Serum trypsinogen activation peptide in the assessment of the diagnosis and severity of acute pancreatic damage: a pilot study using a new determination technique.

OBJECTIVES: To evaluate the clinical value of a new direct and competitive immunoassay for trypsinogen activation peptide (TAP) determination in acute pancreatitis (AP). METHODS: The subjects were 34 patients with AP (22 mild, 12 severe), 12 patients with nonpancreatic acute abdominal pain (AA), 11 healthy subjects (HS), and 16 consecutive patients who underwent therapeutic ERCP (ERCP). Serum TAP, amylase, and lipase levels were determined in AP, AA, and HS at their initial observation; the AP patients were also studied for 6 consecutive days after admission. In the ERCP patients, serum TAP, amylase, and lipase levels, as well as urine TAP and amylase levels, were determined before and 6 hours after endoscopy. RESULTS: Serum TAP levels on admission were 0.35 +/- 1.60 OD (mean +/- SD) in AP patients and 0.005 +/- 0.001 OD in AA patients, while HS patients had no detectable serum TAP levels. ERCP patients had no detectable serum TAP levels before and 6 hours after the ERCP, whereas urine TAP concentrations were 1.72 +/- 3.43 OD and 0.75 +/- 1.49 OD before and 6 hours after the execution of the endoscopy, respectively (P = 0.249). The sensitivities and specificities of serum TAP, amylase, and lipase levels in discriminating between AP and AA were 23.5% and 91.7%, 94.1% and 100%, and 97.1% and 100%, respectively, while those used in the assessment of the severity of AP were 29.9% and 73.5%, 38.8% and 81.2%, and 28.4% and 83.6%, respectively. CONCLUSION: TAP is of limited value in assessing the diagnosis and the severity of acute pancreatic damage.

Pharmacological and toxicological aspects of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548): a novel antineoplastic agent.

4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548) belongs to a novel class of antitumor compounds (termed alkycyclines) and is currently undergoing Phase II clinical trial. In the present study, we investigated the in vitro and in vivo antitumor activity, the pharmacokinetics, and the toxicological profile of this compound. PNU-159548 showed good cytotoxic activity in murine and human cancer cells growing in vitro, with an average concentration for 50% growth inhibition of 15.8 ng/ml. The drug showed strong antitumor efficacy in vivo after i.v. and p.o. administration against rapidly proliferating murine leukemias and slowly growing transplantable human xenografts. At non-toxic doses, PNU-159548 produced complete regression and cures in ovarian, breast, and human small cell lung carcinomas. Fourteen of 16 models studied, including colon, pancreatic, gastric, and renal carcinomas, astrocytoma and melanoma, were found to be sensitive to PNU-159548. In addition, PNU-159548 was effective against intracranially implanted tumors. Toxicological studies revealed myelosuppression as the main toxicity in both mice and dogs. The maximum tolerated doses, after a single administration, were 2.5 mg/kg of body weight in mice, 1.6 mg/kg in rats, and 0.3 mg/kg in dogs. In the cyclic studies, the maximum tolerated doses were 0.18 mg/kg/day (cumulative dose/cycle: 0.54 mg/kg) in rats and 0.05 mg/kg/day (cumulative dose/cycle: 0.15 mg/kg) in dogs. PNU-159548 showed minimal cardiotoxicity, when compared with doxorubicin in the chronic rat model at a dose level inducing similar myelotoxicity. Animal pharmacokinetics, carried out in mice, rats, and dogs, was characterized by high volumes of distribution, plasma clearance of the same order of the hepatic blood flow, and short terminal half-life. These findings support the conclusion that PNU-159548 is an excellent candidate for clinical trials in the treatment of cancer.