Arterial infusion using gabexate mesilate: Is it effective therapy for severe acute pancreatitis?
Severe acute pancreatitis (SAP) remains a lethal disease. It is defined as an inflammatory process of the pancreas with possible peripancreatic tissue and multi-organ involvement inducing multi-organ dysfunction syndrome (MODS) with an increased mortality rate. Protease inhibitors are widely applied to treat acute pancreatitis in Japan, but the protease inhibitors used to treat acute necrotizing pancreatitis cannot easily reach the pancreas when administered intravenously, and, because of ischemia or impaired microcirculation, they hardly penetrate into pancreatic tissue. Recently, continuous regional arterial infusion (CRAI) with protease inhibitor of nafamostat mesilate and antibiotics has proven effective as an initial therapy in Japan. However, evidence supporting the value of CRAI in treating acute pancreatitis is insufficient. Actually, CRAI of protease inhibitors and antibiotics may possibly reduce the mortality rate and incidence of infectious complications in necrotizing pancreatitis. Furthermore, until now, most cases have been used with nafamostat mesilate as protease inhibitor. Therefore, a prospective study was performed to treat SAP with CRAI using gabexate mesilate and investigated the clinical benefits and sequential changes in serum inflammation-related parameters such as cytokines and chemokines. A research article to be published on November 7, 2008 in the World Journal of Gastroenterology addresses this question. The research team led by Dr. ITO from Pancreatic Diseases Branch of Kyushu University in Japan conducted a prospective study to confirm the efficacy of arterial infusions of gabexate mesilate and antibiotics for SAP. This strategy suppresses early inflammation and infection in pancreatic tissue, which controls subsequent systemic inflammation. The level of protease inhibitor in pancreatic tissues after CRAI using nafamostat was 5-fold higher than that delivered by intravenous injection, and trypsin activities in pancreatic tissues are significantly suppressed by CRAI. On the other hand, the level of protease inhibitor in pancreatic tissues after CRAI using gabexate mesilate was 32-fold higher than that delivered by intravenous injection. However, until now, CRAI using gabexate mesilate has not been examined sufficiently. In the present study, therefore, the usefulness of CRAI using gabexate mesilate for patients with SAP was investigated. The reasons for using gabexate mesilate were as follows: (1) Gabexate mesilate is the only intravenous protease inhibitor that has been proven effective in an RCT. (2) Gabexate mesilate has more anticoagulant effect than nafamostat mesilate. (3) Gabexate mesilate induces less hyperkalemia even at high doses compared to nafamostat mesilate. (4) In Japan, most studies on CRAI have used nafamostat mesilate, and more needs to be understood about gabexate mesilate.
Out of 18 patients fulfilled clinical diagnostic criteria for SAP in Japan, 9 patients underwent CRAI, while 9 patients underwent conventional systemic protease inhibitor and antibiotics therapy (non-CRAI). CRAI was initiated within 72 h of the onset of pancreatitis. Gabexate mesilate (2400 mg/d) was continuously administered for 3 to 5 d. The clinical benefits and sequential changes in serum inflammation-related parameters were examined. The duration of abdominal pain in the CRAI group was 1.9 ± 0.26 d, whereas that in the non-CRAI group was 4.3 ± 0.50. The duration of SIRS in the CRAI group was 2.2 ± 0.22 d, whereas that in the non-CRAI group was 3.2 ± 0.28. Abdominal pain and SIRS disappeared significantly in a short period of time after the initiation of CRAI using gabexate mesilate. The average length of hospitalization significantly differed between the CRAI and non-CRAI groups, 53.3 ± 7.9 and 87.4 ± 13.9 d, respectively. During the first two weeks, levels of serum CRP and the IL6/IL10 ratio in the CRAI group tended to have a rapid decrease compared to those in the non-CRAI group.
Essentially, a large-scale randomized controlled trial (RCT) should be necessary to verify the effects of CRAI, but to conduct such a study on patients with highly lethal SAP seems to be unethical in Japan. A future RCT might consider enrolling patients with relatively mild and less fatal SAP group like the present study. This study suggests that CRAI using gabexate mesilate was effective against SAP in terms of yielding clinical benefits for patients with SAP, and thus may provide a new strategy of treatment for SAP.
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