Gastronews AGA

1. Is There a Drug on the
Horizon for Acute
Pancreatitis?
Nov. 14, 2015
At the present time specific drug
therapy for acute pancreatitis is actively
under investigation.
Yan Bi, MD, PhD
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
Santhi Swaroop Vege, MD
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
This article appeared in the October/November issue of AGA Perspectives.
Acute pancreatitis is a serious disease and is the most common gastrointestinal cause of hospital admission.
While the majority of patients present w ith a mild disease requiring only a short hospital stay, about 20 to 30

2. percent of patients develop moderate to severe disease, associated w ith higher morbidity and mortality rates,
and larger associated health-care costs.
While current medical management of acute pancreatitis still focuses on supportive care — including fluid
resuscitation, pain control, nutrition support and treatment of local or systemic complications — advances in
basic research and a better understanding of the pathophysiology in pancreatitis has led to the development of
some potential pharmacologic therapies that target the various steps in the pathogenesis of the disease.
How ever, w e have to emphasize that there is no firm evidence so far to advise any drugs in clinical use and all
the discussion below is about emerging information.
Premature trypsin activation is considered an early event in the development of acute pancreatitis. Somatostatin
is a hormone that inhibits basal and stimulated pancreatic enzyme secretion. Conflicting results have been
reported using somatostatin or its analogues in acute pancreatitis management since 1980. The largest
prospective multicenter randomized study show ed no benefit of octreotide in the treatment of acute pancreatitis
in terms of mortality, complications, duration of pain, the need of surgical interventions or the length of the
hospital stay.1
How ever, a recent study from China show ed high-dose octreotide administration w ithin 48 hours
of onset of acute pancreatitis appears to reduce the risk of developing severe acute pancreatitis and partly
attenuate severe acute pancreatitis. In another study, TNF-α, IL-6, IL- 10, APACHE II scores, incidences of
sepsis, multiple organ dysfunction and mortality w ere significantly low er in the somatostatin group compared to
placebo.2
These studies have limitations and currently octreoctide or somatostatin cannot be recommended as
treatment for acute pancreatitis,
Proteases are potential effective targets for acute pancreatitis therapy as they are markedly activated in severe
acute pancreatitis and their activation is related to vasospasm, microthrombosis and pancreatic necrosis.
Aprotinin is the first protease inhibitor used in clinical trials for acute pancreatitis. How ever, no benefits w ere
observed w hen administered either intravenously or intraperitoneally.3-6
Intravenous delivery of the new er
generation of protease inhibitors gabexate mesylate (FOY), nafamostat mesilate and ulinastatin have
demonstrated a reduction in complications and mortality but the trials are very small and metaanalysis failed to
show benefits of these medications.7-9
Continuous regional intra-arterial infusion (CRAI) delivers medicine through one of the arteries that supplies the
affected pancreas, therefore the drug concentration in the pancreas can reach up to 32 times higher w ith minimal
toxic effects compared to routine intravenous administration. Clinical trials have show n that nafamostat mesylate
(FUT-175), a broad spectrum protease inhibitor through CRAI and imipenem, resulted in a quicker resolution of
abdominal pain, systemic inflammatory response syndrome resolution, low ered serum C reactive protein and the
IL6/IL10 ratio, decreased the need for surgical therapy, decreased pancreatic necrosis infection, shortened
hospitalization time, and reduced mortality in patients w ith severe acute pancreatitis.10-13
CRAI therapy should be
initiated w ithin 48 hours after the onset of acute necrotizing pancreatitis.14,15
How ever, these studies also have methodologic problems and meta-analysis of 2 RCTs did not show a
significant reduction in mortality. Thus, this invasive therapy is not recommended unless future, better-conducted
trails show a benefit.
Drug therapy for acute pancreatitis is actively under investigation and future understanding of the
disease pathophysiology and better designed trials are needed to make significant advances in the
management of this disease.

3. Another promising pharmacological target is TNF-α, w hich is critical in the pathogenesis of severe acute
pancreatitis, including pancreatic and peri-pancreatic necrosis, systemic inflammatory response syndrome and
persistent organ failure. In experimental acute pancreatitis animal models, serum TNF-α activity increases w ithin
three hours of the induction of acute pancreatitis and its serum level is significantly higher in severe disease
compared to mild disease. TNF-α activity can be blocked by mono-clonal or polyclonal antibodies and the
synthesis of TNF-α can be blocked by pentoxyfylline, a nonselective phosphodiesterase inhibitor. In a recent
double-blinded randomized control pilot trial, pentoxifylline decreased the necessity of ICU admissions, and
shortened ICU stays and prolonged hospitalization time (more than 4 days).16
It is an oral medication that can be
safely and easily given to all patients w ithout the need to predict the severity of the acute pancreatitis. Despite
the theoretical increased risk of infectious complications, no adverse effects w ere noted in the patients receiving
pentoxifylline in the pilot trial. Pentoxifylline may also have independent benefits besides blocking TNF –α, like
effects on rheology and renal protection. NIH has recently funded a larger, randomized controlled study to further
confirm the promising results.
The discrepancy betw een animal studies and human clinical trials can be explained by many things, including
flaw s in clinical trial designs, inadequate dosages of medication and suboptimal drug delivery (timing and route).
In addition, the reliability of the acute pancreatitis animal model in human disease is also unclear.
In summary, at the present time specific drug therapy for acute pancreatitis is actively under investigation and
future understanding of the disease pathophysiology and better designed, randomized clinical trials are needed
to make significant advances. Significant improvement in acute pancreatitis animal models or modern technology
for in vitro human pancreas culturing system are crucial to better understanding the pathophysiology. At the
present time, a reliable method to predict the moderately severe and severe types of acute pancreatitis is not
available. Hence, the ideal drug to treat acute pancreatitis should be safe, cheap and easily administered to all
patients in any clinical setting.
Dr. Bi has no disclosures to report.
Dr. Vege consults with UptoDate and CalciMedica.
References
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4. 16. Vege, S.S., et al., Pentoxifylline Treatment in Severe Acute Pancreatitis: A Pilot, Double-Blind, Placebo- Controlled, Randomized Trial. Gastroenterology,
2015. 149(2): p. 318-320 e3