123 results on '"Anti-HIV Drugs"'
Search Results
2. Nanomaterial-based electrochemical sensors for anti-HIV drug monitoring: Innovations, challenges, and prospects
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Lahcen, Abdellatif Ait and Slaughter, Gymama
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- 2025
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Catalog
3. Adaptation of the REINVENT neural network architecture to generate potential HIV-1 entry inhibitors
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D. A. Varabyeu, A. D. Karpenko, A. V. Tuzikov, and A. M. Andrianov
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generative ai ,reinforcement learning ,computer-aided drug design ,molecular docking ,hiv-1 ,gp120 protein ,anti-hiv drugs ,Electronic computers. Computer science ,QA75.5-76.95 - Abstract
Objectives. The main purpose of this work is to adapt the architecture of the REINVENT neural network to generate potential inhibitors of the HIV-1 envelope protein gp120 using in the learning process with reinforcement of molecular docking on GPUs.Methods. To modify the initial network model, molecular docking on GPUs implemented in the learning process with reinforcement was used, and an algorithm was developed that allows converting the representations of connections generated by the SMILES network into the PDBQT format necessary for docking. To accelerate the learning of the neural network in the modified version of the REINVENT model, the AutoDock-Vina-GPU-2.1 docking program was used, and to clarify the results of its work, the procedure for revaluing the affinity of compounds to the target using the RFScore-4 evaluation function was used.Results. Using a modified version of the REINVENT model, more than 60,000 compounds were obtained, of which about 52,000 molecules have a binding energy value to the HIV-1 gp120 protein comparable to the value calculated for the HIV-1 inhibitor NBD-14204, used in calculations as a positive control. Of the 52,000 compounds selected, about 34,000 molecules satisfy the restrictions imposed on a potential drug to ensure its bioavailability when taken orally.Conclusion. The results obtained allow us to demonstrate the effectiveness of an adapted neural network by the example of designing new potential inhibitors of the gp120 HIV-1 protein capable of blocking the CD4- binding site of the gp120 virus envelope protein and preventing its penetration into host cells. more...
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- 2024
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4. Formulation and characterization of liposomes containing drug absorption enhancers for optimized anti-HIV and antimalarial drug delivery.
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Kheoane, Poloko Stephen, Enslin, Gillian Mary-Anne, and Tarirai, Clemence
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Most of the current clinically used anti-HIV and antimalarial drugs have low bioavailability, either due to poor solubility and permeability, rapid clearance from anatomical reservoirs and poor retention at their site of action (e.g. due to the p-glycoprotein efflux system), and extreme first-pass metabolism (e.g. by the cytochrome P450 enzymes). Hence, new approaches such as the incorporation of drug absorption enhancers (DAEs) (also referred to as bioenhancers) into dosage forms, and exploration of nanocarriers such as liposomes as novel dosage forms, are needed and may provide a viable means that could improve the bioavailability of both anti-HIV and antimalarial drugs. Liposomes loaded with efavirenz or mefloquine in combination with drug absorption enhancers, as well as placebo dosage forms, were prepared using a thin-lipid film hydration technique and characterized for their particle size and zeta potentials, entrapment efficiency, in vitro drug release, and in vitro drug permeability. Liposomes were further investigated for their biocompatibility (safety) using H-4-II-E liver cells in vitro. Drug-loaded liposomes prepared using l-α-phospatidylcholine, dioleoyl (DOPC) and cholesterol (CHOL) (1:1 mol/mol) as well as liposomes made of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), CHOL, and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (4:6:26 mol/mol/mol) exhibited the best results in terms of their entrapment efficiency, particle size, zeta potential, in vitro drug release, and permeability. DSPC:CHOL:DPPC liposomes released EFV-based formulations better than DPPC:CHOL liposomes for immediate release behaviour. DOPC:CHOL liposomes produced a controlled release and more drug was released in the presence of DAEs for both EFV (0.4-fold higher) and MQ-based (sevenfold higher) formulations in the first 2 h. However, these liposomes were less biocompatible (< 50% cell viability) with liver cells. DOPC:CHOL and DSPC:CHOL:DPPC liposomes could provide a useful nano-formulation platform, which could ensure drug loading, followed by sustained release of both anti-HIV and antimalaria drugs. [ABSTRACT FROM AUTHOR] more...
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- 2023
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5. Evaluation of COVID-19 protease and HIV inhibitors interactions
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Tran Linh, Tam Dao Ngoc Hien, Elhadad Heba, Hien Nguyen Minh, and Huy Nguyen Tien
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covid-19 ,sars-cov-2 ,docking study ,anti-hiv drugs ,protease inhibitors ,Pharmaceutical industry ,HD9665-9675 - Abstract
The epidemic of the novel coronavirus disease (COVID-19) that started in 2019 has evoked an urgent demand for finding new potential therapeutic agents. In this study, we performed a molecular docking of anti-HIV drugs to refine HIV protease inhibitors and nucleotide analogues to target COVID-19. The evaluation was based on docking scores calculated by AutoDock Vina and top binding poses were analyzed. Our results suggested that lopinavir, darunavir, atazanavir, remdesivir, and tipranavir have the best binding affinity for the 3-chymotrypsin-like protease of COVID-19. The comparison of the binding sites of three drugs, namely, darunavir, atazanavir and remdesivir, showed an overlap region of the protein pocket. Our study showed a strong affinity between lopinavir, darunavir, atazanavir, tipranavir and COVID-19 protease. However, their efficacy should be confirmed by in vitro studies since there are concerns related to interference with their active sites. more...
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- 2022
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6. Anti-HIV drugs lopinavir/ritonavir activate bitter taste receptors.
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Chen, Shurui, Zhou, Xinyi, Lu, Yongcheng, Xu, Keman, Wen, Jiao, and Cui, Meng
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BITTERNESS (Taste) , *ANTI-HIV agents , *TASTE receptors , *RITONAVIR , *HIV-positive children - Abstract
Lopinavir and ritonavir (LPV/r) are the primary anti-human immunodeficiency virus (HIV) drugs recommended by the World Health Organization for treating children aged 3 years and above who are infected with the HIV. These drugs are typically available in liquid formulations to aid in dosing for children who cannot swallow tablets. However, the strong bitter taste associated with these medications can be a significant obstacle to adherence, particularly in young children, and can jeopardize the effectiveness of the treatment. Studies have shown that poor palatability can affect the survival rate of HIV-infected children. Therefore, developing more child-friendly protease inhibitor formulations, particularly those with improved taste, is critical for children with HIV. The molecular mechanism by which lopinavir and ritonavir activate bitter taste receptors, TAS2Rs, is not yet clear. In this study, we utilized a calcium mobilization assay to characterize the activation of bitter taste receptors by lopinavir and ritonavir. We discovered that lopinavir activates TAS2R1 and TAS2R13, while ritonavir activates TAS2R1, TAS2R8, TAS2R13, and TAS2R14. The development of bitter taste blockers that target these receptors with a safe profile would be highly desirable in eliminating the unpleasant bitter taste of these anti-HIV drugs. [ABSTRACT FROM AUTHOR] more...
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- 2023
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7. Gaps and solutions of HIV testing, care, and treatment in Iran during 2018-2019
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SeyedAhmad SeyedAlinaghi, Behnam Farhoudi, Parvin Afsar Kazerooni, Mohammad Mehdi Gouya, Zeinab Najafi, Ali-Akbar Haghdoost, Hamid Sharifi, Katayoun Tayeri, Hengameh Namdari Tabar, Nima Ghalekhani, and Omid Dadras more...
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hiv testing ,antiretroviral therapy ,anti-hiv drugs ,hiv infection diagnosis ,hiv/aids testing. ,Medicine - Published
- 2021
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8. Current status of the small molecule anti-HIV drugs in the pipeline or recently approved.
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Umumararungu, Théoneste, Nyandwi, Jean Baptiste, Katandula, Jonathan, Twizeyimana, Eric, Claude Tomani, Jean, Gahamanyi, Noël, Ishimwe, Nestor, Olawode, Emmanuel Oladayo, Habarurema, Gratien, Mpenda, Matabishi, Uyisenga, Jeanne Primitive, and Saeed, Shamsaldeen Ibrahim more...
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AIDS , *NUCLEOSIDE reverse transcriptase inhibitors , *NON-nucleoside reverse transcriptase inhibitors , *ANTI-HIV agents , *HIV infections - Abstract
[Display omitted] Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) with high morbidity and mortality rates. Treatment of AIDS/HIV is being complicated by increasing resistance to currently used antiretroviral (ARV) drugs, mainly in low- and middle-income countries (LMICs) due to drug misuse, poor drug supply and poor treatment monitoring. However, progress has been made in the development of new ARV drugs, targeting different HIV components (Fig. 1). This review aims at presenting and discussing the progress made towards the discovery of new ARVs that are at different stages of clinical trials as of July 2024. For each compound, the mechanism of action, target biomolecule, genes associated with resistance, efficacy and safety, class, and phase of clinical trial are discussed. These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) – islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) – Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new classes which can delay the development of resistance. [ABSTRACT FROM AUTHOR] more...
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- 2024
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9. 2016—2020年我院门诊艾滋病抗病毒药使用情况分析.
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高爱苹, 黄 灿, 田艳平, 郑永红, 贾金梅, and 朱晓虹
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ANTI-HIV agents , *EMTRICITABINE-tenofovir , *AIDS patients , *HIV infections , *TENOFOVIR , *HOSPITAL patients , *DRUG abuse treatment - Abstract
OBJECTIVE: To investigate the application status and trend of anti-HIV drugs in outpatient department of this hospital, and analyze the application rationality. METHODS: Retrospective analysis method was performed to analyze the number, gender, age and frequency of visits of AIDS patients, patients with pre-exposure prevention and post-exposure blockade of HIV infection in outpatient department of the hospital from 2016 to 2020. According to the defined daily dose method recommended by WHO, defined daily dose system(DDDs), consumption sum of self-paid drugs, defined daily cost (DDC) and consumption sum ranking / DDDs ranking (B/ A) of all anti-HIV drugs in this hospital were analyzed and evaluated. RESULTS: From 2016 to 2019, the number of outpatients in this hospital for AIDS patients and patients with pre-exposure prevention and post-exposure blockade of HIV infection increased year by year, and decreased slightly in 2020. From 2016 to 2020, among the anti-HIV drugs in outpatient department of this hospital, the top five drugs ranked by DDDs were tenofovir, lamivudine, efavirenz, lopinavir, ritonavir and and zidomivir divudine, all of which were national free drugs, and the DDDs of tenofovir, lamivudine and efavirenz ranked the top three. The DDDs of self-paid drugs were relatively low, and the DDDs of some self-paid drugs increased in 2019, such as emtricitabine and tenofovir, and rilpivirine. The dosage and DDDs of elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide fumarate increased significantly in 2020. The DDC of self-paid drugs was higher, ranging from 40 yuan to 96 yuan, of which the DDC of rilpivirine was 40 yuan, and the DDC of dotiabalamib was 96 yuan; the B/ A of self-paid drugs were <1. CONCLUSIONS: The varieties of anti-HIV drugs in outpatient department of the hospital can basically meet the clinical needs, and the application of anti-HIV drugs is basically reasonable. [ABSTRACT FROM AUTHOR] more...
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- 2022
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10. Molecular Mechanisms of HIV Protease Inhibitors Against HPV-Associated Cervical Cancer: Restoration of TP53 Tumour Suppressor Activities
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Lilian Makgoo, Salerwe Mosebi, and Zukile Mbita
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cervical cancer ,human papilloma virus ,p53 ,HIV protease inhibitors ,E6 ,anti-HIV drugs ,Biology (General) ,QH301-705.5 - Abstract
Cervical cancer is a Human Papilloma virus-related disease, which is on the rise in a number of countries, globally. Two essential oncogenes, E6 and E7, drive cell transformation and cancer development. These two oncoproteins target two of the most important tumour suppressors, p53 and pRB, for degradation through the ubiquitin ligase pathway, thus, blocking apoptosis activation and deregulation of cell cycle. This pathway can be exploited for anticancer therapeutic interventions, and Human Immunodeficiency Virus Protease Inhibitors (HIV-PIs) have attracted a lot of attention for this anticancer drug development. HIV-PIs have proven effective in treating HPV-positive cervical cancers and shown to restore impaired or deregulated p53 in HPV-associated cervical cancers by inhibiting the 26S proteasome. This review will evaluate the role players, such as HPV oncoproteins involved cervical cancer development and how they are targeted in HIV protease inhibitors-induced p53 restoration in cervical cancer. This review also covers the therapeutic potential of HIV protease inhibitors and molecular mechanisms behind the HIV protease inhibitors-induced p53-dependent anticancer activities against cervical cancer. more...
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- 2022
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11. Gaps and solutions of HIV testing, care, and treatment in Iran during 2018-2019.
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SeyedAlinaghi, SeyedAhmad, Farhoudi, Behnam, Kazerooni, Parvin Afsar, Gouya, Mohammad Mehdi, Najafi, Zeinab, Haghdoost, Ali-Akbar, Sharifi, Hamid, Tayeri, Katayoun, Tabar, Hengameh Namdari, Ghalekhani, Nima, and Dadras, Omid more...
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Introduction: Human immunodeficiency virus (HIV) test-treat-retain cascade analysis, is a model to identify gaps at every stage of service delivery, and formulate potential solutions to enhance coverage of these services, as we aimed to carry out in the present study. Material and methods: In order to detect problems, develop solutions, and further prioritize them at different stages of HIV cascade, Fishbone analysis model (WHO 2018) was used. At first, an Excel file including 15 sheets was constructed, each sheet for a significant demographic data of sub-group covering all key populations. Within each sheet, cascade diagram for diagnostic services, connection to services, treatment, and suppression of viral load was demonstrated. Excel file was sent to 28 key persons. Participants were instructed to identify problems in each stage and list all probable reasons for every specific problem. These reasons were classified into six groups based on Fishbone model, including: 1) policies/guidelines; 2) service/program management; 3) human resources; 4) supplies; 5) services delivery methods; and 6) patient/client-related factors. Subsequently, participants were instructed to propose their potential solutions to address these obstacles. Finally, four key informants prioritized the problems and suggested solutions. Results: Analysis of the most important solutions (with 10-12 scores) proposed by key persons of the five groups, including the increase of society awareness, addressing the stigma of HIV disease in mass media, collaboration between politics and health parties to enhance society knowledge, expanding the treatment and counseling centers and facilities across the country, healthcare workers training to provide valid and reliable guidance and information to people who live with HIV, and refer them to designated centers for care, counseling, and treatment as well as appropriate patient detection, mapping procedure, and gathering precise statistics, and finally, employment of professional caregivers in counseling and testing centers. Conclusions: Based on the identified gaps, innovative strategies to improve HIV testing and early case detection, particularly for key populations, are critical to reach the 90-90-90 target of the UNIAID. [ABSTRACT FROM AUTHOR] more...
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- 2021
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12. Stability Indicating Analytical Method for Estimation of Related substances of Anti-HIV Drugs in Fixed dose Tablet Formulation by RP-HPLC.
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PATEL, PARTH, PASHA, T. Y., PATEL, SHYAMAL, VIHOL, BHUPAT, SOLANKI, SAGAR, and SADIWALA, JUHI
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ANTI-HIV agents , *HIGH performance liquid chromatography , *GRADIENT elution (Chromatography) , *LAMIVUDINE , *EFAVIRENZ - Abstract
Related substance is a test which quantitates impurities in formulation. This research paper presents a logical and scientific development & validation of analytical method for estimation of impurities of Lamivudine, Tenofovir disoproxil fumarate & Efavirenz in fixed dose tablet formulation. Estimation of impurities of Lamivudine, Tenofovir disoproxil fumarate & Efavirenz in fixed dose tablet formulation was conducted by RPHPLC. The separation was achieved under optimized chromatographic condition on an Inertsil ODS-3 150×4.6mm; 5μm column with mobile phase-A consist of 20mM acetate buffer pH-3.8±0.05: Methanol (95:5 %v/v) & mobile phase-B consist of 20mM acetate buffer pH-3.8±0.05: Methanol (5:95 %v/v) with gradient elution at a flow rate of 1.0 mL/min using 35°C column oven temperature with PDA detection at 260 nm. The method was validated as per ICH and USP guideline and the values were found to be within the limits. So, the proposed method was found to be simple, linear, accurate, precise, robust and specific. [ABSTRACT FROM AUTHOR] more...
- Published
- 2021
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13. Eficacia y seguridad en condiciones clínicas reales del raltegravir en un hospital de referencia del seguro social peruano.
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Pichardo-Rodriguez, Rafael, Saavedra-Velasco, Marcos, Mendo-Urbina, Fernando, Muñoz-Medina, Carlos, Zegarra del Rosario-Alvarado, Saarah C., and Antonio Grandez-Urbina, J.
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Introducción: El Rategravir pertenece a los inhibidores de integrasas, quedando demostrado y aprobado por diversos ensayos clínicos como un potente antirretroviral seguro y eficaz para el tratamiento de pacientes infectados con el virus de inmunodeficiencia humana (VIH), con buena tolerancia y baja toxicidad, incluyéndose en el esquema de tercera línea o rescate y se inicia cuando los esquemas de primera y segunda línea han fracasado. Objetivo: Evaluar la eficacia y seguridad en condiciones clínicas reales del uso de Raltegravir dentro de los esquemas de la Terapia Antiretroviral de Gran Actividad (TARGA) en pacientes con infección por VIH en un hospital de referencia del seguro social en Perú. Métodos: Se realizó un estudio observacional retrospectivo en pacientes con diagnóstico de infección por VIH que iniciaron tratamiento dentro del esquema TARGA basados en Raltegravir con seguimiento y control a los 6 meses. Se presentaron medidas de resumen de frecuencias y porcentajes para las variables cualitativas, así como medias y desviación estándar para las variables cuantitativas en base a los resultados de las pruebas de normalidad. Los datos fueron procesados y analizados en el software estadístico SPSS versión 22. Resultados: El género masculino fue el más afectado con un 76%(n=119) del total. El rango de edad más frecuente fue el comprendido entre los 45 a 55 años (25,4%; n=40). Las comorbilidades más frecuentes fueron Diabetes mellitus e Hipertensión arterial, con reducción exponencial de la carga viral y elevación de los niveles de linfocitos CD4. Conclusión: El Raltegravir es eficaz para el tratamiento de pacientes VIH. [ABSTRACT FROM AUTHOR] more...
- Published
- 2021
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14. Oral environment and taste function of Japanese HIV-infected patients treated with antiretroviral therapy.
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Shintani, T., Fujii, T., Yamasaki, N., Kitagawa, M., Iwata, T., Saito, S., Okada, M., Ogawa, I., Unei, H., Hamamoto, K., Nakaoka, M., Kurihara, H., and Shiba, H.
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ORAL microbiology , *BACTERIA , *CANDIDA , *HIV infections , *HIV-positive persons , *HUMIDITY , *ORAL hygiene , *SALIVA , *SENSES , *TASTE , *TASTE disorders , *TOOTH care & hygiene , *ANTIRETROVIRAL agents , *CD4 lymphocyte count , *DISEASE risk factors - Abstract
The aim of the study was to evaluate the oral environment and the taste function of Japanese HIV-infected patients treated with antiretroviral therapy. Their median age of 73 patients taking anti-HIV drugs was 46 years. The median period of taking anti-HIV drugs was 30 months. The oral condition was evaluated by measurement of oral moisture, amount of saliva secretion, the number of oral bacteria, presence of oral candida, a taste test, and the number of missing teeth. The levels of oral moisture and secreted saliva were significantly lower in the HIV-infected group than in the healthy volunteer (control) group. The HIV-infected group showed a more robust decrease in taste sensation than the control group. The number of missing teeth was significantly higher in the HIV-infected group than in the control group. Furthermore, all of the evaluated oral conditions were worse in the HIV-infected patients whose CD4+ T lymphocyte counts were less than 500/mm3 than in the control group. It became clear that the patients taking anti-HIV drugs, especially the CD4+ count < 500/mm3 group, had a deteriorated oral environment and dysgeusia, suggesting that the management of oral hygiene is necessary to maintain oral health, which leads to systemic health. [ABSTRACT FROM AUTHOR] more...
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- 2020
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15. LDH hybrid thermosensitive hydrogel for intravaginal delivery of anti-HIV drugs.
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Tian, Wenxue, Han, Shangcong, Huang, Xia, Han, Mei, Cao, Jie, Liang, Yan, and Sun, Yong
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ANTI-HIV agents , *HYDROGELS , *LAYERED double hydroxides , *BODY temperature , *HIV infection transmission , *HIV , *TRANSITION temperature - Abstract
Microbicides based on hydrogel have become an effective way to prevent the HIV replication and transmission because of their convenience and prolonging drug release. In this study, a hybrid thermo-sensitive hydrogel constituted by nanosized layered double hydroxides and poloxamer 407 (P407) was constructed and co-loaded with both hydrophobic and hydrophilic drug. The LDH-P407 hydrogel could achieve sol–gel transition at body temperature. The in vivo experiment showed that LDH-P407 hydrogel can achieve controlled release of theaflavin and Nile red (hydrophobic drug model) into blood by vaginal drug delivery, meanwhile the hydrogel showed barely mucosal irritation. In addition, ex vivo experiment showed that the nifeviroc-loaded LDH-P407 hydrogel was able to specifically bind co-receptor CCR5 of DCs cells. Therefore, the LDH-P407 hydrogel would be a promising carrier for intravaginal delivery of anti-HIV drugs. [ABSTRACT FROM AUTHOR] more...
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- 2019
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16. Evaluation of COVID-19 protease and HIV inhibitors interactions
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Dao Ngoc Hien Tam Tam, Heba Elhadad, Linh Tran, Nguyen Minh Hien, and Nguyen Tien Huy
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medicine.medical_treatment ,protease inhibitors ,Pharmaceutical Science ,Pharmacology ,medicine.disease_cause ,anti-hiv drugs ,COVID-19 ,SAR-CoV-2 ,docking study ,anti-HIV drugs ,medicine ,HIV Protease Inhibitor ,Darunavir ,Pharmaceutical industry ,Coronavirus ,Protease ,Chemistry ,virus diseases ,Lopinavir ,General Medicine ,Atazanavir ,sars-cov-2 ,covid-19 ,Docking (molecular) ,HD9665-9675 ,Tipranavir ,medicine.drug - Abstract
The epidemic of the novel coronavirus disease (COVID-19) that started in 2019 has evoked an urgent demand for finding new potential therapeutic agents. In this study, we performed a molecular docking of anti-HIV drugs to refine HIV protease inhibitors and nucleotide analogues to target COVID-19. The evaluation was based on docking scores calculated by AutoDock Vina and top binding poses were analyzed. Our results suggested that lopinavir, darunavir, atazanavir, remdesivir, and tipranavir have the best binding affinity for the 3-chymotrypsin-like protease of COVID-19. The comparison of the binding sites of three drugs, namely, darunavir, atazanavir and remdesivir, showed an overlap region of the protein pocket. Our study showed a strong affinity between lopinavir, darunavir, atazanavir, tipranavir and COVID-19 protease. However, their efficacy should be confirmed by in vitro studies since there are concerns related to interference with their active sites. more...
- Published
- 2022
17. HIV - recentes avanços na pesquisa de fármacos HIV - highlights in drug research
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Wilson Cunico, Claudia R. B. Gomes, and Walcimar T. Vellasco Junior
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anti-HIV drugs ,AIDS ,new drugs ,Chemistry ,QD1-999 - Abstract
The development of new antiretroviral drugs is a dynamic process that is continuously fueled by identification of new molecular targets and new compounds for know targets. The current available drugs can be classified into five categories: nucleoside analogues reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and entry inhibitors (fusion inhibitors and CCR5 antagonist). In addition, the maturation inhibitors may be considered as potential target for chemotherapeutic intervention. This review presents some anti-HIV agents that have already gone through the advance development process for final approval for the treatment of AIDS. more...
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- 2008
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18. Efetividade da terapia anti-retroviral dupla e tríplice em crianças infectadas pelo HIV Effectiveness of dual and triple antiretroviral therapy in the treatment of HIV-infected children
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Roberta M. C. Romanelli, Jorge A. Pinto, Laura J. Melo, Mariana A. Vasconcelos, and Rafael de Matos Pereira
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Síndrome da imunodeficiência adquirida ,agentes anti-HIV ,terapêutica ,Acquired immunodeficiency syndrome ,anti-HIV drugs ,therapy ,Pediatrics ,RJ1-570 - Abstract
OBJETIVOS: Como iniciar a terapia anti-retroviral é uma questão amplamente discutida no manejo de crianças infectadas pelo HIV. O objetivo deste estudo foi comparar a efetividade da terapia dupla e tríplice em uma coorte de crianças infectadas pelo HIV. MÉTODO: Este estudo foi realizado em um serviço de referência para assistência à criança infectada da Faculdade de Medicina da UFMG. Foram incluídas crianças que iniciaram o primeiro regime anti-retroviral entre janeiro de 1998 e dezembro de 2000, com seguimento até dezembro de 2001. O evento final para análise foi a primeira falha terapêutica ou óbito. RESULTADOS: Foram analisados 101 pacientes, sendo 58 (57,4%) e 43 (42,6%) com terapia dupla e tríplice, respectivamente. Não houve diferença entre os grupos quanto ao sexo, idade, contagem de linfócitos CD4+ e carga viral basal. A média de duração da terapia dupla foi de 26,3 meses (IC95% 21,3-31,3) e da terapia tríplice, de 34,3 meses (IC95% 29,2-39,5%). Falha terapêutica ocorreu em 33 (56,9%) pacientes em terapia dupla e 11 (25,6%) em terapia tríplice (log rank 5,03; p = 0,025). O risco relativo de falha para terapia dupla foi 2,2 vezes maior (IC = 1,3-3,9). O percentual de linfócitos T CD4+ inicial foi preditor de risco para falha terapêutica (p = 0,001). Pacientes em terapia tríplice apresentaram maior redução da carga viral (p = 0,001). CONCLUSÃO: A terapia tríplice permaneceu eficaz por mais tempo e apresentou melhor resposta virológica do que a terapia dupla nesta coorte de crianças infectadas pelo HIV, justificando a sua escolha como regime preferencial de tratamento.OBJECTIVE: The use of antiretroviral therapy in HIV-infected children has been a widely discussed issue. The aim of this study was to compare the effectiveness of dual nucleoside analogue reverse transcriptase inhibitor (NRTI) regimens and three-drug regimens [2NRTI+ non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI)] in a cohort of HIV-infected children. METHODS: The study was carried out in a referral center for the management of infected children, which is affiliated with the School of Medicine of Universidade Federal de Minas Gerais (UFMG). Those children whose antiretroviral therapy was implemented between January 1998 and December 2000 and who were followed up until December 2001 were included in the study. Therapeutic failure or death was regarded as the endpoint in our analysis. RESULTS: A total of 101 patients were assessed, 58 (57.4%) on dual therapy and 43 (42.6%) on triple therapy. No statistically significant difference was observed between the groups in terms of gender, age, CD4+ count and baseline viral load. The average duration of dual therapy was 26.3 months (95%CI 21.3-31.3) and that of triple therapy was 34.3 months (95%CI 29.2-39.5%). There was therapeutic failure in 33 (56.9%) patients on dual therapy and in 11 (25.6%) patients on triple therapy (log rank = 5.03; p = 0.025). The relative risk of therapeutic failure of the dual therapy was 2.2 times higher (95%CI = 1.3-3.9). The percentage of initial CD4+ T cells was a predictor of risk for therapeutic failure (p = 0.001). Patients on triple therapy showed a more remarkable reduction in their viral load (p = 0.001). CONCLUSION: Triple therapy was efficient for a longer time period and showed better virologic response than dual therapy in this cohort of HIV-infected children. Therefore, triple therapy should be the treatment of choice. more...
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- 2006
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19. Computer-aided discovery of anti-HIV agents.
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Jorgensen, William L.
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ANTI-HIV agents , *COMPUTER-aided design , *NON-nucleoside reverse transcriptase inhibitors , *BIOLOGICAL assay , *CRYSTALLOGRAPHY , *FREE energy (Thermodynamics) - Abstract
A review is provided on efforts in our laboratory over the last decade to discover anti-HIV agents. The work has focused on computer-aided design and synthesis of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) with collaborative efforts on biological assaying and protein crystallography. Numerous design issues were successfully addressed including the need for potency against a wide range of viral variants, good aqueous solubility, and avoidance of electrophilic substructures. Computational methods including docking, de novo design, and free-energy perturbation (FEP) calculations made essential contributions. The result is novel NNRTIs with picomolar and low-nanomolar activities against wild-type HIV-1 and key variants that also show much improved solubility and lower cytotoxicity than recently approved drugs in the class. [ABSTRACT FROM AUTHOR] more...
- Published
- 2016
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20. Repurposing of the anti-HIV drug emtricitabine as a hydrogen-bonded cleft for bipyridines via cocrystallization
- Author
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Gonzalo Campillo-Alvarado, Leonard R. MacGillivray, Elizabeth A. Keene, and Dale C. Swenson
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Hydrogen ,Chemistry ,Hydrogen bond ,Supramolecular chemistry ,chemistry.chemical_element ,General Chemistry ,Condensed Matter Physics ,Emtricitabine ,Combinatorial chemistry ,Bipyridine ,chemistry.chemical_compound ,medicine ,Anti-hiv drugs ,General Materials Science ,Repurposing ,medicine.drug - Abstract
We report supramolecular repurposing of emtricitabine (FTC, trade name: Emtriva®), a blockbuster FDA-approved anti-HIV agent. FTC is revealed to act as a hydrogen-bonded cleft for bipyridine recognition. The supramolecular repurposing is realized by the generation of four cocrystals through liquid-assisted grinding. The clefts comprise discrete three-component assemblies sustained by a combination of hydrogen bonds and π⋯π interactions. more...
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- 2020
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21. The structural effect on volumetric and acoustic properties of aqueous anti-HIV drugs (Emtricitabine and Lamivudine) at various temperatures.
- Author
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Devunuri, Nagaraju, Amminabavi, Nagaraj, Chennuri, Bharath Kumar, Losetty, Venkatramana, and Gardas, Ramesh L.
- Subjects
- *
VOLUMETRIC analysis , *AQUEOUS solutions , *ANTI-HIV agents , *LAMIVUDINE , *TEMPERATURE effect , *EMTRICITABINE - Abstract
In this work, density ( ρ ) and speed of sound ( u ) data were measured for aqueous solutions of two drugs namely Emtricitabine and Lamivudine in the various concentrations, m from (293.15 to 318.15) K and at 0.1 MPa pressure. The measured density and speed of sound data were used to calculate the apparent molar volume ( V ϕ ) and the isentropic compressibility ( κ s ), using Laplace–Newton's equation. The apparent molar volume at infinite dilutions ( V ϕ ∞ ) of drugs has been evaluated from linear equation. The temperature dependence of apparent molar volume at infinite dilution ( V ϕ ∞ ) can be expressed as the second-order polynomial equation, in turn apparent molar expansibility ( E ϕ ∞ ) at infinite dilution was calculated. These parameters have been used to understand the effect of temperature on interactions between drugs and water. Moreover, the structure making and breaking ability of drugs are analyzed at experimental conditions. [ABSTRACT FROM AUTHOR] more...
- Published
- 2016
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22. 基于专利计量分析的抗 HIV 药物发展趋势研究.
- Author
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张婷 and 贾晓峰
- Abstract
In recent years, there is a sharp increase in the number of HIV infections, which have become a major threat to human health diseases. In order to research deeply the status and development trends of anti-HIV drugs, we retrieved the anti-HIV drugs' patents in the Derwent Innovations Index, and used the TDA to cleaning the data. We used the method of patentometrics by visual analysis tools to analyze patent literatures of anti-HIV drugs on number of patent application quantity, priority countries, patent assignees and technical fields. After analyzing and processing, we found that the number of anti-HIV drugs' patent applications is relatively stable in recent years; patent applications are mainly in the United States, Canada and China; technical fields of anti-HIV drugs are mainly concentrated in natural products, fermentation industry and heterocyclic compounds. The number of patent applications in the United States is far ahead of other countries, owing strong technical strength. Although China has certain advantages in the number of patent applications, there is still a wide gap as compared with foreign countries. [ABSTRACT FROM AUTHOR] more...
- Published
- 2015
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23. Anti-HIV-drug and phyto-flavonoid combination against SARS-CoV-2: a molecular docking-simulation base assessment
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Shasank S. Swain, Satya R. Singh, Tahziba Hussain, Alaka Sahoo, and Sanghamitra Pati
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Drug ,Combination therapy ,Anti-HIV Agents ,phyto-flavonoid ,medicine.medical_treatment ,media_common.quotation_subject ,030303 biophysics ,severe acute respiratory syndrome ,Molecular Dynamics Simulation ,Pharmacology ,Ligands ,Molecular Docking Simulation ,03 medical and health sciences ,Structural Biology ,Humans ,Medicine ,Protease Inhibitors ,Protease inhibitor (pharmacology) ,Molecular Biology ,Darunavir ,media_common ,Flavonoids ,0303 health sciences ,Protease ,SARS-CoV-2 ,business.industry ,fungi ,virus diseases ,General Medicine ,COVID-19 Drug Treatment ,Coronavirus ,Docking (molecular) ,molecular docking-simulation ,anti-HIV drugs ,business ,Viral genome replication ,Research Article ,medicine.drug - Abstract
At the health emergence, no such potent prophylactic therapy is available to control the deadly emerged Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). However, existing antiviral, anti-inflammatory, antimalarial drugs is the only option against SARS-CoV-2, but it may be harmful to patients without more clinical evidence. As an alternative solution, we proposed a newer hypothesis using the selective 10 potent anti-HIV drugs and flavonoid class of phytochemicals from previous reports to use in combination against SARS-CoV-2. Primarily, 10 anti-HIV protease inhibitor drugs and 10 phyto-flavonoids as ligands in molecular docking study against the putative target, the SARS-CoV-2-main protease (Mpro) ID: 6Y2E), as an essential enzyme in viral genome replication. According to molecular docking and drug-ability scores of each ligand, the anti-HIV drug, the darunavir (with a docking score, −10.25 kcal/mol and drug-likeness rating, 0.60) and the quercetin-3-rhamnoside (with a docking score, −10.90 kcal/mol and drug-likeness rating, 0.82) were selected for further analysis in combined effect. Perceptibly, the combined ‘anti-HIV drug and phyto-flavonoid’ docking complex has actively interacted with eight strong H-bonds with stability, briefly elucidated through RMRD-, RMSF- Rg-plots and MM/PBSA-binding energy calculation during 100 ns than the individual against SARS-CoV-2-Mpro. Thus, the ‘anti-HIV-drug-phyto-flavonoid’ combination therapy could be used against SARS-CoV-2 after some experimental validation. Communicated by Ramaswamy H. Sarma more...
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- 2021
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24. HIV Patients Have Impaired Diastolic Function that is Not Aggravated by Anti-Retroviral Treatment.
- Author
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Fontes-Carvalho, Ricardo, Mancio, Jennifer, Marcos, Acúrcio, Sampaio, Francisco, Mota, Margarida, Rocha Gonçalves, Francisco, Gama, Vasco, Azevedo, Ana, and Leite-Moreira, Adelino
- Abstract
Purpose: Recent studies have shown that HIV infection is independently associated with heart failure. Diastolic dysfunction (DD) is frequent in HIV patients, but it is unclear whether this is an effect of the HIV infection itself or of the anti-retroviral therapy (ART). Our aim was to compare diastolic function in HIV treatment-naïve, HIV-ART patients and controls. Methods: We prospectively enrolled 206 consecutive patients with HIV-1 infection and 30 controls, selected by frequency matching for age and sex. HIV patients were divided in two subgroups: ART-naïve ( n = 88) and ART ( n = 118). Diastolic function was assessed and graded by echocardiography, according to modern consensus criteria and using tissue Doppler analysis. Results: Compared to controls, ART-naïve patients had lower E' velocities (E' septal: 10.2 ± 2.4 vs 11.9 ± 2.6 cm/s, p = 0.02), higher E/E' ratio (7.8 ± 1.9 vs 6.9 ± 1.6, p = 0.02) and higher prevalence of DD (19 % vs 3.3 %, p = 0.05). HIV patients under ART also had worse diastolic function compared to controls (E' septal: 10.3 ± 2.5 cm/s; p < 0.01; E/E'ratio: 8.0 ± 2.0, p < 0.01; DD prevalence: 23 %; p = 0.01), but no significant differences were found between ART-naïve and ART HIV subgroups. In multivariable logistic regression analysis, age and body mass index were the only independent predictors of reduced diastolic reserve in HIV patients. Regarding systolic function, there were no significant differences in ejection fraction or S' velocities between controls and HIV subgroups. Conclusions: HIV treatment-naïve patients have reduced diastolic reserve that is not worsened by ART. These data reinforce the association of diastolic dysfunction with the HIV infection itself and not with the anti-retroviral therapy. [ABSTRACT FROM AUTHOR] more...
- Published
- 2015
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25. Synergistic activity of tenofovir and nevirapine combinations released from polycaprolactone matrices for potential enhanced prevention of HIV infection through the vaginal route.
- Author
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Dang, Nhung T.T., Sivakumaran, Haran, Harrich, David, Shaw, Paul N., Davis-Poynter, Nicholas, and Coombes, Allan G.A.
- Subjects
- *
TENOFOVIR , *NEVIRAPINE , *HIV prevention , *DRUG synergism , *POLYCAPROLACTONE , *COMBINATION drug therapy , *VAGINA , *CONTROLLED release drugs , *THERAPEUTICS - Abstract
Polycaprolactone (PCL) matrices were simultaneously loaded with the antiviral agents, tenofovir (TFV) and nevirapine (NVP), in combination to provide synergistic activity in the prevention of HIV transmission through the vaginal route. TFV and NVP were incorporated in PCL matrices at theoretical loadings of 10%TFV–10% NVP, 5%TFV–5%NVP and 5%TFV–10%NVP, measured with respect to the PCL content of the matrices. Actual TFV loadings ranged from 2.1% to 4.2% equating to loading efficiencies of about 41–42%. The actual loadings of NVP were around half those of TFV (1.2–1.9%), resulting in loading efficiencies ranging from 17.2% to 23.5%. Approximately 80% of the initial content of TFV was released from the PCL matrices into simulated vaginal fluid (SVF) over a period of 30 days, which was almost double the cumulative release of NVP (40–45%). The release kinetics of both antivirals over 30 days were found to be described most satisfactorily by the Higuchi model. In vitro assay of release media containing combinations of TFV and NVP released from PCL matrices confirmed a potential synergistic/additive effect of the released antivirals on HIV-1 infection of HeLa cells. These findings indicate that PCL matrices loaded with combinations of TFV and NVP provide an effective strategy for the sustained vaginal delivery of antivirals with synergistic/additive activity. [ABSTRACT FROM AUTHOR] more...
- Published
- 2014
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26. Quantitative structure-activity relationship studies of diarylpyrimidine derivatives as anti-HIV drugs using new three-dimensional structure descriptors.
- Author
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Tong, Jianbo, Zhong, Li, Zhao, Xiang, Liu, Shuling, and Wang, Ping
- Abstract
A novel three-dimensional holographic vector of atomic interaction field (3D-HoVAIF) was used to describe the chemical structures of 34 wild-type DAPYs, 33 mutant form L100I, 30 mutant form Y181C and 29 mutant form Y188L as anti-HIV drugs. Here four quantitative structure activity relationship models were built by partial least square regression. The estimation stability and prediction ability of models were strictly analyzed by both internal and external validations. The correlation coefficient ( R), leave-one-out cross-validation correlation coefficient ( Q) and predicted values versus experimental ones of external samples ( Q) were 0.925, 0.769 and 0.949 for 34 diarylpyrimidines; 0.899, 0.788 and 0.889 for 33 mutant form L100I; 0.844, 0.761 and 0.935 for 30 mutant form Y181C; 0.890, 0.757 and 0.912 for 29 mutant form Y188L. These values indicated that the built PLS models had both favorable estimation stability and good prediction capabilities. Furthermore, the satisfactory results showed that 3D-HoVAIF could preferably express the information related to the biological activity of DAPY derivatives. [ABSTRACT FROM AUTHOR] more...
- Published
- 2014
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27. Role of Structural Flexibility of HIV-1 Integrase in the Design of Potent Anti-HIV Drugs
- Author
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Vinuth Chikkamath and Anantha Naik Nagappa
- Subjects
Flexibility (engineering) ,business.industry ,Hiv 1 integrase ,Anti-hiv drugs ,Medicine ,business ,Virology - Published
- 2018
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28. Flexibility of Important HIV-1 Targets and in silico Design of anti- HIV Drugs
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Evans C. Coutinho, Driss Cherqaoui, Satya P. Gupta, Ismail Hdoufane, Imane Bjij, Blessy Joseph, and Elvis A. F. Martis
- Subjects
Flexibility (engineering) ,business.industry ,In silico ,Human immunodeficiency virus (HIV) ,Anti-hiv drugs ,Medicine ,Computational biology ,business ,medicine.disease_cause - Published
- 2018
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29. Determination of the Anti‐HIV Drug Nevirapine Using Electroactive 2D Material Pd@rGO Decorated with MoS 2 Quantum Dots
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Rajiv Prakash, Preeti Tiwari, and Narsingh R. Nirala
- Subjects
Materials science ,Nevirapine ,Nanocomposite ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Quantum dot ,medicine ,Anti-hiv drugs ,0210 nano-technology ,medicine.drug - Published
- 2018
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30. NCp7: targeting a multitask protein for next-generation anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders
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Luca Sancineto, Nunzio Iraci, Oriana Tabarrini, and Claudio Santi
- Subjects
0301 basic medicine ,Multiple stages ,Drug ,Anti-HIV Agents ,media_common.quotation_subject ,Virus Replication ,Viral Proteins ,03 medical and health sciences ,Nucleic Acids ,Drug Discovery ,Anti-hiv drugs ,Humans ,Pharmacology ,Drug Discovery3003 Pharmaceutical Science ,Amino Acid Sequence ,Chaperone activity ,Amino Acid Sequence, Anti-HIV Agents, Humans, Nucleic Acids, Nucleocapsid Proteins, Protein Binding, Viral Proteins, Virus Replication ,media_common ,Chemistry ,Nucleocapsid Proteins ,3. Good health ,030104 developmental biology ,Biochemistry ,Nucleic acid ,Protein Binding - Abstract
Nucleocapsid protein 7 (NCp7) represents a viable target not yet reached by the currently available antiretrovirals. It is a small and highly basic protein, which is essential for multiple stages of the viral replicative cycle, with its structure preserved in all viral strains, including clinical isolates. NCp7 can be inhibited covalently, noncovalently and by shielding the nucleic acid (NA) substrates of its chaperone activity. Although covalent NCp7 inhibitors have already been detailed in the first part of this review series, the focus here is based on noncovalent and NA-binder inhibitors and on the analysis of the NCp7 3D structure to deliver fruitful insights for future drug design strategies. more...
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- 2018
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31. Computational analysis of CYP3A4-mediated metabolism to investigate drug interactions between anti-TB and anti-HIV drugs in HIV/TB co-infection.
- Author
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Mannu, Jayakanthan, Jenardhanan, Pranitha, and Mathur, Premendu
- Abstract
The treatment of human immunodeficiency virus (HIV)-related tuberculosis (TB) includes combination therapy, in which antiretroviral drugs and anti-TB drugs are co-administered. The complexities associated with the treatment of dual infection by Mycobacterium tuberculosis and HIV include occurrence of drug-drug interactions, in addition to pill burden, overlapping drug toxicity, and immune reconstitution inflammatory syndrome. Drug-drug interactions can occur between these drugs toward cytochrome P450 3A4 (CYP3A4), a drug-metabolizing enzyme. A thorough understanding of these interactions can prevent occurrence of treatment failures and drug toxicity. Molecular docking studies were carried out for FDA-approved drugs, to predict binding mechanism of anti-TB drugs with CYP3A4 and to compare them with our previous studies on antiretroviral drugs, in order to infer possible occurrence of drug-drug interactions. The core regimen of anti-TB treatment viz., rifampin (RIF), isoniazid (INH), and pyrazinamide (PZA) showed similar binding mode (i.e., competitive binding) via utilizing the same binding residue, Arg212 in CYP3A4. This regimen also shared similar binding mode with antiretroviral protease inhibitors except tipranavir, nelfinavir, lopinavir, and atazanavir. Contraindicated drug interactions were not observed between non-nucleoside reverse transcriptase inhibitors, delavirdine, efavirenz, and etravirine; and anti-TB drugs, RIF, INH, and PZA. The contraindications occurring within anti-TB drugs can be negated with inhibitory effect of INH to induction effect of RIF toward CYP3A4. We evaluated the importance of Arg212 along with Ser119, Ala370, Arg372, and heme moiety for mediating oxidative metabolism of drugs. These drug interaction details were incorporated into our web server by creating a database called 'CYP3A4 DDI' and it is open accessible from . [ABSTRACT FROM AUTHOR] more...
- Published
- 2014
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32. Uninformative variable elimination assisted by Gram–Schmidt Orthogonalization/successive projection algorithm for descriptor selection in QSAR.
- Author
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Omidikia, Nematollah and Kompany-Zareh, Mohsen
- Subjects
- *
GRAM-Schmidt process , *ORTHOGONALIZATION , *QSAR models , *REGRESSION analysis , *LEAST squares , *ANTI-HIV agents - Abstract
Abstract: Employment of Uninformative Variable Elimination (UVE) as a robust variable selection method is reported in this study. Each regression coefficient represents the contribution of the corresponding variable in the established model, but in the presence of uninformative variables as well as collinearity reliability of the regression coefficient's magnitude is suspicious. Successive Projection Algorithm (SPA) and Gram–Schmidt Orthogonalization (GSO) were implemented as pre-selection technique for removing collinearity and redundancy among variables in the model. Uninformative variable elimination-partial least squares (UVE-PLS) was performed on the pre-selected data set and Cvalue's were calculated for each descriptor. In this case the Cvalue's of UVE assisted by SPA or GSO could be used in order to rank the variables according to their importance. Leave-many-out cross-validation (LMO-CV) was applied to ordered descriptors for selecting optimal number of descriptors. Selwood data including 31 molecules and 53 descriptors, and anti-HIV data including 107 molecules and 160 descriptors were utilized in this study. When GSO pre-selection method is used for the Selwood data and SPA for the anti-HIV data set, obtained results were desired not only in the prediction ability of the constructed model but also in the number of selected informative descriptors. By applying GSO-UVE-PLS to the Selwood data, in an optimized condition, seven descriptors out of 53 were selected with q2 =0.769 and R 2 =0.915. Also applying SPA-UVE-PLS on the anti-HIV data, nine descriptors were selected out of 160 with q2 =0.81, R 2 =0.84 and Q2 F3 =0.8. [Copyright &y& Elsevier] more...
- Published
- 2013
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33. Clinical development of monoclonal antibody-based drugs in HIV and HCV diseases.
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Flego, Michela, Ascione, Alessandro, Cianfriglia, Maurizio, and Vella, Stefano
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ANTIVIRAL agents , *DRUG resistance , *COMMUNICABLE diseases , *MONOCLONAL antibodies , *HIV , *HEPATITIS C virus - Abstract
Today there are many licensed antiviral drugs, but the emergence of drug resistant strains sometimes invalidates the effects of the current therapies used in the treatment of infectious diseases. Compared to conventional antiviral drugs, monoclonal antibodies (mAbs) used as pharmacological molecules have particular physical characteristics and modes of action, and, therefore, they should be considered as a distinct therapeutic class. Despite being historically validated, antibodies may represent a novel tool for combatting infectious diseases. The current high cost of mAbs' production, storage and administration (by injection only) and the consequent obstacles to development are outweighed by mAbs' clinical advantages. These are related to a low toxicity combined with high specificity and versatility, which allows a specific antibody to mediate various biological effects, ranging from the virus neutralization mechanisms to the modulation of immune responses. This review briefly summarizes the recent technological advances in the field of immunoglobulin research, and the current status of mAb-based drugs in clinical trials for HIV and HCV diseases. For each clinical trial the available data are reported and the emerging conceptual problems of the employed mAbs are highlighted. This overview helps to give a clear picture of the efficacy and challenges of the mAbs in the field of these two infectious diseases which have such a global impact. [ABSTRACT FROM AUTHOR] more...
- Published
- 2013
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34. Lamivudine salts with improved solubilities.
- Author
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Martins, Felipe T., Bonfilio, Rudy, De Araújo, Magali B., and Ellena, Javier
- Subjects
- *
LAMIVUDINE , *DRUG solubility , *ANTI-HIV agents , *CRYSTAL structure , *NUCLEOSIDES , *DNA structure , *X-ray diffraction - Abstract
To optimize solubility of drugs, current strategies mainly focus on engineering and screening of smart crystal phases. Two salts of the anti-human immunodeficiency virus (HIV) drug lamivudine-namely, lamivudine hydrochloride and lamivudine hydrochloride monohydrate, were prepared in the course of screening the crystallization conditions of lamivudine duplex, an uncommon DNA-mimic, double-stranded helical structure made up of partially protonated drug pairs. Here, water solubilities of lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex are reported. The aqueous solubility of this anti-HIV drug was significantly increased in both salts and also in lamivudine duplex in relation to the water solubility of lamivudine form II. In comparison with the lamivudine form II incorporated into therapeutic formulations, the drug solubility was increased at a temperature of 299 ± 2 K by factors of 1.2, 3.3, and 4.5 in lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex, respectively, demonstrating that this solid-state property of lamivudine can be improved by crystal engineering strategies. Solubility profiles were understood on the basis of structural and solvent-solute interaction approaches. At last, correlations between solubility and crystal structures allowed for a rational approach to understand how this physicochemical feature could be enhanced by engineering new salts of the drug. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2143-2154, 2012 [ABSTRACT FROM AUTHOR] more...
- Published
- 2012
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35. A Potential In Vitro and In Vivo anti-HIV Drug Screening System for Chinese Herbal Medicines.
- Author
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Feng, Long, Wang, Li, Ma, Yun-yun, Li, Min, and Zhao, Guo-Qiang
- Abstract
Chinese herbal medicines are often applied as an alternative therapy for viral diseases. However, the development of anti-HIV herbal drugs has proceeded slowly, partly because of the lack of a high-throughput system for screening these drugs. The present study evaluated 16 herbal medicines for anti-HIV activities in vitro and in vivo. Herbal medicines were first screened for the ability to regulate C-X-C receptor 4 ( CXCR4) and C-C receptor 5 ( CCR5) promoter activities. A single-round pseudotyped HIV-luciferase reporter virus system (HIV-Luc) was used to identify potential anti-HIV mechanisms. CD4
+ T cells from healthy volunteers were examined for changes in CXCR4 and CCR5 levels. HIV-1 replication was evaluated by ELISA. Spica Prunellae and Herba Andrographitis were found to down-regulate the activities of both the CXCR4 and CCR5 promoters. Also, Spica Prunellae and Herba Andrographitis (>1000 µ m) inhibited HIV-1 in a dose-dependent manner. CXCR4 and CCR5 levels were reduced in CD4+ T cells from healthy volunteers ( p < 0.05). Spica Prunellae and Herba Andrographitis (EC50 : 3.18 and 5.49 µg/mL, respectively) could suppress cell fusion and decrease p24 antigen. In conclusion, the data demonstrated that Spica Prunellae and Herba Andrographitis possessed anti-HIV-1 capabilities, perhaps through the inhibition of the CXCR4 and CCR5 promoters and HIV-1 replication. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR] more...- Published
- 2012
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36. HIV-1 protease inhibition potential of functionalized polyoxometalates
- Author
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Flütsch, Andreas, Schroeder, Thilo, Grütter, Markus G., and Patzke, Greta R.
- Subjects
- *
ANTI-HIV agents , *PROTEASE inhibitors , *POLYOXOMETALATES , *ANTINEOPLASTIC agents , *ANTIVIRAL agents , *BIOCOMPATIBILITY , *NUCLEAR magnetic resonance , *DRUG synergism - Abstract
Abstract: Polyoxometalates (POMs) are interesting biomedical agents due to their versatile anticancer and antiviral properties, such as remarkable anti-HIV activity. Although POMs are tunable and easily accessible inorganic drug prototypes in principle, their full potential can only be tapped by enhancing their biocompatibility, for example, through organic functionalization. We have therefore investigated the HIV-1 protease inhibition potential of functionalized Keggin- and Dawson-type POMs with organic side chains. Their inhibitory performance was furthermore compared to other POM types, and the buffer dependence of the results is discussed. In addition, chemical shift mapping NMR experiments were performed to exclude POM–substrate interactions. Whereas the introduction of organic side chains into POMs is a promising approach in principle, the influence of secondary effects on the reaction system also merits detailed investigation. [Copyright &y& Elsevier] more...
- Published
- 2011
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37. Current insights into anti-HIV drug discovery and development: a review of recent patent literature (2014–2017)
- Author
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Peng Zhan, Zhongxia Zhou, Xiaofang Zuo, Gaochan Wu, Dongwei Kang, Zhipeng Huo, and Xinyong Liu
- Subjects
0301 basic medicine ,Drug ,medicine.medical_specialty ,Anti-HIV Agents ,Chemistry, Pharmaceutical ,media_common.quotation_subject ,Patent literature ,HIV Infections ,macromolecular substances ,Drug resistance ,01 natural sciences ,Patents as Topic ,03 medical and health sciences ,Drug Resistance, Viral ,Drug Discovery ,Anti-hiv drugs ,Animals ,Humans ,Medicine ,Intensive care medicine ,media_common ,Pharmacology ,business.industry ,General Medicine ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,Drug Design ,business - Abstract
To deal with the rapid emergence of drug resistance challenges, together with the difficulty to eradicate the virus, off-target effects and significant cumulative drug toxicities, it is still imperative to develop next-generation anti-HIV agents with novel chemical classes or new mechanisms of action.We primarily focused on current strategies to discover novel anti-HIV agents. Moreover, examples of anti-HIV lead compounds were mainly selected from recently patented publications (reported between 2014 and 2017). In particular, 'privileged structure'-focused substituents decorating approach, scaffold hopping, natural-product diversification and prodrug are focused on. Furthermore, exploitation of new compounds with unexplored mechanisms of action and medicinal chemistry strategies to deplete the HIV reservoir were also described. Perspectives that could inspire future anti-HIV drug discovery are delineated.Even if a large number of patents have been disclosed recently, additional HIV inhibitors are still required, especially novel chemical skeletons displaying a unexploited mechanism of action. Current medicinal chemistry strategies are inadequate, and appropriate and new methodologies and technologies should be exploited to identify novel anti-HIV drug candidates in a time- and cost- effective manner. more...
- Published
- 2018
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38. Virologic and Immunologic Effectiveness of Tipranavir/Ritonavir (TPV/r)- Versus Darunavir/Ritonavir (DRV/r)-Based Regimens in Clinical Practice.
- Author
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Antoniou, Tony, Raboud, J.M., Diong, C., Su, D., Dewhurst, N., Buckley, V., Kovacs, C., Rachlis, A., Brunetta, J., Smith, G., Gough, K., Fletcher, D., and Loutfy, M.R.
- Abstract
Background: Although both tipranavir and darunavir are important options for the management of patients with multidrug resistant HIV, there are at present no studies comparing the effectiveness and safety of these 2 antiretroviral drugs in this population of patients. Objective: To compare the effectiveness and safety of ritonavir (TPV/r)- and darunavir/ritonavir (DRV/ r)-based therapies in treatment-experienced patients (n = 38 and 47, respectively). Methods: Multicenter, retrospective cohort study. Results: The median baseline viral load and CD4 count were 4.7 copies/mL (interquartile range [IQR] 4.3, 5.2) and 168 cells/mm 3 (IQR 80, 252) for TPV/r patients and 4.7 copies/mL (IQR 3.7, 5.1) and 171 cells/mm3 (IQR 92, 290) for DRV/r patients. The median number of years on antiretroviral therapy (ART) prior to starting DRV/r or TPV/r were 12.7 (10.2-15.5) and 10.5 (8.4-12.6), respectively (P < .01). Current raltegravir (RAL) use (odds ratio [OR] 5.53, 95% CI 1.08-28.34) was significantly associated with virologic suppression at week 24 in multivariable logistic regression models, whereas the use of TPV/r was not significantly associated with virologic suppression compared to DRV/r (OR 0.93, 95% CI 0.27-3.18, P = .91). Conclusion: No significant difference was observed between DRV/r and TPV/r in terms of virologic suppression. [ABSTRACT FROM PUBLISHER] more...
- Published
- 2010
- Full Text
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39. Eastern extension of azoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternatives
- Author
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Leung, Cheryl S., Zeevaart, Jacob G., Domaoal, Robert A., Bollini, Mariela, Thakur, Vinay V., Spasov, Krasimir A., Anderson, Karen S., and Jorgensen, William L.
- Subjects
- *
HIV virus enzymes , *REVERSE transcriptase , *AZOLES , *NUCLEOSIDES , *ENZYME inhibitors , *DRUG design , *STRUCTURE-activity relationship in pharmacology , *ANTIRETROVIRAL agents - Abstract
Abstract: Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase is being pursued with the assistance of free energy perturbation (FEP) calculations to predict relative free energies of binding. Extension of azole-containing inhibitors into an ‘eastern’ channel between Phe227 and Pro236 has led to the discovery of potent and structurally novel derivatives. [Copyright &y& Elsevier] more...
- Published
- 2010
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- View/download PDF
40. Surface modifications of nanocarriers for effective intracellular delivery of anti-HIV drugs
- Author
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Gunaseelan, Simi, Gunaseelan, Krishnan, Deshmukh, Manjeet, Zhang, Xiaoping, and Sinko, Patrick J.
- Subjects
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THERAPEUTICS , *HIV infections , *ANTIVIRAL agents , *DRUG delivery systems , *NANOTECHNOLOGY , *LAMIVUDINE , *AIDS , *AZIDOTHYMIDINE , *DENDRITIC cells - Abstract
Abstract: A variety of nanocarriers such as bioconjugates, dendrimers, liposomes, and nanoparticles have been widely evaluated as potential targeted drug delivery systems. Passive targeting of nanoscale carriers is based on a size-flow-filtration phenomenon that is usually limited to tumors, the reticular endothelial system, and possibly lymph nodes (LNs). In fact, targeting the delivery of drugs to pivotal physiological sites such as the lymph nodes has emerged as a promising strategy in treating HIV disease. Ligands for specific cell surface receptors can be displayed on nanocarriers in order to achieve active targeting. The approach has been extensively used preclinically in cancer where certain receptors are over-expressed at various stages of the disease. Unfortunately, markers of HIV infection are lacking and latently infected cells do not show any signs of infection on their surface. However, the disease naturally targets only a few cell types. The HIV receptor CD4, coreceptors (CCR5 and CXCR4), and some receptors relatively specific for macrophages provide potentially valuable surface targets for drug delivery to all susceptible cells in patients infected by HIV. This review focuses on nanoscale targeting with an emphasis on surface modifications of drug delivery nanocarriers for active targeting. A number of related issues, including HIV biology, targets, pharmacokinetics, and intracellular fate as well as literature-cited examples of emerging surface-modified targeted carrier systems are discussed. [Copyright &y& Elsevier] more...
- Published
- 2010
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41. Comparative description of haplotype structure and genetic diversity of MDR1 (ABCB1) in HIV-positive and HIV-negative populations
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Benish, Rebekah L., Rodriguez, Benigno, Zimmerman, Peter A., and Mehlotra, Rajeev K.
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COMPARATIVE studies , *VIRAL genetics , *HIV-positive persons , *HIV , *SUBSTRATES (Materials science) , *DRUGS , *GENETIC polymorphisms , *GENE expression , *P-glycoprotein - Abstract
Abstract: Human P-glycoprotein (P-gp), encoded by MDR1 (ABCB1), is an efflux transporter with a wide specificity for substrates/drugs, including HIV protease inhibitors which are commonly used in HIV/AIDS treatment. Three single nucleotide polymorphisms (SNPs) in MDR1 have been shown to affect P-gp expression and function, and may affect HIV/AIDS treatment outcome: 1236C>T [G412G, exon-12], 2677G>T/A [A893S/T, exon-21] and 3435C>T [I1145I, exon-26]. In the present study, our aims were (i) to compare the 3-SNP MDR1 haplotype structure and genetic diversity between North American HIV-positive and HIV-negative individuals belonging to four major ethnic groups and (ii) to determine whether the haplotype structure and genetic diversity observed in these ethnically admixed populations differ from that in ethnically non-admixed populations. For these aims, we analyzed a cohort of 447 HIV/AIDS patients (White [n =193], Black [n =235], Hispanic [n =17], and Asian [n =2]). Results obtained for these patients were compared with the results for (i) HIV-negative individuals (n =356) and (ii) various HapMap and Environmental Genome Project populations. We observed that the genetic characteristics of MDR1 were largely consistent between HIV-positive and HIV-negative populations, but there were striking interethnic differences in the genetic characteristics of MDR1 in both populations. Although it appeared that the genetic characteristics of MDR1 were largely consistent between ethnically admixed and non-admixed populations, genetic characterization of the admixed populations remains to be done. Thus, our results provide useful comparative insights about the genetic characteristics of MDR1 that could be extrapolated across population groups worldwide. For a meaningful interpretation of these results regarding HIV/AIDS treatment outcome, MDR1 haplotype/diplotype structure data, genetic characterization of population admixture, and polymorphisms in other relevant drug transporter and/or metabolizing enzyme genes should be considered in future clinical studies. [Copyright &y& Elsevier] more...
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- 2010
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42. Validation and clinical application of a high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantitative determination of 10 anti-retrovirals in human peripheral blood mononuclear cells
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Elens, L., Veriter, S., Yombi, J.C., Di Fazio, V., Vanbinst, R., Lison, D., Wallemacq, P., Vandercam, B., and Haufroid, V.
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ANTIRETROVIRAL agents , *BLOOD testing , *QUANTITATIVE chemical analysis , *DRUG monitoring , *HIGH performance liquid chromatography , *TANDEM mass spectrometry - Abstract
Abstract: This paper reports the validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method that allows the quantification of 10 antiretroviral (ARV) drugs in peripheral blood mononuclear cells (PBMCs) using 6 different isotopic internal standards (IS) and its clinical application. PBMCs are isolated from blood by density gradient centrifugation and drugs are extracted with a 60% methanol (MeOH) solution containing the 6 IS. The cell extract is then injected in the HPLC system and analytes are separated on a Symmetry Shield RP18 2.1mm×50mm column. The different molecules are then detected by MS/MS in electrospray positive or negative ionisation modes and data are recorded using the multiple reaction monitoring (MRM) mode. Calibration curves are constructed in the range of 0.25–125ng/ml of cell extract by a 1/x 2 weighted quadratic regression. The regression coefficients obtained are always greater than 0.99 and back calculated values always comprised in the range of ±15% from their nominal concentration. Mean extraction recoveries are greater than 80% for all analytes and the method is accurate and precise with CV and bias lower than 9.4%. The lower limits of quantification (LLOQ) of the different drugs range from 0.0125 to 0.2ng/ml of cell extract. This method was successfully applied to a cohort of 98 HIV-infected patients treated with Kaletra® (400/100mg of lopinavir/ritonavir (LPV/RTV) twice a day, n =48) or with Stocrin® (600mg once a day, n =50) and has been tested for cellular quantification of tipranavir (TPV) in 2 patients treated with Aptivus® (500mg twice a day). The patients treated by Kaletra® showed mean cell-associated concentrations (CC) of 1819.0 and 917.2ng/ml, for LPV and RTV, respectively. Patients treated with Stocrin® showed mean CC of 2388.11ng/ml while both patients under Aptivus® showed TPV CC of 4322.7 and 1078.0ng/ml, respectively. This method can be used to analyze ARV drug concentrations within the target tissue. [Copyright &y& Elsevier] more...
- Published
- 2009
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43. Simultaneous determination of maraviroc and raltegravir in human plasma by HPLC-UV.
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Notari, Stefania, Tommasi, Chiara, Nicastri, Emanuele, Bellagamba, Rita, Tempestilli, Massimo, Pucillo, Leopoldo Paolo, Narciso, Pasquale, and Ascenzi, Paolo
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HIV infections , *BLOOD plasma , *SOLID phase extraction , *NITROGEN , *HIV-positive persons - Abstract
Therapeutic drug monitoring is pivotal to improve the management of HIV infection. Here, a new HPLC–UV method to quantify simultaneously maraviroc and raltegravir levels in human plasma is reported. Remarkably, this is the first method for maraviroc determination in human plasma. The volume of the plasma sample was 600 μL. This method involved automated solid-phase extraction with Oasis HLB Cartridge 1 cc (30 mg divinylbenzene and N-vinylpyrrolidone) and evaporation in a water bath under nitrogen stream. The extracted samples were reconstituted with 200 μL 50/50 of mobile-phase solution (0.01 M KH2PO4 and acetonitrile). Twenty microliters of these samples were injected into a HPLC–UV system, the analytes were eluted on an analytical dC18 Atlantis column (150 mm × 4.6 mm I.D.) with a particle size of 5 μm. The mobile phase (0.01 M KH2PO4 and acetonitrile) was delivered at 1.0 mL/min with isocratic elution. The total run time for a single analysis was 10 min; maraviroc and raltegravir were detected by UV at 197 and 300 nm. The calibration curves were linear up to 2,500 ng/mL. The absolute recovery ranged between 93 and 100%. The HPLC–UV method reported here has been validated and is currently applied to monitor plasma levels of maraviroc and raltegravir in HIV-infected patients. © 2009 IUBMB IUBMB Life, 61(4):470–475, 2009 [ABSTRACT FROM AUTHOR] more...
- Published
- 2009
- Full Text
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44. TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs
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Rao, Kavitha S., Reddy, Maram K., Horning, Jayme L., and Labhasetwar, Vinod
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HIGHLY active antiretroviral therapy , *CENTRAL nervous system , *BLOOD-brain barrier , *P-glycoprotein , *PROTEASE inhibitors , *NANOPARTICLES - Abstract
Abstract: We have shown that nanoparticles (NPs) conjugated to trans-activating transcriptor (TAT) peptide bypass the efflux action of P-glycoprotein and increase the transport of the encapsulated ritonavir, a protease inhibitor (PI), across the blood-brain-barrier (BBB) to the central nervous system (CNS). A steady increase in the drug parenchyma/capillary ratio over time without disrupting the BBB integrity suggests that TAT-conjugated NPs are first immobilized in the brain vasculature prior to their transport into parenchyma. Localization of NPs in the brain parenchyma was further confirmed with histological analysis of the brain sections. The brain drug level with conjugated NPs was 800-fold higher than that with drug in solution at two weeks. Drug clearance was seen within four weeks. In conclusion, TAT-conjugated NPs enhanced the CNS bioavailability of the encapsulated PI and maintained therapeutic drug levels in the brain for a sustained period that could be effective in reducing the viral load in the CNS, which acts as a reservoir for the replicating HIV-1 virus. [Copyright &y& Elsevier] more...
- Published
- 2008
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45. Modulation of heme and myristate binding to human serum albumin by anti-HIV drugs.
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Fanali, Gabriella, Bocedi, Alessio, Ascenzi, Paolo, and Fasano, Mauro
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ALBUMINS , *HIV prevention , *BLOOD plasma , *SERUM albumin , *BLOOD proteins , *FATTY acids - Abstract
Human serum albumin (HSA) has an extraordinary ligand‐binding capacity, and transports Fe(III)heme and medium‐ and long‐chain fatty acids. In human immunodeficiency virus‐infected patients the administered drugs bind to HSA and act as allosteric effectors. Here, the binding of Fe(III)heme to HSA in the presence of three representative anti‐HIV drugs and myristate is investigated. Values of the dissociation equilibrium constant Kd for Fe(III)heme binding to HSA were determined at different myristate concentrations, in the absence and presence of anti‐HIV drugs. Nuclear magnetic relaxation dispersion profiles of HSA–Fe(III)heme were measured, at different myristate concentrations, in the absence and presence of anti‐HIV drugs. Structural bases for anti‐HIV drug binding to HSA are provided by automatic docking simulation. Abacavir and nevirapine bind to HSA with Kd values of 1 × 10−6 and 2 × 10−6 m, respectively. Therefore, at concentrations used in therapy (in the 1–5 × 10−6 m range) abacavir and nevirapine bind to HSA and increase the affinity of heme for HSA. In the presence of abacavir or nevirapine, the affinity is not lowered by myristate. FA7 should therefore be intended as a secondary binding site for abacavir and nevirapine. Binding of atazanavir is limited by the large size of the drug, although preferential binding may be envisaged to a site positively coupled with FA1 and FA2, and negatively coupled to FA7. As a whole, these results provide a foundation for the comprehension of the complex network of links modulating HSA‐binding properties. [ABSTRACT FROM AUTHOR] more...
- Published
- 2007
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46. Dissolution test for lamivudine tablets: Optimization and statistical analysis
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Fernandes, Christian, Junqueira, Roberto Gonçalves, Campos, Ligia Maria Moreira, and Pianetti, Gerson Antônio
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GENERIC drugs , *ORGANIC compounds , *LIQUID chromatography , *ANALYTICAL chemistry - Abstract
Abstract: A comparison of different methods for dissolution test used by five different manufacturer laboratories of lamivudine tablets is made, evaluated, and discussed. Dissolution medium (water and hydrochloric acid pH 1.2), apparatus (paddles and baskets) and time (30 and 60min) were analyzed. The determination was accomplished by spectrophotometry at 270nm. Analysis of variance (ANOVA) factorial design 5×2×2×2 with six repetitions, with post hoc multiple comparisons between means conducted by Duncan test at 0.05 significance level was used. After the comparative analysis of the results, optimal dissolution conditions were determined as follows: water as dissolution medium, paddles at the stirring speed of 50rpm as apparatus and time of 30min. The method was applied to the dissolution test of samples from eleven batches of tablets, produced by five different laboratories. [Copyright &y& Elsevier] more...
- Published
- 2006
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47. Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase
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Jorgensen, William L., Ruiz-Caro, Juliana, Tirado-Rives, Julian, Basavapathruni, Aravind, Anderson, Karen S., and Hamilton, Andrew D.
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DNA polymerases , *REVERSE transcriptase , *MONTE Carlo method , *PHARMACEUTICAL chemistry - Abstract
Abstract: Design principles are delineated for non-nucleoside inhibitors for HIV-1 reverse transcriptase (NNRTIs). Simultaneous optimization of binding affinity for wild-type RT, tolerance for viral mutations, and physical properties is pursued. Automated lead generation with the growing program BOMB, Monte Carlo simulations with free-energy perturbation theory for lead optimization, and property analysis with QikProp are featured. An initial 30μM lead has been optimized rapidly to the 10nM level. [Copyright &y& Elsevier] more...
- Published
- 2006
- Full Text
- View/download PDF
48. Allosteric modulation of anti-HIV drug and ferric heme binding to human serum albumin.
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Bocedi, Alessio, Notari, Stefania, Menegatti, Enea, Fanali, Gabriella, Fasano, Mauro, and Ascenzi, Paolo
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ALLOSTERIC regulation , *PHYSIOLOGICAL control systems , *HEME , *HEMOGLOBINS , *ALBUMINS , *LIGAND binding (Biochemistry) , *BIOCHEMISTRY - Abstract
Human serum albumin (HSA), the most prominent protein in plasma, is best known for its exceptional capacity to bind ligands (e.g. heme and drugs). Here, binding of the anti-HIV drugs abacavir, atazanavir, didanosine, efavirenz, emtricitabine, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, and zidovudine to HSA and ferric heme–HSA is reported. Ferric heme binding to HSA in the absence and presence of anti-HIV drugs was also investigated. The association equilibrium constant and second-order rate constant for the binding of anti-HIV drugs to Sudlow's site I of ferric heme–HSA are lower by one order of magnitude than those for the binding of anti-HIV drugs to HSA. Accordingly, the association equilibrium constant and the second-order rate constant for heme binding to HSA are decreased by one order of magnitude in the presence of anti-HIV drugs. In contrast, the first-order rate constant for ligand dissociation from HSA is insensitive to anti-HIV drugs and ferric heme. These findings represent clear-cut evidence for the allosteric inhibition of anti-HIV drug binding to HSA by the heme. In turn, anti-HIV drugs allosterically impair heme binding to HSA. Therefore, Sudlow's site I and the heme cleft must be functionally linked. [ABSTRACT FROM AUTHOR] more...
- Published
- 2005
- Full Text
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49. Binding of Anti-HIV Drugs to Human Serum Albumin.
- Author
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Bocedi, Alessio, Notaril, Stefania, Narciso, Pasquale, Bolli, Alessandro, Fasano, Mauro, and Ascenzi, Paolo
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ALBUMINS , *BLOOD plasma , *BLOOD proteins , *REVERSE transcriptase , *AMINO acids , *TRYPTOPHAN - Abstract
Human serum albumin (HSA), the most prominent protein in plasma, is best known for its exceptional ligand (i.e., drug) binding capacity. Here, values of the dissociation equilibrium constant ( K d ) for the binding of HIV protease and reverse transcriptase inhibitors to HSA are reported. The binding of abacavir, atazanavir, didanosine, efavirenz, emtricitabine, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, zalcitabine, and zidovudine to the Sudlow site I (i.e., the warfarin cleft) located in the subdomain IIA involves the alteration of the HSA structure around Trp214 and induces intrinsic tryptophan fluorescence quenching. Accordingly, ibuprofen that primarily binds to the Sudlow site II located in the subdomain IIIA does not affect the HSA intrinsic tryptophan fluorescence and the binding of anti-HIV drugs to the Sudlow site I. Accounting for the physiological concentration of HSA (= 7.0 × 10 -4 M), the average anti-HIV drug concentration in plasma (= 1.0 × 10 -4 M), and K d values for the binding of anti-HIV drugs to HSA (ranging between 4.4 × 10 -5 M and 3.8 × 10 -4 M), it appears that the fraction of HIV protease and reverse transcriptase inhibitors bound to HSA ranges between 63% and 91%. This represents a significant drawback in the anti-HIV therapy and management, the anti-HIV drug concentration required to achieve 90% protease and reverse transcriptase inhibition in the presence of plasma proteins appears to be at least one order of magnitude higher than that required in their absence. IUBMB Life, 56: 609-614, 2004 [ABSTRACT FROM AUTHOR] more...
- Published
- 2004
- Full Text
- View/download PDF
50. HIV-chemotherapy and -prophylaxis: new drugs, leads and approaches
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De Clercq, Erik
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HIV infections , *DRUG therapy , *ANTIBIOTICS , *ANTI-infective agents - Abstract
In recent years, significant progress has been made towards the chemotherapy (and prophylaxis) of HIV infections. This progress is situated at three different levels. (i) New anti-HIV drugs have been approved for clinical use and have entered the market: the virus entry inhibitor enfuvirtide (Fuzeon™), the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (Emtriva™), the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir disoproxil fumarate (Viread™) and the HIV protease inhibitor (PI) atazanavir (Reyataz™). (ii) Other compounds have proceeded through preclinical and/or clinical development: CXCR4 antagonists (i.e. AMD070), CCR5 antagonists (i.e. SCH-C), NRTIs (such as amdoxovir), NNRTIs (such as etravirine), integrase inhibitors (such as S-1360) and PIs (such as tipranavir). (iii) Yet other compounds, acting by novel mechanisms, have recently been identified as anti-HIV agents that seem worthy of further (pre)clinical development: cell receptor CD4 down-modulators (i.e. cyclotriazadisulfonamides), viral envelope gp120-binding agents such as plant lectins and glycopeptide antibiotics, HIV integrase inhibitors such as the pyranodipyrimidine V-165, and two new classes of compounds (i.e. N-aminoimidazoles and pyridine oxide derivatives) which seem to interfere with a post-integration, transcription transactivation event. Taken together, it is obvious that the approaches for the treatment of HIV infections in recent years have become both more diverse and more efficient. [Copyright &y& Elsevier] more...
- Published
- 2004
- Full Text
- View/download PDF
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