Characterisation of the vascular and inflammatory lesions induced by the PDE4 inhibitor CI-1044 in the dog.

Phosphodiesterase 4 (PDE4) inhibitors are potential therapeutic agents but vascular injury and perivascular inflammation occurs frequently during preclinical toxicology testing of these drugs. The lesions induced by PDE4 inhibitors have been described mainly in rats but there is limited data available for monkeys and no data for dogs. Here we present the toxicological profile of CI-1044, a PDE4 inhibitor, administered orally to dogs.

An integrated metabonomic approach to describe temporal metabolic disregulation induced in the rat by the model hepatotoxin allyl formate.

The time-related metabolic events in rat liver, plasma, and urine following hepatotoxic insult with allyl formate (75 mg/kg) were studied using a combination of high-resolution liquid state and magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopic methods together with pattern recognition analysis. The metabonomics results were compared with the results of conventional plasma chemistry and histopathological assessments of liver damage. Various degrees of liver damage were observed in different animals, and this variation was reflected in all of the analyses.

Hepatotoxin-induced hypertyrosinemia and its toxicological significance.

A (1)H Nuclear Magnetic Resonance (NMR) spectroscopic investigation of the effects of single doses of four model hepatotoxins on male Sprague-Dawley rats showed that hypertyrosinemia was induced by three of the treatments (ethionine 300 mg/kg, galactosamine hydrochloride 800 mg/kg and isoniazid 400 mg/kg) but not by the fourth (thioacetamide 200 mg/kg). Concomitant histopathological and clinical chemistry analyses showed that hypertyrosinemia could occur with or without substantial hepatic damage and that substantial hepatic damage could occur without hypertyrosinemia. However, in the rats dosed with galactosamine hydrochloride, which showed highly variable amounts of liver damage at ca.

Pharmaco-metabonomic phenotyping and personalized drug treatment.

There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion.

Hepatotoxin-induced hypercreatinaemia and hypercreatinuria: their relationship to one another, to liver damage and to weakened nutritional status.

Hypercreatinuria is a well-known feature of liver and testicular toxicity and we have recently proposed that hepatotoxin-induced hypercreatinuria would arise as a consequence of increased cysteine synthesis associated with the provision of protective substances (glutathione and/or taurine). Here a direct relationship between hepatotoxin-induced hypercreatinaemia and hypercreatinuria is shown and the possible relationships of hepatotoxin-induced hypercreatinaemia and hypercreatinuria to hepatic damage and to weakened nutritional status are examined. Male Sprague-Dawley rats were dosed with a variety of model hepatotoxins at two dose levels per toxin.

An hypothesis for a mechanism underlying hepatotoxin-induced hypercreatinuria.

As part of a wider metabonomic investigation into the early detection and discrimination of site-specific hepatotoxicity, male Sprague-Dawley rats were dosed with the model hepatotoxins allyl formate, ethionine and alpha-naphthylisothiocyanate (ANIT). Urine samples collected pre- and post-dose were examined by (1)H nuclear magnetic resonance (NMR) spectroscopy and the toxin-induced changes in urinary taurine and creatine excretion were quantified. Hypertaurinuria and hypercreatinuria were observed following allyl formate dosing, hypertaurinuria with no change in creatine excretion was observed after ethionine dosing, and hypotaurinuria and hypercreatinuria were observed after ANIT dosing.