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A novel nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulfonyl) ethyl]-1-nitrosourea (TCNU) tauromustine, has been investigated in a broad anti-tumour screen and, in depth toxicology and initial pharmacokinetics carried out. TCNU and its two metabolites were found to exhibit equal or better oral efficacy than that of BCNU, CCNU, MeCCNU or chorozotocin against L1210 leukemia, Walker mammary carcinoma, Lewis Lung, Harding Passey melanoma and colon carcinoma C26. The toxicological profile of TCNU after acute and 3 months treatment was similar in mice and rats to that of CCNU, with the exception that, TCNU did not cause the chronic liver disturbances found for CCNU. In dogs treated for 6 weeks with TCNU leucopenia and thrombocytopenia were the major side effects. Parent TCNU was found in all dogs. The absorption was fast, the maximum level being reach after 25 mins and the mean absorption time was 22 mins. The mean half life was 16.1 mins after intravenous and 17.4 after oral administration. The combination of these factors make TCNU an interesting clinical candidate.

Using telemetry, the effects on cardiovascular parameters after single intravenous administration (0.5 mg/kg) of recombinant human insulin-like growth factor-I (rhIGF-I) were studied in conscious and unrestrained dogs. Insulin (1.1 IU/kg) was used as a reference compound. Telemetry transmitters were implanted subcutaneously with a pressure catheter in the femoral artery and electrodes for ECG subcutaneously. Cardiovascular effects and changes in blood glucose levels induced with rhlGF-I were similar to those induced with insulin. Heart rate increased continuously for about 90 min. after treatment, regardless of compound. Thereafter, heart rate slowly decreased but did not fully reach predose values 4 hr after treatment. Both systolic and diastolic blood pressure decreased continuously for about 90 min. and remained low for up to 4 hr after treatment. Treatment with rhIGF-I or insulin did not influence dp/dt values. Treatment with glucose intravenously to abolish the rhIGF-I-induced hypoglycaemia reduced the heart rate, but caused a substantial increase in dp/dt and a slight increase in blood pressure. RhIGF-I and insulin induced an almost identical onset and degree of hypoglycaemia. Blood glucose reached a minimum level 1 hr after treatment and was almost returned to normal 4 hr after treatment. There was an increase in the amplitude of the T-waves, though this effect occurred earlier and was longer lasting with insulin than with rhIGF-I. After 4 hr, the T-wave amplitude was normal with rhIGF-I but remained high with insulin. These T-wave effects were probably due to an increase in the transport of potassium or calcium since they decreased in plasma. This suggests that the effects of rhIGF-I and insulin are highly comparable and that the cardiovascular changes induced by rhIGF-I are likely caused by its insulin-like activity. As shown by the recorded cardiovascular responses induced by rhIGF-1 and insulin, the telemetric recording system makes it possible to evaluate the effects of different drugs in a continuous way that is not possible with conventional techniques. This new telemetric technique can be of significant importance in the process of future drug development.

Studies on biliary concentrations of susalimod were conducted in rat, dog and monkey to clarify the interspecies differences observed in toxicology studies with respect to hepatobiliary toxicity after long-term administration of the compound. Dose-related bile duct hyperplasia appeared only in dogs at doses 2 7 5 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mglkglday respectively. Biliary excretion was investigated after intraduodenal administration of susalimod in anaesthetised animals. In addition excretion routes were determined by collecting urine and faeces following a radiolabelled intravenous dose. Susalimod was extensively excreted via the bile in all animal species, ~9 0 % 1 , mainly as non-conjugated parent compound. However, the local concentrations in bile varied between the species. Highest concentrations were obtained in the dog. The bile/plasma concentration ratio was 3400 in the dog, 300 in the monkey and 50 in the rat. In the dog, bile duct concentrations of susalimod about 30,000 pmolll was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were 57000 pmol/l at plasma concentrations similar to those obtained at the highest doses in the toxicology studies. From these results supported by a previous biliary excretion study in conscious dogs with chronic bile fistula receiving repeated administration of susalimod (Pihlman et ul. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.Susalimod ( fig. 1) was developed based on experience with sulfasalazine. Sulfasalazine has been used in the treatment of inflammatory bowel disease for more than 50 years, based on the principle of a local effect of active metabolites formed by bacterial azoreductase in the colon, 5-aminosalicylic acid and sulfapyridine (Peppercorn 1990). In recent years the drug has also been successfully used in rheumatoid arthritis (Rains et al. 1995). It has been postulated that the beneficial effect observed in rheumatoid arthritis might be attributed to the parent drug rather than its metabolites (Pullar rt ul. 1985;Neuman et al. 1986). Susalimod was designed to retain sulfasalazine's immunomodulating activities of importance in the treatment of rheumatoid arthritis, such as inhibition of the production of proinflammatory cytokines and suppression of the proliferation of lymphocytes (Williams et a/. 1993). The chemical modification of sulfasalazine also aimed at stabilizing the molecule in the presence of azoreductase, and to increase lipophilicity for improving the intestinal absorption. Although the absorption of susalimod was increased up to ten times compared to sulfasalazine in a rat intestinal absorption model (Pihlman, unpublished results), preliminary preclinical pharmacokinetic studies exhibited only low systemic exposure in animals, indicating a high first-pass elimination. Species-specific bile duct toxicity ap...