Background:Acute variceal bleeding is a serious complication of liver cirrhosis, which has an attendant mortality of approximately 60% over two years, and a variety of treatments, such as balloon tamponade, endoscopic varix ligation, sclerotherapy, histoacryl injection and vasoactive drugs, have been used. The aims of the present trial were to compare the effectiveness and complications of somatostatin and vasopressin in the treatment of acute variceal bleeding.Methods:Forty-three cirrhotic patients, with endoscopically proven acute variceal bleeding, were included in this trial. Both drugs were given as continuous intravenous infusions for 48 hours. Twenty patients received the somatostatin (250 mcg per hr after a bolus of 50 mcg) and twenty-three the vasopressin (0.4 units per min).Results:There were no significant differences between the two groups in relation to age, sex, etiology of cirrhosis, Child-Pugh classification, characteristics of bleeding episode, laboratory findings before randomization and units of transfused blood during therapy. Rebleeding, within 6 hours after beginning of therapy, was regarded as failure to control initial bleeding, and was observed in 3 (13.0%) of the patients who received vasopressin and in 1 (5.0%) treated with somatostatin (p>0.05). Five patients in both the somatostatin (25.0%) and vasopressin (21.7%) groups rebled during the first 5 days following the initial therapy (p>0.05). Meaningful complications related to the use of vasopressin were observed in 5 patients (chest pain or abdominal pain requiring nitroglycerin), but no complications were associated with the use of somatostatin (p<0.05). The mortalities during hospitalization were similar in both the treatment groups. Two of the vasopressin and 1 of the somatostatin group died due to the uncontrolled rebleeding, and 1 of the vasopressin group died due to hepatic failure (2 weeks later after therapy).Conclusion:This study showed no differences in the effectiveness of somatostatin and vasopressin, but the somatostatin group had a lower risk of the complications.
Fab-PE38 used in this study is B3(Fab)-ext-PE38, and it is an antibody toxin that is made by fusing theAntibody toxins are made by fusing toxins to specific antibodies that selectively bind to cancer cells (1). (B3(Fab)-ext-PE38) 2 is the disulfide-bridged dimer of monomer B3(Fab)-ext-PE38 (2). We used the B3 monoclonal antibody as a model antibody, and it binds to a carbohydrate antigen found on many carcinomas (3, 4). PE38 is a 38-kDa derivative of Pseudomonas exotoxin (PE) 2 that catalyzes ADP-ribosylation of protein elongation factor 2 and inactivates it (5, 6). PE38 is a truncated form of the polypeptide that cannot bind to target cells by itself.B3(Fab)-ext-PE38 contains the light chain (V L -C L ) and the long chain in which the Fd chain (V H -C H1 ) is fused to PE38. The ext connects the Fd chain and PE38, producing the long Fd(V H -C H1 )-ext-PE38 chain. The Fab domain is formed by the formation of an interchain disulfide bond between the light chain and Fd chain. Two cysteines for this interchain disulfide bond are the one located at the end of C L domain of the light chain and the other one at the end of the C H1 domain of the long chain. The Fab toxin has two advantages over the single chain Fv(scFv) toxin in which two variable domains (V H and V L ) of antibody are connected with flexible linker. First, the refolding yield of Fab toxin is 10-fold higher than that of scFv toxin (7,8). Second, the stability of the Fab antibody toxin is higher than that of scFv toxin (9, 10).(B3(Fab)-ext-PE38) 2 has higher cytotoxicity than the monomeric B3(scFv)-PE38. Specifically, it has about 11-fold higher cytotoxicity in the CRL-1739 cell line than that of B3(scFv)-PE38 (2). The dimer is produced by the formation of a disulfide bond bridge between two monomers with the Cys residue located in the ext region in the Fd(V H -C H1 )-ext-PE38 chain. This disulfide bond is formed by the random collision of two Cys residues in two monomers. In our previous report, the refolding yield of the dimer was 0.06% (2). This is very low when compared with the yield of the monomer, which was ϳ10%.A dimeric antibody toxin is predicted to have several advantages over monomeric antibody toxins. The existence of two antigen binding domains should confer an increase in binding avidity. A dimeric antibody toxin will deliver two toxins at the same time to target cells, which enables it to kill target cells with a higher cytotoxicity than monomeric antibody toxin. Dimeric antibody toxin should also be more stable than scFv toxin.Streptococcal protein G is known to bind to IgG. It has a serum albumin binding domain and three IgG binding domains. It has been identified that the third IgG binding domain (domain III) of Streptococcal protein G binds to the Fab fragment of IgG (11).In this study, we focused on producing the dimer from the monomers that had already been refolded and purified. We constructed recombinant tandem repeats of Streptococcal protein G domain III and used it to make complexes that have multiple monomers bound. We found...
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