Conditions: Acute Pancreatitis (AP) Gallstone Pancreatitis Alcoholic Pancreatitis Trauma Acute Pancreatitis Hypertriglyceridemia Acute Pancreatitis Idiopathic (Unknown) Acute Pancreatitis Medication Induced Acute Pancreatitis Cancer Acute Pancreatitis Miscellaneous (i.e. Acute on Chronic Pancreatitis)
Keywords: Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) pancreatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 83
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine the effects (good and bad) of giving a drug called pentoxifylline to patients with acute pancreatitis.

Detailed description:
Participants were randomized to either the treatment group (Pentoxifylline medication) or the control group (Placebo).

Participant took a pill orally, starting from the time of admission. Participants received a total of 9 doses over the three days of hospitalization (72 hours).

Research blood draws were done at baseline and on 5 successive days or until the time of discharge, whichever occured earlier. The study gathered clinical follow up information up to 4 months following hospitalization regarding the diagnosis of acute pancreatitis.

Arms:
arm 1: Pentoxifylline, 400 mg, 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses. arm 2: Placebo 3 times daily by mouth from time of enrollment until 72 hours from enrollment. Subjects to receive up to a maximum of 9 doses.

Interventions: intervention 1: Pentoxifylline intervention 2: Placebo
Intervention descriptions: intervention 1: Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate (cAMP), activates protein kinase A (PKA), inhibits Tumor Necrosis Factor (TNF) and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability (known as a haemorrheologic effect), reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation.Pentoxifylline is also an antagonist at adenosine 2 receptors intervention 2: A harmless pill that has no therapeutic effect, used as a control in testing of investigational drug

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
Pentoxifylline Treatment in 
Acute Pancreatitis:  A Double-
Blind Placebo-Controlled 
Randomized Trial 
NCT 02487225 
January 9, 2017 


TITLE AND SUMMARY PAGE  
Project Title: Pentoxifylline Treatment in Acute Pancreatitis; A Double-Blind Placebo-
Controlled Randomized Trial  
 
Principal Investigator:  
Santhi Swaroop Vege, MD 
Section of Gastroenterology and Hepatology 
Professor of Medicine  
Mayo Clinic College of Medicine 
200 First Street SW 
Phone: 507-284-2478 
Fax: 507-266-9081 
vege.santhi@mayo.edu 
  
Participating Investigators: 
Suresh T. Chari, M.D.  
Conor Loftus, M.D. 
Magdalen A. Clemens 
 
Project Summary:  
Background. Acute pancreatitis (AP) is a cause of significant morbidity and mortality and 
effective therapeutic regimens to treat this condition are lacking. Extensive experimental 
evidence indicates that tumor necrosis factor alpha (TNF-) contributes to the pathogenesis of 
multiple organ failure (main cause of morbidity and mortality) in AP, suggesting a possible role 
for inhibition of TNF- in the treatment of AP. There is no effective drug therapy for AP and 
hardly any human experience about the role of pentoxifylline in AP Methods: Randomized, 
double-blind, placebo-controlled study comparing three times daily dosing with Pentoxifylline 
from the time of admission until 72 hours of hospitalization in patients presenting with AP. 
Seventy-five patients will be enrolled in both the "treatment" and "placebo" groups (150 patients 
total).  This study will be performed at Mayo Clinic, Rochester. Primary outcomes: Determine 
changes in CRP, TNF-, IL-6, and IL-8 levels from admission baseline at one week.  
Significance: If our hypothesis is confirmed this trial will be a landmark development in the 
treatment of AP. A simple, safe, and inexpensive drug that can be given to all patients with AP, 
in all settings, will be available to decrease the significant morbidity and mortality due to this 
disease. 
 
PROJECT DESCRIPTION 
Specific Aims:  
Aim1: Determine if oral pentoxifylline will improve clinical outcomes in AP. Persistent SIRS 
and organ failure, pancreatic and/or peripancreatic necrosis and infection (determinants) will be 
primary endpoints, while death (infrequent), length of stay, and the need for ICU and 
intervention will be secondary endpoints. These are all identified in the revised Atlanta 
classification as outcomes of interest.    Hypothesis:  Pentoxifylline will decrease the occurrence 
of any one of the following adverse outcomes in AP:  pancreatic and/or peripancreatic necrosis 
and infection, persistent organ failure, prolonged hospital stay, need for ICU, and intervention 
and death in patients with AP. 


 
Aim2: Determine if oral pentoxifylline will decrease serum levels of inflammatory markers. 
Hypothesis: Pentoxifylline will reduce levels of CRP, TNF-α, IL-6, and IL-8, and this reduction 
will correlate with clinical outcomes in patients with AP. 
 
 
 Background and Significance:  
Acute pancreatitis, an inflammation of the pancreas gland, is the most common gastrointestinal 
hospital discharge diagnosis and averages $2.6 billion in costs per year. Yet, as common as it is, 
there is no specific drug to treat this disease. There has been no drug trial in AP since the 
beginning of this century. Based on previous animal studies and a pilot study in humans at our 
institution, pentoxifylline has shown to block the inflammation in this disease. A larger study 
must be performed before the efficacy of this drug can be confirmed. A successful study would 
provide a breakthrough in AP therapy, paving the way for a simple, safe, and inexpensive drug to 
be available world-wide to treat this disease. This novel approach would be a major 
advancement in the treatment of this disease.  
 
Acute pancreatitis (AP) is a common inflammatory condition of the pancreas leading to the 
hospitalization of millions of patients annually worldwide. While the majority of patients (~80%) 
have mild, self-limiting disease with low mortality, severe acute pancreatitis (SAP) is associated 
with high morbidity and mortality (20-40%) and prolonged hospital stays.  Specific 
pharmacological therapies, such as aprotinin, glucagon, gabexate, somatostatin and lexipafant, 
have not been shown to have any advantage in randomized controlled trials.  As a result, 
treatment for AP is mainly supportive involving bowel rest, aggressive intravenous fluid 
resuscitation and pain control -a targeted therapy for AP is therefore urgently needed.  
 
Significance 
The morbidity, mortality, and increased costs in acute pancreatitis (AP) are mainly due to the 
more serious forms, moderate and severe, described in the latest revised Atlanta  
classification(4).  The accepted important clinical outcomes of AP include systemic 
inflammatory response syndrome (SIRS), pancreatic and/or peripancreatic necrosis and 
infection, persistent organ failure, length of hospital stay, admittance to the intensive care unit 
(ICU) or intensive care intervention, and death. In our prospective study, 31% of 137 
consecutively admitted patients with AP had moderate or severe AP,10 while in another study 
half of the 619 patients with AP, who had a computed tomography (CT) scan at our institution 
had such serious disease (unpublished data). Two important reasons for the significant morbidity 
and mortality seen in AP are the inability to accurately predict these serious forms in the early 
stages and the absence of an effective drug that could prevent the progression to such serious 
forms. It is for this reason current guidelines for the treatment of AP, recommend “supportive 
care” as the main treatment.(2) The many available predictors of severity in AP have reached a 
plateau for their efficacy(5) and thus there is no reliable way at admission to predict those who 
will require a drug to prevent the adverse outcomes. Hence, all patients need to be targeted. If all 
are to be given a drug, it has to 
be inexpensive, easy to administer, and safe. Pentoxifylline meets all these criteria and can be 
administered in both academic and community settings. Complicated interventions like 
intravenous and intra-arterial therapies are not the ideal therapies for this purpose. With this 
background, it can be clearly appreciated that a simple, safe, and inexpensive drug that could be 


administered to all patients diagnosed with AP in academic, as well as in community settings, is 
urgently needed. Clinical drug intervention trials in AP are conspicuously absent since the 
negative lexipafant study in 2001.(11) This is due to the inherent difficulties in conducting such 
trials and the lack of drugs with good efficacy in experimental animals. Extensive animal studies 
suggest that TNF-α is an important inflammatory mediator in AP.(12-15) TNF-α is the 
prototypic member of a cytokine family that regulates essential biologic functions such as 
cell differentiation, proliferation and apoptosis.(9,16) By up-regulating several different genes, 
such as cytokines, chemokines, NF-kB, cell adhesion molecules, and inducible nitric oxide 
synthase, TNF-α promotes a proinflammatory action.(17) In AP, TNF-α, IL-6 and IL-8 have 
been demonstrated to be substantially up-regulated in the pancreatic acinar cells.(17-21) C-
reactive protein (CRP) is another inflammatory marker that has been found to be elevated in 
greater proportion of patients with more serious forms of the disease. Since TNF-α appears to 
play a central role in the pathogenesis of severe AP, it is possible that inhibition of TNF-α would 
ameliorate the course of AP.(22,23) Mortality of experimental pancreatitis is dramatically 
reduced in TNF-α and IL-6 knockout laboratory animals.(24 )AP-related complications were 
ameliorated in rats given anti-TNF antibody.(8,25) Polyclonal blockade of TNF-α significantly 
reduced the biochemical manifestations of AP and a soluble TNF-receptor antagonist yielded a 
reduction in the severity and mortality of experimental AP.(26) Pentoxifylline has been used for 
years in peripheral vascular disease with high degree of safety and is also a TNF-α blocker. It is 
rapidly and extensively absorbed from the GI tract, peak plasma levels of the drug and active 
metabolites reach between 2 to 4 hours after a single oral dose of 400 mg extended release form 
and remain active for extended periods. Hence dosing every 8 hours has been effective for many 
years for disorders like claudication. Its use in alcoholic hepatitis, another TNF-α mediated 
inflammatory condition, has been well-established.(27) Human studies in cirrhosis,(28) cardiac 
surgery,(29) and hemodialysis(30) not only demonstrated its safety with regards to infection, 
hemorrhagic complications and renal complications but its beneficial effect all with the oral 8 
hourly dosing (intravenous form not easily available in the US). We have already demonstrated 
the capability to successfully complete a clinical trial in AP at our institution due to the factors 
elaborated in the specific aims section, and the results were encouraging with regards to the 
safety of pentoxifylline (investigational drug#: 104240) and possible efficacy. We propose this 
study would validate the efficacy and safety of oral pentoxifylline to decrease the morbidity and 
mortality and reduce the levels of inflammatory markers in all patients presenting with AP. 
 
Preliminary Results:  
We have already successfully conducted a pilot double-blinded, placebo-controlled, allocation-
blinded RCT of oral pentoxifylline in patients with AP with any one of several reported 
predictors of severe disease. By selecting many reported predictors of severity, we attempted to 
avoid as many patients with a mild form of the disease as possible. Both groups had 14 patients, 
evenly matched for age and sex; APACHE II and SIRS scores at admission; and pancreatic 
and/or peri-pancreatic necrosis. Compared to the placebo group, the pentoxifylline group 
experienced a 29% reduction in length of hospital stay, a 29% reduction in the need for an ICU 
stay, a 21% reduction in persistent organ failure, and a 7% reduction in pancreatic necrosis or 
fluid collection. The reductions translated to having no patients with: hospital stays over 10 days, 
an ICU need, persistent organ failure, interventions, or death in the pentoxifylline group . 
However, with the small sample size of this pilot study, these clinically significant differences 
failed to achieve statistical significance except for ICU need. There was no difference in the 


inflammatory markers between the two groups over a short period of three days. We concluded 
that it is feasible to conduct a drug intervention study in a single institution, and pentoxifylline 
appeared safe and decreased the length of stay and the need for ICU intervention. With larger 
numbers, besides validating the above findings, we expect to see a beneficial 
 
Experimental Design or Project Summary:  
 
Acute pancreatitis (AP) is an inflammation of the pancreas gland and the most common 
gastrointestinal discharge diagnosis (approximately 280,000 admissions in 2009). It has resulted 
in $2.6 billion, annually, in health care costs, mainly due to the more serious forms of the 
disease. Lack of any specific drug to treat the condition and predictors to identify patients who 
will develop more serious forms of the disease contribute to this. Long-term objectives of the 
study are to find a drug to treat this disease, improve patient outcomes, and reduce the costs of 
health care. Based on our experience with animals and a small, human subjects pilot study, our 
hypothesis and specific aims are: 
 
1. Pentoxifylline, administered within 72 hours of diagnosis, improves the clinical outcomes 
and decreases the occurrence of more serious forms of AP. 
 
2. Pentoxifylline reduces the blood levels of inflammatory markers, which correlates with 
improvement in clinical outcomes. This study is a novel, exploratory clinical study of the 
effect of a drug that has a proven role in animal studies in blocking the inflammatory 
response in AP. It is also a high reward study that will lead to a breakthrough in the 
treatment of AP and challenge the age old recommendation of supportive treatment 
alone. 
 
The study will have 2 groups of 75 patients each, all with AP, randomly assigned to either the 
drug or a placebo, which looks like the drug, for a period of 3 days or until the time they are 
discharged, if hospital discharge is within 7 days of admission. The levels of markers of 
inflammation (CRP, IL-6, IL-8 and TNF-α) will be measured at baseline and on 5 successive 
days or until the time of discharge, whichever occurs earlier. Determination of group size was 
based on the previous pilot study to decrease any of the important adverse outcomes, providing 
for a dropout rate of 10% during the study.  During 2012, 263 patients with AP were admitted to 
this institution, which possesses the needed infrastructure for successful completion of clinical 
drug intervention trials. In the stipulated period of 2 years by the NIH, the required number of 
patients for the study could be recruited.  
 
This project represents a single center study at Mayo Clinic Rochester. The trial is a randomized, 
double-blind, placebo-controlled study design.  
 
Subjects: Subjects will be adult patients 18 years of age and greater which will be recruited from 
Mayo Clinic and admitted to the hospital with acute pancreatitis as defined by at least two of the 
following:  
 amylase and/or lipase greater than 3 times the upper limit of normal values,  
 characteristic cross-sectional imaging,               
 characteristic pain syndrome.  


 
 If patients give consent to be in the study the PI may contact those patients before formally 
enrolling them in the study. By overseeing that one of the team (a study coordinator, PI, and co-
investigator) is present during the weekends, we anticipate that those eligible patients during the 
weekend period are not going to be excluded.  
 
Patients admitted within 24 hours with AP diagnosis will be included, with the exception of 
those meeting the exclusion criteria. Those patients that have been identified with  AP diagnosis 
within 72 hours will be approached by the study coordinator and also by the principal 
investigator (PI) (whenever feasible) to explain the study and obtain written consent. 
 
Inclusion criteria  
 Enrollment within 72 hours of diagnosis of AP 
 Ability to give informed consent or a legal adult representative LAR able to give 
informed consent for subject when needed as defined but LAR use guidelines. 
 Adult subjects of age ≥18 years. 
 
 
Exclusion Criteria:  
 Moderate or severe congestive heart failure,  
 History of seizure disorders or demyelinating disease, 
 Nursing mothers,  
 Pregnancy, 
 History of prior tuberculosis or risk factors for tuberculosis 
 Evidence of non- corticosteroid immunosuppression (such as malignancy, chronic renal 
failure, chemotherapy within 60 days, and HIV) 
 Evidence of active hemorrhage,  
 Paralytic ileus with severe nausea and vomiting.  
 
 
 Laboratory test and assessments: 
 
Test / 
Procedure  
Day 0  
Day 1  
Day 2  
Day 3  
Day 4  
Day 5  
TNF-a*  
X  
X  
X  
X  
X  
X  
IL-6*  
X  
X  
X  
X  
X  
X  
IL-8*  
X  
X  
X  
X  
X  
X  
Pregnancy Test X 
 
CRP  
X*  
X * 
X*  
X * 
X*  
X*  
 
 
* Note:  The C-RP, TNF-a, IL-6, IL-8 tests  are charged to the research study.    All other tests 
listed are clinical standard care for acute pancreatitis.   
The pregnancy test may be done as standard of care and will be closely monitored by study staff 
to assure completion before subject receives study medication.   
Follow up process may be done by telephone contact or review of medical records dependant on 
subjects follow-up information availability.  Some subjects may do their follow up visits at a 


local facility not return to Mayo Clinic Rochester for follow up visit within the 4 month  time  
frame ( plus or minus 15 days). Thus their medical record may not be available in the Mayo 
Network system.  Then a telephone contact may be done to acquire the follow up information.    
 
Randomization:  
Randomization will be performed by the pharmacy under the direction of the study statistician, 
using randomized blocks, to ensure all clinical study personnel are blinded to patient allocation 
throughout the study. Subjects will be randomized into two groups. The "treatment group" will 
receive Pentoxifylline 400 mg one to three times daily by mouth from the time of enrollment 
until 72 hours from enrollment. Subjects will receive up to maximum of 9 doses of this 
medication. The "control" group will receive placebo dosing at similar intervals. Randomization 
will occur in a block fashion.  Study medication will be administered at 1x/day if creatinine 
clearance < or =30ml/min. per the manufacture prescribing information.  All other treatment for 
AP (fluid resuscitation, antibiotics, surgical intervention, pain control, etc.) will be at the 
discretion of the primary care team. However, the study investigators will ask primary teams to 
follow standardized treatment guidelines for acute pancreatitis (to control for intravenous 
hydration and enteral nutrition, which may influence IL levels). 
 
Blinding: Both subjects and investigators will be blinded to the randomization. 
 
Sample Size:    
We propose testing   75 patients in each study arm.  Our primary outcome will be whether the 
patient develops any of the following outcomes of moderate or severe AP: hospital stay longer 
than 10 days, admittance to the ICU, persistent organ failure, pancreatic and/or peripancreatic 
necrosis and infection, SIRS, need for intervention, or death. In our pilot study, 7.1% of the 
patients on pentoxifylline experienced at least one of these outcomes, compared to 28.6% of 
those on the placebo. If extrapolated to the larger RCT, this reduction in events of these critical 
outcomes (7.1% vs. 28.6%) would represent a significant and meaningful difference for patients. 
Using a 5% 2-sided type I error, 58 patients in each group would be needed to achieve 80% 
power to detect the anticipated difference. In order to account for the unlikely event of up to 10% 
study dropout, we plan to enroll 64 patients in each group. We will use a randomized block 
design stratifying for predicted disease severity (mild, moderate, or severe). 
  
Adverse event management: Most of the side effects observed with long clinical use of 
pentoxifylline are mild and uncommon. Any unexplained hemorrhage of any magnitude will 
result in stopping the drug. Any of the serious events listed in the drug package insert and 
informed consent form will result in stopping of the drug if alternative explanation is not found.  
Adverse events experienced by subject during the study will be evaluated by the investigator 
Adverse events will be documented and reported in the IRB annual continuing review.  Serious 
adverse events will be evaluated by both the investigator and found to be related to study  then 
DSMB will be contacted.  Serious adverse events will reported according to the FDA and IRB 
policies and guidelines. 
 
 
 
 
 


DSMB 
For this safety analysis, the study statistician will prepare a blinded assessment of adverse events 
and severe adverse events by study group. The DSMB, consisting of clinical experts in GI and 
AP who are not involved in the study will review the blinded report to assess whether they feel 
either study group is experiencing more adverse events or severe adverse events or more-severe 
adverse events or severe adverse events. If the DSMB concludes that one group has greater risk, 
the study statistician will determine whether that group was randomized to pentoxifylline or 
placebo; if the pentoxifylline group is at risk, the study team will stop enrolling patients 
and administering the study drug, but will continue to monitor follow-up in previously enrolled 
patients. DSMB will be constituted by clinicians having experience in TNF- blockade therapy. 
 
DSMB will receive general updates as well as having contact meeting not less than once a year 
(per FDA regulation) with either face-to-face, or  telephone conference call or e-mail contact.  
Face-to-face meetings will be conducted as all member schedules allow. If unable to do face-to-
face then telephone conferencing or e-mail will be utilized.   
 
Data Collection and Handling: TNF-α, Il-6, and Il-8 will be handled by the research blood 
draw division of Mayo Clinic per usual practice. The C-RP testing on days1, 3,  4 and 5 will be 
handled by the research blood draw division of Mayo Clinic per usual practice. The clinical and 
research laboratory data will be recorded every day until discharge. Early discharges before 
completion of 3 days of drug or 5 days of study of markers after drug administration is not 
considered as protocol violation and data until the time of discharge will be recorded for the 
purpose of analysis. Data Safety Monitoring Board (DSMB) will be constituted by clinicians 
having experience in TNF-α blockade therapy.  
 
Data Analysis: All access to data will be password protected. Analysis will be on an-intent-to 
treat basis. Outcomes will primarily be descriptive statistics such as means and percents. 
Continuous secondary end points will be analyzed with the t-test if the data are normally 
distributed and the Wilcoxon Rank Sum test if non-normal. Analyses of dichotomous secondary 
end points will use either the Chi-squared test or Fisher's Exact Test comparing proportions. 
Kaplan-Meier will be used to estimate survival.  An interim analysis of data for preliminary 
review of less than target accrual may be done.   
 
Feasibility:  Nearly 250 patients with acute pancreatitis are seen at Mayo Clinic hospitals every 
year. Assuming ~60% of them are directly admitted to Mayo Clinic (not transferred from 
outside), and 50% agree to participate in the study it would take 24 months at Mayo to recruit 
150 patients. If recruitment goals are not reached at Mayo Clinic after ~24months, the study may 
have to be extended for 6 months more. Deliverables:  
We expect to publish at least one manuscript in a major academic journal as a result of this work. 
Our hope is that any reduction of morbidity or mortality from the novel therapy will have a 
profound effect on the treatment of acute pancreatitis and lead to future expanded clinical trials.  
 
 
 
 
 
TAILED MILESTONES SCHEDULE 


Endpoints:  
 
May 2015   Mayo Institutional Review Boards (IRB) approval. 
 
June 2015  Approximate NIH will release funds when IRB approved protocol is provided.   
 
July 2015 - Approximate Patient enrollment begins at Mayo 
 
April 2016  Approximate Data Safety Monitoring Board (DSMB) contact via teleconference or 
E-mail meeting to meet biannually and/or not less-than once a year. 
 
June 2017  - Approximate  Data analysis complete and manuscript submitted for publication  
 
 
 
 
 
 
 
 
 
 
 
 
 
REFERENCES 


1. Peery AF, Dellon ES, Lund J, Crockett SD, McGowan CE, Bulsiewicz WJ, Gangarosa LM, 
Thiny MT, Stizenberg K, Morgan DR, Ringel Y, Kim HP, Dibonaventura MD, Carroll CF, Allen 
JK, Cook SF, Sandler RS, Kappelman MD, Shaheen NJ. Burden of gastrointestinal disease in the 
United States: 2012 update. Gastroenterology. 2012 Nov;143(5):1179-87 e1-3. 3480553. 
 
2. Tenner S, Baillie J, Dewitt J, Vege S. Corrigendum: American College of Gastroenterology 
Guidelines: Management of acute pancreatitis. Am J Gastroenterol. 2014;109(2):302. 
 
3. Freeman ML, Werner J, van Santvoort HC, Baron TH, Besselink MG, Windsor JA, Horvath 
KD, vanSonnenberg E, Bollen TL, Vege SS. Interventions for necrotizing pancreatitis: summary 
of a multidisciplinary consensus conference. Pancreas. 2012 Nov;41(8):1176-94. 
 
4. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG, Vege 
SS. Classification of acute pancreatitis--2012: revision of the Atlanta classification and 
definitions by international consensus. Gut. 2013 Jan;62(1):102-11. 
 
5. Mounzer R, Langmead CJ, Wu BU, Evans AC, Bishehsari F, Muddana V, Singh VK, Slivka 
A, Whitcomb DC, Yadav D, Banks PA, Papachristou GI. Comparison of existing clinical scoring 
systems to predictpersistent organ failure in patients with acute pancreatitis. Gastroenterology. 
2012 Jun;142(7):1476-82. 
 
6. Chen D, Wang W, Wang J. Influence of anti-TNF alpha monocolonal antibody on intestinal 
barrier in rats with acute pancreatitis. Chinese medical sciences journal = Chung-kuo i hsueh k'o 
hsueh tsa chih /Chinese Academy of Medical Sciences. 2000 Dec;15(4):257. 
 
7. Gomez-Cambronero L, Camps B, de La Asuncion JG, Cerda M, Pellin A, Pallardo FV, 
Calvete J, Sweiry JH, Mann GE, Vina J, Sastre J. Pentoxifylline ameliorates cerulein-induced 
pancreatitis in rats: role of glutathione and nitric oxide. The Journal of pharmacology and 
experimental therapeutics. 2000 May; 293(2):670-6. 
 
8. Hughes CB, Gaber LW, Mohey el-Din AB, Grewal HP, Kotb M, Mann L, Gaber AO. 
Inhibition of TNF alpha improves survival in an experimental model of acute pancreatitis. The 
American surgeon. 1996 Jan;62(1): 8-13. 
 
9. Malleo G, Mazzon E, Genovese T, Di Paola R, Muia C, Centorrino T, Siriwardena AK, 
Cuzzocrea S. Etanercept attenuates the development of cerulein-induced acute pancreatitis in 
mice: a comparison with TNF-alpha genetic deletion. Shock. 2007 May;27(5):542-51. 
 
10. Talukdar R, Clemens M, Vege SS. Moderately severe acute pancreatitis: prospective 
validation of this new subgroup of acute pancreatitis. Pancreas. 2012 Mar;41(2):306-9. 
 
 
 
 
11. Johnson CD, Kingsnorth AN, Imrie CW, McMahon MJ, Neoptolemos JP, McKay C, Toh 
SK, Skaife P, Leeder PC, Wilson P, Larvin M, Curtis LD. Double blind, randomised, placebo 


controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and 
prevention of organ failure in predicted severe acute pancreatitis. Gut. 2001 Jan;48(1):62-9. 
1728186. 
 
12. Balog A, Gyulai Z, Boros LG, Farkas G, Takacs T, Lonovics J, Mandi Y. Polymorphism of 
the TNF-alpha, HSP70-2, and CD14 genes increases susceptibility to severe acute pancreatitis. 
Pancreas. 2005 Mar; 30(2):e46-50. 
 
13. Brivet FG, Emilie D, Galanaud P. Pro- and anti-inflammatory cytokines during acute severe 
pancreatitis: an early and sustained response, although unpredictable of death. Parisian Study 
Group on Acute Pancreatitis. Crit Care Med. 1999 Apr;27(4):749-55. 
 
14. Kaufmann P, Tilz GP, Lueger A, Demel U. Elevated plasma levels of soluble tumor necrosis 
factor receptor (sTNFRp60) reflect severity of acute pancreatitis. Intensive Care Med. 1997 
Aug;23(8):841-8. 
 
15. Vaccaro MI, Ropolo A, Grasso D, Calvo EL, Ferreria M, Iovanna JL, Lanosa G. Pancreatic 
acinar cellssubmitted to stress activate TNF-alpha gene expression. Biochem Biophys Res 
Commun. 2000 Feb 16;268(2):485-90. 
 
16. Phillips PA, McCarroll JA, Park S, Wu MJ, Pirola R, Korsten M, Wilson JS, Apte MV. Rat 
pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix 
turnover. Gut. 2003 Feb;52(2):275-82.. 
 
17. Kusske AM, Rongione AJ, Reber HA. Cytokines and acute pancreatitis. Gastroenterology. 
1996 Feb;110(2):639-42. 
 
18. Grewal HP, Kotb M, el Din AM, Ohman M, Salem A, Gaber L, Gaber AO. Induction of 
tumor necrosis factor in severe acute pancreatitis and its subsequent reduction after hepatic 
passage. Surgery. 1994 Feb;115(2):213-21. 
 
19. McKay CJ, Gallagher G, Brooks B, Imrie CW, Baxter JN. Increased monocyte cytokine 
production in association with systemic complications in acute pancreatitis. Br J Surg. 1996 
Jul;83(7):919-23. 
 
20. Norman JG, Fink GW, Franz MG. Acute pancreatitis induces intrapancreatic tumor necrosis 
factor geneexpression. Arch Surg. 1995 Sep;130(9):966-70. 
 
21. Zyromski N, Murr MM. Evolving concepts in the pathophysiology of acute pancreatitis. 
Surgery. 2003Mar;133(3):235-7. 
 
 
 
22. Denham W, Fink G, Yang J, Ulrich P, Tracey K, Norman J. Small molecule inhibition of 
tumor necrosis factor gene processing during acute pancreatitis prevents cytokine cascade 


progression and attenuates pancreatitis severity. The American surgeon. 1997 Dec;63(12):1045-
9; discussion 9-50. 
 
23. Oruc N, Ozutemiz AO, Yukselen V, Nart D, Celik HA, Yuce G, Batur Y. Infliximab: a new 
therapeutic agent in acute pancreatitis? Pancreas. 2004 Jan;28(1):e1-8. 
 
24. Denham W, Yang J, Fink G, Denham D, Carter G, Ward K, Norman J. Gene targeting 
demonstrates additive detrimental effects 
 
25. Grewal HP, Mohey el Din A, Gaber L, Kotb M, Gaber AO. Amelioration of the physiologic 
and biochemical 
changes of acute pancreatitis using an anti-TNF-alpha polyclonal antibody. Am J Surg. 1994 
Jan;167(1): 214-8; discussion 8-9. 
 
26. Norman JG, Fink GW, Messina J, Carter G, Franz MG. Timing of tumor necrosis factor 
antagonism is critical in determining outcome in murine lethal acute pancreatitis. Surgery. 1996 
Sep;120(3):515-21. 
  
27. Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, Shakil O. Pentoxifylline improves 
short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. 
Gastroenterology. 2000 Dec; 119(6):1637-48. 
 
28. Lebrec D, Thabut D, Oberti F, Perarnau J, Condat B, Barraud H, Saliba F, Carbonell N, 
Renard P, Ramond M, Moreau R, Poynard T, Pentocir Group. Pentoxifylline does not decrease 
short-term mortality but does reduce complications in patients with advanced cirrhosis. 
Gastroenterology. 2010 May;138(5):1755-62. 
 
29. Iskesen I,Kurdal A, Kahraman N, Cerrahoglu M, Sirin B. Preoperative oral pentoxifylline for 
management of cytokine reactions in cardiac surgery. Heart Surg Forum. 2009 Apr;12(2):E100-
E4. 
 
30. Gonzalez-Espinoza L, Rojas-Campos E, Medina-Perez M, Pena-Quintero P, Gomez-Navarro 
B, Cueto-Manzano AM. Pentoxifylline decreases serum levels of tumor necrosis factor alpha, 
interleukin 6 and Creactive protein in hemodialysis patients: results of a randomized double-
blind, controlled clinical trial. Nephrol Dial Transplant. 2012 May;27(5):2023-8. 
 
31. Kylanpaa ML, Repo H, Puolakkainen PA. Inflammation and immunosuppression in severe 
acute pancreatitis. World journal of gastroenterology : WJG. 2010 Jun 21;16(23):2867-72. 
2887581. 
 
32. Papachristou GI, Clermont G, Sharma A, Yadav D, Whitcomb DC. Risk and markers of 
severe acute pancreatitis. Gastroenterol Clin North Am. 2007 Jun;36(2):277-96, viii. 
 
33. Galloway SW, Kingsnorth AN. Reduction in circulating levels of CD4-positive lymphocytes 
in acute pancreatitis: relationship to endotoxin, interleukin 6 and disease severity. The British 
journal of surgery. 1994 Feb;81(2):312. 


 
34. Pooran N, Indaram A, Singh P, Bank S. Cytokines (IL-6, IL-8, TNF): early and reliable 
predictors of severe acute pancreatitis. J Clin Gastroenterol. 2003 Sep;37(3):263-6. 
 
35. Coelho AM, Kunitake TA, Machado MC, Martins JO, Patzina RA, D'Albuquerque LA, 
Jukemura J. Is there a therapeutic window for pentoxifylline after the onset of acute pancreatitis? 
Acta cirurgica brasileira /Sociedade Brasileira para Desenvolvimento Pesquisa em Cirurgia. 
2012 Jul;27(7):487-93. 
 
36. Kapetanos D, Kokozidis G, Christodoulou D, Mistakidis K, Sigounas D, Dimakopoulos K, 
Kitis G, Tsianos EV. A randomized controlled trial of pentoxifylline for the prevention of post-
ERCP pancreatitis. Gastrointest Endosc. 2007 Sep;66(3):513-8. 
 
37. Farkas G, Marton J, Mandi Y, Leindler L. Surgical management and complex treatment of 
infected pancreatic necrosis: 18-year experience at a single center. Journal of gastrointestinal 
surgery : officialjournal of the Society for Surgery of the Alimentary Tract. 2006 Feb;10(2):278-
85. 
38. Vakhrushev Ia M, Trusov VV, Solov'eva NE. [Trial of the combined use of trental and 
solcoseryl in treating patients with chronic pancreatitis]. Ter Arkh. 1988;60(2):129-32. 
 
39. Bakker OJ, van Santvoort HC, van Brunschot S, Geskus RB, Besselink MG, Bollen TL, van 
Eijck CH, Fockens P, Hazebroek EJ, Nijmeijer RM, Poley JW, van Ramshorst B, Vleggaar FP, 
Boermeester MA, Gooszen HG, Weusten BL, Timmer R. Endoscopic transgastric vs surgical 
necrosectomy for infected necrotizing pancreatitis: a randomized trial. JAMA: the journal of the 
American Medical Association. 2012 Mar 14:307(10):1053-61.