Pharmacological management of pancreatitis

doi:10.1016/j.coph.2005.06.007

Current Opinion in Pharmacology

Volume 5, Issue 6, December 2005, Pages 578-582

https://doi.org/10.1016/j.coph.2005.06.007 Get rights and content

Pancreatitis is a common disease with substantial morbidity and mortality. Pharmacological therapy for the prevention and treatment of pancreatitis is an intense subject of investigation. The use of proteinase inhibitors such as gabexate mesylate in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (ERCP) has been disappointing. Initial studies using ulinastatin are promising but additional dose-response studies are needed. Somatostatin, but not octreotide, is likely to be effective in the prevention of post-ERCP pancreatitis. Rectal diclofenac might provide a simple, cheap alternative but large-scale studies are again needed. New insights into the role of proteinase-activated receptor-2 in the pancreas add to the complexity of the mechanisms involved in the pathophysiology of pancreatitis, and the development of specific agonists and antagonists of this receptor is necessary to assess their therapeutic potential in the prevention and management of pancreatitis.

Introduction

Approximately 210 000 patients with acute pancreatitis are admitted to hospital in the US annually [1]. Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis occurs in 1–7% of patients based on a consensus definition. This definition relies upon new or worsened abdominal pain and serum amylase levels ≥ three-fold above normal values 24 h after the procedure, and requiring at least two days of hospitalization (from the Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy) [2]. A subset of patients will develop chronic pancreatitis, a condition characterized by pain and malabsorption.

Cellular events leading to pancreatitis involve an inflammatory cascade with premature activation of trypsin in acinar cells [3]. This can result from trypsinogen autoactivation or trypsinogen activation by the lysosomal enzyme cathepsin-B. Trypsin activates a subset of enzymes, leading to the release of cytokines from acinar cells and recruitment of inflammatory cells. Additional evidence for a role of trypsin in pancreatitis comes from patients with hereditary pancreatitis, a genetic condition in which the trypsinogen gene is mutated [4]. This mutation leads to persistent trypsinogen activity, resulting in recurrent episodes of pancreatitis that can eventually progress to chronic pancreatitis [5].

Although drug development has boomed, which is reflected partially in the rising cost of drugs used in the treatment of pancreatic disease [6], the availability of effective drugs in the prevention and management of pancreatitis remains limited. Routine pharmacological prophylaxis for the prevention of ERCP-related pancreatitis is not recommended by current guidelines. This review focuses on the role of somatostatin and proteinase inhibitors in the prevention and treatment of pancreatitis. Furthermore, we address new insights into the pathophysiology of pancreatitis arising from results in rodent studies, as well as potential future pharmacotherapeutic strategies.

Section snippets

Gabexate mesylate

Gabexate mesylate is a synthetic serine proteinase inhibitor. It is small (molecular weight of 417 Da), non-antigenic and has a half-life of 55 s. Studies on its efficacy in the prevention of post-ERCP pancreatitis were initiated in Japan in the 1970s [7, 8]. In 1996, Cavallini et al. [9] showed that a 13 h infusion of gabexate mesylate reduced the incidence of post-ERCP pancreatitis in humans from 8% to 2%. However, concerns over the high costs associated with a 13 h infusion prompted

Proteinase inhibitors

Despite the large number of trials, no clear benefit of proteinase inhibitors has been demonstrated in pancreatitis. Seta et al. [30] completed a meta-analysis of randomized, placebo-controlled trials of aprotinin (four studies) and gabexate mesylate (six studies) in the treatment of acute pancreatitis. Overall, no effect on mortality was found, as was the case when aprotinin and gabexate mesylate were separated out in subgroup analyses. However, this meta-analysis is problematic as it combines

Leukotriene receptor antagonist (monelukast sodium)

Cysteinyl or peptide leukotrienes (LTC₄, LTD₄ and LTE₄) are inflammatory mediators formed via the lipooxygenase pathway that can play a role in inflammatory as well as nociceptive aspects of pancreatitis. Cartmell et al. [33] studied the effect of the cysteinyl leukotriene receptor antagonist montelukast sodium (10 mg once a day) on pain in a double-blind, placebo-controlled crossover study of patients with chronic pancreatitis. There was no significant difference in pain between groups as

Role of the proteinase-activated receptor-2 in the rodent pancreas

Proteinase-activated receptor-2 (PAR2) is a G-protein-coupled receptor; it is activated by proteolytic cleavage of the extracellular N-terminal domain by the serine proteinases tryptase and trypsin, allowing the new N-terminus to activate the receptor [35, 36, 37]. As trypsin and tryptase have long been known to play an important role in the inflammatory aspects of pancreatitis, it is not surprising that the physiological role of PAR2 in the pancreas has become a subject of investigation.

Conclusions

Although a 13 h infusion of gabexate mesylate significantly reduced post-ERCP pancreatitis, the effectiveness of a 6.5 h infusion is questionable. The substantial costs, prolonged infusion time and risk of anaphylactic complications make widespread use of gabexate mesylate unlikely. Ulinastatin has a short infusion time but additional studies are needed to determine its efficacy. Somatostatin (but not octreotide) could prove useful in the prevention of post-ERCP pancreatitis, and it will be

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

This work is supported by an AGA Research Scholar Award.

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It is hypothesized that protease inhibitors play an essential role in survival of venomous animals through protecting peptide/protein toxins from degradation by proteases in their prey or predators. However, the biological function of protease inhibitors in scorpion venoms remains unknown. In the present study, a trypsin inhibitor was purified and characterized from the venom of scorpion Mesobuthus eupeus, which enhanced the biological activities of crude venom components in mice when injected in combination with crude venom. This protease inhibitor, named MeKTT-1, belonged to Kunitz-type toxins subfamily. Native MeKTT-1 selectively inhibited trypsin with a K_ivalue of 130 nmol·L⁻¹. Furthermore, MeKTT-1 was shown to be a thermo-stable peptide. In animal behavioral tests, MeKTT-1 prolonged the pain behavior induced by scorpion crude venom, suggesting that protease inhibitors in scorpion venom inhibited proteases and protect the functionally important peptide/protein toxins from degradation, consequently keeping them active longer. In conclusion, this was the first experimental evidence about the natural existence of serine protease inhibitor in the venom of scorpion Mesobuthus eupeus, which preserved the activity of venom components, suggests that scorpions may use protease inhibitors for survival.
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Citation Excerpt :
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Pharmacological management of pancreatitis

Introduction

Section snippets

Gabexate mesylate

Proteinase inhibitors

Leukotriene receptor antagonist (monelukast sodium)

Role of the proteinase-activated receptor-2 in the rodent pancreas

Conclusions

References and recommended reading

Acknowledgements

Gastroenterology

J Gastrointest Surg

Biochim Biophys Acta

Am J Gastroenterol

Clin Gastroenterol Hepatol

Clin Gastroenterol Hepatol

Gastrointest Endosc

Gut

Gastrointest Endosc

Endoscopy

Gastroenterology

Gastrointest Endosc

Br J Surg

Gastrointest Endosc

Gastroenterology

Endoscopy

Scand J Gastroenterol

Eur J Biochem

Gastroenterology

Am J Physiol Gastrointest Liver Physiol

Complications of ERCP

Gastroinest Endoscopy