Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH.

Background & Aims: The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH).

Methods: This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B.

Farnesoid X receptor agonist for the treatment of chronic hepatitis B: A safety study.

The nuclear farnesoid X receptor (FXR) regulates bile acid homeostasis and is a drug target for metabolic liver diseases. FXR also plays an important role in hepatitis B virus (HBV) DNA transcription. In vitro and in mice, FXR agonist treatment leads to inhibition of viral replication and a decline in viral proteins, pregenomic RNA (pgRNA) and HBV DNA levels.

Feasibility of non-invasive pressure support ventilation in infants with respiratory failure after extubation: a pilot study.

Objective: To evaluate the feasibility and effects of non-invasive pressure support ventilation (NIV) on the breathing pattern in infants developing respiratory failure after extubation.

Design: Prospective pilot clinical study; each patient served as their own control.

Setting: A nine-bed paediatric intensive care unit of a tertiary university hospital.

The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naïve hepatitis C patients.

Unlabelled: The anti-hepatitis C virus (HCV) effect and safety of three different oral doses of the cyclophilin inhibitor Debio 025 in combination with pegylated interferon-alpha2a (PEG IFN-alpha2a) were investigated in a multicenter, randomized, double-blind, placebo-controlled escalating dose-ranging phase II study in treatment-naïve patients with chronic hepatitis C. Doses of 200, 600, and 1,000 mg/day Debio 025 in combination with PEG IFN-alpha2a 180 microg/week for 4 weeks were compared with monotherapy with either 1,000 mg/day Debio 025 or 180 microg/week PEG IFN-alpha2a. In patients with genotypes 1 and 4, the 600- and 1,000-mg combination treatments induced a continuous decay in viral load that reached -4.

The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus.

Unlabelled: Debio-025 is an oral cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus activity in vitro. Its effect on viral load as well as its influence on intracellular Cyp levels was investigated in a randomized, double-blind, placebo-controlled study. Mean hepatitis C viral load decreased significantly by 3.

Inhibition of human immunodeficiency virus type 1 replication in human cells by Debio-025, a novel cyclophilin binding agent.

Debio-025 is a synthetic cyclosporine with no immunosuppressive capacity but a high inhibitory potency against cyclophilin A (CypA)-associated cis-trans prolyl isomerase (PPIase) activity. A lack of immunosuppressive effects compared to that of cyclosporine was demonstrated both in vitro and in vivo. For three cyclosporines, the inhibitory potential against PPIase activity was quantitatively correlated with that against human immunodeficiency virus type 1 (HIV-1) replication.

Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice.

Inhibition of mitochondrial permeability transition pore (mPTP) opening by cyclosporin A or ischemic postconditioning attenuates lethal reperfusion injury. Its impact on major post-myocardial infarction events, including worsening of left ventricular (LV) function and death, remains unknown. We sought to determine whether pharmacological or postconditioning-induced inhibition of mPTP opening might improve functional recovery and survival following myocardial infarction in mice.

Evaluation of a cyclophilin inhibitor in hepatitis C virus-infected chimeric mice in vivo.

Unlabelled: Cyclosporin A (CsA) inhibits replication of the HCV subgenomic replicon, and this effect is believed to not be mediated by its immunosuppressive action. We found that DEBIO-025, a novel non-immunosuppressive cyclophilin inhibitor derived from CsA, inhibited HCV replication in vitro more potently than CsA. We also examined the inhibitory effect of DEBIO-025 on naive HCV genotypes 1a or 1b in vivo using chimeric mice with human hepatocytes.

The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro.

Cyclosporin A (CsA) inhibits the in vitro replication of HCV subgenomic replicons. We here report on the potent anti-HCV activity of the non-immunosuppressive cyclosporin DEBIO-025. The 50% effective concentration for inhibition of HCV subgenomic replicon replication in Huh 5-2 cells (luciferase assay) by DEBIO-025 was 0.

Naturally occurring capsid substitutions render HIV-1 cyclophilin A independent in human cells and TRIM-cyclophilin-resistant in Owl monkey cells.

In this study, we asked if a naturally occurring HIV-1 variant exists that circumvents CypA dependence in human cells. To address this issue, we sought viruses for CypA independence using Debio-025, a cyclosporine A (CsA) analog that disrupts CypA-capsid interaction. Surprisingly, viral variants from the Main group replicate even in the presence of the drug.

Measuring end-expiratory lung volume and pulmonary mechanics to detect early lung function impairment in rabbits.

We investigated whether end-expiratory lung volume (EELV) or lung mechanical parameters are more sensitive for the detection of a compromised gas exchange during bronchoconstriction and after surfactant depletion. EELV was determined via SF(6) multiple breath wash-outs in mechanically ventilated rabbits while a positive end-expiratory pressure (PEEP) of 1, 3 or 7 cm H(2)O was maintained. Airway resistance (R(aw)) and parenchymal elastance (H) were estimated from the pulmonary input impedance measured at each PEEP level by means of forced oscillations.

Prevalence of nosocomial infections in Swiss children's hospitals.

Objective: To acquire data on pediatric nosocomial infections (NIs), which are associated with substantial morbidity and mortality and for which data are scarce.

Design: Prevalence survey and evaluation of a new comorbidity index.

Setting: Seven Swiss pediatric hospitals.

Effect of increasing inspiratory time on respiratory mechanics in mechanically ventilated neonates.

Objective: To investigate the effect of inspiratory time and inspiratory flow on the respiratory mechanics of intubated and ventilated neonates.

Design: Physiology study.

Setting: Tertiary university neonatal intensive care unit.

[Heliox in pediatrics].

Heliox is composed of oxygen and helium and its low specific gravity allows a modification of the gas flow within the airway. Breathing heliox favors a laminar flow and therefore decreases the work of breathing. Its usefulness in the child is established in croup or in post-extubation stridor.

Successful management of severe respiratory failure combining heliox with noninvasive high-frequency percussive ventilation.

Heliox has been shown to be beneficial in the management of different obstructive pulmonary disorders. High-frequency percussive ventilation has recently been advocated to treat lung injury in children with reduced lung compliance. We report our experience of combining heliox with noninvasive high-frequency percussive ventilation in a 5-yr-old boy with severe acute respiratory failure resulting from advanced cystic fibrosis lung disease.