DOCSLIB.ORG

Ana Rita Ramos Diniz De Quadros E Costa

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ana Rita Ramos Diniz De Quadros E Costa UNIVERSIDADE DE LISBOA FACULDADE DE FARMÁCIA ! NEW PREVENTION AND TREATMENT STRATEGIES FOR HIV INFECTION Ana Rita Ramos Diniz de Quadros e Costa Orientadores: Prof. Doutor Nuno Eduardo Moura dos Santos Taveira Prof. Doutor José António Frazão Moniz Pereira Tese especialmente elaborada para a obtenção do grau de Doutor em Farmácia, especialidade Microbiologia 2018 UNIVERSIDADE DE LISBOA FACULDADE DE FARMÁCIA ! NEW PREVENTION AND TREATMENT STRATEGIES FOR HIV INFECTION Ana Rita Ramos Diniz de Quadros e Costa Orientadores: Prof. Doutor Nuno Eduardo Moura dos Santos Taveira Prof. Doutor José António Frazão Moniz Pereira Tese especialmente elaborada para a obtenção do grau de Doutor em Farmácia, especialidade Microbiologia Júri Presidente: Doutora Matilde da Luz dos Santos Duque da Fonseca e Castro, Professora Catedrática e Diretora da Faculdade de Farmácia da Universidade de Lisboa, Presidente do júri por delegação de competências; Vogais: Doutor Bruno Filipe Carmelino Cardoso Sarmento, Investigador Auxiliar do Instituto de Investigação e Inovação em Saúde da Universidade do Porto; Doutor Nuno Eduardo Moura dos Santos Costa Taveira, Professor Catedrático do Instituto Universitário Egas Moniz, Orientador; Doutora Maria Helena de Sousa Barroso, Professora Associada do Instituto Universitário Egas Moniz; Doutora Emília de Jesus da Encarnação Valadas, Professora Associada da Faculdade de Medicina da Universidade de Lisboa; Doutor João Manuel Braz Gonçalves. Professor Associado com Agregação da Faculdade de Farmácia da Universidade de Lisboa. 2018 Todas as afirmações efetuadas no presente documento são da exclusiva responsabilidade da sua autora, não cabendo qualquer responsabilidade à Faculdade de Farmácia, Universidade de Lisboa pelos conteúdos nele apresentados. Ana Rita Ramos Diniz de Quadros e Costa teve o apoio financeiro da Fundação para a Ciência e Tecnologia através de uma bolsa de doutoramento (SFRH/BD/89140/2012). !i !ii “An inefficient virus kills its host. A clever virus stays with it” – James Lovelock !iii !iv Ao Flávio e ao Francisco !v AGRADECIMENTOS Quanto iniciei o meu doutoramento, tinha acabado de concluir o Mestrado Integrado em Ciên- cias Farmacêuticas e não sabia ao certo o que me esperava. Ao longo destes anos aprendi muito. Aprendi que fazer investigação é gerir tempo, recursos e expectativas. É ir ao laboratório à meia noite ou ao sábado revelar um ensaio, porque são as células e os vírus que mandam e ditam os time-points. É repetir 10 vezes a mesma experiência, para um dia ela dar certo e fi- carmos a pensar “Valeu a pena! Vamos comemorar!”. É ter orgulho em ver um artigo publicado com o nosso nome, fruto do nosso trabalho. E acima de tudo é ficar com a sensação de que se sabe muito pouco, pois ainda há tanta coisa para aprender sobre o tema que estudamos. Ao longo deste percurso, muitas pessoas contribuiram para a realização desta tese e deixo aqui os meus sinceros agradecimentos. Em primeiro lugar agradeço ao meu orientador, o Professor Nuno Taveira pela oportunidade de fazer este doutoramento no seu grupo, pelos valiosos conselhos, incentivo e paciência em to- das as fases deste longo percurso. Obrigada por tudo o que me ensinou, pelos constantes de- safios e por nunca ter desistido de mim. Agradeço também ao Professor José Moniz Pereira, Coordenador do Departamento de Micro- biologia da Faculdade de Farmácia por me ter permitido desenvolver o meu trabalho cientifico na sua unidade e pela sua co-orientação. Aos meus colegas de laboratório Francisco Martin, Rita Calado, Marta Calado, Inês Moranguin- ho, João Perdigão, Carla Silva, Andreia Martins, Claudia Palladino, Marta Giria, Inês Figueiredo, Joana Duarte, Rita Mateus, Joana Vital e Cheila Rocha obrigada pela boa-disposição, amizade, entreajuda, picnics e jantares que partilhámos. O excelente ambiente do nosso grupo deve-se a todos vocês! À Inês Bártolo, obrigada pela oportunidade de trabalhar contigo no nosso projeto e por todo o teu apoio. Contigo aprendi muitas coisas. És uma grande mulher, mãe e profissional. Obrigada Pedro Borrego por estares sempre disponivel para me ajudar a ultrapassar os ob- stáculos que surgiram e sempre com a tua boa-disposição contagiante! És uma referência para mim. À Fundação para a Ciência e Tecnologia agradeço o apoio financeiro que me permitiu desen- volver o meu trabalho. Aos meus pais, obrigada por todo o apoio, segurança e motivação que sempre me deram. Tudo aquilo que consegui alcançar foi graças a vocês. Ao meu filho Francisco, que com um sorriso apaga todas as minhas preocupações. Tu vieste dar luz aos meus dias e mostrar-me que o melhor do mundo é ser tua mãe. Ao meu marido Flávio, o meu melhor amigo e companheiro nos bons e maus momentos, obri- gada pela tua compreensão, amor e dedicação. Tu deste-me a força que precisei e tornaste o caminho mais fácil. Obrigada por tudo, do fundo do coração. !vi PREFACE The research described in this thesis was performed from January of 2012 to April of 2017 at Research Institute for Medicines (iMed ULisboa), Faculty of Pharmacy, Lisbon University, under the supervision of Prof. Doctor Nuno Taveira and the co-supervision of Prof. Doctor José Moniz Pereira. The major findings were communicated in the form of research papers published in peer re- viewed international journals or in preparation, oral communications and poster communica- tions in national and international conferences. This thesis is based on the following publications: Manuscripts in international journals Original manuscripts Diniz AR, Borrego P, Martin F, Figueiredo I, Gomes P, Gonçalves F, Caixas U, Vaz Pinto I, Bara- hona, I, Bártolo I, Taveira N. (2018) Differences in susceptibility patterns of isolates from HIV-2 infected patients to raltegravir and dolutegravir. (submitted to Scientific Reports, currently un- der revision) Briz V, Sepúlveda-Crespo D, Diniz AR, Borrego P, Rodes B, de la Mata FJ, Gómez R, Taveira N, Muñoz-Fernández MA. (2015) Development of water-soluble polyanionic carbosilane den- drimers as novel and highly potent topical anti-HIV-2 microbicides. Nanoscale. 7, p.14669-83 Bártolo I*, Diniz AR*, Borrego P, Ferreira JP, Bronze MR, Barroso H, Pinto R, Cardoso C, Pinto JF, Diaz RC, Broncano PG, Muñoz-Fernández MA, Taveira N. Evaluation of the fusion inhibitor P3 peptide as a potential microbicide to prevent HIV transmission in women. (submitted to Plos- One) *These authors contributed equally to this work. Reviews Diniz AR, Martin F, Martins AR, Bártolo I, Taveira N. Antiretroviral treatment of HIV-2 infection. (submitted) Manuscripts in portuguese journals Reviews Diniz AR, Canhões R, Taveira N. (2015) Pre-exposure prophylaxis for prevention of HIV infec- tion. Revista Portuguesa de Farmacoterapia, vol. 7, p. 15-33. !vii Oral communications in international conferences Taveira N, Diniz AR, Borrego P, Martin F, Gomes P, Gonçalves F, Caixas U, Vaz Pinto I, Barahona, I, Bártolo I. Dolutegravir has a highly potent activity against most primary HIV-2 isolates includ- ing those that have acquired resistance to Raltegravir. – June 1-5, 2017 – ASM Microbe – New Orleans, USA. Diniz AR, Borrego P, Bártolo I, Taveira N. Entry inhibitors are less effective at preventing cell- associated HIV-2 infection than HIV-1. – May 23-24, 2016 – ICHA 2016: 18th International Con- ference on HIV and AIDS – London, United Kingdom; Bártolo I, Diniz AR, Borrego P, Taveira N. Pre-clinical evaluation of a new vaginal microbicide gel for prevention of HIV infection – March 20-24, 2016 – Keystone Symposia Conference, HIV Vac- cines – Resort at Squaw Creek, Olympic Valley, Califórnia, EUA; Oral communications in portuguese conferences Diniz AR, Borrego P, Martin F, Gomes P, Gonçalves F, Caixas U, Vaz Pinto I, Barahona, I, Bártolo I, Taveira N. Dolutegravir has a highly potent activity against most primary HIV-2 isolates includ- ing those that are resistant to raltegravir. – 3-9 May, 2017 – redeSAÚDE’s 4th Annual Confer- ence, ULisboa Innovation Week – Lisbon, Portugal. Calado R, Duarte J, Diniz AR, Borrego P, Marcelino JM, Bártolo I, Clemente S, Taveira N. Expres- sion and antigenecity of gp120 and C2-V3-C3 polypeptides from different HIV-1 genetic forms – July 2nd 2014 – 6th iMed.ULisboa Postgraduate Students Meeting – Faculty of Pharmacy, Lisbon University – Lisbon, Portugal; Diniz AR, Briz V, Borrego P, Palladino C, Rodés C, de la Mata FJ, Gómez R, Muñoz-Fernández MA, Taveira N. Inhibition of cell-free and cell-associated HIV-2 infection: new compounds and new assays. – April 5, 2014 – HIV-2, the forgotten virus. – Molecular Medicine Institute, Lisbon, Portugal. Poster communications in international conferences Bártolo I, Diniz AR, Borrego P, Taveira N. Pre-clinical evaluation of a new vaginal microbicide gel for prevention of HIV infection – March, 20-24 – 2016 Keystone Symposia Conference, HIV Vac- cines – Resort at Squaw Creek, Olympic Valley, Califórnia, EUA; Diniz AR, Briz V, Borrego P, Palladino C, Rodés C, de la Mata FJ, Gómez R, Muñoz-Fernández MA, Taveira N. Entry Inhibitors and Carbosilane Dendrimers are Potent Inhibitors of Cell-free and Cell-Associated HIV-2 Infection – March, 22-27, 2015 – Keystone Symposia Conference, HIV Vaccines: Adaptive Immunity and Beyond – Fairmont Banff Springs, Banff, Alberta, Canada; Calado R, Duarte J, Diniz AR, Borrego P, Marcelino JM, Bártolo I, Clemente S, J Wilton, Taveira N. Envelope C2-V3-C3-specific antibodies correlate with neutralization activity in plasma from HIV-1 infected patients from Angola – March 22-27, 2015 – Keystone Symposia Conference, HIV Vaccines: Adaptive
Load more

Recommended publications
  • Cenicriviroc CSF Abstract Page 1 of 3 Title: Cerebrospinal Fluid Exposure
    Cenicriviroc CSF Abstract Title: Cerebrospinal fluid exposure of cenicriviroc in HIV-positive individuals with cognitive impairment Authors: Jasmini Alagaratnam1, Laura Else2, Sujan Dilly Penchala2, Elizabeth Challenger2, Ken Legg1, Claire Petersen1, Brynmor Jones3, Ranjababu Kulasegaram4, Star Seyedkazemi5, Eric Lefebvre5, Saye Khoo2 and Alan Winston1 1. Division of Infectious Diseases, Department of Medicine, Imperial College London, London W2 1PG 2. Department of Pharmacology, University of Liverpool, Liverpool L69 7SX, UK 3. Department of Radiology, Imperial College Healthcare NHS Trust, London W2 1NY 4. St. Thomas’ Hospital, London W6 8RP, UK 5. Clinical Development, Allergan plc, South San Francisco, USA Page 1 of 3 Cenicriviroc CSF Abstract Abstract Background: Cenicriviroc, a dual C-C chemokine receptor type 2 (CCR2) and type 5 (CCR5) antagonist, is a potential adjunctive therapy, along with antiretroviral therapy (ART), for the management of HIV-associated cognitive disorders. Materials and Methods: Virologically suppressed persons living with HIV (PLWH) with a clinical diagnosis of HIV-related cognitive impairment intensified ART with cenicriviroc once daily, dose dependent on current ART, for eight weeks. Subjects with current or previous use of CCR5 inhibitors were not eligible. We assessed cerebrospinal fluid (CSF) exposure of cenicriviroc and CSF albumin at week 8, and changes in cognitive function over 8 weeks. Cenicriviroc concentration was determined using reverse phase high-performance liquid chromatography (HPLC) with geometric mean (GM) and 95% confidence intervals (CI) calculated. The proposed cenicriviroc target concentration was above the 90% effective concentration (EC90) for cenicriviroc (0.17 ng/mL), with the lower limit of quantification (LLQ) 0.24 ng/mL taken as target concentration.
    [Show full text]
  • Emerging Therapies in NASH
    Emerging Therapies in NASH Stephen A Harrison, MD, FACP, FAASLD COL (ret.), USA, MC Visiting Professor of Hepatology Radcliffe Department of Medicine, University of Oxford Medical Director, Pinnacle Clinical Research President, Summit Clinical Research San Antonio, TX Disclosures • Scientific advisor or consultant for Akero, Alentis, Altimmune, Arrowhead, Axcella, Canfite, Cirius, CiVi Biopharma, Cymabay, Echosens, Fibronostics, Forest Labs, Galectin, Genfit, Gilead, Hepion, HistoIndex, Intercept, Madrigal, Medpace, Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, PathAI, Poxel, Liminal, Ridgeline, Sagimet, Terns, Viking, 89 Bio. • Stock options: Akero, Cirius, Galectin, Genfit, Hepion, HistoIndex, PathAI, Metacrine, NGM Bio, Northsea. • Grant/Research support: Akero, Axcella, BMS, Cirius, CiVi Biopharma, Conatus, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer,Sagimet, Viking. Goals of NASH Treatment • Improve metabolic abnormalities • Decrease inflammation • Prevent/arrest/reverse liver fibrosis – AASLD recommends pharmacological treatments aimed primarily at improving liver disease should generally be limited to those with biopsy-proven NASH and fibrosis • Prevent advanced liver disease, liver failure, liver cancer and related outcomes • Systemic outcomes (eventually) Chalasani N et al. Hepatology. 2018;67:328-35. Lifestyle Recommendations for Treating NASH Caloric intake Weight loss Exercise No heavy alcohol reduction of 3%
    [Show full text]
  • Investor Presentation
    Participants Company overview Pharmaceuticals Oncology Financial review Conclusion Appendix References Q1 2021 Results Investor presentation 1 Investor Relations │ Q1 2021 Results Participants Company overview Pharmaceuticals Oncology Financial review Conclusion Appendix References Disclaimer This presentation contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995, that can generally be identified by words such as “potential,” “expected,” “will,” “planned,” “pipeline,” “outlook,” or similar expressions, or by express or implied discussions regarding potential new products, potential new indications for existing products, potential product launches, or regarding potential future revenues from any such products; or regarding the impact of the COVID-19 pandemic on certain therapeutic areas including dermatology, ophthalmology, our breast cancer portfolio, some newly launched brands and the Sandoz retail and anti-infectives business, and on drug development operations; or regarding potential future, pending or announced transactions; regarding potential future sales or earnings of the Group or any of its divisions; or by discussions of strategy, plans, expectations or intentions; or regarding the Group’s liquidity or cash flow positions and its ability to meet its ongoing financial obligations and operational needs; or regarding our collaboration with Molecular Partners to develop, manufacture and commercialize potential medicines for the prevention and treatment of COVID- 19 and our joining of the industry-wide efforts to meet global demand for COVID-19 vaccines and therapeutics by leveraging our manufacturing capacity and capabilities to support the production of the Pfizer-BioNTech vaccine and to manufacture the mRNA and bulk drug product for the vaccine candidate CVnCoV from CureVac.
    [Show full text]
  • The CCR5-Delta32 Variant Might Explain Part of the Association Between COVID-19 and the Chemokine-Receptor Gene Cluster
    medRxiv preprint doi: https://doi.org/10.1101/2020.11.02.20224659; this version posted November 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. The CCR5-delta32 variant might explain part of the association between COVID-19 and the chemokine-receptor gene cluster 1,8,12* 1,8* 2,8,9,10,11 Juan Gómez, Elías Cuesta-Llavona, Guillermo M. Albaiceta, Marta 3 4,8,9,12 2,8,10,11 García-Clemente, Carlos López-Larrea, Laura Amado-Rodríguez, Inés 8,10 3 3 1,8 1,8 López-Alonso, Tamara Hermida, Ana I. EnrÍquez, Helena Gil , Belén Alonso, 1,8 1 1,8,9,12 Sara Iglesias, Beatriz Suarez-Alvarez,4,8,12 Victoria Alvarez, Eliecer Coto *These authors contributed equally to this work. 1 Genética Molecular, Hospital Universitario Central Asturias, Oviedo, Spain. 2 Unidad de Cuidados Intensivos Cardiológicos, Hospital Universitario Central Asturias, Oviedo, Spain. 3 Neumología, Hospital Universitario Central Asturias, Oviedo, Spain. 4 Inmunología, Hospital Universitario Central Asturias, Oviedo, Spain. 5 Urgencias, Hospital Universitario Central Asturias, Oviedo, Spain. 8 Instituto de Investigación Sanitaria del Principado deAsturias, ISPA, Oviedo, Spain. 9 Universidad de Oviedo, Oviedo, Spain. 10 CIBER-Enfermedades Respiratorias. Instituto de Salud Carlos III. Madrid, Spain. 11 Instituto Universitario de Oncología del Principado de Asturias. Oviedo, Spain. 12 Red de Investigación Renal (REDINREN), Madrid, Spain. Correspondenceto: Dr.EliecerCoto Hospital Univ. Central Asturias 33011 – Oviedo – Spain Tel. 34.985.10.55.00 Email: [email protected] 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
    [Show full text]
  • Exposure-Response Relationship of Cenicriviroc with Week 24 Virologic Outcomes in Treatment-Naïve HIV-1-Infected Adults with 202 CCR5-Tropic Virus (PK/PD ANALYSIS) E
    STUDY Exposure-Response Relationship of Cenicriviroc with Week 24 Virologic Outcomes in Treatment-Naïve HIV-1-Infected Adults with 202 CCR5-Tropic Virus (PK/PD ANALYSIS) E. Lefebvre1, J. Enejosa1, M. Béliveau2, C. Jomphe2, J.F. Marier2, C.R. Rayner3, P.F. Smith4, J. Gathe5 1Tobira Therapeutics, Inc., San Francisco, CA, USA, 2Pharsight Consulting Services, Montreal, Canada, 3d3 Medicine, Melbourne, Australia, 4d3 Medicine, Montville, NJ, USA, 5Therapeutic Concepts, Houston, TX, USA Background • Cenicriviroc (CVC) is a novel, once-daily, potent, CCR5 and CCR2 antagonist that has recently completed Phase 2b • The current preplanned pharmacokinetics (PK)/pharmacodynamics (PD) analyses of the Phase 2b study were evaluation for the treatment of HIV-1 infection in treatment-naïve adults (Study 202; NCT01338883).a carried out to assess the PK of CVC, using a population approach, and to determine the relationship between CVC exposure and virologic outcomes at Week 24. • The Week 24 primary analysis of the Phase 2b, dose-finding study comparing CVC 100 mg and 200 mg with efavirenz (EFV), in combination with emtricitabine/tenofovir (FTC/TDF), demonstrated favourable tolerability for CVC and comparable virologic success (HIV-1 RNA <50 copies/mL; FDA Snapshot) for CVC (73–76%) and EFV (71%). Virologic non-response was higher with CVC (12–14%) than with EFV (4%).1 aNote that the Week 48 analysis from this Phase 2b study will be presented at this conference (Feinberg et al.; Abstract PS4/1). Methods Study Design • A 2-compartmental population PK model was derived from the rich samples and subsequently used to predict individual CVC exposures from the sparse samples.
    [Show full text]
  • Meeting Report: 26Th International Conference on Antiviral Research Q
    Antiviral Research 100 (2013) 276–285 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Review Meeting report: 26th International Conference on Antiviral Research q R. Anthony Vere Hodge Vere Hodge Antivirals Ltd, Old Denshott, Leigh, Reigate, Surrey, UK article info abstract Article history: The 26th International Conference on Antiviral Research (ICAR) was held in San Francisco, California from Received 2 August 2013 May 11 to 15, 2013. This article summarizes the principal invited lectures at the meeting. The opening Accepted 8 August 2013 symposium on the legacy of the late Antonín Holy´ included presentations on his pioneering work with Available online 21 August 2013 nucleotide analogs, which led to the development of several antiviral drugs including tenofovir. This drug has transformed the treatment of HIV infection and has recently become the first-line therapy for chronic Keywords: hepatitis B. The Gertrude Elion Award lecturer described the anti-HIV activities of the CCR5 inhibitor Human immunodeficiency virus cenicriviroc and the reverse transcriptase inhibitor festinavirÒ, and also reviewed the evaluation of bio- Hepatitis B degradable nanoparticles with adjuvant activity. The William Prusoff Award winner reported on the cre- Hepatitis C Herpesviruses ation of NAOMI, a computer model with 21 enzymes to predict the activity of nucleoside analogs against Antiviral therapy hepatitis C virus (HCV). Other invited lecturers discussed the development of countermeasures against severe dengue and the potential of RNA virus capping and repair enzymes as drug targets. Topics in the clinical symposium included the current status of the anti-HCV compounds sovaprevir, ACH-3102, miravirsen and ALS-2200; the evaluation of single-tablet regimens for HIV infection; and the investiga- tion of cytomegalovirus resistance to CMX001.
    [Show full text]
  • Guidelines for the Use of Antiretroviral Agents in Adults and Adolescent Living With
    Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC) How to Cite the Adult and Adolescent Guidelines: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/ AdultandAdolescentGL.pdf. Accessed [insert date] [insert page number, table number, etc. if applicable] It is emphasized that concepts relevant to HIV management evolve rapidly. The Panel has a mechanism to update recommendations on a regular basis, and the most recent information is available on the HIVinfo Web site (http://hivinfo.nih.gov). What’s New in the Guidelines? August 16, 2021 Hepatitis C Virus/HIV Coinfection • Table 18 of this section has been updated to include recommendations regarding concomitant use of fostemsavir or long acting cabotegravir plus rilpivirine with different hepatitis C treatment regimens. June 3, 2021 What to Start • Since the release of the last guidelines, updated data from the Botswana Tsepamo study have shown that the prevalence of neural tube defects (NTD) associated with dolutegravir (DTG) use during conception is much lower than previously reported. Based on these new data, the Panel now recommends that a DTG-based regimen can be prescribed for most people with HIV who are of childbearing potential. Before initiating a DTG-based regimen, clinicians should discuss the risks and benefits of using DTG with persons of childbearing potential, to allow them to make an informed decision.
    [Show full text]
  • 14-258 Phrma HIV/AIDS2014 0819.Indd
    2014 MEDICINES IN DEVELOPMENT REPORT HIV/AIDS PRESENTED BY AMERICA’S BIOPHARMACEUTICAL RESEARCH COMPANIES Biopharmaceutical Company Researchers Are Developing More Than 40 Medicines and Vaccines For HIV Infection Treatment and Prevention Medicines and Vaccines in Globally, approximately 35 million people effective therapies, and preventative Development for HIV Infection are infected with human immunodefi - vaccines. These medicines and vaccines ciency virus (HIV), the virus that causes are either in clinical trials or awaiting Application acquired immune defi ciency syndrome review by the U.S. Food and Drug Submitted (AIDS). However, new infections have Administration (FDA). Phase III dropped by 38 percent since 2001, Phase II The 44 medicines and vaccines in the according to UNAIDS, the Joint United Phase I development pipeline include: Nations Programme on HIV/AIDS. • A fi rst-in-class medicine intended to In the United States, more than 25 prevent HIV from breaking through 1.1 million people are living with HIV the cell membrane. and 15.8 percent of those are unaware they are infected, according to the • A cell therapy that modifi es a U.S. Centers for Disease Control and patient’s own cells in an attempt to Prevention (CDC). Although the U.S. make them resistant to HIV. HIV/AIDS-related death rate has fallen 16 by more than 80 percent since the introduction of antiretroviral therapies in Contents 1995, new HIV infections have stabilized HIV Medicines and Vaccines in at approximately 50,000 each year, Development ......................................2 according to the CDC. Incremental Innovation in HIV/AIDS Treatment .......................... 4 Since AIDS was fi rst reported in 1981, Access to HIV/AIDS Medicines in nearly 40 medicines have been approved Exchange Plans ...................................5 to treat HIV infection in the United Facts About HIV/AIDS ........................7 States.
    [Show full text]
  • A Novel Small Molecule CCR5 Inhibitor Active Against R5-Tropic HIV-1S
    www.nature.com/scientificreports OPEN Activity and structural analysis of GRL-117C: a novel small molecule CCR5 inhibitor active against R5- Received: 24 September 2018 Accepted: 1 March 2019 tropic HIV-1s Published: xx xx xxxx Hirotomo Nakata1,2, Kenji Maeda 3, Debananda Das 1, Simon B. Chang1, Kouki Matsuda3, Kalapala Venkateswara Rao4, Shigeyoshi Harada5, Kazuhisa Yoshimura5, Arun K. Ghosh4 & Hiroaki Mitsuya1,2,3 CCR5 is a member of the G-protein coupled receptor family that serves as an essential co-receptor for cellular entry of R5-tropic HIV-1, and is a validated target for therapeutics against HIV-1 infections. In the present study, we designed and synthesized a series of novel small CCR5 inhibitors and evaluated their antiviral activity. GRL-117C inhibited the replication of wild-type R5-HIV-1 with a sub-nanomolar IC50 value. These derivatives retained activity against vicriviroc-resistant HIV-1s, but did not show activity against maraviroc (MVC)-resistant HIV-1. Structural modeling indicated that the binding of compounds to CCR5 occurs in the hydrophobic cavity of CCR5 under the second extracellular loop, and amino acids critical for their binding were almost similar with those of MVC, which explains viral cross- resistance with MVC. On the other hand, one derivative, GRL-10018C, less potent against HIV-1, but more potent in inhibiting CC-chemokine binding, occupied the upper region of the binding cavity with its bis-THF moiety, presumably causing greater steric hindrance with CC-chemokines. Recent studies have shown additional unique features of certain CCR5 inhibitors such as immunomodulating properties and HIV-1 latency reversal properties, and thus, continuous eforts in developing new CCR5 inhibitors with unique binding profles is necessary.
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • NASH in HIV-Infected Patients
    European Workshop on NASH in Clinical Practice Barcelona 22-23th November 2019 NASH in HIV-infected patients Berend van Welzen, MD Infectious Diseases specialist University Medical Center Utrecht, the Netherlands Disclosures No conflicts of interest HIV: a short summary • Opportunistic infections and malignancies • Shift from deadly disease toward manageable, chronic illness • Current focus on comorbidities • Therapy is getting easier (STR, dual therapy) HIV: a short summary (II) • Nucleoside Reverse Transcriptase Inhibitors (Zidovudine, Didanosine, Stavudine, Lamivudine, Abacavir, Tenofovir, Emtricitabine) • Non-Nucleoside Reverse Transcriptase Inhibitors (Nevirapine, Efavirenz, Rilpivirine, Doravirine, Etravirine) • Protease inhibitors (PI) (Saquinavir, Indinavir, Ritonavir, Atazanavir, Darunavir) • Fusion/entry inhibitors (Maraviroc, Enfuvirtide, Ibalizumab) • Integrase inhibitors (INSTI) (Raltegravir, Elvitegravir, Dolutegravir, Bictegravir) Epidemiology Risk factors: High BMI, waist circumference, Type II Diabetes, Hypertension, Triglycerides and high CD4 cell count. Maurice et al. AIDS 2017, 31:1621–1632 ‘Head-to-Head’ Kardashian et al. (2017) Price et al. (2014) • MRI based diagnosis • Liver-spleen attenuation • ̴ 200 study subjects • ̴ 700 male study subjects • Excluding CVD • Women 17 vs 33% • Men 41 vs 33% (ns) • 13% (HIV+) vs 19% (HIV-) • Association with genetic polymorphisms & di- deoxynucleoside exposure Kardashian et al. AIDS 2017 Jan 28;31(3):365-373. Price et al. Am J Gastroenterol. 2014 May;109(5):695-704 Pathophysiology
    [Show full text]
  • Cytokines and Chemokines in SARS-Cov-2 Infections—Therapeutic Strategies Targeting Cytokine Storm
    biomolecules Review Cytokines and Chemokines in SARS-CoV-2 Infections—Therapeutic Strategies Targeting Cytokine Storm Alexandra Pum 1, Maria Ennemoser 1, Tiziana Adage 2 and Andreas J. Kungl 1,3,* 1 Institute Of Pharmaceutical Sciences, Karl-Franzens-University Graz, Schubertstrasse 1, 8010 Graz, Austria; [email protected] (A.P.); [email protected] (M.E.) 2 Brain Implant Therapeutics (BIT) Pharma, Leonhardstrasse 109, 8010 Graz, Austria; [email protected] 3 Antagonis Biotherapeutics GmbH, Strasserhofweg 77, 8045 Graz, Austria * Correspondence: [email protected] Abstract: The recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the cause of coronavirus disease (COVID-19) and the associated ongoing pandemic, frequently leads to severe respiratory distress syndrome and pneumonia with fatal consequences. Although several factors of this infection and its consequences are not completely clear, the presence and involvement of specific chemokines is undoubtedly crucial for the development and progression of COVID-19. Cytokine storm and the often-resulting cytokine release syndrome (CRS) are patho- physiological hallmarks in COVID-19 infections related to its most severe and fatal cases. In this hyperinflammatory event, chemokines and other cytokines are highly upregulated and are therefore not fulfilling their beneficial function in the host response anymore but causing harmful effects. Here, we present the recent views on the involvement of chemokines and selected cytokines in COVID-19 and the therapeutics currently in clinical development targeting or interfering with them, discussing their potentials in the treatment of COVID-19 infections. Keywords: chemokines; SARS-CoV-2; COVID-19; coronavirus; cytokine storm Citation: Pum, A.; Ennemoser, M.; Adage, T.; Kungl, A.J.
    [Show full text]