Gabexate mesilate in acute pancreatitis: neither a miracle nor a mirage, merely the search of optimal dosage

Sir I read the comments of Prof. Bradley i on the GISPAC study 2 with interest. However, I believe that some aspects of this commentary should be discussed. First of all, the intracellular activation of trypsinogen is currently believed to initiate acute pancreatitis 3. Recently, Hartwig et al. 4 in a beautifully performed study, showed that, in an experimental model of secretagogue-induced acute pancreatitis, large amounts of trypsinogen are present in the interstitium and are transported via portal and lymphatic circulation; activation of extracellular trypsinogen induces haemorrhagic necrosis in a setting of mild oedematous pancreatitis. Furthermore, in the same study, the authors also showed that gabexate mesilate, as well as soybean trypsin inhibitor, significantly decrease trypsinogen activation peptide levels both in lymph and blood, thus reducing pancreatic injury. As regards age, this is only one of the criteria included in the Glasgow score which was used as a reference for including patients with acute pancreatitis in the GISPAC study. We have recently reported 5 that, based on the results of a stepwise multivariate logistic regression analysis, patients over 55 years of age presented a significant risk (greater than 3) of developing severe acute pancreatitis with respect to patients under 55 years of age. These findings suggest that age strongly influences the course of acute pancreatitis, thus confirming the previous results of Imrie et al. 6 and Ranson et al. I. Thus, in our opinion, the assumption made by Prof. Bradley, who considers age as a selection bias in the GISPAC study, is not valid. We agree with Prof. Bradley that metanalyses are never substitutes for controlled clinical studies, but the efficacy of gabexate mesilate in the treatment of severe acute pancreatitis has recently been confirmed by Chen et al. 8. These authors have reported, in a prospective study involving 52 patients with severe acute pancreatitis, that gabexate mesilate at a dosage of 100 mg/h for 7 days results in improved survival in patients with acute pancreatitis and organ dysfunction. In conclusion, I do not believe that gabexate mesilate has been seen as a miracle drug or as a mirage by the authors of papers until now 2. In fact, the GISPAC study was carried out to deter-

Sir Notwithstanding

Dr. Pezzilli’s

considered

response to m y Edi-

torial, and his admirable enthusiasm for gabexate mesilate, my principal points stand as previously stated: 1. We still don’t know whether the intrapancreatic activation of trypsin is the chicken or the egg. 2. Although age is a well recognized predictor of severity for acute pancreatitis, an artificial elevation of severity can occur with its use in elderly populations. 3. The efficacy of gabexate mesilate in ameliorating acute pan-

mine an optimum dosage regimen for gabexate mesilate. Furthermore, my personal opinion is that this drug has a role in a multimodality therapeutic approach in patients with severe acute pancreatitis.

R. Pezzilli Emergency Department,

“Sant’Orsola” Hospital, Bologna, Italy. Fax: +39-051-6364794

’ Bradley EL. Gabexate mesilate in acute pancreatitis: miracle or mirage? Digest Liver Dis 2001;33:12-3. * Pezzilli R, Miglioli M, and the Italian Acute Pancreatitis Study Group (GISPAC). Multicentre comparative study of two schedules of gabexate mesilate in the treatment of acute pancreatitis. Digest Liver Dis 2001;33:49-57. 3 Hofbauer B, Saluja AK, Lerch MM, Bhagat L, Bhatia M, Lee HS, et al. Intra-acinar cell activation of trypsinogen during caemlein-induced pancreatitis in rats. A m .I Physiol 1998;275:G352-62. 4 Hartwig W, Jimenez RE, Werner .I, Lewandrowski KB, Warshaw AL. Fernandez-de1 Castillo C. Interstitial trypsinogen release and its relevance to the transformation of mild into necrotiring pancreatitis in rats. Gastroenterology 1999;117:717-25. 5 Pezzilli R, Billi P, Morselli-Labate AM. Severity of acute pancreatitis: relationship with etiology, sex and age. Hepatogastroenterology 1998;45:1859-64. 6 Imrie CW, Benjamin IS, Ferguson JC, McKay AJ, Mackenzie I, O’Neill J, et al. A single-centre double-blind trial of Trasylol therapy in primary acute pancreatitis. Br J Surg 1978;65:337-41. ’ Ranson JHC, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 1974;139:69-81. * Chen HM, Chen JC, Hwang TL, Jan YY, Chen M E Prospective and randomized study of gabexate mesilate for the treatment of severe acute pancreatitis with organ dysfunction. Hepatogastroenterology 2000;47: 1147-50.

creatitis has NOT been established by existing trials.

beyond reasonable

doubt

I challenge Dr. Pezzilli and the members of GISPAC group to conduct a multi-institutional, randomized, dose-controlled, doubleblinded study of appropriate

power to address this unsettled issue.

Sincerely Edward 1. Bradley Ill