 10.5 +/- 1.3 g/dL versus 11.5 +/- 1.3 g/dL (P < 0.0001) and 32 +/- 4% versus 35 +/- 4% (P < 0.0001). The intradialytic percent variation (%Delta) of Hct and body weight were 10 +/- 6% and -6.3 +/- 3.5%. There was a close inverse correlation between %Delta of Hct and Hb and %Delta of body weight (P < 0.0001). In patients with body weight losses 2.5 kg or more per session, the mean %Delta of Hct was 12 +/- 7%. In the 16 patients studied 24 hours after the end of the dialysis session, Hct and Hb values remained significantly higher compared with the predialysis levels (P < 0.001), suggesting a slow reequilibration of the intravascular volume in the first 24 hours after hemodialysis. For these reasons, predialysis samples for monitoring the target Hb and Hct levels in patients treated by rHuEPO should be considered with caution.

  19. Evaluation of dog owners' perceptions concerning radiation therapy

    PubMed Central

    Denneberg, Nanna Åkerlund; Egenvall, Agneta

    2009-01-01

    Background External radiation therapy (RT) has been available for small animals in Sweden since 2006. This study was designed to obtain information on owner experiences and perceptions related to RT of cancer in their dogs. Another survey was used to determine the attitudes about use of RT in a group of Swedish veterinarians. Their responses were analyzed and compared to their level of knowledge of oncology and RT. Methods Owners of all dogs (n = 23) who had undergone RT for malignancy at Jönköping Small Animal Hospital between March 2006 to September 2007 were interviewed. A questionnaire was given to a selected group of veterinarians. Results All 23 owners responded. All owners thought that their dog did well during RT and most that their dog was also fine during the following phase when acute RT-related skin reactions occur and heal. Three owners stated that their dog had pain that negatively impacted quality of life because of radiation dermatitis. Five owners reported that RT positively impacted quality of life of the dog during the first weeks after RT because palliation was achieved. The owners were not disturbed by the efforts required of them. All but one owner (22 of 23) stated that they would make the same decision about RT again if a similar situation occurred. The most important factor for this decision was the chance to delay occurrence of tumour-related discomfort. The chance for cure was of less importance but still essential, followed by expected side effects. Time commitments, travel, number of treatments required and financial cost; all had low impact. The veterinarian survey showed that less background knowledge of small animal oncology/RT was associated with more negative expectations of RT for small animals. Conclusion The results show that for these owners, RT was a worthwhile treatment modality and that the discomfort for the dog was manageable and acceptable relative to the benefits. Improved continuing education about small animal RT in

  20. A fuller picture: evaluating an art therapy programme in a multidisciplinary mental health service.

    PubMed

    Brady, Catherina; Moss, Hilary; Kelly, Brendan D

    2017-03-01

    Art therapy has a long history in mental healthcare, but requires an enhanced evidence base in order to better identify its precise role in contemporary services. This paper describes an evaluation of an art therapy programme in an acute adult psychiatry admission unit in Ireland. A mixed method research design was used. Quantitative data were collected through a survey of 35 staff members and 11 service users. Qualitative data included free text comments collected in the survey and individual feedback from service users. Both methods aimed to assess the role of art therapy as part of a multidisciplinary mental health service. Thematic content analysis was employed to analyse qualitative data. Staff demonstrated overwhelming support for art therapy as one element within multidisciplinary services available to patients in the acute psychiatry setting, Qualitative feedback associated art therapy with improvements in quality of life and individual support, and emphasised its role as a non-verbal intervention, especially useful for those who find talking therapy difficult. Creative self-expression is valued by staff and service users as part of the recovery process. Recommendations arising from the research include continuing the art therapy service, expanding it to include patients under rehabilitation, provision of information and education sessions to staff, and further research to identify other potential long-term effects. The low response of staff and small sample in this study, however, must be noted as limitations to these findings.

  1. In vitro and in vivo evaluation of hypericin for photodynamic therapy of equine sarcoids.

    PubMed

    Martens, A; de Moor, A; Waelkens, E; Merlevede, W; De Witte, P

    2000-01-01

    The therapeutic potential of the photodynamic compound, hypericin, in the treatment of equine sarcoids was evaluated. The in vitro cytotoxicity was assessed using three equine cell lines and the observed phototoxic effect was comparable to that on different highly sensitive human cell lines and significantly influenced by the energy density used although independent of the cell type. The in vivo antitumoural action of photodynamic therapy using hypericin was evaluated on three equine sarcoids in a donkey. Four intratumoural injections were given and the tumours were illuminated daily during 25 days. An 81% reduction in tumour volume was obtained at the end of therapy and 2 months later, a 90% reduction was observed. Further experimental work should be performed, but these results suggest that photodynamic therapy using hypericin has a potential for the non-invasive treatment of equine sarcoids.

  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. Evaluation of ifosfamide salvage therapy for metastatic canine osteosarcoma.

    PubMed

    Batschinski, K; Dervisis, N G; Kitchell, B E

    2014-12-01

    A retrospective study was performed to assess toxicity and response rate of ifosfamide salvage treatment for dogs diagnosed with metastatic osteosarcoma (OSA). Dogs diagnosed with OSA and previously treated with standard chemotherapy were included in the study. Nineteen dogs met the inclusion criteria, and 17 dogs were evaluable for response. Ifosfamide doses ranged from 375 to 425 mg m(-2) (median dose 375 mg m(-2)), with a median of two doses administered per dog (range 1-7 doses). The overall response to ifosfamide was 11.8% [complete response (CR) = 1/17, partial response (PR) = 1/17, stable disease (SD) = 2/17, progressive disease (PD) = 13/17]. Two dogs were hospitalized due to ifosfamide toxicosis. The median survival duration from the first dose of ifosfamide to death was 95 days. Ifosfamide was well tolerated, but minor anti-tumour activity was observed.

  4. 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…

  5. 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…

  6. 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…

  7. 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…

  8. A Field Training Model for Creative Arts Therapies: Report from a 3-Year Program Evaluation

    ERIC Educational Resources Information Center

    Orkibi, Hod

    2012-01-01

    Clinical field training is an essential component of educating future therapists. This article discusses a creative arts therapies field training model in Israel as designed and modified from 3 years of program evaluation in a changing regulatory context. A clinical seminar structure puts beginning students in the role of participant-observer in…

  9. 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…

  10. 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…

  11. Complementary therapies in healthcare: design, implementation and evaluation of an elective course for undergraduate students.

    PubMed

    van der Riet, Pamela; Francis, Lyn; Levett-Jones, Tracy

    2011-03-01

    Complementary therapies are making a significant and cost effective contribution to the health of the community, especially in relation to chronic disease management and prevention of disease. Because of the increased use of complementary therapies, nurses, and other health professionals need to be familiar with specific practices so that they can assist clients to make informed decisions in the use of these therapies. Importantly, with the increased interest in complementary therapies, there is a need to ensure these practices are safe, cause no harm and are used to enhance the well-being of patients. This paper reports on the design, implementation and evaluation of a complementary therapies course and a linked Thai cultural studies tour. The course was implemented at The University of Newcastle for the first time in 2009 with an enrollment of 200 students. It is an elective course for both nursing students and those from other disciplines. In this paper we describe the reasons for the introduction of this course and its value in nursing education. We then provide an overview of the course and report on evaluation results from both the course and the Thai cultural studies tour.

  12. Evaluation of the effect of appropriate antimicrobial therapy on mortality associated with Acinetobacter nosocomialis bacteraemia.

    PubMed

    Kuo, Shu-Chen; Lee, Yi-Tzu; Yang, Su-Pen; Chiang, Mei-Chun; Lin, Yi-Tsung; Tseng, Fan-Chen; Chen, Te-Li; Fung, Chang-Phone

    2013-07-01

    Appropriate antimicrobial therapy is effective for severe infections caused by Acinetobacter baumannii, but efficacy for other Acinetobacter species remains to be established. The current study was designed to determine whether appropriate antimicrobial therapy reduces the mortality of patients with Acinetobacter nosocomialis bacteraemia. A 9-year retrospective study of 266 patients with monomicrobial A. nosocomialis bacteraemia was conducted at a large teaching hospital in Taiwan. Multivariable analysis was performed to evaluate the impact on 14-day mortality according to clinical characteristics, severity of disease and use of appropriate antimicrobial therapy. The influence of APACHE II score on the impact of appropriate antimicrobial therapy was analysed by including an interaction term. The overall 14-day mortality was 9.4%. Multivariable analysis revealed that APACHE II score was the only factor significantly associated with mortality (odds ratio, 1.18; 95% confidence interval, 1.11-1.25; p <0.001). Appropriate antimicrobial therapy was not associated with reduced mortality regardless of disease severity. In the subgroup analyses in patients with different clinical conditions, APACHE II score was consistently an independent factor for 14-day mortality, and appropriate antimicrobial therapy did not affect the mortality in any group. In conclusion, severity of disease, based on the APACHE II score, was the independent risk factor for 14-day mortality for patients with monomicrobial A. nosocomialis bacteraemia, even in different clinical conditions. In contrast, appropriate antimicrobial therapy did not reduce the 14-day mortality. The result highlighted a different effect of appropriate antimicrobial therapy on infections caused by two phenotypically undifferentiated Acinetobacter.

  13. 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.

  14. Image guidance, treatment planning and evaluation of cancer interstitial focal therapy using liposomal radionuclides

    NASA Astrophysics Data System (ADS)

    Ware, Steve William

    Focally ablative therapy of cancer has gained significant interest recently. Improvements in diagnostic techniques have created possibilities for treatment which were once clinically unfeasible. Imaging must be capable of allowing accurate diagnosis, staging and planning upon initiation of therapy. Recent improvements in MRI and molecular imaging techniques have made it possible to accurately localize lesions and in so doing, improve the accuracy of proposed focal treatments. Using multimodality imaging it is now possible to target, plan and evaluate interstitial focal treatment using liposome encapsulated beta emitting radionuclides in a variety of cancer types. Since most absorbed dose is deposited early and heterogeneously in beta-radionuclide therapy, investigation of the resultant molecular and cellular events during this time is important for evaluating treatment efficacy. Additionally, investigating a multifocal entity such as prostate cancer is helpful for determining whether MRI is capable of discriminating the proper lesion for therapy. Correlation of MRI findings with histopathology can further improve the accuracy of interstitial focal radionuclide therapy by providing non-invasive surrogates for tissue compartment sizes. In the application of such therapies, compartmental sizes are known to heavily influence the distribution of injected agents. This has clear dosimetric implications with the potential to significantly alter the efficacy of treatment. The hypothesis of this project was that multimodality imaging with magnetic resonance imaging (MRI), autoradiography (AR), and single photon emission computed tomography (SPECT) could be used to target, plan, and evaluate interstitial focal therapy with non-sealed source, liposome-encapsulated 186Re beta emitting radionuclides. The specific aims of this project were to 1) Identify suitable targets for interstitial focal therapy. This was done by retrospectively analyzing MRI data to characterize the tumor

  15. 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

  16. 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.

  17. 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

  18. Evaluation of oxidative and nitrosative stress in relapsing remitting multiple sclerosis: effect of corticosteroid therapy.

    PubMed

    Seven, Aru; Aslan, Mahmure; Incir, Said; Altıntaş, Ayşe

    2013-01-01

    This study is designed to evaluate the roles of oxidative and nitrosative stress in serum and cerebrospinal fluid (CSF) of relapsing remitting multiple sclerosis (RRMS) patients. Oxidative stress markers thiobarbituric acid reactive substances (TBARS), 8-epi-PGF2α, conjugated diene and nitrosative stress markers nitrotyrosine, nitrit-nitrate were analysed in serum and CSF of 20 newly diagnosed RRMS patients before and after methyl prednysolone (MP) therapy (1000 mg/day i.v., for 5 days) and in healthy control group.TBARS and conjugated diene were analysed spectrophotometrically, nitrite-nitrate fluorometrically, 8-epi-PGF2α and nitrotyrosine were measured by ELISA. Serum conjugated diene (p < 0.001) and 8-epi-PGF2α (p < 0.05) levels were significantly higher in RRMS patients before MP therapy with respect to control group. MP therapy caused a significant decrease only in 8-epi-PGF2α level (p < 0.05). Serum nitrotyrosine levels were significantly lower in RRMS patients both before (p < 0.001) and after (p < 0.001) MP therapy with respect to controls. Serum nitrite-nitrate levels were significantly lower (p < 0.05) in RRMS patients before therapy compared to controls. Nitrotyrosine and nitrite-nitrate levels in CSF of RRMS patients were significantly higher (p < 0.001) before therapy compared to normal pressure hydrocephalia control group. Our findings reveal increased oxidative stress in serum of RRMS patients and the benefical role of MP therapy in relieving oxidative stress.As to nitrosative stress, nitrotyrosine and nitrite-nitrate levels were increased in CSF and decreased in serum.

  19. Clinical evaluation of physical therapy in the management of internal derangement of the temporomandibular joint.

    PubMed

    Kirk, W S; Calabrese, D K

    1989-02-01

    This clinical cross-sectional study examines the favorable functional improvement in patients undergoing physical therapy for mild to moderate internal disc derangements of the temporomandibular joint. Sixty-eight patients with internal derangements were treated with physical therapeutic modalities as described by Rocabado. A success rate of 86% was achieved in patients with early- to mid-opening and late- to mid-closing clicks of the temporomandibular joint. Approximately one third of these patients required short-term occlusal bite appliances to assist in their management. A success rate of 7% was achieved in patients with late-opening and late-closing clicks. No patient with clicking on mediolateral movement was successfully managed with physical therapy. Likewise, patients with nonreducing anteriorly displaced discs of the temporomandibular joint did not respond well to physical therapy. Pain management was evaluated separately and showed subjective improvement in 82% of patients with mild to moderate disc dysfunction and pain. Only 29% of patients with late-opening clicking or locked joints experienced pain relief. When patients were classified according to occurrence of the clicking phenomenon, interesting trends relating to duration of symptoms were found. Twenty-two patients who did not respond favorably to physical therapy underwent surgical procedures. Findings in these patients offer suggestions about why nonsurgical therapy is not successful in certain cases.

  20. 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.

  1. The impact evaluation of physical therapy on the quality of life of cerebrovascular stroke patients.

    PubMed

    Paula Caleffi Segura, Ana; Veloso Fontes, Sissy; Maiumi Fukujima, Marcia; de Andrade Matas, Sandro Luiz

    2006-09-01

    This study aimed to evaluate the impact of physical therapy on the quality of life of patients presenting with a motor deficit caused by ischemic stroke at the median cerebral artery. Physical therapeutic intervention consisted of three sessions per week of conventional kinesiotherapy; 50 min each, for three consecutive months. The sample comprised 18 patients aged between 18 and 72 years old, evaluated according to the Stroke Impact Scale. There was a significant difference for the following domains: strength (P < 0.001), daily life activities (P < 0.001), mobility (P = 0.001), manual function (P = 0.004) and social participation (P=0.001). We were able to conclude that physical therapy, performed for up to three 50-min weekly sessions for 3 consecutive months, resulted in the reduction of motor deficits and functional improvement, consequently promoting favorable effects on the quality of life of patients presenting with motor deficit due to ischemic stroke.

  2. 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

  3. 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

  4. 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

  5. Dual-mode 5-element transducer for image-guided interstitial ultrasound therapy: In vitro evaluation

    NASA Astrophysics Data System (ADS)

    Owen, N. R.; Bouchoux, G.; Murillo-Rincon, A.; Merouche, S.; Birer, A.; Chapelon, J. Y.; Berriet, R.; Fleury, G.; Lafon, C.

    2009-04-01

    Interstitial probes with dual-mode transducers are effective devices to guide and monitor with ultrasound imaging the application of ultrasound therapy. Here, a dual-mode 5-element transducer, with oscillatory motion for sector imaging and directive therapy, was characterized and evaluated in vitro with porcine liver. The transducer had 3.8×3.0-mm2 elements, a 20×3.0-mm2 aperture, and was cylindrically focused to 14-mm. In therapy mode, elements were maximally efficient, 72±4% (ave±std), at 5.6-MHz. In imaging mode, the pulse-echo impulse response for each electrically-matched element was 160±16 ns long at -6 dB, and insertion loss was minimally 9.8±0.5 dB at 5.2-MHz. Electrical crosstalk was less than -57 dB at 5.6-MHz. Lateral resolution, measured by scanning a wire of 0.1-mm diameter wire though the focal plane, was 1.0-mm at -6 dB. During experiment, an initial B-mode image was formed over a 140° sector. Then, therapy was applied for 90 s, with 18-W/cm2 transducer surface intensity, at each of 5 angles (Δθ = 20°) to form volumes of composite protein denaturization. Pulse-echo data were collected periodically to monitor therapy with real-time M-mode imaging. After therapy, another B-mode image was formed, and the depth of protein denaturization was measured by gross histology. B-mode images adequately represented the liver structure. Analysis of M-mode images was consistent with gross histology.

  6. 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

  7. 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.

  8. 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.

  9. 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

  10. A data-driven approach for evaluating multi-modal therapy in traumatic brain injury

    PubMed Central

    Haefeli, Jenny; Ferguson, Adam R.; Bingham, Deborah; Orr, Adrienne; Won, Seok Joon; Lam, Tina I.; Shi, Jian; Hawley, Sarah; Liu, Jialing; Swanson, Raymond A.; Massa, Stephen M.

    2017-01-01

    Combination therapies targeting multiple recovery mechanisms have the potential for additive or synergistic effects, but experimental design and analyses of multimodal therapeutic trials are challenging. To address this problem, we developed a data-driven approach to integrate and analyze raw source data from separate pre-clinical studies and evaluated interactions between four treatments following traumatic brain injury. Histologic and behavioral outcomes were measured in 202 rats treated with combinations of an anti-inflammatory agent (minocycline), a neurotrophic agent (LM11A-31), and physical therapy consisting of assisted exercise with or without botulinum toxin-induced limb constraint. Data was curated and analyzed in a linked workflow involving non-linear principal component analysis followed by hypothesis testing with a linear mixed model. Results revealed significant benefits of the neurotrophic agent LM11A-31 on learning and memory outcomes after traumatic brain injury. In addition, modulations of LM11A-31 effects by co-administration of minocycline and by the type of physical therapy applied reached statistical significance. These results suggest a combinatorial effect of drug and physical therapy interventions that was not evident by univariate analysis. The study designs and analytic techniques applied here form a structured, unbiased, internally validated workflow that may be applied to other combinatorial studies, both in animals and humans. PMID:28205533

  11. Retrospective evaluation of caspofungin therapy in invasive aspergillosis (RECAM-IA).

    PubMed

    Wisniewski, Tami; Klimko, Nikolay; Laverdiere, Michel; Kiertiburanakul, Sasisopin; Kliasova, Galina; Trenschel, Rudolf; Kumar, Ritesh N

    2011-07-01

    To evaluate caspofungin in high-risk invasive aspergillosis (IA) patient, a retrospective review of patient characteristics, antifungal therapies and clinical outcomes on hospitalised patients at sites in Russia, Canada, Germany, and Thailand was performed. Fifty-five patients were included, six with proven and 49 with probable aspergillosis; 76.4% had haematological diseases, 80% were on immunosuppressive drugs, 32.7% were neutropenic at caspofungin initiation. Median duration of prior antifungal therapy was 9 days (range 1-232). Reasons for initiating caspofungin included: disease refractory to first-line antifungal (49.1%) and toxicities with prior antifungals (18.2%). Median caspofungin therapy duration was 14 days (range 2-62), with a median of 13 days (range 1-62) as monotherapy. Favourable responses were observed in 45.5% of the patients, complete responses in 40% and partial responses in 5.5%; 74.5% survived 7 days after completion of caspofungin therapy with 69.1% having been successfully discharged from the hospital. Few patients (14.6%) on caspofungin switched because of suspected resistance, lack of response or adverse events. There were no increases in hospital stay as a result of adverse events or drug-drug interactions related to caspofungin; 7.3% of patients had a mean value of 13 (± 14.11) days of increased stay attributable to treatment failure. Caspofungin was well-tolerated. It exhibited effectiveness and high survival in treating severe IA patients.

  12. Evaluating the Primary Prevention of Ischemic Stroke of Oral Antithrombotic Therapy in Head and Neck Cancer Patients with Radiation Therapy

    PubMed Central

    Hsu, Chin-Wei

    2016-01-01

    Although previous studies demonstrated the risk of ischemic stroke (IS) in patients with head and neck cancer (HNC), the impact of oral antithrombotic therapy (OAT) on this risk has not yet been assessed. We aimed to evaluate the effectiveness and safety of OAT in patients with HNC treated with RT. This retrospective cohort study was performed using the National Health Insurance Research Database of Taiwan. A total of 37,638 patients diagnosed with HNC included in the study were classified as users and nonusers of OAT. Primary outcome was IS or transient ischemic attack (TIA), and secondary outcomes were death and major bleeding. The Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). There was no significant difference in the risk of IS or TIA between patients on continuous OAT and nonusers (adjusted HR, 0.812; 95% CI, 0.199–3.309). The risk of major bleeding was not significantly different between the groups. From a national population database, we did not find an association between OAT and decreasing risk of ischemic stroke/TIA or increasing hazard of major bleeding. PMID:27990433

  13. Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy

    DTIC Science & Technology

    2012-07-01

    Mediated by Listeria -Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy PRINCIPAL INVESTIGATOR: David J. Chung, M D , Ph D...CONTRACT NUMBER Evaluation of Immune Responses Mediated by Listeria -Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy 5b...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The purpose of this project is to study the immunomodulatory effect of Listeria on

  14. Novel approach to lung stereotactic body radiation therapy plan evaluation and delivery

    NASA Astrophysics Data System (ADS)

    Jurkovic, Ines-Ana

    Stereotactic body radiation therapy is currently being used as an efficient treatment for Stage I/II medically inoperable and surgically unrespectable non small cell and metastatic lung cancer. Hypofractional dose and dose escalation used in stereotactic body radiation therapy have the potential of increasing the likelihood of the tumor control and the long term progression free survival. Currently available commercial treatment planning systems are capable of calculating accurate dose distributions for static case, where the tumor and surrounding healthy tissues are not moving during the dose delivery. However, respiratory induced organ motion can result in significant movement of the lesion leading to the discrepancies between the dose delivered and the dose planned. The precision and conformity of the stereotactic body radiation therapy makes it very susceptible to motion, i.e. patient respiration can lead to significant dose delivery errors. Conventional stereotactic body radiation therapy treatment plans use free breathing three-dimensional computed tomography images where margins are added to delineated gross tumor volume to create planning tumor volume and avoid geometrical misses of the target. The specific hypothesis of the study is that the true four-dimensional delivery of the four-dimensional plans will allow for more accurate radiation therapy treatment and critical organ sparing along with radiobiological evaluation of the dose distributions. The specific aims are designed to provide in depth understanding of the radiation therapy treatments and influence of the four-dimensional planning and delivery, heterogeneity corrections and various radiobiological factors on the outcome. The primary focus of the Specific Aim 1 was the evaluation of the tumor volume based on the four-dimensional computed tomography scan data through its motion, volume and computed tomography number. The results indicated that tumor motion parameters will exceed the typical

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. Evaluating the use of gas discharge visualization to measure massage therapy outcomes

    PubMed Central

    Haun, Jolie; Patel, Nitin; Schwartz, Gary; Ritenbaugh, Cheryl

    2017-01-01

    Background The purpose of this study was to evaluate the short-term effects of massage therapy using gas discharge visualization (GDV), a computerized biophysical electrophoton capture (EPC), in tandem with traditional self-report measures to evaluate the use of GDV measurement to assess the bioenergetic whole-person effects of massage therapy. Methods This study used a single treatment group, pre–post-repeated measures design with a sample of 23 healthy adults. This study utilized a single 50-min full-body relaxation massage with participants. GDV measurement method, an EPC, and traditional paper-based measures evaluating pain, stress, muscle tension, and well-being were used to assess intervention outcomes. Results Significant differences were found between pre- and post-measures of well-being, pain, stress, muscle tension, and GDV parameters. Pearson correlations indicate the GDV measure is correlated with pain and stress, variables that impact the whole person. Conclusions This study demonstrates that GDV parameters may be used to indicate significant bioenergetic change from pre- to post-massage. Findings warrant further investigation with a larger diverse sample size and control group to further explore GDV as a measure of whole-person bioenergetic effects associated with massage. PMID:26087069

  20. [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.

  1. 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.

  2. Evaluation of the hemodynamic impact of continuous renal replacement therapy in healthy dogs.

    PubMed

    Shimokawa Miyama, Takako; Itamoto, Kazuhito; Yoshioka, Chihiro; Minami, Koji; Okawa, Takumi; Fujisaki, Yuka; Hiraoka, Hiroko; Mizuno, Takuya; Okuda, Masaru

    2010-04-01

    We performed continuous renal replacement therapy (CRRT) on clinically healthy dogs to evaluate the effects of CRRT on hemodynamics. Heart rate, arterial blood pressure, and central venous pressure of the dogs (n=6) were recorded during the procedure, which was performed under general anesthesia. Throughout the CRRT, heart rate and arterial blood pressure were stable. Central venous pressure increased after CRRT termination but returned to the basal level within 30 min. In this study, hemodynamic alterations, including hypotension, hypertension, and arrhythmias, were not observed during CRRT. These observations suggest that the CRRT protocol used in the present study can be safely applied to clinical cases with acute renal failure.

  3. Clinical and research implications of the evaluation of women's group therapy for anorgasmia: a review.

    PubMed

    Kuriansky, J B; Sharpe, L

    1981-01-01

    This paper reviews some important clinical and research implications of studies which have evaluated the effectiveness of short-term behavioral group therapy for anorgasmia. Though formal research data on curative factors is very sparse, the experience of sharing within a group, and the focus on arousal seem consistent with treatment outcome; however, the emphasis on assertiveness and the woman-only approach may have countertherapeutic as well as therapeutic effects. A potentially important intervening variable is the woman's level of ego development. The use of certain assessment scales and criteria for success of treatment are critiqued, and recommendations made for further study.

  4. Nursing issues in renal replacement therapy: organization, manpower assessment, competency evaluation and quality improvement processes.

    PubMed

    Graham, Patricia; Lischer, Eileen

    2011-01-01

    For the patient with acute kidney injury, continuous renal replacement therapy (CRRT) is a treatment option that has application for the hemodynamically unstable critically ill patient. The decision to initiate a continuous renal replacement modality depends not only on the physician, either the nephrologist or intensivist, but also on the availability of specially trained nursing resources. This article will explore the nursing collaborative model of care at a large university-based research and teaching Medical Center in Southern California. The focus will be on nursing issues in CRRT including organization of educational programs, manpower assessment, competency evaluation, and quality improvement processes.

  5. 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

  6. A national evaluation of the Australian Occupational Therapy Competency Standards (1994): a multistakeholder perspective.

    PubMed

    Rodger, Sylvia; Clark, Michele; Banks, Rebecca; O'Brien, Mia; Martinez, Kay

    2009-12-01

    This paper summarises results from an evaluation of the adequacy and utility of the Australian Competency Standards for Entry-Level Occupational Therapists (OT AUSTRALIA, 1994a). It comprised a two-part study, incorporating an online survey of key national stakeholders (n = 26), and 13 focus groups (n = 152) conducted throughout Australia with occupational therapy clinicians, academics, OT AUSTRALIA association and Occupational Therapy Registration Board representatives, as well as university program accreditors. The key recommendations were that: (i) urgent revision to reflect contemporary practice, paradigms, approaches and frameworks is required; (ii) the standards should exemplify basic competence at graduation (not within two years following); (iii) a revision cycle of five years is required; (iv) the Australian Qualifications Framework should be retained, preceded by an introduction describing the scope and nature of occupational therapy practice in the national context; (v) access to the standards should be free and unrestricted to occupational therapists, students and the public via the OT AUSTRALIA (national) website; (vi) the standards should incorporate a succinct executive summary and additional tools or templates formatted to enable occupational therapists to develop professional portfolios and create working documents specific to their workplace; and (vii) language must accommodate contextual variation while striking an appropriate balance between providing instruction and encouraging innovation in practice.

  7. 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

  8. Evaluation of factors contributed in nonadherence to medication therapy in children asthma.

    PubMed

    Mirsadraee, Raheleh; Gharagozlou, Mohammad; Movahedi, Masoud; Behniafard, Nasrin; Nasiri, Rasoul

    2012-03-01

    Asthma is one of the most common chronic inflammatory disorders in children. Nonadherence to medical therapy is a major cause of poor clinical outcome the objective of this study was evaluating factors, which are resulted in nonadherence to medical therapy in children with asthma.In this descriptive study, 150 children with asthma and nonadherent to medication therapy were enrolled. General information and probable causes of nonadherence were recorded in self-report questionnaire and data were analyzed. In our study, 57.3% of children were male. Approximately 43%of children belonged to age group 6-9 years old. Prevalence of probable causes of nonadherence to treatment were concern about treatment expenses(34.7%) ,fear of cardiac complications(34.7%), concern about drug dependency(38.7%), belief to growth inhibition(30.7%) and fear of osteopenia (32%). There was statistically significant reverse association between treatment with multi-drug regimens and concern about bone mineral abnormalities, cardiac complications and drug dependency (p=0.0001, 0.014 and 0.012 respectively). In addition, there was a significant association between mild asthma and fear about drug dependency (p=0.001).According to our results, factors such as prolonged duration of treatment, various therapeutic regimens, and receiving multiple drugs before diagnosis of asthma pose the highest frequencies for nonadherence.

  9. Physical therapy assessment tools to evaluate disease progression and phenotype variability in Golden Retriever muscular dystrophy.

    PubMed

    Gaiad, T P; Silva, M B; Silva, G C A; Caromano, F A; Miglino, M A; Ambrósio, C E

    2011-10-01

    Dogs suffering from Golden Retriever muscular dystrophy (GRMD) present symptoms that are similar to human patients with Duchenne muscular dystrophy (DMD). Phenotypic variability is common in both cases and correlates with disease progression and response to therapy. Physical therapy assessment tools were used to study disease progression and assess phenotypic variability in dogs with GRMD. At 5 (T0), 9 (T1), 13 (T2) and 17 (T3)months of age, the physical features, joint ranges of motion (ROM), limb and thorax circumferences, weight and creatine kinase (CK) levels were assessed in 11 dogs with GRMD. Alterations of physical features were higher at 13 months, and different disease progression rates were observed. Passive ROM decreased until 1 year old, which was followed by a decline of elbow and tarsal ROM. Limb and thorax circumferences, which were corrected for body weight, decreased significantly between T0 and T3. These measurements can be used to evaluate disease progression in dogs with GRMD and to help discover new therapies for DMD patients.

  10. Effectiveness of cognitive behavioral therapy: An evaluation of therapies provided by trainees at a university psychotherapy training center

    PubMed Central

    Hiltunen, Arto J; Kocys, Elo; Perrin-Wallqvist, Renée

    2013-01-01

    At the psychotherapy training center at Karlstad University, a study was carried out to examine the levels of symptom change and satisfaction with therapy in a heterogeneous population of clients treated using cognitive behavioral therapy (CBT) by less experienced trainee therapists with limited theoretical education. The clients received an average of 11 therapy sessions. The results suggested that CBT performed by less experienced trainee therapists can be effective. According to client estimations, a statistically significant reduction in symptoms, measured using the Symptoms Checklist, was achieved for seven of nine variables (p ≤ .006), as well as a significant increase in satisfaction with life (p ≤ .001). Also, the pre- and posttherapy measurements using the Montgomery–Åsberg Depression Rating Scale showed a statistically significant improvement in the clients’ condition. According to the therapists’ estimations, 64% (SD = 32.01) of the clients experienced a significant improvement in their condition. In addition, the results of a survey of client satisfaction demonstrated that the clients were very pleased with the therapy received. Also the therapists were, to a great extent, satisfied with the treatment process itself, including the supervision received, and very satisfied with the client alliance. A correlation analysis between the clients’ perceived level of improvement and therapist satisfaction showed a strong correlation between the two variables (r = .50, p < .005). By including the Comparative Psychotherapy Process Scale (CPPS) in our study it was possible to measure trueness to therapy form. An analysis of the CPPS results confirmed that the form of therapy used at the training site was more strongly CBT than psychodynamic interpersonal treatment (p ≤ .001). The CBT subscale score indicated that the therapy was characteristic of CBT, confirming that the interventions used in the therapy belong to the CBT

  11. 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

  12. Balance evaluation techniques and physical therapy in post-stroke patients: A literature review.

    PubMed

    Lendraitienė, Eglė; Tamošauskaitė, Agnė; Petruševičienė, Daiva; Savickas, Raimondas

    A stroke (cerebrovascular accident - CVA) is a significant social-economic issue. Approximately 15-30% of all patients develop life-long disability, 20% require over 3 months of specialized care in healthcare institutions, and the majority of the patients never recover the ability to maintain a proper vertical position. Such CVA sequelae as balance disturbances not only negatively affect patients' daily physical activity, but also result in social isolation. A number of standardized clinical scales, tests, and instrumental examination techniques have been proposed for evaluating not only post-CVA balance function, but also any changes in this function following various interventions. Even though scientific literature lists numerous methods and instruments for the improvement of balance after a CVA, not all of them are equally effective, and there have been rather controversial evaluations of some techniques. Nevertheless, the application of the majority of the techniques as complementary or alternative measures to traditional physical therapy (PT) frequently yields better results.

  13. 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.

  14. 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.

  15. A prospective 9-month human clinical evaluation of Laser-Assisted New Attachment Procedure (LANAP) therapy.

    PubMed

    Nevins, Marc; Kim, Soo-Woo; Camelo, Marcelo; Martin, Ignacio Sanz; Kim, David; Nevins, Myron

    2014-01-01

    This investigation was designed and implemented as a single-center, prospective study to evaluate the clinical response to the Laser-Assisted New Attachment Procedure (LANAP). Eight patients with advanced periodontitis were enrolled and treated with full-mouth LANAP therapy and monitored for 9 months. Fullmouth clinical measurements, including clinical attachment level (CAL), probing depth (PD), and recession, were provided at baseline and after 9 months of healing by a single calibrated examiner, including a total of 930 sites and 444 sites with initial PD equal to or greater than 5 mm. Clinical results for the 930 sites measured pre- and postoperatively revealed that mean PD was reduced from 4.62 ± 2.29 mm to 3.14 ± 1.48 mm after 9 months (P < .05). CAL decreased from 5.58 ± 2.76 mm to 4.66 ± 2.10 mm (P < .05) and recession increased from 0.86 ± 1.31 mm to 1.52 ± 1.62 after 9 months (P < .05). For the subset of 444 sites with initial PD greater than or equal to 5 mm, the PD decreased from 6.50 ± 2.07 mm to 3.92 ± 1.54 mm (P < .05) and CAL decreased from 7.42 ± 2.70 mm to 5.78 ± 2.06 mm (P < .05). As demonstrated by the clinical evaluation, the majority of treated sites demonstrated clinical improvement. LANAP therapy should be further investigated with long-term clinical trials to compare the stability of clinical results with conventional therapy.

  16. 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.

  17. In vitro evaluation of wound healing and antimicrobial potential of ozone therapy.

    PubMed

    Borges, Gabriel Álvares; Elias, Silvia Taveira; da Silva, Sandra Márcia Mazutti; Magalhães, Pérola Oliveira; Macedo, Sergio Bruzadelli; Ribeiro, Ana Paula Dias; Guerra, Eliete Neves Silva

    2017-03-01

    Although ozone therapy is extensively applied when wound repair and antimicrobial effect are necessary, little is known about cellular mechanisms regarding this process. Thus, this study aimed to evaluate ozone cytotoxicity in fibroblasts (L929) and keratinocytes (HaCaT) cell lines, its effects on cell migration and its antimicrobial activity. Cells were treated with ozonated phosphate-buffered saline (8, 4, 2, 1, 0.5 and 0.25 μg/mL ozone), chlorhexidine 0.2% or buffered-solution, and cell viability was determined through MTT assay. The effect of ozone on cell migration was evaluated through scratch wound healing and transwell migration assays. The minimum inhibitory concentrations for Candida albicans and Staphylococcus aureus were determined. Ozone showed no cytotoxicity for the cell lines, while chlorhexidine markedly reduced cell viability. Although no significant difference between control and ozone-treated cells was observed in the scratch assay, a considerable increase in fibroblasts migration was noticed on cells treated with 8 μg/mL ozonated solution. Ozone alone did not inhibit growth of microorganisms; however, its association with chlorhexidine resulted in antimicrobial activity. This study confirms the wound healing and antimicrobial potential of ozone therapy and presents the need for studies to elucidate the molecular mechanisms through which it exerts such biological effects.

  18. 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".

  19. 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

  20. The mechanism of local tumor irradiation combined with interleukin 2 therapy in murine renal carcinoma: histological evaluation of pulmonary metastases.

    PubMed

    Dezso, B; Haas, G P; Hamzavi, F; Kim, S; Montecillo, E J; Benson, P D; Pontes, J E; Maughan, R L; Hillman, G G

    1996-09-01

    We have demonstrated that tumor irradiation enhanced the therapeutic effect of interleukin 2 (IL-2) on pulmonary metastases from a murine renal adenocarcinoma, Renca. To investigate the mechanism of interaction between tumor irradiation and IL-2 therapy, we have histologically evaluated the effects of each therapy alone or in combination on Renca pulmonary metastases. Following treatment of established lung metastases with irradiation and IL-2 therapy, lung sections were processed for H&E or immunohistochemical staining. We found that tumor irradiation or IL-2 therapy locally induced vascular damage, resulting in multifocal hemorrhages and mononuclear cell mobilization in the lung tissue. This effect was amplified in lungs treated with the combined therapy. Immunohistochemistry showed that irradiation produced a macrophage influx into irradiated tumor nodules, and systemic IL-2 therapy induced T-cell infiltration in tumor nodules. Lungs treated with the combined therapy exhibited massive macrophage, T-cell, and natural killer cell mobilization in disintegrating tumor nodules and in the lung tissue. This combined therapy caused a decrease in the number of proliferating tumor cells and an increase in the number of apoptotic cells, which were more marked than with either therapy alone. We suggest that the macrophages mobilized by radiation-induced tissue injury could play a role in phagocytosis of apoptotic tumor cells, processing and presenting of tumor antigens for a systemic immune response activated by IL-2. Tumor destruction may result from the concomitant action of activated T cells, natural killer cells, and macrophages infiltrating the tumor nodules.

  1. 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

  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. 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.

  4. 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

  5. Prevalence of diabetes mellitus and hypertension among Indian glaucoma patients and evaluation of systemic therapy.

    PubMed

    Dave, Abhishek; Bali, Shveta Jindal; Sharma, Reetika; Khurana, Aruj K; Gupta, Raghav; Dada, Tanuj

    2013-10-01

    To study the prevalence and systemic control and evaluate the adequacy of therapy of diabetes mellitus (DM) and hypertension (HT) in glaucoma patients visiting a tertiary care eye facility at a university hospital. Consecutive cases with primary open-angle glaucoma (POAG) or primary angle-closure glaucoma (PACG) attending the outpatient services were evaluated for the presence of DM and HT and any systemic/ocular medications being taken were recorded. Of 615 glaucoma cases evaluated, 281 (45.7 %) were POAG and 334 (54.3 %) were PACG. The mean age was 58.19 ± 10.8 years with males comprising 60.5 % of the study group. Two hundred and ninety-two (47.5 %) glaucoma patients had HT and 181 (29.4 %) had DM, including 97 (15.8 %) patients who had both. One hundred and thirty-three (47.3 %) patients with POAG and 159 (47.6 %) patients with PACG had HT. Ninety-seven (34.5 %) POAG patients and 84 (25.1 %) PACG patients were diabetics. One hundred and sixty-one (55.1 %) HT patients had blood pressure above control levels and 88 (48.6 %) diabetics had uncontrolled blood sugars. Twenty-eight (9.6 %) patients with HT were found to be taking combined systemic and topical β-blocker therapy. A large majority of adult glaucoma patients had concurrent systemic disease, which was not adequately controlled. Patients were using systemic medications with known interactions with ocular hypotensive medications. This study highlights the unmet need for better coordination between ophthalmologists and physicians to improve the overall health of glaucoma patients.

  6. Conjugates of phosphorylated zalcitabine and lamivudine with SiO2 nanoparticles: Synthesis by CuAAC click chemistry and preliminary assessment of anti-HIV and antiproliferative activity.

    PubMed

    Vasilyeva, Svetlana V; Shtil, Alexander A; Petrova, Albina S; Balakhnin, Sergei M; Achigecheva, Polina Y; Stetsenko, Dmitry A; Silnikov, Vladimir N

    2017-03-01

    Conjugates of phosphorylated dideoxynucleoside antiviral drugs dideoxycytidine (zalcitabine) and lamivudine with SiO2 nanoparticles were obtained via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry between a nucleoside triphosphate containing an alkynyl group at the γ-phosphate or azidothymidine triphosphate and SiO2 nanoparticles containing alkyl azide or alkynyl groups, respectively. 4-(Prop-2-yn-1-yloxy)butylamino group has been attached to the γ-phosphate group of dideoxycytidine (zalcitabine) and lamivudine 5'-triphosphates via the phosphoramidate linkage. New compounds were shown to be potent killers of human colon carcinoma cells. Anti-HIV activity of the conjugates was demonstrated as well. The conjugates of phosphorylated lamivudine and dideoxycytidine (zalcitabine) showed higher potency than the parent nucleosides. The conjugate of phosphorylated azidothymidine was less active against HIV-1 than the parent nucleoside probably because of the replacement of its 3'-azido group by 1,2,3-triazole ring. These results show an opportunity for using SiO2 nanoparticles as a transport for delivering phosphorylated nucleosides to cells in order to increase their efficiency as antiviral and anticancer drugs.

  7. 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

  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. 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].

  10. 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.

  11. 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

  12. 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

  13. Survey Evaluating the Practice of Children's Hospitals Having Pharmacist Collaborative Drug Therapy Management Protocols

    PubMed Central

    Welsh, Chelsea; Miah, Rukshana

    2016-01-01

    OBJECTIVES: The purpose of this study is to determine how frequently children's hospitals in the United States are using pharmacist-physician collaborative drug therapy management (CDTM), and to characterize their use in this population. METHODS: A phone survey was created to collect data regarding the use of pharmacist-physician CDTM at children's hospitals. Children's hospitals were called between February 2014 and April 2014. Data were collected from either a clinical pharmacist or pharmacy director. Pharmacists were asked to answer questions regarding hospital demographics as well as to what extent and for which medications they use CDTM. Differences between types of hospitals were evaluated using Fisher exact test. RESULTS: A total of 171 children's hospitals were identified; 51.5% hospitals (n = 88) completed the survey. Of the 88 hospitals that completed the survey, 32 (31.7%) had some level of CDTM in place. Of the 28 children's hospitals with CDTM in place that completed the survey, all allowed pharmacists to modify doses and monitor therapy, and 75% provided pharmacists with the ability to initiate the first dose. The specific medications that were included in the CDTM protocols in children's hospitals included vancomycin (n = 23), aminoglycosides (n = 22), anticoagulation medications (n = 7), and total parenteral nutrition (n = 3). Training was required for pharmacists to participate in CDTM protocols at most hospitals (n = 26). Lack of support from medical staff was the most common perceived barrier. No differences were identified between types of children's hospitals. CONCLUSION: CDTM protocols are practiced in about one third of the children's hospitals. Pharmacists commonly initiate, monitor, and modify therapies as part of these protocols. The most frequently included medications were vancomycin and aminoglycosides. PMID:28018151

  14. 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

  15. "Barriers to Cognitive Behavioral Therapy Homework Completion Scale- Depression Version": Development and Psychometric Evaluation.

    PubMed

    Callan, Judith A; Dunbar-Jacob, Jacqueline; Sereika, Susan M; Stone, Clement; Fasiczka, Amy; Jarrett, Robin B; Thase, Michael E

    2012-01-01

    We conducted a two-phase study to develop and evaluate the psychometric properties of an instrument to identify barriers to Cognitive Behavioral Therapy (CBT) homework completion in a depressed sample. In Phase I, we developed an item pool by interviewing 20 depressed patients and 20 CBT therapists. In Phase II, we created and administered a draft instrument to 56 people with depression. Exploratory Factor Analysis revealed a 2-factor oblique solution of "Patient Factors" and "Therapy/Task Factors." Internal consistency coefficients ranged from .80 to .95. Temporal stability was demonstrated through Pearson correlations of .72 (for the therapist/task subscale) to .95 (for the patient subscale) over periods of time that ranged from 2 days to 3 weeks. The patient subscale was able to satisfactorily classify patients (75 to 79 %) with low and high adherence at both sessions. Specificity was .66 at both time points. Sensitivity was .80 at sessions B and .77 at session C. There were no consistent predictors of assignment compliance when measured by the Assignment Compliance Rating Scale (Primakoff, Epstein, & Covi, 1986). The Rating Scale and subscale scores did, however, correlate significantly with assignment non-compliance (.32 to .46).

  16. 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.

  17. A virtual approach to evaluate therapies for management of multiple myeloma induced bone disease.

    PubMed

    Ji, Bing; Genever, Paul G; Fagan, Michael J

    2016-03-01

    Multiple myeloma bone disease is devastating for patients and a major cause of morbidity. The disease leads to bone destruction by inhibiting osteoblast activity while stimulating osteoclast activity. Recent advances in multiple myeloma research have improved our understanding of the pathogenesis of multiple myeloma-induced bone disease and suggest several potential therapeutic strategies. However, the effectiveness of some potential therapeutic strategies still requires further investigation and optimization. In this paper, a recently developed mathematical model is extended to mimic and then evaluate three therapies of the disease, namely: bisphosphonates, bortezomib and TGF-β inhibition. The model suggests that bisphosphonates and bortezomib treatments not only inhibit bone destruction, but also reduce the viability of myeloma cells. This contributes to the current debate as to whether bisphosphonate therapy has an anti-tumour effect. On the other hand, the analyses indicate that treatments designed to inhibit TGF-β do not reduce bone destruction, although it appears that they might reduce the viability of myeloma cells, which again contributes to the current controversy regarding the efficacy of TGF-β inhibition in multiple myeloma-induced bone disease.

  18. Preparation and evaluation of amoxicillin loaded dual molecularly imprinted nanoparticles for anti-Helicobacter pylori therapy.

    PubMed

    Wu, Zhihui; Hou, Jiapeng; Wang, Yuyan; Chai, Miaolin; Xiong, Yan; Lu, Weiyue; Pan, Jun

    2015-12-30

    This paper reports studies on preparation and evaluation of amoxicillin loaded dual molecularly imprinted nanoparticles (Amo/Dual-MIPs) designed for anti-H. pylori therapy. Both MNQA and AmoNa were chosen as templates to prepare Dual-MIPs using inverse microemulsion polymerization method. NQA was modified with myristic acid (MNQA) to become amphiphilic and assist in leaving NQA cavities on the surface of Dual-MIPs for H. pylori adhesion. AmoNa was applied to produce imprinting sites in Dual-MIPs for rebinding AmoNa to exert its anti-H. pylori effect. Batch rebinding test demonstrated a preferential rebinding effect of NQA toward the Dual-MIPs. In vivofluorescence imaging showed the prolonged residence time of Dual-MIPs in H. pylori infected mice stomachs after intragastric administration of nanoparticles.In vivo H. pylori clearance tests indicated Amo/Dual-MIPs had a better aniti-H. pylori effect than amoxicillin powder did. In conclusion, Amo/Dual-MIPs may provide an alternative drug delivery strategy for anti-H. pylori therapy.

  19. Laboratory evaluation of a new delivery system to improve patient compliance with chelation therapy.

    PubMed

    Lombardo, T; Frontini, V; Ferro, G; Sergi, P; Guidice, A; Lombardo, G

    1996-03-01

    As thalassaemia patients live longer, compliance with chelation therapy becomes more and more of a problem. Teenagers rebel against the continual need for treatment, and young adults with jobs, active social lives and families, find it hard to find the time to prepare and deliver their treatments. In an effort to find a solution to this problem, we evaluated a non-electronic, disposable pump (Infusor 5 ml/h, Baxter Healthcare) to determine its suitability for high dose desferrioxamine (DFO) infusions. We wanted an infusion time of 12 h to support overnight delivery in the patient's home. Because of DFOs viscosity, infusion times vary at different concentrations. We found the optimal prescription for total delivery within 12 h to be a dose of 70 mg/kg x patient's body weight diluted in constant volume of 40 ml of water for injection. Our tests were carried out in vitro and the results show that the 5 ml/h Infusor may be used to deliver high dose DFO chelation therapy within 12 h. The variability of the flow rate, dependent on the concentration of the solution, and the absence of a warning system, are more than compensated for by the simplicity of the pump.

  20. Evaluation of the Photodynamic Therapy effect using a tumor model in Chorioallantoic Membrane with Melanoma cells

    NASA Astrophysics Data System (ADS)

    Buzzá, Hilde H.; Pires, Layla; Bagnato, Vanderlei S.; Kurachi, Cristina

    2014-03-01

    Photodynamic Therapy (PDT) is a type of cancer treatment that is based on the interaction of light (with specific wavelength), a photosensitizing agent and molecular oxygen. The photosensitizer (PS) is activated by light and reacts with oxygen resulting in the production of singlet oxygen that is highly reactive and responsible for the cell death. The Chick Chorioallantoic Membrane (CAM) model is a transparent membrane that allows visualization and evaluation of blood vessels and structural changes, where a tumor model was developed. Two induction tumor models were investigated: tumor biopsy or cell culture. It was used a murine melanoma cell B16F10 in culture and a biopsy from a xenograft tumor in hairless mouse. Two PS were tested: Photodithazine® and Photogem®, a chlorine and porphyrin compounds, respectively. Using intravenous administration, the light-drug interval was of 30 minutes, 1 and 3 hours. Illumination was performed at 630 nm and 660 nm, and the vascular and tumor response was monitored and analyzed. The PS distribution was checked with confocal microscopy. This model can be useful to study several parameters of PDT and the effect of this therapy in the cancer treatment since it allows direct visualization of its effects.

  1. 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

  2. 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.

  3. Evaluation of Ferric and Ferrous Iron Therapies in Women with Iron Deficiency Anaemia

    PubMed Central

    Berber, Ilhami; Erkurt, Mehmet Ali; Aydogdu, Ismet; Kuku, Irfan

    2014-01-01

    Introduction. Different ferric and ferrous iron preparations can be used as oral iron supplements. Our aim was to compare the effects of oral ferric and ferrous iron therapies in women with iron deficiency anaemia. Methods. The present study included 104 women diagnosed with iron deficiency anaemia after evaluation. In the evaluations performed to detect the aetiology underlying the iron deficiency anaemia, it was found and treated. After the detection of the iron deficiency anaemia aetiology and treatment of the underlying aetiology, the ferric group consisted of 30 patients treated with oral ferric protein succinylate tablets (2 × 40 mg elemental iron/day), and the second group consisted of 34 patients treated with oral ferrous glycine sulphate tablets (2 × 40 mg elemental iron/day) for three months. In all patients, the following laboratory evaluations were performed before beginning treatment and after treatment. Results. The mean haemoglobin and haematocrit increases were 0.95 g/dL and 2.62% in the ferric group, while they were 2.25 g/dL and 5.91% in the ferrous group, respectively. A significant difference was found between the groups regarding the increase in haemoglobin and haematocrit values (P < 0.05). Conclusion. Data are submitted on the good tolerability, higher efficacy, and lower cost of the ferrous preparation used in our study. PMID:25006339

  4. Synthesis and biological evaluation of new chlorin derivatives as potential photosensitizers for photodynamic therapy.

    PubMed

    Asano, Ryuji; Nagami, Amon; Fukumoto, Yuki; Yazama, Futoshi; Ito, Hideyuki; Sakata, Isao; Tai, Akihiro

    2013-04-15

    Three new water-soluble chlorin derivatives 3, 5 and 8 for potential use as photosensitizers in photodynamic therapy (PDT) for cancer were synthesized from photoprotoporphyrin IX dimethyl ester (1). The in vivo biodistribution and clearance of chlorin derivatives 3, 5 and 8 were investigated in tumor-bearing mice. Iminodiacetic acid derivative 8 showed the greatest tumor-selective accumulation among the new chlorin derivatives with maximum accumulation in tumor tissue at 3h after intravenous injection and rapid clearance from normal tissues within 24h after injection. The in vivo therapeutic efficacy of PDT using 8 was evaluated by measuring tumor growth rates in tumor-bearing mice with 660 nm light-emitting diode irradiation at 3h after injection of 8. Tumor growth was significantly inhibited by PDT using 8. These results indicate that iminodiacetic acid derivative 8 is useful as a new photosensitizer to overcome the disadvantages of photosensitizers that are currently in clinical use.

  5. Sexual violence therapy group in a women's correctional facility: a preliminary evaluation.

    PubMed

    Karlsson, Marie E; Bridges, Ana J; Bell, Jessica; Petretic, Patricia

    2014-06-01

    This pilot study was an evaluation of an 8-week exposure-based therapy group targeting sexual trauma in incarcerated women, an underserved population with high rates of trauma exposure. Preliminary findings from 14 female prisoners showed significant decreases in depressive and anxiety symptoms from pre- to posttreatment. Of the women who were above the screening cutoff for possible posttraumatic stress disorder (PTSD; n = 13), depression (n = 12), and generalized anxiety disorder (GAD; n = 12) at pretreatment, approximately 60% had recovered, meaning they had symptom reductions that placed them below the cutoff at posttreatment (n = 8 for PTSD; n = 8 for depression, and n = 9 for GAD). In addition, 85% of participants reported a clinically significant reduction in depressive symptoms and 50% in GAD symptoms. The findings show promise for successful group treatment of sexual violence sequelae in incarcerated women.

  6. Practical evaluations on heating characteristics of thin microwave antenna for intracavitary thermal therapy.

    PubMed

    Saito, Kazuyuki; Tsubouchi, Kousuke; Takahashi, Masaharu; Ito, Koichi

    2010-01-01

    Microwave thermal therapy is one of the modalities for cancer treatment. There are several schemes of microwave heating. The authors have been studying thin coaxial antenna for intracavitary microwave heating aiming at the treatment of bile duct carcinoma. Up to now, the heating characteristics of the antenna are investigated by numerical simulation and experiment for finding a possibility of the treatment. In this study, in order to consider practical situations of the treatment, heating characteristics of the antenna inserted into a metallic stent is evaluated by numerical simulations. Moreover, the relation between coagulation size of the tissue and the radiation power from the antenna is investigated experimentally. It must be considered, when the input power of the antenna is high (around several tens of watts). From these investigations, some useful results for practical treatments were found.

  7. Lectin-directed enzyme activated prodrug therapy (LEAPT): Synthesis and evaluation of rhamnose-capped prodrugs.

    PubMed

    Garnier, Philippe; Wang, Xiang-Tao; Robinson, Mark A; van Kasteren, Sander; Perkins, Alan C; Frier, Malcolm; Fairbanks, Antony J; Davis, Benjamin G

    2010-12-01

    The lectin-directed enzyme activated prodrug therapy (LEAPT) bipartite drug delivery system utilizes glycosylated enzyme, localized according to its sugar pattern, and capped prodrugs released by that enzyme. In this way, the sugar coat of a synthetic enzyme determines the site of release of a given drug. Here, prodrugs of doxorubicin and 5-fluorouracil capped by the nonmammalian l-rhamnosyl sugar unit have been efficiently synthesized and evaluated for use in the LEAPT system. Both are stable in blood, released by synthetically d-galactosylated rhamnosidase enzyme, and do not inhibit the uptake of the synthetic enzyme to its liver target. These results are consistent with their proposed mode of action and efficacy in models of liver cancer, and confirm modular flexibility in the drugs that may be used in LEAPT.

  8. Evaluation of a tyrosine kinase peptide microarray for tyrosine kinase inhibitor therapy selection in cancer

    PubMed Central

    Labots, Mariette; Gotink, Kristy J; Dekker, Henk; Azijli, Kaamar; van der Mijn, Johannes C; Huijts, Charlotte M; Piersma, Sander R; Jiménez, Connie R; Verheul, Henk M W

    2016-01-01

    Personalized cancer medicine aims to accurately predict the response of individual patients to targeted therapies, including tyrosine kinase inhibitors (TKIs). Clinical implementation of this concept requires a robust selection tool. Here, using both cancer cell lines and tumor tissue from patients, we evaluated a high-throughput tyrosine kinase peptide substrate array to determine its readiness as a selection tool for TKI therapy. We found linearly increasing phosphorylation signal intensities of peptides representing kinase activity along the kinetic curve of the assay with 7.5–10 μg of lysate protein and up to 400 μM adenosine triphosphate (ATP). Basal kinase activity profiles were reproducible with intra- and inter-experiment coefficients of variation of <15% and <20%, respectively. Evaluation of 14 tumor cell lines and tissues showed similar consistently high phosphorylated peptides in their basal profiles. Incubation of four patient-derived tumor lysates with the TKIs dasatinib, sunitinib, sorafenib and erlotinib primarily caused inhibition of substrates that were highly phosphorylated in the basal profile analyses. Using recombinant Src and Axl kinase, relative substrate specificity was demonstrated for a subset of peptides, as their phosphorylation was reverted by co-incubation with a specific inhibitor. In conclusion, we demonstrated robust technical specifications of this high-throughput tyrosine kinase peptide microarray. These features required as little as 5–7 μg of protein per sample, facilitating clinical implementation as a TKI selection tool. However, currently available peptide substrates can benefit from an enhancement of the differential potential for complex samples such as tumor lysates. We propose that mass spectrometry-based phosphoproteomics may provide such an enhancement by identifying more discriminative peptides. PMID:27980342

  9. 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.

  10. Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy.

    PubMed

    Popovic, Mikulas; Tenner-Racz, Klara; Pelser, Colleen; Stellbrink, Hans-Jurgen; van Lunzen, Jan; Lewis, George; Kalyanaraman, Vaniambadi S; Gallo, Robert C; Racz, Paul

    2005-10-11

    Here we report a long-term persistence of HIV-1 structural proteins and glycoproteins in germinal centers (GCs) of lymph nodes (LNs) in the absence of detectable virus replication in patients under highly active antiretroviral therapy (HAART). The persistence of viral structural proteins and glycoproteins in GCs was accompanied by specific antibody responses to HIV-1. Seven patients during the chronic phase of HIV-1 infection were analyzed for the presence of the capsid protein (HIV-1p24), matrix protein (HIV-1p17), and envelope glycoproteins (HIV-1gp120/gp41), as well as for viral RNA (vRNA) in biopsy specimens from LNs obtained before initiation of therapy and during HAART that lasted from 5 to 13 months. In parallel, these patients were also monitored for viremia and specific anti-HIV-1 antibody responses to structural proteins and glycoproteins both before and during treatment. Before-therapy viral levels, as determined by RT-PCR, ranged from 3 x 10(3) to 6.3 x 10(5) copies of vRNA per ml, whereas during treatment, vRNA was under detectable levels (<25 copies per ml). The pattern of vRNA detection in peripheral blood was concordant with in situ hybridization results of LN specimens. Before treatment, vRNA associated with follicular dendritic cells (FDCs) was readily detected in GCs of LNs of the patients, whereas during therapy, vRNA was consistently absent in the GCs of LN biopsies of treated patients. In contrast to vRNA hybridization results, viral structural proteins and glycoproteins, evaluated by immunohistochemical staining, were present and persisted in the GC light zone of LNs in abundant amounts not only before initiation of therapy but also during HAART, when no vRNA was detected in GCs. Consistent with immunohistochemical findings, specific antibody responses to HIV-1p17, -p24, and -gp120/gp41, as evaluated by ELISA and virus neutralization, persisted in patients under therapy for up to 13 months of follow-up. The implications of these findings are

  11. Evaluation of TorsinA as a target for Parkinson disease therapy in mouse models.

    PubMed

    Li, Xinru; Lee, Jenny; Parsons, Dee; Janaurajs, Karen; Standaert, David G

    2012-01-01

    Parkinson disease (PD) is a common and disabling disorder. No current therapy can slow or reverse disease progression. An important aspect of research in this field is target validation, a systematic approach to evaluating the likelihood that modification of a certain molecule, mechanism or biological pathway may be useful for the development of pharmacological or molecular treatments for the disease. TorsinA, a member of the AAA+ family of chaperone proteins, has been proposed as a potential target of neuroprotective therapy. TorsinA is found in Lewy bodies in human PD, and can suppress toxicity in cellular and invertebrate models of PD. Here, we evaluated the neuroprotective properties of torsinA in mouse models of PD based on intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as recombinant adeno associated virus (rAAV) induced overexpression of alpha-synuclein (α-syn). Using either transgenic mice with overexpression of human torsinA (hWT mice) or mice in which torsinA expression was induced using an rAAV vector, we found no evidence for protection against acute MPTP intoxication. Similarly, genetic deletion of the endogenous mouse gene for torsinA (Dyt1) using an rAAV delivered Cre recombinase did not enhance the vulnerability of dopaminergic neurons to MPTP. Overexpression of α-syn using rAAV in the mouse substantia nigra lead to a loss of TH positive neurons six months after administration, and no difference in the degree of loss was observed between transgenic animals expressing forms of torsinA and wild type controls. Collectively, we did not observe evidence for a protective effect of torsinA in the mouse models we examined. Each of these models has limitations, and there is no single model with established predictive value with respect to the human disease. Nevertheless, these data do seem to support the view that torsinA is unlikely to be successfully translated as a target of therapy for human PD.

  12. Sensitive analysis of anti-HIV drugs, efavirenz, lopinavir and ritonavir, in human hair by liquid chromatography coupled with tandem mass spectrometry.

    PubMed

    Huang, Yong; Gandhi, Monica; Greenblatt, Ruth M; Gee, Winnie; Lin, Emil T; Messenkoff, Nicholas

    2008-11-01

    A highly sensitive and selective method using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) was developed and validated for the measurement of three antiretroviral agents, efavirenz, lopinavir and ritonavir, in human hair. Hair samples from adherent HIV-infected patients on antiretroviral therapies were cut into about 1 mm length segments and drugs were extracted by first shaking the samples with methanol in a 37 degrees C water bath overnight (>14 h), followed by methyl tert-butyl ether/ethyl acetate (1:1) extraction under weak alkaline conditions. The extracted lopinavir and ritonavir were separated by reversed-phase chromatography and detected by tandem mass spectrometry in electrospray positive ionization mode with multiple reaction monitoring (MRM), while efavirenz was monitored in negative ionization MRM mode. This method was validated from 0.01 to 4.0 ng/mg hair for ritonavir and 0.05-20 ng/mg hair for lopinavir and efavirenz by using 2 mg of a human hair sample. The interday and intraday assay precision (coefficients of variation, CV) for spiked quality control (QC) samples at low, medium and high concentrations were within 15% and accuracy ranged from 89% to 110%. Assay reproducibility was also demonstrated by analysis of incurred hair QC samples (CV <14%). No significant matrix ionization suppression was observed. This developed method allowed for the monitoring of these target medications in the hair samples of HIV-infected women on antiretroviral therapy in an observational study using small amounts of hair.

  13. 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

  14. Cost effectiveness of physiotherapy, manual therapy, and general practitioner care for neck pain: economic evaluation alongside a randomised controlled trial

    PubMed Central

    Bos, Ingeborg B C Korthals-de; Hoving, Jan L; van Tulder, Maurits W; Mölken, Maureen P M H Rutten-van; Adèr, Herman J; de Vet, Henrica C W; Koes, Bart W; Vondeling, Hindrik; Bouter, Lex M

    2003-01-01

    Objective To evaluate the cost effectiveness of physiotherapy, manual therapy, and care by a general practitioner for patients with neck pain. Design Economic evaluation alongside a randomised controlled trial. Setting Primary care. Participants 183 patients with neck pain for at least two weeks recruited by 42 general practitioners and randomly allocated to manual therapy (n=60, spinal mobilisation), physiotherapy (n=59, mainly exercise), or general practitioner care (n=64, counselling, education, and drugs). Main outcome measures Clinical outcomes were perceived recovery, intensity of pain, functional disability, and quality of life. Direct and indirect costs were measured by means of cost diaries that were kept by patients for one year. Differences in mean costs between groups, cost effectiveness, and cost utility ratios were evaluated by applying non-parametric bootstrapping techniques. Results The manual therapy group showed a faster improvement than the physiotherapy group and the general practitioner care group up to 26 weeks, but differences were negligible by follow up at 52 weeks. The total costs of manual therapy (€447; £273; $402) were around one third of the costs of physiotherapy (€1297) and general practitioner care (€1379). These differences were significant: P<0.01 for manual therapy versus physiotherapy and manual therapy versus general practitioner care and P=0.55 for general practitioner care versus physiotherapy. The cost effectiveness ratios and the cost utility ratios showed that manual therapy was less costly and more effective than physiotherapy or general practitioner care. Conclusions Manual therapy (spinal mobilisation) is more effective and less costly for treating neck pain than physiotherapy or care by a general practitioner. What is already known on this topicThe cost of treating neck pain is considerableMany conservative interventions are available, such as prescription drugs, yet their cost effectiveness has not been

  15. Gene therapy for HIV/AIDS: the potential for a new therapeutic regimen.

    PubMed

    Fanning, Greg; Amado, Rafael; Symonds, Geoff

    2003-08-01

    Human Immunodeficiency Virus (HIV) is the etiologic agent of Acquired Immunodeficiency Syndrome (AIDS). HIV/AIDS is a disease that, compared with the not so distant past, is now better held in check by current antiretroviral drugs. However, it remains a disease not solved. Highly active antiretroviral therapy (HAART) generally uses two non-nucleoside and one nucleoside reverse transcriptase (RT) inhibitor or two non-nucleoside RT and one protease inhibitor. HAART is far more effective than the mono- or duo-therapy of the past, which used compounds like the nucleoside reverse transcriptase inhibitor AZT or two nucleoside reverse transcriptase inhibitors. However, even with the relatively potent drug cocktails that comprise HAART, there are the issues of (i). HIV escape mutants, (ii). an apparent need to take the drugs in an ongoing manner, and (iii). the drugs' side effects that are often severe. This review speaks to the potential addition to these potent regimens of another regimen, namely the genetic modification of target hematopoietic cells. Such a new treatment paradigm is conceptually attractive as it may yield the constant intracellular expression of an anti-HIV gene that acts to inhibit HIV replication and pathogenicity. A body of preclinical work exists showing the inhibition of HIV replication and decreased HIV pathogenicity by anti-HIV genetic agents. This preclinical work used hematopoietic cell lines and primary cells as the target tissue. More recently, several clinical trials have sought to test this concept in vivo.

  16. Drug evaluation: ADA-transduced hematopoietic stem cell therapy for ADA-SCID.

    PubMed

    Taupin, Phillippe

    2006-06-01

    San Raffaele Telethon Institute for Gene Therapy is developing an adenosine deaminase-transduced hematopoietic stem cell therapy for the potential intravenous treatment of adenosine deaminase deficiency in severe combined immunocompromised individuals.

  17. Evaluation of ADA gene expression and transduction efficiency in ADA/SCID patients undergoing gene therapy.

    PubMed

    Carlucci, F; Tabucchi, A; Aiuti, A; Rosi, F; Floccari, F; Pagani, R; Marinello, E

    2004-10-01

    A capillary electrophoresis (CE) method was developed for ADA/SCID diagnosis and monitoring of enzyme replacement therapy, as well as for exploring the transfection efficiency for different retroviral vectors in gene therapy.

  18. Action-oriented evaluation of an in-home family therapy program for families at risk for foster care placement.

    PubMed

    McWey, Lenore M; Humphreys, Julie; Pazdera, Andrea L

    2011-04-01

    The purpose of this study was to conduct an action-oriented evaluation of an in-home family therapy program serving families deemed at risk for the placement of children in foster care. In this study, feedback was solicited from both clients and therapists. Results indicate "duality" associated with several aspects of in-home family therapy, including the opportunity to observe families in their own homes versus the vulnerability some families feel when therapy is conducted in-home; therapists suggesting that sufficient training is required for in-home family therapy to be effective versus clients' opinions that therapists' lived experiences are more relevant; and the importance of the therapeutic alliance versus feelings of abandonment upon termination. Implications for researchers and practitioners are discussed.

  19. Mathematical Modeling and Evaluation of Human Motions in Physical Therapy Using Mixture Density Neural Networks

    PubMed Central

    Vakanski, A; Ferguson, JM; Lee, S

    2016-01-01

    Objective The objective of the proposed research is to develop a methodology for modeling and evaluation of human motions, which will potentially benefit patients undertaking a physical rehabilitation therapy (e.g., following a stroke or due to other medical conditions). The ultimate aim is to allow patients to perform home-based rehabilitation exercises using a sensory system for capturing the motions, where an algorithm will retrieve the trajectories of a patient’s exercises, will perform data analysis by comparing the performed motions to a reference model of prescribed motions, and will send the analysis results to the patient’s physician with recommendations for improvement. Methods The modeling approach employs an artificial neural network, consisting of layers of recurrent neuron units and layers of neuron units for estimating a mixture density function over the spatio-temporal dependencies within the human motion sequences. Input data are sequences of motions related to a prescribed exercise by a physiotherapist to a patient, and recorded with a motion capture system. An autoencoder subnet is employed for reducing the dimensionality of captured sequences of human motions, complemented with a mixture density subnet for probabilistic modeling of the motion data using a mixture of Gaussian distributions. Results The proposed neural network architecture produced a model for sets of human motions represented with a mixture of Gaussian density functions. The mean log-likelihood of observed sequences was employed as a performance metric in evaluating the consistency of a subject’s performance relative to the reference dataset of motions. A publically available dataset of human motions captured with Microsoft Kinect was used for validation of the proposed method. Conclusion The article presents a novel approach for modeling and evaluation of human motions with a potential application in home-based physical therapy and rehabilitation. The described approach

  20. Adult-onset hypogonadism: evaluation and role of testosterone replacement therapy

    PubMed Central

    Davidiuk, Andrew J.

    2016-01-01

    Testosterone deficiency (TD) has become a growing concern in the field of men’s sexual health, with an increasing number of men presenting for evaluation of this condition. Given the increasing demand for testosterone replacement therapy (TRT), a panel of experts met in August of 2015 to discuss the treatment of men who present for evaluation in the setting of low or normal gonadotropin levels and the associated signs and symptoms of hypogonadism. This constellation of factors can be associated with elements of both primary and secondary hypogonadism. Because this syndrome commonly occurs in men who are middle-aged and older, it was termed adult-onset hypogonadism (AOH). AOH can be defined by the following elements: low levels of testosterone, associated signs and symptoms of hypogonadism, and low or normal gonadotropin levels. Although there are significant benefits of TRT for patients with AOH, candidates also need to understand the potential risks. Patients undergoing TRT will need to be monitored regularly because there are potential complications that can develop with long-term use. This review is aimed at providing a deeper understanding of AOH, discussing the benefits and risks of TRT, and outlining each modality of TRT in use for AOH. PMID:28078213

  1. 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

  2. Development and initial evaluation of Transdiagnostic Behavior Therapy (TBT) for veterans with affective disorders.

    PubMed

    Gros, Daniel F

    2014-12-15

    Considerable attention has focused on the growing need for evidence-based psychotherapy for veterans with affective disorders within the Department of Veteran Affairs. Despite, and possibly due to, the large number of evidence-based protocols available, several obstacles remain in their widespread delivery within Veterans Affairs Medical Centers. In part as an effort to address these concerns, newer transdiagnostic approaches to psychotherapy have been developed to provide a single treatment that is capable of addressing several, related disorders. The goal of the present investigation was to develop and evaluate a transdiagnostic psychotherapy, Transdiagnostic Behavior Therapy (TBT), in veterans with affective disorders. Study 1 provided initial support for transdiagnostic presentation of evidence-based psychotherapy components in veterans with principal diagnoses of affective disorders (n=15). These findings were used to inform the development of the TBT protocol. In Study 2, an initial evaluation of TBT was completed in a second sample of veterans with principal diagnoses of affective disorders (n=29). The findings of Study 2 demonstrated significant improvements in symptoms of depression, anxiety, stress, posttraumatic stress, and related impairment across participants with various principal diagnoses. Together, the investigation provided preliminary support for effectiveness of TBT in veterans with affective disorders.

  3. Evaluation of bacteriochlorophyll-reconstituted low-density lipoprotein nanoparticles for photodynamic therapy efficacy in vivo

    PubMed Central

    Marotta, Diane E; Cao, Weiguo; Wileyto, E Paul; Li, Hui; Corbin, Ian; Rickter, Elizabeth; Glickson, Jerry D; Chance, Britton; Zheng, Gang; Busch, Theresa M

    2011-01-01

    Aim To evaluate the novel nanoparticle reconstituted bacteriochlorin e6 bisoleate low-density lipoprotein (r-Bchl-BOA-LDL) for its efficacy as a photodynamic therapy agent delivery system in xenografts of human hepatoblastoma G2 (HepG2) tumors. Materials & methods Bchl-BOA was encapsulated in the nanoparticle low-density lipoprotein (LDL), a native particle whose receptor’s overexpression is a cancer signature for a number of neoplasms. Evaluation of r-Bchl-BOA-LDL as a potential photosensitizer was performed using a tumor response and foot response assay. Results & discussion When compared with controls, tumor regrowth was significantly delayed at injected murine doses of 2 µmole/kg r-Bchl-BOA-LDL after illumination at fluences of 125, 150 or 175 J/cm2. Foot response assays showed that although normal tissue toxicity accompanied the higher fluences it was significantly reduced at the lowest fluence tested. Conclusion This research demonstrates that r-Bchl-BOA-LDL is an effective photosensitizer and a promising candidate for further investigation. PMID:21542686

  4. 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

  5. A detailed evaluation of TomoDirect 3DCRT planning for whole-breast radiation therapy.

    PubMed

    Fields, Emma C; Rabinovitch, Rachel; Ryan, Nicole E; Miften, Moyed; Westerly, David C

    2013-01-01

    The goal of this work was to develop planning strategies for whole-breast radiotherapy (WBRT) using TomoDirect three-dimensional conformal radiation therapy (TD-3DCRT) and to compare TD-3DCRT with conventional 3DCRT and TD intensity-modulated radiation therapy (TD-IMRT) to evaluate differences in WBRT plan quality. Computed tomography (CT) images of 10 women were used to generate 150 WBRT plans, varying in target structures, field width (FW), pitch, and number of beams. Effects on target and external maximum doses (EMD), organ-at-risk (OAR) doses, and treatment time were assessed for each parameter to establish an optimal planning technique. Using this technique, TD-3DCRT plans were generated and compared with TD-IMRT and standard 3DCRT plans. FW 5.0cm with pitch = 0.250cm significantly decreased EMD without increasing lung V20Gy. Increasing number of beams from 2 to 6 and using an additional breast planning structure decreased EMD though increased lung V20Gy. Changes in pitch had minimal effect on plan metrics. TD-3DCRT plans were subsequently generated using FW 5.0cm, pitch = 0.250cm, and 2 beams, with additional beams or planning structures added to decrease EMD when necessary. TD-3DCRT and TD-IMRT significantly decreased target maximum dose compared to standard 3DCRT. FW 5.0cm with 2 to 6 beams or novel planning structures or both allow for TD-3DCRT WBRT plans with excellent target coverage and OAR doses. TD-3DCRT plans are comparable to plans generated using TD-IMRT and provide an alternative to conventional 3DCRT for WBRT.

  6. Prognosis of invasive breast cancer after adjuvant therapy evaluated with VEGF microvessel density and microvascular imaging.

    PubMed

    Li, Ying; Wei, Xi; Zhang, Sheng; Zhang, Jin

    2015-11-01

    The aim of this study was to investigate the role of ultrasonographic microvascular imaging in the evaluation of prognosis of patients with invasive breast cancer treated by adjuvant therapies. A total of 121 patients with invasive breast cancer underwent ultrasonographic contrast-enhanced imaging, vascular endothelial growth factor (VEGF) staining, and microvessel density (MVD) counts. The parameters of microvascular imaging and the expression of VEGF and MVD in primary breast cancer were calculated. The correlation between these factors and the overall and progression-free survival rate were analyzed using the Kaplan-Meier method. Among 121 cases, the positive VEGF cases were 75 and negative ones were 46. The cut point of 52.3 was calculated by the regressive curve for MVD counts. The data showed the mean intensity (MI) was positively associated with both the MVD counts (r = .51, p < .001) and VEGF expression (r = .35, p < .001). For the prognosis of patients, high VEGF expression and MVD counts were associated with reduced progressive and survival times (PFS, p = .032 and p = .034; OS, p = .041 and p = .038, respectively). The correlation between parameters of microvascular imaging, VEGF expressive status, and the MVD counts were established. The cut point of mean intensity (MI = 40) was used to investigate as an independent predictor for PFS (p = .021) and OS (p = .025), respectively, due to a strong correlation between MVD counts and VEGF expression in patients with invasive breast cancer. The microvascular imaging could be a visual and helpful tool to predict the prognosis of patients with invasive breast cancer treated by adjuvant therapies.

  7. 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.

  8. 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

  9. 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

  10. 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

  11. Evaluation of research trends in physical therapy through analysis of articles published at the world confederation for physical therapy congress

    PubMed Central

    Lee, Wan-hee; Jeong, Ju-Ri; Hahn, Joohee

    2016-01-01

    [Purpose] The purpose of this study was to examine research trends in physical therapy through analysis of articles published at the 2015 World Confederation for Physical Therapy Congress. [Subjects and Methods] A total of 1,339 were analyzed (presentations: 346, posters: 993). The number of papers per subject area, number of oral presentations and posters, and the number of moderator nations and regional publications were analyzed by subject area. The mean and standard deviation was used for statistical analysis. [Results] Of 1,339 items published, the musculoskeletal spine was the most common theme, with 89. Among oral presentations, 24 had cardiorespiratory themes; among poster presentations, themes related to the elderly were the most common, at 76. Eleven moderators were from Australia, and the most frequent regional source of papers was Japan, with 238. [Conclusion] The 2015 WCPT Congress published papers in a variety of subject areas; Australia and the UK presented many papers, but Japan had the most of any region, at 238. PMID:28174476

  12. Evaluation of research trends in physical therapy through analysis of articles published at the world confederation for physical therapy congress.

    PubMed

    Lee, Wan-Hee; Jeong, Ju-Ri; Hahn, Joohee

    2016-12-01

    [Purpose] The purpose of this study was to examine research trends in physical therapy through analysis of articles published at the 2015 World Confederation for Physical Therapy Congress. [Subjects and Methods] A total of 1,339 were analyzed (presentations: 346, posters: 993). The number of papers per subject area, number of oral presentations and posters, and the number of moderator nations and regional publications were analyzed by subject area. The mean and standard deviation was used for statistical analysis. [Results] Of 1,339 items published, the musculoskeletal spine was the most common theme, with 89. Among oral presentations, 24 had cardiorespiratory themes; among poster presentations, themes related to the elderly were the most common, at 76. Eleven moderators were from Australia, and the most frequent regional source of papers was Japan, with 238. [Conclusion] The 2015 WCPT Congress published papers in a variety of subject areas; Australia and the UK presented many papers, but Japan had the most of any region, at 238.

  13. 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

  14. 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.

  15. 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

  16. Cross-neutralizing anti-HIV-1 human single chain variable fragments(scFvs) against CD4 binding site and N332 glycan identified from a recombinant phage library

    PubMed Central

    Khan, Lubina; Kumar, Rajesh; Thiruvengadam, Ramachandran; Parray, Hilal Ahmad; Makhdoomi, Muzamil Ashraf; Kumar, Sanjeev; Aggarwal, Heena; Mohata, Madhav; Hussain, Abdul Wahid; Das, Raksha; Varadarajan, Raghavan; Bhattacharya, Jayanta; Vajpayee, Madhu; Murugavel, K. G.; Solomon, Suniti; Sinha, Subrata; Luthra, Kalpana

    2017-01-01

    More than 50% of HIV-1 infection globally is caused by subtype_C viruses. Majority of the broadly neutralizing antibodies (bnAbs) targeting HIV-1 have been isolated from non-subtype_C infected donors. Mapping the epitope specificities of bnAbs provides useful information for vaccine design. Recombinant antibody technology enables generation of a large repertoire of monoclonals with diverse specificities. We constructed a phage recombinant single chain variable fragment (scFv) library with a diversity of 7.8 × 108 clones, using a novel strategy of pooling peripheral blood mononuclear cells (PBMCs) of six select HIV-1 chronically infected Indian donors whose plasma antibodies exhibited potent cross neutralization efficiency. The library was panned and screened by phage ELISA using trimeric recombinant proteins to identify viral envelope specific clones. Three scFv monoclonals D11, C11 and 1F6 selected from the library cross neutralized subtypes A, B and C viruses at concentrations ranging from 0.09 μg/mL to 100 μg/mL. The D11 and 1F6 scFvs competed with mAbs b12 and VRC01 demonstrating CD4bs specificity, while C11 demonstrated N332 specificity. This is the first study to identify cross neutralizing scFv monoclonals with CD4bs and N332 glycan specificities from India. Cross neutralizing anti-HIV-1 human scFv monoclonals can be potential candidates for passive immunotherapy and for guiding immunogen design. PMID:28332627

  17. 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.

  18. 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

  19. 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

  20. Alcohol-Focused Spouse Involvement and Behavioral Couples Therapy: Evaluation of Enhancements to Drinking Reduction Treatment for Male Problem Drinkers

    ERIC Educational Resources Information Center

    Walitzer, Kimberly S.; Dermen, Kurt H.

    2004-01-01

    This study evaluated the effects of alcohol-focused spouse involvement and behavioral couples therapy (BCT) in group drinking reduction treatment for male problem drinkers. Sixty-four male clients and their female partners were randomly assigned to 1 of 3 conditions: treatment for problem drinkers only (PDO), couples alcohol-focused treatment, or…

  1. 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…

  2. An Evaluation of Auditory Verbal Therapy Using the Rate of Early Language Development as an Outcome Measure

    ERIC Educational Resources Information Center

    Hogan, Sarah; Stokes, Jacqueline; White, Catherine; Tyszkiewicz, Elizabeth; Woolgar, Alexandra

    2008-01-01

    Providing unbiased data concerning the outcomes of particular intervention methods is imperative if professionals and parents are to assimilate information which could contribute to an "informed choice". An evaluation of Auditory Verbal Therapy (AVT) was conducted using a formal assessment of spoken language as an outcome measure. Spoken…

  3. 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...

  4. Evaluation of Immune Responses Mediated by Listeria-Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy

    DTIC Science & Technology

    2014-07-01

    by Listeria -Stimulated Human Dendritic Cells: Implications for Cancer Vaccine Therapy PRINCIPAL INVESTIGATOR: David J. Chung, MD, PhD...5a. CONTRACT NUMBER Evaluation of Immune Responses Mediated by Listeria -Stimulated Human Dendritic Cells: Implications for Cancer Vaccine...ABSTRACT The purpose of this project is to study the immunomodulatory effect of Listeria on human dendritic cells (DCs) to optimize Listeria - based

  5. Homology modeling and molecular interaction field studies of α-glucosidases as a guide to structure-based design of novel proposed anti-HIV inhibitors

    NASA Astrophysics Data System (ADS)

    da Silva, C. H. Tomich, P.; Carvalho, Ivone; Taft, C. A.

    2005-02-01

    For AIDS therapy, there are currently a number of compounds available for multiple targets already approved by the FDA and in clinic, e.g. protease inhibitors, reverse transcriptase inhibitors (NRTI, NNRTI), fusion inhibitors, CCR4, CCR5 among others. Some pharmaceuticals act against the virus before the entrance of HIV into the host cells. One of these targets is the glucosidase protein. This novel fusion target has been recently explored because the synthesis of viral glycoproteins depends on the activity of enzymes, such as glucosidase and transferase, for the elaboration of the polysaccharides. In this work we have built an homology model of Saccharomyces cerevisiae glucosidase and superimposed all relevant glucosidase-like enzymes in complex with carbohydrates, and calculated as well molecular interaction fields in our S. cerevisiae active site model. Our results suggest that there are two saccharide binding sites which are the most important for the binding of inhibitors with this family of enzymes which supports the possibility of inhibitors containing only two sugar units. Based on these results, we have proposed a novel pseudo-dissacharide which is a potential pharmaceutical for AIDS treatment.

  6. Use of mutated self-cleaving 2A peptides as a molecular rheostat to direct simultaneous formation of membrane and secreted anti-HIV immunoglobulins.

    PubMed

    Yu, Kenneth K; Aguilar, Kiefer; Tsai, Jonathan; Galimidi, Rachel; Gnanapragasam, Priyanthi; Yang, Lili; Baltimore, David

    2012-01-01

    In nature, B cells produce surface immunoglobulin and secreted antibody from the same immunoglobulin gene via alternative splicing of the pre-messenger RNA. Here we present a novel system for genetically programming B cells to direct the simultaneous formation of membrane-bound and secreted immunoglobulins that we term a "Molecular Rheostat", based on the use of mutated "self-cleaving" 2A peptides. The Molecular Rheostat is designed so that the ratio of secreted to membrane-bound immunoglobulins can be controlled by selecting appropriate mutations in the 2A peptide. Lentiviral transgenesis of Molecular Rheostat constructs into B cell lines enables the simultaneous expression of functional b12-based IgM-like BCRs that signal to the cells and mediate the secretion of b12 IgG broadly neutralizing antibodies that can bind and neutralize HIV-1 pseudovirus. We show that these b12-based Molecular Rheostat constructs promote the maturation of EU12 B cells in an in vitro model of B lymphopoiesis. The Molecular Rheostat offers a novel tool for genetically manipulating B cell specificity for B-cell based gene therapy.

  7. Antibody Conjugation Approach Enhances Breadth and Potency of Neutralization of Anti-HIV-1 Antibodies and CD4-IgG

    PubMed Central

    Gavrilyuk, Julia; Ban, Hitoshi; Uehara, Hisatoshi; Sirk, Shannon J.; Saye-Francisco, Karen; Cuevas, Angelica; Zablowsky, Elise; Oza, Avinash; Seaman, Michael S.; Burton, Dennis R.

    2013-01-01

    Broadly neutralizing antibodies PG9 and PG16 effectively neutralize 70 to 80% of circulating HIV-1 isolates. In this study, the neutralization abilities of PG9 and PG16 were further enhanced by bioconjugation with aplaviroc, a small-molecule inhibitor of virus entry into host cells. A novel air-stable diazonium hexafluorophosphate reagent that allows for rapid, tyrosine-selective functionalization of proteins and antibodies under mild conditions was used to prepare a series of aplaviroc-conjugated antibodies, including b12, 2G12, PG9, PG16, and CD4-IgG. The conjugated antibodies blocked HIV-1 entry through two mechanisms: by binding to the virus itself and by blocking the CCR5 receptor on host cells. Chemical modification did not significantly alter the potency of the parent antibodies against nonresistant HIV-1 strains. Conjugation did not alter the pharmacokinetics of a model IgG in blood. The PG9-aplaviroc conjugate was tested against a panel of 117 HIV-1 strains and was found to neutralize 100% of the viruses. PG9-aplaviroc conjugate IC50s were lower than those of PG9 in neutralization studies of 36 of the 117 HIV-1 strains. These results support this new approach to bispecific antibodies and offer a potential new strategy for combining HIV-1 therapies. PMID:23427154

  8. Internet-Based Cognitive Behavioral Therapy for Insomnia: A Health Economic Evaluation

    PubMed Central

    Thiart, Hanne; Ebert, David Daniel; Lehr, Dirk; Nobis, Stephanie; Buntrock, Claudia; Berking, Matthias; Smit, Filip; Riper, Heleen

    2016-01-01

    Study Objectives: Lost productivity caused by insomnia is a common and costly problem for employers. Although evidence for the efficacy of Internet-based cognitive behavioral therapy for insomnia (iCBT-I) already exists, little is known about its economic effects. This study aims to evaluate the cost-effectiveness and cost-benefit of providing iCBT-I to symptomatic employees from the employer's perspective. Methods: School teachers (N = 128) with clinically significant insomnia symptoms and work-related rumination were randomized to guided iCBT-I or a waitlist-control-group, both with access to treatment as usual. Economic data were collected at baseline and 6-mo follow-up. We conducted (1) a cost-effectiveness analysis with treatment response (Reliable Change [decline of 5.01 points] and Insomnia Severity Index < 8 at 6-month follow-up) as the outcome and (2) a cost-benefit analysis. Because both analyses were performed from the employer's perspective, we focused specifically on absenteeism and presenteeism costs. Statistical uncertainty was estimated using bootstrapping. Results: Assuming intervention costs of €200 ($245), cost-effectiveness analyses showed that at a willingness-to-pay of €0 for each positive treatment response, there is an 87% probability that the intervention is more cost effective than treatment as usual alone. Cost-benefit analyses led to a net benefit of €418 (95% confidence interval: −593.03 to 1,488.70) ($512) per participant and a return on investment of 208% (95% confidence interval: −296.52 to 744.35). The reduction in costs was mainly driven by the effects of the intervention on presenteeism and to a lesser degree by reduced absenteeism. Conclusions: Focusing on sleep improvement using iCBT-I may be a cost-effective strategy in occupational health care. Clinical Trials Registration: Title: Online Recovery Training for Better Sleep in Teachers with High Psychological Strain. German Clinical Trial Register (DRKS), URL: https

  9. Gene therapy for the treatment of AIDS: animal models and human clinical experience.

    PubMed

    Amado, R G; Mitsuyasu, R T; Zack, J A

    1999-05-15

    Although antiretroviral drug therapy has had a significant impact on the natural history of HIV infection, complete virus eradication still remains an unattainable goal. Drug-mediated virological control only occurs transiently, in part as a result of the development of drug resistance. Gene therapy for the treatment of AIDS is a promising area of research that has as its goal the replacement of the HIV-infected cellular pool with cells engineered to resist virus replication. A variety of anti-HIV genes have been designed and tested in laboratory systems, and available results from pilot clinical trials demonstrate the safety and feasibility of this approach. Obstacles to effective application of this technology include partial protection of HIV resistance genes, lack of effective vectoring systems, and unregulated gene expression. Herein, we review recent advances in transduction methods, data from in vivo preclinical studies in relevant animal models, and emerging results derived from pilot clinical gene therapy studies.

  10. 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

  11. Randomized controlled trials and real-world observational studies in evaluating cardiovascular safety of inhaled bronchodilator therapy in COPD

    PubMed Central

    Kardos, Peter; Worsley, Sally; Singh, Dave; Román-Rodríguez, Miguel; Newby, David E; Müllerová, Hana

    2016-01-01

    Long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA) bronchodilators and their combination are recommended for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Although the efficacy of LAMAs and LABAs has been well established through randomized controlled trials (RCTs), questions remain regarding their cardiovascular (CV) safety. Furthermore, while the safety of LAMA and LABA monotherapy has been extensively studied, data are lacking for LAMA/LABA combination therapy, and the majority of the studies that have reported on the CV safety of LAMA/LABA combination therapy were not specifically designed to assess this. Evaluation of CV safety for COPD treatments is important because many patients with COPD have underlying CV comorbidities. However, severe CV and other comorbidities are often exclusion criteria for RCTs, contributing to a lack in external validity and generalizability. Real-world observational studies are another important tool to evaluate the effectiveness and safety of COPD therapies in a broader population of patients and can improve upon the external validity limitations of RCTs. We examine what is already known regarding the CV and cerebrovascular safety of LAMA/LABA combination therapy from RCTs and real-world observational studies, and explore the advantages and limitations of data derived from each study type. We also describe an ongoing prospective, observational, comparative post-authorization safety study of a LAMA/LABA combination therapy (umeclidinium/vilanterol) and LAMA monotherapy (umeclidinium) versus tiotropium, with a focus on the relative merits of the study design. PMID:27932872

  12. Evaluation of the functional effects of a course of Bobath therapy in children with cerebral palsy: a preliminary study.

    PubMed

    Knox, Virginia; Evans, Andrew Lloyd

    2002-07-01

    This study aimed to evaluate functional effects of Bobath therapy in children with cerebral palsy (CP). Fifteen children with a diagnosis of CP were recruited (9 males, 6 females; mean age 7 years 4 months, SD 2 years 8 months; age range 2 to 12 years). Types of motor disorder were as follows: spastic quadriplegia (n=9); spastic diplegia (n=4); athetoid quadriplegia (n=1), and ataxia (n=1). Participants were distributed across the following Gross Motor Function Classification levels: level I, n=1; level II, n=4; level III, n=5; level IV, n=4; and level V, n=1. Children awaiting orthopaedic intervention were excluded. A repeated measures design was used with participants tested with the Gross Motor Function Measure (GMFM) and Pediatric Evaluation of Disability Inventory (PEDI) at 6-weekly intervals (baseline, before and after Bobath therapy, and follow-up). As the data were of ordinal type, non-parametric statistics were used, i.e. Wilcoxon's test. Participants showed a significant improvement in scores in the following areas following Bobath therapy compared with the periods before and after Bobath therapy: GMFM total score (p=0.009); GMFM goal total (p=0.001); PEDI self care skills (p=0.036); and PEDI caregiver assistance total score (p=0.012). This demonstrates that in this population, gains were made in motor function and self care following a course of Bobath therapy.

  13. Randomized controlled trials and real-world observational studies in evaluating cardiovascular safety of inhaled bronchodilator therapy in COPD.

    PubMed

    Kardos, Peter; Worsley, Sally; Singh, Dave; Román-Rodríguez, Miguel; Newby, David E; Müllerová, Hana

    2016-01-01

    Long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA) bronchodilators and their combination are recommended for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Although the efficacy of LAMAs and LABAs has been well established through randomized controlled trials (RCTs), questions remain regarding their cardiovascular (CV) safety. Furthermore, while the safety of LAMA and LABA monotherapy has been extensively studied, data are lacking for LAMA/LABA combination therapy, and the majority of the studies that have reported on the CV safety of LAMA/LABA combination therapy were not specifically designed to assess this. Evaluation of CV safety for COPD treatments is important because many patients with COPD have underlying CV comorbidities. However, severe CV and other comorbidities are often exclusion criteria for RCTs, contributing to a lack in external validity and generalizability. Real-world observational studies are another important tool to evaluate the effectiveness and safety of COPD therapies in a broader population of patients and can improve upon the external validity limitations of RCTs. We examine what is already known regarding the CV and cerebrovascular safety of LAMA/LABA combination therapy from RCTs and real-world observational studies, and explore the advantages and limitations of data derived from each study type. We also describe an ongoing prospective, observational, comparative post-authorization safety study of a LAMA/LABA combination therapy (umeclidinium/vilanterol) and LAMA monotherapy (umeclidinium) versus tiotropium, with a focus on the relative merits of the study design.

  14. First- and Second-Line Targeted Systemic Therapy in Hepatocellular Carcinoma—An Update on Patient Selection and Response Evaluation

    PubMed Central

    von Felden, Johann; Schulze, Kornelius; Gil-Ibanez, Ines; Werner, Tobias; Wege, Henning

    2016-01-01

    Advanced hepatocellular carcinoma (HCC) with vascular invasion and/or extrahepatic spread and preserved liver function, according to stage C of the Barcelona Clinic Liver Cancer (BCLC) classification, has a dismal prognosis. The multi-targeted tyrosine-kinase receptor inhibitor (TKI) sorafenib is the only proven active substance in systemic HCC therapy for first-line treatment. In this review, we summarize current aspects in patient selection and management of side effects, and provide an update on response evaluation during first-line sorafenib therapy. Since second-line treatment options have been improved with the successful completion of the RESORCE trial, demonstrating a survival benefit for second-line treatment with the TKI regorafenib, response monitoring during first-line therapy will be critical to deliver optimal systemic therapy in HCC. To this regard, specific side effects, in particular worsening of arterial hypertension and diarrhea, might suggest treatment response during first-line sorafenib therapy; however, clear predictive clinical markers, as well as laboratory test or serum markers, are not established. Assessment of radiologic response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) is helpful to identify patients who do not benefit from sorafenib treatment. PMID:27916795

  15. 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

  16. Integration and evaluation of automated Monte Carlo simulations in the clinical practice of scanned proton and carbon ion beam therapy.

    PubMed

    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

    2014-08-21

    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

  17. 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

  18. 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.

  19. Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson's disease.

    PubMed

    Mittermeyer, Gabriele; Christine, Chadwick W; Rosenbluth, Kathryn H; Baker, Suzanne L; Starr, Philip; Larson, Paul; Kaplan, Paul L; Forsayeth, John; Aminoff, Michael J; Bankiewicz, Krystof S

    2012-04-01

    We report the results of a long-term follow-up of subjects in a phase 1 study of AAV2-hAADC (adeno-associated virus type 2-human aromatic L-amino acid decarboxylase) gene therapy for the treatment of Parkinson's disease (PD). Ten patients with moderately advanced PD received bilateral putaminal infusions of either a low or a high dose of AAV2-hAADC vector. An annual positron emission tomography (PET) imaging with [(18)F]fluoro-L-m-tyrosine tracer was used for evaluation of AADC expression, and a standard clinical rating scale [Unified Parkinson's Disease Rating Scale (UPDRS)] was used to assess effect. Our previous analysis of the 6-month data suggested that this treatment was acutely safe and well tolerated. We found that the elevated PET signal observed in the first 12 months persisted over 4 years in both dose groups. A significantly increased PET value compared with the presurgery baseline was maintained over the 4-year monitoring period. The UPDRS in all patients off medication for 12 hr improved in the first 12 months, but displayed a slow deterioration in subsequent years. This analysis demonstrates that apparent efficacy continues through later years with an acceptable safety profile. These data indicate stable transgene expression over 4 years after vector delivery and continued safety, but emphasize the need for a controlled efficacy trial and the use of a higher vector dose.

  20. 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.

  1. Emotional Prosody Measurement (EPM): a voice-based evaluation method for psychological therapy effectiveness.

    PubMed

    van den Broek, Egon L

    2004-01-01

    The voice embodies three sources of information: speech, the identity, and the emotional state of the speaker (i.e., emotional prosody). The latter feature is resembled by the variability of the F0 (also named fundamental frequency of pitch) (SD F0). To extract this feature, Emotional Prosody Measurement (EPM) was developed, which consists of 1) speech recording, 2) removal of speckle noise, 3) a Fourier Transform to extract the F0-signal, and 4) the determination of SD F0. After a pilot study in which six participants mimicked emotions by their voice, the core experiment was conducted to see whether EPM is successful. Twenty-five patients suffering from a panic disorder with agoraphobia participated. Two methods (story-telling and reliving) were used to trigger anxiety and were compared with comparable but more relaxed conditions. This resulted in a unique database of speech samples that was used to compare the EPM with the Subjective Unit of Distress to validate it as measure for anxiety/stress. The experimental manipulation of anxiety proved to be successful and EPM proved to be a successful evaluation method for psychological therapy effectiveness.

  2. 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.

  3. A critical evaluation of worst case optimization methods for robust intensity-modulated proton therapy planning

    SciTech Connect

    Fredriksson, Albin Bokrantz, Rasmus

    2014-08-15

    Purpose: To critically evaluate and compare three worst case optimization methods that have been previously employed to generate intensity-modulated proton therapy treatment plans that are robust against systematic errors. The goal of the evaluation is to identify circumstances when the methods behave differently and to describe the mechanism behind the differences when they occur. Methods: The worst case methods optimize plans to perform as well as possible under the worst case scenario that can physically occur (composite worst case), the combination of the worst case scenarios for each objective constituent considered independently (objectivewise worst case), and the combination of the worst case scenarios for each voxel considered independently (voxelwise worst case). These three methods were assessed with respect to treatment planning for prostate under systematic setup uncertainty. An equivalence with probabilistic optimization was used to identify the scenarios that determine the outcome of the optimization. Results: If the conflict between target coverage and normal tissue sparing is small and no dose-volume histogram (DVH) constraints are present, then all three methods yield robust plans. Otherwise, they all have their shortcomings: Composite worst case led to unnecessarily low plan quality in boundary scenarios that were less difficult than the worst case ones. Objectivewise worst case generally led to nonrobust plans. Voxelwise worst case led to overly conservative plans with respect to DVH constraints, which resulted in excessive dose to normal tissue, and less sharp dose fall-off than the other two methods. Conclusions: The three worst case methods have clearly different behaviors. These behaviors can be understood from which scenarios that are active in the optimization. No particular method is superior to the others under all circumstances: composite worst case is suitable if the conflicts are not very severe or there are DVH constraints whereas

  4. 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.

  5. Formative evaluation of antiretroviral therapy scale-up efficiency in sub-Saharan Africa.

    PubMed

    Wagner, Glenn; Ryan, Gery; Taylor, Stephanie

    2007-11-01

    With millions in need of HIV antiretroviral therapy (ART) in the developing world, and scarce human and fiscal resources available, we conducted a formative evaluation of scale-up operations at clinics associated with AIDS Healthcare Foundation in Africa to identify lessons learned for improving scale-up efficiency. Site visits were made to six selected clinics in Uganda, Zambia, and South Africa, during which semistructured interviews with key stake-holders and observation of client flows and clinic operations were performed. This evaluation revealed the following lessons related to factors that are critical to efficient ART scale-up: (1) to ensure steady ART uptake, it is important to involve the community and community leaders in outreach, HIV education, and program decision-making; (2) minimizing bottlenecks to smooth patient flow requires efficient staff allocation to appropriate clinical duties, streamlined clinic visit schedule protocols, and tapping clients and the HIV community as a key source of labor; (3) to minimize clients dropping out of care, structures should be developed that enable clients to provide support and a "safety net" for helping each other remain in care; (4) computerized record management systems are essential for accurate antiretroviral inventory and dispensing records, quality assurance monitoring, and client enrollment records and visit scheduling; (5) effective organizational management and human resource policies are essential to maintain high job performance and satisfaction and limit burnout; (6) to maximize impact on social and economic health, it is important for ART programs to develop effective mechanisms for coordinating and referring clients to support service organizations.

  6. In Vitro Cytotoxicity Evaluation of Four Vital Pulp Therapy Materials on L929 Fibroblasts

    PubMed Central

    Wadajkar, Aniket S.; Nguyen, Kytai T.; Zhu, Qiang; Komabayashi, Takashi

    2014-01-01

    The aim of this study was to evaluate cytotoxicity of direct pulp capping materials such as Dycal, Life, ProRoot MTA, and Super-Bond C&B on L929 fibroblasts. Freshly mixed or set materials were prepared and eluted by incubation with cell culture medium for working time period (fresh) or for 6 hours (set). The cells were exposed to media containing elutes for 24 hours, after which the cell survival was evaluated by MTS assays. In freshly mixed materials, average ± standard deviation % cell viabilities were 40.2 ± 14.0%, 43.7 ± 16.0%, 72.9 ± 12.7%, and 66.0 ± 13.6% for Dycal, Life, ProRoot MTA, and Super-Bond C&B, respectively. There was no statistical difference in cell viabilities among material groups, whereas in set materials, the cell viabilities were 48.7 ± 14.8%, 37.2 ± 10.6%, 46.7 ± 15.2%, and 100 ± 21.9% for Dycal, Life, ProRoot MTA, and Super-Bond C&B, respectively. Super-Bond C&B showed more cell viabilities than the other three material groups (P < 0.05). The four vital pulp therapy materials had similar cytotoxicity when the materials were fresh. Super-Bond C&B was less cytotoxic than Dycal, Life, and ProRoot MTA after the materials were set, which suggests the use of SB-C&B in future in vivo clinical investigations. PMID:24724032

  7. Evaluation of the impact of the cancer therapy everolimus on the central nervous system in mice.

    PubMed

    Dubois, Martine; Le Joncour, Vadim; Tonon, Marie-Christine; Anouar, Youssef; Proust, François; Morin, Fabrice; Gandolfo, Pierrick; Joly, Florence; Hilber, Pascal; Castel, Hélène

    2014-01-01

    Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as

  8. Economic evaluation of mobile phone text message interventions to improve adherence to HIV therapy in Kenya

    PubMed Central

    Patel, Anik R.; Kessler, Jason; Braithwaite, R. Scott; Nucifora, Kimberly A.; Thirumurthy, Harsha; Zhou, Qinlian; Lester, Richard T.; Marra, Carlo A.

    2017-01-01

    Abstract Background: A surge in mobile phone availability has fueled low cost short messaging service (SMS) adherence interventions. Multiple systematic reviews have concluded that some SMS-based interventions are effective at improving antiretroviral therapy (ART) adherence, and they are hypothesized to improve retention in care. The objective of this study was to evaluate the cost-effectiveness of SMS-based adherence interventions and explore the added value of retention benefits. Methods: We evaluated the cost-effectiveness of weekly SMS interventions compared to standard care among HIV+ individuals initiating ART for the first time in Kenya. We used an individual level micro-simulation model populated with data from two SMS-intervention trials, an East-African HIV+ cohort and published literature. We estimated average quality adjusted life years (QALY) and lifetime HIV-related costs from a healthcare perspective. We explored a wide range of scenarios and assumptions in one-way and multivariate sensitivity analyses. Results: We found that SMS-based adherence interventions were cost-effective by WHO standards, with an incremental cost-effectiveness ratio (ICER) of $1,037/QALY. In the secondary analysis, potential retention benefits improved the cost-effectiveness of SMS intervention (ICER = $864/QALY). In multivariate sensitivity analyses, the interventions remained cost-effective in most analyses, but the ICER was highly sensitive to intervention costs, effectiveness and average cohort CD4 count at ART initiation. SMS interventions remained cost-effective in a test and treat scenario where individuals were assumed to initiate ART upon HIV detection. Conclusions: Effective SMS interventions would likely increase the efficiency of ART programs by improving HIV treatment outcomes at relatively low costs, and they could facilitate achievement of the UNAIDS goal of 90% viral suppression among those on ART by 2020. PMID:28207516

  9. 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

  10. Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study

    PubMed Central

    Fasching, P. A.; Fehm, T.; Kellner, S.; de Waal, J.; Rezai, M.; Baier, B.; Baake, G.; Kolberg, H.-C.; Guggenberger, M.; Warm, M.; Harbeck, N.; Würstlein, R.; Deuker, J.-U.; Dall, P.; Richter, B.; Wachsmann, G.; Brucker, C.; Siebers, J. W.; Fersis, N.; Kuhn, T.; Wolf, C.; Vollert, H.-W.; Breitbach, G.-P.; Janni, W.; Landthaler, R.; Kohls, A.; Rezek, D.; Noesslet, T.; Fischer, G.; Henschen, S.; Praetz, T.; Heyl, V.; Kühn, T.; Krauß, T.; Thomssen, C.; Kümmel, S.; Hohn, A.; Tesch, H.; Mundhenke, C.; Hein, A.; Rauh, C.; Bayer, C. M.; Jacob, A.; Schmidt, K.; Belleville, E.; Hadji, P.; Wallwiener, D.; Grischke, E.-M.; Beckmann, M. W.; Brucker, S. Y.

    2014-01-01

    Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1–5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5–10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information. PMID:25568468

  11. 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

  12. 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

  13. 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

  14. 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

  15. Evaluation of multielement catheter-cooled interstitial ultrasound applicators for high-temperature thermal therapy.

    PubMed

    Nau, W H; Diederich, C J; Burdette, E C

    2001-07-01

    Catheter-cooled (CC) interstitial ultrasound applicators were evaluated for their use in high-temperature coagulative thermal therapy of tissue. Studies in ex vivo beef muscle were conducted to determine the influences of applied electrical power levels (5-20 W per element), catheter flow rate (20-60 ml min(-1)), circulating water temperature (7-40 degrees C), and frequency (7-9 MHz) on temperature distribution and thermal lesion geometry. The feasibility of using multiple interstitial applicators to thermally coagulate a predetermined volume of tissue was also investigated. Results of these studies revealed that the directional shape of the thermal lesions is maintained with increasing time and power. Radial depths of the thermal lesions ranged from 10.7 +/- 0.7 mm after heating for 4 min with an applied power level of 5 W, to 16.2 +/- 1.4 mm with 20 W. The axial length of the thermal lesions is controlled tightly by the number of active transducers. A catheter flow rate of 20 to 40 ml min(-1) (52.2 +/- 5.5 kPa at 40 ml min(-1)) with 22 degrees C water was determined to provide sufficient cooling of the transducers for power levels used in this study. In vivo temperatures measured in the center of a 3-cm-diam peripheral implant of four applicators in pig thigh muscle reached 89.3 degrees C after 4 min of heating, with boundaries of coagulation clearly defined by applicator position and directivity. Conformability of heating in a clinically relevant model was demonstrated by inserting two directional CC applicators with a 2 cm separation within an in vivo canine prostate, and generating a thermal lesion measuring 3.8 cm x 2.2 cm in cross section while directing energy away from, and protecting the rectum. Maximum measured temperatures at midgland exceeded 90 degrees C within 20 min of heating. The results of this study demonstrate the utility of single or multiple CC applicators for conformal thermal coagulation and high temperature thermal therapy, with potential

  16. 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

  17. 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

  18. 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…

  19. 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…

  20. Mindfulness-Based Cognitive Therapy: Evaluating Current Evidence and Informing Future Research

    ERIC Educational Resources Information Center

    Coelho, Helen F.; Canter, Peter H.; Ernst, Edzard

    2007-01-01

    Mindfulness-based cognitive therapy (MBCT) is a recently developed class-based program designed to prevent relapse or recurrence of major depression (Z. V. Segal, J. M. G. Williams, & J. Teasdale, 2002). Although research in this area is in its infancy, MBCT is generally discussed as a promising therapy in terms of clinical effectiveness. The aim…

  1. Evaluation of Outpatient Parenteral Antimicrobial Therapy at a Veterans Affairs Hospital.

    PubMed

    Spivak, Emily Sydnor; Kendall, Brian; Orlando, Patricia; Perez, Christian; De Amorim, Marina; Samore, Matthew; Pavia, Andrew T; Hersh, Adam L

    2015-09-01

    We reviewed outpatient parenteral antimicrobial therapy at a Veterans Affairs Medical Center to identify opportunities for antimicrobial stewardship intervention. A definite or possible modification would have been recommended in 60% of courses. Forty-one percent of outpatient parenteral antimicrobial therapy courses were potentially avoidable, including 22% involving infectious diseases consultation.

  2. 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.

  3. Stem cell directed gene therapy.

    PubMed

    Engel, B C; Kohn, D B

    1999-05-01

    A potential therapeutic approach to HIV-1 infection is the genetic modification of cells of a patient to make them resistant to HIV-1. Hematopoietic stem cells are an attractive target for gene therapy of AIDS because of their ability to generate a broad repertoire of mature T lymphocytes, as well as the monocytic cells (macrophages, dendritic cells and microglia) which are also involved in HIV-1 pathogenesis. A number of synthetic "anti-HIV-1 genes" have been developed which inhibit HIV-1 replication. However, current methods for gene transfer into human hematopoietic stem cells, using retroviral vectors derived from the Moloney murine leukemia virus, have been minimally effective. Clinical trials performed to date in which hematopoietic cells from HIV-1-positive patients have been transduced with retroviral vectors and then reinfused have produced low to undetectable levels of gene-containing peripheral blood leukocytes. New vector delivery systems, such as lentiviral vectors, need to be developed to ensure efficient gene transfer and persistent transgene expression to provide life-long resistance to the cells targeted by HIV-1.

  4. Evaluation of three automatic oxygen therapy control algorithms on ventilated low birth weight neonates.

    PubMed

    Morozoff, Edmund P; Smyth, John A

    2009-01-01

    Neonates with under developed lungs often require oxygen therapy. During the course of oxygen therapy, elevated levels of blood oxygenation, hyperoxemia, must be avoided or the risk of chronic lung disease or retinal damage is increased. Low levels of blood oxygen, hypoxemia, may lead to permanent brain tissue damage and, in some cases, mortality. A closed loop controller that automatically administers oxygen therapy using 3 algorithms - state machine, adaptive model, and proportional integral derivative (PID) - is applied to 7 ventilated low birth weight neonates and compared to manual oxygen therapy. All 3 automatic control algorithms demonstrated their ability to improve manual oxygen therapy by increasing periods of normoxemia and reducing the need for manual FiO(2) adjustments. Of the three control algorithms, the adaptive model showed the best performance with 0.25 manual adjustments per hour and 73% time spent within target +/- 3% SpO(2).

  5. 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

  6. Effect of service-learning on knowledge about older people and faculty teaching evaluations in a physical therapy class.

    PubMed

    Beling, Janna

    2003-01-01

    The major purpose of this study was to identify the knowledge, misconceptions, and bias regarding aging among graduate physical therapy students and to determine whether service-learning modified any of these variables. A cohort of 40 students in a graduate physical therapy program was randomly divided into an experimental (service-learning) or control (no service-learning) group. General knowledge and attitudes about aging were measured by Palmore's Facts on Aging Quiz I. The Wilson Student Evaluation of Faculty tool measured student evaluations of a faculty member at the end of the semester. Two-way analyses of variance with repeated measures revealed that all students increased their knowledge about aging, p < .05. However, students who initially had negative attitudes toward older adults significantly improved their attitudes only after the service-learning experience, p < .05. A t-test revealed that teaching evaluation scores were significantly lower in the service-learning course, p < .05. The results suggest that service-learning effectively enhanced both the knowledge and attitudes of physical therapy students toward the older adult. Although service-learning imparted better learning for the student, there was some risk to the faculty member as evidenced by lower teaching evaluations.

  7. A responsive evaluation of mental health treatment in Cambodia: Intentionally addressing poverty to increase cultural responsiveness in therapy.

    PubMed

    Seponski, Desiree M; Lewis, Denise C; Megginson, Maegan C

    2014-01-01

    Mental health issues are significant contributors to the global burden of disease with the highest incidence in resource poor countries; 90% of those in need of mental health treatment reside in low resource countries but receive only 10% of the world's resources. Cambodia, the eighth least developed country in the world, serves as one example of the need to address mental health concerns in low-income, resource poor countries. The current study utilises responsive evaluation methodology to explore how poverty-stricken Cambodian clients, therapists and supervisors experience Western models of therapy as culturally responsive to their unique needs. Quantitative and qualitative data were triangulated across multiple stakeholders using numerous methods including a focus group, interviews, surveys, case illustrations and live supervision observation and analysed using constant comparative analysis. Emerging findings suggest that poverty, material needs, therapy location and financial situations greatly impact the daily lives and mental health conditions of Cambodians and hinder clients' therapeutic progress. The local community needs and context of poverty greatly hinder clients' therapeutic progress in therapy treatment and when therapy does not directly address the culture of poverty, clients did not experience therapy as valuable despite some temporary decreases in mental health symptoms.

  8. Imaging techniques to evaluate cell therapy in peripheral artery disease: state of the art and clinical trials.

    PubMed

    Grimaldi, Vincenzo; Schiano, Concetta; Casamassimi, Amelia; Zullo, Alberto; Soricelli, Andrea; Mancini, Francesco Paolo; Napoli, Claudio

    2016-05-01

    Cell-based therapies, as potential approach to cure peripheral artery disease (PAD), have been clinically investigated after promising results in preclinical models. The so far published studies are very heterogeneous, as different cell sources, cell types, amounts of administered cells and delivering strategies have been used. Overall, cell therapies for PAD bring about a general improvement of patient's clinical condition, even though conclusions cannot be established due to the small size and non-randomized design of these trials. In this context, non-invasive imaging techniques, aimed to monitor angiogenesis and neovascularization after cell therapy, will help the follow-up of clinical studies. However, still much work is needed to establish advanced imaging procedure to overcome the limitation of the current techniques and to accumulate more data in large populations of patients. Here, we report the main imaging techniques employed to evaluate the outcome of the different cell-based therapies in PAD. Moreover, we focus on both published and ongoing clinical trials utilizing cell therapy in PAD.

  9. HIV-1 Transmission during Early Antiretroviral Therapy: Evaluation of Two HIV-1 Transmission Events in the HPTN 052 Prevention Study

    PubMed Central

    Rodrigo, Allen G.; Hudelson, Sarah E.; Piwowar-Manning, Estelle; Wang, Lei; Eshleman, Susan H.; Cohen, Myron S.; Swanstrom, Ronald

    2013-01-01

    In the HPTN 052 study, transmission between HIV-discordant couples was reduced by 96% when the HIV-infected partner received suppressive antiretroviral therapy (ART). We examined two transmission events where the newly infected partner was diagnosed after the HIV-infected partner (index) initiated therapy. We evaluated the sequence complexity of the viral populations and antibody reactivity in the newly infected partner to estimate the dates of transmission to the newly infected partners. In both cases, transmission most likely occurred significantly before HIV-1 diagnosis of the newly infected partner, and either just before the initiation of therapy or before viral replication was adequately suppressed by therapy of the index. This study further strengthens the conclusion about the efficacy of blocking transmission by treating the infected partner of discordant couples. However, this study does not rule out the potential for HIV-1 transmission to occur shortly after initiation of ART, and this should be recognized when antiretroviral therapy is used for HIV-1 prevention. PMID:24086252

  10. Evaluation of the Effectiveness of Acupuncture Therapy by Verbal Pain Scale in Patients with Abdominal Pain of Familial Mediterranean Fever.

    PubMed

    Becel, Sinan; Sezgin, Yılmaz; Akçay, Fatih

    2016-10-01

    In this study, we evaluated the effectiveness of acupuncture therapy based on Verbal Pain Scale (VPS) scores in familial Mediterranean fever (FMF) patients admitted to the emergency department with attacks of abdominal pain. This observational study was conducted in Erzurum Regional Training and Research Hospital between August 2014 and December 2014. Twenty patients admitted to the emergency department with FMF attacks were included in the study. Acupuncture therapy was applied to three points including LI4 (Hegu), ST25 (Tianshu), and Ren12 (Zhongwan). The VPS test was applied to the patients before and after the treatment. Average VPS scores were found to be 8.45±0.75 before the treatment and 2.10±0.85 after the treatment. The difference of the VPS scores before and after treatment was statistically significant (p=0.001). To our knowledge, this is the first study evaluating the effectiveness of acupuncture therapy in the treatment of FMF attacks. Our results suggest that acupuncture therapy can be used as an effective treatment method in patients with FMF attacks.

  11. 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.

  12. Development and evaluation of zinc phthalocyanine nanoemulsions for use in photodynamic therapy for Leishmania spp.

    NASA Astrophysics Data System (ADS)

    Betzler de Oliveira de Siqueira, Luciana; da Silva Cardoso, Verônica; Almeida Rodrigues, Igor; Lúcia Vazquez-Villa, Ana; Pereira dos Santos, Elisabete; da Costa Leal Ribeiro Guimarães, Bruno; dos Santos Cerqueira Coutinho, Cristal; Vermelho, Alane Beatriz; Ricci Junior, Eduardo

    2017-02-01

    Photodynamic therapy (PDT) combines light with photosensitizers (PS) for production of reactive oxygen species (ROS) that can kill infectious microorganisms such as bacteria, fungi and protozoa. The application of nanotechnology has enabled the advancement of PDT because many PS are insoluble in water, necessitating a nanocarrier as a physiologically acceptable carrier. Nanoemulsions are efficient nanocarriers for solubilizing liposoluble drugs, like the PS, in water. Cutaneous (CL) and mucocutaneous leishmaniasis (ML) are caused by different species of the genus Leishmania, transmitted to humans by sandfly bites. Parasites are hosted in skin macrophages producing ulcerative lesions. Thus, a topical treatment, effective and inexpensive, for CL and ML is preferable to systemic interventions. There are topical treatments like paromomycin and amphotericin B, but they have many local side effects or a very high cost, limiting their use. This work aimed to develop a zinc phthalocyanine (photosensitizer) oil-in-water nanoemulsion, essential clove oil and polymeric surfactant (Pluronic® F127) for the formulation of a topical delivery system for use in PDT against Leishmania amazonensis and Leishmania infantum. The nanoemulsion was produced by a high-energy method and characterized by size, polydispersity, morphology, pH, content and stability studies. The toxicity in the dark and the photobiological activity of the formulations were evaluated in vitro for Leishmania and macrophages. The formulation presented was pH compatible with topical use, approximately 30 nm in size, with a polydispersity index ≤0.1 and remained stable at room and refrigerator temperature during the stability study (60 days). The zinc phthalocyanine nanoemulsion is effective in PDT against Leishmania spp.; use against skin infections can be a future application of this topical formulation, avoiding the use of oral or injectable medications, decreasing systemic adverse effects.

  13. 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.

  14. Development and evaluation of fixed dose bi therapy sublingual tablets for treatment stress hypertension and anxiety

    PubMed Central

    El-Nabarawi, Mohamed A.; Tayel, Saadia A.; Soliman, Nadia A.; Abo Enin, Hadel A.

    2013-01-01

    Objective: A stress induced rise in the blood pressure. Some believe that patients with hypertension are characterized by a generalized state of increased anxiety. Aim: The purpose of this study is to prepare a fixed dose bi therapy using bisoprolol hemifumarate (BH) as antihypertensive drug and buspirone hydrochloride (BuHCl) as anxiolytic drug, which can be used to treat both diseases concomitantly. Using sublingual tablets is hopeful to improve the BuHCl poor oral bioavailability and to facilitate administration to patients experiencing problems with swallowing. Materials and Methods: A total of 5mg BH and 10mg BuHCl were selected based on compatibility study. A 3×22 full factorial design was adopted for the optimization of the tablets prepared by direct compression method. The effects of the filler type, the binder molecular weight, and the binder type were studied. The prepared formulae were evaluated according to their physical characters as hardness, friability, disintegration time (new modified method and in vivo disintegration time) and wetting properties. In vitro drugs dissolute, permeation through the buccal mucosa and the effect of storage were analyzed by a new valid high pressure liquid chromatography (HPLC) method. Bioavailability study of the selected formula study was carried out and followed by the clinical. Results: The optimized tablet formulation showed accepted average weight, hardness, wetting time, friability, content uniformity, disintegration time (less than 3 min). Maximum drug release could be achieved with in 10 min. In addition enhancing drug permeation through the buccal mucosa and, the maximum concentration of the drug that reached the blood was in the first 10 min which means a rapid onset of action and improved the extent of both drug's absorption. Conclusion: The results revealed that sublingual (F6) tablets containing both drugs would maintain rapid onset of action, and increase bioavailability. BuHCl with BH can be attributed

  15. Development and evaluation of zinc phthalocyanine nanoemulsions for use in photodynamic therapy for Leishmania spp.

    PubMed

    de Oliveira de Siqueira, Luciana Betzler; da Silva Cardoso, Verônica; Rodrigues, Igor Almeida; Vazquez-Villa, Ana Lúcia; Dos Santos, Elisabete Pereira; da Costa Leal Ribeiro Guimarães, Bruno; Dos Santos Cerqueira Coutinho, Cristal; Vermelho, Alane Beatriz; Junior, Eduardo Ricci

    2017-02-10

    Photodynamic therapy (PDT) combines light with photosensitizers (PS) for production of reactive oxygen species (ROS) that can kill infectious microorganisms such as bacteria, fungi and protozoa. The application of nanotechnology has enabled the advancement of PDT because many PS are insoluble in water, necessitating a nanocarrier as a physiologically acceptable carrier. Nanoemulsions are efficient nanocarriers for solubilizing liposoluble drugs, like the PS, in water. Cutaneous (CL) and mucocutaneous leishmaniasis (ML) are caused by different species of the genus Leishmania, transmitted to humans by sandfly bites. Parasites are hosted in skin macrophages producing ulcerative lesions. Thus, a topical treatment, effective and inexpensive, for CL and ML is preferable to systemic interventions. There are topical treatments like paromomycin and amphotericin B, but they have many local side effects or a very high cost, limiting their use. This work aimed to develop a zinc phthalocyanine (photosensitizer) oil-in-water nanoemulsion, essential clove oil and polymeric surfactant (Pluronic(®) F127) for the formulation of a topical delivery system for use in PDT against Leishmania amazonensis and Leishmania infantum. The nanoemulsion was produced by a high-energy method and characterized by size, polydispersity, morphology, pH, content and stability studies. The toxicity in the dark and the photobiological activity of the formulations were evaluated in vitro for Leishmania and macrophages. The formulation presented was pH compatible with topical use, approximately 30 nm in size, with a polydispersity index ≤0.1 and remained stable at room and refrigerator temperature during the stability study (60 days). The zinc phthalocyanine nanoemulsion is effective in PDT against Leishmania spp.; use against skin infections can be a future application of this topical formulation, avoiding the use of oral or injectable medications, decreasing systemic adverse effects.

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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.

  1. An in vitro evaluation of drugs used in the Kenyan ART program

    PubMed Central

    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