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1. Boceprevir or Telaprevir Based Triple Therapy against Chronic Hepatitis C in HIV Coinfection: Real-Life Safety and Efficacy

Author

Sanjay Bhagani, Stefan Scholten, Karin Neukam, Juergen K. Rockstroh, Antonio Rivero, Antonio Collado, Manuel Márquez, Marcel Stoeckle, Daniela Munteanu, Marcial Delgado, Thomas A. Lutz, Stefan Mauss, Mattias Mandorfer, Juan A. Pineda, Annette Haberl, Antonio Rivero-Juárez, Luis F. López-Cortés, Jan Fehr, Ignacio de los Santos-Gil, [Neukam,K, Pineda,Ja] Unit of Infectious Diseases and Microbiology, Valme University Hospital and Seville Institute of Biomedicine (IBiS), Seville, Spain. [Neukam,K, Rivero-Juárez,A, López-Cortés,LF, Márquez,M, de los Santos-Gil,I, Rivero,A, Pineda,JA] RIS-HEP07 Study Group of the Spanish AIDS Research Network. [Munteanu,DI, Rockstroh,JK] Department of Medicine I, Bonn University Hospital, Bonn-Venusberg, Germany. [Munteanu,DI] Matei Bals National Institute of Infectious Diseases, Bucharest, Romania. [Rivero-Juárez,A, Rivero,A] Unit of Infectious Diseases, Reina Sofía University Hospital, Maimónides Institute of Biomedical Investigation of Cordoba (IMIBIC), Cordoba, Spain. [Lutz,T] Infektiologikum Frankfurt, Frankfurt/Main, Germany. [Fehr,J] Division of Infectious Diseases & Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. [Mandorfer,M] Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna and Vienna HIV & Liver Study Group, Vienna, Austria. [Bhagani,S] Department of Infectious Diseases/HIV Medicine, Royal Free London NHS Foundation Trust, London, United Kingdom. [López-Cortés,LF] Infectious Diseases, Microbiology and Preventive Medicine, Virgen del Rocío University Hospital and Seville Institute of Biomedicine (IBiS), Seville, Spain. [Haberl,A] Department of Medicine II, Frankfurt University Hospital, Frankfurt/Main, Germany. [Stoeckle,M] Division of Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland. [Márquez,M] Unit of Infectious Diseases, Virgen de la Victoria University Hospital, Malaga, Spain. [Scholten,S] Praxis Hohenstaufenring, Cologne, Germany. [de los Santos-Gil, I] Infectious Diseases Unit, La Princesa University Hospital, Madrid, Spain. [Mauss,S] Center for HIV and Hepatogastroenterology, Dusseldorf, Germany. [Collado,A] Infectious Diseases Unit, Torrecardenas University Hospital, Almeria, Spain. [Delgado,M] Unit of Infectious Diseases, Carlos Haya Regional University Hospital, Malaga, Spain., This work was supported by the RD12/ 0017/0012 (RIS-HEP07 Study Group), the Ministerio de Sanidad y Servicios Sociales (grant number EC11-304), the Fundación Progreso y Salud, Consejería de Salud de la Junta de Andalucía (grant number PI-0492-2012) and the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant number 134277 and SHCS project number 688). The Instituto de Salud Carlos III (grant number CP13/00187 and grant number Programa-I3SNS). The European AIDS Clinical Society Exchange Medical Programme. The Fundación Progreso y Salud of the Junta de Andalucía (grant number RH-0024-2013)., and University of Zurich

Subjects
Male, Diseases::Virus Diseases::Hepatitis, Viral, Human::Hepatitis C::Hepatitis C, Chronic [Medical Subject Headings], Hepacivirus, Organisms::Viruses::Hepatitis Viruses::Hepacivirus [Medical Subject Headings], lcsh:Medicine, HIV Infections, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], medicine.disease_cause, Diseases::Virus Diseases::RNA Virus Infections::Retroviridae Infections::Lentivirus Infections::HIV Infections [Medical Subject Headings], Gastroenterology, Telaprevir, 10234 Clinic for Infectious Diseases, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], chemistry.chemical_compound, Diseases::Virus Diseases::Coinfection [Medical Subject Headings], Medicine, lcsh:Science, Masculino, Oligopéptidos, Multidisciplinary, biology, Adulto, Coinfection, Femenino, virus diseases, Geographicals::Geographic Locations::Europe [Medical Subject Headings], Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleosides::Ribonucleosides::Ribavirin [Medical Subject Headings], Middle Aged, Humanos, 3. Good health, Europe, Treatment Outcome, Female, Europa, Oligopeptides, Hepatitis C crónica, medicine.drug, Research Article, Adult, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, Proline, Hepatitis C virus, Check Tags::Male [Medical Subject Headings], 610 Medicine & health, 1100 General Agricultural and Biological Sciences, Organisms::Viruses::RNA Viruses::Retroviridae::Lentivirus::Lentiviruses, Primate::HIV [Medical Subject Headings], Prolina, 1300 General Biochemistry, Genetics and Molecular Biology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Oligopeptides [Medical Subject Headings], Boceprevir, Internal medicine, Ribavirin, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], Humans, ddc:610, Rivavirina, Adverse effect, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome [Medical Subject Headings], 1000 Multidisciplinary, Mediana edad, business.industry, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Cyclic::Imino Acids::Proline [Medical Subject Headings], lcsh:R, VIH, HIV, Hepatitis C, Chronic, biology.organism_classification, medicine.disease, Virology, digestive system diseases, Infecciones por VIH, Clinical trial, Check Tags::Female [Medical Subject Headings], chemistry, lcsh:Q, Coinfección, Resultado del tratamiento, business
Abstract

BackgroundandAims Clinical trials oftherapy againstchronichepatitis Cvirus(HCV)infection including bocepre-vir(BOC)ortelaprevir(TVR) pluspegylatedinterferon andribavirin (PR) have reported con-siderably higherresponserates thanthoseachievedwithPR alone. Thisstudy soughttoevaluate the efficacyandsafety oftriple therapy includingBOCorTVR incombination withPRinHIV/HCV-coinfectedpatients underreal-lifeconditions. Methods Inamulticentrestudy conducted in24sites throughout five Europeancountries,allHIV/HCV-coinfected patients whoinitiated acombinationofBOC orTVRplusPR andwhohadatleast60weeks offollow-up, wereanalyzed. Sustained virologic response 12weeks afterthescheduledendoftherapy date(SVR12) andtherate ofdiscontinuations duetoadverseevents(AE) were evaluated. PLOSONE|DOI:10.1371/journal.pone.0125080 April29,2015 1/13OPENACCESSCitation:NeukamK,MunteanuDI,Rivero-JuarezA,LutzT,FehrJ,MandorferM,etal.(2015)BoceprevirorTelaprevirBasedTripleTherapyagainstChronicHepatitisCinHIVCoinfection:Real-LifeSafetyandEfficacy.PLoSONE10(4):e0125080.doi:10.1371/journal.pone.0125080AcademicEditor:WenyuLin,HarvardMedicalSchool,UNITEDSTATESReceived:January5,2015Accepted:March20,2015Published:April29,2015Copyright:©2015Neukametal.ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.DataAvailabilityStatement:Allrelevantdataarewithinthepaper.Funding:ThisworkwassupportedbytheRD12/0017/0012(RIS-HEP07StudyGroup),theMinisteriodeSanidadyServiciosSociales(grantnumberEC11-304),theFundacionProgresoySalud,ConsejeriadeSaluddelaJuntadeAndalucia(grantnumberPI-0492-2012)andtheframeworkoftheSwissHIVCohortStudy,supportedbytheSwissNationalScienceFoundation(grantnumber134277andSHCSprojectnumber688).K.N.istherecipientofaMiguelServetresearchgrantfromtheInstituto

Published
2015

2. Boceprevir or Telaprevir Based Triple Therapy against Chronic Hepatitis C in HIV Coinfection: Real-Life Safety and Efficacy.

Author

Neukam K, Munteanu DI, Rivero-Juárez A, Lutz T, Fehr J, Mandorfer M, Bhagani S, López-Cortés LF, Haberl A, Stoeckle M, Márquez M, Scholten S, de Los Santos-Gil I, Mauss S, Rivero A, Collado A, Delgado M, Rockstroh JK, and Pineda JA

Subjects
Adult, Coinfection drug therapy, Coinfection pathology, Drug-Related Side Effects and Adverse Reactions, Europe, Female, HIV drug effects, HIV Infections pathology, HIV Infections virology, Hepacivirus drug effects, Hepatitis C, Chronic virology, Humans, Male, Middle Aged, Proline administration & dosage, Ribavirin administration & dosage, Treatment Outcome, HIV Infections drug therapy, Hepatitis C, Chronic drug therapy, Oligopeptides administration & dosage, Proline analogs & derivatives
Abstract

Background and Aims: Clinical trials of therapy against chronic hepatitis C virus (HCV) infection including boceprevir (BOC) or telaprevir (TVR) plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than those achieved with PR alone. This study sought to evaluate the efficacy and safety of triple therapy including BOC or TVR in combination with PR in HIV/HCV-coinfected patients under real-life conditions., Methods: In a multicentre study conducted in 24 sites throughout five European countries, all HIV/HCV-coinfected patients who initiated a combination of BOC or TVR plus PR and who had at least 60 weeks of follow-up, were analyzed. Sustained virologic response 12 weeks after the scheduled end of therapy date (SVR12) and the rate of discontinuations due to adverse events (AE) were evaluated., Results: Of the 159 subjects included, 127 (79.9%) were male, 45 (34.4%) were treatment-naïve for PR and 60 (45.4%) showed cirrhosis. SVR12 was observed in 31/46 (67.4%) patients treated with BOC and 69/113 (61.1%) patients treated with TVR. Overall discontinuations due to AE rates were 8.7% for BOC and 8% for TVR. Grade 3 or 4 hematological abnormalities were frequently observed; anemia 7%, thrombocytopenia 17.2% and neutropenia 16.4%., Conclusion: The efficacy and safety of triple therapy including BOC or TVR plus PR under real-life conditions of use in the HIV/HCV-coinfected population was similar to what is observed in clinical trials. Hematological side effects are frequent but manageable.

Published
2015
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3. The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists.

Author

Fuchs A, Rempel V, and Müller CE

Subjects
Animals, CHO Cells, Cricetulus, Structure-Activity Relationship, Biological Products pharmacology, Biphenyl Compounds pharmacology, Cannabinoid Receptor Agonists pharmacology, Lignans pharmacology, Receptor, Cannabinoid, CB1 agonists, Receptor, Cannabinoid, CB2 agonists
Abstract

Magnolol (4-allyl-2-(5-allyl-2-hydroxyphenyl)phenol), the main bioactive constituent of the medicinal plant Magnolia officinalis, and its main metabolite tetrahydromagnolol were recently found to activate cannabinoid (CB) receptors. We now investigated the structure-activity relationships of (tetrahydro)magnolol analogs with variations of the alkyl chains and the phenolic groups and could considerably improve potency. Among the most potent compounds were the dual CB1/CB2 full agonist 2-(2-methoxy-5-propyl-phenyl)-4-hexylphenol (61a, K(i) CB1:0.00957 µM; K(i) CB2:0.0238 µM), and the CB2-selective partial agonist 2-(2-hydroxy-5-propylphenyl)-4-pentylphenol (60, K(i) CB1:0.362 µM; K(i ) CB2:0.0371 µM), which showed high selectivity versus GPR18 and GPR55. Compound 61b, an isomer of 61a, was the most potent GPR55 antagonist with an IC50 value of 3.25 µM but was non-selective. The relatively simple structures, which possess no stereocenters, are easily accessible in a four- to five-step synthetic procedure from common starting materials. The central reaction step is the well-elaborated Suzuki-Miyaura cross-coupling reaction, which is suitable for a combinatorial chemistry approach. The scaffold is versatile and may be fine-tuned to obtain a broad range of receptor affinities, selectivities and efficacies.

Published
2013
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