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Sample records for evaluate anti-hiv therapy

  1. Design, synthesis and anti-HIV-1 evaluation of hydrazide-based peptidomimetics as selective gelatinase inhibitors.

    PubMed

    Yang, Liang; Wang, Ping; Wu, Ji-Feng; Yang, Liu-Meng; Wang, Rui-Rui; Pang, Wei; Li, Yong-Gang; Shen, Yue-Mao; Zheng, Yong-Tang; Li, Xun

    2016-05-01

    As our ongoing work on research of gelatinase inhibitors, an array of hydrazide-containing peptidomimetic derivatives bearing quinoxalinone as well as spiro-heterocyclic backbones were designed, synthesized, and assayed for their in vitro enzymatic inhibitory effects. The results demonstrated that both the quinoxalinone (series I and II) and 1,4-dithia-7-azaspiro[4,4]nonane-based hydrazide peptidomimetics (series III) displayed remarkably selectivity towards gelatinase A as compared to APN, with IC50 values in the micromole range. Structure-activity relationships were herein briefly discussed. Given evidences have validated that gelatinase inhibition may be contributable to the therapy of HIV-1 infection, all the target compounds were also submitted to the preliminary in vitro anti-HIV-1 evaluation. It resulted that gelatinase inhibition really has positive correlation with anti-HIV-1 activity, especially compounds 4m and 7h, which gave enhanced gelatinase inhibition in comparison with the positive control LY52, and also decent anti-HIV-1 potencies. The FlexX docking results provided a straightforward insight into the binding pattern between inhibitors and gelatinase, as well as the selective inhibition towards gelatinase over APN. Collectively, our research encouraged potent gelatinase inhibitors might be used in the development of anti-HIV-1 agents. And else, compounds 4m and 7h might be promising candidates to be considered for further chemical optimization. PMID:27039251

  2. 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

  3. 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. PMID:26598461

  4. Development of HIV vectors for anti-HIV gene therapy.

    PubMed Central

    Poeschla, E; Corbeau, P; Wong-Staal, F

    1996-01-01

    Current gene therapy protocols for HIV infection use transfection or murine retrovirus mediated transfer of antiviral genes into CD4+ T cells or CD34+ progenitor cells ex vivo, followed by infusion of the gene altered cells into autologous or syngeneic/allogeneic recipients. While these studies are essential for safety and feasibility testing, several limitations remain: long-term reconstitution of the immune system is not effected for lack of access to the macrophage reservoir or the pluripotent stem cell population, which is usually quiescent, and ex vivo manipulation of the target cells will be too expensive and impractical for global application. In these regards, the lentivirus-specific biologic properties of the HIVs, which underlie their pathogenetic mechanisms, are also advantageous as vectors for gene therapy. The ability of HIV to specifically target CD4+ cells, as well as non-cycling cells, makes it a promising candidate for in vivo gene transfer vector on one hand, and for transduction of non-cycling stem cells on the other. Here we report the use of replication-defective vectors and stable vector packaging cell lines derived from both HIV-1 and HIV-2. Both HIV envelopes and vesicular stomatitis virus glycoprotein G were effective in mediating high-titer gene transfer, and an HIV-2 vector could be cross-packaged by HIV-1. Both HIV-1 and HIV-2 vectors were able to transduce primary human macrophages, a property not shared by murine retroviruses. Vesicular stomatitis virus glycoprotein G-pseudotyped HIV vectors have the potential to mediate gene transfer into non-cycling hematopoietic stem cells. If so, HIV or other lentivirus-based vectors will have applications beyond HIV infection. Images Fig. 1 PMID:8876146

  5. Combinatorial Anti-HIV Gene Therapy: Using a Multi-Pronged Approach to Reach Beyond HAART

    PubMed Central

    Peterson, Christopher W; Younan, Patrick; Jerome, Keith R; Kiem, Hans-Peter

    2013-01-01

    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 recently been explored, including disruption of the CCR5 and 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 nonhuman primates. 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 in order to mount a suitably robust defense against spreading infection. PMID:23364313

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

    PubMed

    Garg, Himanshu; Joshi, Anjali

    2016-05-01

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

  7. Comparison of Classifier Fusion Methods for Predicting Response to Anti HIV-1 Therapy

    PubMed Central

    Altmann, André; Rosen-Zvi, Michal; Prosperi, Mattia; Aharoni, Ehud; Neuvirth, Hani; Schülter, Eugen; Büch, Joachim; Struck, Daniel; Peres, Yardena; Incardona, Francesca; Sönnerborg, Anders; Kaiser, Rolf; Zazzi, Maurizio; Lengauer, Thomas

    2008-01-01

    Background Analysis of the viral genome for drug resistance mutations is state-of-the-art for guiding treatment selection for human immunodeficiency virus type 1 (HIV-1)-infected patients. These mutations alter the structure of viral target proteins and reduce or in the worst case completely inhibit the effect of antiretroviral compounds while maintaining the ability for effective replication. Modern anti-HIV-1 regimens comprise multiple drugs in order to prevent or at least delay the development of resistance mutations. However, commonly used HIV-1 genotype interpretation systems provide only classifications for single drugs. The EuResist initiative has collected data from about 18,500 patients to train three classifiers for predicting response to combination antiretroviral therapy, given the viral genotype and further information. In this work we compare different classifier fusion methods for combining the individual classifiers. Principal Findings The individual classifiers yielded similar performance, and all the combination approaches considered performed equally well. The gain in performance due to combining methods did not reach statistical significance compared to the single best individual classifier on the complete training set. However, on smaller training set sizes (200 to 1,600 instances compared to 2,700) the combination significantly outperformed the individual classifiers (p<0.01; paired one-sided Wilcoxon test). Together with a consistent reduction of the standard deviation compared to the individual prediction engines this shows a more robust behavior of the combined system. Moreover, using the combined system we were able to identify a class of therapy courses that led to a consistent underestimation (about 0.05 AUC) of the system performance. Discovery of these therapy courses is a further hint for the robustness of the combined system. Conclusion The combined EuResist prediction engine is freely available at http://engine.euresist.org. PMID

  8. Asymmetric Total Synthesis of (+)- and (−)-Clusianone and (+)- and (−)Clusianone Methyl Enol Ether via ACC Alkylation and Evaluation of their Anti-HIV Activity

    PubMed Central

    Garnsey, Michelle R.; Matous, James A.; Kwiek, Jesse J.; Coltart, Don M.

    2011-01-01

    The total asymmetric synthesis of (+)- and (−)-clusianone and (+)- and (−)-clusianone methyl enol ether is reported. Asymmetric induction is achieved through the use of ACC alkylation, providing the key intermediates with an er of 99:1. The four synthetic compounds were evaluated for their anti-HIV activity. Both (+)- and (−)-clusianone displayed significant anti-HIV activity. PMID:21414776

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

    PubMed Central

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

    2014-01-01

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

  10. Evaluation of PD 404,182 as an anti-HIV and anti-herpes simplex virus microbicide.

    PubMed

    Chamoun-Emanuelli, Ana M; Bobardt, Michael; Moncla, Bernard; Mankowski, Marie K; Ptak, Roger G; Gallay, Philippe; Chen, Zhilei

    2014-01-01

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

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

    PubMed

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

    2012-01-01

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

  12. 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

  13. 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

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

    PubMed

    Behbahani, Mandana

    2014-01-01

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

  15. The highly specific carbohydrate-binding protein cyanovirin-N: structure, anti-HIV/Ebola activity and possibilities for therapy.

    PubMed

    Barrientos, Laura G; Gronenborn, Angela M

    2005-01-01

    Cyanovirin-N (CV-N), a cyanobacterial lectin, is a potent viral entry inhibitor currently under development as a microbicide against a broad spectrum of enveloped viruses. CV-N was originally identified as a highly active anti-HIV agent and later, as a virucidal agent against other unrelated enveloped viruses such as Ebola, and possibly other viruses. CV-N's antiviral activity appears to involve unique recognition of N-linked high-mannose oligosaccharides, Man-8 and Man-9, on the viral surface glycoproteins. Due to its distinct mode of action and opportunities for harnessing the associated interaction for therapeutic intervention, a substantial body of research on CV-N has accumulated since its discovery in 1997. In this review we focus in particular on structural studies on CV-N and their relationship to biological activity. PMID:15638789

  16. Evaluation of anti-HIV-1 activity of a new iridoid glycoside isolated from Avicenna marina, in vitro.

    PubMed

    Behbahani, Mandana

    2014-11-01

    This study was carried out to check the efficacy of methanol seed extract of Avicenna marina and its column chromatographic fractions on Peripheral Blood Mono nuclear Cells (PBMCs) toxicity and HIV-1 replication. The anti-HIV-1 activities of crude methanol extract and its fractions were performed by use of real-time polymerase chain reaction (PCR) assay and HIV-1 p24 antigen kit. A time of drug addiction approach was also done to identify target of anti-HIV compound. The activity of the extracts on CD4, CD3, CD19 and CD45 expression in lymphocytes population was performed by use of flow cytometry. The most active anti-HIV agent was detected by spectroscopic analysis as 2'-O-(4-methoxycinnamoyl) mussaenosidic acid. The apparent effective concentrations for 50% virus replication (EC50) of methanol extract and iridoid glycoside were 45 and 0.1 μg/ml respectively. The iridoid glycoside also did not have any observable effect on the proportion of CD4, CD3, CD19 and CD45 cells or on the intensity of their expressions on PBMCs. In addition, the expression level of C-C chemokine receptor type 5 (CCR5) and chemokine receptor type 4 (CXCR4) on CD4(+) T cells were decreased in cells treated with this iridoid glycoside. The reduction of these two HIV coreceptors and the result of time of addition study demonstrated that this iridoid glycoside restricts HIV-1 replication on the early stage of HIV infection. PMID:25239814

  17. 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

  18. 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. PMID:21291416

  19. 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

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

    PubMed Central

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

    1994-01-01

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

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

    PubMed

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

    2011-10-01

    In a continuing study of novel anti-HIV agents with drug-like structures and properties, 30 1'-O-, 1'-S-, 4'-O- and 4'-substituted-2',3'-seco-3'-nor DCP and DCK analogues (8-37) were designed and synthesized. All newly synthesized seco-compounds were screened against HIV-1(NL4-3) and a multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR) strain in the TZM-bl cell line, using seco-DCK (7) and 2-ethyl-DCP (4) as controls. Several compounds (14, 18, 19, 22-24, and 32) exhibited potent anti-HIV activity with EC(50) values ranging from 0.93 to 1.93 μM and therapeutic index (TI) values ranging from 20 to 39. 1'-O-Isopropoxy-2',3'-seco-3'-nor-DCP (12) showed the greatest potency among the newly synthesized compounds with EC(50) values of 0.47 and 0.88 μM, and TI of 96 and 51, respectively, against HIV-1(NL4-3) and RTMDR strains. The seco-compounds exhibited better chemical stability in acidic conditions compared with DCP and DCK compounds. Overall, the results suggested that seco-DCP analogues with simplified structures may be more favorable for development as novel anti-HIV candidates. PMID:21864952

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

    PubMed Central

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

    2011-01-01

    In a continuing study of novel anti-HIV agents with drug-like structures and properties, 30 1′-O-, 1′-S-, 4′-O- and 4′-substituted-2′,3′-seco-3′-nor DCP and DCK analogues (8–37) were designed and synthesized. All newly synthesized seco-compounds were screened against HIV-1NL4-3 and a multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR) strain in the TZM-bl cell line, using seco-DCK (7) and 2-ethyl-DCP (4) as controls. Several compounds (14, 18, 19, 22–24, and 32) exhibited potent anti-HIV activity with EC50 values ranging from 0.93 to 1.93 μM and therapeutic index (TI) values ranging from 20 to 39. 1′-O-Isopropoxy-2′,3′-seco-3′-nor-DCP (12) showed the greatest potency among the newly synthesized compounds with EC50 values of 0.47 and 0.88 μM, and TI of 96 and 51, respectively, against HIV-1NL4-3 and RTMDR strains. The seco-compounds exhibited better chemical stability in acidic conditions compared with DCP and DCK compounds. Overall, the results suggested that seco-DCP analogues with simplified structures may be more favorable for development as novel anti-HIV candidates. PMID:21864952

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

    PubMed

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

    2016-05-01

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

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

    PubMed

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

    2016-06-15

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

  5. Naturally derived anti-HIV agents.

    PubMed

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

    2005-07-01

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

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

    PubMed

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

    2015-01-01

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

  7. Targeting CCR5 for anti-HIV research.

    PubMed

    Gu, W-G; Chen, X-Q

    2014-11-01

    Highly active antiretroviral therapy (HAART) is the only approach for human immunodeficiency virus (HIV) infection treatment at present. Although HAART is effective in controlling the progression of infection, it is impossible to eradicate the virus from patients. The patients have to live with the virus. Alternative ways for the cure of HIV infection have been investigated. As the major co-receptor for HIV-1 infection, C-C motif chemokine receptor 5 (CCR5) is naturally an ideal target for anti-HIV research. The first CCR5 antagonist, maraviroc, has been approved for the treatment of HIV infection. Several other CCR5 antagonists are in clinical trials. CCR5 delta32 is a natural genotype, conferring resistance to CCR5 using HIV-1 strains. Gene therapy research targeting this mutant has been conducted for HIV infection treatment. A Berlin patient has been cured of HIV infection by the transplantation of stem cells from a CCR5 delta32 genotype donor. The infusion of an engineered zinc finger nuclease (ZFN)-modified autologous cluster of differentiation 4 (CD4) T cells has been proved to be a promising direction recently. In this study, the anti-HIV research targeting CCR5 is summarized, including CCR5 antagonist development, stem cell transplantation, and gene therapy. PMID:25027072

  8. 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

  9. Anti-AIDS agents. 30. Anti-HIV activity of oleanolic acid, pomolic acid, and structurally related triterpenoids.

    PubMed

    Kashiwada, Y; Wang, H K; Nagao, T; Kitanaka, S; Yasuda, I; Fujioka, T; Yamagishi, T; Cosentino, L M; Kozuka, M; Okabe, H; Ikeshiro, Y; Hu, C Q; Yeh, E; Lee, K H

    1998-09-01

    Oleanolic acid (1) was identified as an anti-HIV principle from several plants, including Rosa woodsii (leaves), Prosopis glandulosa (leaves and twigs), Phoradendron juniperinum (whole plant), Syzygium claviflorum (leaves), Hyptis capitata (whole plant), and Ternstromia gymnanthera (aerial part). It inhibited HIV-1 replication in acutely infected H9 cells with an EC50 value of 1.7 microg/mL, and inhibited H9 cell growth with an IC50 value of 21.8 microg/mL [therapeutic index (T. I.) 12.8]. Pomolic acid, isolated from R. woodsii and H. capitata, was also identified as an anti-HIV agent (EC50 1.4 microg/mL, T. I. 16.6). Although ursolic acid did show anti-HIV activity (EC50 2.0 microg/mL), it was slightly toxic (IC50 6.5 microg/mL, T. I. 3.3). A new triterpene (11) was also isolated from the CHCl3-soluble fraction of R. woodsii, though it showed no anti-HIV activity. The structure of 11 was determined to be 1beta-hydroxy-2-oxopomolic acid by spectral examination. Based on these results, we examined the anti-HIV activity of oleanolic acid- or pomolic acid-related triterpenes isolated from several plants. In addition, we previously demonstrated that derivatives of betulinic acid, isolated from the leaves of S. claviflorum as an anti-HIV principle, exhibited extremely potent anti-HIV activity. Accordingly, we prepared derivatives of oleanolic acid and evaluated their anti-HIV activity. Among the oleanolic acid derivatives, 18 demonstrated most potent anti-HIV activity, with an EC50 value of 0. 0005 microg/mL and a T. I. value of 22 400. PMID:9748372

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

    PubMed

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

    2015-08-01

    Previously, compounds which inhibit the HIV-1 replication cycle were found in overlapping peptide libraries covering the whole sequence of an HIV-1 matrix (MA) protein constructed with the addition of an octa-arginyl group. The two top lead compounds are sequential fragments MA-8L and MA-9L. In the present study, the addition of chloroquine in cell-based anti-HIV assays was proven to be an efficient method with which to find anti-HIV compounds among several peptides conjugated by cell-penetrating signals such as an octa-arginyl group: the conjugation of an octa-arginyl group to individual peptides contained in whole proteins in combination with the addition of chloroquine in cells is a useful assay method to search active peptides. To find more potent fragment peptides, individual peptides between MA-8L and MA-9L, having the same peptide chain length but with sequences shifted by one amino acid residue, were synthesized in this paper and their anti-HIV activity was evaluated with an anti-HIV assay using chloroquine. As a result, the peptides in the C-terminal side of the series, which are relatively close to MA-9L, showed more potent inhibitory activity against both X4-HIV-1 and R5-HIV-1 than the peptides in the N-terminal side. PMID:26094944

  11. Anti-HIV activity of thiosemicarbazone and semicarbazone derivatives of (+/-)-3-menthone.

    PubMed

    Mishra, Vibha; Pandeya, S N; Pannecouque, Christophe; Witvrouw, Myriam; De Clercq, E

    2002-05-01

    A series of thiosemicarbazones and semicarbazone derivatives of (+/-)-3-menthone have been synthesized and their anti-HIV activity evaluated against HIV-1(III(B))and HIV-2 (ROD). The studies revealed that maximum protection is offered by chloro-substituted derivatives 2 and 7 against HIV-1 (III(B)) and HIV-2 (ROD). PMID:12210774

  12. [Anti-HIV drugs and drug delivery system].

    PubMed

    Obaru, K; Mitsuya, H

    1998-03-01

    A number of candidate drugs for therapy of HIV-1 infection which show significant activity against the virus in vitro were reported; however, many of them have been dropped from drug development due to (i) insufficient intracellular activation in certain human target cells (particularly in case of nucleoside reverse transcriptase inhibitors), (ii) poor pharmacokinetic profiles, or (iii) intolerable in vitro and/or in vivo toxicities. To circumvent some of these problems, certain drug delivery systems have been applied and several candidate drugs including two novel nucleoside reverse transcriptase inhibitors, abacavir and adefovir, have acquired favorable properties in the clinical setting. This paper reviews several avenues for developing prodrugs of anti-HIV-1 agents to overcome their inherent limitations. PMID:9549371

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2007-10-01

    In an attempt to combine the anti-HIV inhibitory capacity of reverse transcriptase (RT) inhibitors (NRTIs) and integrase (IN) inhibitors (INIs), several heterodimer analogues of the previously reported [d4T]-PABC-[INI] and [d4T]-OABC-[INI] prototypes have been prepared. In these novel series, we wished to extend our results to conjugates which incorporated an enzymatically labile aminoacid unit (L-alanine) connected to d4T through a self-immolative para- or ortho-aminobenzyl carbonate (PABC or OABC) spacer. Among the novel heterodimers, several derivatives show a potent anti-HIV-1 activity, which proved comparable to that of the [L-708,906]-PABC-[d4T] Heterodimer A prototype. However, although the compounds proved inhibitory to HIV-1, they were less potent than the parent compounds from which they were derived. PMID:18035829

  15. Synthesis and biological evaluation of tricyclic guanidine analogues of batzelladine K for antimalarial, antileishmanial, antibacterial, antifungal and anti-HIV activities

    PubMed Central

    Ahmed, Nafees; Brahmbhatt, Keyur G.; Khan, Shabana I.; Jacob, Melissa; Tekwani, Babu L.; Sabde, Sudeep; Mitra, Debashis; Singh, Inder Pal; Khan, Ikhlas A.; Bhutani, Kamlesh K.

    2012-01-01

    Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV-1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine-sensitive D6 strain with IC50 1.25 and 0.88 μM and chloroquine-resistant W2 strain with IC50 1.64 and 1.07 μM, respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC50 2.39 and 2.78 μM and IC90 11.27 and 12.76 μM respectively. Three analogues 12c, 14c and 14i were the most active against various pathogenic bacteria and fungi with IC50 <3.02 μM and MIC/MBC/MFC <6 μM. Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV-1. Our study demonstrated that the tricyclic guanidine compounds provide new structral class for broad spectrum activity. PMID:23534411

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

    PubMed

    Xu, Liang; Zhang, Tao; Xu, Xiaoyu; Chong, Huihui; Lai, Wenqing; Jiang, Xifeng; Wang, Chao; He, Yuxian; Liu, Keliang

    2015-08-01

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

  17. Inexpensive Designer Antigen for Anti-HIV Antibody Detection with High Sensitivity and Specificity ▿

    PubMed Central

    Talha, Sheikh M.; Salminen, Teppo; Chugh, Deepti A.; Swaminathan, Sathyamangalam; Soukka, Tero; Pettersson, Kim; Khanna, Navin

    2010-01-01

    A novel recombinant multiepitope protein (MEP) has been designed that consists of four linear, immunodominant, and phylogenetically conserved epitopes, taken from human immunodeficiency virus (HIV)-encoded antigens that are used in many third-generation immunoassay kits. This HIV-MEP has been evaluated for its diagnostic potential in the detection of anti-HIV antibodies in human sera. A synthetic MEP gene encoding these epitopes, joined by flexible peptide linkers in a single open reading frame, was designed and overexpressed in Escherichia coli. The recombinant HIV-MEP was purified using a single affinity step, yielding >20 mg pure protein/liter culture, and used as the coating antigen in an in-house immunoassay. Bound anti-HIV antibodies were detected by highly sensitive time-resolved fluorometry, using europium(III) chelate-labeled anti-human antibody. The sensitivity and specificity of the HIV-MEP were evaluated using Boston Biomedica worldwide HIV performance, HIV seroconversion, and viral coinfection panels and were found to be comparable with those of commercially available anti-HIV enzyme immunoassay (EIA) kits. The careful choice of epitopes, high epitope density, and an E. coli-based expression system, coupled with a simple purification protocol and the use of europium(III) chelate-labeled tracer, provide the capability for the development of an inexpensive diagnostic test with high degrees of sensitivity and specificity. PMID:20089793

  18. New developments in anti-HIV chemotherapy.

    PubMed

    De Clercq, E

    2001-11-01

    -resistant HIV strains [second generation NNRTIs, such as capravirine and the novel quinoxaline, quinazolinone, phenylethylthiazolylthiourea (PETT) and emivirine (MKC-442) analogues], or, as in the case of PIs, a different, non-peptidic scaffold [i.e. cyclic urea (DMP 450), 4-hydroxy-2-pyrone (tipranavir)]. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating from cell-free enzymatic assays to the mode of action of these agents in intact cells. A number of compounds (i.e. zintevir and L-chicoric acid, on the one hand; and CGP64222 on the other hand) have recently been found to interact with virus-cell binding and viral entry in contrast to their proposed modes of action targeted at the integrase and transactivation process, respectively. PMID:11562282

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

    PubMed

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

    2015-11-01

    Unciaphenol (2), an oxygenated analogue of the Bergman cyclization product of the enediyne uncialamycin (1), has been isolated along with 1 from cultures of the actinomycete Streptomyces uncialis. It is proposed that the C-22 OH substituent in 2 might arise from the attack of a nucleophilic oxygen species on the p-benzyne diradical intermediate IA in the Bergman cyclization of 1. 2 shows in vitro anti-HIV activity against viral strains that are resistant to clinically utilized anti-retroviral therapies. PMID:26465962

  20. 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

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

    PubMed

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

    2015-01-01

    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

  2. Molecular Modeling, Synthesis, and Anti-HIV Activity of Novel Isoindolinedione Analogues as Potent Non-nucleoside Reverse Transcriptase Inhibitors.

    PubMed

    Kumari, Garima; Singh, Ramendra K

    2016-02-01

    Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti-HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti-HIV activity and the molecules having sulfonamide linkages were the most potent HIV-RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood-brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti-HIV drugs. In vitro screening was performed using HIV-1 strain IIIB in MT-4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV-1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under in vitro conditions. Some of these molecules have shown good anti-HIV activity at 3-4 nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV-1. Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti-HIV activity at 3-4 nm concentrations. PMID:26212217

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

    PubMed

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

    2016-07-19

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

  4. Hydrogen bonds of anti-HIV active aminophenols

    NASA Astrophysics Data System (ADS)

    Belkov, M. V.; Ksendzova, G. A.; Skornyakov, I. V.; Sorokin, V. L.; Tolstorozhev, G. B.; Shadyro, O. I.

    2011-05-01

    Analysis of IR-Fourier spectra from solutions and crystals of antiviral sulfo-containing aminophenols has shown that various types of intramolecular and intermolecular interactions can occur in molecules of these compounds. Three types of intramolecular hydrogen bonds (O-HṡṡṡN, O-HṡṡṡO=S=O, and N-HṡṡṡO=S=O) are formed in CCl4 solutions of the sulfo-containing aminophenols. The formation of intermolecular H-bonds involving the NH- and OH-groups and the preservation of the intramolecular O-HṡṡṡO=S=O H-bond are characteristic of the anti-HIV active aminophenol crystals. Spectral attributes are determined in order to distinguish between the anti-HIV active and inactive sulfo-containing aminophenols.

  5. Synthetic galactomannans with potent anti-HIV activity.

    PubMed

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

    2015-10-01

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

  6. 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. PMID:26754878

  7. Aaptamine Derivatives with Antifungal and Anti-HIV-1 Activities from the South China Sea Sponge Aaptos aaptos

    PubMed Central

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

    2014-01-01

    Five new alkaloids of aaptamine family, compounds (1–5) and three known derivatives (6–8), have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated by spectroscopic analyses, as well as by comparison with the literature data. Compounds 1–2 are characterized with triazapyrene lactam skeleton, whereas compounds 4–5 share an imidazole-fused aaptamine moiety. These compounds were evaluated in antifungal and anti-HIV-1 assays. Compounds 3, 7, and 8 showed antifungal activity against six fungi, with MIC values in the range of 4 to 64 μg/mL. Compounds 7–8 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 μM. PMID:25532563

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

    PubMed

    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

    2015-09-21

    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. PMID:26274532

  9. 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.

  10. Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids.

    PubMed

    Kashiwada, Yoshiki; Aoshima, Akihiro; Ikeshiro, Yasumasa; Chen, Yuh-Pan; Furukawa, Hiroshi; Itoigawa, Masataka; Fujioka, Toshihiro; Mihashi, Kunihide; Cosentino, L Mark; Morris-Natschke, Susan L; Lee, Kuo-Hsiung

    2005-01-17

    (+)-1(R)-Coclaurine (1) and (-)-1(S)-norcoclaurine (3), together with quercetin 3-O-beta-D-glucuronide (4), were isolated from the leaves of Nelumbo nucifera (Nymphaceae), and identified as anti-HIV principles. Compounds 1 and 3 demonstrated potent anti-HIV activity with EC50 values of 0.8 and <0.8 microg/mL, respectively, and therapeutic index (TI) values of >125 and >25, respectively. Compound 4 was less potent (EC50 2 microg/mL). In a structure-activity relationship study, other benzylisoquinoline, aporphine, and bisbenzylisoquinoline alkaloids, including liensinine (14), negferine (15), and isoliensinine (16), which were previously isolated from the leaves and embryo of Nelumbo nucifera, were evaluated for anti-HIV activity. Compounds 14-16 showed potent anti-HIV activities with EC50 values of <0.8 microg/mL and TI values of >9.9, >8.6, and >6.5, respectively. Nuciferine (12), an aporphine alkaloid, had an EC50 value of 0.8 microg/mL and TI of 36. In addition, synthetic coclaurine analogs were also evaluated. Compounds 1, 3, 12, and 14-16 can serve as new leads for further development of anti-AIDS agents. PMID:15598565

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

    PubMed

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

    2016-08-01

    Prevention plays an invaluable role in the fight against HIV/AIDS. The use of microbicides is considered an interesting potential approach for topical pre-exposure prophylaxis of HIV sexual transmission. The prospects of having an effective product available are expected to be fulfilled in the near future as driven by recent and forthcoming results of clinical trials. Different dosage forms and delivery strategies have been proposed and tested for multiple microbicide drug candidates presently at different stages of the development pipeline. One particularly interesting approach comprises the application of nanomedicine principles to the development of novel anti-HIV microbicides, but its implications to efficacy and safety are not yet fully understood. Nanotechnology-based systems, either presenting inherent anti-HIV activity or acting as drug nanocarriers, may significantly influence features such as drug solubility, stability of active payloads, drug release, interactions between active moieties and virus/cells, intracellular drug delivery, drug targeting, safety, antiviral activity, mucoadhesive behavior, drug distribution and tissue penetration, and pharmacokinetics. The present manuscript provides a comprehensive and holistic overview of these topics as relevant to the development of vaginal and rectal microbicides. In particular, recent advances pertaining inherently active microbicide nanosystems and microbicide drug nanocarriers are discussed. PMID:26829288

  12. Recent development of new substituted indole and azaindole derivatives as anti-HIV agents.

    PubMed

    Ölgen, Süreyya

    2013-10-01

    Human immunodeficiency virus-1 (HIV-1) infections cause global health problems. Indole derivatives have been considered as one of the promising HIV inhibitors. Recent inventions have focused on substituted indole and azaindole derivatives that possess unique antiviral activities against HIV-1. In this review, the evaluation of recent advances in substituted indole and azaindole derivatives for the treatment or prevention of HIV-1 and acquired immune deficiency syndrome (AIDS) has been focused. In this respect, compounds having drug and bio-active properties, including their synthesis and pharmacologic properties have been reported. In addition, anti-HIV properties of compounds, the structural features of inhibitors, the current progress in terms of therapeutic interventions and the leading groups in the field are discussed. Moreover, clinical and ADME (Absorption, Distribution, Metabolism, Elimination) properties of some clinically important compounds such as BMS-378806, L-737126 and IDX899 are reported. PMID:23895189

  13. Model for inter-epithelial flow of an anti-HIV microbicidal drug delivery formulation

    NASA Astrophysics Data System (ADS)

    Szeri, Andrew; Katz, David

    2005-11-01

    We consider the spreading characteristics of a Newtonian and a non-Newtonian fluid between compliant surfaces. This is a model for inter-epithelial flow of an anti-HIV microbicidal drug delivery formulation. Squeezing and gravity drive the flow. Owing to the large shear viscosity and narrow flow domain with compliant walls, the problem is an application of elastohydrodynamic lubrication theory. Dimensional analysis and numerical simulation reveal the influence of shear viscosity, wall compliance, longitudinal pressure gradient, formulation volume and channel dimensions on the area coated by the formulation. This area is a function of: (i) a dimensionless parameter which measures the relative importance of gravity-driven and compliance-driven flows, and (ii) time made dimensionless by the compliance and the shear viscosity. The coated area is of central importance in the functioning and evaluation of candidate microbicide delivery systems.

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

    NASA Astrophysics Data System (ADS)

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

    2012-02-01

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

  15. Action of anti-HIV drugs and resistance: reverse transcriptase inhibitors and protease inhibitors.

    PubMed

    Imamichi, Tomozumi

    2004-01-01

    Currently, 20 drugs have been approved for Human Immunodeficiency Virus type-1 (HIV-1) clinical therapy. These drugs inhibit HIV-1 reverse transcriptase, protease, or virus entry. Introduction of a combination therapy with reverse transcriptase inhibitors and protease inhibitors has resulted in a drastic decrease in HIV-1 related mortality. Although the combination therapy can suppress viral replication below detection levels in current available assays, low levels of on-going viral replication still persist in some patients. Long-term administration of the combination therapy may increase selective pressure against viruses, and subsequently induce emergence of multiple drug-resistant HIV-1 variants. Attempts have been made to design novel antiretroviral drugs that would be able to suppress replication of the resistant variants. At present, several investigational drugs are being tested in clinical trials. These drugs target not only the resistant variants, but also improvement in oral bioavilability or other viral proteins such as HIV-1 integrase, ribonuclease H, and HIV-1 entry (CD4 attachment inhibitors, chemokine receptors antagonists, and fusion inhibitors). Understanding mechanism(s) of action of the drugs and mechanisms of drug resistance is necessary for successful designs in the next generation of anti-HIV-1 drugs. In this review, the mechanisms of action of reverse transcriptase- and protease-inhibitors, and the mechanism of resistance to these inhibitors, are described. PMID:15579086

  16. 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. PMID:12294481

  17. 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.

  18. Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents.

    PubMed

    Iwasa, K; Moriyasu, M; Tachibana, Y; Kim, H S; Wataya, Y; Wiegrebe, W; Bastow, K F; Cosentino, L M; Kozuka, M; Lee, K H

    2001-11-01

    Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts. PMID:11597468

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

    PubMed

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

    2015-02-15

    2-Deoxy-α-d-ribose-1-phosphate is of great interest as it is involved in the biosynthesis and/or catabolic degradation of several nucleoside analogues of biological and therapeutic relevance. However due to the lack of a stabilising group at its 2-position, it is difficult to synthesize stable prodrugs of this compound. In order to overcome this lack of stability, the synthesis of carbasugar analogues of 2-deoxyribose-1-phosphate was envisioned. Herein the preparation of a series of prodrugs of two carbocyclic analogues of 2-deoxyribose-1-phosphate using the phosphoramidate ProTide technology, along with their biological evaluation against HIV and cancer cell proliferation, is reported. PMID:25616343

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

    PubMed

    Nair, Vasu; Okello, Maurice

    2015-01-01

    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. PMID:26184144

  1. Anti-HIV-1 Activity of Elafin Depends on Its Nuclear Localization and Altered Innate Immune Activation in Female Genital Epithelial Cells

    PubMed Central

    Yao, Xiao-Dan; Henrick, Bethany M.; Ball, T. Blake; Plummer, Francis A.; Wachihi, Charles; Kimani, Joshua; Rosenthal, Kenneth L.

    2012-01-01

    Elafin (E) and its precursor trappin-2 (Tr) are alarm antiproteases with antimicrobial and immunomodulatory activities. Tr and E (Tr/E) have been associated with HIV-1 resistance. We recently showed that Tr/E reduced IL-8 secretion and NF-κB activation in response to a mimic of viral dsRNA and contributed to anti-HIV activity of cervicovaginal lavage fluid (CVL) of HIV-resistant (HIV-R) commercial sex workers (CSWs). Additionally, Tr, and more so E, were found to inhibit attachment/entry and transcytosis of HIV-1 in human endometrial HEC-1A cells, acting through virus or cells. Given their immunomodulatory activity, we hypothesized that Tr/E could exert anti-HIV-1 activity at multiple levels. Here, using tagged and untagged Tr/E proteins, we comparatively evaluated their protease inhibitory, anti-HIV-1, and immunomodulatory activities, and cellular distribution. E appeared to function as an autocrine/paracrine factor in HEC-1A cells, and anti-HIV-1 activity of E depended on its unmodified N-terminus and altered cellular innate activation, but not its antiprotease activity. Specifically, exogenously added N-terminus-unmodified E was able to enter the nucleus and to reduce viral attachment/entry and transcytosis, preferentially affecting R5-HIV-1ADA, but not X4-HIV-1IIIB. Further, anti-HIV-1 activity of E was associated with significantly decreased HIV-1-triggered IL-8 release, attenuated NF-κB/p65 nuclear translocation, and significantly modulated mRNA expression of innate sensors TLR3 and RIG-I in HEC-1A cells. Most importantly, we found that elevated Tr/E in CVLs of HIV-R CSWs were associated with lower mRNA levels of TLRs 2, 3, 4 and RIG-I in the genital ECs from this cohort, suggesting a link between Tr/E, HIV-1 resistance and modulated innate viral recognition in the female genital mucosa. Collectively, our data indicate that unmodified N-terminus is critical for intranuclear localization and anti-HIV-1 activity of E. We also propose that E-mediated altered

  2. Evaluation of anti-HIV-1 mutagenic nucleoside analogues.

    PubMed

    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

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

    PubMed

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

    2016-07-01

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

  4. Synthesis, gp120 binding and anti-HIV activity of fatty acid esters of 1,1-linked disaccharides

    PubMed Central

    Bachan, Stewart; Fantini, Jacques; Joshi, AnJali; Garg, Himanshu; Mootoo, David R.

    2011-01-01

    Inspired by the anti-human immunodeficiency virus (HIV) activity of analogues of β-galactosylceramide (GalCer), a set of mono- and di- saccharide fatty acid esters were designed as GalCer mimetics and their binding to the V3 loop peptide of HIV-1 and anti-HIV activity evaluated. 1,1-linked Gal-Man and Glu-Man disaccharides with an ester on the Man subunit bound the V3 loop peptide and inhibited HIV infectivity in single round infection assays with the TZM-bl cell line. IC50's were in the 50 μM range with no toxicity to the cells at concentrations up to 200 μM. These compounds appear to inhibit virus entry at early steps in viral infection since they were inactive if added post viral entry. Although these compounds were found to bind to the V3 loop peptide of gp120, it is not clear that this interaction is responsible for their anti-HIV activity because the relative binding affinity of closely related analogues did not correlate with their antiviral behavior. The low cytotoxicity of these 1,1-linked disaccharide fatty acid esters, combined with the easy accessibility to structurally diverse analogues make these molecules attractive leads for new topical anti-viral agents. PMID:21783371

  5. Anti-HIV-1 integrase compounds from Dioscorea bulbifera and molecular docking study.

    PubMed

    Chaniad, Prapaporn; Wattanapiromsakul, Chatchai; Pianwanit, Somsak; Tewtrakul, Supinya

    2016-06-01

    Context Dioscorea bulbifera L. (Dioscoreaceae) has been used in a traditional Thai longevity medicine preparation. Isolation of inhibitors from natural products is a potential source for continuous development of new HIV-1 integrase (IN) inhibitors. Objective The objective of this study is to isolate the compounds and evaluate their anti-HIV-1 IN activity, as well as to predict the potential interactions of the compounds with an IN. Materials and methods The ethyl acetate and water fractions (1-100 μg/mL) of Dioscorea bulbifera bulbils were isolated and tested for their anti-HIV-1 IN activity using the multiplate integration assay (MIA). The interactions of the active compounds with IN were investigated using a molecular docking method. Results and discussions The ethyl acetate and water fractions of Dioscorea bulbifera bulbils afforded seven compounds. Among these, allantoin (1), 2,4,3',5'-tetrahydroxybibenzyl (2), and 5,7,4'-trihydroxy-2-styrylchromone (5) were isolated for the first time from this plant. Myricetin (4) exhibited the most potent activity with an IC50 value of 3.15 μM, followed by 2,4,6,7-tetrahydroxy-9,10-dihydrophenanthrene (3, IC50 value= 14.20 μM), quercetin-3-O-β-d-glucopyranoside (6, IC50 value = 19.39 μM) and quercetin-3-O-β-d-galactopyranoside (7, IC50 value = 21.80 μM). Potential interactions of the active compounds (3, 4, 6, and 7) with the IN active site were additionally investigated. Compound 4 showed the best binding affinity to IN and formed strong interactions with various amino acid residues. These compounds interacted with Asp64, Thr66, His67, Glu92, Asp116, Gln148, Glu152, Asn155, and Lys159, which are involved in both the 3'-processing and strand transfer reactions of IN. In particular, galloyl, catechol, and sugar moieties were successful inhibitors for HIV-1 IN. PMID:26864337

  6. 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. PMID:26711310

  7. Self-delivery Multifunctional Anti-HIV Hydrogels for Sustained Release

    PubMed Central

    Li, Jiayang; Li, Xinming; Kuang, Yi; Gao, Yuan; Du, Xuewen; Shi, Junfeng; Xu, Bing

    2014-01-01

    None of the clinical trials of anti-HIV gels based on conventional polymers or lipid emulsions is successful, suggesting the need of new molecular design of the anti-HIV gels. This paper reports the conversion of anti-HIV prodrugs into self-delivery supramolecular hydrogels. By covalently conjugating reverse transcriptase inhibitors to a versatile self-assembly motif, we obtained the hydrogelators that self-assemble to form supramolecular nanofibers as the matrices of hydrogels in a weak acidic condition. Upon the treatment of prostate acid phosphatase (PAP), the hydrogels exhibit drastically enhanced elasticity. The hydrogelators are biocompatible and able to release the inhibitors under physiological condition. The use of the self-assembly motif as a self-delivery agent containing non-steroid anti-inflammatory drug (NSAID) renders this hydrogel to be both anti-inflammatory and anti-HIV. This work illustrates an unprecedented approach for designing multifunctional supramolecular hydrogels that may serve as potential anti-HIV hydrogels for sustained drug release. PMID:23616384

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2015-12-01

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

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

    SciTech Connect

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

    2008-10-03

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

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

    PubMed

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

    2015-01-01

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

  12. 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

  13. Synthesis and anti-HIV activity of 4-(naphthalen-1-yl)-1,2,5-thiadiazol-3-hydroxyl derivatives.

    PubMed

    Rai, Diwakar; Chen, Wenmin; Zhan, Peng; Liu, Hong; Tian, Ye; Liang, Xin; De Clercq, Erik; Pannecouque, Christophe; Balzarini, Jan; Liu, Xinyong

    2014-10-01

    A series of 4-(naphthalen-1-yl)-1,2,5-thiadiazol-3-hydroxyl derivatives (Ia-Im and IIa-IIe) designed as novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) was synthesized via an expeditious route and evaluated for their anti-HIV activities in MT-4 cell cultures. All the synthesized compounds were structurally confirmed by spectral analyses. Biological results showed that three analogues displayed moderate inhibitory activity against wild-type (wt) HIV-1 replication with EC(50) values ranging from 16 to 22 μm. Molecular docking of compound Ih with wt HIV-1 RT was performed to understand the binding mode between these inhibitors and the wt HIV-1 RT and to rationalize some SARs. PMID:24674646

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2014-09-15

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

  16. 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

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

    PubMed Central

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

    2012-01-01

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

  18. Carolignans from the Aerial Parts of Euphorbia sikkimensis and Their Anti-HIV Activity.

    PubMed

    Jiang, Cheng; Luo, Pan; Zhao, Yu; Hong, Jialing; Morris-Natschke, Susan L; Xu, Jun; Chen, Chin-Ho; Lee, Kuo-Hsiung; Gu, Qiong

    2016-03-25

    Seven new carolignans, including two pairs of enantiomers (±)-erythro-7'-methylcarolignan E (1a/1b) and (±)-threo-7'-methylcarolignan E (2a/2b), (+)-threo-carolignan E (3a), (+)-erythro-carolignan E (4a), and (-)-erythro-carolignan Z (5), together with four known lignans (3b, 4b, 6, and 7) and six polyphenols (8-13) were isolated from the aerial parts of Euphorbia sikkimensis. The structures of the new compounds were elucidated by spectroscopic analysis, and their absolute configurations were determined by electronic circular dichroism calculations. Seven of the isolates were examined for anti-HIV effects, and compounds 1a and 1b showed moderate anti-HIV activity with EC50 values of 6.3 and 5.3 μM. PMID:26756779

  19. A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity

    PubMed Central

    Balzarini, Jan; Andrei, Graciela; Balestra, Emanuela; Huskens, Dana; Vanpouille, Christophe; Introini, Andrea; Zicari, Sonia; Liekens, Sandra; Snoeck, Robert; Holý, Antonín; Perno, Carlo-Federico; Margolis, Leonid; Schols, Dominique

    2013-01-01

    Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4+ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host

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

    PubMed

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

    2015-12-18

    Two new alkaloids, flueggether A (1) and virosinine A (2), were isolated from a Chinese medicinal plant, Flueggea virosa. Their structures were assigned via spectroscopic methods with the absolute configurations of 1 and 2 being established by X-ray diffraction analysis and calculated electronic circular dichroism data, respectively. Compound 1 represents the first example with an ether bridge of Securinega alkaloid oligomers, and 2 bears a new heterocyclic backbone. Both alkaloids showed mild in vitro anti-HIV activity. PMID:26632657

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

    PubMed

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

    2012-10-01

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

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

    PubMed

    Hodgson, David M; Man, Stanislav

    2011-08-22

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

  3. Methamphetamine inhibits Toll-like receptor 9-mediated anti-HIV activity in macrophages.

    PubMed

    Cen, Ping; Ye, Li; Su, Qi-Jian; Wang, Xu; Li, Jie-Liang; Lin, Xin-Qin; Liang, Hao; Ho, Wen-Zhe

    2013-08-01

    Toll-like receptor 9 (TLR9) is one of the key sensors that recognize viral infection/replication in the host cells. Studies have demonstrated that methamphetamine (METH) dysregulated host cell innate immunity and facilitated HIV infection of macrophages. In this study, we present new evidence that METH suppressed TLR9-mediated anti-HIV activity in macrophages. Activation of TLR9 by its agonist CpG-ODN 2216 inhibits HIV replication, which was demonstrated by increased expression of TLR9, interferon (IFN)-α, IFN regulatory factor-7 (IRF-7), myeloid differentiation factor 88 (MyD88), and myxovirus resistance gene A (MxA) in macrophages. However, METH treatment of macrophages greatly compromised the TLR9 signaling-mediated anti-HIV effect and inhibited the expression of TLR9 downstream signaling factors. Dopamine D1 receptor (D1R) antagonists (SCH23390) could block METH-mediated inhibition of anti-HIV activity of TLR9 signaling. Investigation of the underlying mechanisms of the METH action showed that METH treatment selectively down-regulated the expression of TLR9 on macrophages, whereas it had little effect on the expression of other TLRs. Collectively, our results provide further evidence that METH suppresses host cell innate immunity against HIV infection by down-regulating TLR9 expression and its signaling-mediated antiviral effect in macrophages. PMID:23751096

  4. 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

  5. Testing anti-HIV activity of antiretroviral agents in vitro using flow cytometry analysis of CEM-GFP cells infected with transfection-derived HIV-1 NL4-3.

    PubMed

    Frezza, Caterina; Grelli, Sandro; Federico, Maurizio; Marino-Merlo, Francesca; Mastino, Antonio; Macchi, Beatrice

    2016-06-01

    An assay, specifically optimized to evaluate the anti-HIV activity of antiretrovirals by flow cytometry analysis, is described. As widely used anti-HIV agents, zidovudine (AZT), abacavir (ABC), 2',3'-dideoxyinosine (DDI), lamivudine (3TC), nevirapine (NVP), and efavirenz (EFV), and as drugs of recent approval raltegravir (RAL), etravirine (ETR), and rilpivirine (RPV), were utilized as reference drugs. HIV-1 NL4-3 virus was prepared by transfection of HEK293T cells with purified plasmid DNA and quantified by p24 antigen-capture assay. For infection, CEM-GFP cells were exposed to vehicle or to several concentrations of the drugs for 2 hr at 37 °C before HIV-1 NL4-3 was added to each sample. The adsorption was prolonged for 3 hr at 37 °C. After 72 hr of incubation, HIV-induced GFP expression in infected CEM-GFP cells was assessed by flow cytometry analysis and expressed as % positive cells. For comparison, p24 production in supernatants was assessed by a commercial ELISA kit. On the basis of IC50 values, the anti-HIV activity, as assayed by this method, was EFV > 3TC > AZT > NVP > DDI > ABC and ETR > RPV > RAL. The comparison between the IC50 values calculated through flow cytometry and p24 production revealed overlapping results, showing that the optimized protocol of CEM-GFP infection with HIV NL4-3 is a suitable method to perform quantitative, rapid and low-expensive screening tests to evaluate the in vitro effect of new candidate anti-HIV drugs. PMID:26519867

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

    PubMed Central

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

    2008-01-01

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

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

    PubMed Central

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

    2010-01-01

    In a continued study, 23 3′R,4′R-di-O-(−)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5–27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 μM to 0.14 μM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 μM; TI 310 and 200, respectively), and were two-fold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 μM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5–10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates. PMID:20728367

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

    PubMed

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

    2010-09-15

    In a continued study, 23 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5-27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 microM to 0.14 microM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 microM; TI 310 and 200, respectively), and were twofold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 microM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5-10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates. PMID:20728367

  9. Biophysical Property and Broad Anti-HIV Activity of Albuvirtide, a 3-Maleimimidopropionic Acid-Modified Peptide Fusion Inhibitor

    PubMed Central

    Chong, Huihui; Yao, Xue; Zhang, Chao; Cai, Lifeng; Cui, Sheng; Wang, Youchun; He, Yuxian

    2012-01-01

    Albuvirtide (ABT) is a 3-maleimimidopropionic acid (MPA)-modified peptide HIV fusion inhibitor that can irreversibly conjugate to serum albumin. Previous studies demonstrated its in vivo long half-life and potent anti-HIV activity. Here, we focused to characterize its biophysical properties and evaluate its antiviral spectrum. In contrast to T20 (Enfuvirtide, Fuzeon), ABT was able to form a stable α-helical conformation with the target sequence and block the fusion-active six-helix bundle (6-HB) formation in a dominant-negative manner. It efficiently inhibited HIV-1 Env-mediated cell membrane fusion and virus entry. A large panel of 42 HIV-1 pseudoviruses with different genotypes were constructed and used for the antiviral evaluation. The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B′, CRF07_BC and CRF01_AE recombinants that are currently circulating in China. Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20. Taken together, our data indicate that the chemically modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor. PMID:22403678

  10. Short Communication: Anti-HIV-1 Envelope Immunoglobulin Gs in Blood and Cervicovaginal Samples of Beninese Commercial Sex Workers

    PubMed Central

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

    2014-01-01

    Abstract Characterization of the immune correlates of protection against HIV infection is crucial for the development of preventive strategies. This study examined HIV-1 envelope (Env) glycoproteins, specifically immunoglobulin G (IgG), in systemic and mucosal compartments of female Beninese commercial sex workers (CSWs). Samples of 23 HIV-1-positive and 20 highly exposed HIV-1-seronegative (HESN) CSWs were studied. HIV-1 Env-specific IgG detection in sera and cervicovaginal lavages (CVLs) from the study population was done by cell-based ELISA. The HIV neutralizing activity was evaluated with a neutralization assay. The HIV-1-specific antibody-dependent cellular cytotoxicity (ADCC) response of the cohort was measured with a FACS-based assay evaluating the ADCC-mediated elimination of gp120-coated target cells. No anti-HIV-1 Env-specific IgG neutralizing or ADCC activities were detected in samples from HESN CSWs. Samples from HIV-1-infected CSWs presented ADCC activity in both sera and CVLs. Anti-Env IgG from sera and CVLs from HIV-1-infected CSWs preferentially recognized Env in its CD4-bound conformation. HIV-1-infected CSWs have ADCC-mediating IgG that preferentially recognizes Env in its CD4-bound conformation at the mucosal site. PMID:25354025

  11. Brief Report: Seminal Plasma Anti-HIV Antibodies Trigger Antibody-dependent Cellular Cytotoxicity: Implications for HIV Transmission.

    PubMed

    Parsons, Matthew S; Madhavi, Vijaya; Ana-Sosa-Batiz, Fernanda; Center, Rob J; Wilson, Kim M; Bunupuradah, Torsak; Ruxrungtham, Kiat; Kent, Stephen J

    2016-01-01

    Recent evidence from HIV vaccine trials in humans and non-human primates suggests that nonneutralizing antibody functions, such as antibody-dependent cellular cytotoxicity (ADCC), are an important component of vaccine-mediated protection. Whether anti-HIV ADCC antibodies are present in seminal fluid, however, is not known. We assessed whether anti-HIV antibodies within seminal plasma mediate ADCC and activate natural killer (NK) cells. Using matched blood and seminal plasma samples, we detected anti-HIV IgG within samples from all 11 HIV-infected donors. Furthermore, anti-HIV antibodies within the seminal plasma triggered detectable ADCC in 9 of 11 donors and activated NK cells in 6 of 11 donors. The ability of seminal plasma-derived IgG to activate NK cells in an anti-HIV antibody-dependent manner was enhanced when IgG were enriched and other seminal plasma components were removed. These observations have relevance for understanding natural immunity to HIV infection and provide assistance with HIV vaccine design. PMID:26761269

  12. Anti-HIV Designer T Cells Progressively Eradicate a Latently Infected Cell Line by Sequentially Inducing HIV Reactivation then Killing the Newly Gp120-Positive Cells

    PubMed Central

    Sahu, Gautam K; Sango, Kaori; Selliah, Nithianandan; Ma, Qiangzhong; Skowron, Gail; Junghans, Richard P

    2013-01-01

    The current antiretroviral therapy (ART) can effectively reduce plasma HIV loads to undetectable levels, but cannot eliminate latently infected resting memory CD4 T cells that persist for the lifetime of infected patients. Therefore, designing new therapeutic approaches to eliminate these latently infected cells or the cells that produce HIV upon reactivation from latency is a priority in the ART era in order to progress to a cure of HIV. Here, we show that “designer” T cells expressing chimeric antigen receptor (CAR), CD4-CD28-CD3ζ, can target and kill HIV Env-expressing cells. Further, they secrete effector cytokines upon contact with HIV Env+ target cells that can reactivate latent HIV in a cell line model, thereby exposing those cells to recognition and killing by anti-HIV CAR+ T cells. Taken to the limit, this process could form the basis for an eventual functional or sterilizing cure for HIV in patients. PMID:24074590

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

    SciTech Connect

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

    1993-12-31

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

  14. The application of phosphoramidate ProTide technology to acyclovir confers anti-HIV inhibition

    PubMed Central

    Derudas, Marco; Carta, Davide; Brancale, Andrea; Vanpouille, Christophe; Lisco, Andrea; Margolis, Leonid; Balzarini, Jan; McGuigan, Christopher

    2009-01-01

    Recently it has been reported that phosphorylated acyclovir (ACVa) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell free system. To deliver phosphorylated ACV inside cells we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derivatived ProTides show anti-HIV activity at non-cytotoxic concentrations; ester and aryl variation was tolerated. ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) type -1, -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships, but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modelling studies have been performed in order to better understand the antiviral behaviour of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive. PMID:19645484

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

    NASA Astrophysics Data System (ADS)

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

    2008-11-01

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

  16. Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation

    PubMed Central

    Mouquet, Hugo; Scheid, Johannes F.; Zoller, Markus J.; Krogsgaard, Michelle; Ott, Rene G.; Shukair, Shetha; Artyomov, Maxim N.; Pietzsch, John; Connors, Mark; Pereyra, Florencia; Walker, Bruce D.; Ho, David D.; Wilson, Patrick C.; Seaman, Michael S.; Eisen, Herman N.; Chakraborty, Arup K.; Hope, Thomas J.; Ravetch, Jeffrey V.; Wardemann, Hedda; Nussenzweig, Michel C.

    2013-01-01

    During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV disfavours homotypic bivalent antibody binding1–3. Here we show that during the human antibody response to HIV, somatic mutations that increase antibody affinity also increase breadth and neutralizing potency. Surprisingly, the responding naive and memory B cells produce polyreactive antibodies, which are capable of bivalent heteroligation between one high-affinity anti-HIV-gp140 combining site and a second low-affinity site on another molecular structure on HIV. Although cross-reactivity to self-antigens or polyreactivity is strongly selected against during B-cell development4, it is a common serologic feature of certain infections in humans, including HIV, Epstein-Barr virus and hepatitis C virus. Seventy-five per cent of the 134 monoclonal anti-HIV-gp140 antibodies cloned from six patients5 with high titres of neutralizing antibodies are polyreactive. Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV. PMID:20882016

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

    PubMed

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

    2015-01-22

    Fucoidans are sulfated polysaccharides derived from marine brown algae. In the current work the anti-HIV activity of three fucoidans, extracted from three brown seaweeds Sargassum mcclurei, Sargassum polycystum and Turbinara ornata and collected from Nha Trang bay, Vietnam was investigated. Fucoidans extracted from the three species displayed similar antiviral activities with a mean IC50 ranging from 0.33 to 0.7 μg/ml while displaying no cell toxicity. Our results showed that the anti-HIV activity of fucoidans is not primarily linked to the sulfate content and the appropriate position of sulfate groups in the fucoidan backbones was also not associated with the antiviral activity. Fucoidans inhibited HIV-1 infection when they were pre-incubated with the virus but not with the cells, and not after infection, blocking the early steps of HIV entry into target cells. These data contribute to a better understanding of the influence of fucoidans structural characteristics on their biological activity. PMID:25439876

  18. 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

  19. Novel multi-component nanopharmaceuticals derived from poly(ethylene) glycol, retro-inverso-Tat nonapeptide and saquinavir demonstrate combined anti-HIV effects

    PubMed Central

    Wan, Li; Zhang, Xiaoping; Gunaseelan, Simi; Pooyan, Shahriar; Debrah, Olivia; Leibowitz, Michael J; Rabson, Arnold B; Stein, Stanley; Sinko, Patrick J

    2006-01-01

    Background Current anti-AIDS therapeutic agents and treatment regimens can provide a dramatically improved quality of life for HIV-positive people, many of whom have no detectable viral load for prolonged periods of time. Despite this, curing AIDS remains an elusive goal, partially due to the occurrence of drug resistance. Since the development of resistance is linked to, among other things, fluctuating drug levels, our long-term goal has been to develop nanotechnology-based drug delivery systems that can improve therapy by more precisely controlling drug concentrations in target cells. The theme of the current study is to investigate the value of combining AIDS drugs and modifiers of cellular uptake into macromolecular conjugates having novel pharmacological properties. Results Bioconjugates were prepared from different combinations of the approved drug, saquinavir, the antiviral agent, R.I.CK-Tat9, the polymeric carrier, poly(ethylene) glycol and the cell uptake enhancer, biotin. Anti-HIV activities were measured in MT-2 cells, an HTLV-1-transformed human lymphoid cell line, infected with HIV-1 strain Vbu 3, while parallel studies were performed in uninfected cells to determine cellular toxicity. For example, R.I.CK-Tat9 was 60 times more potent than L-Tat9 while the addition of biotin resulted in a prodrug that was 2850 times more potent than L-Tat9. Flow cytometry and confocal microscopy studies suggest that variations in intracellular uptake and intracellular localization, as well as synergistic inhibitory effects of SQV and Tat peptides, contributed to the unexpected and substantial differences in antiviral activity. Conclusion Our results demonstrate that highly potent nanoscale multi-drug conjugates with low non-specific toxicity can be produced by combining moieties with anti-HIV agents for different targets onto macromolecules having improved delivery properties. PMID:16635263

  20. Screening Platform toward New Anti-HIV Aptamers Set on Molecular Docking and Fluorescence Quenching Techniques.

    PubMed

    Oliviero, Giorgia; Stornaiuolo, Mariano; D'Atri, Valentina; Nici, Fabrizia; Yousif, Ali Munaim; D'Errico, Stefano; Piccialli, Gennaro; Mayol, Luciano; Novellino, Ettore; Marinelli, Luciana; Grieco, Paolo; Carotenuto, Alfonso; Noppen, Sam; Liekens, Sandra; Balzarini, Jan; Borbone, Nicola

    2016-02-16

    By using a new rapid screening platform set on molecular docking simulations and fluorescence quenching techniques, three new anti-HIV aptamers targeting the viral surface glycoprotein 120 (gp120) were selected, synthesized, and assayed. The use of the short synthetic fluorescent peptide V35-Fluo mimicking the V3 loop of gp120, as the molecular target for fluorescence-quenching binding affinity studies, allowed one to measure the binding affinities of the new aptamers for the HIV-1 gp120 without the need to obtain and purify the full recombinant gp120 protein. The almost perfect correspondence between the calculated Kd and the experimental EC50 on HIV-infected cells confirmed the reliability of the platform as an alternative to the existing methods for aptamer selection and measuring of aptamer-protein equilibria. PMID:26810800

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

    PubMed

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

    2015-04-15

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

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

    PubMed Central

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

    2008-01-01

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

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

    PubMed

    De Clercq, Erik

    2009-04-01

    In 2008, 25 years after the human immunodeficiency virus (HIV) was discovered as the then tentative aetiological agent of acquired immune deficiency syndrome (AIDS), exactly 25 anti-HIV compounds have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir); non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine, efavirenz and etravirine); protease inhibitors (PIs: saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir); cell entry inhibitors [fusion inhibitors (FIs: enfuvirtide) and co-receptor inhibitors (CRIs: maraviroc)]; and integrase inhibitors (INIs: raltegravir). These compounds should be used in drug combination regimens to achieve the highest possible benefit, tolerability and compliance and to diminish the risk of resistance development. PMID:19108994

  4. Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor.

    PubMed

    Nair, Vasu; Okello, Maurice; Mishra, Sanjay; Mirsalis, Jon; O'Loughlin, Kathleen; Zhong, Yu

    2014-08-01

    Integration of viral DNA into human chromosomal DNA catalyzed by HIV integrase represents the "point of no return" in HIV infection. For this reason, HIV integrase is considered a crucial target in the development of new anti-HIV therapeutic agents. We have discovered a novel HIV integrase inhibitor 1, that exhibits potent antiviral activity and a favorable metabolism profile. This paper reports on the pharmacokinetics and toxicokinetics of compound 1 and the relevance of these findings with respect to further development of this integrase-targeted antiviral agent. Oral administration of compound 1 in Sprague Dawley rats revealed rapid absorption. Drug exposure increased with increasing drug concentration, indicative of appropriate dose-dependence correlation. Compound 1 exhibited suitable plasma half-life, extensive extravascular distribution and acceptable bioavailability. Toxicity studies revealed no compound-related clinical pathology findings. There were no changes in erythropoietic, white blood cell or platelet parameters in male and female rats. There was no test-article related change in other clinical chemistry parameters. In addition, there were no detectable levels of bilirubin in the urine and there were no treatment-related effects on urobilinogen or other urinalysis parameters. The preclinical studies also revealed that the no observed adverse effect level and the maximum tolerated dose were both high (>500mg/kg/day). The broad and significant antiviral activity and favorable metabolism profile of this integrase inhibitor, when combined with the in vivo pharmacokinetic and toxicokinetic data and their pharmacological relevance, provide compelling and critical support for its further development as an anti-HIV therapeutic agent. PMID:24821255

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

    PubMed

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

    2016-05-01

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

  6. Transdermal delivery of dideoxynucleoside-type anti-HIV drugs. 1. Stability studies for hairless rat skin permeation.

    PubMed

    Kim, D D; Chien, Y W

    1995-09-01

    The stability of dideoxynucleoside-type anti-HIV drugs in solution when in contact with hairless rat skin was investigated in order to study the feasibility of their transdermal delivery. The freshly excised dorsal region of hairless rat skin was mounted on Valia-Chien skin permeation cells, and both epidermis (donor) and dermis (receptor) were extracted with isotonic phosphate buffer (pH 7.4) at 37 degrees C for 24 h. Zalcitabine (DDC), didanosine (DDI), and zidovudine (AZT) were found to be stable in the extract of the epidermis at 37 degrees C for at least 30 h. However, DDC and DDI degraded in the extract of the dermis following first-order kinetics at both 25 and 37 degrees C, while AZT was stable at 37 degrees C for at least 30 h. The degradation mechanism(s) of DDC and DDI was (were) studied by analyzing HPLC chromatograms and by evaluating the drug stability in the extract which was filtered to remove any microbes. An unidentified peak produced by DDC in the dermis extract did not appear when the drug was added to the filtered extract, which suggested a bacterial degradation of DDC. On the other hand, DDI was unstable even in the filtered extract and produced a degradation product which corresponded to hypoxanthine, which suggested that a cutaneous enzyme is also involved in the degradation of DDI. DDC was stabilized by the addition of 0.01% (w/v) of an antibacterial agent, such as thimerosal or gentamicin, in the receptor solution, while DDI was stabilized by 0.01% (w/v) purine nucleoside phosphorylase inhibitor, i.e., p-chloromercuribenzoic acid. These results show the importance of stability studies when designing skin permeation experiments using hairless rat since compounds with similar chemical structures can have different stability profiles when in contact with hairless rat skin. PMID:8537882

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2016-08-01

    In the present study, fifteen novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one (6a-o) derivatives were designed as inhibitor of HIV-1 RT using ligand based drug design approach and in-silico evaluated for drug-likeness properties. Designed compounds were synthesized, characterized and in-vitro evaluated for RT inhibitory activity against wild HIV-1 RT strain. Among the tested compounds, four compounds (6a, 6b, 6j and 6o) exhibited significant inhibition of HIV-1 RT (IC50⩽10μg/ml). All synthesized compounds were also evaluated for anti-HIV-1 activity as well as cytotoxicity on T lymphocytes, in which compounds 6b and 6l exhibited significant anti-HIV activity (EC50 values 4.72 and 5.45μg/ml respectively) with good safety index. Four compounds (6a, 6b, 6j and 6o) found significantly active against HIV-1 RT in the in-vitro assay were in-silico evaluated against two mutant RT strains as well as one wild strain. Further, titled compounds were evaluated for in-vitro antibacterial (Escherichia coli, Pseudomonas putida, Staphylococcus aureus and Bacillus cereus) and antifungal (Candida albicans and Aspergillus niger) activities. PMID:27288643

  9. The Evaluation Phase of Systemic Family Therapy.

    ERIC Educational Resources Information Center

    Caille, Philippe

    1982-01-01

    Describes the initial evaluation phase of family therapy, which clarifies the circular interaction maintaining the symptom, the family structure, and its relationship to the therapist. Suggests using first sessions to collect data and organize it meaningfully. Presents phenomenological and mythical models of family functioning as guides for…

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

    PubMed

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

    2015-06-01

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

  11. A beta-galactose-specific lectin isolated from the marine worm Chaetopterus variopedatus possesses anti-HIV-1 activity.

    PubMed

    Wang, Jian-Hua; Kong, Jing; Li, Wei; Molchanova, Valentina; Chikalovets, Irina; Belogortseva, Natalia; Luk'yanov, Pavel; Zheng, Yong-Tang

    2006-01-01

    A 30 kDa beta-galactose-specific lectin named CVL was isolated from the polychaete marine worm Chaetopterus variopedatus (Annelida) and its anti-HIV-1 activity in vitro was determined. Results showed that CVL inhibited cytopathic effect induced by HIV-1 and the production of viral p24 antigen. The EC(50) values were 0.0043 and 0.057 microM, respectively. Time-of-addition analysis of anti-HIV-1 activity indicated its action was at the early stage of virus replication. CVL could blocked the cell-to-cell fusion process of HIV infected and uninfected cells with an EC(50) of 0.073 microM. The inhibition of HIV-1 entry into host cells was demonstrated by using fluorescence-based real-time quantify PCR. At CVL concentration of 0.33 microM and 0.07 microM, 86% and 21% virus attachment were blocked, respectively. The anti-HIV-1 action of CVL might relate to blockade of HIV-1 entry into cells. PMID:16316787

  12. 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.

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

    PubMed

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

    2015-01-01

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

  14. 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

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

    PubMed

    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

  16. 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

  17. 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.

  18. 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.

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

    PubMed

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

    2004-01-01

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

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

    PubMed Central

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

    2012-01-01

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

  1. The anti-HIV activity of ADS-J1 targets the HIV-1 gp120

    SciTech Connect

    Armand-Ugon, Mercedes; Clotet-Codina, Imma; Tintori, Cristina; Manetti, Fabrizio; Clotet, Bonaventura; Botta, Maurizio; Este, Jose A. . E-mail: jaeste@irsicaixa.es

    2005-12-05

    Recent data suggest that heparin sulfates may bind to a CD4 induced epitope in the HIV-1 gp120 that constitutes the coreceptor binding site. We have studied the mechanism of action of ADS-J1, a non-peptidic compound selected by docking analysis to interact with gp41 and to interfere with the formation of N-36/C-34 complexes in sandwich ELISA experiments. We show that ADS-J1 blocked the binding of wild-type HIV-1 NL4-3 strain to MT-4 cells but not virus-cell binding of a polyanion-resistant virus. However, ADS-J1 blocked the replication of polyanion-resistant, T-20- and C34-resistant HIV-1, suggesting a second mechanism of action. Development of resistance to ADS-J1 on the polyanion-resistant HIV-1 led to mutations in gp120 coreceptor binding site and not in gp41. Time of addition experiments confirmed that ADS-J1, but not polyanions such as dextran sulfate or AR177, worked at a step that mimics the activity of an HIV coreceptor antagonist but prior to gp41-dependent fusion. We conclude that ADS-J1 may bind to the HIV coreceptor binding site as its mechanism of anti-HIV activity.

  2. 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.

  3. A broad spectrum anti-HIV inhibitor significantly disturbs V1/V2 domain rearrangements of HIV-1 gp120 and inhibits virus entry.

    PubMed

    Berinyuy, Emiliene; Soliman, Mahmoud E S

    2016-01-01

    Inhibition of human immunodeficiency virus (HIV) entry into target human cells is considered as a critical strategy for preventing HIV infection. Conformational shifts of the HIV-1 envelope glycoprotein (gp120) facilitates the attachment of the virus to target cells, therefore gp120 remains an attractive target for antiretroviral therapy development. Compound 18A has been recently identified as a broad-spectrum anti-HIV inhibitor. It was proposed that 18A disrupts rearrangements of V1/V2 region in gp120; however, the precise mechanism by which 18A interferes with the inherent motion of V1/V2 domain remains obscure. In this report, we elaborate on the binding mode of compound 18A to the closed conformation of a soluble cleaved gp120 and further examine the dynamic motion of V1/V2 region in both gp120 and the gp120-18A complex via all-atom molecular dynamics simulations. In this work, comparative molecular dynamic analyses revealed that 18A makes contact with Leu179, Ile194, Ile424, Met426 W427, E370 and Met475 in the main hydrophobic cavity of the unliganded gp120 and disrupts the restructuring of V1/V2 domain observed in apo gp120. The unwinding of α1 and slight inversion of β2 in gp120 leads to the shift of VI/V2 domain away from the V3 N-terminal regions and toward the outer domain. Stronger contacts between Trp425 and Trp112 rings may contribute to the reduced flexibility of α1 observed upon 18A binding thereby inhibiting the shifts of the V1/V2 region. Binding of 18A to gp120: (1) decreases the overall flexibility of the protein and (2) inhibits the formation a gp120 conformation that closely ressembles a CD4-bound-like conformation. Information gained from this report not only elaborates on important dynamic features of gp120, but will also assist with the future designs of potent gp120 inhibitors as anti-HIV. PMID:26446906

  4. First Membrane Proximal External Region-Specific Anti-HIV1 Broadly Neutralizing Monoclonal IgA1 Presenting Short CDRH3 and Low Somatic Mutations.

    PubMed

    Benjelloun, Fahd; Oruc, Zeliha; Thielens, Nicole; Verrier, Bernard; Champier, Gael; Vincent, Nadine; Rochereau, Nicolas; Girard, Alexandre; Jospin, Fabienne; Chanut, Blandine; Genin, Christian; Cogné, Michel; Paul, Stephane

    2016-09-01

    Mucosal HIV-1-specific IgA have been described as being able to neutralize HIV-1 and to block viral transcytosis. In serum and saliva, the anti-HIV IgA response is predominantly raised against the envelope of HIV-1. In this work, we describe the in vivo generation of gp41-specific IgA1 in humanized α1KI mice to produce chimeric IgA1. Mice were immunized with a conformational immunogenic gp41-transfected cell line. Among 2300 clones screened by immunofluorescence microscopy, six different gp41-specific IgA with strong recognition of gp41 were identified. Two of them have strong neutralizing activity against primary HIV-1 tier 1, 2, and 3 strains and present a low rate of somatic mutations and autoreactivity, unlike what was described for classical gp41-specific IgG. Epitopes were identified and located in the hepted repeat 2/membrane proximal external region. These Abs could be of interest in prophylactic treatment to block HIV-1 penetration in mucosa or in chronically infected patients in combination with antiretroviral therapy to reduce viral load and reservoir. PMID:27481846

  5. A new lectin from the sea worm Serpula vermicularis: isolation, characterization and anti-HIV activity.

    PubMed

    Molchanova, Valentina; Chikalovets, Irina; Chernikov, Oleg; Belogortseva, Natalia; Li, Wei; Wang, Jian-Hua; Yang, Dong-Yun Ou; Zheng, Yong-Tang; Lukyanov, Pavel

    2007-03-01

    A GlcNAc-specific lectin was isolated from the sea worm Serpula vermicularis (SVL) (Annelida) and purified by ion-exchange, affinity and gel permeation chromatography. SVL was a homotetrameric protein with native molecular mass of about 50 kDa, and consisted of identical subunits of 12.7 kDa. The carbohydrate content of 1.9% suggested that the lectin was a glycoprotein, and mainly composed by aspartic and glutamic acids, glycine, valine and serine; with relatively lower content of basic amino acids and cysteine. The first 15 residues of the N-terminal region were determined as ADTPCQMLGSRYGWR. It was stable at pH 6-9 and at temperatures up to 40 degrees C. SVL was Ca(2+)-independent lectin that agglutinated native and trypsinized human erythrocytes. Hapten inhibition studies indicated that SVL showed binding specificity only for N-acetyl-d-glucosamine and its derivatives among the monosaccharides tested and required the presence of hydroxyl group at the C-3 of GlcNAc. The presence of hydrophobic p-nitrophenyl aglycone improved inhibitory potency of N-acetyl-d-glucosamine. Ovomucoid and ovalbumin were found to be inhibitors among the glycoproteins used for inhibition assay. The anti-HIV-1 (human immunodeficiency virus) activity of SVL in vitro was determined: SVL inhibited the production of viral p24 antigen and cytopathic effect induced by HIV-1. The EC(50) values were 0.23 and 0.15 microg x mL(-1) respectively. PMID:17258940

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

    PubMed Central

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

    2010-01-01

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

  7. 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. PMID:25700657

  8. 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

  9. 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.

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

    PubMed Central

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

    2012-01-01

    The advent of highly active antiretroviral therapy (HAART) has significantly improved the prognosis for human immunodeficiency virus (HIV)-infected patients, however the adverse side effects associated with prolonged HAART therapy use continue. Although systemic viral load can be undetectable, the virus remains sequestered in anatomically privileged sites within the body. Nanotechnology-based delivery systems are being developed to target the virus within different tissue compartments and are being evaluated for their safety and efficacy. The current review outlines the various nanomaterials that are becoming increasingly used in biomedical applications by virtue of their robustness, safety, multimodality, and multifunctionality. Nanotechnology can revolutionize the field of HIV medicine by not only improving diagnosis, but also by improving delivery of antiretrovirals to targeted regions in the body and by significantly enhancing the efficacy of the currently available antiretroviral medications. PMID:23055735

  11. [Evaluation of integrative group therapy with children].

    PubMed

    Hain, C; Többen, B; Schulz, W

    2001-01-01

    The purpose of this study consists in the investigation of the effectiveness of an Integrative Group Therapy involving children from a social focus area. The research has been made on a group therapy covering a total of 22 therapeutic sessions with six "marginalised children" aged seven to nine attending the second class of a primary school. The children suffered from considerable concentration and attention problems affecting their achievements at school. The dominating symptom with three of these children has been aggressiveness, with two of them it has been social withdrawal and insecurity and one child suffered from psychosomatic complaints. The success of the treatment was determined by different target areas (symptomatic features, adaptive function, individual therapeutic goals, assessment of the treatment), having been assessed by different persons of reference (parents, teachers, therapists). According to the results the effectiveness of the Integrative Group Therapy with children has to be regarded unsatisfactory. The average effect size (averaged over all the scales of CBCL and TRF) amounts to 0.32. Considering only those scales where there have been peculiarities at the preliminary measuring, the average effect size amounts to 0.39. According to the individual case evaluation the treatment may be considered successful with one child, yet with another child a definite negative development has been noticed, and with four of the children no or slightly positive changes have been registered. The Integrative Group Therapy seems to be inapplicable to children with aggressive problems. In conclusion the results will be discussed and proposals for an improvement of the treatment are being made. PMID:11471423

  12. 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. PMID:26647083

  13. Diarylpyrimidine-dihydrobenzyloxopyrimidine hybrids: new, wide-spectrum anti-HIV-1 agents active at (sub)-nanomolar level.

    PubMed

    Rotili, Dante; Tarantino, Domenico; Artico, Marino; Nawrozkij, Maxim B; Gonzalez-Ortega, Emmanuel; Clotet, Bonaventura; Samuele, Alberta; Esté, José A; Maga, Giovanni; Mai, Antonello

    2011-04-28

    Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY-DABO hybrids (1-4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies. PMID:21438533

  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. PMID:3143568

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

    PubMed

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

    2012-06-01

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

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

    PubMed Central

    Liu, Hongshan; Xu, Shiqing; Cheng, Ming; Chen, Ying; Xia, Peng; Qian, Keduo; Xia, Yi; Yang, Zheng-Yu; Chen, Chin-Ho; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung

    2011-01-01

    Six 3′R,4′R-di-O-(S)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) and two 3′R,4′R-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives were designed, synthesized, and evaluated for inhibition of HIV-1NL4-3 replication in TZM-bl cells. 2-Ethyl-2′-monomethyl-1′-oxa- and -1′-thia-DCP (5a, 6a), as well as 2-ethyl-1′-thia-DCP (7a) exhibited potent anti-HIV activity with EC50 values of 30, 38 and 54 nM and therapeutic indexes of 152.6, 48.0 and 100.0, respectively, which were better than or comparable to those of the lead compound 2-ethyl-DCP in the same assay. 4-Methyl-1′-thia-DCK (8a) also showed significant inhibitory activity with an EC50 of 128 nM and TI of 237.9. PMID:21871800

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

    PubMed

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

    2011-10-01

    Six 3'R,4'R-di-O-(S)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) and two 3'R,4'R-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives were designed, synthesized, and evaluated for inhibition of HIV-1(NL4-3) replication in TZM-bl cells. 2-Ethyl-2'-monomethyl-1'-oxa- and -1'-thia-DCP (5a, 6a), as well as 2-ethyl-1'-thia-DCP (7a) exhibited potent anti-HIV activity with EC(50) values of 30, 38 and 54 nM and therapeutic indexes of 152.6, 48.0 and 100.0, respectively, which were better than or comparable to those of the lead compound 2-ethyl-DCP in the same assay. 4-Methyl-1'-thia-DCK (8a) also showed significant inhibitory activity with an EC(50) of 128 nM and TI of 237.9. PMID:21871800

  18. Increase of anti-HIV activity of C-peptide fusion inhibitors using a bivalent drug design approach.

    PubMed

    Ling, Yanbo; Xue, Huifang; Jiang, Xifeng; Cai, Lifeng; Liu, Keliang

    2013-09-01

    We reported the design of fusion inhibitors with improved activity using a multivalent inhibitor design strategy. First, we chose C29 as the template sequence, which is a 29-mer peptide derived from HIV-1 gp41 CHR domain and has anti-HIV activity of IC50 118 nM in a cell-cell fusion assay. We optimized the crosslink sites and linkers of the template peptide. We found that N-terminal crosslink caused activity improvement based on the multivalent co-operative effect. Especially, the IC50 of peptide (CAcaC29)2 was improved from 49.02 (monomeric form) to 5.71 nM. Compared with long peptides, short peptides may be more suitable to analyze the co-operative effect. So we selected a shorter peptide C22 to synthesize the bivalent inhibitors. Due its weak helicity, no co-operative effect appeared. Therefore, we chose SC22EK, which were introduced salt bridges to consolidate the helicity based on the natural sequence C22. The cross-linked (CAcaSC22EK)2 was four times more potent than the monomer SC22EK in anti-HIV activity, with an IC50 value of 4.92 nM close to the high active peptide fusion inhibitor C34. The strategy used in this study may be used to design new fusion inhibitors to interfere similar processes. PMID:23906421

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

    PubMed Central

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

    2014-01-01

    Screening of a small library of natural product extracts derived from endophytic fungi of the Sonoran desert plants in a cell-based anti-HIV assay involving T-cells infected with the HIV-1 virus identified the EtOAc extract of a fermentation broth of Alternaria tenuissima QUE1Se inhabiting the stem tissue of Quercus emoryi as a promising candidate for further investigation. Bioactivity-guided fractionation of this extract led to the isolation and identification of two new metabolites, altertoxins V (1) and VI (2) together with the known compounds, altertoxins I (3), II (4), and III (5). The structures of 1 and 2 were determined by detailed spectroscopic analysis and those of 3–5 were established by comparison with reported data. When tested in our cell-based assay at concentrations insignificantly toxic to T-cells, altertoxins V (1), I (3), II (4), and III (5) completely inhibited replication of the HIV-1 virus at concentrations of 0.50, 2.20, 0.30, and 1.50 μM respectively. Our findings suggest that the epoxyperylene structural scaffold in altertoxins may be manipulated to produce potent anti-HIV therapeutics. 2014 Elsevier Ltd. All rights reserved. PMID:25260957

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

    PubMed

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

    2016-07-18

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

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

    PubMed

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

    2014-11-01

    Screening of a small library of natural product extracts derived from endophytic fungi of the Sonoran desert plants in a cell-based anti-HIV assay involving T-cells infected with the HIV-1 virus identified the EtOAc extract of a fermentation broth of Alternaria tenuissima QUE1Se inhabiting the stem tissue of Quercus emoryi as a promising candidate for further investigation. Bioactivity-guided fractionation of this extract led to the isolation and identification of two new metabolites, altertoxins V (1) and VI (2) together with the known compounds, altertoxins I (3), II (4), and III (5). The structures of 1 and 2 were determined by detailed spectroscopic analysis and those of 3-5 were established by comparison with reported data. When tested in our cell-based assay at concentrations insignificantly toxic to T-cells, altertoxins V (1), I (3), II (4), and III (5) completely inhibited replication of the HIV-1 virus at concentrations of 0.50, 2.20, 0.30, and 1.50 μM, respectively. Our findings suggest that the epoxyperylene structural scaffold in altertoxins may be manipulated to produce potent anti-HIV therapeutics. PMID:25260957

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  5. Toward the development of a single-round infection assay based on EGFP reporting for anti-HIV-1 drug discovery

    PubMed Central

    Soezi, Mahdieh; Memarnejadian, Arash; Aminzadeh, Saeed; Zabihollahi, Rezvan; Sadat, Seyed Mehdi; Amini, Safieh; Hekmat, Soheila; Aghasadeghi, Mohammad Reza

    2015-01-01

    Background: The rapid increase of HIV-1 strains resistant to current antiretroviral drugs is a challenge for successful AIDS therapy. This necessitates the development of novel drugs, and to this end, availability of screening systems for in vitro drug discovery is a priority. Herein, we report the modification of a previously developed system for increased sensitivity, ease of use, and cost-efficiency, based on the application of the EGFP marker. Methods: A PCR-amplified gfp gene (gfp) was cloned into pmzNL4-3, the plasmid already designed to produce single-cycle replicable virions, in frame with the reverse-transcriptase gene to construct the pmzNL4-3/GFP plasmid. GFP-mzNL4-3 pseudo-typed virions, as the first progeny viruses, were recovered from the culture supernatant of HEK293T cells co-transfected with pmzNL4-3/GFP and the helper plasmids pSPAX2 and pMD2G, which respectively encode HIV-1 Gag-Pol and vesicular stomatitis virus glycoprotein. Single-cycle replication and virion production were assessed by syncytia formation, p24 antigen assays, and electron and fluorescence microscopy. Results: The incorporation of EGFP into the viral particles allowed their quantification by fluorometry, flow-cytometry, and fluorescence microscopy; however, this modification did not affect the single-round infectivity or production rate of the GFP fluorescence-emitting virions. Conclusions: Our results certify the development of a rapid, inexpensive, and safe GFP-reporting single-cycle replicable system for anti-HIV drug discovery. Further experiments are needed to measure the validity and robustness of the assay. PMID:26989744

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

    ERIC Educational Resources Information Center

    Beshers, Sarah C.

    2007-01-01

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

  7. Evaluation of Measures of Proficiency in Occupational Therapy. Final Report.

    ERIC Educational Resources Information Center

    American Occupational Therapy Association, Rockville, MD.

    This report presents the final scope, methods, and results of the evaluation of proficiency measures in occupational therapy. The intended purpose of the investigation was to evaluate and analyze the reliability and validity of measurements that are predictive of competence and proficiency at entry levels in occupational therapy. Each level of the…

  8. HIV Entry Inhibitors and Their Potential in HIV Therapy

    PubMed Central

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

    2013-01-01

    This review discusses recent progress in the development of anti-HIV agents targeting the viral entry process. The three main classes (attachment inhibitors, co-receptor binding inhibitors, and fusion inhibitors) are further broken down by specific mechanism of action and structure. Many of these inhibitors are in advanced clinical trials, including the HIV maturation inhibitor bevirimat, from the authors’ laboratories. In addition, the CCR5 inhibitor maraviroc has recently been FDA-approved. Possible roles for these agents in anti-HIV therapy, including treatment of virus resistant to current drugs, are also discussed. PMID:18720513

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

    PubMed

    D'Souza, Jayesh

    2010-01-01

    South Africa has one of the highest rates of HIV/AIDS in the world. Much blame for this has been laid on the apathy of the South African government and the cultural traits of South Africans. AIDS prevention research calls for early childhood education to raise awareness of the causes, dangers, and prevention of HIV/AIDS. This study involved surveys among a select sample of South African adolescents to determine their sexual attitudes before and after a cognitive-behavioral intervention. Overall, the results did not make a significant difference in their attitudes, suggesting pre-adolescent sex education might prove to be a more useful tool in anti-HIV/AIDS education. Risky sexual behavior, under the influence of alcohol, also serves as a warning to educate young consumers of alcohol. PMID:22192941

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

    PubMed

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

    2016-06-01

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

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

    PubMed

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

    2015-05-01

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

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

    PubMed

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

    2008-08-22

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

  13. 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

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

    NASA Astrophysics Data System (ADS)

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

    2008-08-01

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

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

    PubMed

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

    2013-06-15

    Human apolipoprotein-B mRNA-editing catalytic polypeptide-like 3G (A3G) is a cytidine deaminase that restricts retroviruses, endogenous retro-elements and DNA viruses. A3G plays a key role in the anti-HIV-1 innate cellular immunity. The HIV-1 Vif protein counteracts A3G mainly by leading A3G towards the proteosomal machinery and by direct inhibition of its enzymatic activity. Both activities involve direct interaction between Vif and A3G. Disrupting the interaction between A3G and Vif may rescue A3G antiviral activity and inhibit HIV-1 propagation. Here, mapping the interaction sites between A3G and Vif by peptide array screening revealed distinct regions in Vif important for A3G binding, including the N-terminal domain (NTD), C-terminal domain (CTD) and residues 83-99. The Vif-binding sites in A3G included 12 different peptides that showed strong binding to either full-length Vif, Vif CTD or both. Sequence similarity was found between Vif-binding peptides from the A3G CTD and NTD. A3G peptides were synthesized and tested for their ability to counteract Vif action. A3G 211-225 inhibited HIV-1 replication in cell culture and impaired Vif dependent A3G degradation. In vivo co-localization of full-length Vif with A3G 211-225 was demonstrated by use of FRET. This peptide has the potential to serve as an anti-HIV-1 lead compound. Our results suggest a complex interaction between Vif and A3G that is mediated by discontinuous binding regions with different affinities. PMID:23545135

  16. [Spondyloarthropathies--clinical evaluation and physical therapy].

    PubMed

    Vlak, Tonko

    2004-01-01

    Spondyloarthropathy is a group of chronic autoimmune disorders including ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, acute anterior uveitis and undifferentiated spondyloarthropathies. The spondyloarthropathies share common clinical, radiological, and genetic features that are clearly distinct from other inflammatory rheumatic diseases. The major goal in the management of patients with rheumatic disorders is to control or cure the disease and to preserve and control function and health status. To measure treatments' efficacy standardized assessment of organ morphology, function, and of health status are required. The instruments for measuring health status or quality of life cover a variety of dimensions of health, including physical, social, and emotional functioning. Measurements used to evaluate the efficacy of treatments in ankylosing spondylitis include spinal and chest movement, duration and severity of morning stiffness, and quality of sleep. Health status indices such as the HAQ or AIMS are not readily applicable to spondyloarthropaties. It is reason to use some others: 1. Functional status measure S-HAQ for patients with spondylitis by adding five items to the HAQ, to cover the activities identified as most problematic; 2. Functional index for the assessment of ankylosing spondylitis (Dougados Functional Index - DFI) - it is valid and reliable and shows sufficient responsiveness; S-HAQ appears at least as sensitive to change as the Dougados Index; 3. The Leeds Disability Questionnaire assesses disability in ankylosing spondylitis, inquiring about four areas of function: mobility, bending down, reaching up and neck movements, and postures; 4. The Bath Ankylosing Spondylitis Functional Index (BASFI) 10 item self-administered questionnaire to assess function and activities of daily living in patients with ankylosing spondylitis. Physical therapy is one of the most important way to

  17. Performance Evaluation of Occupational Therapy Students: A Reliability Study.

    ERIC Educational Resources Information Center

    Polatajko, Helene; And Others

    1993-01-01

    Two occupational therapists rated 13 students after 1-week placements, using the Performance Evaluation of Occupational Therapy Students (PEOTS). The instrument had good interrater reliability but test-retest reliability was difficult to evaluate. Preliminary findings support the use of PEOTS as an evaluation tool. (JOW)

  18. Evaluating College Student Interest in Pet Therapy

    ERIC Educational Resources Information Center

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

    2009-01-01

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

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

    ERIC Educational Resources Information Center

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

    2006-01-01

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

  20. Insights into the mechanism of inhibition of CXCR4: identification of Piperidinylethanamine analogs as anti-HIV-1 inhibitors.

    PubMed

    Das, Debananda; Maeda, Kenji; Hayashi, Yasuhiro; Gavande, Navnath; Desai, Darshan V; Chang, Simon B; Ghosh, Arun K; Mitsuya, Hiroaki

    2015-04-01

    The cellular entry of HIV-1 into CD4(+) T cells requires ordered interactions of HIV-1 envelope glycoprotein with C-X-C chemokine receptor type 4 (CXCR4) receptors. However, such interactions, which should be critical for rational structure-based discovery of new CXCR4 inhibitors, remain poorly understood. Here we first determined the effects of amino acid substitutions in CXCR4 on HIV-1NL 4 - 3 glycoprotein-elicited fusion events using site-directed mutagenesis-based fusion assays and identified 11 potentially key amino acid substitutions, including D97A and E288A, which caused >30% reductions in fusion. We subsequently carried out a computational search of a screening library containing ∼604,000 compounds, in order to identify potential CXCR4 inhibitors. The computational search used the shape of IT1t, a known CXCR4 inhibitor, as a reference and employed various algorithms, including shape similarity, isomer generation, and docking against a CXCR4 crystal structure. Sixteen small molecules were identified for biological assays based on their high shape similarity to IT1t, and their putative binding modes formed hydrogen bond interactions with the amino acids identified above. Three compounds with piperidinylethanamine cores showed activity and were resynthesized. One molecule, designated CX6, was shown to significantly inhibit fusion elicited by X4 HIV-1NL 4 - 3 glycoprotein (50% inhibitory concentration [IC50], 1.9 μM), to inhibit Ca(2+) flux elicited by stromal cell-derived factor 1α (SDF-1α) (IC50, 92 nM), and to exert anti-HIV-1 activity (IC50, 1.5 μM). Structural modeling demonstrated that CX6 bound to CXCR4 through hydrogen bond interactions with Asp97 and Glu288. Our study suggests that targeting CXCR4 residues important for fusion elicited by HIV-1 envelope glycoprotein should be a useful and feasible approach to identifying novel CXCR4 inhibitors, and it provides important insights into the mechanism by which small-molecule CXCR4 inhibitors exert

  1. 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

  2. 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.

  3. Nullbasic, a potent anti-HIV tat mutant, induces CRM1-dependent disruption of HIV rev trafficking.

    PubMed

    Lin, Min-Hsuan; Sivakumaran, Haran; Apolloni, Ann; Wei, Ting; Jans, David A; Harrich, David

    2012-01-01

    Nullbasic, a mutant of the HIV-1 Tat protein, has anti-HIV-1 activity through mechanisms that include inhibition of Rev function and redistribution of the HIV-1 Rev protein from the nucleolus to the nucleoplasm and cytoplasm. Here we investigate the mechanism of this effect for the first time, establishing that redistribution of Rev by Nullbasic is not due to direct interaction between the two proteins. Rather, Nullbasic affects subcellular localization of cellular proteins that regulate Rev trafficking. In particular, Nullbasic induced redistribution of exportin 1 (CRM1), nucleophosmin (B23) and nucleolin (C23) from the nucleolus to the nucleus when Rev was coexpressed, but never in its absence. Inhibition of the Rev:CRM1 interaction by leptomycin B or a non-interacting RevM10 mutant completely blocked redistribution of Rev by Nullbasic. Finally, Nullbasic did not inhibit importin β- or transportin 1-mediated nuclear import, suggesting that cytoplasmic accumulation of Rev was due to increased export by CRM1. Overall, our data support the conclusion that CRM1-dependent subcellular redistribution of Rev from the nucleolus by Nullbasic is not through general perturbation of either nuclear import or export. Rather, Nullbasic appears to interact with and disrupt specific components of a Rev trafficking complex required for its nucleocytoplasmic shuttling and, in particular, its nucleolar accumulation. PMID:23251541

  4. Ontogeny of Recognition Specificity and Functionality for the Broadly Neutralizing Anti-HIV Antibody 4E10

    PubMed Central

    Finton, Kathryn A. K.; Friend, Della; Jaffe, James; Gewe, Mesfin; Holmes, Margaret A.; Larman, H. Benjamin; Stuart, Andrew; Larimore, Kevin; Greenberg, Philip D.; Elledge, Stephen J.; Stamatatos, Leonidas; Strong, Roland K.

    2014-01-01

    The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual structural elements and recognition specificities or properties that often lead to autoreactivity. The ontogeny of 4E10, an autoreactive antibody with unexpected combining site flexibility, was delineated through structural and biophysical comparisons of the mature antibody with multiple potential precursors. 4E10 gained affinity primarily by off-rate enhancement through a small number of mutations to a highly conserved recognition surface. Controverting the conventional paradigm, the combining site gained flexibility and autoreactivity during ontogeny, while losing thermostability, though polyspecificity was unaffected. Details of the recognition mechanism, including inferred global effects due to 4E10 binding, suggest that neutralization by 4E10 may involve mechanisms beyond simply binding, also requiring the ability of the antibody to induce conformational changes distant from its binding site. 4E10 is, therefore, unlikely to be re-elicited by conventional vaccination strategies. PMID:25254371

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-10-01

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

  7. 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.

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

    PubMed

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

    2016-04-14

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

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

    PubMed Central

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

    2015-01-01

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

  10. 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.

  11. A simplified and less expensive strategy for confirming anti HIV-1 screening results in a diagnostic laboratory in Lubumbashi, Zaire.

    PubMed

    Laleman, G; Kambale, M; Van Kerckhoven, I; Kapila, N; Konde, M; Selemani, U; Piot, P; van der Groen, G

    1991-12-01

    The conventional algorithm for HIV testing based on the confirmation of all positive anti-HIV screening reactions by Western blot (WB) is too expensive for developing countries. We investigated the validity of confirming positive screening assay reactions by a second screening test, limiting the use of the supplemental assay to the discrepant test results (algorithm 3), or screening all sera with 2 different assays and retesting all discrepant results by a supplemental assay (algorithm 4) on a panel of 519 sera in a regional reference laboratory in Lubumbashi, Zaire. Combining the Vironostika anti-HTLV-III ELISA with HIV Chek 1 + 2 or Clonatec Rapid HIV 1/2 Ab on all samples and retesting the discrepant results in WB or a line immunoassay (INNO-LIA) (algorithm 4), yielded a sensitivity of 100% and specificities of 98.4% and 99.0% respectively, at costs of 7.3 US $ and 9.3 US $ per test, respectively, for a 40% prevalence of HIV antibody positive samples. The conventional algorithm scored a sensitivity of 97.1% and a specificity of 100% for 11.3 US $ per test. The testing strategy of combining HIV Chek 1 + 2 and Clonatec Rapid HIV 1/2 Ab, an interesting option for small isolated centra, had a 96.6% sensitivity, but yielded only a slightly better specificity of 99.0%, as compared to 97.8% for HIV Chek alone. The price of combining the two simple assays using algorithm 3 was 6.8 US $ per test, using algorithm 4 was 10.6 US $. HIV testing strategies based on ELISA and a simple HIV test are a valuable alternative for reference laboratories faced with a high prevalence of HIV positive samples. PMID:1789703

  12. 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±5.533nm and mean zeta potential of -34.4±0.539mV. 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 5.974h. 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. PMID:26943973

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

    PubMed

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

    2015-01-01

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

  14. MULTIPLE WAYS OF TARGETING APOBEC3/VIF INTERACTIONS FOR ANTI-HIV-1 DRUG DEVELOPMENT

    PubMed Central

    Smith, Jessica L.; Bu, Wei; Burdick, Ryan C.; Pathak, Vinay K.

    2009-01-01

    Human immunodeficiency virus type 1 (HIV-1) infections and the resulting acquired immunodeficiency syndrome (AIDS) pandemic remain a global challenge in the absence of a protective vaccine and because of rapid selection of drug-resistant viral variants in response to all currently available antiviral therapies. Development of new and highly active antiviral agents would greatly facilitate effective clinical management of HIV-1 infections and delay the onset of AIDS. Recent advances in our understanding of intracellular immunity conferred by host cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F), and the mechanism by which the virally encoded Virion Infectivity Factor (Vif) protein induces their proteasomal degradation, provide fresh opportunities for the development of novel antiviral treatments. Interestingly, the interactions between Vif-A3G and Vif-A3F that overcome this host defense mechanism are structurally distinct, and provide two potential targets for antiviral drug development. This review provides an overview of the current knowledge of APOBEC3/Vif interactions and recent efforts to target these interactions for antiviral drug development. PMID:19837465

  15. Migration of CD8+ T Cells into the Central Nervous System Gives Rise to Highly Potent Anti-HIV CD4dimCD8bright T Cells in a Wnt Signaling-Dependent Manner.

    PubMed

    Richards, Maureen H; Narasipura, Srinivas D; Seaton, Melanie S; Lutgen, Victoria; Al-Harthi, Lena

    2016-01-01

    The role of CD8(+) T cells in HIV control in the brain and the consequences of such control are unclear. Approximately 3% of peripheral CD8(+) T cells dimly express CD4 on their surface. This population is known as CD4(dim)CD8(bright) T cells. We evaluated the role of CD4(dim)CD8(bright) and CD8 single positive T cells in HIV-infected brain using NOD/SCID/IL-2rcγ(-/-) mice reconstituted with human PBMCs (NSG-huPBMC). All three T cell populations (CD4 single positive, CD8 single positive, and CD4(dim)CD8(bright)) were found in NSG-huPBMC mouse brain within 2 wk of infection. Wnts secreted from astrocytes induced CD4(dim)CD8(bright) T cells by 2-fold in vitro. Injection of highly purified CD8 single positive T cells into mouse brain induced CD4(dim)CD8(bright) T cells by 10-fold, which were proliferative and exhibited a terminally differentiated effector memory phenotype. Brain CD4(dim)CD8(bright) T cells from HIV-infected mice exhibited anti-HIV-specific responses, as demonstrated by induction of CD107ab post exposure to HIV peptide-loaded targets. Further, higher frequency of CD4(dim)CD8(bright) T cells (R = -0.62; p ≤ 0.001), but not CD8 single positive T cells (R = -0.24; p ≤ 0.27), negatively correlated with HIV gag mRNA transcripts in HIV-infected NSG-huPBMC brain. Together, these studies indicate that single positive CD8(+) T cells entering the CNS during HIV infection can give rise to CD4(dim)CD8(bright) T cells, likely through a Wnt signaling-dependent manner, and that these cells are associated with potent anti-HIV control in the CNS. Thus, CD4(dim)CD8(bright) T cells are capable of HIV control in the CNS and may offer protection against HIV-associated neurocognitive disorders. PMID:26582945

  16. 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…

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

    PubMed

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

    2016-01-01

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

  18. Formulation Development of Retrocyclin 1 Analog RC-101 as an Anti-HIV Vaginal Microbicide Product▿

    PubMed Central

    Sassi, A. B.; Cost, M. R.; Cole, A. L.; Cole, A. M.; Patton, D. L.; Gupta, P.; Rohan, L. C.

    2011-01-01

    RC-101 is a synthetic microbicide analog of retrocyclin, which has shown in vitro activity against X4 and R5 HIV-1. In an effort to develop a safe and effective RC-101 vaginal microbicide product, we assessed safety in ex vivo macaque and human models and efficacy using in vitro and ex vivo models. A polyvinyl-alcohol vaginal film containing RC-101 (100 μg/film) was developed. Formulation assessment was conducted by evaluating disintegration, drug content, mechanical properties, and stability. Efficacy was evaluated by in vitro peripheral blood mononuclear cells (PBMC) assay and ex vivo human ectocervical tissue explant model. Ex vivo safety studies were conducted by exposing RC-101 to an excised monkey reproductive tract and excised human ectocervical tissue. RC-101 100 μg films were shown to be safe to human and monkey tissue and effective against HIV-1 in vitro and ex vivo in human ectocervical tissue. The 90% inhibitory concentration (IC90) for RC-101 films at 2,000 μg (IC90 = 57.5 μM) using an ex vivo model was 10-fold higher than the IC90 observed using an in vitro model (IC90 = 5.0 μM). RC-101 films were stable for 1 month at 25°C, with in vitro bioactivity maintained for up to 6 months. RC-101 was developed in a quick-dissolve film formulation that was shown to be safe in an ex vivo model and effective in in vitro and ex vivo models. RC-101 film formulations were shown to maintain bioactivity for a period of 6 months. Findings from the present study contribute to the development of a safe and effective topical microbicide product. PMID:21321138

  19. Anti-HIV-1 protease triterpenoid saponins from the seeds of Aesculus chinensis.

    PubMed

    Yang, X W; Zhao, J; Cui, Y X; Liu, X H; Ma, C M; Hattori, M; Zhang, L H

    1999-11-01

    Eight bioactive triterpenoid saponins (1-8) were isolated from the seeds of Aesculus chinensis, four of which are novel compounds. The major saponins were identified as escin Ia (1), Ib (2), isoescin Ia (3) and Ib (4), while the new compounds were identified as 22alpha-tigloyl-28-acetylprotoaescigenin-3beta-O-¿beta -D-glucopyranos yl (1-2) ¿beta-D-glucopyranosyl (1-4)-beta-D-glucopyranosiduronic acid (escin IVc, 5), 22alpha-angeloyl-28-acetylprotoaescigenin-3beta-O-¿bet a-D-glucopyrano syl (1-2) ¿beta-D-glucopyranosyl (1-4)-beta-D-glucopyranosiduronic acid (escin IVd, 6), 28-tigloylprotoaescigenin-3beta-O-¿beta-D-glucopyranosyl (1-2) ¿beta-D-glucopyranosyl (1-4)-beta-D-glucopyranosiduronic acid (escin IVe, 7), and 28-angeloylprotoaescigenin-3beta-O-¿beta-D-glucopyranosyl (1-2) ¿beta-D-glucopyranosyl (1-4)-beta-D-glucopyranosiduronic acid (escin IVf, 8). The structures were determined by chemical and spectroscopic methods. All the above compounds were evaluated for their inhibitory activity against HIV-1 protease. PMID:10579862

  20. 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

  1. 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

  2. Evaluation of neutron radiation field in carbon ion therapy

    NASA Astrophysics Data System (ADS)

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

    2016-01-01

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

  3. Pathologic Evaluation of Breast Cancer after Neoadjuvant Therapy

    PubMed Central

    Park, Cheol Keun; Jung, Woo-Hee; Koo, Ja Seung

    2016-01-01

    Breast cancer, one of the most common cancers in women, has various treatment modalities. Neoadjuvant therapy (NAT) has been used in many clinical trials because it is easy to evaluate the treatment response to therapeutic agents in a short time period; consequently, NAT is currently a standard treatment modality for large-sized and locally advanced breast cancers, and its use in early-stage breast cancer is becoming more common. Thus, chances to encounter breast tissue from patients treated with NAT is increasing. However, systems for handling and evaluating such specimens have not been established. Several evaluation systems emphasize a multidisciplinary approach to increase the accuracy of breast cancer assessment. Thus, detailed and systematic evaluation of clinical, radiologic, and pathologic findings is important. In this review, we compare the major problems of each evaluation system and discuss important points for handling and evaluating NAT-treated breast specimens. PMID:27068026

  4. 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. PMID:23554549

  5. 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.

  6. 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

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

    PubMed Central

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

    2013-01-01

    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

  8. 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

  9. Rapid Transient Production in Plants by Replicating and Non-Replicating Vectors Yields High Quality Functional Anti-HIV Antibody

    PubMed Central

    Sainsbury, Frank; Sack, Markus; Stadlmann, Johannes; Quendler, Heribert; Fischer, Rainer; Lomonossoff, George P.

    2010-01-01

    Background The capacity of plants and plant cells to produce large amounts of recombinant protein has been well established. Due to advantages in terms of speed and yield, attention has recently turned towards the use of transient expression systems, including viral vectors, to produce proteins of pharmaceutical interest in plants. However, the effects of such high level expression from viral vectors and concomitant effects on host cells may affect the quality of the recombinant product. Methodology/Principal Findings To assess the quality of antibodies transiently expressed to high levels in plants, we have expressed and characterised the human anti-HIV monoclonal antibody, 2G12, using both replicating and non-replicating systems based on deleted versions of Cowpea mosaic virus (CPMV) RNA-2. The highest yield (approximately 100 mg/kg wet weight leaf tissue) of affinity purified 2G12 was obtained when the non-replicating CPMV-HT system was used and the antibody was retained in the endoplasmic reticulum (ER). Glycan analysis by mass-spectrometry showed that the glycosylation pattern was determined exclusively by whether the antibody was retained in the ER and did not depend on whether a replicating or non-replicating system was used. Characterisation of the binding and neutralisation properties of all the purified 2G12 variants from plants showed that these were generally similar to those of the Chinese hamster ovary (CHO) cell-produced 2G12. Conclusions Overall, the results demonstrate that replicating and non-replicating CPMV-based vectors are able to direct the production of a recombinant IgG similar in activity to the CHO-produced control. Thus, a complex recombinant protein was produced with no apparent effect on its biochemical properties using either high-level expression or viral replication. The speed with which a recombinant pharmaceutical with excellent biochemical characteristics can be produced transiently in plants makes CPMV-based expression vectors

  10. 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.

  11. Design and Synthesis of DiselenoBisBenzamides (DISeBAs) as Nucleocapsid Protein 7 (NCp7) Inhibitors with anti-HIV Activity.

    PubMed

    Sancineto, Luca; Mariotti, Alice; Bagnoli, Luana; Marini, Francesca; Desantis, Jenny; Iraci, Nunzio; Santi, Claudio; Pannecouque, Christophe; Tabarrini, Oriana

    2015-12-24

    The interest in the synthesis of Se-containing compounds is growing with the discovery of derivatives exhibiting various biological activities. In this manuscript, we have identified a series of 2,2'-diselenobisbenzamides (DISeBAs) as novel HIV retroviral nucleocapsid protein 7 (NCp7) inhibitors. Because of its pleiotropic functions in the whole viral life cycle and its mutation intolerant nature, NCp7 represents a target of great interest which is not reached by any anti-HIV agent in clinical use. Using the diselenobisbenzoic scaffold, amino acid, and benzenesulfonamide derivatives were prepared and biologically profiled against different models of HIV infection. The incorporation of amino acids such as glycine and glutamate into DISeBAs 7 and 8 resulted in selective anti-HIV activity against both acutely and chronically infected cells as well as an interesting virucidal effect. DISeBAs demonstrated broad antiretroviral activity, encompassing HIV-1 drug-resistant strains including clinical isolates, as well as simian immunodeficiency virus (SIV). Time of addition experiments, along with the observed dose dependent inhibition of the Gag precursor proper processing, confirmed that their mechanism of action is based on NCp7 inhibition. PMID:26613134

  12. 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. PMID:25681721

  13. Evaluating an Educational Module on Home Inotrope Therapy.

    PubMed

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

    2015-01-01

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

  14. 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

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

    PubMed Central

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

    2014-01-01

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

  16. 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. PMID:25408560

  17. 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.

  18. Technical evaluation of TomoTherapy automatic roll correction.

    PubMed

    Laub, Steve; Snyder, Michael; Burmeister, Jay

    2015-01-01

    The TomoTherapy Hi·Art System allows the application of rotational corrections as a part of the pretreatment image guidance process. This study outlines a custom method to perform an end-to-end evaluation of the TomoTherapy Hi·Art roll correction feature. A roll-sensitive plan was designed and delivered to a cylindrical solid water phantom to test the accuracy of roll corrections, as well as the ability of the automatic registration feature to detect induced roll. Cylindrical target structures containing coaxial inner avoidance structures were placed adjacent to the plane bisecting the phantom and 7 cm laterally off central axis. The phantom was positioned at isocenter with the target-plane parallel to the couch surface. Varying degrees of phantom roll were induced and dose to the targets and inner avoidance structures was measured using Kodak EDR2 films placed in the target-plane. Normalized point doses were compared with baseline (no roll) data to determine the sensitivity of the test and the effectiveness of the roll correction feature. Gamma analysis comparing baseline, roll-corrected, and uncorrected films was performed using film analysis software. MVCT images were acquired prior to plan delivery. Measured roll was compared with induced roll to evaluate the automatic registration feature's ability to detect rotational misalignment. Rotations beyond 0.3° result in statistically significant deviation from baseline point measurements. Gamma pass rates begin to drop below 90% at approximately 0.5° induced rotation at 3%/3 mm and between 0.2° and 0.3° for 2%/2 mm. With roll correction applied, point dose measurements for all rotations are indistinguishable from baseline, and gamma pass rates exceed 96% when using 3% and 3 mm as evaluation criteria. Measured roll via the automatic registration algorithm agrees with induced rotation to within the test sensitivity for nearly all imaging settings. The TomoTherapy automatic registration system accurately detects

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Morse, M A

    2001-02-01

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

  1. 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. PMID:26953542

  2. 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.

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

    PubMed

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

    2014-02-01

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

  4. 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…

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

    PubMed Central

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

    1990-01-01

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

  6. Using behavior analysis to examine the outcomes of unproven therapies: an evaluation of hyperbaric oxygen therapy for children with autism.

    PubMed

    Lerman, Dorothea C; Sansbury, Tesa; Hovanetz, Alyson; Wolever, Erin; Garcia, Amber; O'Brien, Erin; Adedipe, Hellen

    2008-01-01

    It has become increasingly common for parents of children with autism to supplement behavior analytic interventions with therapies that have not yet been subjected to adequate scientific scrutiny. When caregivers elect to use unproven therapies despite advice to the contrary, practitioners should employ the methods of applied behavior analysis to experimentally evaluate the outcomes. Controlled evaluations of unproven therapies can be challenging, however, particularly when ongoing behavioral services are supplemented with biomedical interventions. This paper describes the methods and results of a behavior analytic evaluation of hyperbaric oxygen therapy, an unproven intervention that has been growing in popularity over the past several years. Three young children with autism participated. No benefits of the therapy were evident beyond those obtained through the behavioral intervention alone. Considerations for conducting this type of research are highlighted, along with suggestions for practitioners. PMID:22477688

  7. Using Behavior Analysis to Examine the Outcomes of Unproven Therapies: An Evaluation of Hyperbaric Oxygen Therapy for Children with Autism

    PubMed Central

    Lerman, Dorothea C; Sansbury, Tesa; Hovanetz, Alyson; Wolever, Erin; Garcia, Amber; O'Brien, Erin; Adedipe, Hellen

    2008-01-01

    It has become increasingly common for parents of children with autism to supplement behavior analytic interventions with therapies that have not yet been subjected to adequate scientific scrutiny. When caregivers elect to use unproven therapies despite advice to the contrary, practitioners should employ the methods of applied behavior analysis to experimentally evaluate the outcomes. Controlled evaluations of unproven therapies can be challenging, however, particularly when ongoing behavioral services are supplemented with biomedical interventions. This paper describes the methods and results of a behavior analytic evaluation of hyperbaric oxygen therapy, an unproven intervention that has been growing in popularity over the past several years. Three young children with autism participated. No benefits of the therapy were evident beyond those obtained through the behavioral intervention alone. Considerations for conducting this type of research are highlighted, along with suggestions for practitioners. PMID:22477688

  8. 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

  9. The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities*

    PubMed Central

    Barroso-González, Jonathan; El Jaber-Vazdekis, Nabil; García-Expósito, Laura; Machado, José-David; Zárate, Rafael; Ravelo, Ángel G.; Estévez-Braun, Ana; Valenzuela-Fernández, Agustín

    2009-01-01

    The existence of drug-resistant human immunodeficiency virus (HIV) viruses in patients receiving antiretroviral treatment urgently requires the characterization and development of new antiretroviral drugs designed to inhibit resistant viruses and to complement the existing antiretroviral strategies against AIDS. We assayed several natural or semi-synthetic lupane-type pentacyclic triterpenes in their ability to inhibit HIV-1 infection in permissive cells. We observed that the 30-oxo-calenduladiol triterpene, compound 1, specifically impaired R5-tropic HIV-1 envelope-mediated viral infection and cell fusion in permissive cells, without affecting X4-tropic virus. This lupane derivative competed for the binding of a specific anti-CCR5 monoclonal antibody or the natural CCL5 chemokine to the CCR5 viral coreceptor with high affinity. 30-Oxo-calenduladiol seems not to interact with the CD4 antigen, the main HIV receptor, or the CXCR4 viral coreceptor. Our results suggest that compound 1 is a specific CCR5 antagonist, because it binds to the CCR5 receptor without triggering cell signaling or receptor internalization, and inhibits RANTES (regulated on activation normal T cell expressed and secreted)-mediated CCR5 internalization, intracellular calcium mobilization, and cell chemotaxis. Furthermore, compound 1 appeared not to interact with β-chemokine receptors CCR1, CCR2b, CCR3, or CCR4. Thereby, the 30-oxo-calenduladiol-associated anti-HIV-1 activity against R5-tropic virus appears to rely on the selective occupancy of the CCR5 receptor to inhibit CCR5-mediated HIV-1 infection. Therefore, it is plausible that the chemical structure of 30-oxo-calenduladiol or other related dihydroxylated lupane-type triterpenes could represent a good model to develop more potent anti-HIV-1 molecules to inhibit viral infection by interfering with early fusion and entry steps in the HIV life cycle. PMID:19386595

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

    SciTech Connect

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

    2010-01-01

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

  11. Discovery of novel anti-HIV-1 agents based on a broadly neutralizing antibody against the envelope gp120 V3 loop: a computational study.

    PubMed

    Andrianov, Alexander M; Kashyn, Ivan A; Tuzikov, Alexander V

    2014-12-01

    A computer-aided search for novel anti-HIV-1 agents able to mimic the pharmacophore properties of broadly neutralizing antibody (bNAb) 3074 was carried out based on the analysis of X-ray complexes of this antibody Fab with the MN, UR29, and VI191 peptides from the V3 loop of the HIV envelope protein gp120. Using these empirical data, peptidomimetic candidates of bNAb 3074 were identified by a public, web-oriented virtual screening platform (pepMMsMIMIC) and models of these candidates bound to the above V3 peptides were generated by molecular docking. The docking calculations identified four molecules exhibiting a high affinity to all of the V3 peptides. These molecules were selected as the most probable peptidomimetics of bNAb 3074. Finally, the stability of the complexes of these molecules with the MN, UR29, and VI191 V3 peptides was estimated by molecular dynamics and free energy simulations. Specific binding to the V3 loop was accomplished primarily by π-π interactions between the aromatic rings of the peptidomimetics and the conserved Phe-20 and/or Tyr-21 of the V3 immunogenic crown. In a mechanism similar to that of bNAb 3074, these compounds were found to block the tip of the V3 loop forming its invariant structural motif that contains residues critical for cell tropism. Based on these findings, the compounds selected are considered as promising basic structures for the rational design of novel, potent, and broad-spectrum anti-HIV-1 therapeutics. PMID:24251545

  12. 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.

  13. 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

  14. 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

  15. New pathways for evaluating potential acute stroke therapies.

    PubMed

    Fisher, Marc; Cheung, Kenneth; Howard, George; Warach, Steven

    2006-05-01

    Pharmacological therapy for acute ischemic stroke remains limited to one successful, approved treatment: tissue plasminogen activator within 3 h of stroke onset. Many neuroprotective drugs and a few other thrombolytics were evaluated in clinical trials, but none demonstrated unequivocal success and were approved by regulatory agencies. The development paradigm for such therapies needs to provide convincing evidence of efficacy and safety to obtain approval by the Food and Drug Administration (FDA). The FDA modernization act of 1997 stated that such evidence could be derived from one large phase III trial with a clinical endpoint and supportive evidence. Drugs being developed for acute ischemic stroke can potentially be approved under this act by coupling a major phase III trial with supportive evidence provided by a phase IIB trial demonstrating an effect on a relevant biomarker such as magnetic resonance imaging or computed tomography assessment of ischemic lesion growth. Statistical approaches have been developed to optimize the design of such an imaging-based phase IIB study, for example approaches that modify randomization probabilities to assign larger proportions of patients to the 'winning' strategy (i.e. 'pick the winner' strategies) with an interim assessment to reduce the sample size requirement. Demonstrating a treatment effect on a relevant imaging-based biomarker should provide supportive evidence for a new drug application, if a subsequent phase III trial with a clinical outcome demonstrates a significant treatment effect. PMID:18706045

  16. Evaluation of Helicobacter pylori eradication by triple therapy plus Lactobacillus acidophilus compared to triple therapy alone.

    PubMed

    Medeiros, J A da Silva; Gonçalves, T M F O; Boyanova, L; Pereira, M I de Correia; de Carvalho, J N da Silva Paiva; Pereira, A M de Sousa; Cabrita, A M Silvério

    2011-04-01

    The purpose of this study was to evaluate the influence of adding Lactobacillus acidophilus to a triple regimen for Helicobacter pylori eradication in untreated patients with peptic ulcers or ulcer-scars. This was a pre-randomized, single-blind, interventional, treatment-efficacy study with active controls and parallel-assignment, set in Coimbra, Portugal, on 62 consecutive H. pylori-positive untreated adults with peptic ulcers or ulcer-scars, diagnosed by gastroduodenoscopy, with pre-treatment direct Gram-staining and culture of gastric biopsies. The first 31 patients received esomeprazole 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg (EAC), all b.i.d., for 8 days. The remaining 31 added L. acidophilus, 5 × 10(9) organisms per capsule, 3 + 2 i.d. for 8 days (EACL). The main outcome measure was (13)C urea breath test (UBT), ≥6 weeks after completion of therapy. Successful eradication (UBT-negativity after treatment), was similar in both groups (EAC = 80.6%; EACL = 83.9%, p = 0.740) by both intention-to-treat and per-protocol analysis. The non-eradicated strains were susceptible in vitro to both antibiotics. Adding L. acidophilus to EAC triple therapy did not increase H. pylori eradication rates. Considering the cost and the burden of ingesting five extra capsules daily, supplementing the EAC therapy with L. acidophilus, at this dose, shows no benefit. Further studies with different dosages and duration of treatment, and other probiotics or probiotic combinations are required to improve eradication. PMID:21207091

  17. 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

  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

    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 further investigated

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  1. 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

  2. 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

  3. 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…

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

    PubMed

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

    2011-06-01

    There has been much recent literature on the technical parameters of electroconvulsive therapy (ECT) with regard to improving efficacy and minimizing adverse effects, but relatively little on ECT service delivery. This paper will discuss the development and characteristics of an ECT service at a teaching hospital in metropolitan Sydney, New South Wales, Australia. A mixture of qualitative and quantitative methods, including a selective literature review and audit of ECT use were used. The results of the audit were compared with the 2007 revision of the Royal Australian and New Zealand College of Psychiatrists' clinical memorandum on ECT. We discuss issues, such as the optimal site for ECT delivery, ECT mental health nurse coordinator role, credentialing of psychiatrists, registrar supervision, and the development of an ECT committee. A significant finding of the audit was that the majority of patients were treated under the New South Wales Mental Health Act, and voluntary patients were more likely to have a diagnosis of a depressive disorder, whereas involuntary patients were more likely to have a non-mood disorder diagnosis. This study has shown that auditing of ECT practices and services by mental health nurses is essential for quality improvement processes. The audit highlighted areas of service delivery that should be subject to review and evaluation against professional standards. PMID:21492361

  5. 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.

  6. 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

  7. A review of trials evaluating nonstatin lipid-lowering therapies.

    PubMed

    Ansell, Benjamin J

    2009-01-01

    Recently reported clinical trials raise doubts on the effectiveness of nonstatin lipid-lowering therapies in reducing the residual risk of cardiovascular events after statin monotherapy. Addition of -torcetrapib to statin therapy increased overall mortality in coronary patients despite a marked increase in high-density lipoprotein cholesterol. Combining ezetimibe with statin therapy neither further reduces carotid atherosclerosis nor slows aortic stenosis, and it has not been shown to be superior to statin monotherapy in reducing cardiovascular events. Clinical trials currently in progress will more clearly delineate the cardiovascular effects of adding either ezetimibe or extended-release niacin/laropiprant to statin therapy. PMID:19080730

  8. 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

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

    PubMed Central

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

    2013-01-01

    Central memory (TCM) and transitional memory (TTM) 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 TCM and TTM 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 TCM/TTM lymphocyte subsets, which encompass the HIV reservoir, by affecting redox-sensitive cell death pathways. PMID:24309931

  10. Superiority of the S,S conformation in diverse pharmacological processes: Intestinal transport and entry inhibition activity of novel anti-HIV drug lead.

    PubMed

    Fanous, Joseph; Swed, Avi; Joubran, Salim; Hurevich, Mattan; Britan-Rosich, Elena; Kotler, Moshe; Gilon, Chaim; Hoffman, Amnon

    2015-11-30

    Chirality is an important aspect in many pharmacological processes including drug transport and metabolism. The current investigation examined the stereospecific transport and entry inhibitory activity of four diastereomers derived from a small (macrocyclic) molecule that has two chiral centers. These molecules were designed to mimic the interaction between CD4 and gp120 site of HIV-1 and thereby to function as entry inhibitor(s). Intestinal permeability was assessed by ex-vivo model using excised rat intestine mounted in side-by-side diffusion chambers. The entry inhibitory activity was monitored using indicator HeLa-CD4-LTR-beta-gal cells (MAGI assay). The (S/S) diastereomer, named CG-1, exhibited superiority in both unrelated tested biological processes: (I) high transport through the intestine and (II) entry inhibition activity (in the low μM range). The permeability screening revealed a unique transporter-mediated absorption pathway of CG-1, suggesting a significant role of the molecule's conformation on the mechanism of intestinal absorption. Here we highlight that only the S,S enantiomer (CG-1) has both (I) promising anti HIV-1 entry inhibitory properties and (II) high transporter mediated intestinal permeability. Hence we suggest preference in pharmacological processes to the S,S conformation. This report augments the knowledge regarding stereoselectivity in receptor mediated and protein-protein interaction processes. PMID:26392249

  11. In Vivo Anti-HIV Activity of the Heparin-Activated Serine Protease Inhibitor Antithrombin III Encapsulated in Lymph-Targeting Immunoliposomes

    PubMed Central

    Asmal, Mohammed; Whitney, James B.; Luedemann, Corinne; Carville, Angela; Steen, Robert; Letvin, Norman L.; Geiben-Lynn, Ralf

    2012-01-01

    Endogenous serine protease inhibitors (serpins) are anti-inflammatory mediators with multiple biologic functions. Several serpins have been reported to modulate HIV pathogenesis, or exhibit potent anti-HIV activity in vitro, but the efficacy of serpins as therapeutic agents for HIV in vivo has not yet been demonstrated. In the present study, we show that heparin-activated antithrombin III (hep-ATIII), a member of the serpin family, significantly inhibits lentiviral replication in a non-human primate model. We further demonstrate greater than one log10 reduction in plasma viremia in the nonhuman primate system by loading of hep-ATIII into anti-HLA-DR immunoliposomes, which target tissue reservoirs of viral replication. We also demonstrate the utility of hep-ATIIII as a potential salvage agent for HIV strains resistant to standard anti-retroviral treatment. Finally, we applied gene-expression arrays to analyze hep-ATIII-induced host cell interactomes and found that downstream of hep-ATIII, two independent gene networks were modulated by host factors prostaglandin synthetase-2, ERK1/2 and NFκB. Ultimately, understanding how serpins, such as hep-ATIII, regulate host responses during HIV infection may reveal new avenues for therapeutic intervention. PMID:23133620

  12. Anti-HIV drug development: structural features and limitations of present day drugs and future challenges in the successful HIV/AIDS treatment.

    PubMed

    Kumari, Garima; Singh, Ramendra K

    2013-01-01

    Acquired Immune Deficiency Syndrome (AIDS), an immuno-compromized condition, a sequel to untreated human immunodeficiency virus (HIV) infection, inviting several life-threatening diseases, has become one of the most fatal disorders in the recent past because of HIV strain variance due to mutations, passive latency and reservoirs helping in replenishing and reviving the HIV-1 proviral DNA. Scientific efforts have led to the discovery of several effective drugs against HIV and lowered the morbidity and mortality all over the world. However, despite availability of a good number of anti-HIV drugs, the problem, for the foreseeable reasons, stands out as the most chronic disease due to the less tolerability and low accessibility of drugs, life-long expensive treatment, and above all, the emergence of drug resistant viral strains. This review dwells upon HIV infection and its proliferation inside the host system, drug targets, different types of drugs, their structural features and mode of interaction with viral targets and drug regimens. It further focuses on topics of latest interest regarding drug development, fixed dose combinations (FDCs), the limitations of present day drugs with their structural features along with their pharmacodynamics, pharmacokinetics and pharmacogenomics and the challenges in finding a permanent cure for HIV/AIDS. PMID:23092282

  13. A novel class of anti-HIV agents with multiple copies of enfuvirtide enhances inhibition of viral replication and cellular transmission in vitro.

    PubMed

    Chang, Chien-Hsing; Hinkula, Jorma; Loo, Meiyu; Falkeborn, Tina; Li, Rongxiu; Cardillo, Thomas M; Rossi, Edmund A; Goldenberg, David M; Wahren, Britta

    2012-01-01

    We constructed novel HIV-1 fusion inhibitors that may overcome the current limitations of enfuvirtide, the first such therapeutic in this class. The three prototypes generated by the Dock-and-Lock (DNL) technology to comprise four copies of enfuvirtide tethered site-specifically to the Fc end of different humanized monoclonal antibodies potently neutralize primary isolates (both R5-tropic and X4-tropic), as well as T-cell-adapted strains of HIV-1 in vitro. All three prototypes show EC(50) values in the subnanomolar range, which are 10- to 100-fold lower than enfuvirtide and attainable whether or not the constitutive antibody targets HIV-1. The potential of such conjugates to purge latently infected cells was also demonstrated in a cell-to-cell viral inhibition assay by measuring their efficacy to inhibit the spread of HIV-1(LAI) from infected human peripheral blood mononuclear cells to Jurkat T cells over a period of 30 days following viral activation with 100 nM SAHA (suberoylanilide hydroxamic acid). The IgG-like half-life was not significantly different from that of the parental antibody, as shown by the mean serum concentration of one prototype in mice at 72 h. These encouraging results provide a rationale to develop further novel anti-HIV agents by coupling additional antibodies of interest with alternative HIV-inhibitors via recombinantly-produced, self-assembling, modules. PMID:22844444

  14. A Novel Class of Anti-HIV Agents with Multiple Copies of Enfuvirtide Enhances Inhibition of Viral Replication and Cellular Transmission In Vitro

    PubMed Central

    Chang, Chien-Hsing; Hinkula, Jorma; Loo, Meiyu; Falkeborn, Tina; Li, Rongxiu; Cardillo, Thomas M.; Rossi, Edmund A.; Goldenberg, David M.; Wahren, Britta

    2012-01-01

    We constructed novel HIV-1 fusion inhibitors that may overcome the current limitations of enfuvirtide, the first such therapeutic in this class. The three prototypes generated by the Dock-and-Lock (DNL) technology to comprise four copies of enfuvirtide tethered site-specifically to the Fc end of different humanized monoclonal antibodies potently neutralize primary isolates (both R5-tropic and X4-tropic), as well as T-cell-adapted strains of HIV-1 in vitro. All three prototypes show EC50 values in the subnanomolar range, which are 10- to 100-fold lower than enfuvirtide and attainable whether or not the constitutive antibody targets HIV-1. The potential of such conjugates to purge latently infected cells was also demonstrated in a cell-to-cell viral inhibition assay by measuring their efficacy to inhibit the spread of HIV-1LAI from infected human peripheral blood mononuclear cells to Jurkat T cells over a period of 30 days following viral activation with 100 nM SAHA (suberoylanilide hydroxamic acid). The IgG-like half-life was not significantly different from that of the parental antibody, as shown by the mean serum concentration of one prototype in mice at 72 h. These encouraging results provide a rationale to develop further novel anti-HIV agents by coupling additional antibodies of interest with alternative HIV-inhibitors via recombinantly-produced, self-assembling, modules. PMID:22844444

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

    PubMed

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

    2016-01-01

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

  16. Experimental ulcerative herpetic keratitis. III. Evaluation of hyperimmune gammaglobulin therapy.

    PubMed Central

    Carter, C A; Easty, D L

    1981-01-01

    The value of hyperimmune gammaglobulin (HGG) therapy in ulcerative herpetic keratitis was assessed in rabbits. HGG treated of early disease in normal rabbits was very effective, producing a 10-fold rise in the virus concentration needed to infect 50% of sites (CID50) and an 88% inhibition of ulceration after 2 days. The efficacy of the gammaglobulin preparations tested depended on their anti-HSV antibody content. Established disease was considerably less responsive to HGG therapy. No conclusive effect of HGG therapy could be demonstrated in rabbits with a previous HSV skin infection ('immunised'). Corticosteroid-induced geographic ulceration in immunised rabbits was not prevented by concurrent HGG therapy. The findings indicate that HGG is unlikely to represent a useful therapy for ulcerative herpetic keratitis but that it may be valuable in primary disease and in long-term prophylaxis. PMID:6167281

  17. 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,…

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

    PubMed

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

    2015-03-01

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

  19. 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

  20. 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…

  1. Music therapy research in Ibero-American countries: an overview focused on assessment and clinical evaluation.

    PubMed

    Sabbatella, Patricia L

    2005-12-01

    The aim of this article is to present an overview of some contemporary ideas concerning the status of music therapy research in Ibero-American countries, with a focus on assessment and clinical evaluation of music therapy clinical practice. PMID:16597778

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

    PubMed

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

    2011-06-01

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

  3. 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

  4. 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

    2013-01-01

    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. PMID:24309931

  5. 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. PMID:21268157

  6. 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. PMID:27238871

  7. Hormones and acne: pathophysiology, clinical evaluation, and therapies.

    PubMed

    Thiboutot, D

    2001-09-01

    Hormonal aspects of acne are of particular interest in treating adult women. A review of the role of hormones in the pathogenesis of acne, guidelines for the workup of a suspected endocrine disorder, and an overview of the use of hormonal therapy in women with endocrine problems and in normal women is presented. PMID:11594669

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

    ERIC Educational Resources Information Center

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

    2009-01-01

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

  9. 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…

  10. 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…

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

    PubMed Central

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

    2012-01-01

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

  12. Optimization, delivery and evaluation of intensity modulated arc therapy

    NASA Astrophysics Data System (ADS)

    Oliver, Michael R.

    Intensity modulated arc therapy (IMAT) is a radiation therapy technique whereby the shape of the cone beam of radiation changes as it rotates around the patient. This is in contrast to other more commonly delivered forms of advanced radiation therapy, Intensity Modulated Radiation Therapy (IMRT) or helical tomotherapy. IMRT is a radiation technique where a patient is treated with a cone beam of radiation from a number of fixed beam directions, where the shapes and weights of the radiation beams are varied and tomotherapy is treated with a fan beam of radiation that follows a helical trajectory. In this thesis two aspects of IMAT were investigated: optimization of treatment plans and delivery of plans in conjunction with and without respiratory motion management. Optimization of IMAT deliveries consisted of two studies. In the first study, an algorithm that uses dosimetric ray tracing to set multi-leaf collimator (MLC) positions then directly optimizes the MLC positions to create IMAT treatment plans with only beam shape variations was developed and tested in three phantom studies and a clinical case. The second study investigated variable angular dose rate deliveries to a concave target and assessed the optimization strategy including arc initialization strategy, angular sampling and delivery efficiency. IMAT delivery with and without respiratory gated radiation delivery was studied with dose measurement using radiographic film in a motion phantom. In addition, simulations based on delivered log files were used to confirm that motion management for IMAT is effective and within dosimetric tolerances. As a pilot test, plans from IMRT and tomotherapy for partial breast irradiation were first studied, comparing them to conventional treatments. An IMAT plan was generated for one patient, demonstrating feasibility and was compared with IMRT and tomotherapy. This thesis has introduced a new IMAT optimization algorithm with and without variable angular dose rate, applied

  13. Enhanced Anti-HIV Functional Activity Associated with Gag-Specific CD8 T-Cell Responses▿ †

    PubMed Central

    Julg, B.; Williams, K. L.; Reddy, S.; Bishop, K.; Qi, Y.; Carrington, M.; Goulder, P. J.; Ndung'u, T.; Walker, B. D.

    2010-01-01

    Effective HIV-specific T-cell immunity requires the ability to inhibit virus replication in the infected host, but the functional characteristics of cells able to mediate this effect are not well defined. Since Gag-specific CD8 T cells have repeatedly been associated with lower viremia, we examined the influence of Gag specificity on the ability of unstimulated CD8 T cells from chronically infected persons to inhibit virus replication in autologous CD4 T cells. Persons with broad (≥6; n = 13) or narrow (≤1; n = 13) Gag-specific responses, as assessed by gamma interferon enzyme-linked immunospot assay, were selected from 288 highly active antiretroviral therapy (HAART)-naive HIV-1 clade C-infected South Africans, matching groups for total magnitude of HIV-specific CD8 T-cell responses and CD4 T-cell counts. CD8 T cells from high Gag responders suppressed in vitro replication of a heterologous HIV strain in autologous CD4 cells more potently than did those from low Gag responders (P < 0.003) and were associated with lower viral loads in vivo (P < 0.002). As previously shown in subjects with low viremia, CD8 T cells from high Gag responders exhibited a more polyfunctional cytokine profile and a stronger ability to proliferate in response to HIV stimulation than did low Gag responders, which mainly exhibited monofunctional CD8 T-cell responses. Furthermore, increased polyfunctionality was significantly correlated with greater inhibition of viral replication in vitro. These data indicate that enhanced suppression of HIV replication is associated with broader targeting of Gag. We conclude that it is not the overall magnitude but rather the breadth, magnitude, and functional capacity of CD8 T-cell responses to certain conserved proteins, like Gag, which predict effective antiviral HIV-specific CD8 T-cell function. PMID:20335261

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

    PubMed Central

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

    2016-01-01

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

  15. Preformulation and stability in biological fluids of the retrocyclin RC-101, a potential anti-HIV topical microbicide

    PubMed Central

    2011-01-01

    Background RC-101, a cationic peptide retrocyclin analog, has in vitro activity against HIV-1. Peptide drugs are commonly prone to conformational changes, oxidation and hydrolysis when exposed to excipients in a formulation or biological fluids in the body, this can affect product efficacy. We aimed to investigate RC-101 stability under several conditions including the presence of human vaginal fluids (HVF), enabling the efficient design of a safe and effective microbicide product. Stability studies (temperature, pH, and oxidation) were performed by HPLC, Circular Dichroism, and Mass Spectrometry (LC-MS/MS). Additionally, the effect of HVF on formulated RC-101 was evaluated with fluids collected from healthy volunteers, or from subjects with bacterial vaginosis (BV). RC-101 was monitored by LC-MS/MS for up to 72 h. Results RC-101 was stable at pH 3, 4, and 7, at 25 and 37°C. High concentrations of hydrogen peroxide resulted in less than 10% RC-101 reduction over 24 h. RC-101 was detected 48 h after incubation with normal HVF; however, not following incubation with HVF from BV subjects. Conclusions Our results emphasize the importance of preformulation evaluations and highlight the impact of HVF on microbicide product stability and efficacy. RC-101 was stable in normal HVF for at least 48 h, indicating that it is a promising candidate for microbicide product development. However, RC-101 stability appears compromised in individuals with BV, requiring more advanced formulation strategies for stabilization in this environment. PMID:21801426

  16. Evaluation of quantum dots for photodynamic therapy (Invited Paper)

    NASA Astrophysics Data System (ADS)

    Dayal, Smita; Krolicki, Robert; Burda, Clemens

    2005-04-01

    Photodynamic therapy (PDT) is an emerging therapy for cancer treatment that shows the greater selectivity towards the malignant cells. Semiconductor nanoparticles are a novel class of photosensitizers with properties that are not easily available with conventional PDT reagents. Their potential properties such as improved luminescence, resistance to photobleaching, and the possibility to modify the surface chemically make them suitable candidates for PDT. In this report, we discuss the synthesis of ternary CdSe1-x Tex nanoparticles along with well known CdSe QDs and their potential in generating the singlet oxygen state by Foerster Resonance Energy Transfer (FRET) to a PDT reagent or by direct triplet-triplet energy transfer to molecular oxygen.

  17. Evaluation of Vitamin C for Adjuvant Sepsis Therapy

    PubMed Central

    2013-01-01

    Abstract Significance: Evidence is emerging that parenteral administration of high-dose vitamin C may warrant development as an adjuvant therapy for patients with sepsis. Recent Advances: Sepsis increases risk of death and disability, but its treatment consists only of supportive therapies because no specific therapy is available. The characteristics of severe sepsis include ascorbate (reduced vitamin C) depletion, excessive protein nitration in microvascular endothelial cells, and microvascular dysfunction composed of refractive vasodilation, endothelial barrier dysfunction, and disseminated intravascular coagulation. Parenteral administration of ascorbate prevents or even reverses these pathological changes and thereby decreases hypotension, edema, multiorgan failure, and death in animal models of sepsis. Critical Issues: Dehydroascorbic acid appears to be as effective as ascorbate for protection against microvascular dysfunction, organ failure, and death when injected in sepsis models, but information about pharmacodynamics and safety in human subjects is only available for ascorbate. Although the plasma ascorbate concentration in critically ill and septic patients is normalized by repletion protocols that use high doses of parenteral ascorbate, and such doses are tolerated well by most healthy subjects, whether such large amounts of the vitamin trigger adverse effects in patients is uncertain. Future Directions: Further study of sepsis models may determine if high concentrations of ascorbate in interstitial fluid have pro-oxidant and bacteriostatic actions that also modify disease progression. However, the ascorbate depletion observed in septic patients receiving standard care and the therapeutic mechanisms established in models are sufficient evidence to support clinical trials of parenteral ascorbate as an adjuvant therapy for sepsis. Antioxid. Redox Signal. 19, 2129–2140. PMID:23682970

  18. 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.

  19. Will dapivirine redeem the promises of anti-HIV microbicides? Overview of product design and clinical testing.

    PubMed

    das Neves, José; Martins, João Pedro; Sarmento, Bruno

    2016-08-01

    Microbicides are being developed in order to prevent sexual transmission of HIV. Dapivirine, a non-nucleoside reverse transcriptase inhibitor, is one of the leading drug candidates in the field, currently being tested in various dosage forms, namely vaginal rings, gels, and films. In particular, a ring allowing sustained drug release for 1month is in an advanced stage of clinical testing. Two parallel phase III clinical trials are underway in sub-Saharan Africa and results are expected to be released in early 2016. This article overviews the development of dapivirine and its multiple products as potential microbicides, with particular emphasis being placed on clinical evaluation. Also, critical aspects regarding regulatory approval, manufacturing, distribution, and access are discussed. PMID:26732684

  20. 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. PMID:18406920

  1. Evaluation of Staphylococcus aureus Eradication Therapy in Vascular Surgery

    PubMed Central

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

    2016-01-01

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

  2. Evaluating complementary and alternative therapies for cancer patients.

    PubMed

    Cassileth, B R

    1999-01-01

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

  3. 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.

  4. Murine leukemia virus-based Tat-inducible long terminal repeat replacement vectors: a new system for anti-human immunodeficiency virus gene therapy.

    PubMed

    Cannon, P M; Kim, N; Kingsman, S M; Kingsman, A J

    1996-11-01

    We have constructed new murine leukemia virus (MLV)-based vectors (TIN vectors) which, following integration, contain human immunodeficiency virus (HIV) type 1 U3 and R sequences in place of the MLV U3 and R regions. This provides, for the first time, single transcriptional unit retroviral vectors under the control of Tat. TIN vectors have several advantages for anti-HIV gene therapy applications. PMID:8892960

  5. Murine leukemia virus-based Tat-inducible long terminal repeat replacement vectors: a new system for anti-human immunodeficiency virus gene therapy.

    PubMed Central

    Cannon, P M; Kim, N; Kingsman, S M; Kingsman, A J

    1996-01-01

    We have constructed new murine leukemia virus (MLV)-based vectors (TIN vectors) which, following integration, contain human immunodeficiency virus (HIV) type 1 U3 and R sequences in place of the MLV U3 and R regions. This provides, for the first time, single transcriptional unit retroviral vectors under the control of Tat. TIN vectors have several advantages for anti-HIV gene therapy applications. PMID:8892960

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

    PubMed Central

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

    2012-01-01

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

  7. 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…

  8. 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,…

  9. 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.

  10. AEROSOL THERAPY IN BRONCHOPULMONARY DISEASE—A Critical Evaluation

    PubMed Central

    Olsen, Arthur M.

    1962-01-01

    Aerosol therapy has three principal objectives: Mobilization of bronchial secretions, relief of bronchospasm and topical chemotherapy. It has become an important tool in the treatment of bronchopulmonary diseases. The equipment for inhalation therapy, however, should be adequate. Both large-capacity and small-capacity nebulizers must be available, and they must be the kind that will produce a mist with most of its particles only 0.5 to 2.5 micra in diameter. These nebulizers may be used alone or in conjunction with a variety of appliances that will deliver the aerosols to the respiratory tract. The use of humidifying agents as aerosols is extremely helpful in patients with retained bronchopulmonary secretions. In some patients who have particularly thick or gelatinous secretions and in patients with mucoviscidosis, ordinary water or saline solution is often not enough. Hypertonic saline may be of value in these cases, and it is suggested that half-molar (2.9 per cent) saline be administered in 10 per cent propylene glycol. In these cases, preparations containing detergents (tyloxypal) or other preparations containing enzymes (desoxyribonuclease or trypsin) may be given by the aerosol technique, with care not to cause irritation. The bronchodilator aerosol agents are of proved benefit in the treatment of bronchospastic disorders and are indicated in most cases of asthma and in those cases of emphysema in which there is definite evidence of associated bronchospasm. The value of the aerosol method of administering chemotherapeutic and antibiotic drugs has probably been overrated, and it is suspected that much of the benefit previously attributed to the therapeutic agent was actually a result of humidification and liquefaction. PMID:14481907

  11. The Alpha Stem Cell Clinic: a model for evaluating and delivering stem cell-based therapies.

    PubMed

    Trounson, Alan; DeWitt, Natalie D; Feigal, Ellen G

    2012-01-01

    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

  12. Evaluation of Vacuum Assisted Closure Therapy for Soft Tissue Injury in Open Musculoskeletal Trauma

    PubMed Central

    Gill, S.P.S.; Sheopaltan, Sunil Kumar; Singh, Pulkesh; Dinesh; Sigh, Jasveer; Rastogi, Prateek; Mishra, L.N.

    2016-01-01

    Introduction The application of controlled levels of negative or sub atmospheric pressure for a prolonged period of time on a wound had shown to accelerate removal of excess fluid and promote hyperaemia, which eventually promote wound healing. Aim The study was conducted with the aim to evaluate the effectiveness of Vacuum Assisted Closure (VAC) therapy for soft tissue injury in open musculoskeletal trauma. Materials and Methods Twenty cases of complex musculoskeletal wound involving different parts of body were included in this progressive randomized study. In patients, aggressive debridement was done before the application of VAC therapy. Controlled negative pressure was uniformly applied to the wound. Dressings were changed after every 4 to 5 days. The evaluation of results included healing rate of the wound, eradication of infection, complication rate, and number of secondary procedures. Results VAC therapy over the wound was administered for an average of 20.4 days ±6.72 days (range 14 to 42 days). There was decrease in wound size attained by VAC therapy ranged from 2.6 to 24.4cm2, with an average reduction of 10.55 cm2. Three wounds were infected at the start of VAC therapy. However, all patients were cleared of bacterial infection by the end of VAC therapy. Conclusion VAC therapy using negative pressure promote Wound healing by increasing local capillary perfusion and increased rate of granulation tissue formation, decreases the duration of wound healing and requires fewer painful dressing change. PMID:27190906

  13. 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

  14. [A comparative evaluation of the efficacy of magneto- and laser therapy in patients with osteoarthrosis deformans].

    PubMed

    Selivonenko, V G; Syvolap, V D; Porada, L V; Medvedeva, V N; Boev, S S; Morozov, A I; Slin'ko, V G; Berest, S M; Garbuz, L N; Sholokh, S G

    1997-01-01

    A comparative evaluation of efficacy of magneto- and laser therapy was carried out in 82 patients with osteoarthrosis deformans. The magnetic field and laser irradiation dispelled the pain syndrome and synovitis manifestations. It is recommendable that the multiple-modality therapy of patients with osteoarthrosis deformans should involve magneto- and laser therapy (15 to 20 procedures per one course) that improve results of the treatment being received and allow the time of hospitalization to be reduced at an average by 5 bed-days. Laser appeared to be a very effective mode of treatment. No unfavourable side effects were recordable. PMID:9491734

  15. 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

  16. 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.

  17. 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.

  18. Evaluation of photodynamic therapy in adhesion protein expression

    PubMed Central

    PACHECO-SOARES, CRISTINA; MAFTOU-COSTA, MAIRA; DA CUNHA MENEZES COSTA, CAROLINA GENÚNCIO; DE SIQUEIRA SILVA, ANDREZA CRISTINA; MORAES, KAREN C.M.

    2014-01-01

    Photodynamic therapy (PDT) is a treatment modality that has clinical applications in both non-neoplastic and neoplastic diseases. PDT involves a light-sensitive compound (photosensitizer), light and molecular oxygen. This procedure may lead to several different cellular responses, including cell death. Alterations in the attachment of cancer cells to the substratum and to each other are important consequences of photodynamic treatment. PDT may lead to changes in the expression of cellular adhesion structure and cytoskeleton integrity, which are key factors in decreasing tumor metastatic potential. HEp-2 cells were photosensitized with aluminum phthalocyanine tetrasulfonate and zinc phthalocyanine, and the proteins β1-integrin and focal adhesion kinase (FAK) were assayed using fluorescence microscopy. The verification of expression changes in the genes for FAK and β1 integrin were performed by reverse transcription-polymerase chain reaction (RT-PCR). The results revealed that HEp-2 cells do not express β-integrin or FAK 12 h following PDT. It was concluded that the PDT reduces the adhesive ability of HEp-2 cells, inhibiting their metastatic potential. The present study aimed to analyze the changes in the expression and organization of cellular adhesion elements and the subsequent metastatic potential of HEp-2 cells following PDT treatment. PMID:25013490

  19. 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.

  20. 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.

  1. Significance and problems in evaluations of pathological responses to neoadjuvant therapy for breast cancer.

    PubMed

    Kurosumi, Masafumi

    2006-01-01

    Neoadjuvant therapy consists of systemic drug treatments before surgery for a primary cancer. Currently, several neoadjuvant therapy regimens for breast cancer that use various cytotoxic as well as endocrine-therapeutic and molecular-targeting agents have been performed in clinical practice and/or studies. In neoadjuvant therapy, pre-treatment pathological examination using materials obtained by a core needle biopsy (CNB) is necessary, and pathological diagnosis and evaluation of the biological status, such as hormone receptors and HER-2 over-expression are confirmed. In addition, CNB in the inter-phase of chemotherapy is also thought to be useful for assessment of therapeutic effects before regimens have been completed. After surgery, the therapeutic effects of neoadjuvant therapy have been mainly evaluated on the basis of pathological findings and a pathological complete response (pCR) is considered to be the main target of neoadjuvant therapy. Results of most of clinical studies including NSABP protocol B-18 and B-27 have confirmed the prognostic significance of pCR in neoadjuvant therapy and indicated the significance of pathological evaluation. However, universally accepted pathological response criteria have not been established, but evaluations of the main invasive tumor, intraductal components and regional lymph nodes are thought to be necessary. Additionally, evaluation of the effects below pCR also need examining in a study using a mild anti-cancer drug, such as hormone-therapeutic agent, and the survival outcomes of patients below pCR need to be examined and compared between each grade. PMID:16929118

  2. Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor.

    PubMed

    Dousson, Cyril; Alexandre, François-René; Amador, Agnès; Bonaric, Séverine; Bot, Stéphanie; Caillet, Catherine; Convard, Thierry; da Costa, Daniel; Lioure, Marie-Pierre; Roland, Arlène; Rosinovsky, Elodie; Maldonado, Sébastien; Parsy, Christophe; Trochet, Christophe; Storer, Richard; Stewart, Alistair; Wang, Jingyang; Mayes, Benjamin A; Musiu, Chiara; Poddesu, Barbara; Vargiu, Luana; Liuzzi, Michel; Moussa, Adel; Jakubik, Jocelyn; Hubbard, Luke; Seifer, Maria; Standring, David

    2016-03-10

    Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant. PMID:26804933

  3. Evaluation and Targeted Therapy of Voiding Dysfunction in Children.

    PubMed

    Palmer, Lane S

    2016-06-01

    Significant strides have been made over the past two decades in more precisely evaluating and managing children with voiding complaints. A thorough history should offer insight into the possible causes for the presenting complaints and this should be supplemented by physical examination, urine studies, and select imaging. Uroflowmetry and external sphincter electromyography with measurement of postvoid residual urine should allow for accurate diagnosis using categories offered by the International Children's Continence Society. This ability to make an accurate diagnosis should naturally lead to the use of treatment options (urotherapy, pharmacotherapy, biofeedback, and neuromodulation) that specifically target the responsible cause of the complaints rather than simply their symptoms. PMID:26883053

  4. 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

  5. Structural and Thermodynamic Basis of Epitope Binding by Neutralizing and Nonneutralizing Forms of the Anti-HIV-1 Antibody 4E10

    PubMed Central

    Rujas, Edurne; Gulzar, Naveed; Morante, Koldo; Tsumoto, Kouhei; Scott, Jamie K.

    2015-01-01

    ABSTRACT The 4E10 antibody recognizes the membrane-proximal external region (MPER) of the HIV-1 Env glycoprotein gp41 transmembrane subunit, exhibiting one of the broadest neutralizing activities known to date. The neutralizing activity of 4E10 requires solvent-exposed hydrophobic residues at the apex of the complementarity-determining region (CDR) H3 loop, but the molecular basis for this requirement has not been clarified. Here, we report the cocrystal structures and the energetic parameters of binding of a peptide bearing the 4E10-epitope sequence (4E10ep) to nonneutralizing versions of the 4E10 Fab. Nonneutralizing Fabs were obtained by shortening and decreasing the hydrophobicity of the CDR-H3 loop (termed ΔLoop) or by substituting the two tryptophan residues of the CDR-H3 apex with Asp residues (termed WDWD), which also decreases hydrophobicity but preserves the length of the loop. The analysis was complemented by the first crystal structure of the 4E10 Fab in its ligand-free state. Collectively, the data ruled out major conformational changes of CDR-H3 at any stage during the binding process (equilibrium or transition state). Although these mutations did not impact the affinity of wild-type Fab for the 4E10ep in solution, the two nonneutralizing versions of 4E10 were deficient in binding to MPER inserted in the plasma membrane (mimicking the environment faced by the antibody in vivo). The conclusions of our structure-function analysis strengthen the idea that to exert effective neutralization, the hydrophobic apex of the solvent-exposed CDR-H3 loop must recognize an antigenic structure more complex than just the linear α-helical epitope and likely constrained by the viral membrane lipids. IMPORTANCE The broadly neutralizing anti-HIV-1 4E10 antibody blocks infection caused by nearly all viral strains and isolates examined thus far. However, 4E10 (or 4E10-like) antibodies are rarely found in HIV-1-infected individuals or elicited through vaccination

  6. Evaluating the cost of therapy for restenosis: considerations for brachytherapy.

    PubMed

    Weintraub, W S

    1996-11-01

    Costs have become increasingly important in medicine in recent years as demand for services has outstripped readily available resources. Clinical microeconomics offers an approach to understanding cost and outcomes in an environment of economic scarcity. In this article the types of costs and methods for determining cost are presented. In addition, methods for assessing outcome and outcome in relation to cost are developed. Restenosis after coronary angioplasty is a prime example of a clinical problem requiring economic evaluation. This is because it results in little serious morbidity except for recurrent chest pain, but it has serious economic consequences which occur some time after the original angioplasty. This makes the economic assessment of restenosis complicated. The application of health care microeconomic principles to brachytherapy for restenosis in the coronary arteries is presented. PMID:8960526

  7. 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

  8. 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…

  9. 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…

  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. 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…

  12. 76 FR 13404 - Cancer Therapy Evaluation Program Intellectual Property Option to Collaborator

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-11

    ... Register of April 6, 2010 (FR Vol. 65, No. 65), the National Cancer Institute, Division of Cancer Treatment... HUMAN SERVICES Cancer Therapy Evaluation Program Intellectual Property Option to Collaborator AGENCY: National Institutes of Health, HHS. ACTION: Notice. SUMMARY: The National Cancer Institute, Division...

  13. 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…

  14. 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…

  15. 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…

  16. 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.

  17. Systematic evaluation of methyl ester bioisosteres in the context of developing alkenyldiarylmethanes (ADAMs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) for anti-HIV-1 chemotherapy.

    PubMed

    Hoshi, Ayako; Sakamoto, Takeshi; Takayama, Jun; Xuan, Meiyan; Okazaki, Mari; Hartman, Tracy L; Buckheit, Robert W; Pannecouque, Christophe; Cushman, Mark

    2016-07-01

    The alkenyldiarylmethanes (ADAMs) are a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting HIV-1. Four chemically and metabolically stabilized ADAMs incorporating N-methoxyimidoyl halide replacements of the methyl esters of the lead compound were previously reported. In this study, twenty-five new ADAMs were synthesized in order to investigate the biological consequences of installing nine different methyl ester bioisosteres at three different locations. Attempts to define a universal rank order of methyl ester bioisosteres and discover the 'best' one in terms of inhibitory activity versus HIV-1 reverse transcriptase (RT) led to the realization that the potencies are critically dependent on the surrounding structure at each location, and therefore the definition of universal rank order is impossible. This investigation produced several new non-nucleoside reverse transcriptase inhibitors in which all three of the three methyl esters of the lead compound were replaced by methyl ester bioisosteres, resulting in compounds that are more potent as HIV-1 RT inhibitors and antiviral agents than the lead compound itself and are expected to also be more metabolically stable than the lead compound. PMID:27234889

  18. Synthesis and biological evaluation of 1,3,3,4-tetrasubstituted pyrrolidine CCR5 receptor antagonists. Discovery of a potent and orally bioavailable anti-HIV agent.

    PubMed

    Ma, Dawei; Yu, Shanghai; Li, Ben; Chen, Li; Chen, Renhai; Yu, Kunqian; Zhang, Linqi; Chen, Zhiwei; Zhong, Dafang; Gong, Zheng; Wang, Renxiao; Jiang, Hualiang; Pei, Gang

    2007-02-01

    A series of 1,3,3,4-tetrasubstituted pyrrolidine containing CCR5 receptor antagonists were designed, which were elaborated either by condensation of a lithium salt of 3-(N,N-dibenzyl)aminopropionic acid methyl ester with ethyl benzoformate or by Baylis-Hillman reaction of ethyl acrylate with ethyl benzoformate and subsequent 1,4-addition of benzylamine, in the key steps. These compounds bearing 4-(N,N-disubstituted)amino piperidine units showed low nanomolar potency against the CCR5 receptor, whereas molecules with a 4-phenylpiperidine moiety displayed poor activity. Asymmetric synthesis of the most potent compound 23 a gave rise to the (3R,4S)-enantiomer 30 and the (3S,4R)-enantiomer 31, which showed IC(50) values of 2.9 and 385.9 nM, respectively. These results indicated that (3R,4S)-configuration in the series of compounds is favored for their interaction with the CCR5 receptor. The possible binding mode of these antagonists with the CCR5 receptor was discussed using a computer-modeling method. Compound 30 displayed excellent replication inhibition of seven genetically diverse R5 HIV-1 strains in the PBMC model, in a concentration-dependent manner with EC(50) values ranging from 0.3 nM to 30 nM. This molecule showed oral bioavailabilities of 41.2 % and 21.6 % in rats and dogs, respectively. Thus, compound 30 is a promising candidate for the treatment of HIV-1 infection. PMID:17163560

  19. 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

  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 Central

    Kamata, Masakazu; Kim, Patrick Y.; Ng, Hwee L.; Ringpis, Gene-Errol E.; Kranz, Emiko; Chan, Joshua; O'Connor, Sean; Yang, Otto O.; Chen, Irvin S.Y.

    2015-01-01

    Chimeric antigen receptors (CARs) are artificially engineered receptors that confer a desired specificity to immune effector T cells. As an HIV-1-specific CAR, CD4ζ CAR has been extensively tested in vitro as well as in clinical trials. T cells modified with this CAR mediated highly potent anti-HIV-1 activities in vitro and were well-tolerated in vivo, but exerted limited effects on viral load and reservoir size due to poor survival and/or functionality of the transduced cells in patients. We hypothesize that ectopic expression of CD4ζ on CD8+ T cells renders them susceptible to HIV-1 infection, resulting in poor survival of those cells. To test this possibility, highly purified CD8+ T cells were genetically modified with a CD4ζ-encoding lentiviral vector and infected with HIV-1. CD8+ T cells were vulnerable to HIV-1 infection upon expression of CD4ζ as evidenced by elevated levels of p24Gag in cells and culture supernatants. Concurrently, the number of CD4ζ-modified CD8+ T cells was reduced relative to control cells upon HIV-1 infection. To protect these cells from HIV-1 infection, we co-expressed two anti-HIV-1 shRNAs previously developed by our group together with CD4ζ. This combination vector was able to suppress HIV-1 infection without impairing HIV-1-dependent effector activities of CD4ζ. In addition, the number of CD4ζ-modified CD8+ T cells maintained similar levels to that of the control even under HIV-1 infection. These results suggest that protecting CD4ζ-modified CD8+ T cells from HIV-1 infection is required for prolonged HIV-1-specific immune surveillance. PMID:25998390

  1. A Mathematical Model of Antiretroviral Therapy Evaluation for HIV Type 1

    NASA Astrophysics Data System (ADS)

    Raimundo, Silvia Martorano; Venturino, Ezio; Mo Yang, Hyun

    2009-09-01

    Treating HIV-infected patients with a combination of several antiretroviral drugs can lead to emergence of the drug-resistant strain. This work proposes a mathematical model to evaluate the emergence of HIV-1 drug resistant during antiretroviral therapy. The model assumes that all susceptible individuals who can be infected by the wildtype strain (sensible to the treatment) or by drug-resistant virus receive antiretroviral therapy. Patients on treatment regimen can evolve to a state of success or failure and for the individuals in therapeutic fail the therapeutic schema is changed. The analysis of system is performed. The existence and stability of the steady states are considered. We address an analytical expression for the reproductive number in a community where antiretroviral therapy are widely used to treat HIV and where both drug sensitive and drug resistant strains are co-circulating.

  2. 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

  3. Dolutegravir: clinical efficacy and role in HIV therapy.

    PubMed

    Fantauzzi, Alessandra; Mezzaroma, Ivano

    2014-07-01

    The human immunodeficiency virus type-1 (HIV-1) integrase enzyme has recently emerged as a primary alternative target to block viral replication, and integrase strand transfer inhibitors (INSTIs) are now considered an alternative 'third agent' class of antiretroviral (ARV) drugs. Dolutegravir is the first next-generation INSTI showing some novel and intriguing characteristics: it has a favorable pharmacokinetic profile with a prolonged intracellular halflife, rendering feasible a once daily dosing without the need for pharmacokinetic boosting. Secondly, it is largely metabolized via uridine diphosphate glucuronosyltransferase-1A1 with a minor component of cytochrome P450 isoforms, thus allowing a low grade of drug-drug interactions, so that its metabolic profile consents co-administration with the majority of the other ARV drugs without dose adjustments. Lastly, but no less important, virological studies have clearly demonstrated that dolutegravir has a significant activity against HIV-1 isolates showing raltegravir and/or elvitegravir associated resistance mutations. The attributes of once daily administration and the potential to treat INSTI-resistant viruses make dolutegravir an interesting and promising new agent in the treatment of both naïve and experienced HIV-1 subjects. In this review, the main concerns on dolutegravir efficacy are focused through the analysis of the currently available data from clinical studies in naïve and experienced patients, evaluating its possible place within the anti-HIV-1 drug armamentarium. The development of newer once daily, single tablet coformulations improved drug adherence and maximized the success of ARV therapy. Pharmacokinetic studies and dose-ranging trials suggested that dolutegravir is a good candidate for a single tablet regimen in one or more new coformulated pills that will be available in the near future. PMID:24982751

  4. Dolutegravir: clinical efficacy and role in HIV therapy

    PubMed Central

    Fantauzzi, Alessandra

    2014-01-01

    The human immunodeficiency virus type-1 (HIV-1) integrase enzyme has recently emerged as a primary alternative target to block viral replication, and integrase strand transfer inhibitors (INSTIs) are now considered an alternative ‘third agent’ class of antiretroviral (ARV) drugs. Dolutegravir is the first next-generation INSTI showing some novel and intriguing characteristics: it has a favorable pharmacokinetic profile with a prolonged intracellular halflife, rendering feasible a once daily dosing without the need for pharmacokinetic boosting. Secondly, it is largely metabolized via uridine diphosphate glucuronosyltransferase-1A1 with a minor component of cytochrome P450 isoforms, thus allowing a low grade of drug–drug interactions, so that its metabolic profile consents co-administration with the majority of the other ARV drugs without dose adjustments. Lastly, but no less important, virological studies have clearly demonstrated that dolutegravir has a significant activity against HIV-1 isolates showing raltegravir and/or elvitegravir associated resistance mutations. The attributes of once daily administration and the potential to treat INSTI-resistant viruses make dolutegravir an interesting and promising new agent in the treatment of both naïve and experienced HIV-1 subjects. In this review, the main concerns on dolutegravir efficacy are focused through the analysis of the currently available data from clinical studies in naïve and experienced patients, evaluating its possible place within the anti-HIV-1 drug armamentarium. The development of newer once daily, single tablet coformulations improved drug adherence and maximized the success of ARV therapy. Pharmacokinetic studies and dose-ranging trials suggested that dolutegravir is a good candidate for a single tablet regimen in one or more new coformulated pills that will be available in the near future. PMID:24982751

  5. A randomised controlled trial evaluating family mediated exercise (FAME) therapy following stroke

    PubMed Central

    Galvin, Rose; Cusack, Tara; Stokes, Emma

    2008-01-01

    Background Stroke is a leading cause of disability among adults worldwide. Evidence suggests that increased duration of exercise therapy following stroke has a positive impact on functional outcome following stroke. The main objective of this randomised controlled trial is to evaluate the impact of additional family assisted exercise therapy in people with acute stroke. Methods/Design A prospective multi-centre single blind randomised controlled trial will be conducted. Forty patients with acute stroke will be randomised into either an experimental or control group. The experimental group will receive routine therapy and additional lower limb exercise therapy in the form of family assisted exercises. The control group will receive routine therapy with no additional formal input from their family members. Participants will be assessed at baseline, post intervention and followed up at three months using a series of standardised outcome measures. A secondary aim of the project is to evaluate the impact of the family mediated exercise programme on the person with stroke and the individual(s) assisting in the delivery of exercises using a qualitative methodology. The study has gained ethical approval from the Research Ethics Committees of each of the clinical sites involved in the study. Discussion This study will evaluate a structured programme of exercises that can be delivered to people with stroke by their 'family members/friends'. Given that the progressive increase in the population of older people is likely to lead to an increased prevalence of stroke in the future, it is important to reduce the burden of this illness on the individual, the family and society. Family mediated exercises can maximise the carry over outside formal physiotherapy sessions, giving patients the opportunity for informal practice. Trial Registration The protocol for this study is registered with the US NIH Clinical trials registry (NCT00666744) PMID:18570643

  6. Creating culturally responsive family therapy models and research: introducing the use of responsive evaluation as a method.

    PubMed

    Seponski, Desiree M; Bermudez, J Maria; Lewis, Denise C

    2013-01-01

    Models of marriage and family therapy (MFT) typically reflect Western values and norms, and although cultural adaptations are made, many models/frameworks continue to be inappropriate or inadequate for use with non-Western cultures. Worldwide, therapists are examining ways of using MFT models in a culturally sensitive manner, especially when working with clients who are seen as having minority status or perceived as "other" by the dominant group. This essay suggests the use of responsive evaluation as a theoretically consistent methodology for creating and evaluating culturally responsive therapies. This approach rigorously evaluates each unique client/therapist context, culture, power, needs, and beliefs. We describe responsive evaluation and discuss how each component addresses the research needs of examining culturally responsive family therapies. A case illustration is offered delineating the process of conducting culturally responsive therapy with a Cambodian sample using solution-focused and narrative therapy. PMID:25073841

  7. Evaluative comparison of systemic aspirin therapy effects on gingival bleeding in post non-surgical periodontal therapy individuals

    PubMed Central

    Sundram, Elanchezhiyan; Kharaharilal, Panishankar; Ilavarasu, Sugumari; Renukadevi; Nalini, Esther; Karunamoorthy, Venilla

    2012-01-01

    Background: Gingival bleeding is considered as an important clinical sign for diagnosis of periodontal disease pathogenesis. Immune inflammatory reactions caused by local factors are considered as essential reasons for gingival bleeding, as also for the systemic bleeding disorders. In disease-free conditions of gingiva, the bleeding disorders are considered to be the main contender for bleeding. Other than these variables, many systemic drugs including systemic aspirin could also cause gingival bleeding. The main aim of the study was to evaluate the effect of buffered aspirin therapy on gingival bleeding. Materials and Methods: Totally, 36 systemically healthy individuals were included in the 15-day randomized, double-blinded, placebo-controlled clinical trial. The 15 days were divided as: control period for the first 7 days and study period for the following 7 days. On the 1st day, all individuals were given oral prophylaxis after recording gingival parameters such as Plaque Index, probing depth, and Bleeding Index, and then blood samples were collected for hematological investigations. Then, all individuals were administered placebo capsules for 1 week as once daily dose. On the 8th day, all procedures were repeated and the individuals were prescribed with 325 coated aspirin capsules for 1 week. On the 15th day, all parameters were repeated and the results were statistically analyzed. Results: In the study period, the parameters such as Bleeding Index, bleeding time, and prothrombin time were increased significantly, compared to the control period. Conclusion: The variables such as systemic drug therapy should be considered for the examination of gingiva while the diagnosis is considered mainly based on gingival bleeding. PMID:23066256

  8. 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

  9. Evaluation of factors associated with relapse in telaprevir-based triple therapy for chronic hepatitis C

    PubMed Central

    Kondo, C; Atsukawa, M; Tsubota, A; Shimada, N; Abe, H; Aizawa, Y

    2016-01-01

    Background and Rationale: Most patients with chronic hepatitis C show virological response to telaprevir-based triple therapy, and achieve an end-of-treatment response (ETR). However, some patients showing ETR develop virological relapse. This study was carried out to evaluate factors associated with relapse after triple therapy. Materials and Methods: A prospective, multicentric study was conducted in chronic hepatitis C patients who received telaprevir-based triple therapy. We evaluated independent variables such as age, with or without cirrhosis, prior treatment response to interferon (IFN) therapy, IL28B genotype, core amino acid (aa) 70 mutation, drug adherence, white blood cell counts, hemoglobin level, and serum low-density lipoprotein (LDL) cholesterol level. The characteristics of the patients who relapsed after achieving ETR were compared with those who did not. Results: Among 168 patients, 157 patients achieved ETR (93.5%) and 11 discontinued. Of these 157 patients, relapse occurred in 21 patients (13.4%). Nineteen patients (90.5%) of 21 relapsed patients had the IL28B non-TT genotype (P = 1.79 × 10-9). Multivariate analysis identified core amino acid 70 [P = 0.018, crude odds ratio (OR): 6.927] and the IL28B genotype (P = 3.758 × 10-5, crude OR: 39.311) as significantly independent factors that influenced the relapse-related variables. Among the 49 patients with the IL28B non-TT, 18 patients had core aa70 mutation and 31 patients had core aa70 wild-type. In addition, 66.7% (12/18) of those with core aa70 mutation and 22.6% (7/31) of those with core aa70 wild-type developed relapse (P = 0.005). Discussion: Core aa70 mutation and the IL28B non-TT genotype were identified as independent factors that influenced relapse after achievement of ETR for telaprevir-based triple therapy. PMID:26732192

  10. 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

  11. Approach to Modeling, Therapy Evaluation, Drug Selection, and Biomarker Assessments for a Multicenter Pre-Clinical Drug Screening Consortium for Acute Therapies in Severe Traumatic Brain Injury: Operation Brain Trauma Therapy.

    PubMed

    Kochanek, Patrick M; Bramlett, Helen M; Dixon, C Edward; Shear, Deborah A; Dietrich, W Dalton; Schmid, Kara E; Mondello, Stefania; Wang, Kevin K W; Hayes, Ronald L; Povlishock, John T; Tortella, Frank C

    2016-03-15

    Traumatic brain injury (TBI) was the signature injury in both the Iraq and Afghan wars and the magnitude of its importance in the civilian setting is finally being recognized. Given the scope of the problem, new therapies are needed across the continuum of care. Few therapies have been shown to be successful. In severe TBI, current guidelines-based acute therapies are focused on the reduction of intracranial hypertension and optimization of cerebral perfusion. One factor considered important to the failure of drug development and translation in TBI relates to the recognition that TBI is extremely heterogeneous and presents with multiple phenotypes even within the category of severe injury. To address this possibility and attempt to bring the most promising therapies to clinical trials, we developed Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug screening consortium for acute therapies in severe TBI. OBTT was developed to include a spectrum of established TBI models at experienced centers and assess the effect of promising therapies on both conventional outcomes and serum biomarker levels. In this review, we outline the approach to TBI modeling, evaluation of therapies, drug selection, and biomarker assessments for OBTT, and provide a framework for reports in this issue on the first five therapies evaluated by the consortium. PMID:26439468

  12. 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

  13. 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.

  14. 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

  15. Evaluating Large-scale Blood Transfusion Therapy for the Current Ebola Epidemic in Liberia

    PubMed Central

    Gutfraind, Alexander; Meyers, Lauren Ancel

    2015-01-01

    Background. To combat the 2014–2015 Ebola virus disease (EVD) epidemic in West Africa, the World Health Organization urged the rapid evaluation of convalescent whole blood (CWB) and plasma (CP) transfusion therapy. However, the feasibility and likely impacts of broad implementation of transfusions are yet unknown. Methods. We extended an Ebola virus transmission model published by the Centers for Disease Control and Prevention to include hospital-based convalescent donations and transfusions. Using recent epidemiological estimates for EVD in Liberia and assuming that convalescent transfusions reduce the case-fatality rate to 12.5% (range, 7.5%–17.5%), we projected the impacts of a countrywide ramp-up of transfusion therapy. Results. Under the 10% case-hospitalization rate estimated for Liberia in September 2014, large-scale CP therapy is expected to save 3586 lives by October 2015 (3.1% mortality reduction; 95% confidence interval [CI], .52%–4.5%). Under a higher 30% hospitalization rate, CP transfusions are expected to save 151 lives (0.9% of the total; 95% CI, .21%–11%). Conclusions. Transfusion therapy for EVD is a low-cost measure that can potentially save many lives in West Africa but will not measurably influence the prevalence. Under all scenarios considered, CP transfusions are predicted to achieve greater reductions in mortality than CWB. PMID:25635118

  16. Metastatic renal cell carcinoma imaging evaluation in the era of anti-angiogenic therapies.

    PubMed

    Sirous, Reza; Henegan, John C; Zhang, Xu; Howard, Candace M; Souza, Frederico; Smith, Andrew D

    2016-06-01

    During the last decade, the arsenal of anti-angiogenic (AAG) agents used to treat metastatic renal cell carcinoma (RCC) has grown and revolutionized the treatment of metastatic RCC, leading to improved overall survival compared to conventional chemotherapy and traditional immunotherapy agents. AAG agents include inhibitors of vascular endothelial growth factor receptor signaling pathways and mammalian target of rapamycin inhibitors. Both of these classes of targeted agents are considered cytostatic rather than cytotoxic, inducing tumor stabilization rather than marked tumor shrinkage. As a result, decreases in tumor size alone are often minimal and/or occur late in the course of successful AAG therapy, while tumor devascularization is a distinct feature of AAG therapy. In successful AAG therapy, tumor devascularization manifests on computed tomography images as a composite of a decrease in tumor size, a decrease in tumor attenuation, and the development of tumor necrosis. In this article, we review Response Evaluation Criteria in Solid Tumors (RECIST)-the current standard of care for tumor treatment response assessment which is based merely on changes in tumor length-and its assessment of metastatic RCC tumor response in the era of AAG therapies. We then review the features of an ideal tumor imaging biomarker for predicting metastatic RCC response to a particular AAG agent and serving as a longitudinal tumor response assessment tool. Finally, a discussion of the more recently proposed imaging response criteria and new imaging trends in metastatic RCC response assessment will be reviewed. PMID:27193601

  17. 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.

  18. 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.

  19. Longevity: a critical factor in evaluating the effectiveness of periodontal therapy.

    PubMed

    Moskow, B S

    1987-04-01

    A 47-year-old male patient with an advanced form of adult periodontitis presented for evaluation and treatment in 1963. There were several angular bony lesions and 3 molar teeth had an extremely questionable prognosis. The patient was treated by scaling, root planing and gingivectomy, with no attempt to alter the existing morphology of the effected alveolar bone. 23 years following periodontal therapy, there were marked changes of the contour of the marginal bone crest throughout, minimal pocket depth and acceptable gingival form. The patient was seen at regular 5-6 months intervals for maintenance therapy and his home care regimen was exemplary. Advanced cases of periodontitis can be treated successfully by simplistic methods if the "repair potential" of the patient is good and if regular maintenance visits and meticulous plaque control are carried out. PMID:3294918

  20. Evaluation of manual-based cognitive-behavioral therapy for bulimia nervosa in a service setting.

    PubMed

    Tuschen-Caffier, B; Pook, M; Frank, M

    2001-03-01

    In the present study manual-based cognitive-behavioral therapy for bulimia nervosa was evaluated on an unselected sample of an out-patient service facility. A total of 73 female patients who asked for treatment received the primary diagnosis of bulimia nervosa. Of these, 67 took up treatment. Treatment was completed by 66 patients. Outcome variables were the number of binge episodes along with questionnaire scores for restraint eating, emotional eating, body dissatisfaction and depressiveness. At the end of treatment and 1 year after the end of treatment significant improvements were found in all outcome variables. Effect sizes for outcome variables were within the range of those of controlled research. Therefore, the present study delivered empirical evidence that manual-based cognitive-behavioral therapy is an effective treatment for bulimia nervosa not only within the restricted area of research. PMID:11227811

  1. 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

  2. Evaluation of results of conservative therapy in patients with transient osteoporosis of hip.

    PubMed

    Guler, Olcay; Ozyurek, Selahattin; Cakmak, Selami; Isyar, Mehmet; Mutlu, Serhat; Mahirogullari, Mahir

    2015-09-01

    The present study aimed to review the general characteristics of 18 cases diagnosed with transient osteoporosis of the hip (TOH) in our hospital within a 3-year period and to present their follow-up results after conservative treatment. A retrospective evaluation was made of the treatment and results of follow-up of TOH cases using physical examination and laboratory findings, hip radiographs and magnetic resonance imaging (MRI) and Harris Hip Scores (HHS). The mean duration of complaints of 6 females (mean age, 34.3±4.3 years) and 12 males (mean age, 40.7±10.5 years) was 6.1±2.7 weeks before the treatment. Three female patients had a history of giving birth by cesarean delivery. None of the patients had any history of trauma. MRI revealed increased intensity in T2 sequences and decreased intensity in T1 sequences in the proximal aspect of the femur. None of the patients had subchondral collapse or intra-articular effusion. For 3 female patients who were breastfeeding, no medical therapy was given, but only hyperbaric oxygen (HBO) therapy and forearm crutches. As standard management, the other patients were prevented from weight-bearing with the use of forearm crutches and medical therapy of diclofenac sodium, acetylsalicylic acid, and risedronate sodium was administered and additional HBO therapy. Clinical and radiological improvements were observed in all patients. None of the patients had avascular necrosis (AVN) of the femoral head. There was no record of therapy-related complications. While HHS was 55.6±7.8 before the treatment, it increased to 88.8±5.8 in the 3rd month and to 96.0±1.8 in the 6th month after the treatment. This change in score over time was found to be significant. PMID:26435236

  3. Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy.

    PubMed

    Virani, Sean A; Dent, Susan; Brezden-Masley, Christine; Clarke, Brian; Davis, Margot K; Jassal, Davinder S; Johnson, Christopher; Lemieux, Julie; Paterson, Ian; Sebag, Igal A; Simmons, Christine; Sulpher, Jeffrey; Thain, Kishore; Thavendiranathan, Paaldinesh; Wentzell, Jason R; Wurtele, Nola; Côté, Marc André; Fine, Nowell M; Haddad, Haissam; Hayley, Bradley D; Hopkins, Sean; Joy, Anil A; Rayson, Daniel; Stadnick, Ellamae; Straatman, Lynn

    2016-07-01

    Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients. PMID:27343741

  4. Evaluating Sarconesiopsis magellanica blowfly-derived larval therapy and comparing it to Lucilia sericata-derived therapy in an animal model.

    PubMed

    Díaz-Roa, Andrea; Gaona, María A; Segura, Nidya A; Ramírez-Hernández, Alejandro; Cortés-Vecino, Jesús A; Patarroyo, Manuel A; Bello, Felio

    2016-02-01

    Larval therapy is used as alternative treatment for hard-to-heal chronic and infected wounds. Lucilia sericata is the most used blowfly species. However, it has been shown recently that Sarconesiopsis magellanica larval excretions and secretions have potent antibacterial activity; this blowfly belongs to the Calliphoridae family. The present work has dealt with evaluating larval therapy using S. magellanica on wounds induced in diabetic rabbits and its action was compared to the effect induced by L. sericata. Twelve New Zealand White rabbits (Oryctolagus cuniculus) were used; they were divided into 4 groups, the first two being treated with larval therapy derived from both aforementioned necrophagous blowflies, an antibiotic was used in the third and the fourth was used as control. All the animals were wounded on the back and infected with Pseudomonas aeruginosa and Staphylococcus aureus. Samples of the secretion from each animal's infected wound were taken and sown on blood agar. The colony forming units were then counted. The PUSH scale was used for the macroscopic evaluation of the wounds. Bacterial control was encountered 48 h post-treatment in the treatments involving larval therapy and to a lesser extent with the antibiotic. Likewise, wound debridement was quicker and more efficient with larval therapy compared to the antibiotic group; however, wound closing time was 23 days in all treatments. The group treated with S. magellanica larvae had relatively quicker evolution until the proliferation phase and the start of maturation, even though there were no significant differences between both blowfly species evaluated here regarding treatments by the end of the treatment period. The present study has validated the diabetic rabbit model for inducing chronic wounds regarding larval therapy and has likewise confirmed the effectiveness of S. magellanica-derived larval therapy as an alternative for curing and healing wounds. PMID:26546725

  5. 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.

  6. Clinical evaluation of cefotaxime for therapy of lower respiratory tract infections.

    PubMed Central

    Schleupner, C J; Engle, J C

    1982-01-01

    A clinical trial was designed to evaluate the efficacy and safety of cefotaxime, a new semisynthetic, broad-spectrum cephalosporin, in the therapy of community-and hospital-acquired pneumonias. Thirty-nine males (mean age, 65 years) were treated for 41 episodes of pneumonia. Only five patient did not have a serious underlying disease; 15 had two or more significant disorders. Sixty-six percent of these pneumonias were due to Streptococcus pneumoniae or Haemophilus influenzae. The minimal inhibitory concentrations for all bacterial isolates ranged from 0.008 to 4 micrograms/ml. Peak serum cefotaxime levels during therapy ranged from 12 to 124 micrograms/ml 1 h after a 1-g dose. Satisfactory bacteriological and clinical responses were observed in 85% of the cases. Four episodes of pulmonary superinfections due to cefotaxime-resistant gram-negative bacilli were noted, each in a patient being mechanically ventilated. Pseudomonas was involved in each of these superinfections, and three were fatal. No serious toxicity or adverse reaction to cefotaxime was seen. The results of this study suggest that cefotaxime is an affective and well-tolerated new cephalosporin antimicrobial agent for the therapy of pneumonia due to susceptible organisms. PMID:6280600

  7. Metabolomic evaluation of the response to endocrine therapy in patients with prostate cancer.

    PubMed

    Huang, Gang; Liu, Xinru; Jiao, Li; Xu, Chuanliang; Zhang, Zhongxiao; Wang, Linhui; Li, Yun; Yang, Chun; Zhang, Weidong; Sun, Yinghao

    2014-04-15

    Timely evaluation of the response to endocrine therapy in patients with prostate cancer (PCa) may optimize treatment regimens and improve long-term prognosis. We used the liquid chromatography-mass spectrometry (LC-MS)-based metabolomic technique to identify serum biomarkers indicative of disease progression and therapeutic benefit. The mean serum levels of seven metabolites, including deoxycholic acid (DCA), glycochenodeoxycholate (GCDC), l-tryptophan, docosapentaenoic acid (DPA), arachidonic acid, deoxycytidine triphosphate, and pyridinoline, differed significantly between untreated PCa patients and healthy controls. In patients who did not develop castration-resistant prostate cancer (CRPC) for at least 2 years (good responders), these metabolite levels reverted to near healthy control levels during endocrine therapy. In contrast, the metabolite levels remained abnormal in patients who developed CRPC within 1 year (poorly responsive patients). Three of these biomarkers (DCA, GCDC, and DPA) are mainly involved in cholesterol metabolism, underscoring the importance of elevated cholesterol to PCa progression. These metabolites may serve as predictive biomarkers for assessing the therapeutic response of PCa patients to endocrine therapy. PMID:24556387

  8. Murine Model Imitating Chronic Wound Infections for Evaluation of Antimicrobial Photodynamic Therapy Efficacy.

    PubMed

    Fila, Grzegorz; Kasimova, Kamola; Arenas, Yaxal; Nakonieczna, Joanna; Grinholc, Mariusz; Bielawski, Krzysztof P; Lilge, Lothar

    2016-01-01

    It is generally acknowledged that the age of antibiotics could come to an end, due to their widespread, and inappropriate use. Particularly for chronic wounds alternatives are being thought. Antimicrobial Photodynamic Therapy (APDT) is a potential candidate, and while approved for some indications, such as periodontitis, chronic sinusitis and other niche indications, its use in chronic wounds is not established. To further facilitate the development of APDT in chronic wounds we present an easy to use animal model exhibiting the key hallmarks of chronic wounds, based on full-thickness skin wounds paired with an optically transparent cover. The moisture-retaining wound exhibited rapid expansion of pathogen colonies up to 8 days while not jeopardizing the host survival. Use of two bioluminescent pathogens; methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa permits real time monitoring of the pathogens. The murine model was employed to evaluate the performance of four different photosensitizers as mediators in Photodynamic Therapy. While all four photosensitizers, Rose Bengal, porphyrin TMPyP, New Methylene Blue, and TLD1411 demonstrated good to excellent antimicrobial efficacy in planktonic solutions at 1 to 50 μM concentrations, whereas in in vivo the growth delay was limited with 24-48 h delay in pathogen expansion for MRSA, and we noticed longer growth suppression of P. aeruginosa with TLD1411 mediated Photodynamic Therapy. The murine model will enable developing new strategies for enhancement of APDT for chronic wound infections. PMID:27555843

  9. 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

  10. 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

  11. Adjuvant sorafenib therapy in patients with resected hepatocellular carcinoma: evaluation of predictive factors.

    PubMed

    Zhang, Wei; Zhao, Gang; Wei, Kai; Zhang, Qingxiang; Ma, Weiwei; Wu, Qiang; Zhang, Ti; Kong, Dalu; Li, Qiang; Song, Tianqiang

    2015-04-01

    Currently there is no predictor for survival after adjuvant sorafenib in patients with hepatocellular carcinoma (HCC) who have undergone curative resection. Thirty-eight patients who underwent curative resection of HCC received adjuvant sorafenib therapy between August 2009 and March 2012. Clinicopathological parameters including patient factors, tumor factors, liver background, and inflammatory factors (before surgery and dynamic changes after sorafenib therapy) were evaluated to identify predictors for overall survival (OS) and recurrence-free survival (RFS). The recurrence rate, mortality rate, and clinicopathological data were also compared. Increased NLR after sorafenib (HR = 3.199, 95 % CI 1.365-7.545, P = 0.008), increased GGT after sorafenib (HR = 3.204, 95 % CI 1.333-7.700, P = 0.009), and the presence of portal vein thrombosis (HR = 2.381, 95 % CI 1.064-5.328, P = 0.035) were risk factors related to RFS. By contrast, increased NLR after sorafenib was the only independent risk factor related to OS (HR = 4.647, 95 % CI 1.266-17.053, P = 0.021). Patients with increased NLR or increased GGT after sorafenib had a higher incidence of recurrence and death. Patients who had increased NLR tended to have higher preoperative levels of NLR and GGT. There were no differences in clinicopathological factors in patients with increased GGT and decreased GGT. In conclusion, increased NLR predicted a worse OS and RFS in patients with HCC who underwent curative resection with adjuvant sorafenib therapy. Increased GGT predicted a worse OS. NLR and GGT can be monitored dynamically before and after sorafenib therapy. PMID:25750040

  12. 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

  13. Evaluation of Senna singueana leaf extract as an alternative or adjuvant therapy for malaria

    PubMed Central

    Hiben, Mebrahtom Gebrelibanos; Sibhat, Gereziher Gebremedhin; Fanta, Biruk Sintayehu; Gebrezgi, Haile Desta; Tesema, Shewaye Belay

    2015-01-01

    The emergence of malarial resistance to most antimalarial drugs is the main factor driving the continued effort to identify/discover new agents for combating the disease. Moreover, the unacceptably high mortality rate in severe malaria has led to the consideration of adjuvant therapies. Senna singueana leaves are traditionally used against malaria and fever. Extracts from the leaves of this plant demonstrated in vitro and in vivo antioxidant activities, which in turn could reduce the severity of malaria. Extracts from the root bark of this plant exhibited antiplasmodial activity; however, the leaves are the more sustainable resource. Thus, S. singueana leaf was selected for in vivo evaluation as a potential alternative or adjuvant therapy for malaria. Using malaria [Plasmodium berghei ANKA, chloroquine (CQ) sensitive]-infected Swiss albino mice of both sexes, 70% ethanol extract of S. singueana leaves (alone and in combination with CQ) was tested for antimalarial activity and adjuvancy potential. The 4-day suppressive test was used to evaluate antimalarial activity. The dose of S. singueana extract administered was safe to mice and exhibited some parasite suppression effect: extract doses of 200 mg/kg/d, 400 mg/kg/d, and 800 mg/kg/d caused 34.54%, 44.52%, and 47.32% parasite suppression, respectively. Concurrent administration of the extract with CQ phosphate at varied dose levels indicated that the percentage of parasite suppression of this combination was higher than administering CQ alone, but less than the sum of the effects of the extract and CQ acting separately. In conclusion, the study indicated that 70% ethanol extract of S. singueana leaf was safe to mice and possessed some parasite suppression effect. Coadministration of the extract with CQ appeared to boost the overall antimalarial effect, indicating that the combination may have a net health benefit if used as an adjuvant therapy. PMID:26870688

  14. 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. PMID:24396837

  15. 99mTc-MIBI Washout Rate to Evaluate the Effects of Steroid Therapy in Cardiac Sarcoidosis.

    PubMed Central

    Sarai, Masayoshi; Motoyama, Sadako; Kato, Yasuchika; Kawai, Hideki; Ito, Hajime; Takada, Kayoko; Yoda, Ryuji; Toyama, Hiroshi; Morimoto, Shin-ichiro; Ozaki, Yukio

    2013-01-01

    Objective We sought to determine the usefulness of the 99mTc-MIBI (MIBI) washout rate for the evaluation of steroid therapy in cardiac sarcoidosis (CS). Methods: Eleven CS patients underwent MIBI myocardial SPECT both before and 6 months after initiating steroid therapy. The washout rate (WOR) of MIBI was calculated using early and delayed polar map images. The washout score (WOS) of MIBI was derived from the difference between the early and delayed total defect scores (TDS). Results: Serum ACE and BNP exhibited significant improvement after the therapy (p = 0.004, p = 0.045). In the LV function, EDV and E/A ratio exhibited significant improvement after the therapy (p = 0.041, p = 0.007), while there were no significant differences between before and after therapy in EF or ESV. Early and delayed TDS showed no significant differences between before and after the therapy. In contrast, WOR differed significantly (p <. 0001), while WOS did not differ significantly between before and after the therapy. Conclusion: The washout rate of MIBI is suitable for assessment of cardiac function in CS with steroid therapy, being especially better than the washout score of MIBI for assessment of disease activity of mild myocardial damage in CS with steroid therapy.

  16. 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

  17. Anti-AIDS agents 65: investigation of the in vitro oxidative metabolism of 3',4'-Di-O-(-)-camphanoyl-(+)-cis-khellactone derivatives as potent anti-hiv agents.

    PubMed

    Suzuki, Madoka; Li, Yutai; Smith, Philip C; Swenberg, James A; Martin, David E; Morris-Natschke, Susan L; Lee, Kuo-Hsiung

    2005-11-01

    3',4'-Di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) is a synthetic khellactone ester that exhibits potent in vitro anti-human immunodeficiency virus (HIV) activity with a mechanism distinct from clinically used anti-HIV agents. Several series of mono- and di-substituted DCK derivatives (DCKs) have previously been synthesized, and their structure-activity relationships are well established. To optimize DCK as a drug lead and to guide further structural modifications, metabolic stabilities and metabolite structures were analyzed. In vitro metabolic stabilities of DCKs in human liver microsomes were assessed using high performance liquid chromatography (HPLC) with UV detection to establish structure-metabolism relationships (SMRs). HPLC coupled with ion trap mass spectrometry was used to identify the metabolite structures. The results indicated that DCKs undergo rapid oxidation on the lipophilic camphanoyl moieties and the substituents on the khellactone do not alter the rate or the metabolic pathways for this compound type. Our SMR and metabolite analysis study suggested that the two camphanoyl ester moieties are the determinants of the low metabolic stability and that structural alteration in the two esters may be necessary to improve metabolic profiles of DCKs. PMID:16087699

  18. 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.

  19. Physician Evaluation of Internet Health Information on Proton Therapy for Prostate Cancer

    PubMed Central

    Shah, Anand; Paly, Jonathan J.; Efstathiou, Jason A.; Bekelman, Justin E.

    2014-01-01

    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. PMID:23245278

  20. 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.

  1. A proposed integrated approach for the preclinical evaluation of phage therapy in Pseudomonas infections.

    PubMed

    Danis-Wlodarczyk, Katarzyna; Vandenheuvel, Dieter; Jang, Ho Bin; Briers, Yves; Olszak, Tomasz; Arabski, Michal; Wasik, Slawomir; Drabik, Marcin; Higgins, Gerard; Tyrrell, Jean; Harvey, Brian J; Noben, Jean-Paul; Lavigne, Rob; Drulis-Kawa, Zuzanna

    2016-01-01

    Bacteriophage therapy is currently resurging as a potential complement/alternative to antibiotic treatment. However, preclinical evaluation lacks streamlined approaches. We here focus on preclinical approaches which have been implemented to assess bacteriophage efficacy against Pseudomonas biofilms and infections. Laser interferometry and profilometry were applied to measure biofilm matrix permeability and surface geometry changes, respectively. These biophysical approaches were combined with an advanced Airway Surface Liquid infection model, which mimics in vitro the normal and CF lung environments, and an in vivo Galleria larvae model. These assays have been implemented to analyze KTN4 (279,593 bp dsDNA genome), a type-IV pili dependent, giant phage resembling phiKZ. Upon contact, KTN4 immediately disrupts the P. aeruginosa PAO1 biofilm and reduces pyocyanin and siderophore production. The gentamicin exclusion assay on NuLi-1 and CuFi-1 cell lines revealed the decrease of extracellular bacterial load between 4 and 7 logs and successfully prevents wild-type Pseudomonas internalization into CF epithelial cells. These properties and the significant rescue of Galleria larvae indicate that giant KTN4 phage is a suitable candidate for in vivo phage therapy evaluation for lung infection applications. PMID:27301427

  2. Evaluating efficacy of bacteriophage therapy against Staphylococcus aureus infections using a silkworm larval infection model.

    PubMed

    Takemura-Uchiyama, Iyo; Uchiyama, Jumpei; Kato, Shin-ichiro; Inoue, Tetsuyoshi; Ujihara, Takako; Ohara, Naoya; Daibata, Masanori; Matsuzaki, Shigenobu

    2013-10-01

    Silkworm larva has recently been recognized as an alternative model animal for higher mammals to evaluate the effects of antibiotics. In this study, we examined the efficacy of the bacteriophage (phage) therapy, which harnesses phages as antibacterial agents, against Staphylococcus aureus infections, using the silkworm larval infection model. Two newly isolated staphylococcal phages, S25-3 and S13', were used as therapeutic phage candidates. They were assigned to two different lytic phage genera, Twort-like and AHJD-like viruses, based on their morphologies and the N-terminal amino acid sequences of the major capsid proteins. Both had a broad host range and strong lytic activity and showed preservative quality. Administration of these phages alone caused no adverse effects in the silkworm larvae. Moreover, the viruses showed life-prolonging effects in the silkworm larval infection model 10 min, 6 h, 12 h, and 24 h following infection. Such phage effects in the silkworm larval model were almost paralleled to the therapeutic efficacies in mouse models. These results suggest that phages S25-3 and S13' are eligible as therapeutic candidates and that the silkworm larval model is valid for the evaluation of phage therapy as well as mouse models. PMID:23869440

  3. 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". PMID:25029375

  4. 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

  5. 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.

  6. Dosimetric evaluation of a MOSFET detector for clinical application in photon therapy.

    PubMed

    Kohno, Ryosuke; Hirano, Eriko; Nishio, Teiji; Miyagishi, Tomoko; Goka, Tomonori; Kawashima, Mitsuhiko; Ogino, Takashi

    2008-01-01

    Dosimetric characteristics of a metal oxide-silicon semiconductor field effect transistor (MOSFET) detector are studied with megavoltage photon beams for patient dose verification. The major advantages of this detector are its size, which makes it a point dosimeter, and its ease of use. In order to use the MOSFET detector for dose verification of intensity-modulated radiation therapy (IMRT) and in-vivo dosimetry for radiation therapy, we need to evaluate the dosimetric properties of the MOSFET detector. Therefore, we investigated the reproducibility, dose-rate effect, accumulated-dose effect, angular dependence, and accuracy in tissue-maximum ratio measurements. Then, as it takes about 20 min in actual IMRT for the patient, we evaluated fading effect of MOSFET response. When the MOSFETs were read-out 20 min after irradiation, we observed a fading effect of 0.9% with 0.9% standard error of the mean. Further, we applied the MOSFET to the measurement of small field total scatter factor. The MOSFET for dose measurements of small field sizes was better than the reference pinpoint chamber with vertical direction. In conclusion, we assessed the accuracy, reliability, and usefulness of the MOSFET detector in clinical applications such as pinpoint absolute dosimetry for small fields. PMID:20821164

  7. 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

  8. Retrospective evaluation of cotrimoxazole use as preventive therapy in people living with HIV/AIDS in Boru Meda Hospital

    PubMed Central

    2014-01-01

    Background Drug use evaluation is a performance improvement method that focuses on evaluating and improving drug use process to achieve optimal patient outcomes. Drug use evaluation helps in identifying, preventing or resolving actual and potential drug related problems. The objective of the study was to evaluate the use of cotrimoxazole as preventive therapy in people living with HIV/AIDS in Boru Meda Hospital, Northeast Ethiopia. Methods A retrospective drug use evaluation was conducted on patients’ medical history records based on a validated drug use evaluation criteria according to the national guideline. Medical history records of 248 patients were selected using systematic sampling method. Results The result showed that 49.6% of the patients were at WHO clinical stage III at the start of cotrimoxazole preventive therapy. In this study, the use of cotrimoxazole preventive therapy was consistent with the guideline in the rationale for indication (97.98%), dose (96.77%), and its use despite the presence of contraindications (91.93%). Problems regarding drug-drug interaction were identified in 49.59% of cases, and 20.97% of patients discontinued cotrimoxazole preventive therapy due to different reasons. Conclusions In most patients cotrimoxazole preventive therapy was consistent with the national guideline regarding the rationale for indication, dose, discontinuation and its use in the presence of contraindications. PMID:24507658

  9. 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

  10. Technology evaluation: PRO-542, Progenics Pharmaceuticals inc.

    PubMed

    Mukhtar, M; Parveen, Z; Pomerantz, R J

    2000-12-01

    Progenics's rCD4-IgG2 (PRO-542) is a recombinant fusion protein, which has been developed using the company's Universal Antiviral Binding (UnAB) technology, and is in phase I/II clinical trials for the treatment of human immunodeficiency virus type I (HIV-1) infection [273391]. At the beginning of 1997, Progenics received a Phase II Small Business Innovation Research Program (SBIR) grant from the National Institute of Allergy and Infectious diseases (NIAID) to fund the development of PRO-542 [236048]. A further grant of $2.7 million was awarded in August 1998 for the clinical evaluation of PRO-542 and other anti-HIV therapies [294200]. Progenics is collaborating with the Aaron Diamond AIDS Research Center (ADARC) in New York and the Center for Disease Control and Prevention in Atlanta [178410]. In February 2000, Progenics and Genzyme Transgenics Corp signed an agreement to continue the development of a transgenic source of PRO-542. Genzyme will develop transgenic goats that produce PRO-542 in their milk in exchange for undisclosed fees and milestone payments. Genzyme will supply PRO-542 to Progenics for clinical trials with a possibility for eventual commercial supply [357291]. Following on from this, in October 2000, Progenics received an SBIR grant to fund a two-year project with Genzyme Transgenics into the development of cost-effective methods for the manufacture of PRO-542, by optimization of the production of the drug in the milk of transgenic dairy animals [385982]. In August 2000, Punk, Ziegel & Company predicted that Progenics Pharmaceuticals will become sustainably profitable in 2003 following the launch of PRO-542 and GMK (Progenics Pharmaceuticals) in 2002 [390063]. PMID:11249748

  11. 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.

  12. 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. PMID:22729251

  13. 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

  14. Development and evaluation of polycrystalline cadmium telluride dosimeters for accurate quality assurance in radiation therapy

    NASA Astrophysics Data System (ADS)

    Oh, K.; Han, M.; Kim, K.; Heo, Y.; Moon, C.; Park, S.; Nam, S.

    2016-02-01

    For quality assurance in radiation therapy, several types of dosimeters are used such as ionization chambers, radiographic films, thermo-luminescent dosimeter (TLD), and semiconductor dosimeters. Among them, semiconductor dosimeters are particularly useful for in vivo dosimeters or high dose gradient area such as the penumbra region because they are more sensitive and smaller in size compared to typical dosimeters. In this study, we developed and evaluated Cadmium Telluride (CdTe) dosimeters, one of the most promising semiconductor dosimeters due to their high quantum efficiency and charge collection efficiency. Such CdTe dosimeters include single crystal form and polycrystalline form depending upon the fabrication process. Both types of CdTe dosimeters are commercially available, but only the polycrystalline form is suitable for radiation dosimeters, since it is less affected by volumetric effect and energy dependence. To develop and evaluate polycrystalline CdTe dosimeters, polycrystalline CdTe films were prepared by thermal evaporation. After that, CdTeO3 layer, thin oxide layer, was deposited on top of the CdTe film by RF sputtering to improve charge carrier transport properties and to reduce leakage current. Also, the CdTeO3 layer which acts as a passivation layer help the dosimeter to reduce their sensitivity changes with repeated use due to radiation damage. Finally, the top and bottom electrodes, In/Ti and Pt, were used to have Schottky contact. Subsequently, the electrical properties under high energy photon beams from linear accelerator (LINAC), such as response coincidence, dose linearity, dose rate dependence, reproducibility, and percentage depth dose, were measured to evaluate polycrystalline CdTe dosimeters. In addition, we compared the experimental data of the dosimeter fabricated in this study with those of the silicon diode dosimeter and Thimble ionization chamber which widely used in routine dosimetry system and dose measurements for radiation

  15. 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

  16. Quality-of-life evaluation in an interferon therapy after radical surgery in cutaneous melanoma patients.

    PubMed

    Rataj, Dorota; Jankowiak, Barbara; Krajewska-Kułak, Elzbieta; Van Damme-Ostapowicz, Katarzyna; Nowecki, Zbigniew I; Rutkowski, Piotr; Niczyporuk, Wiaczesław

    2005-01-01

    Melanoma is the fastest growing solid tumor in men and women, and despite accounting for only 4% of skin cancer cases, it accounts for more than 79% of skin cancer-related deaths. The present study was designed to evaluate the impact of interferon (IFN) treatment on patients' quality of life (QOL) after radical surgery of cutaneous melanoma. The tests were carried out in a group of patients treated in the Department of Soft Tissue and Bone Cancer, Institute of Oncology, in Warsaw. The present study included 2 groups of the patients, 110 persons each. One group consisted of patients who had been subjected to radical surgery of cutaneous melanoma, and the other one consisted of 110 patients treated with a supplementary interferon alfa-2b (IFN-alpha-2b) therapy. Data were collected by means of an anonymous QLQ-C30 (version 2.0.) questionnaire elaborated and provided by the European Organisation for Research and Treatment of Cancer. The QLQ-C30 questionnaire consisted of 43 questions. The IFN-alpha-2b treatment significantly affected patients' physical condition, mental health, and social life. The emotional state of the patients was more affected during IFN-alpha-2b treatment. Somatic symptoms were also increased in those patients. The IFN-alpha-2b therapy also significantly affected family and social life. In spite of several adverse effects, the patients assessed their QOL as good. The IFN-alpha-2b treatment is troublesome for the melanoma patients. It is important that the treating physician and nurse should be aware of the 4 major categories of IFN-alpha-2b toxicity: constitutional, neuropsychiatric, hepatic, and hematologic. A number of steps can be taken to minimize the morbidity associated with IFN-alpha-2b therapy, resulting in an improvement in both QOL and patient compliance. PMID:15915059

  17. [Clinical evaluation of pivmecillinam in the maintenance therapy of chronic urinary tract infection (author's transl)].

    PubMed

    Tamaya, T; Tsurusaki, T; Kusanishi, H; Okada, H; Yamamoto, H; Ahara, M; Murakami, A; Takano, N; Obata, T; Shimura, T; Iwasaki, T; Nakata, Y; Futaoka, S; Ohshima, K; Furuta, N; Murakami, T; Ohtani, I; Sugihara, Y; Yuasa, M; Mizunoya, F; Ota, S; Fujita, H; Ueha, I; Katoh, K

    1981-09-01

    In order to evaluate the efficacy and safety of pivmecillinam (melysin tablet, PMPC), PMPC was administered to 78 chronic UTI cases in the field of obstetrics and gynecology (posthysterectomy infection, chronic cystitis, chronic pyelonephritis and etc.). In principle, daily 400 mg of PMPC was administered for 2 weeks. (1) Overall clinical efficacy judged by doctor was evaluated in 78 cases and the result was; excellent in 17, good in 37, fair in 10, poor in 13 and unknown in 1 case with the effectiveness rate of 69.2%. (2) Overall clinical efficacy judged by 'criteria for clinical evaluation in complicated UTI' recommended by UTI study member was evaluated in 54 cases and the result was; excellent in 15, good in 20 and poor in 19 cases with the overall efficacy rate of 64.8%, the result of which was similar to that of doctor's judgement. (3) Efficacy on pyuria was evaluated in 72 cases and it was cleared in 27, decreased in 25, unchanged in 20 and unknown in 6 cases. Efficacy on bacteriuria was evaluated in 72 cases and it was eliminated in 44, decreased in 9, replaced in 8, unchanged in 8 and unknown in 9 cases. (4) Side effect, considered by doctors to be caused by PMPC administration, was noticed in 3 out of 78 cases (3.8%), all of which was mild gastrointestinal disturbance and the administration of PMPC was continued. Abnormal change of laboratory finding considered by doctors to be caused by PMPC administration was noticed in 1 out of 78 cases, which was slight elevation of GOT and GPT values. It is therefore considered that PMPC appear to be useful drug for the maintenance therapy of chronic UTI in the field of obstetrics and gynecology. PMID:6276586

  18. 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

  19. 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

  20. 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

  1. Molecular Imaging Probes for Diagnosis and Therapy Evaluation of Breast Cancer

    PubMed Central

    Meng, Qingqing; Li, Zheng

    2013-01-01

    Breast cancer is a major cause of cancer death in women where early detection and accurate assessment of therapy response can improve clinical outcomes. Molecular imaging, which includes PET, SPECT, MRI, and optical modalities, provides noninvasive means of detecting biological processes and molecular events in vivo. Molecular imaging has the potential to enhance our understanding of breast cancer biology and effects of drug action during both preclinical and clinical phases of drug development. This has led to the identification of many molecular imaging probes for key processes in breast cancer. Hormone receptors, growth factor receptor, and angiogenic factors, such as ER, PR, HER2, and VEGFR, have been adopted as imaging targets to detect and stage the breast cancer and to monitor the treatment efficacy. Receptor imaging probes are usually composed of targeting moiety attached to a signaling component such as a radionuclide that can be detected using dedicated instruments. Current molecular imaging probes involved in breast cancer diagnosis and therapy evaluation are reviewed, and future of molecular imaging for the preclinical and clinical is explained. PMID:23533377

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

    PubMed Central

    Genever, Paul G.; Fagan, Michael J.

    2015-01-01

    Summary 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. © 2015 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd. PMID:26198466

  3. 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.

  4. Project placements for undergraduate occupational therapy students: design, implementation and evaluation.

    PubMed

    Prigg, Alison; Mackenzie, Lynette

    2002-01-01

    This study aimed to document the process undertaken to incorporate project placements as an effective fieldwork option for second- and third-year occupational therapy students, by evaluating the experience of both students and supervisors and identifying areas for improvement. Project placements are full- or part-time placements where a project is completed by a student under the supervision of an occupational therapist. The study is primarily descriptive, and includes a pre-post design using qualitative and quantitative data. The results indicate that the objectives of the study were achieved. Both supervisors and students expressed positive views about the placements. Students also identified changes that could improve the placements. Second- and third-year students gave similar ratings about aspects of the learning experiences during the project placements. The small cohort of third-year students and the low response rate from supervisors limited results. These project placements have shown an applicable model for students in earlier years of the course instead of the usual practice of non-traditional fieldwork being focused on final-year students. The project placements described are presented as one more potential fieldwork model in the range currently offered by curricula worldwide. Future research needs to concentrate on the longitudinal impact of these placements on the developing practice and attitudes of occupational therapy students. PMID:12374998

  5. Evaluation of Antimicrobial Therapy of Blood Culture Positive Healthcare-Associated Infections in Children

    PubMed Central

    Vaara, Martti; Anttila, Veli-Jukka; Hoppu, Kalle; Laaksonen, Raisa; Airaksinen, Marja

    2015-01-01

    Aim Knowledge of the quality of antimicrobial therapy (AMT) used for invasive healthcare-associated infections (HAIs) in paediatrics is scarce. Influence of the final information about the isolated pathogen on the subsequent targeted AMT was investigated in our study. Methods Data on 149 children (0–17 years) with blood culture positive HAIs were collected. The causative microbes under investigation were Staphylococcus aureus, Staphylococcus epidermidis, streptococci, Gram negative rods, and mixed infections were likewise included. For adjusting the antimicrobial regimen, an expert panel evaluated the quality of the targeted AMT and the delay of 72 hours after final microbiology results. AMT was regarded as inappropriate if the pathogen was totally resistant to the used antimicrobials (i) or if the chosen therapy was of not optimal efficacy against the pathogen (ii). Results 17% of the patients received inappropriate AMT. Half of these infections 13/26 (50%) were treated with an antimicrobial to which the isolate was resistant. Three (3/13, 23%) of these patients received antimicrobials which were totally ineffective according to in vitro data. Suboptimal or too broad spectrum AMT was administered to 13/26 (50%) patients. The most common causes of inappropriate use were the use of beta-lactams in oxacillin-resistant Staphylococcus epidermidis infections and vancomycin given in oxacillin-sensitive Staphylococcus aureus infections. Conclusion Approximately 17% of the selected cohort received inappropriate AMT. More attention should be paid to the appropriate use of antimicrobials, and training of prescribers should be urgently provided. PMID:26539831

  6. 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. PMID:24797176

  7. Biological Evaluation of pH-Responsive Polymer-Caged Nanobins for Breast Cancer Therapy

    PubMed Central

    Lee, Sang-Min; Ahn, Richard W.; Chen, Feng; Fought, Angela J.; O'Halloran, Thomas V.; Cryns, Vincent L.; Nguyen, SonBinh T.

    2013-01-01

    A series of doxorubicin-loaded polymer-caged nanobins (PCNDXR) were evaluated in vivo in a murine MDA-MB-231 xenograft model of triple-negative breast cancer. The cross-linked polymer cage in PCNDXR offers protection for the drug payload while serving as a pH-responsive trigger that enhances drug release in the acidic environments commonly seen in solid tumors and endosomes. Varying the degree of cross-linking in the polymer cage allows the surface potential of PCNDXR, and thus the in vivo circulation lifetime of the nanocarriers, to be tuned. Given these design advantages, the present study provides the first in vivo evidence that PCNDXR can effectively inhibit tumor growth in a murine model of breast cancer. Importantly, PCNDXR was well-tolerated by mice, and drug encapsulation attenuated the toxicity of free doxorubicin. Taken together, this study demonstrates the potential utility of the PCN platform in cancer therapy. PMID:20738118

  8. Evaluation of high-dose daptomycin for therapy of experimental Staphylococcus aureus foreign body infection

    PubMed Central

    Schaad, Heinz J; Bento, Manuela; Lew, Daniel P; Vaudaux, Pierre

    2006-01-01

    Background Daptomycin is a novel cyclic lipopeptide whose bactericidal activity is not affected by current antibiotic resistance mechanisms displayed by S. aureus clinical isolates. This study reports the therapeutic activity of high-dose daptomycin compared to standard regimens of oxacillin and vancomycin in a difficult-to-treat, rat tissue cage model of experimental therapy of chronic S. aureus foreign body infection. Methods The methicillin-susceptible S. aureus (MSSA) strain I20 is a clinical isolate from catheter-related sepsis. MICs, MBCs, and time-kill curves of each antibiotic were evaluated as recommended by NCCLS, including supplementation with physiological levels (50 mg/L) of Ca2+ for daptomycin. Two weeks after local infection of subcutaneously implanted tissue cages with MSSA I20, each animal received (i.p.) twice-daily doses of daptomycin, oxacillin, or vancomycin for 7 days, or was left untreated. The reductions of CFU counts in each treatment group were analysed by ANOVA and Newman-Keuls multiple comparisons procedures. Results The MICs and MBCs of daptomycin, oxacillin, or vancomycin for MSSA strain I20 were 0.5 and 1, 0.5 and 1, or 1 and 2 mg/L, respectively. In vitro elimination of strain I20 was more rapid with 8 mg/L of daptomycin compared to oxacillin or vancomycin. Twice-daily administered daptomycin (30 mg/kg), oxacillin (200 mg/kg), or vancomycin (50 mg/kg vancomycin) yielded bactericidal antibiotic levels in infected cage fluids throughout therapy. Before therapy, mean (± SEM) viable counts of strain I20 were 6.68 ± 0.10 log10 CFU/mL of cage fluid (n = 74). After 7 days of therapy, the mean (± SEM) reduction in viable counts of MSSA I20 was 2.62 (± 0.30) log10 CFU/mL in cages (n = 18) of daptomycin-treated rats, exceeding by >2-fold (P < 0.01) the viable count reductions of 0.92 (± 0.23; n = 19) and 0.96 (± 0.24; n = 18) log10 CFU/mL in cages of oxacillin-treated and vancomycin-treated rats, respectively. Viable counts in cage

  9. Evaluation of ferric and ferrous iron therapies in women with iron deficiency anaemia.

    PubMed

    Berber, Ilhami; Diri, Halit; Erkurt, Mehmet Ali; Aydogdu, Ismet; Kaya, Emin; 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

  10. Whole-body dose evaluation with an adaptive treatment planning system for boron neutron capture therapy.

    PubMed

    Takada, Kenta; Kumada, Hiroaki; Isobe, Tomonori; Terunuma, Toshiyuki; Kamizawa, Satoshi; Sakurai, Hideyuki; Sakae, Takeji; Matsumura, Akira

    2015-12-01

    Dose evaluation for out-of-field organs during radiotherapy has gained interest in recent years. A team led by University of Tsukuba is currently implementing a project for advancing boron neutron capture therapy (BNCT), along with a radiation treatment planning system (RTPS). In this study, the authors used the RTPS (the 'Tsukuba-Plan') to evaluate the dose to out-of-field organs during BNCT. Computed tomography images of a whole-body phantom were imported into the RTPS, and a voxel model was constructed for the Monte Carlo calculations, which used the Particle and Heavy Ion Transport Code System. The results indicate that the thoracoabdominal organ dose during BNCT for a brain tumour and maxillary sinus tumour was 50-360 and 120-1160 mGy-Eq, respectively. These calculations required ∼29.6 h of computational time. This system can evaluate the out-of-field organ dose for BNCT irradiation during treatment planning with patient-specific irradiation conditions. PMID:25520378

  11. A model evaluation study for treatment planning of laser-induced thermal therapy.

    PubMed

    Fahrenholtz, Samuel J; Moon, Tim Y; Franco, Michael; Medina, David; Danish, Shabbar; Gowda, Ashok; Shetty, Anil; Maier, Florian; Hazle, John D; Stafford, Roger J; Warburton, Tim; Fuentes, David

    2015-01-01

    A cross-validation analysis evaluating computer model prediction accuracy for a priori planning magnetic resonance-guided laser-induced thermal therapy (MRgLITT) procedures in treating focal diseased brain tissue is presented. Two mathematical models are considered. (1) A spectral element discretisation of the transient Pennes bioheat transfer equation is implemented to predict the laser-induced heating in perfused tissue. (2) A closed-form algorithm for predicting the steady-state heat transfer from a linear superposition of analytic point source heating functions is also considered. Prediction accuracy is retrospectively evaluated via leave-one-out cross-validation (LOOCV). Modelling predictions are quantitatively evaluated in terms of a Dice similarity coefficient (DSC) between the simulated thermal dose and thermal dose information contained within N = 22 MR thermometry datasets. During LOOCV analysis, the transient model's DSC mean and median are 0.7323 and 0.8001 respectively, with 15 of 22 DSC values exceeding the success criterion of DSC ≥ 0.7. The steady-state model's DSC mean and median are 0.6431 and 0.6770 respectively, with 10 of 22 passing. A one-sample, one-sided Wilcoxon signed-rank test indicates that the transient finite element method model achieves the prediction success criteria, DSC ≥ 0.7, at a statistically significant level. PMID:26368014

  12. Preclinical evaluation of dual action intranasal formulation intended for postoperative/cancer associated therapies.

    PubMed

    El-Setouhy, Doaa Ahmed; Ahmed, Sami; Badawi, Alia Abd El-Latif; El-Nabarawi, Mohamed Ahmed; Sallam, Nada

    2015-08-30

    Granisetron hydrochloride is a potent antiemetic yet experiencing first pass metabolism. Ketorolac tromethamine is a potent analgesic NSAID that is known to cause gastrointestinal complications. The purpose of this study is to prepare combined in situ nasal copolymer thermal gel combining both drugs for the management of postoperative and cancer associated nausea, vomiting and pain while avoiding the problems associated with their therapy. In situ gelling nasal formulations with/without different mucoadhesive polymers were prepared and evaluated. Viscosity of different formulations was measured and correlated to in-vitro drug release. Selected formulae were evaluated for in-vivo mucociliary transit time. Based on in-vitro release pattern and mucociliary transit time, the selected formula F4 was evaluated for chemical and thermal anti-nociception activity in rats following intranasal or intraperitoneal administration. Only the intra-nasal administration of the selected formulation F4 showed significant analgesia against chemical nociception during both the early and late phases. Also, intranasal administration of the selected formulation F4 showed significant analgesia against thermal nociception. F4 intranasal formulation may offer higher therapeutic value than oral administration as it may not only avoid granisetron first pass metabolism but may also minimize ketorolac gastrointestinal adverse effects as well. PMID:25917526

  13. 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.

  14. Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy.

    PubMed Central

    Mittereder, N; March, K L; Trapnell, B C

    1996-01-01

    Development of adenovirus vectors as potential therapeutic agents for multiple applications of in vivo human gene therapy has resulted in numerous preclinical and clinical studies. However, lack of standardization of the methods for quantifying the physical concentration and functionally active fraction of virions in these studies has often made comparison between various studies difficult or impossible. This study was therefore carried out to define the variables for quantification of the concentration of adenovirus vectors. The methods for evaluation of total virion concentration included electron microscopy and optical absorbance. The methods for evaluation of the concentration of functional virions included detection of gene transfer (transgene transfer and expression) and the plaque assay on 293 cells. Enumeration of total virion concentration by optical absorbance was found to be a precise procedure, but accuracy was dependent on physical disruption of the virion to eliminate artifacts from light scattering and also on a correct value for the extinction coefficient. Both biological assays for enumerating functional virions were highly dependent on the assay conditions and in particular the time of virion adsorption and adsorption volume. Under optimal conditions, the bioactivity of the vector, defined as the fraction of total virions which leads to detected target cell infection, was determined to be 0.10 in the plaque assay and 0.29 in the gene transfer assay. This difference is most likely due to the fact that detection by gene transfer requires only measurement of levels of transgene expression in the infected cell whereas plaque formation is dependent on a series of biological events of much greater complexity. These results show that the exact conditions for determination of infectious virion concentration and bioactivity of recombinant adenovirus vectors are critical and must be standardized for comparability. These observations may be very useful in

  15. Optimization of Collimator Trajectory in Volumetric Modulated Arc Therapy: Development and Evaluation for Paraspinal SBRT

    SciTech Connect

    Zhang Pengpeng; Happersett, Laura; Yang Yingli; Yamada, Yoshiya; Mageras, Gig; Hunt, Margie

    2010-06-01

    Purpose: To develop a collimator trajectory optimization paradigm for volumetric modulated arc therapy (VMAT) and evaluate this technique in paraspinal stereotactic body radiation therapy (SBRT). Method and Materials: We propose a novel VMAT paradigm, Coll-VMAT, which integrates collimator rotation with synchronized gantry rotation, multileaf collimator (MLC) motion, and dose-rate modulation. At each gantry angle a principal component analysis (PCA) is applied to calculate the primary cord orientation. The collimator angle is then aligned so that MLC travel is parallel to the PCA-derived direction. An in-house VMAT optimization follows the geometry-based collimator trajectory optimization to obtain the optimal MLC position and monitor units (MU) at each gantry angle. A treatment planning study of five paraspinal SBRT patients compared Coll-VMAT to standard VMAT (fixed collimator angle) and static field IMRT plans. Plan evaluation statistics included planning target volume (PTV) V95%, PTV-D95%, cord-D05%, and total beam-on time. Results: Variation of collimator angle in Coll-VMAT plans ranges from 26 deg. to 54 deg., with a median of 40 deg. Patient-averaged PTV V95% (94.6% Coll-VMAT vs. 92.1% VMAT and 93.3% IMRT) and D95% (22.5 Gy vs. 21.4 Gy and 22.0 Gy, respectively) are highest with Coll-VMAT, and cord D05% (9.8 Gy vs. 10.0 Gy and 11.7 Gy) is lowest. Total beam-on time with Coll-VMAT (5,164 MU) is comparable to standard VMAT (4,868 MU) and substantially lower than IMRT (13,283 MU). Conclusion: Collimator trajectory optimization-based VMAT provides an additional degree of freedom that can improve target coverage and cord sparing of paraspinal SBRT plans compared with standard VMAT and IMRT approaches.

  16. Efficacy of combination therapy for systolic blood pressure in patients with severe systolic hypertension: the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study.

    PubMed

    Neutel, Joel M; Smith, David H G; Weber, Michael A; Schofield, Lesley; Purkayastha, Das; Gatlin, Marjorie

    2005-11-01

    Systolic hypertension is predominant among patients over 50 years of age, is a more important cardiovascular risk factor than diastolic blood pressure, and is more difficult to control than diastolic blood pressure. Consequently, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends combination therapy as first-line treatment for patients with stage 2 hypertension. In the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study, 24-hour ambulatory blood pressure monitoring was used to identify patients with systolic hypertension and to determine the impact of 8 weeks of treatment with either amlodipine besylate/benazepril HCl 5/20 mg combination therapy (n=149), amlodipine besylate 5 mg (n=146), or benazepril HCl 20 mg (n=148). Combination therapy was significantly more effective in reducing systolic blood pressure and pulse pressure than either monotherapy (p<0.0001). Significantly greater percentages of patients in the combination group compared with either monotherapy achieved blood pressure control (p<0.0001). Adverse events were low in all three treatment arms, with less peripheral edema in the combination group than in the amlodipine-treated group. The combination of amlodipine besylate/benazepril HCl given to patients with stage 2 systolic hypertension resulted in significantly greater reductions in blood pressure and pulse pressure than those seen with monotherapy and was at least as well tolerated as the separate components. This data supports the recommendation of the JNC 7 for the use of combination therapy in patients with stage 2 hypertension. PMID:16278521

  17. Exposure therapy changes dysfunctional evaluations of somatic symptoms in patients with hypochondriasis (health anxiety). A randomized controlled trial.

    PubMed

    Weck, Florian; Neng, Julia M B; Schwind, Julia; Höfling, Volkmar

    2015-08-01

    Dysfunctional evaluations of somatic symptoms are considered a central factor in maintaining hypochondriasis. The aim of the current study was to investigate whether exposure therapy (ET) without cognitive restructuring is sufficient to change dysfunctional evaluations of somatic symptoms. The current study was based on a randomized controlled trial and compared patients with hypochondriasis (N=73) receiving ET or cognitive therapy (CT) to a wait list (WL) control group. In both the ET and CT groups, dysfunctional symptom evaluations changed significantly compared with the WL group. No differences between the ET and CT groups emerged. The relationship between the treatment condition (active treatment vs. WL) and reductions in health anxiety was mediated by changes in somatic symptom evaluations only in a specific card sorting procedure. We conclude that addressing dysfunctional symptom evaluations is a necessary precondition for the effective treatment of hypochondriasis. However, the results indicate that ET and CT appear to change those processes to a similar degree. PMID:26093823

  18. 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

  19. Structure of an anti-HIV-1 hammerhead ribozyme complex with a 17-mer DNA substrate analog of HIV-1 gag RNA and a mechanism for the cleavage reaction: 750 MHz NMR and computer experiments.

    PubMed

    Ojha, R P; Dhingra, M M; Sarma, M H; Myer, Y P; Setlik, R F; Shibata, M; Kazim, A L; Ornstein, R L; Rein, R; Turner, C J; Sarma, R H

    1997-10-01

    The structure of an anti-HIV-1 ribozyme-DNA abortive substrate complex was investigated by 750 MHz NMR and computer modeling experiments. The ribozyme was a chimeric molecule with 30 residues-18 DNA nucleotides, and 12 RNA residues in the conserved core. The DNA substrate analog had 17 residues. The chimeric ribozyme and the DNA substrate formed a shortened ribozyme-abortive substrate complex of 47 nucleotides with two DNA stems (stems I and III) and a loop consisting of the conserved core residues. Circular dichroism spectra showed that the DNA stems assume A-family conformation at the NMR concentration and a temperature of 15 degrees C, contrary to the conventional wisdom that DNA duplexes in aqueous solution populate entirely in the B-form. It is proposed that the A-family RNA residues at the core expand the A-family initiated at the core into the DNA stems because of the large free energy requirement for the formation of A/B junctions. Assignments of the base H8/H6 protons and H1' of the 47 residues were made by a NOESY walk. In addition to the methyl groups of all T's, the imino resonances of stems I and III and AH2's were assigned from appropriate NOESY walks. The extracted NMR data along with available crystallographic data, were used to derive a structural model of the complex. Stems I and III of the final model displayed a remarkable similarity to the A form of DNA; in stem III, a GC base pair was found to be moving into the floor of the minor groove defined by flanking AT pairs; data suggest the formation of a buckled rhombic structure with the adjacent pair; in addition, the base pair at the interface of stem III and the loop region displayed deformed geometry. The loop with the catalytic core, and the immediate region of the stems displayed conformational multiplicity within the NMR time scale. A catalytic mechanism for ribozyme action based on the derived structure, and consistent with biochemical data in the literature, is proposed. The complex

  20. Evaluation on lung cancer patients' adaptive planning of TomoTherapy utilising radiobiological measures and Planned Adaptive module.

    PubMed

    Su, Fan-Chi; Shi, Chengyu; Mavroidis, Panayiotis; Rassiah-Szegedi, Prema; Papanikolaou, Niko

    2009-01-01

    Adaptive radiation therapy is a promising concept that allows individualised, dynamic treatment planning based on feedback of measurements. The TomoTherapy Planned Adaptive application, integrated to the helical TomoTherapy planning system, enables calculation of actual dose delivered to the patient for each treatment fraction according to the pretreatment megavoltage computed tomography (MVCT) scan and image registration. As a result, new fractionation treatment plans are available if correction is necessary. In order to evaluate therealclinicaleffect,biologicaldoseis preferred to physical dose. A biological parameter, biologically effective uniform dose ([Formula: see text]), has the advantages of not only reporting delivered dose but also facilitating the analysis of dose-response relations, which link radiation dose to the clinical effect. Therefore, in this study, four lung patients' adaptive plans were evaluated using the [Formula: see text] in addition to physical doses estimated from the TomoTherapy Planned Adaptive module. Higher complication-free tumour control probability (P(+))(of about 8%) was observed in patients treated with larger dose-per-fraction by using the [Formula: see text] in addition to the physical dose. Moreover, a significant increase of 13.2% in the P(+) for the adaptive TomoTherapy plan in one of the lung cancer patients was also observed, which indicates the clinical benefit of adaptive TomoTherapy. PMID:20376282

  1. A Nonfucosylated Variant of the anti-HIV-1 Monoclonal Antibody b12 Has Enhanced FcγRIIIa-Mediated Antiviral Activity In Vitro but Does Not Improve Protection against Mucosal SHIV Challenge in Macaques

    PubMed Central

    Moldt, Brian; Shibata-Koyama, Mami; Rakasz, Eva G.; Schultz, Niccole; Kanda, Yutaka; Dunlop, D. Cameron; Finstad, Samantha L.; Jin, Chenggang; Landucci, Gary; Alpert, Michael D.; Dugast, Anne-Sophie; Parren, Paul W. H. I.; Nimmerjahn, Falk; Evans, David T.; Alter, Galit; Forthal, Donald N.; Schmitz, Jörn E.; Iida, Shigeru; Poignard, Pascal; Watkins, David I.

    2012-01-01

    Eliciting neutralizing antibodies is thought to be a key activity of a vaccine against human immunodeficiency virus (HIV). However, a number of studies have suggested that in addition to neutralization, interaction of IgG with Fc gamma receptors (FcγR) may play an important role in antibody-mediated protection. We have previously obtained evidence that the protective activity of the broadly neutralizing human IgG1 anti-HIV monoclonal antibody (MAb) b12 in macaques is diminished in the absence of FcγR binding capacity. To investigate antibody-dependent cellular cytotoxicity (ADCC) as a contributor to FcγR-associated protection, we developed a nonfucosylated variant of b12 (NFb12). We showed that, compared to fully fucosylated (referred to as wild-type in the text) b12, NFb12 had higher affinity for human and rhesus macaque FcγRIIIa and was more efficient in inhibiting viral replication and more effective in killing HIV-infected cells in an ADCC assay. Despite these more potent in vitro antiviral activities, NFb12 did not enhance protection in vivo against repeated low-dose vaginal challenge in the simian-human immunodeficiency virus (SHIV)/macaque model compared to wild-type b12. No difference in protection, viral load, or infection susceptibility was observed between animals given NFb12 and those given fully fucosylated b12, indicating that FcγR-mediated activities distinct from FcγRIIIa-mediated ADCC may be important in the observed protection against SHIV challenge. PMID:22457527

  2. Evaluation of the quality of life of patients with maxillofacial defects after prosthodontic therapy with obturator prostheses.

    PubMed

    Depprich, R; Naujoks, C; Lind, D; Ommerborn, M; Meyer, U; Kübler, N R; Handschel, J

    2011-01-01

    The purpose of this study was to investigate how patients with maxillofacial defects evaluate their quality of life after maxillectomy and prosthodontic therapy with obturator prostheses. 43 patients were included in the study (25 female, 18 male). 31 (72%) patients completed a standardized questionnaire of 143 items and then answered additional questions in a standardized interview. Global quality of life after prosthodontic therapy with obturator prostheses was 64% (±22.9) on average. Functioning of the obturator prosthesis, impairment of ingestion, speech and appearance, the extent of therapy, and the existence of pain had significant impact on the quality of life (p<0.005). Orofacial rehabilitation of patients with maxillofacial defects using obturator prostheses is an appropriate treatment modality. To improve the situation of patients prior to and after maxillectomy sufficient information about the treatment, adequate psychological care and speech therapy should be provided. PMID:20980129

  3. 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

  4. Antibody conjugation approach enhances breadth and potency of neutralization of anti-HIV-1 antibodies and CD4-IgG.

    PubMed

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

    2013-05-01

    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

  5. Use of Mutated Self-Cleaving 2A Peptides as a Molecular Rheostat to Direct Simultaneous Formation of Membrane and Secreted Anti-HIV Immunoglobulins

    PubMed Central

    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. PMID:23209743

  6. [Clinical evaluation of the efficacy of external therapies of traditional Chinese medicine in treatment of cancer pain].

    PubMed

    Zhu, Shi-jie; Jia, Li-qun; Li, Pei-wen

    2011-01-01

    There lack scientific methods for evaluating the treatment of cancer pain with external therapies of traditional Chinese medicine (TCM). The level of clinical study in this field needs to be improved. The authors assert that when external therapies of TCM are applied to treat cancer pain, different types of cancer pain should be distinguished and treatment should be applied according to such a differentiation. Under this framework scientific evaluation can be conducted. The authors also assert that the findings of randomized, blinded and controlled trials should be given particular attention, and it is necessary to include titration of morphine into clinical trails of external therapies for the treatment of cancer pain, not only complying with the three-ladder principle for treating cancer pain suggested by the World Health Organization, but also not influencing the effect evaluation of external therapies of TCM on cancer pain. Patient diaries recording pain were revised as observation indexes. The primary indicator of efficacy was the pain intensity score and the secondary indicators were the equivalent of morphine and the remission rate of pain. The time to onset, remission duration and comparison of assessment of pain influence can mirror the characteristics of external therapies of TCM on cancer pain. PMID:21227027

  7. Structure-activity and cross-resistance evaluations of a series of human immunodeficiency virus type-1-specific compounds related to oxathiin carboxanilide.

    PubMed Central

    Buckheit, R W; Kinjerski, T L; Fliakas-Boltz, V; Russell, J D; Stup, T L; Pallansch, L A; Brouwer, W G; Dao, D C; Harrison, W A; Schultz, R J

    1995-01-01

    A series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide (UC84) were evaluated for activity against the human immunodeficiency virus (HIV) to determine structural requirements for anti-HIV activity. Twenty-seven compounds representative of the more than 400 Uniroyal Chemical Company (UC) compounds were evaluated for structure-activity relationships. Several of the compounds evaluated were highly active, with 50% effective concentrations in the nanomolar range and therapeutic indices of > 1,000. Highly synergistic anti-HIV activity was observed for each compound when used in combination with 3'-azido-3'-deoxythymidine; additive to slightly synergistic interactions were observed with the compounds used in combination with dideoxycytidine. In combination with the NNRTI costatolide, only UC38 synergistically inhibited HIV type 1. Residues in the RT which, when mutated, impart resistance to the virus isolates selected in cell culture, against virus variants with site-directed mutations, and against RTs containing defined single amino acid changes. The mutations included changes in RT amino acids 100, 101, 103, 106, 108, and 181. The results with isolates selected in cell culture indicate that the carboxanilide compounds interact with the RT at two vulnerable sites, selecting UC-resistant virus isolates with the Y-to-C mutation at position 181 (Y181C) or the L100I substitution. A resistant virus isolate containing both Y181C combination with calanolide A, an NNRTI which retains activity against virus with the single Y181C mutation, UC10 rapidly selected a virus isolate with the K103N mutation. The merits of selecting potential candidate anti-HIV agents to be used in rational combination drugs design as part of an armamentarium of highly active anti-HIV compounds are discussed. PMID:8593008

  8. 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

  9. First clinical evaluation of an atrial haemodynamic sensor lead for automatic optimization of cardiac resynchronization therapy

    PubMed Central

    Duncker, David; Delnoy, Peter Paul; Nägele, Herbert; Mansourati, Jacques; Mont, Lluís; Anselme, Frédéric; Stengel, Petra; Anselmi, Francesca; Oswald, Hanno; Leclercq, Christophe

    2016-01-01

    Aims One option to improve cardiac resynchronization therapy (CRT) responder rates lies in the optimization of pacing intervals. A haemodynamic sensor embedded in the SonRtip atrial lead measures cardiac contractility and provides a systematic automatic atrioventricular and interventricular delays optimization. This multi-centre study evaluated the safety and performance of the lead, up to 1 year. Methods and results A total of 99 patients were implanted with the system composed of the lead and a CRT-Defibrillator device. Patients were followed at 1, 3, 6, and 12 months post-implant. The primary safety objective was to demonstrate that the atrial lead complication free rate was superior to 90% at 3-months follow-up visit. A lead handling questionnaire was filled by implanting investigators. Lead electrical performances and the performance of the system to compute AV and VV delays were evaluated at each study visit over 1 year. The complication free rate at 3 months post-implant was 99.0% [95%CI 94.5–100.0%], P < 0.001. Electrical performances of the lead were adequate whatever the atrial lead position and remained stable over the study period. The optimization algorithm was able to compute AV and VV delays in 97% of patients, during >75% of the weeks. Conclusion The atrial lead is safe to implant and shows stable electrical performance over time. It therefore offers a promising tool for automatic CRT optimization to further improve responder rates to CRT. PMID:25976907

  10. Formulation Design and Development of a Unani Transdermal Patch for Antiemetic Therapy and Its Pharmaceutical Evaluation.

    PubMed

    Saleem, Mohd Nauman; Idris, Mohammad

    2016-01-01

    The Transdermal Drug Delivery System (TDDS) is one of the novel routes for systemic delivery of drugs through intact skin. A transdermal patch (TP) is a medicated patch that is placed on skin for delivery of medication through skin into the blood stream. The aim of present study was to formulate and evaluate a Unani transdermal patch that could be used for antiemetic therapy. The incorporation of Unani ingredients, namely, Khardal (Brassica nigra), Zanjabeel (Zingiber officinale), Podina (Mentha arvensis), and Sirka (Vinegar) were envisaged. The TP was prepared by solvent evaporation technique and was evaluated for organoleptic characteristics and other physicochemical properties, such as thickness, weight uniformity, folding endurance, moisture content, drug content, and tolerability and acceptability of patch. The in vitro permeation study of the patch was carried out through Franz diffusion cell using egg shell membrane as barrier membrane. Phosphate buffer pH 7.4 was used as dissolution medium and the temperature was maintained at 37 ± 1°C. The in vitro permeation study of the prepared TP indicated a time dependent increase in drug release throughout the study. The percentage of cumulative drug release was found to be 77.38% in 24 hours. The study shows a new approach to work in Unani pharmaceutics. PMID:27403377

  11. Evaluating an oncology systemic therapy computerized physician order entry system using international guidelines.

    PubMed

    Gandhi, Sonal; Tyono, Ivan; Pasetka, Mark; Trudeau, Maureen

    2014-03-01

    Chemotherapy is prone to medication error resulting from complexities in ordering and administration. Computerized physician order entry (CPOE) has been established as an important tool to minimize such errors and hence improve patient safety. As a leading Canadian advisory body in oncology, Cancer Care Ontario (CCO) has been a champion in developing and implementing its own cancer systemic therapy CPOE, the Oncology Patient Information System (OPIS). This article reviews and consolidates principles for oncology CPOE systems as found in the literature and in guidelines created by three international oncology organizations (American Society of Clinical Oncology, Clinical Oncological Society of Australia, and CCO). It then evaluates OPIS by these standards and provides a working example of what a cancer CPOE system should look like. This document can therefore be used as a framework to help develop and evaluate cancer CPOE platforms in different national settings. As end users, oncologists are considered key stakeholders in developing such systems and thus should be well informed about CPOE principles to help make decisions on the appropriate implementation of these platforms in their local practice settings. In addition, oncologists are also important champions for the successful uptake of oncology CPOE platforms and would benefit from a better understanding of whether proposed or existing local CPOE systems meet established standards. PMID:24254406

  12. Formulation and evaluation of drug-loaded targeted magnetic microspheres for cancer therapy

    PubMed Central

    Enriquez, Gerald G; Rizvi, Syed AA; D’Souza, Martin J; Do, Duc P

    2013-01-01

    Enhanced and targeted drug delivery using biodegradable microspheres is emerging as a promising approach for cancer therapy. The main objective of the present research was to formulate, characterize, and evaluate iron oxide (magnetic) containing a bovine serum albumin-based microsphere drug delivery system, capable of efficiently delivering sulforaphane, a histone deacetylase inhibitor, for an extended period of time in vivo. Magnetic microspheres were prepared by spray-drying and characterized for their physicochemical properties and dissolution profile. Further, they were evaluated for therapeutic efficacy in in vitro and in vivo systems. In vitro studies in B16 melanoma cells revealed that there was about 13%–16% more inhibition of cell viability when either 30 μM or 50 μM of sulforaphane was used with iron oxide in the polymeric carrier. Data from in vivo studies in C57BL/6 mice revealed that the magnetic microspheres (localized to the tumor site with the help of a strong magnet) inhibited 18% more tumor growth as compared with sulforaphane in solution. In addition, there was a 40% reduction in histone deacetylation levels in mice treated with iron oxide microspheres containing sulforaphane. Thus, magnetic microspheres are shown to be an effective drug delivery system for anticancer drugs. PMID:23630421

  13. Developments and strategies for inhaled antibiotic drugs in tuberculosis therapy: a critical evaluation.

    PubMed

    Hoppentocht, M; Hagedoorn, P; Frijlink, H W; de Boer, A H

    2014-01-01

    Inhaled antibiotics have been a valuable tool in treating pulmonary infections in cystic fibrosis patients for decades, and the pulmonary route is now becoming increasingly interesting for other infectious diseases like tuberculosis too. Especially with multidrug and extensively drug-resistant tuberculosis emerging, great effort is put into the improvement of pulmonary antibiotic administration to fight this global threat. Several reviews have been written on inhalable antibiotics, giving clear overviews of the compounds of interest. Furthermore, various formulation studies and administration strategies are on-going with these compounds. What is often missing is a critical evaluation of these developments. Several risks may be involved varying from obtaining insufficient local drug concentrations to adverse side effects and unwanted changes in physiological processes from the excipients used. In this manuscript, the pros and cons and feasibility of recent advances in pulmonary antibiotic tuberculosis therapy are presented and critically evaluated. Furthermore, the advantages of dry powder inhalation over wet nebulisation for inhaled antibiotics in developing countries where prevalence of tuberculosis is highest are discussed. It has to be concluded that a greater effort in good inhaler development and more research in the physico-chemical properties of the compounds of interest are needed. PMID:24189498

  14. An Evaluation of Trauma Focused Cognitive Behavioral Therapy for Children in Zambia

    PubMed Central

    Murray, Laura K; Familiar, Itziar; Skavenski, Stephanie; Jere, Elizabeth; Cohen, Judy; Imasiku, Mwiya; Mayeya, John; Bass, Judith K; Bolton, Paul

    2013-01-01

    Objectives To monitor and evaluate the feasibility of implementing Trauma Focused-Cognitive Behavioral Therapy (TF-CBT) to address trauma and stress-related symptoms in orphans and vulnerable children (OVC) in Zambia as part of ongoing programming within a non-governmental organization (NGO). Methods As part of ongoing programming, voluntary care-workers administered locally validated assessments to identify children who met criteria for moderate to severe trauma symptomatology. Local lay counselors implemented TF-CBT with identified families, while participating in ongoing supervision. Fifty-eight children and adolescents aged 5–18 completed the TF-CBT treatment, with pre- and post-assessments. Results The mean number of traumas reported by the treatment completers (N=58) was 4.11. Post assessments showed significant reductions in severity of trauma symptoms (p<0.0001), and severity of shame symptoms (p<0.0001). Conclusions Our results suggest that TF-CBT is a feasible treatment option in Zambia for OVC. A decrease in symptoms suggests that a controlled trial is warranted. Implementation factors monitored suggest that it is feasible to integrate and evaluate evidence-based mental health assessments and intervention into programmatic services run by an NGO in low/middle resource countries. Results also support the effectiveness of implementation strategies such as task shifting, and the apprenticeship model of training and supervision. PMID:23768939

  15. Synthesis and Biological Evaluation of 2-Thioxopyrimidin-4(1H)-one Derivatives as Potential Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

    PubMed Central

    Khalifa, Nagy M.; Al-Omar, Mohamed A.

    2014-01-01

    A series of new 5-allyl-6-benzylpyrimidin-4(3H)-ones bearing different substituents at the C-2 position of the pyrimidine core have been synthesized and evaluated for their in vitro activities against human immunodeficiency virus type 1 (HIV-1) in the human T-lymphotropic type (MT-4 cell cultures). The majority of the title compounds showed moderate to good activities against HIV-1. Amongst them, 5-allyl-6-benzyl-2-(3-hydroxypropylthio)pyrimidin-4(3H)-one analogue 11c exhibited the most potent anti-HIV-1 activity (IC50 0.32 µM). The biological testing results clearly indicated that the substitution at C-2 position of the pyrimidine ring could increase the anti-HIV-1 reverse transcriptase (RT) activity. PMID:25397597

  16. Evaluation of Cynanchum otophyllum glucan sulfate against human immunodeficiency virus and herpes simplex virus as a microbicide agent

    PubMed Central

    Tao, Jian; Yang, Jing; Chen, Chaoyin; Cao, Xiaomei; Zhao, Shenglan; Ben, Kunlong

    2011-01-01

    Objective: The root of Cynanchum otophyllum—also known as Qing Yang Sheng—is a traditional ethnical Chinese medicine. The objective of this study was to evaluate in vitro activities and safety of C. otophyllum glucan sulfate (PS20) against Human Immunodeficiency Virus (HIV) and Herpes Simplex Virus (HSV). Materials and Methods: Anti-HIV activity was detected with syncytial formation assay and quantitative P24 Enzyme-Linked Immunosorbent Assay (ELISA). Anti-HSV activity was detected with plaque reduction assay; cytotoxicity was tested with MTT colorimetric assay; and anti-bacterial activity was tested with microdilution method. Anti-HIV mechanism was investigated with fusion inhibition, time of addition, and pretreatment. Results: The 50% Inhibition Concentration (IC50) of PS20 for HIV-1IIIB, HIV-Ada-M, HIV-1Bal, HSV-I, and -II were 0.26 ± 0.02 mM, 0.46 ± 0.02 mM, 0.90 ± 0.04 mM, 3.45 ± 0.85 μM, and 0.70 ± 0.22 mM, respectively. Selectivity Indices (SI) were 653, 50, 39, 85, and 362, respectively. Studies on anti-HIV mechanism of PS20 showed that the target molecule should be the envelope protein. The 50% Cytotoxicity Concentrations (CC50) of PS20 for HeLa and ME-180 cell lines and human foreskin fibroblast cells was more than 70 μM. The Minimum Inhibitory Concentration (MIC) for vaginal lactobacilli was more than 1000 μM. Conclusion: PS20 possesses anti-HIV and HSV effect and low cytotoxicity to epithelium cells and vaginal lactobacilli. It may be considered as a potential microbicide agent for further investigation. PMID:22021996

  17. Simplified negative pressure wound therapy: clinical evaluation of an ultraportable, no-canister system.

    PubMed

    Hudson, Donald A; Adams, Kevin G; Van Huyssteen, Adriaan; Martin, Robin; Huddleston, Elizabeth M

    2015-04-01

    The aim of this study was to evaluate a prototype negative pressure wound therapy (NPWT) system that has been developed to simplify NPWT for wounds at the lower end of the acuity scale. The new device has a single preset pressure of -80 mmHg, is single use and operates without an exudate canister. The disposable NPWT system (PICO™) was tested in a prospective, non-comparative, multicentre clinical trial to assess device functionality and clinical acceptance. Twenty patients were recruited for a maximum treatment period of 14 days. The NPWT devices were fitted with data log chips to enable longitudinal assessment of negative pressure and leak rates during therapy. Sixteen (80%) patients had closed surgical wounds, two (10%) patients had traumatic wounds and two (10%) patients received meshed split thickness skin grafts. The mean study duration was 10·7 days (range: 5-14 days) and the mean dressing wear time per individual patient was 4·6 days (range: 2-11). Fifty-five percent of wounds had closed by the end of the 14-day study or earlier, with a further 40% of wounds progressing to closure. Real-time pressure monitoring showed continuous delivery of NPWT. Three cases are discussed representing different wound locations and different patient factors that can increase the risk of post-surgical complications. Clinical studies of the disposable NPWT system confirmed the ability of the simplified single-use device to function consistently over the expected wear time. The anticipated reduced costs, ease of use and increased mobility of patients using this system may enable NPWT benefits to be available to a greater proportion of patients. PMID:23647737

  18. Evaluation of a commercially-available block for spatially fractionated radiation therapy.

    PubMed

    Buckey, Courtney; Stathakis, Sotirios; Cashon, Ken; Gutierrez, Alonso; Esquivel, Carlos; Shi, Chengyu; Papanikolaou, Nikos

    2010-01-01

    In this paper, we present the dosimetric characteristics of a commercially-produced universal GRID block for spatially fractioned radiation therapy. The dosimetric properties of the GRID block were evaluated. Ionization chamber and film measurements using both Kodak EDR2 and Gafchromic EBT film were performed in a solid water phantom to determine the relative output of the GRID block as well as its spatial dosimetric characteristics. The surface dose under the block and at the openings was measured using ultra thin TLDs. After introducing the GRID block into the treatment planning system, a treatment plan was created using the GRID block and also by creating a GRID pattern using the multi-leaf collimator. The percent depth doses measured with film showed that there is a shift of the dmax towards shallower depths for both energies (6 MV and 18 MV) under investigation. It was observed that the skin dose at the GRID openings was higher than the corresponding open field by a factor as high as 50% for both photon energies. The profiles showed the transmission under the block was in the order of 15-20% for 6 MV and 30% for 18 MV. The MUs calculated for a real patient using the block were about 80% less than the corresponding MUs for the same plan using the multileaf collimator to define the GRID. Based on this investigation, this brass GRID compensator is a viable alternative to other solid compensators or MLC-based fields currently in use. Its ease of creation and use give it decided advantages. Its ability to be created once and used for multiple patients (by varying the collimation of the linear accelerator jaws) makes it attractive from a cost perspective. We believe this compensator can be put to clinical use, and will allow more centers to offer GRID therapy to their patients. PMID:20717082

  19. 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. PMID:26052072

  20. 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

  1. Development and evaluation of oxaliplatin and irinotecan co-loaded liposomes for enhanced colorectal cancer therapy.

    PubMed

    Zhang, Bo; Wang, Tianqi; Yang, Shaomei; Xiao, Yanan; Song, Yunmei; Zhang, Na; Garg, Sanjay

    2016-09-28

    Drug combinations are widely employed in chemotherapy for colorectal cancer treatment. However, traditional cocktail combination in clinic causes the uncertainty of the treatment, owing to varying pharmacokinetics of different drugs. The aim of this study was to design co-loaded liposomes to achieve the synchronised delivery and release. Oxaliplatin and irinotecan hydrochloride, as one of recommended combination schemes for the treatment of colorectal cancer in clinic, were co-loaded into the liposomes. The particle sizes of the liposomes were <200nm with uniform size distribution. In vitro release study showed that both drugs could be synchronously released from the liposomes, which means the optimized synergistic ratio of two drugs could be achieved. In vitro cellular uptake revealed that co-loaded liposomes could efficiently deliver different drugs into the same cells, indicating their potential as carriers for enhancing the cancer therapy. CLSM images of cryo-sections for in vivo co-delivery study also revealed that co-loaded liposomes had superior ability to co-deliver both the cargoes into the same tumor cells. Besides, in vivo NIRF imaging indicated that the liposomes could increase the drug accumulation in tumor compared with free drug. In vitro cytotoxicity evaluation demonstrated that co-loaded liposomes exhibited higher cytotoxicity than the mixture of single loaded liposomes in both CT-26 and HCT-116 cells. Furthermore, co-loaded liposomes also presented superior anti-tumor activity in CT-26 bearing BALB/c mice. In vivo safety assessment demonstrated that liposomes had lower toxicities than their solution formulations. These results indicated that oxaliplatin and irinotecan hydrochloride co-loaded liposomes would be an efficient formulation for improving colorectal cancer therapy with potential clinical applications. PMID:27432750

  2. Four-week histologic evaluation of grafted calvarial defects with adjunctive hyperbaric oxygen therapy in rats

    PubMed Central

    2016-01-01

    Purpose The aim of this study was to characterize the healing in the grafted calvarial defects of rats after adjunctive hyperbaric oxygen therapy. Methods Twenty-eight male Sprague-Dawley rats (body weight, 250–300 g) were randomly divided into two treatment groups: with hyperbaric oxygen therapy (HBO; n=14) and without HBO (NHBO; n=14). Each group was further subdivided according to the bone substitute applied: biphasic calcium phosphate (BCP; n=7) and surface-modified BCP (mBCP; n=7). The mBCP comprised BCP coated with Escherichia-coli-derived recombinant human bone morphogenetic protein-2 (ErhBMP-2) and epigallocatechin-3-gallate (EGCG). Two symmetrical circular defects (6-mm diameter) were created in the right and left parietal bones of each animal. One defect was assigned as a control defect and received no bone substitute, while the other defect was filled with either BCP or mBCP. The animals were allowed to heal for 4 weeks, during which those in the HBO group underwent 5 sessions of HBO. At 4 weeks, the animals were sacrificed, and the defects were harvested for histologic and histomorphometric analysis. Results Well-maintained space was found in the grafted groups. Woven bone connected to and away from the defect margin was formed. More angiogenesis was found with HBO and EGCG/BMP-2 (P<0.05). None of the defects achieved complete defect closure. Increased new bone formation with HBO or EGCG/BMP-2 was evident in histologic evaluation, but it did not reach statistical significance in histometric analysis. A synergic effect between HBO and EGCG/BMP-2 was not found. Conclusions Within the limitations of this study, the present findings indicate that adjunctive HBO and EGCG/BMP-2 could be beneficial for new bone formation in rat calvarial defects. PMID:27588214

  3. Evaluation of L-thyroxine replacement therapy in children with congenital hypothyroidism.

    PubMed

    Chiovato, L; Giusti, L; Tonacchera, M; Ciampi, M; Mammoli, C; Lippi, F; Lapi, P; Bargagna, S; Dini, P; Ferretti, G

    1991-12-01

    The outcome of L-thyroxine (L-T4) replacement therapy in children with congenital hypothyroidism (CH) remains to be completely evaluated. In this paper the overall pattern of response to L-T4 replacement therapy was studied in a group of 19 children with CH diagnosed by neonatal screening (10 with hypoplastic/aplastic thyroid disease, group H/A; 9 with gland ectopy, group E) who were followed-up for 60 +/- 27 months (mean +/- SD). With 1 exception serum T4 at diagnosis was greater than 2 micrograms/dl in children of group E and less than 2 micrograms/dl in those of group H/A. The initial dose of L-T4 (8-10 micrograms/kg BW/day) was modified in relation to age and weight in order to maintain serum TSH less than or equal to 5 microU/ml and FT3 in the normal range. A general inverse correlation between serum TSH and FT4 or FT3 concentrations was found, and the mean levels of serum FT4 and FT3 were significantly higher according to the following order of TSH results: low TSH (0-0.5 microU/ml) greater than normal (greater than 0.5-5 microU/ml) greater than elevated TSH (greater than 5 microU/ml). TSH levels less than or equal to 5 microU/ml were associated with FT4 values in the upper half of the normal range (54% of observations) or even higher (46%). Elevation of serum FT4 alone with FT3 values in the normal range did not result in clinical thyrotoxicosis, alteration of growth or premature craniosynostosis.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1806614

  4. 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.

  5. Evaluation of electrical stimulation for ischemic wound therapy: a feasibility study using the lapine wound model.

    PubMed

    Morris, Kimberly A; McGee, Michael F; Jasper, John J; Bogie, Kath M

    2009-04-01

    Chronic wounds are a major secondary complication for many people with impaired mobility. Electrical stimulation (ES) has been recommended as a adjunctive therapy, however optimal treatment paradigms have not been established. Our group seeks to determine the basic mechanisms underlying ES wound therapy, an area where understanding is currently limited. A feasibility study was carried out to develop the Ahn/Mustoe lapine wound model for systematic investigation of the effects of electrical stimulation on ischemic wound therapy. A standardized surgical procedure incorporated a hybrid stimulation system comprising an implantable mini-stimulator and surface electrodes, with creation of repeatable ischemic wounds. Twenty mature male New Zealand white rabbits (3 kg weight) were employed to evaluate the effects of two empirically selected stimulation paradigms applied continuously for 7-21 days, using each animal as its own control. Outcomes measures included transcutaneous blood gas levels, histology, total RNA content and analysis of alpha2 (I) collagen (COL-I), type IV collagen (COL-IV), alpha1 (V) collagen (COL-V), and vascular endothelial growth factor (VEGF) expression using real-time quantitative PCR. All markers for stimulated wounds showed increased activity relative to non-stimulated control wounds between 7 and 14 days following injury, with peak activity at 14 days. By 21 days post-injury, all activity had returned to near baseline level. VEGF and COL-IV levels were found to be significantly higher for pattern A (110 mus pulse width) compared to pattern B (5 mus pulse width) at 14 days, implying that pattern A may be more effective at promoting angiogenesis. All wounds were fully re-epithelialized by 10 days post-injury. Both COL-I and COL-V showed statistically significant (P < 0.05) increased activity between day 7 and day 14 for pattern A, potentially indicating a continued effect on matrix remodeling. The early closure of all wounds implies that the

  6. 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

  7. Experimental re-evaluation of flunarizine as add-on antiepileptic therapy

    PubMed Central

    Thakur, Anamika; Sahai, A. K.; Thakur, J. S.

    2011-01-01

    Background: Experimental studies have found several calcium channel blockers with anticonvulsant property. Flunarizine is one of the most potent calcium channel blockers, which has shown anticonvulsant effect against pentylenetetrazole (PTZ) and maximal electroshock (MES)-induced seizures. However, further experimental and clinical trials have shown varied results. We conducted a PTZ model experimental study to re-evaluate the potential of flunarizine for add-on therapy in the management of refractory epilepsy. Materials and Methods: Experiments were conducted in PTZ model involving Swiss strain mice. Doses producing seizures in 50% and 99% mice, i.e. CD50 and CD99 values of PTZ were obtained from the dose-response study. Animals received graded, single dose of sodium valproate (100–300 mg/kg), lamotrigine (3–12 mg/kg) and flunarizine (5–20 mg/kg), and then each group of mice was injected with CD99 dose of PTZ (65mg/kg i.p.). Another group of mice received single ED50 dose (dose producing seizure protection in 50% mice) of sodium valproate and flunarizine separately in left and right side of abdomen. Results were analysed by Kruskal–Wallis ANOVA on Ranks test. Results: As compared to control, sodium valproate at 250 mg/kg and 300 mg/kg produced statistical significant seizure protection. At none of the pre-treatment dose levels of lamotrigine, the seizure score with PTZ differed significantly from that observed in the vehicle-treated group. Pre-treatment with flunarizine demonstrated dose-dependent decrease in the seizure score to PTZ administration. As compared to control group, flunarizine at 20 mg/kg produced statistical significant seizure protection. Conclusion: As combined use of sodium valproate and flunarizine has shown significant seizure protection in PTZ model, flunarizine has a potential for add-on therapy in refractory cases of partial seizures. It is therefore, we conclude that further experimental studies and multicenter clinical trials

  8. 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

  9. 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

  10. 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

  11. Three-dimensional cell culturing by magnetic levitation for evaluating efficacy/toxicity of photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Sabino, Luis G.; Menezes, Priscila F. C.; Bagnato, Vanderlei S.; Souza, Glauco; Killian, Thomas C.; Kurachi, Cristina

    2014-03-01

    We used three dimensional cell cultures (3D) based on the magnetic levitation method (MLM) to evaluate cytotoxicity of photodynamic therapy (PDT). First, we decorated Hep G2 and MDA-MB-321 cells with NanoShuttle by introducing it in the media and incubated overnight. Next day, we transferred the cells to a 6-well plate and placed a magnetic driver on the top of the plate to start levitation. We monitored the formation of the 3D cell culture by optical microscopy and after four days, we added the photosensitizer Photogem (PG) in the culture media in concentrations of 50, 25, 12.5, 6.25μg/ml. We incubated them for 24 hours, after that we washed the cultures with PBS and added fresh media. Samples were then illuminated for 600s using a 630nm LED-based device, generating light intensities of 30 mW/cm2 in a total light fluence of 18 J/cm2. Following the illumination, we added fresh media, and 30 hours later, the 3D structures were broken using a pipettor and the cells seeded in 96 well plates, 105 cells per well, with a magnetic drive placed on the bottom of the plate to create cell culture dots. After 24 hours, we used a MTT assay to evaluate PDT cytotoxicity. The PDT effect, evaluated by the half maximal effective concentration (EC50), in MDA-MB-231 cells (EC50 =3.14 μg/ml) is more aggressive compared to the effect of PDT in Hep G2 cells (EC50 = 7.48 μg/ml). It suggests that the cell culture structure and its interaction facilitated the PG uptake and consequently elevated the Photodynamic effect for MDA-MB-231.

  12. 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.

  13. 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...

  14. 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…

  15. Accuracy and cost-benefit of pooled versus singleton screening blood donations for anti-HIV: impact on different blood bank set-ups.

    PubMed

    Novack, Lena; Pliskin, Joseph S; Shinar, Eilat; Safi, Jamal; Sarov, Batia

    2006-10-01

    This study evaluates the accuracy and cost-benefit of implementing a pooled screening procedure in blood banks in general and especially in developing countries. The sensitivity of pooled testing was found to be relatively high, with the lowest levels estimated at about 98% for pools consisting of three, six, and 12 samples. Screening in pools of up to 12 samples is expected to be economically beneficial in countries with HIV prevalence rates of 8-10%, which cannot afford the cost of care for an HIV-infected patient. PMID:17034705

  16. 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

  17. Preclinical In Vivo Evaluation of Npe6-Mediated Photodynamic Therapy on Normal Vasculature

    PubMed Central

    Moy, Wesley J.; Patel, Shreyas J.; Lertsakdadet, Ben S.; Arora, Rajan P.; Nielsen, Katherine M.; Kelly, Kristen M.; Choi, Bernard

    2012-01-01

    Background and Objective Current treatments of port-wine stain birthmarks typically involve use of a pulsed dye laser (PDL) combined with cooling of the skin. Currently, PDL therapy protocols result in varied success, as some patients experience complete blanching, while others do not. Over the past decade, we have studied the use of photodynamic therapy (PDT) as either a replacement or adjuvant treatment option to photocoagulate both small and large vasculature. The objective of the current study was to evaluate a PDT protocol that involves use of an alternate intravascular photosensitizer mono-L-aspartylchlorin-e6 (NPe6) activated by an array of low-cost light emitting diodes. Study Design/Materials and Methods To monitor the microvasculature, a dorsal window chamber model was installed on 22 adult male mice. The light source consisted of a custom-built LED array that emitted 10 W at a center wavelength of 664 nm (FWHM = 20 nm). The light source was positioned at a fixed distance from the window chamber to achieve a fixed irradiance of 127 mW/cm2. A retroorbital injection of NPe6 (5 mg/kg) was performed to deliver the drug into the bloodstream. Laser irradiation was initiated immediately after injection. To monitor blood-flow dynamics in response to PDT, we used laser speckle imaging. We employed a dose–response experimental design to evaluate the efficacy of NPe6-mediated PDT. Results We observed three general hemodynamic responses to PDT: (1) At low radiant exposures, we did not observe any persistent vascular shutdown; (2) at intermediate radiant exposures, we observed an acute decrease in blood flow followed by gradual restoration of blood flow over the 7-day monitoring period; and (3) at high radiant exposures, we observed acute vascular shutdown that persisted during the entire 7-day monitoring period. Dose–response analysis enabled identification of 85 J/cm2 as a characteristic radiant exposure required to achieve persistent vascular shutdown at Day 7

  18. A multicenter evaluation of oral pressure therapy for the treatment of obstructive sleep apnea

    PubMed Central

    Colrain, Ian M.; Black, Jed; Siegel, Lawrence C.; Bogan, Richard K.; Becker, Philip M.; Farid-Moayer, Mehran; Goldberg, Rochelle; Lankford, D. Alan; Goldberg, Andrew N.; Malhotra, Atul

    2013-01-01

    Objective We aimed to evaluate the impact of a novel noninvasive oral pressure therapy (OPT) (Winx®, ApniCure) system on polysomnographic measures of sleep-disordered breathing, sleep architecture, and sleep stability in obstructive sleep apnea (OSA). Subjects and methods A 4-week, multicenter, prospective, open-label, randomized, crossover, first-night order of control vs treatment, single-arm trial was conducted in five American Academy of Sleep Medicine (AASM) – accredited sleep clinics and one research laboratory. Sixty-three subjects (analysis cohort) were studied from a screening cohort of 367 subjects. The analysis cohort was 69.8% men, ages 53.6 ± 8.9 years (mean ± SD), body mass index of 32.3 ± 4.5 kg/m2, with mild to severe OSA. At treatment initiation, subjects received random assignment to one night with and one without (control) treatment, and they were assessed again following 28 nights of treatment. Breathing and sleep architecture were assessed each night based on blind scoring by a single centralized scorer using AASM criteria. Results Average nightly usage across the take-home period was 6.0 ± 1.4 h. There were no severe or serious device-related adverse events (AEs). Median apnea–hypopnea index (AHI) was 27.5 events per hour on the control night, 13.4 events per hour on the first treatment night, and 14.8 events per hour after 28 days of treatment. A clinically significant response (treatment AHI ≤10/h and ≤50% of control values) was seen in 20 of the 63 subjects evaluated. Rapid eye movement percentage (REM%) was significantly increased, and N1%, stage shifts to N1 sleep, overall stage shifts, total awakenings, and arousals per hour were all significantly reduced at both treatment nights compared to controls. Mean Epworth sleepiness scale (ESS) was significantly reduced from 12.1 to 8.6 (Cohen d effect size, 0.68) in those untreated for two or more weeks prior to OPT study participation and remained unchanged in subjects who

  19. 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

  20. Endogenous MCM7 MicroRNA Cluster as a Novel Platform to Multiplex Small Interfering and Nucleolar RNAs for Combinational HIV-1 Gene Therapy

    PubMed Central

    Chung, Janet; Zhang, Jane; Li, Haitang; Ouellet, Dominique L.; DiGiusto, David L.

    2012-01-01

    Abstract Combinational therapy with small RNA inhibitory agents against multiple viral targets allows efficient inhibition of viral production by controlling gene expression at critical time points. Here we explore combinations of different classes of therapeutic anti-HIV-1 RNAs expressed from within the context of an intronic MCM7 (minichromosome maintenance complex component-7) platform that naturally harbors 3 microRNAs (miRNAs). We replaced the endogenous miRNAs with anti-HIV small RNAs, including small interfering RNAs (siRNAs) targeting HIV-1 tat and rev messages that function to induce post-transcriptional gene silencing by the RNA interference pathway, a nucleolar-localizing RNA ribozyme that targets the conserved U5 region of HIV-1 transcripts for degradation, and finally nucleolar trans-activation response (TAR) and Rev-binding element (RBE) RNA decoys designed to sequester HIV-1 Tat and Rev proteins inside the nucleolus. We demonstrate the versatility of the MCM7 platform in expressing and efficiently processing the siRNAs as miRNA mimics along with nucleolar small RNAs. Furthermore, three of the combinatorial constructs tested potently suppressed viral replication during a 1-month HIV challenge, with greater than 5-log inhibition compared with untransduced, HIV-1-infected CEM T lymphocytes. One of the most effective constructs contains an anti-HIV siRNA combined with a nucleolar-localizing U5 ribozyme and TAR decoy. This represents the first efficacious example of combining Drosha-processed siRNAs with small nucleolar ribonucleoprotein (snoRNP)-processed nucleolar RNA chimeras from a single intron platform for effective inhibition of viral replication. Moreover, we demonstrated enrichment/selection for cells expressing levels of the antiviral RNAs that provide optimal inhibition under the selective pressure of HIV. The combinations of si/snoRNAs represent a new paradigm for combinatorial RNA-based gene therapy applications. PMID:22834872

  1. MR defecography: a diagnostic test for the evaluation of pelvic floor motion in patients with dyssynergic defecation after biofeedback therapy

    PubMed Central

    Nikjooy, Afsaneh; Maroufi, Nader; Ebrahimi Takamjani, Ismaeil; Hadizdeh Kharazi, Homayoun; Mahjoubi, Bahar; Azizi, Rasoul; Haghani, Hamid

    2015-01-01

    Background: Dyssynergic defecation is a major cause of chronic functional constipation as a common digestive complaint. We clinically evaluated the effects of biofeedback therapy on the pelvic floor motion indices through magnetic resonance (MR) defecography, quality of life and depression in patients with dyssynergic defecation. Methods: In this clinical trial study, among patients referring to the Colorectal Clinic of Hazrat Rasoul Hospital, 22 subjects were randomly assigned into two equal groups (n= 11) to receive either standard only or biofeedback and standard therapy. Dynamic changes of the pelvic floor were measured by MR defecography. During the simulated defecation, two MR defecography dynamic indices including abnormal anorectal angle change and perineal descent were measured before and after treatment. The effects of biofeedback therapy on patients’ symptoms, quality of life and severity of depression were assessed and compared with the standard therapy. Statistical analysis was carried out using independent _t-test and Mann-Whitney test. Results: Paradox index (p< 0.001), perineal descent index (p< 0.001), depression (p< 0.1), physical function (p< 0.001), vitality (p< 0.001) and role emotion (p< 0.001) significantly improved in the biofeedback therapy group in contrast to the standard therapy SDT group. Conclusion: Biofeedback therapy appears to be effective in improving symptoms of functional constipation and dysfunction of pelvic floor motion as well as patient’s quality of life and depression state. MR defecography is able to show the changes in dynamic indices of the pelvic floor through biofeedback therapy. PMID:26034741

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

    NASA Astrophysics Data System (ADS)

    Bauer, J.; Sommerer, F.; Mairani, A.; Unholtz, D.; Farook, R.; Handrack, J.; Frey, K.; Marcelos, T.; Tessonnier, T.; Ecker, S.; Ackermann, B.; Ellerbrock, M.; Debus, J.; Parodi, K.

    2014-08-01

    Monte Carlo (MC) simulations of beam interaction and transport in matter are increasingly considered as essential tools to support several aspects of radiation therapy. Despite the vast application of MC to photon therapy and scattered proton therapy, clinical experience in scanned ion beam therapy is still scarce. This is especially the case for ions heavier than protons, which pose additional issues like nuclear fragmentation and varying biological effectiveness. In this work, we present the evaluation of a dedicated framework which has been developed at the Heidelberg Ion Beam Therapy Center to provide automated FLUKA MC simulations of clinical patient treatments with scanned proton and carbon ion beams. Investigations on the number of transported primaries and the dimension of the geometry and scoring grids have been performed for a representative class of patient cases in order to provide recommendations on the simulation settings, showing that recommendations derived from the experience in proton therapy cannot be directly translated to the case of carbon ion beams. The MC results with the optimized settings have been compared to the calculations of the analytical treatment planning system (TPS), showing that regardless of the consistency of the two systems (in terms of beam model in water and range calculation in different materials) relevant differences can be found in dosimetric quantities and range, especially in the case of heterogeneous and deep seated treatment sites depending on the ion beam species and energies, homogeneity of the traversed tissue and size of the treated volume. The analysis of typical TPS speed-up approximations highlighted effects which deserve accurate treatment, in contrast to adequate beam model simplifications for scanned ion beam therapy. In terms of biological dose calculations, the investigation of the mixed field components in realistic anatomical situations confirmed the findings of previous groups so far reported only in

  3. 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

  4. Clinical evaluation of a commercial orthopedic metal artifact reduction tool for CT simulations in radiation therapy

    PubMed Central

    Li, Hua; Noel, Camille; Chen, Haijian; Harold Li, H.; Low, Daniel; Moore, Kevin; Klahr, Paul; Michalski, Jeff; Gay, Hiram A.; Thorstad, Wade; Mutic, Sasa

    2012-01-01

    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 γ 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

  5. Pharmaco-informatics: more precise drug therapy from 'multiple model' (MM) adaptive control regimens: evaluation with simulated vancomycin therapy.

    PubMed

    Jelliffe, R W; Bayard, D; Schumitzky, A; Milman, M; Van Guilder, M

    1995-01-01

    A multiple model (MM) stochastic control of dosage regimens permits essentially optimal use of the information contained in either a population pharmacokinetic model or in a MM Bayesian updated parameter set to achieve and maintain selected therapeutic goals with optimal precision. The regimens are visibly more precise than those achieved using mean parameter values. Feedback has now also been incorporated into the MM software. An evaluation of MM adaptive control precision versus control achieved using population mean parameter values is presented using a real population model (Vancomycin). Further feedback control was evaluated, incorporating simulated clinical errors in the preparation and administration of doses. PMID:8591381

  6. Multi-function microsystem for cells migration analysis and evaluation of photodynamic therapy procedure in coculture

    PubMed Central

    Jastrzebska (Jedrych), Elzbieta; Grabowska-Jadach, Ilona; Chudy, Michal; Dybko, Artur; Brzozka, Zbigniew

    2012-01-01

    Cell migration is an important physiological process, which is involved in cancer metastasis. Therefore, the investigation of cell migration may lead to the development of novel therapeutic approaches. In this study, we have successfully developed a microsystem for culture of two cell types (non-malignant and carcinoma) and for analysis of cell migration dependence on distance between them. Finally, we studied quantitatively the influence of photodynamic therapy (PDT) procedures on the viability of pairs of non-malignant (MRC5 or Balb/3T3) and carcinoma (A549) cells coculture. The proposed geometry of the microsystem allowed for separate introduction of two cell lines and analysis of cells migration dependence on distance between the cells. We found that a length of connecting microchannel has an influence on cell migration and viability of non-malignant cells after PDT procedure. Summarizing, the developed microsystem can constitute a new tool for carrying out experiments, which offers a few functions: cell migration analysis, carcinoma and non-malignant cells coculture, and evaluation of PDT procedure in the various steps of cell migration. PMID:24339849

  7. Evaluation of an occupational therapy mentorship program: effects on therapists' skills and family-centered behavior.

    PubMed

    King, Gillian; Tam, Cynthia; Fay, Linda; Pilkington, Martha; Servais, Michelle; Petrosian, Hasmik

    2011-08-01

    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 center. Self- and peer-report measures of family-centered behavior, critical thinking ability, listening/interactive communication skill, and clinical behavior were collected before and after an 11-month facilitated, collaborative group mentorship intervention. Significant pre-post changes associated with intervention were found on 9 of 12 outcome measures, including information provision, respectful treatment, self-confidence, and listening and clinical skill. Changes were not found on the more trait-like variables of open-mindedness, interpersonal sensitivity, and interpersonal skill. Experienced therapists had higher scores than new therapists on most variables, including family-centered behavior, listening skill, and clinical skill. Implications regarding the utility of mentorship programs in children's rehabilitation centers are discussed. PMID:20950057

  8. Evaluation of E1A Double Mutant Oncolytic Adenovectors in Anti-Glioma Gene Therapy

    PubMed Central

    Ulasov, Ilya V.; Tyler, Matthew A.; Rivera, Angel A.; Nettelbeck, Dirk M.; Douglas, Joanne T.; Lesniak, Maciej S.

    2008-01-01

    Malignant glioma, in particular glioblastoma multiforme (GBM), represents one of the most devastating cancers currently known and existing treatment regimens do little to change patient prognosis. Conditionally replicating adenoviral vectors (CRAds) represent attractive experimental anti-cancer agents with potential for clinical application. However, early protein products of the wild type adenovirus backbone—such as E1A—limit CRAds’ replicative specificity. In this study, we evaluated the oncolytic potency and specificity of CRAds in which p300/CPB and/or pRb binding capacities of E1A were ablated to reduce non-specific replicative cytolysis. In vitro cytopathic assays, quantitative PCR analysis, Western blot, and flow cytometry studies demonstrate the superior anti-glioma efficacy of a double-mutated CRAd, Ad2/24CMV, which harbors mutations that reduce E1A binding to p300/CPB and pRb. When compared to its single-mutated and wild type counterparts, Ad2/24CMV demonstrated attenuated replication and cytotoxicity in representative normal human brain while displaying enhanced replicative cytotoxicity in malignant glioma. These results have implications for the development of double-mutated CRAd vectors for enhanced GBM therapy. PMID:18649343

  9. Evaluation of CD46 re-targeted adenoviral vectors for clinical ovarian cancer intraperitoneal therapy.

    PubMed

    Hulin-Curtis, S L; Uusi-Kerttula, H; Jones, R; Hanna, L; Chester, J D; Parker, A L

    2016-07-01

    Ovarian cancer accounts for >140 000 deaths globally each year. Typically, disease is asymptomatic until an advanced, incurable stage. Although response to cytotoxic chemotherapy is frequently observed, resistance to conventional platinum-based therapies develop rapidly. Improved treatments are therefore urgently required. Virotherapy offers great potential for ovarian cancer, where the application of local, intraperitoneal delivery circumvents some of the limitations of intravenous strategies. To develop effective, adenovirus (Ad)-based platforms for ovarian cancer, we profiled the fluid and cellular components of patient ascites for factors known to influence adenoviral transduction. Levels of factor X (FX) and neutralizing antibodies (nAbs) in ascitic fluid were quantified and tumor cells were assessed for the expression of coxsackie virus and adenovirus receptor (CAR) and CD46. We show that clinical ascites contains significant levels of FX but consistently high CD46 expression. We therefore evaluated in vitro the relative transduction of epithelial ovarian cancers (EOCs) by Ad5 (via CAR) and Ad5 pseudotyped with the fiber of Ad35 (Ad5T*F35++) via CD46. Ad5T*F35++ achieved significantly increased transduction in comparison to Ad5 (P<0.001), independent of FX and nAb levels. We therefore propose selective transduction of CD46 over-expressing EOCs using re-targeted, Ad35-pseudotyped Ad vectors may represent a promising virotherapy for ovarian cancer. PMID:27229159

  10. 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. PMID:26405934

  11. Use of an Electronic Patient Record system to evaluate restorative treatment following root canal therapy.

    PubMed

    Shelley, Peter Q; Johnson, Bradford R; BeGole, Ellen A

    2007-10-01

    Electronic Patient Record (EPR) systems are rapidly gaining acceptance as an important tool for managing patient information. The purpose of this project was to evaluate the use of an EPR system for assessment of quality of care in an academic dental institution. The primary outcome of interest was the timeliness and completeness of restorative care following completion of nonsurgical root canal therapy. An initial query of the EPR database was performed using the following inclusion criteria: root canal treatment performed in the postgraduate endodontics clinic between September 2002 and June 2004, patient age > or =18 years old, and posterior tooth (premolars and molars). A total of 925 patients with 1,014 endodontically treated teeth met the inclusion criteria. A random sample of 30 percent of the treated teeth (302 teeth on 281 patients) was selected for detailed review. This sample of 302 teeth was then screened to determine if any restorative treatment had been performed between September 2002 and November 2005. Forty-eight percent (n=146) of the 302 teeth did not receive any form of permanent restoration over the time period studied. Twenty-five percent (n=75) of the teeth received a buildup only, and 27 percent (n=82) received the recommended treatment, a full occlusal coverage restoration. This study documents the use of an EPR system to objectively and efficiently assess one aspect of quality of care in a dental school environment. PMID:17923711

  12. 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.

  13. Economic Evaluation of Brief Psychodynamic Interpersonal Therapy in Patients with Multisomatoform Disorder

    PubMed Central

    Chernyak, Nadja; Sattel, Heribert; Scheer, Marsel; Baechle, Christina; Kruse, Johannes; Henningsen, Peter; Icks, Andrea

    2014-01-01

    Background A brief psychodynamic interpersonal therapy (PIT) in patients with multisomatoform disorder has been recently shown to improve health-related quality of life. Aims To assess cost-effectiveness of PIT compared to enhanced medical care in patients with multisomatoform disorder. Method An economic evaluation alongside a randomised controlled trial (International Standard Randomised Controlled Trial Number ISRCTN23215121) conducted in 6 German academic outpatient centres was performed. Incremental cost-effectiveness ratio (ICER) was calculated from the statutory health insurance perspective on the basis of quality adjusted life years (QALYs) gained at 12 months. Uncertainty surrounding the cost-effectiveness of PIT was presented by means of a cost-effectiveness acceptability curve. Results Based on the complete-case analysis ICER was 41840 Euro per QALY. The results did not change greatly with the use of multiple imputation (ICER = 44222) and last observation carried forward (LOCF) approach to missing data (ICER = 46663). The probability of PIT being cost-effective exceeded 50% for thresholds of willingness to pay over 35 thousand Euros per QALY. Conclusions Cost-effectiveness of PIT is highly uncertain for thresholds of willingness to pay under 35 thousand Euros per QALY. PMID:24465387

  14. 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.

  15. Evaluation of sand as a shielding material for radiation therapy facilities

    SciTech Connect

    Walker, W.J.; Darwish, S.M.; Fitzgerald, L.T.

    1996-06-01

    Radiation protective barriers are designed to ensure that dose equivalent received by any individual does not exceed the applicable maximum permissible value. Materials used conventionally for shielding high energy radiotherapy facilities included concrete, lead, and steel. The choice of a shielding material is dictated by economic factors, the availability of space, and the energy range of the radiation to be attenuated. The use of silica sand to shield Megavoltage teletherapy rooms has only been recently considered for the purpose of lowering construction costs, compared to that of concrete, as well as reducing construction time. This work discusses the design and shielding evaluation of two radiation therapy facilities, which have recently been commissioned, in which the secondary barriers were designed using sand as the shielding material. For these facilities the exterior and interior walls as well as the roof were first constructed using slabs of concrete to form a shell in which sand was poured to fill the space between the slabs. Primary walls for the vault were constructed only of concrete. The sand used had a moisture content of approximately 5% and a density of about 100 lb/ft{sup 3}. In order to minimize settling over time, the sand was poured from a height of about 25 feet so that maximum compacting effect was obtained under gravity. Because of the lack of attenuation data for sand, barrier evaluation has first considered the concrete thickness required to provide adequate shielding, and the equivalent sand thickness was then determined based on the ratio of sand density to that of concrete. Post construction radiation surveys of both facilities have shown that radiation exposure levels are within the permissible limits and they proved that using sand as a shielding material is adequate and prudent.

  16. Evaluation of the Impact of the Cancer Therapy Everolimus on the Central Nervous System in Mice

    PubMed Central

    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

  17. 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. PMID:18240896

  18. Calibration and evaluation of a magnetically tracked ICE probe for guidance of left atrial ablation therapy

    NASA Astrophysics Data System (ADS)

    Linte, Cristian A.; Rettmann, Maryam E.; Dilger, Ben; Gunawan, Mia S.; Arunachalam, Shivaram P.; Holmes, David R., III; Packer, Douglas L.; Robb, Richard A.

    2012-02-01

    The novel prototype system for advanced visualization for image-guided left atrial ablation therapy developed in our laboratory permits ready integration of multiple imaging modalities, surgical instrument tracking, interventional devices and electro-physiologic data. This technology allows subject-specific procedure planning and guidance using 3D dynamic, patient-specific models of the patient's heart, augmented with real-time intracardiac echocardiography (ICE). In order for the 2D ICE images to provide intuitive visualization for accurate catheter to surgical target navigation, the transducer must be tracked, so that the acquired images can be appropriately presented with respect to the patient-specific anatomy. Here we present the implementation of a previously developed ultrasound calibration technique for a magnetically tracked ICE transducer, along with a series of evaluation methods to ensure accurate imaging and faithful representation of the imaged structures. Using an engineering-designed phantom, target localization accuracy is assessed by comparing known target locations with their transformed locations inferred from the tracked US images. In addition, the 3D volume reconstruction accuracy is also estimated by comparing a truth volume to that reconstructed from sequential 2D US images. Clinically emulating validation studies are conducted using a patient-specific left atrial phantom. Target localization error of clinically-relevant surgical targets represented by nylon fiducials implanted within the endocardial wall of the phantom was assessed. Our studies have demonstrated 2.4 +/- 0.8 mm target localization error in the engineering-designed evaluation phantoms, 94.8 +/- 4.6 % volume reconstruction accuracy, and 3.1 +/- 1.2 mm target localization error in the left atrial-mimicking phantom. These results are consistent with those disseminated in the literature and also with the accuracy constraints imposed by the employed technology and the clinical

  19. 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.

  20. Evaluation of Parotid Gland Function following Intensity Modulated Radiation Therapy for Head and Neck Cancer

    PubMed Central

    Lee, Seok Ho; Kim, Tae Hyun; Kim, Joo Young; Park, Sung Yong; Pyo, Hong Ryull; Shin, Kyung Hwan; Kim, Dae Yong; Kim, Joo Young

    2006-01-01

    Purpose This study was undertaken to determine the parotid gland tolerance dose levels following intensity modulated radiation therapy (IMRT) for treating patients who suffered with head and neck cancer. Materials and Methods From February 2003 through June 2004, 34 head and neck patients with 6 months of follow-up were evaluated for xerostomia after being treated by IMRT. Their median age was 59 years (range: 29~78). Xerostomia was assessed using a 4-question xerostomia questionnaire score (XQS) and a test for the salivary flow rates (unstimulated and stimulated: USFR and SSFR, respectively). The patients were also given a validated LENT SOMA scale (LSS) questionnaire. Evaluations were performed before IMRT and at 1, 3 and 6 months after IMRT. Results All 34 patients showed significant changes in the XQS, LSS and Salivary Flow rates (USFR and SSFR) after IMRT. No significant changes in the XQS or LSS were noted in 12 patients who received a total parotid mean dose of ≤3,100 cGy at 1, 3 and 6 months post-IMRT relative to the baseline values. However, for the 22 patients who received >3,100 cGy, significant increases in the XQS and LSS were observed. The USFR and SSFR from the parotid glands in 7 patients who received ≤2,750 cGy were significantly preserved at up to 6 months after IMRT. However, the USFR and SSFR in 27 patients who were treated with >2,750 cGy were significantly lower than the baseline values at all times after IMRT. Conclusion We suggest that the total parotid mean dose should be limited to ≤2,750 cGy to preserve the USFR and SSFR and so improve the subsequent quality of life. PMID:19771265

  1. 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

  2. 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

  3. A Multiple siRNA-Based Anti-HIV/SHIV Microbicide Shows Protection in Both In Vitro and In Vivo Models.

    PubMed

    Boyapalle, Sandhya; Xu, Weidong; Raulji, Payal; Mohapatra, Subhra; Mohapatra, Shyam S

    2015-01-01

    Human immunodeficiency virus (HIV) types 1 and 2 (HIV-1 and HIV-2) are the etiologic agents of AIDS. Most HIV-1 infected individuals worldwide are women, who acquire HIV infections during sexual contact. Blocking HIV mucosal transmission and local spread in the female lower genital tract is important in preventing infection and ultimately eliminating the pandemic. Microbicides work by destroying the microbes or preventing them from establishing an infection. Thus, a number of different types of microbicides are under investigation, however, the lack of their solubility and bioavailability, and toxicity has been major hurdles. Herein, we report the development of multifunctional chitosan-lipid nanocomplexes that can effectively deliver plasmids encoding siRNA(s) as microbicides without adverse effects and provide significant protection against HIV in both in vitro and in vivo models. Chitosan or chitosan-lipid (chlipid) was complexed with a cocktail of plasmids encoding HIV-1-specific siRNAs (psiRNAs) and evaluated for their efficacy in HEK-293 cells, PBMCs derived from nonhuman primates, 3-dimensional human vaginal ectocervical tissue (3D-VEC) model and also in non-human primate model. Moreover, prophylactic administration of the chlipid to deliver a psiRNA cocktail intravaginally with a cream formulation in a non-human primate model showed substantial reduction of SHIV (simian/human immunodeficiency virus SF162) viral titers. Taken together, these studies demonstrate the potential of chlipid-siRNA nanocomplexes as a potential genetic microbicide against HIV infections. PMID:26407080

  4. Evaluation of multisystemic therapy pilot services in the Systemic Therapy for At Risk Teens (START) trial: study protocol for a randomised controlled trial

    PubMed Central

    2013-01-01

    depending on whether the outcome is time-to-event or continuous. Discussion The START trial is a pragmatic national trial of sufficient size to evaluate multisystemic therapy, to inform policymakers, service commissioners, professionals, service users and their families about its potential in the UK. It will also provide data on the clinical and cost-effectiveness of usual services provided to youth with serious antisocial behaviour problems. Trial registration ISRCTN77132214 PMID:23962220

  5. Clinical evaluations of an amplitude-based binning algorithm for 4DCT reconstruction in radiation therapy

    SciTech Connect

    Li Hua; Noel, Camille; Garcia-Ramirez, Jose; Low, Daniel; Bradley, Jeffrey; Robinson, Clifford; Mutic, Sasa; Parikh, Parag

    2012-02-15

    Purpose: Phase-binning algorithms are commonly utilized in 4DCT image reconstruction for characterization of tumor or organ shape and respiration motion, but breathing irregularities occurring during 4DCT acquisition can cause considerable image distortions. Recently, amplitude-binning algorithms have been evaluated as a potential improvement to phase-binning algorithms for 4DCT image reconstruction. The purpose of this study was to evaluate the performance of the first commercially available on-line retrospective amplitude-binning algorithm for comparison to the traditional phase-binning algorithm. Methods: Both phantom and clinical data were used for evaluation. A phantom of known geometry was mounted on a 4D motion platform programmed with seven respiratory waves (two computer generated and five patient trajectories) and scanned with a Philips Brilliance Big bore 16-slice CT simulator. 4DCT images were reconstructed using commercial amplitude- and phase-binning algorithms. Image quality of the amplitude- and phase-binned image sets was compared by evaluation of shape and volume distortions in reconstructed images. Clinical evaluations were performed on 64 4DCT patient image sets in a blinded review process. The amplitude- and phase-binned 4DCT maximum intensity projection (MIP) images were further evaluated for 28 stereotactic body radiation therapy (SBRT) cases of total 64 cases. A preliminary investigation of the effects of respiratory amplitude and pattern irregularities on motion artifact severity was conducted. Results: The phantom experiments illustrated that, as expected, maximum inhalation occurred at the 0% amplitude and maximum exhalation occurred at the 50% amplitude of the amplitude-binned 4DCT image sets. The phantom shape distortions were more severe in the images reconstructed from the phase-binning algorithm. In the clinical study, compared to the phase-binning algorithm, the amplitude-binning algorithm yielded fewer or less severe motion

  6. Evaluation of an Optimized Injection System for Retinal Gene Therapy in Human Patients.

    PubMed

    Fischer, M Dominik; Hickey, Doron G; Singh, Mandeep S; MacLaren, Robert E

    2016-08-01

    Many retinal gene therapy clinical trials require subretinal injections of small volumes of adeno-associated viral (AAV) vector solutions in patients with retinal dystrophies, using equipment not specifically designed for this purpose. We therefore evaluated an optimized injection system in order to identify variables that might influence the rate of injection and final dose of vector delivered. An optimized injection system was assembled with a 41G polytetrafluoroethylene tip for retinal gene therapy. Flow rate was recorded at relevant infusion pressures (2-22 psi [14-152 kPa]), different target pressures (0.02-30 mm Hg [0.003-4 kPa]) and temperatures (18°C vs. 36°C) using a semiautomated Accurus(®) Surgical System. Retention of AAV2/8 and AAV2/8(Y733F) vector was quantified after simulating loading/injection with or without 0.001% Pluronic(®) F-68 (PF-68). The optimized injection system provided a linear flow rate (μl/s)-to-infusion pressure (psi) relationship (y = 0.62x; r(2) = 0.99), independent of temperature and pressure changes relevant for intraocular surgery (18-36°C, 0.02-30 mm Hg). Differences in length of 41G polytetrafluoroethylene tips caused significant variation in flow rate (p < 0.001). Use of PF-68 significantly (p < 0.001) reduced loss of vector genomes in the injection system by 55% (AAV2/8) and 52% (AAV2/8(Y733F)). A customized subretinal injection system assembled using equipment currently available in the operating room can deliver a controlled volume of vector at a fixed rate across a range of possible clinical parameters encountered in vitreoretinal surgery. The inclusion of 0.001% PF-68 had a significant effect on the final dose of vector genomes delivered. The described technique is currently used successfully in a clinical trial. PMID:27480111

  7. A Controlled Evaluation of Family Behavior Therapy in Concurrent Child Neglect and Drug Abuse

    PubMed Central

    Donohue, Brad; Azrin, Nathan H.; Bradshaw, Kelsey; Van Hasselt, Vincent B.; Cross, Chad L.; Urgelles, Jessica; Romero, Valerie; Hill, Heather H.; Allen, Daniel N.

    2015-01-01

    Objective Approximately 50% of Child Protective Service (CPS) referrals abuse drugs; yet, existing treatment studies in this population have been limited to case examinations. Therefore, a family-based behavioral therapy was evaluated in mothers referred from CPS for child neglect and drug abuse utilizing a controlled experimental design. Method 72 mothers evidencing drug abuse or dependence and child neglect were randomly assigned to Family Behavior Therapy (FBT) or Treatment as Usual (TAU). Participants were assessed at baseline, 6- month-, and 10-month post-randomization. Results As hypothesized, intent-to-treat repeated measures analyses revealed mothers referred for child neglect not due to their children being exposed to illicit drugs demonstrated better outcomes in child maltreatment potential from baseline to 6- and 10-month post-randomization assessments when assigned to FBT, as compared with TAU mothers and FBT mothers who were referred due to child drug exposure. Similar results occurred for hard drug use from baseline to 6- and 10-month post-randomization. However, TAU mothers referred due to child drug exposure were also found to decrease their hard drug use more than TAU mothers of non-drug exposed children and FBT mothers of drug exposed children at 6- and 10-month post-randomization. Although effect sizes for mothers assigned to FBT were slightly larger for marijuana use than TAU (medium vs. large), these differences were not statistically significant. Specific to secondary outcomes, mothers in FBT, relative to TAU, increased time employed from baseline to 6- and 10-month post-randomization. Mothers in FBT, compared to TAU, also decreased HIV risk from baseline to 6-month post-randomization. There were no differences in outcome between FBT and TAU for number of days children were in CPS custody and alcohol intoxication, although FBT mothers demonstrated marginal decreases (p = .058) in incarceration from baseline to 6-month post

  8. 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

  9. Evaluation of different fiducial markers for image-guided radiotherapy and particle therapy.

    PubMed

    Habermehl, Daniel; Henkner, Katrin; Ecker, Swantje; Jäkel, Oliver; Debus, Jürgen; Combs, Stephanie E

    2013-07-01

    Modern radiotherapy (RT) techniques are widely used in the irradiation of moving organs. A crucial step in ensuring the correct position of a target structure directly before or during treatment is daily image guidance by computed tomography (CT) or X-ray radiography (image-guided radiotherapy, IGRT). Therefore, combinations of modern irradiation devices and imaging, such as on-board imaging (OBI) with X-rays, or in-room CT such as the tomotherapy system, have been developed. Moreover, combinations of linear accelerators and in-room CT-scanners have been designed. IGRT is of special interest in hypofractionated and radiosurgical treatments where high single doses are applied in the proximity of critical organs at risk. Radiographically visible markers in or in close proximity to the target structure may help to reproduce the position during RT and could therefore be used as external surrogates for motion monitoring. Criteria sought for fiducial markers are (i) visibility in the radiologic modalities involved in radiotherapeutic treatment planning and image guidance, such as CT and kilovoltage (kV) OBI), (ii) low production of imaging artifacts, and (iii) low perturbation of the therapeutic dose to the target volume. Photon interaction with interstitial markers has been shown to be not as important as in particle therapy, where interaction of the particle beam, especially with metal markers, can have a significant impact on treatment. This applies especially with a scanned ion beam. Recently we commenced patient recruitment at our institution within the PROMETHEUS trial, which evaluates a hypofractionation regime, starting with 4 x 10 Gy (RBE), for patients with hepatocellular carcinoma. The aim of this work is, therefore, to evaluate potential implantable fiducial markers for enabling precise patient and thus organ positioning in scanned ion beams. To transfer existing knowledge of marker application from photon to particle therapy, we used a range of commercially

  10. 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. PMID:23285793

  11. 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. PMID:26006046

  12. 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…

  13. Evaluating Acceptance and Commitment Therapy: An Analysis of a Recent Critique

    ERIC Educational Resources Information Center

    Gaudiano, Brandon A.

    2009-01-01

    Acceptance and commitment therapy (ACT) is a newer psychotherapy that has generated much clinical and research interest in recent years. However, the approach has begun to receive strong criticism from proponents of traditional cognitive-behavioral therapy (CBT). Hofmann and Asmundson (2008) recently compared and contrasted ACT and traditional…

  14. 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…

  15. 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

  16. Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: complete protection of rhesus monkeys from mucosal SHIV challenge.

    PubMed

    Sholukh, Anton M; Watkins, Jennifer D; Vyas, Hemant K; Gupta, Sandeep; Lakhashe, Samir K; Thorat, Swati; Zhou, Mingkui; Hemashettar, Girish; Bachler, Barbara C; Forthal, Donald N; Villinger, Francois; Sattentau, Quentin J; Weiss, Robin A; Agatic, Gloria; Corti, Davide; Lanzavecchia, Antonio; Heeney, Jonathan L; Ruprecht, Ruth M

    2015-04-21

    Although IgA is the most abundantly produced immunoglobulin in humans, its role in preventing HIV-1 acquisition, which occurs mostly via mucosal routes, remains unclear. In our passive mucosal immunizations of rhesus macaques (RMs), the anti-HIV-1 neutralizing monoclonal antibody (nmAb) HGN194, given either as dimeric IgA1 (dIgA1) or dIgA2 intrarectally (i.r.), protected 83% or 17% of the RMs against i.r. simian-human immunodeficiency virus (SHIV) challenge, respectively. Data from the RV144 trial implied that vaccine-induced plasma IgA counteracted the protective effector mechanisms of IgG1 with the same epitope specificity. We thus hypothesized that mucosal dIgA2 might diminish the protection provided by IgG1 mAbs targeting the same epitope. To test our hypothesis, we administered HGN194 IgG1 intravenously (i.v.) either alone or combined with i.r. HGN194 dIgA2. We enrolled SHIV-exposed, persistently aviremic RMs protected by previously administered nmAbs; RM anti-human IgG responses were undetectable. However, low-level SIV Gag-specific proliferative T-cell responses were found. These animals resemble HIV-exposed, uninfected humans, in which local and systemic cellular immune responses have been observed. HGN194 IgG1 and dIgA2 used alone and the combination of the two neutralized the challenge virus equally well in vitro. All RMs given only i.v. HGN194 IgG1 became infected. In contrast, all RMs given HGN194 IgG1+dIgA2 were completely protected against high-dose i.r. SHIV-1157ipEL-p challenge. These data imply that combining suboptimal defenses at the mucosal and systemic levels can completely prevent virus acquisition. Consequently, active vaccination should focus on defense-in-depth, a strategy that seeks to build up defensive fall-back positions well behind the fortified frontline. PMID:25769884

  17. Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: Complete protection of rhesus monkeys from mucosal SHIV challenge

    PubMed Central

    Sholukh, Anton M.; Watkins, Jennifer D.; Vyas, Hemant K.; Gupta, Sandeep; Lakhashe, Samir K.; Thorat, Swati; Zhou, Mingkui; Hemashettar, Girish; Bachler, Barbara C.; Forthal, Donald N.; Villinger, Francois; Sattentau, Quentin J.; Weiss, Robin A.; Agatic, Gloria; Corti, Davide; Lanzavecchia, Antonio; Heeney, Jonathan L.; Ruprecht, Ruth M.

    2015-01-01

    Although IgA is the most abundantly produced immunoglobulin in humans, its role in preventing HIV-1 acquisition, which occurs mostly via mucosal routes, remains unclear. In our passive mucosal immunizations of rhesus macaques (RMs), the anti-HIV-1 neutralizing monoclonal antibody (nmAb) HGN194, given either as dimeric IgA1 (dIgA1) or dIgA2 intrarectally (i.r.), protected 83% or 17% of the RMs against i.r. simian-human immunodeficiency virus (SHIV) challenge, respectively. Data from the RV144 trial implied that vaccine-induced plasma IgA counteracted the protective effector mechanisms of IgG1 with the same epitope specificity. We thus hypothesized that mucosal dIgA2 might diminish the protection provided by IgG1 mAbs targeting the same epitope. To test our hypothesis, we administered HGN194 IgG1 intravenously (i.v.) either alone or combined with i.r. HGN194 dIgA2. We enrolled SHIV-exposed, persistently aviremic RMs protected by previously administered nmAbs; RM anti-human IgG responses were undetectable. However, low-level SIV Gag-specific proliferative T-cell responses were found. These animals resemble HIV-exposed, uninfected humans, in which local and systemic cellular immune responses have been observed. HGN194 IgG1 and dIgA2 used alone and the combination of the two neutralized the challenge virus equally well in vitro. All RMs given only i.v. HGN194 IgG1 became infected. In contrast, all RMs given HGN194 IgG1 + dIgA2 were completely protected against high-dose i.r. SHIV-1157ipEL-p challenge. These data imply that combining suboptimal defenses at the mucosal and systemic levels can completely prevent virus acquisition. Consequently, active vaccination should focus on defense-in-depth, a strategy that seeks to build up defensive fall-back positions well behind the fortified frontline. PMID:25769884

  18. In Search of a Gold Standard Scoring System for the Subjective Evaluation of Cosmetic Outcomes Following Breast-Conserving Therapy.

    PubMed

    Racz, Jennifer M; Hong, Nicole Look; Latosinsky, Steven

    2015-01-01

    The absence of a widely accepted method for aesthetic evaluation following breast-conserving surgery for breast cancer limits the ability to evaluate cosmetic outcomes. In this study, two different panel scoring approaches were compared in an attempt to identify a gold standard scoring system for subjectively assessing cosmetic outcomes following breast-conserving therapy. Standardized photographs of each participant were evaluated independently by twelve health care professionals involved in breast cancer diagnosis and treatment using the Danoff four-point scale. Individual Danoff scores were combined using two methods, a random sample "three-panel" score and an iterative "Delphi-panel" score, in order to create a final cosmetic score for each patient. Agreement between these two aggregative approaches was assessed with a weighted kappa (wk) statistic. Patient and professional recruitment occurred at two separate tertiary care multi-disciplinary breast health centers. Women with unilateral breast cancer who underwent breast-conserving therapy (segmental mastectomy or lumpectomy and radiotherapy) and were at least 2 years after radiotherapy were asked to participate. Ninety-seven women were evaluated. The Delphi approach required three rounds of evaluation to obtain greater than 50% agreement in all photographs. The wk statistic between scores generated from the "three-panel" and "Delphi-panel" approaches was 0.80 (95% CI: 0.71-0.89), thus demonstrating substantial agreement. Evaluation of cosmetic outcomes following breast-conserving therapy using a "three-panel" and "Delphi-panel" score provide similar results, confirming the reliability of either approach for subjective evaluation. Simplicity of use and interpretation favors the "three-panel" score. Future work should concentrate on the integration of the three-panel score with objective and patient-reported scales to generate a comprehensive cosmetic evaluation platform. PMID:25940058

  19. 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

  20. Bone Marrow Gene Therapy for HIV/AIDS

    PubMed Central

    Herrera-Carrillo, Elena; Berkhout, Ben

    2015-01-01

    Bone marrow gene therapy remains an attractive option for treating chronic immunological diseases, including acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV). This technology combines the differentiation and expansion capacity of hematopoietic stem cells (HSCs) with long-term expression of therapeutic transgenes using integrating vectors. In this review we summarize the potential of bone marrow gene therapy for the treatment of HIV/AIDS. A broad range of antiviral strategies are discussed, with a particular focus on RNA-based therapies. The idea is to develop a durable gene therapy that lasts the life span of the infected individual, thus contrasting with daily drug regimens to suppress the virus. Different approaches have been proposed to target either the virus or cellular genes encoding co-factors that support virus replication. Some of these therapies have been tested in clinical trials, providing proof of principle that gene therapy is a safe option for treating HIV/AIDS. In this review several topics are discussed, ranging from the selection of the antiviral molecule and the viral target to the optimal vector system for gene delivery and the setup of appropriate preclinical test systems. The molecular mechanisms used to formulate a cure for HIV infection are described, including the latest antiviral strategies and their therapeutic applications. Finally, a potent combination of anti-HIV genes based on our own research program is described. PMID:26193303

  1. Evaluation of hypericin-mediated photodynamic therapy in combination with angiogenesis inhibitor bevacizumab using in vivo fluorescence confocal endomicroscopy

    NASA Astrophysics Data System (ADS)

    Bhuvaneswari, Ramaswamy; Thong, Patricia S. P.; Gan, Yik-Yuen; Soo, Khee; Olivo, Malini

    2010-01-01

    Photodynamic therapy (PDT) is an alternative cancer treatment modality that offers localized treatment using a photosensitizer and light. However, tumor angiogenesis is a major concern following PDT-induced hypoxia as it promotes recurrence. Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), thus preventing angiogenesis. The combination of PDT with antiangiogenic agents such as bevacizumab has shown promise in preclinical studies. We use confocal endomicroscopy to study the antiangiogenic effects of PDT in combination with bevacizumab. This technique offers in vivo surface and subsurface fluorescence imaging of tissue. Mice bearing xenograft bladder carcinoma tumors were treated with PDT, bevacizumab, or PDT and bevacizumab combination therapy. In tumor regression experiments, combination therapy treated tumors show the most regression. Confocal fluorescence endomicroscopy enables visualization of tumor blood vessels following treatment. Combination therapy treated tumors show the most posttreatment damage with reduced cross-sectional area of vessels. Immunohistochemistry and immunofluorescence studies show that VEGF expression is significantly downregulated in the tumors treated by combination therapy. Overall, combining PDT and bevacizumab is a promising cancer treatment approach. We also demonstrate that confocal endomicroscopy is useful for visualization of vasculature and evaluation of angiogenic response following therapeutic intervention.

  2. 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. PMID:25204750

  3. Evaluation of new iodinated acridine derivatives for targeted radionuclide therapy of melanoma using 125I, an Auger electron emitter.

    PubMed

    Gardette, Maryline; Papon, Janine; Bonnet, Mathilde; Desbois, Nicolas; Labarre, Pierre; Wu, Ting-Dee; Miot-Noirault, Elisabeth; Madelmont, Jean-Claude; Guerquin-Kern, Jean-Luc; Chezal, Jean-Michel; Moins, Nicole

    2011-12-01

    The increasing incidence of melanoma and the lack of effective therapy on the disseminated form have led to an urgent need for new specific therapies. Several iodobenzamides or analogs are known to possess specific affinity for melanoma tissue. New heteroaromatic derivatives have been designed with a cytotoxic moiety and termed DNA intercalating agents. These compounds could be applied in targeted radionuclide therapy using (125)I, which emits Auger electrons and gives high-energy, localized irradiation. Two iodinated acridine derivatives have been reported to present an in vivo kinetic profile conducive to application in targeted radionuclide therapy. The aim of the present study was to perform a preclinical evaluation of these compounds. The DNA intercalating property was confirmed for both compounds. After radiolabeling with (125)I, the two compounds induced in vitro a significant radiotoxicity to B16F0 melanoma cells. Nevertheless, the acridine compound appeared more radiotoxic than the acridone compound. While cellular uptake was similar for both compounds, SIMS analysis and in vitro protocol showed a stronger affinity for melanin with acridone derivative, which was able to induce a predominant scavenging process in the melanosome and restrict access to the nucleus. In conclusion, the acridine derivative with a higher nuclear localization appeared a better candidate for application in targeted radionuclide therapy using (125)I. PMID:20567996

  4. 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. PMID:25385089

  5. Anti-AIDS Agents 78 †. Design, Synthesis, Metabolic Stability Assessment, and Antiviral Evaluation of Novel Betulinic Acid Derivatives as Potent Anti-Human Immunodeficiency Virus (HIV) Agents

    PubMed Central

    Qian, Keduo; Yu, Donglei; Chen, Chin-Ho; Huang, Li; Morris-Natschke, Susan L.; Nitz, Theodore J.; Salzwedel, Karl; Reddick, Mary; Allaway, Graham P.; Lee, Kuo-Hsiung

    2009-01-01

    In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives, as well as seven novel 3,28-disubstituted BA analogs were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC50: 0.09 μM), when compared to HIV entry inhibitors 3b (IC9564) and 4 (A43-D). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC50 values of 0.007 μM and 0.006 μM, respectively. These results are slightly better than that of bevirimat (2), which is currently in Phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates. PMID:19388685

  6. Evaluation of Health Plan Interventions to Influence Chronic Opioid Therapy Prescribing

    PubMed Central

    Saunders, Kathleen; Shortreed, Susan; Thielke, Stephen; Turner, Judith A.; LeResche, Linda; Beck, Randi; Von Korff, Michael

    2015-01-01

    Objectives Evaluate health plan interventions targeting physician chronic opioid therapy (COT) prescribing. Methods In 2006, Group Health’s (GH) integrated group practice (IGP) initiated diverse interventions targeting COT prescriber norms and practices. In 2010, the IGP implemented a COT guideline, including a mandated online course for physicians managing COT. These interventions were not implemented in GH’s network practices. We compared trends in GH-IGP and network practices for 2006–12 in the percent of patients receiving COT and their opioid dose. We compared physician beliefs before versus after the mandated course and pre- to post-course changes in COT dosing for IGP physicians who took the course. Results From 2006 to 2012, mean (SE) daily opioid dose among IGP COT patients (intervention setting) declined from 74.1 (1.9) mg. morphine equivalent dose (MED) to 48.3 (1.0) mg. MED. Dose changes among GH network COT patients (control setting) were modest—88.2 (5.0) mg. MED in 2006 to 75.7 (2.3) mg. MED in 2012. Among physicians taking the mandated course in 2011, we observed pre- to post-course changes toward more conservative opioid prescribing beliefs. However, COT dosing trends did not change pre- to post-course. Discussion Following initiatives implemented to alter physician prescribing practices and norms, mean opioid dose prescribed to COT patients declined more in intervention than control practices. Physicians reported more conservative beliefs regarding opioid prescribing immediately after completing an online course in 2011, but the course was not associated with additional reductions in mean daily opioid dose prescribed by physicians completing the course. PMID:25621426

  7. 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.

  8. 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

  9. 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.

  10. [Evaluation of bone mineral density in hyperthyroid patients before and after medical therapy].

    PubMed

    Safi, S; Hassikou, H; Hadri, L; Sbihi, A; Kadiri, A

    2006-03-01

    Osteoporosis is a common complication of hyperthyroidism, but it is not often evaluated. The aim of this study is to examine bone mineral density (BMD) (dual energy X-ray absorptiometry: DEXA) in lumbar spine (L1-L4), femoral neck (FN) and Ward's triangle (TW) in 45 hyperthyroid patients (group A: n 25 active hyperthyroidism, group B: n 20 controlled hyperthyroidism on medical therapy, after a mean of 7 months of euthyroidism), compared to control group (group C: n 22). These 3 groups are adjusted by age, sex, menopausal status and BMI. In hyperthyroid patients (group A), as compared to the control group, we noticed a significant reduction of BMD (z score) in different sites, more markedly in the lumbar spine (p L1-L4: 0,005; p FN: 0,011; p TW: 0,019). In group A, no differences were found between BMD values after adjustment for Z score whatever the menopausal status (p L: 0.12; p FN: 0.33; p TW: 0.09) and degree ofhyperthyroidism (p L: 0.48; p FN: 0.41; p TW: 0.21). The degree of BMD in group B patients was different from that of patients in group A (p L: 0.37; p FN: 0.28; p TW: 0.31). and was significantly lower than in those of group C except for the TW (p L: 0.009; p CF: 0.038; p TW: 0.068). We conclude that it is important to consider that after reaching euthyroidism hyperthyroidism patients present a bone risk. PMID:16596054

  11. Evaluation of adherence to therapy in patients of chronic kidney disease

    PubMed Central

    Sontakke, Smita; Budania, Ritu; Bajait, Chaitali; Jaiswal, Kavita; Pimpalkhute, Sonali

    2015-01-01

    Objective: To evaluate adherence to medication and study factors associated with non-adherence in chronic kidney disease (CKD) patients. Methods: A prospective, cross-sectional, questionnaire based study was conducted in Nephrology department of a super specialty hospital. Patients above 18 years of age, suffering from CKD from six months or more were interviewed using self-designed, semi-structured questionnaire to get information about adherence to medication, diet restriction and lifestyle modification (n = 150). Morisky medication adherence questionnaire was used to calculate overall adherence. In this higher score indicates poor adherence. Main outcome measures included prevalence of non-adherence and factors associated with the same. Results: Average number of medicines taken by each patient was 8.0+1.612 (mean+SD) per day. Non-adherence to medication schedule was reported in 34% patients. Common causes of non-adherence were high cost (21.3%), complex dosing schedule (20%), fear of adverse effects (16%). Sixty-eight% patients were not aware about importance of taking each medicine. Sixteen% stopped taking medicines due to high cost. Forty-two% suggested that government should adopt measures to provide free medicines to poor patients. In Morisky medication adherence questionnaire high, medium and low adherence was reported in 7.3%, 55.3% and 37.3% of patients, respectively. Moderately positive correlation was observed between poor adherence and number of concurrent illnesses and number of medicines taken. Conclusion: Since majority of patients were not aware about importance of taking each medicine, creating awareness about the same is essential for improving adherence to therapy. Measures to provide free medicines to non-affording patients need to be implemented since high cost was other major cause of non-adherence. PMID:26729961