Evaluation of PEG-L-asparaginase in asparagine suppression and anti-drug antibody development in healthy Beagle dogs: A multi-phase preclinical study.

L-asparaginase is a frequently used drug in the treatment of canine malignant lymphoma. Since production and availability of native E. coli-derived L-asparaginase are limited, PEG-L-asparaginase (PEG-ASP) is an alternative. However, recommended doses and dosing intervals are mainly empirically determined. A multi-phase clinical dose-finding study with seven healthy Beagle dogs was conducted to find the minimum effective dose and, potentially, a dosing interval for PEG-ASP in dogs. Plasma concentrations of amino acids and PEG-ASP activity were measured at various time points after administration of different doses of PEG-ASP. Anti-PEG and anti-asparaginase antibody titres were measured. Administration of 10 IU/kg PEG-ASP resulted in asparagine depletion in all dogs, albeit for various durations: for 9 days in all dogs, 15 days in five dogs, 21 days in three dogs and 29 days in one dog. Asparagine suppression occurred at PEG-ASP plasma concentrations < 25 IU/L. Subsequent administrations of a second and third dose of 20 IU/kg and 40 IU/kg PEG-ASP resulted in asparagine suppression at < 9 days in five dogs, accompanied by the development of antibodies against PEG and L-asparaginase. Two dogs with prolonged asparagine suppression after the second and third administration did not develop antibodies. Marked individual variation in the mechanism and duration of response to PEG-ASP was noted. Antibody formation against PEG-ASP was frequently observed and sometimes occurred after one injection. This study suggests that PEG-ASP doses as high as the currently used dose of 40 IU/kg might not be needed in treatment of canine malignant lymphoma.

[Metabolic diseases in psychiatry]. / Stofwisselingsziekten binnen de psychiatrie.

Metabolic diseases can be associated with psychiatric symptoms. We present two case histories that demonstrate the importance of correctly diagnosing a metabolic disease as being the cause of psychiatric symptoms. We also discuss which symptoms or signals may indicate a metabolic disease.

Nucleotide sequence of a cDNA clone encoding a Caenorhabditis elegans homolog of mammalian alkyl-dihydroxyacetonephosphate synthase: evolutionary switching of peroxisomal targeting signals.

The nucleotide sequence is reported of a cDNA clone encoding a Caenorhabditis elegans homolog of guinea pig and human alkyl-dihydroxyacetonephosphate synthase. The open reading frame encodes a protein of 597 amino acids which shows extensive homology with the mammalian enzymes (52% identical and about 76% similar in the overlapping region). In contrast to the mammalian enzymes, which carry a consensus peroxisomal targeting signal type 2 in a cleavable N-terminal presequence, this Caenorhabditis elegans homolog carries a consensus peroxisomal targeting signal type 1 (CKL) at its C-terminus. Expression of this protein in an in vitro transcription/translation system yielded a 65 kDa protein. Recombinant aenorhabditis elegans alkyl-DHAP synthase expressed in the yeast Pichia pastoris was enzymatically active.