A novel thermosensitive in-situ gel of gabexate mesilate for treatment of traumatic pancreatitis: An experimental study.
Gabexate mesilate (GM) is a trypsin inhibitor, and mainly used for treatment of various acute pancreatitis, including traumatic pancreatitis (TP), edematous pancreatitis, and acute necrotizing pancreatitis. However, due to the characteristics of pharmacokinetics, the clinical application of GM still needs frequently intravenous administration to keep the blood drug concentration, which is difficult to manage. Specially, when the blood supply of pancreas is directly damaged, intravenous administration is difficult to exert the optimum therapy effect. To address it, a novel thermosensitive in-situ gel of gabexate mesilate (GMTI) was developed, and the optimum formulation of GMTI containing 20.6% (w/w) P-407 and 5.79% (w/w) P188 with different concentrations of GM was used as a gelling solvent. The effective drug concentration on trypsin inhibition was examined after treatment with different concentrations of GMTI in vitro, and GM served as a positive control. The security of GMTI was evaluated by hematoxylin-eosin (HE) staining, and its curative effect on grade II pancreas injury was also evaluated by testing amylase (AMS), C-reactive protein (CRP) and trypsinogen activation peptide (TAP), and pathological analysis of the pancreas. The trypsin activity was slightly inhibited at 1.0 and 5.0 mg/mL in GM group and GMTI group, respectively (P<0.05 vs. P-407), and completely inhibited at 10.0 and 20.0 mg/mL (P<0.01 vs. P-407). After local injection of 10 mg/mL GMTI to rat leg muscular tissue, muscle fiber texture was normal, and there were no obvious red blood cells and infiltration of inflammatory cells. Furthermore, the expression of AMS, CRP and TAP was significantly increased in TP group as compared with control group (P<0.01), and significantly decreased in GM group as compared with TP group (P<0.01), and also slightly inhibited after 1.0 and 5.0 mg/mL GMTI treatment as compared with TP group (P<0.05), and significantly inhibited after 10.0 and 20.0 mg/mL GMTI treatment as compared with TP group (P<0.01). HE staining results demonstrated that pancreas cells were uniformly distributed in control group, and they were loosely arranged, partially dissolved, with deeply stained nuclei in TP group. Expectedly, after gradient GMTI treatment, pancreas cells were gradually restored to tight distribution, with slightly stained nuclei. This preliminary study indicated that GMTI could effectively inhibit pancreatic enzymes, and alleviate the severity of trauma-induced pancreatitis, and had a potential drug developing and clinic application value.
Department of Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China.|Department of Ultrasound, 161st Hospital of Chinese PLA, Wuhan, 430010, China.
Han-Jing
HJ
Gao
Department of Ultrasound, General Hospital of Beijing Military Region, Beijing, 100700, China.
Qing
Q
Song
Department of Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China.
Fa-Qin
FQ
Lv
Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology, Beijing, 100039, China.
Shan
S
Wang
Department of Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China.
Yi-Ru
YR
Wang
Department of Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China.
Yu-Kun
YK
Luo
Department of Pharmaceutics, Beijing Institute of Pharmacology and Toxicology, Beijing, 100039, China.
Xing-Guo
XG
Mei
Department of Ultrasound, Chinese PLA General Hospital, Beijing, 100853, China. txiner@vip.sina.com.
Jie
J
Tang
D000681:Amylases / Q000378:metabolism; D000818:Animals; D002097:C-Reactive Protein / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D016670:Gabexate / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005782:Gels; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D009842:Oligopeptides / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010195:Pancreatitis / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D020442:Poloxamer / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013696:Temperature; D014950:Wounds, Penetrating / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D003692:Delayed-Action Preparations; D005782:Gels; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; C080396:trypsinogen activation peptide; D020442:Poloxamer; D016670:Gabexate; D002097:C-Reactive Protein; D000681:Amylases
gabexate mesilate thermosensitive in-situ gel; gabexate mesylate; traumatic pancreatitis; treatment; trypsin inhibitor