The toxicokinetic profile of ochratoxin A was studied after the oral or intravenous administration of 50 ng/g b.w. to fish, quail, mouse, rat and monkey. The elimination half-life varied from 0.68 h after oral administration to fish, up to 840 h after intravenous administration to monkey. The distribution volume ranged from 57 ml/kg in fish to 1500 ml/kg in quail. The plasma clearance was most rapid in quail and fish, 72 and 58 ml/kg.h, respectively, while it was only 0.17 ml/kg.h in monkey. The bioavailability was as low as 1.6% in fish but as high as 97% in mouse. The binding abilities of ochratoxin A to plasma proteins were also studied. From these data we calculated the free fraction of toxin in plasma, which we found to be less than 0.2% in all species investigated (including man) except fish. A similar but smaller investigation on the toxicokinetics and binding properties of ochratoxin B was also performed. Ochratoxin B was more readily eliminated and had a lower affinity for plasma proteins, which partly may explain its lower toxicity.
An affinity chromatography step was developed for purification of recombinant B-Domain Deleted Factor VIII (BDDrFVIII) using a peptide ligand selected from a phage display library. The peptide library had variegated residues, contained both within a disulfide bond-constrained ring and flanking the ring. The peptide ligand binds to BDDrFVIII with a dissociation constant of f1 AM both in free solution and when immobilized on a chromatographic resin. The peptide is chemically synthesized and the affinity resin is produced by coupling the peptide to an agarose matrix preactivated with N-hydroxysuccinimide. Coupling conditions were optimized to give consistent and complete ligand incorporation and validated with a robustness study that tested various combinations of processing limits. The peptide affinity chromatographic operation employs conditions very similar to an immunoaffinity chromatography step currently in use for BDDrFVIII manufacture. The process step provides excellent recovery of BDDrFVIII from a complex feed stream and reduces host cell protein and DNA by 3 -4 logs. Process validation studies established resin reuse over 26 cycles without changes in product recovery or purity. A robustness study using a factorial design was performed and showed that the step was insensitive to small changes in process conditions that represent normal variation in commercial manufacturing. A scaled-down model of the process step was qualified and used for virus removal studies. A validation package addressing the safety of the leached peptide included leaching rate measurements under process conditions, testing of peptide levels in product pools, demonstration of robust removal downstream by spiking studies, end product testing, and toxicological profiling of the ligand. The peptide ligand affinity step was scaled up for cGMP production of BDDrFVIII for clinical trials. B 2004 Wiley Periodicals, Inc.
Tissue distribution of the nephrotoxic mycotoxin ochratoxin A was characterized in laying Japanese quail by whole body autoradiography and scintillation counting using 14C-labelled toxin. Periodically for 8 days after one intravenous injection of 14 microCi/bird, corresponding to 70 ng/g body weight, birds were killed, frozen, and sagittal sections of the whole body were placed on X-ray film. In general, the ochratoxin disappeared from the avian body rapidly. Specific retention of radioactivity was seen as a ring-like distribution in yolks and growing follicles. After sectioning, organs and intestinal contents were removed from carcasses in a frozen condition, homogenized, extracted, chromatographed, and the radioactivity in fractions was measured by scintillation spectroscopy. High concentrations of ochratoxin A were found in gastric intestinal contents, probably originating from toxin excreted in the bile.
Summary In a survey during the years 1985, 1986 and 1987 the quality of Swedish feeding grain was followed by the analysis of ochratoxin A in blood collected from swine at slaughter. The swine herds sampled were selected on feed handling procedures used. From information about the feed used, risk parameters for ochratoxin A contamination were identified. The results showed annual variation in the content of ochratoxin A in the grain and that ochratoxin A increased during storage of grain, particularly in the harvest of 1985. Drying of the grain with forced ambient air was found to be inferior to the use of heated forced air. It was also noticed that more than 9 % of the grain was contaminated with ochratoxin A regardless of handling. The pronounced difference between the samples studied was seen mainly as a function of geographical origin, with the island of Gotland having a much higher frequency of positive samples than the rest of Sweden. No correlation between ochratoxin A in swine feed and post mortem signs of infectious diseases in the swine herds was found. Zusammenfassung Die Anwendung von Ochratoxin A in Schweineblut zur Bewertung der Getreidehandhabung Im Rahmen einer Untersuchung wurde in den Jahren 1985, 1986 und 1987 an Hand von Ochratoxin A‐Gehalten in Schweineblut, gesammelt bei der Schlacht, die Qualität von schwedischem Futtergetreide verfolgt. Zur Untersuchung geeignete Schweineherden wurden nach Fütterungsge‐wohnheiten ausgesucht. Informationen über das verwendete Futter dienten zur Identifizierung von Risikoparametern für Ochratoxin A‐Kontamination. Die Ergebnisse zeigen jahreszeitliche Schwankungen für den Ochratoxin A‐Gehalt in Getreide und einen Anstieg der Ochratoxin A‐Konzentration während der Lagerung, besonders für die Ernte 1985. Trocknung des Getreides mit Luft bei Umgebungstemperatur erwies sich als weniger geeignet als der Gebrauch von Warmluft. Mehr als 9 % des Getreides waren, unabhängig von der Handhabung, mit Ochratoxin A kontaminiert. Die deutlichsten Unterschiede zwischen den untersuchten Proben waren hauptsächlich geographischen Ursprungs, wobei auf der Insel Gotland eine sehr viel höhere Frequenz von positiven Proben gefunden wurde als im restlichen Schweden. Es bestand keine Korrelation zwischen Ochratoxin A in Schweinefutter und post mortem Zeichen für Infektionskrankheiten in den untersuchten Schweineherden.
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