ABSTRACT
BACKGROUND: The primary end points of this study were to determine the dose-limiting toxic effects (DLTs), maximum tolerated dose, and a recommended phase II dose of a synthetic serine protease inhibitor, nafamostat mesilate, in combination with full-dose gemcitabine in patients with unresectable locally advanced or metastatic pancreatic cancer. The secondary end point was to assess therapeutic response. PATIENTS AND METHODS: Patients with previously untreated pancreatic cancer received gemcitabine (1 000 mg/m(2) i.v. for 30 min) on days 1, 8, and 15, with nafamostat mesilate (continuous regional arterial infusion for 24 h through a port-catheter system) on days 1, 8, and 15; this regimen was repeated at 28-day intervals. The initial dose of nafamostat mesilate was 2.4 mg/kg and was escalated in increments of 1.2 mg/kg until a dose of 4.8 mg/kg was achieved. A standard '3+3' phase I dose-escalation design was used. Therapeutic response and clinical benefit response were assessed. RESULTS: Twelve patients were enrolled in this study. None of the patients experienced DLTs, and nafamostat mesilate was well tolerated at doses up to 4.8 mg/kg in combination with full-dose gemcitabine. This combination chemotherapy yielded a reduction of a high serum level of the tumor marker CA19-9. Pain was reduced in three of seven patients without oral morphine sulfate. Overall survival was 7.1 months for all patients. CONCLUSION: This phase I study was carried out safely. This combination chemotherapy showed beneficial improvement in health-related quality of life. The recommended phase II dose of nafamostat mesilate in combination with full-dose gemcitabine is 4.8 mg/kg.
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Guanidines/administration & dosage , Pancreatic Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzamidines , Biomarkers, Tumor/blood , CA-19-9 Antigen/blood , Deoxycytidine/therapeutic use , Disease Progression , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Guanidines/chemistry , Humans , Infusions, Intra-Arterial , Male , Maximum Tolerated Dose , Middle Aged , Molecular Structure , Remission Induction , Survival Analysis , Time Factors , Treatment Outcome , GemcitabineABSTRACT
A set of 1,3-propanediamine derivatives connected to carbohydrates (5) has been prepared in four steps from peracetylated sugar and 1,3-dibromo-2-propanol in 60-73% yields. D-Glucose, D-mannose, D-galactose, D-xylose, D-ribose, and maltose are utilized as sugar molecules in this work. The diamine moiety was connected to the C1 carbon of the glycopyranose ring via an O-glycoside bond. All of the anomeric configurations and sugar puckering conformations, except in the D-maltose derivative, were determined by X-ray crystallography of the diazido or dibromo precursors. While glycosidation of peracetylated galactopyranose with 1,3-dibromo-2-propanol in the presence of boron trifluoride afforded both anomers, the neighboring group participation of the 2-acetoxy group yielded a single anomer for the other substrates. This method has been used to synthesize a library of sugar-pendant diamines including an OH-protected derivative (6), and an N,N'-diisopropyl-substituted derivative (7). A similar series of reactions using 2,3-dibromo-1-propanol gave ethylenediamine-type derivatives (11), and bis(bromomethyl)bis(hydroxymethyl)methane (12) gave bisglucose-pendant derivatives (16).
Subject(s)
Diamines/chemical synthesis , Oligosaccharides/chemical synthesis , Carbohydrate Sequence , Indicators and Reagents , Molecular Conformation , Molecular Sequence Data , X-Ray DiffractionABSTRACT
Laparoscopic cholecystectomy using an ultrasound surgical aspirator has been performed in our department since March 1991. The horn cover was altered in order to be inserted through a trocar 10 mm in diameter. The main purpose of this device is to explore Calot's triangle by fragmentation and aspiration of the fatty tissue without damaging the nerves, vessels, and cystic duct. First the serosa of the Calot's triangle is cut via electrocautery with the sharp-angle hook dissector we designed. Then the cystic duct and cystic artery are efficiently exposed by the ultrasound surgical aspirator. This procedure is perfectly adapted for laparoscopic cholecystectomy. We obtained favorable results with the ultrasound surgical aspirator in 135 cases including 40 cases with a negative gallbladder, as evaluated by endoscopic retrograde cholangiography. In conclusion, the ultrasound surgical aspirator is suitable for skeletonizing the cystic duct and cystic artery, and the procedure is perfectly safe.
