Co-administration of CSL112 (apolipoprotein A-I [human]) with atorvastatin and alirocumab is not associated with increased hepatotoxic or toxicokinetic effects in rats.

CSL112 (apolipoprotein A-I, apo AI [human]) is an investigational drug in Phase 3 development for risk reduction of early recurrent cardiovascular events following an acute myocardial infarction (AMI). Although CSL112 is known to be well tolerated with a regimen of four weekly 6 g intravenous infusions after AMI, high doses of reconstituted apo AI preparations can transiently elevate liver enzymes in rats, raising the possibility of additive liver toxicity and toxicokinetic (TK) effects upon co-administration with cholesterol-lowering drugs, i.e.

Nonclinical analysis of the safety, pharmacodynamics, and pharmacokinetics of plasma-derived human FXIII concentrate in animals.

Factor XIII (FXIII) is a coagulation protein which plays a major role in hemostasis by covalently cross-linking fibrin molecules, thereby stabilizing the blood clot and increasing resistance to fibrinolysis. FXIII deficiency, either congenital or acquired, is associated with spontaneous bleeding, increased bleeding time, and poor wound healing. Purified plasma-derived human FXIII concentrate (pd hFXIII) has been available since 1993 for therapeutic use in congenital FXIII deficiency.

Pitfalls in assessing microvascular endothelial barrier function: impedance-based devices versus the classic macromolecular tracer assay.

The most frequently used parameters to describe the barrier properties of endothelial cells (ECs) in vitro are (i) the macromolecular permeability, indicating the flux of a macromolecular tracer across the endothelium, and (ii) electrical impedance of ECs grown on gold-film electrodes reporting on the cell layer's tightness for ion flow. Due to the experimental differences between these approaches, inconsistent observations have been described. Here, we present the first direct comparison of these assays applied to one single cell type (human microvascular ECs) under the same experimental conditions.

Acute and subacute pulmonary toxicity and mortality in mice after intratracheal instillation of ZnO nanoparticles in three laboratories.

Inhalation is the main pathway of ZnO exposure in the occupational environment but only few studies have addressed toxic effects after pulmonary exposure to ZnO nanoparticles (NP). Here we present results from three studies of pulmonary exposure and toxicity of ZnO NP in mice. The studies were prematurely terminated because interim results unexpectedly showed severe pulmonary toxicity.

Analysis of the safety and pharmacodynamics of human fibrinogen concentrate in animals.

Fibrinogen, a soluble 340kDa plasma glycoprotein, is critical in achieving and maintaining hemostasis. Reduced fibrinogen levels are associated with an increased risk of bleeding and recent research has investigated the efficacy of fibrinogen concentrate for controlling perioperative bleeding. European guidelines on the management of perioperative bleeding recommend the use of fibrinogen concentrate if significant bleeding is accompanied by plasma fibrinogen levels less than 1.

Molecular parameters of siRNA--cell penetrating peptide nanocomplexes for efficient cellular delivery.

Cell-penetrating peptides (CPPs) are versatile tools for the intracellular delivery of various biomolecules, including siRNA. Recently, CPPs were introduced that showed greatly enhanced delivery efficiency. However, the molecular basis of this increased activity is poorly understood.

Inflammatory responses to pulmonary application of PEI-based siRNA nanocarriers in mice.

Polymeric non-viral vector systems for pulmonary application of siRNA are promising carriers, but have failed to enter clinical trials because of safety and efficiency problems. Therefore, improving their transfection efficiency, as well as their toxicological profile, is the subject of intensive research efforts. Six different poly(ethylene imine) (PEI)-based nanocarriers, with hydrophilic and hydrophobic PEG modifications, were toxicologically evaluated for pulmonary application in mice.

Poly(ethylene imine) nanocarriers do not induce mutations nor oxidative DNA damage in vitro in MutaMouse FE1 cells.

Genotoxicity information on polymers used for gene delivery is scant, but of great concern, especially when developing polymeric nanocarriers as nonviral vector systems for cancer treatment. The genotoxicity of some engineered nanomaterials, e.g.

Comparative in vivo study of poly(ethylene imine)/siRNA complexes for pulmonary delivery in mice.

Pulmonary siRNA delivery offers a new way to treat various lung diseases. Poly(ethylene imines) (PEIs) are promising cationic nanocarriers and various modifications are still under investigations to improve their cytotoxicity and efficacy for siRNA delivery. In this study, we analyzed two different types of PEI-based nanocomplexes in mice after intratracheal administration regarding their toxicity and efficacy in the lungs.

Toxicity pathway focused gene expression profiling of PEI-based polymers for pulmonary applications.

Polyethylene imine (PEI) based polycations, successfully used for gene therapy or RNA interference in vitro as well as in vivo, have been shown to cause well-known adverse side effects, especially high cytotoxicity. Therefore, various modifications have been developed to improve safety and efficiency of these nonviral vector systems, but profound knowledge about the underlying mechanisms responsible for the high cytotoxicity of PEI is still missing. In this in vitro study, we focused on stress and toxicity pathways triggered by PEI-based vector systems to be used for pulmonary application and two well-known lung toxic particles: fine crystalline silica (CS) and nanosized ZnO (NZO).

PEGylation affects cytotoxicity and cell-compatibility of poly(ethylene imine) for lung application: structure-function relationships.

Poly(ethylene imine) (PEI) has widely been used as non-viral gene carrier due to its capability to form stable complexes by electrostatic interactions with nucleic acids. To reduce cytotoxicity of PEI, several studies have addressed modified PEIs such as block or graft copolymers containing cationic and hydrophilic non-ionic components. Copolymers of PEI and hydrophilic poly(ethylene glycol) (PEG) with various molecular weights and graft densities were shown to exhibit decreased cytotoxicity and potential for DNA and siRNA delivery.

Nonviral siRNA delivery to the lung: investigation of PEG-PEI polyplexes and their in vivo performance.

This study describes the physicobiological characterization of PEI- and PEG-PEI polyplexes containing partially 2'-OMe modified 25/27mer dicer substrate siRNAs (DsiRNAs) and their in vivo behavior regarding biodistribution and systemic bioavailability after pulmonary application as well as their ability to knock down gene expression in the lung. Biophysical characterization included circular dichroism of siRNA in polyplexes, condensation efficiency of polymers and in vitro stability. After in vivo application, biodistribution and kinetics of radiolabeled polyplexes were quantified and recorded over time in three-dimensional SPECT images and by end point scintillation counting.

Surface modification and size dependence in particle translocation during early embryonic development.

Since the mid-1990 s, the number of studies linking air pollutants to preterm and low birth weight, as well as to cardiac birth defects, has grown steadily each year. The critical period in the development of mouse embryos begins with the commencement of gastrulation at day 7.5 of gestation.

In vitro cytotoxic and immunomodulatory profiling of low molecular weight polyethylenimines for pulmonary application.

Polyethylenimines (PEI) are potent non-viral nucleic acid delivery vehicles used for gene delivery and RNA interference (RNAi). For non-invasive pulmonary RNAi therapy the respiratory tissue is an attractive application route, but offers particularly unwanted side-effects like cytotoxicity as well as inflammatory and immune responses. In the current study, we determined the most crucial issues of pulmonary applications for two low molecular weight PEIs in comparison to the well-known lung toxic crystalline silica.