RESUMEN
INTRODUCTION: BAX 855 is a PEGylated human full-length recombinant factor VIII (rFVIII) based on licensed rFVIII (ADVATE). The applied PEGylation technology has been optimized to retain functionality of the FVIII molecule, improve its pharmacokinetic properties and allow less frequent injections while maintaining efficacy. AIM: The aim of this study was to confirm that the excellent safety profile of ADVATE remains unchanged after PEGylation. METHODS: Non-clinical safety studies with BAX 855 and its respective unbound polyethylene glycol (PEG) were conducted in several species. The distribution of a single dose of radiolabelled BAX 855 was further investigated in rats. Publically available safety data on PEG alone and PEGylated biomolecules were summarized and reviewed for specific safety findings attributable to PEG or PEGylated biopharmaceuticals. RESULTS: Safety pharmacology studies in rabbits and macaques and repeated dose toxicity studies in rats and macaques identified no safety issues. Results of a distribution study in rats administered radiolabelled BAX 855 showed that radioactivity was completely excreted; urine was the major elimination route. A 28-day study in rats dosed with the unbound PEG constituent (PEG2ru20KCOOH) of BAX 855 showed no adverse or non-adverse effects. Safety data for PEG and PEG-protein conjugates indicate no safety concerns associated with PEG at clinically relevant dose levels. Although vacuolation of certain cell types has been reported in mammals, no such vacuolation was observed with BAX 855 or with the unbound PEG constituent. CONCLUSION: Non-clinical safety evaluation of PEG and BAX 855 identified no safety signals; the compound is now in clinical development for the treatment of patients with haemophilia A.
Asunto(s)
Factor VIII/efectos adversos , Factor VIII/química , Polietilenglicoles/química , Seguridad , Animales , Factor VIII/metabolismo , Factor VIII/farmacocinética , Femenino , Humanos , Masculino , Polietilenglicoles/efectos adversos , Conejos , Ratas , Distribución Tisular , Vacuolas/efectos de los fármacos , Vacuolas/metabolismoRESUMEN
Aim of the present study was to investigate the detoxification of two abundant mycotoxins, namely ochratoxin A (OTA) and patulin (PAT) which are frequently found in human foods, by lactic acid bacteria. The removal of the two mycotoxins from liquid medium by thirty different LAB strains was analyzed in a screening trial by the use of HPLC coupled with UV- or fluorescence detection. Two highly effective strains were identified; Lactobacillus acidophilus VM 20 caused a decrease of OTA by > or = 95% and Bifidobacterium animalis VM 12 reduced PAT levels by 80%. Subsequently experiments showed that the binding of these compounds depends on different parameters, i.e. the concentration of toxins, the cell density, the pH-value and on the viability of the bacteria. To proof that the decrease of the toxins by LAB from liquid medium results in a reduction of their toxic properties, micronucleus (MCN) assays were conducted with a human derived hepatoma cell line (HepG2). Indeed, a substantial decrease (39-59%) of OTA and PAT induced MCN formation was observed with the most effective strains detected in the chemical analyses. Furthermore, also the inhibition of the cell division rates by the toxins was significantly reduced. These findings indicate that certain LAB strains are able to detoxify the two toxins and may be useful to protect humans and/or animals against the adverse health effects of these compounds.
Asunto(s)
Bifidobacterium/metabolismo , Lactobacillus acidophilus/metabolismo , Ocratoxinas/metabolismo , Patulina/metabolismo , División Celular/efectos de los fármacos , Línea Celular , Cromatografía Líquida de Alta Presión , Rotura Cromosómica/efectos de los fármacos , Medios de Cultivo , Humanos , Concentración de Iones de Hidrógeno , Inactivación Metabólica , Pruebas de Micronúcleos , Ocratoxinas/farmacología , Patulina/farmacología , Espectrofotometría UltravioletaRESUMEN
beta-Glucans (BGs) are polysaccharides that are found in the cell walls of organisms such as bacteria, fungi, and some cereals. The objective of the present study was to investigate the genotoxic and antigenotoxic effects of BG extracted from the mushroom Agaricus brasiliensis (=Agaricus blazei Murrill ss. Heinemann). The mutagenic activity of BG was tested in single-cell gel electrophoresis assays with human peripheral lymphocytes. In addition, the protective effects against the cooked food mutagen 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and (+/-)-anti-B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE), which is the main metabolite of B[a]P, and against ROS (H(2)O(2))-induced DNA damage, were studied. The results showed that the compound itself was devoid of mutagenic activity, and that a significant dose-dependent protective effect against damage induced by hydrogen peroxide and Trp-P-2 occurred in the dose range 20-80 microg/ml. To investigate the prevention of Trp-P-2-induced DNA damage, a binding assay was carried out to determine whether BG inactivates the amine via direct binding. Since no such interactions were observed, it is likely that BG interacts with enzymes involved in the metabolism of the amine.