Value through Innovation22 August 2014

Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

27 publications regarding Infection
  • Author:
    Martin B; Hennecke N; Lohmann V; Kayser A; Neumann-Haefelin C; Kukolj G; Böcher W-O; Thimme R
    Title:
    Restoration of HCV-specific CD8+ T cell function by interferon-free therapy
    Source:
    J Hepatol Article in Press (2014)
    Abstract:
    Background & Aims: Chronic hepatitis C virus (HCV) infection is characterised by a failure of virus-specific CD8+ T cells that is mainly caused by viral escape and T cell exhaustion. Constant antigen stimulation has been suggested to contribute to HCV-specific CD8+ T cell exhaustion. However, IFN-based therapies failed to recover HCV-specific CD8+ T cell function suggesting that the damage to CD8+ T cells may be permanent even after antigen removal. It was therefore the objective of this study to analyse the impact of inhibition of ongoing viral replication by IFN-free therapy with direct acting antivirals (DAA) on the phenotype and function of HCV-specific CD8+ T cells. Methods: Virus-specific CD8+ T cells obtained from a patient cohort of 51 previously untreated chronically infected patients undergoing IFN-free therapy with a combination of faldaprevir (a protease inhibitor) and deleobuvir (a non-nucleoside polymerase inhibitor) with or without ribavirin were analysed ex vivo and after in vitro expansion at baseline, wk4, wk12, and after treatment. Results: Our results show the rapid restoration of proliferative HCV-specific CD8+ T cells in the majority of patients with SVR12 within 4 weeks of therapy suggesting that IFN-free therapy mediated antigen removal may restore CD8+ T cell function. Conclusions: This study indicates a specific restoration of proliferative HCV-specific CD8+ T cells under IFN-free therapy. This is in contrast to PegIFN-based therapies that have been shown not to restore T cell function during and after chronic infection. © 2014 European Association for the Study of the Liver.
  • Author:
    Giaquinto C; Anabwani G; Feiterna-Sperling C; Nuttall J; Mompati K; Königs C; Mensa FJ; Sabo JP; Yong C-L; Macgregor TR; Nguyen T; Quinson A-M
    Title:
    Steady-state pharmacokinetics of nevirapine extended-release tablets in HIV-1-infected children and adolescents: An open-label, multiple-dose, cross-over study
    Source:
    Pediatr Infect Dis J 33 (7), E173-E179 (2014)
    Abstract:
    BACKGROUND: To compare steady-state (ss) pharmacokinetic targets of nevirapine extended-release (NVP-XR) tablets once-daily (QD) with immediate-release (NVP-IR) tablet or oral suspension twice-daily in HIV-1-infected children and adolescents. METHODS: Phase I, open-label, multidose, cross-over study with optional extension phase, in 85 patients 3 to <18 years of age, previously on an NVP-IR-based regimen for .18 weeks with baseline viral load <50 copies/mL. Patients were stratified by age, treated with NVP-IR twice-daily for 11 days, then NVP-XR QD for 10 days. C pre,ss (steady-state, predose concentrations) was obtained from all, and 12-hour NVP-IR and 24-hour NVP-XR steady-state pharmacokinetic profiles were obtained in the pharmacokinetic substudy. Viral loads, CD4 counts and adverse events (AEs) were monitored. RESULTS: Eighty patients completed the trial. Adjusted geometric mean (gMean) Cpre,ss for NVP-XR and NVP-IR exceeded the target of 3000 ng/mL, and the adjusted gMean NVP-XR:NVP-IR ratio (90% confidence interval) for QD normalized and un-normalized Cpre,ss were 91.2% (83.5-99.6%) and 91.8% (83.7-100.7%). gMean 24-hour area under the curve at steady-state NVP-XR:NVP-IR for un-normalized dose was 90.4% and un-normalized Cpre,ss NVP-XR:NVP-IR were 91.0%, 81.9% and 103.7% for the 3 age groups, 3 to <6, 6 to <12 and 12 to <18 years, respectively. gMean values indicated no exposure to subtherapeutic NVP concentrations and viral suppression was adequate and maintained in all QD groups. Most AEs were mild and similar between age groups. No serious or Division of AIDS Grade 4 AEs or AE related treatment discontinuations occurred. CONCLUSIONS: NVP-XR exhibited adequate trough concentrations with equivalent area under the curve at steady-state relative to NVP-IR. NVP-XR was well-tolerated and is a valuable treatment option for HIV-infected children and adolescents. Copyright © 2014 by Lippincott Williams & Wilkins.
  • Author:
    Ma J; He SW; Li H; Guo QC; Pan WW; Wang XJ; Zhang J; Liu LZ; Liu W; Liu Y
    Title:
    First survey of helminths in adult goats in Hunan Province, China
    Source:
    Tropical Biomed 31 (2), 261-269 (2014)
    Abstract:
    The objective of the present survey was to reveal the prevalence of helminths in adult goats in Hunan Province, the People's Republic of China. From July 2010 through February 2013, a total of 479 goats slaughtered in local abattoirs and markets were examined for the presence of helminths using a helminthological approach. Eighty-six percent of the examined goats were infected with at least one species of helminths. In total, 15 genera of helminths were found representing 2 phyla, 3 classes, 5 orders, and 11 families. Oesophagostomum, Ostertagia and Haemonchus were the most prevailing nematode genera, Eurytrema was the predominant trematode genus detected, whereas the infection of adult goats with cestodes was not common, with Cysticercus tenuicollis being the most common genus. The worm burdens showed obvious seasonal variation in that nematodes and cestodes were abundant in summer and winter, and the trematodes peaked in winter, which was consistent with the seasonal precipitation of Hunan Province. The geographical distribution of helminths in goats ascended with altitude. Goats in the mountainous areas were more severely infected with helminths than goats in the hilly areas, whereas infection of goats with helminths was much less in the lake areas. The present investigation highlights the high prevalence of helminths in adult goats in Hunan Province, China, which provides baseline data for assessing the effectiveness of future prevention and controlling measures against helminth infection in adult goats in this province and elsewhere.
  • Author:
    Salazar JC; Cahn P; Della Negra M; De Aquino MZ; Robinson PA; Jelaska A; Mikl J
    Title:
    Efficacy and safety of tipranavir coadministered with ritonavir in HIV-1-infected children and adolescents: 5 years of experience
    Source:
    Pediatr Infect Dis J 33 (4), 396-400 (2014)
    Abstract:
    BACKGROUND:: To evaluate the long-term (up to week 292) safety, efficacy and tolerability of ritonavir-boosted tipranavir in HIV-1-infected pediatric patients. Long-term follow up of patients enrolled in the randomized, open-label pediatric trial (1182.14/PACTG1051). METHODS:: HIV-1-infected pediatric patients (2-18 years) who participated in the PACTG 1051 trial were followed for ritonavir-boosted tipranavir-based regimen efficacy, safety and tolerability through week 292. RESULTS:: In patients <12 years of age, 51/62 (82%) were receiving drug at week 48 and 13/62 (21%) at week 288. Among adolescents (12-18 years of age), 35/53 (66%) were receiving drug at week 48 and 2/53 (4%) at week 288. Among patients 2 to <6 years of age, 18/25 (72%) had viral loads <400 copies/mL at week 48. By week 292, 9/25 (36%) of patients had viral loads <400 copies/mL. Among older patients, week 48 responder rates were 35% (13/37 of patients 6 to <12 years of age) and 32% (17/53 of patients 12 to 18 years of age). By week 292, 6/37 (16%) of those 6 to <12 years of age and 2/53 (4%) of those 12 to 18 years of age had viral loads <400 copies/mL. Overall safety and tolerability profiles were best for children who initiated treatment between 2 and <6 years of age. Drug-related adverse events (investigator defined) were similar across all age groups (55-65%). CONCLUSIONS:: Pediatric patients who begin treatment at the earlier ages, and who are stable on a ritonavir-boosted tipranavir-based regimen at week 48, generally continue to demonstrate good safety, tolerability and virologic efficacy profiles up to 292 weeks of treatment. © 2013 by Lippincott Williams & Wilkins.
  • Author:
    Colbatzky F
    Title:
    Classic Examples in Toxicologic Pathology XXI Seminar offered by the Hannover Graduate School for Veterinary Pathobiology, Neuroinfectiology and Translational Medicine, the Department of Pathology at the University of Veterinary Medicine in Hannover Germany and the European Society of Toxicologic Pathology IAP aktivators
    Source:
    University of Veterinary Medicine in Hannover
  • Author:
    Latli B; Hrapchak M; Gorys V; Llinàs-Brunet M; Campbell SS; Song J; Senanayake CH
    Title:
    Hepatitis C virus serine protease: Synthesis of radioactive and stable isotope-labeled potent inhibitors
    Source:
    J Label Compd Radiopharm Article in Press (2014)
    Abstract:
    Drug candidates labeled with radioactive and stable isotopes are required for absorption, distribution, metabolism, and excretion (ADME) studies, pharmacokinetics, autoradiography, bioanalytical, and other research activities. The findings from these studies are crucial in the development of a drug candidate and its approval for human use. Herein, we report the synthesis of potent and selective hepatitis C virus serine protease inhibitors related to BILN 2061 and BI 201335 labeled with radioactive and stable isotopes. Synthetic efforts were focused on the common substituted thiazole moiety, which is easily accessible via a Hantzsch's reaction of alpha-bromoketones and mono-substituted thioureas. In the radioactive synthesis, commercially available carbon-14 thiourea was utilized to prepare mono-substituted thioureas, which upon condensation with alpha-bromoketones in isopropanol followed by ester hydrolysis gave the desired carbon-14-labeled protease inhibitors. The same strategy was used to prepare these inhibitors labeled with stable isotopes. Mono-substituted thioureas were obtained from commercially available deuterium-labeled intermediates and then condensed with alpha-bromoketones followed by ester hydrolysis to give the deuterium-labeled inhibitors. © 2014 John Wiley & Sons, Ltd.
  • Author:
    Teixeira LH; Tararam CA; Lasaro MO; Camacho AGA; Ersching J; Leal MT; Herrera S; Bruna-Romero O; Soares IS; Nussenzweig RS; Ertl HCJ; Nussenzweig V; Rodrigues MM
    Title:
    Immunogenicity of a prime-boost vaccine containing the circumsporozoite proteins of plasmodium vivax in rodents
    Source:
    Infect Immun 82 (2), 793-807 (2014)
    Abstract:
    Plasmodium vivax is the most widespread and the second most prevalent malaria-causing species in the world. Current measures used to control the transmission of this disease would benefit from the development of an efficacious vaccine.In the case of the deadly parasite P. falciparum, the recombinant RTS,S vaccine containing the circumsporozoite antigen (CSP) consistently protects 30 to 50% of human volunteers against infection and is undergoing phase III clinical trials in Africa with similar efficacy. These findings encouraged us to develop a P. vivax vaccine containing the three circulating allelic forms of P. vivax CSP. Toward this goal, we generated three recombinant bacterial proteins representing the CSP alleles, as well as a hybrid polypeptide called PvCSP-All-CSP-epitopes. This hybrid contains the conserved N and C termini of P. vivax CSP and the three variant repeat domains in tandem. We also generated simian and human recombinant replication-defective adenovirus vectors expressing PvCSP-All-CSP-epitopes. Mice immunized with the mixture of recombinantproteins in a formulation containing the adjuvant poly(I.C) developed high and long-lasting serum IgG titers comparable to those elicited by proteins emulsified in complete Freund's adjuvant. Antibody titers were similar in mice immunized with homologous (protein-protein) and heterologous (adenovirus-protein) vaccine regimens. The antibodies recognized the three allelic forms of CSP, reacted to the repeated and nonrepeated regions of CSP, and recognized sporozoites expressing the alleles VK210 and VK247. The vaccine formulations described in this work should be useful for the further development of an anti-P. vivax vaccine. © 2014, American Society for Microbiology.
  • Author:
    Nishiguchi S; Sakai Y; Kuboki M; Tsunematsu S; Urano Y; Sakamoto W; Tsuda Y; Steinmann G; Omata M
    Title:
    Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection
    Source:
    Liver int 34 (1), 78-88 (2014)
    Abstract:
    Abstract: Background & Aims: Faldaprevir (BI 201335) is a potent once-daily (QD) NS3/4A protease inhibitor for the treatment of patients with genotype-1 (GT-1) hepatitis C virus (HCV). The aim of this study was to evaluate the safety, pharmacokinetics and efficacy of faldaprevir plus pegylated interferon alfa-2a (PegIFN) and ribavirin (RBV) in Japanese patients infected with chronic GT-1 HCV. Methods: Part 1 of this phase II study was a randomized, double-blind, placebo-controlled, dose-ascending study. Treatment-naïve patients received faldaprevir 120 or 240 mg QD, or placebo, plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. In Part 2 (open label), treatment-experienced patients received faldaprevir 240 mg QD plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. Efficacy was assessed using sustained virological response (SVR) 24 weeks after treatment completion. The pharmacokinetics, safety and tolerability of faldaprevir were also assessed. Results: SVR was achieved by 4/6 (67%) treatment-naïve patients treated with faldaprevir 120 mg QD, 5/6 (83%) patients treated with faldaprevir 240 mg QD and 2/4 (50%) patients who received placebo. Of the treatment-experienced patients, 3/6 (50%) achieved SVR. Faldaprevir was well tolerated. There was one serious adverse event, which was not considered to be treatment related. Rash and hyperbilirubinaemia were more frequently reported with faldaprevir than with placebo in treatment-naïve patients, but no cases were severe or serious and none led to discontinuation. Steady-state plasma concentrations of faldaprevir were reached within 7 days of QD dosing. Conclusions: Faldaprevir with PegIFN/RBV was efficacious and well tolerated, supporting further evaluation of this combination in Japanese patients. © 2013 John Wiley & Sons A/S.
  • Author:
    Rey MR; Undi M; Rodriguez-Lecompte JC; Joseph T; Morrison J; Yitbarek A; Wittenberg K; Tremblay R; Crow GH; Ominski KH
    Title:
    A study of the effectiveness of a needle-free injection device compared with a needle and syringe used to vaccinate calves against bovine viral diarrhea and infectious bovine rhinotracheitis viruses
    Source:
    Vet J (Lond) 198 (1), 235-238 (2013)
    Abstract:
    The aim of this study was to compare the effectiveness of a needle-free injection device (NF) with a needle and syringe (NS) when used to vaccinate calves against bovine viral diarrhea virus (BVDV) and infectious bovine rhinotracheitis virus (IBRV). The study was conducted in two independent phases. Ninety-six crossbred beef calves were vaccinated in the spring and 98 beef calves in the autumn. The calves were vaccinated using a NF or NS at 2. months of age (day 0) and again on day 119, with a modified-live virus vaccine containing IBRV, BVDV (types 1 and 2), parainfluenza-3 virus, and bovine respiratory syncytial virus. In each herd 10 calves were left unvaccinated to determine whether exposure to either BVDV or IBRV occurred. Visible vaccine residue at the surface of the skin/hair was apparent immediately following vaccination with NF in 30% of the spring-born calves following both the primary and booster vaccination. In the autumn, visible vaccine residues occurred in 19% and 8% of NF-vaccinated calves following the primary and booster vaccination. Post-vaccination skin reactions recorded on days 21, 42, 119 and 140 occurred with greater frequency in NF-vaccinated calves than NS-vaccinated ones. Blood samples were collected on days 0, 21, 42, 119, and 140 and tested for antibodies to BVDV and IBRV. Vaccination technique had no significant effect on BVDV or IBRV antibody concentrations at any time point. NF was as effective as NS vaccination in eliciting BVDV and IBRV antibody responses. © 2013 Elsevier Ltd.
  • Author:
    Escobar PA; Kemper RA; Tarca J; Nicolette J; Kenyon M; Glowienke S; Sawant SG; Christensen J; Johnson TE; McKnight C; Ward G; Galloway SM; Custer L; Gocke E; O'Donovan MR; Braun K; Snyder RD; Mahadevan B
    Title:
    Corrigendum to "Bacterial mutagenicity screening in the pharmaceutical industry" [Mutat. Res. 752(2) (2013) 99-118]
    Source:
    Mutat Res Rev Mutat Res 753 (2)-155 (2013)
    Abstract:
    no abstract available
  • Author:
    Escobar PA; Kemper RA; Tarca J; Nicolette J; Kenyon M; Glowienke S; Sawant SG; Christensen J; Johnson TE; McKnight C; Ward G; Galloway SM; Custer L; Gocke E; O'Donovan MR; Braun K; Snyder RD; Mahadeva
    Title:
    Corrigendum to "Bacterial mutagenicity screening in the pharmaceutical industry
    Source:
    Mutat Res Rev Mutat Res 752 (2), 99-118 Article in press (2013)
    Abstract:
    no abstract available
  • Author:
    Kramps T; Probst J
    Title:
    Messenger RNA-based vaccines: Progress, challenges, applications
    Source:
    Wiley Interdiscip Rev Syst Biol Med 4 (6), 737-749 (2013)
    Abstract:
    Twenty years after the demonstration that messenger RNA (mRNA) was expressed and immunogenic upon direct injection in mice, the first successful proof-of-concept of specific protection against viral infection in small and large animals was reported. These data indicate wider applicability to infectious disease and should encourage continued translation of mRNA-based prophylactic vaccines into human clinical trials. At the conceptual level, mRNA-based vaccines-more than other genetic vectors-combine the simplicity, safety, and focused immunogenicity of subunit vaccines with favorable immunological properties of live viral vaccines: (1) mRNA vaccines are molecularly defined and carry no excess information. In the environment and upon physical contact, RNA is rapidly degraded by ubiquitous RNases and cannot persist. These characteristics also guarantee tight control over their immunogenic profile (including avoidance of vector-specific immune responses that could interfere with repeated administration), pharmacokinetics, and dosing. (2) mRNA vaccines are synthetically produced by an enzymatic process, just requiring information about the nucleic acid sequence of the desired antigen. This greatly reduces general complications associated with biological vaccine production, such as handling of infectious agents, genetic variability, environmental risks, or restrictions to vaccine distribution. (3) RNA can be tailored to provide potent adjuvant stimuli to the innate immune system by direct activation of RNA-specific receptors; this may reduce the need for additional adjuvants. The formation of native antigen in situ affords great versatility, including intracellular localization, membrane association, posttranslational modification, supra-molecular assembly, or targeted structural optimization of delivered antigen. Messenger RNA vaccines induce balanced immune responses including B cells, helper T cells, and cytotoxic T lymphocytes, rendering them an extremely adaptable platform. This article surveys the design, mode of action, and capabilities of state-of-the-art mRNA vaccines, focusing on the paradigm of influenza prophylaxis. © 2013 John Wiley & Sons, Ltd.
  • Author:
    Rey MR; Undi M; Rodriguez-Lecompte JC; Joseph T; Morrison J; Yitbarek A; Wittenberg K; Tremblay R; Crow GH; Ominski KH
    Title:
    A study of the effectiveness of a needle-free injection device compared with a needle and syringe used to vaccinate calves against bovine viral diarrhea and infectious bovine rhinotracheitis viruses
    Source:
    Br Vet J Article in press (2013)
    Abstract:
    The aim of this study was to compare the effectiveness of a needle-free injection device (NF) with a needle and syringe (NS) when used to vaccinate calves against bovine viral diarrhea virus (BVDV) and infectious bovine rhinotracheitis virus (IBRV). The study was conducted in two independent phases. Ninety-six crossbred beef calves were vaccinated in the spring and 98 beef calves in the autumn. The calves were vaccinated using a NF or NS at 2 months of age (day 0) and again on day 119, with a modified-live virus vaccine containing IBRV, BVDV (types 1 and 2), parainfluenza-3 virus, and bovine respiratory syncytial virus. In each herd 10 calves were left unvaccinated to determine whether exposure to either BVDV or IBRV occurred. Visible vaccine residue at the surface of the skin/hair was apparent immediately following vaccination with NF in 30% of the spring-born calves following both the primary and booster vaccination. In the autumn, visible vaccine residues occurred in 19% and 8% of NF-vaccinated calves following the primary and booster vaccination. Post-vaccination skin reactions recorded on days 21, 42, 119 and 140 occurred with greater frequency in NF-vaccinated calves than NS-vaccinated ones. Blood samples were collected on days 0, 21, 42, 119, and 140 and tested for antibodies to BVDV and IBRV. Vaccination technique had no significant effect on BVDV or IBRV antibody concentrations at any time point. NF was as effective as NS vaccination in eliciting BVDV and IBRV antibody responses. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Zeuzem S; Soriano V; Asselah T; Bronowicki J-P; Lohse AW; Mul.lhaupt B; Schuchmann M; Bourlier.e M; Buti M; Roberts SK; Gane EJ; Stern JO; Vinisko R; Kukolj G; Gallivan J-P; Boc.her W-O; Mensa FJ
    Title:
    Faldaprevir and deleobuvir for HCV genotype 1 infection
    Source:
    N Engl J Med 369 (7), 630-639 (2013)
    Abstract:
    BACKGROUND: Interferon-free regimens would be a major advance in the treatment of patients with chronic hepatitis C virus (HCV) infection. METHODS: In this phase 2b, randomized, open-label trial of faldaprevir (a protease inhibitor) and deleobuvir (a nonnucleoside polymerase inhibitor), we randomly assigned 362 previously untreated patients with HCV genotype 1 infection to one of five groups: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The primary end point was a sustained virologic response 12 weeks after the completion of therapy. RESULTS: The primary end point was met in 59% of patients in the TID16W group, 59% of patients in the TID28W group, 52% of patients in the TID40W group, 69% of patients in the BID28W group, and 39% of patients in the TID28W-NR group. The sustained virologic response 12 weeks after the completion of therapy did not differ significantly according to treatment duration or dosage among ribavirin-containing regimens. This response was significantly higher with TID28W than with TID28W-NR (P = 0.03). Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events. CONCLUSIONS: The rate of a sustained virologic response 12 weeks after the completion of therapy was 52 to 69% among patients who received interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin. Copyright © 2013 Massachusetts Medical Society.
  • Author:
    Nishiguchi S; Sakai Y; Kuboki M; Tsunematsu S; Urano Y; Sakamoto W; Tsuda Y; Steinmann G; Omata M
    Title:
    Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection
    Source:
    Liver Int Article in press (2013)
    Abstract:
    Abstract: Background & Aims: Faldaprevir (BI 201335) is a potent once-daily (QD) NS3/4A protease inhibitor for the treatment of patients with genotype-1 (GT-1) hepatitis C virus (HCV). The aim of this study was to evaluate the safety, pharmacokinetics and efficacy of faldaprevir plus pegylated interferon alfa-2a (PegIFN) and ribavirin (RBV) in Japanese patients infected with chronic GT-1 HCV. Methods: Part 1 of this phase II study was a randomized, double-blind, placebo-controlled, dose-ascending study. Treatment-naïve patients received faldaprevir 120 or 240 mg QD, or placebo, plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. In Part 2 (open label), treatment-experienced patients received faldaprevir 240 mg QD plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. Efficacy was assessed using sustained virological response (SVR) 24 weeks after treatment completion. The pharmacokinetics, safety and tolerability of faldaprevir were also assessed. Results: SVR was achieved by 4/6 (67%) treatment-naïve patients treated with faldaprevir 120 mg QD, 5/6 (83%) patients treated with faldaprevir 240 mg QD and 2/4 (50%) patients who received placebo. Of the treatment-experienced patients, 3/6 (50%) achieved SVR. Faldaprevir was well tolerated. There was one serious adverse event, which was not considered to be treatment related. Rash and hyperbilirubinaemia were more frequently reported with faldaprevir than with placebo in treatment-naïve patients, but no cases were severe or serious and none led to discontinuation. Steady-state plasma concentrations of faldaprevir were reached within 7 days of QD dosing. Conclusions: Faldaprevir with PegIFN/RBV was efficacious and well tolerated, supporting further evaluation of this combination in Japanese patients. © 2013 John Wiley & Sons A/S.
  • Author:
    Macha S; Rose P; Mattheus M; Cinca R; Pinnetti S; Broedl UC; Woerle HJ
    Title:
    Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment
    Source:
    Diabetes Obes Metab Article in press (2013)
    Abstract:
    Aims: This open-label, parallel-group study investigated the effect of various degrees of hepatic impairment on the pharmacokinetics, safety and tolerability of the sodium glucose cotransporter 2 inhibitor empagliflozin. Methods: Thirty-six subjects [8 each with mild, moderate or severe hepatic impairment (Child-Pugh classification), and 12 matched controls with normal hepatic function] received a single 50mg dose of empagliflozin. Results: Empagliflozin was rapidly absorbed. After reaching peak levels, plasma drug concentrations declined in a biphasic fashion. Compared with subjects with normal hepatic function, geometric mean ratios (90% confidence interval) of AUC0-. and Cmax were 123.15% (98.89-153.36) and 103.81% (82.29-130.95), respectively, in patients with mild hepatic impairment, 146.97% (118.02-183.02) and 123.31% (97.74-155.55), respectively, in patients with moderate hepatic impairment, and 174.70% (140.29-217.55) and 148.41% (117.65-187.23), respectively, in patients with severe hepatic impairment. Adverse events, all mild or moderate in intensity, were reported in three subjects with moderate hepatic impairment, two subjects with severe hepatic impairment and six subjects with normal hepatic function. Conclusions: Empagliflozin was well tolerated in subjects with hepatic impairment. Increases in empagliflozin exposure were less than twofold in patients with hepatic impairment; therefore no dose adjustment of empagliflozin is required in patients with hepatic impairment. © 2013 John Wiley &amp; Sons Ltd.
  • Author:
    R. Lewis; L. Chachi; Y. Amrani; P. Bradding
    Title:
    A comparison of b2-adrenoceptor desensitisation induced by olodaterol and formoterol in human lung mast cells and airway smooth muscle cells
    Source:
    ERS, Barcelona, Spain, Sep 7-9, 2013
  • Author:
    Bethell R; Scherer J; Witvrouw M; Paquet A; Coakley E; Hall D
    Title:
    Short communication: Phenotypic protease inhibitor resistance and cross-resistance in the clinic from 2006 to 2008 and mutational prevalences in HIV from patients with discordant tipranavir and darunavir susceptibility phenotypes.
    Source:
    AIDS Res Hum Retroviruses 28 (9), 1019-1024 (2012)
    Abstract:
    To test tipranavir (TPV) or darunavir (DRV) as treatment options for patients with phenotypic resistance to protease inhibitors (Pis), including lopinavir, saquinavir, atazanavir, and fosamprenavir, the PhenoSense GT database was analyzed for susceptibility to DRV or TPV among Pl-resistant isolates. The Monogram Bioseiences HIV database (South San Francisco, CA) containing 7775 clinical isolates (2006-2008) not susceptible to at least one first-generation PI was analyzed. Phenotypic responses [resistant (R), partially susceptible (PS), or susceptible (S)] were defined by upper and lower clinical cut-offs to each PI. Genetypes were screened for amino acid substitutions associated with TPV-R/DRV-S and TPV-S/DRV-R phenotypes. ln all, 4.9% (378) of isolates were resistant to all six Pis and 31.0% (2407) were resistant to none. Among isolates resistant to all four first-generation Pis, DRV resistance increased from 21.2% to 41.9% from 2006 to 2008, respectively, and resistance to TPV remained steady (53.9 to 57.3%, respectively). Higher prevalence Substitutions in DRV-S/TPV-R isolates versus DRV-R/TPV-S isolates, respectively, were 82L/T (44.4% vs. 0%) and 830 (5.8% vs. 0%). Higher prevalence Substitutions in DRV-R/TPV-S virus were 50V (0.0% vs. 28.9%), 54L (1.0% vs. 36.1%), and 76V (0.4% vs. 15.5%). Mutations to help predict discordant susceptibility to DRV and TPV in isolates with reduced susceptibility to other Pis were identified. DRV resistance mutations associated with improved virologic response to TPV were more prevalent in DRV-R/TPV-S isolates. TPV resistance mutations were more prevalent in TPV-R and DRV-S isolates. These results confirm the impact of genotype on phenotype, illustrating how HIV genotype and phenotype data assist regimen optimization.
  • Author:
    Moreau Benoit; O'Meara Jeff A; Bordeleau Josee; Garneau Michel; Godbout Cedrickx; Gorys Vida; Leblanc Melissa; Villemure Elisia; White Peter W; Llinas-Brunet Montse
    Title:
    Discovery of Hepatitis C Virus NS3-4A Protease Inhibitors with Improved Barrier to Resistance and Favorable Liver Distribution
    Source:
    J Med Chem (2013)
    Abstract:
    Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor complexes, we shed light on the complex structural mechanisms by which the D168V and R155K residue mutations confer resistance to NS3 protease inhibitors. Here, we disclose SAR investigation and ADME/PK optimization leading to the identification of inhibitors with significantly improved potency against the key resistant variants and with increased liver partitioning.
  • Author:
    Sturino CF; Bousquet Y; James CA; Deroy P; Duplessis M; Edwards PJ; Halmos T; Minville J; Morency L; Morin S; Thavonekham B; Tremblay M; Duan J; Ribadeneira M; Garneau M; Pelletier A; Tremblay S; Lamorte L; Bethell R; Cordingley MG; Rajotte D; Simoneau B
    Title:
    Identification of potent and orally bioavailable nucleotide competing reverse transcriptase inhibitors: In vitro and in vivo optimization of a series of benzofurano[3,2-d]pyrimidin-2-one derived inhibitors
    Source:
    Bioorg Med Chem Lett 23 (13), 3967-3975 (2013)
    Abstract:
    Recently, a new class of HIV reverse transcriptase (HIV-RT) inhibitors has been reported. The novel mechanism of inhibition by this class involves competitive binding to the active site of the RT enzyme and has been termed Nucleotide-Competing Reverse Transcriptase Inhibitors (NcRTIs). In this publication we describe the optimization of a novel benzofurano[3,2-d]pyrimidin- 2-one series of NcRTIs. The starting point for the current study was inhibitor 2, which had high biochemical and antiviral potency but only moderate permeability in a Caco-2 assay and high B-to-A efflux, resulting in moderate rat bioavailability and low Cmax. We present herein the results and strategies we employed to optimize both the potency as well as the permeability, metabolic stability and pharmacokinetic profile of this series. One of the key observations of the present study was the importance of shielding polar functionality, at least in the context of the current chemotype, to enhance permeability. These studies led to the identification of inhibitors 39 and 45, which display sub-nanomolar antiviral potency in a p24 ELISA assay with significantly reduced efflux ratios (ratios &lt;1.5). These inhibitors also display excellent rat pharmacokinetic profiles with high bioavailabilities and low clearance. © 2013 Elsevier Ltd. All rights reserved.
  • Author:
    Schuchmann M; Kittner J M; Schlaak J F; Klass D M; Eisenbach C; Berg T; Trautwein C; Günther R; Zeuzem S; Gösseringer R; Ehrlich A; Neumann K; Wachtlin D; Sprinzl M F; Zimmermann T; Böcher W O; Galle P R
    Title:
    No beneficial effect of all-trans retinoic acid in previous non-responder patients with chronic hepatitis C: The ATRACTION study, a phase II randomised trial
    Source:
    Dig Liver Dis 45 (4), 323-329 (2013)
    Abstract:
    Background: Preclinical data suggested all-trans retinoic acid (tretinoin) as a potential antiviral agent against chronic hepatitis C infection. Aims: To assess efficacy, safety, and tolerability of tretinoin in combination with peg-interferon and ribavirin in genotype-1 infected patients with prior non-response. Method: We performed an open-label multicentre clinical trial. Patients were randomised to either receive additional tretinoin (45mg/m2/day) for 12 weeks (arm A), or peg-interferon and ribavirin alone (arm B). Primary endpoint was the slope of the third phase of viral decline (M?) as determined in an established kinetic model known to correlate with treatment outcome. Secondary endpoints were additional kinetic parameters, viral response rates, safety, and tolerability. Results: 27 patients in arm A and 30 patients in arm B were treated per protocol until week 12. Viral kinetic parameters did not differ. Rates of early virological response (&gt;2log10 drop at week 12) were similar (10/27 versus 11/30 patients). In arm A, patients experienced a higher rate and intensity of adverse events, most commonly skin and mucosal dryness, and headache. Conclusion: Addition of tretinoin was safe and acceptably well tolerated. However, it did not influence viral kinetics and thus cannot be further considered as a treatment option. © 2012 Editrice Gastroenterologica Italiana S.r.l.
  • Author:
    Blasche S; Mörtl M; Steuber H; Siszler G; Nisa S; Schwarz F; Lavrik I; Gronewold T M A; Maskos K; Donnenberg M S; Ullmann D; Uetz P; Kögl M
    Title:
    The E. coli Effector Protein NleF Is a Caspase Inhibitor
    Source:
    PLoS ONE 8 (3) art.no.58937 (2013)
    Abstract:
    Enterohemorrhagic and enteropathogenic E. coli (EHEC and EPEC) can cause severe and potentially life-threatening infections. Their pathogenicity is mediated by at least 40 effector proteins which they inject into their host cells by a type-III secretion system leading to the subversion of several cellular pathways. However, the molecular function of several effectors remains unknown, even though they contribute to virulence. Here we show that one of them, NleF, binds to caspase-4, -8, and -9 in yeast two-hybrid, LUMIER, and direct interaction assays. NleF inhibits the catalytic activity of the caspases in vitro and in cell lysate and prevents apoptosis in HeLa and Caco-2 cells. We have solved the crystal structure of the caspase-9/NleF complex which shows that NleF uses a novel mode of caspase inhibition, involving the insertion of the carboxy-terminus of NleF into the active site of the protease. In conformance with our structural model, mutagenized NleF with truncated or elongated carboxy-termini revealed a complete loss in caspase binding and apoptosis inhibition. Evasion of apoptosis helps pathogenic E. coli and other pathogens to take over the host cell by counteracting the cell's ability to self-destruct upon infection. Recently, two other effector proteins, namely NleD and NleH, were shown to interfere with apoptosis. Even though NleF is not the only effector protein capable of apoptosis inhibition, direct inhibition of caspases by bacterial effectors has not been reported to date. Also unique so far is its mode of inhibition that resembles the one obtained for synthetic peptide-type inhibitors and as such deviates substantially from previously reported caspase-9 inhibitors such as the BIR3 domain of XIAP. © 2013 Blasche et al.
  • Author:
    McPherson CJ; Aschenbrenner LM; Lacey BM; Fahnoe KC; Lennon MM; Finegan SM; Tadakamalla B; O'Donnell JP; Mueller JP; Tomaras AP
    Title:
    Clinically relevant Gram-negative resistance mechanisms have no effect on the efficacy of MC-1, a novel siderophone-conjugated monocarbam.
    Source:
    Antimicrob Agents Chemother 56 (12), 6334-6342 (2012)
  • Author:
    Beaulieu P L; Bös M; Cordingley M G; Chabot C; Fazal G; Garneau M; Gillard J R; Jolicoeur E; Laplante S; McKercher G; Poirier M; Poupart M A; Tsantrizos Y S; Duan J; Kukolij G
    Title:
    Discovery of the first thumb pocket 1 NS5B polymerase inhibitor (BILB 1941) with demonstrated antiviral activity in patients chronically infected with genotype 1 hepatitis C virus (HCV)
    Source:
    J Med Chem 55 (17), 7650-7666 (2012)
    Abstract:
    Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV. © 2012 American Chemical Society.
  • Author:
    Schernthaner G; Barnett AH; Emser A; Patel S; Troost J; Woerle H-J; von Eynatten M
    Title:
    Safety and tolerability of linagliptin: A pooled analysis of data from randomized controlled trials in 3572 patients with type 2 diabetes melitus.
    Source:
    Diabetes Obes Metab 14 (5), 470-478 (2012)
    Abstract:
    Aims: To assess the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes. Methods: Data were pooled from eight randomized, double-blind, placebo-controlled Phase III clinical trials lasting ?24 weeks. Incidences were calculated with descriptive statistics for the overall population and for subgroups of elderly and renally impaired patients. Results: A total of 2523 patients received linagliptin 5 mg once daily and 1049 patients received placebo. The overall incidence of adverse events (AEs) or serious AEs with linagliptin was similar to placebo (AEs 55.8% vs. 55.0%; serious AEs 2.8% vs. 2.7%). Overall aggregated infection incidence was 19.5% for linagliptin and 21.4% for placebo. Similar or reduced incidence of AEs versus placebo were seen with linagliptin for upper respiratory tract infection (3.3% vs. 4.9%), headache (2.9% vs. 3.1%), urinary tract infection (2.2% vs. 2.7%), blood and lymphatic disorders (1.0% vs. 1.2%), hypersensitivity (0.1% vs. 0.1%), hepatic enzyme increase (0.1% and 0.1%) and serum creatinine increase (0.0% and 0.1%). There was a slight increased frequency of nasopharyngitis (5.9% vs. 5.1%) and cough (1.7% vs. 1.0%) with linagliptin. Hypoglycaemia incidence was 8.2% for linagliptin and 5.1% for placebo; incidence was higher in patients with a background of sulphonylurea therapy (20.7% and 13.3%, respectively). In patients not receiving concomitant sulphonylurea, the hypoglycaemic incidence with linagliptin was very low in both the total population (<1%), and elderly and renally impaired patients (both <1%). Conclusions: This pooled analysis shows that linagliptin is well tolerated, with a low risk of hypoglycaemia.
  • Author:
    Ibrisimovic M; Nagl U; Kneidinger D; Rauch M; Lion T; Klein R
    Title:
    Targeted expression of herpes simplex virus thymidine kinase in adenovirus-infected cells reduces virus titers upon treatment with ganciclovir in vitro.
    Source:
    J Gene Med 14 (1), 3-19 (2012)
    Abstract:
    Background: Adenoviruses are a frequent cause of life-threatening infections in immunocompromised patients. Available therapeutics still cannot completely prevent fatal outcomes. By contrast, herpes viruses are well treatable with prodrugs such as ganciclovir (GCV), which are selectively activated in virus-infected cells by virus-encoded thymidine kinases. This effective group of prodrugs is not applicable to adenoviruses and other DNA viruses because they lack those kinases. Methods: To render adenoviruses amenable to GCV treatment, we generated an adenoviral vector-based delivery system for targeted expression of herpes simplex virus thymidine kinase (HSV-TK) in wild-type adenovirus 5 (wt Ad5)-infected cells. HSV-TK expression was largely restricted to wt virus-infected cells by transcription of the gene from the Ad5 E4 promoter. Its activity is dependent on the adenoviral E1A gene product which is not produced by the vector but is only provided in cells infected with wt adenovirus. The anti-adenoviral effect of HSV-TK expression and concomitant treatment with GCV was assessed in vitro in four different cell lines or primary cells. Results: E4 promoter-mediated HSV-TK background expression was sufficiently low to prevent cytotoxicity in the presence of low-levels GCV in cells not infected with wt Ad5. However, expression was several-fold increased in wt Ad5-infected cells and treatment with low levels of GCV efficiently inhibited wt Ad5 DNA replication. Genome copy numbers and output of infectious particles were reduced by up to>99.99% and cell viability was greatly increased. Conclusions: We extended the concept of enzyme/prodrug therapy to adenovirus infections by selectively sensitizing adenovirus-infected cells to treatment with GCV.
  • Author:
    Bohnhorst B; Lange M; Bartels DB; Bejo L; Hoy L; Peter C
    Title:
    Procalcitonin and valuable clinical symptoms in the early detection of neonatal late-onset bacterial infection.
    Source:
    Acta Paediatr 101 (1), 19-29 (2012)
    Abstract:
    Aim: To evaluate which clinical symptoms indicate proven neonatal bacterial infection (NBI) and whether measuring procalcitonin aside from C-reactive protein and interleukin 6 improves sensitivity and specificity in diagnosis. Methods: In a prospective observational study, clinical symptoms and procalcitonin, C-reactive protein and interleukin 6 were simultaneously determined from the 4th day of life in 170 preterm and term neonates at the first time of suspicion of NBI. Proven NBI was defined as a positive culture of otherwise sterile body fluids or radiologically verified pneumonia in combination with elevated inflammatory markers. Results: Fifty-eight (34%) patients were diagnosed with proven late-onset NBI. In case of proven NBI, odds ratio and 95% confidence intervals were 2.64 (1.06-6.54) for arterial hypotension, 5.16 (2.55-10.43) for feeding intolerance and 9.18 (4.10-20.59) for prolonged capillary refill. Sensitivity of combined determination of C-reactive protein (>10 mg/L) and interleukin 6 (>100 pg/mL) was 91.4%, specificity 80.4%, positive predictive value 70.7% and negative predictive value 94.7%. The additional determination of procalcitonin (>0.7 ng/mL) resulted in 98.3%, 65.2%, 58.8% and 98.6%, respectively. Conclusion: Arterial hypotension, feeding intolerance and especially prolonged capillary refill indicate proven neonatal late-onset bacterial infection, even at the time of first suspicion. Additional measurement of procalcitonin does indeed improve sensitivity to nearly 100%, but is linked to a decline in specificity. Nevertheless, in the high-risk neonatal population, additional procalcitonin measurement can be recommended because all infants with NBI have to be identified.