Ritonavir and Disulfiram May Be Synergistic

Richard Eric Kast
Department of Psychiatry, University of Vermont. Burlington, VT, USA
Summary
Interleukin-18 (IL-18) is one of the mediators
of both pancreas damage and systemic
complications like hypotension and multi-
organ dysfunction during acute pancreatitis.
IL-18 is generated intracellularly from pro-IL-
18 by caspase-1 mediated proteolysis. Active
caspase-1 itself is generated intracellularly by
the action of the inflammasome, autocatalysis
and other stimuli. The anti-retroviral drug
ritonavir inhibits conversion of inactive pro-
caspase-1 to active caspase-1. Since ritonavir
is well tolerated in short-term use it may
therefore prove useful in treating acute
pancreatitis by lowering caspase-1 mediated
IL-18 formation and the many inflammatory
mediators downstream from that. The
alcoholism treatment drug disulfiram has been
in continuous use since the 1950s. It likewise
has a low risk profile. Disulfiram inhibits
several human proteases, among them
caspase-1. Given the current morbidity and
mortality of pancreatitis, research should be
directed to ritonavir and disulfiram as
treatment options for illnesses like
pancreatitis where excessive IL-18
contributes to pathology. The first clinically
used angiotensin converting enzyme inhibitor,
captopril, has shown potent caspase-1
inhibiting activity as well and should be
investigated in rodent models of human
pancreatitis.
Introduction
This short note reviews the role of
interleukin-18 (IL-18) in acute pancreatitis.
IL-18 is a narrow yet important aspect of
acute pancreatitis. Narrow because many
other inflammatory mediators are active in
acute pancreatitis, but important because: a)
many of the other inflammatory mediators
arise secondary to IL-18; and B) we happen to
have several medicines, in use for other
purposes for decades, that pre-clinical and
murine studies have indicated happily have
ability to lower active IL-18 formation. Also
giving IL-18 particular importance is: c) the
cause of early mortality in acute pancreatitis
is mostly due to systemic inflammation, for
which IL-18 is an important driving force [1,
2, 3].
Alcohol abuse and cholelithiasis account for
90% of acute pancreatitis, with autoimmune,
genetic, hyperlipidemia, obesity and other
factors as less common predisposing factors
[1, 2, 3]. Diverse secondary morbidity is seen,
with chronic pain as a common sequela.
Mortality rate is not trivial by multiorgan
dysfunction that in extreme forms leads to
multiorgan failure[1, 2, 3]. The clinical
picture is dominated by fierce pain,
hypotension, and susceptibility to secondary
infection. Hepatitis and pneumonia are
common. Endoscopic or surgical decompres-
sion procedures, necrotic tissue removal can
help. Medical interventions seem limited to

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351
supportive measures, antibiotics for secondary
infection, etc. and have not changed much in
the last 50 years [1, 2, 3]. This short note
presents data indicating that three old drugs,
ritonavir, disulfiram, and captopril, have
potential to lower IL-18 and may therefore be
of benefit in treating pancreatitis.
Pancreatitis and IL-18
The chain of events surrounding IL-18
activation in general is depicted in Figure 1.
That IL-18 is an important and active link in
the generation of human pancreatitis [4, 5, 6,
7, 8, 9]. There are many others. The core
event in acute pancreatitis is pancreatic tissue
destruction by trypsin generation within the
pancreas. To what extent that ectopic trypsin
activation is driven by IL-18 or excessive IL-
18 is driven by events secondary to trypsin
activation is unknown. Whichever is primary
in pancreatic tissue destruction, the systemic
inflammation and multiorgan failure of
pancreatitis that is responsible for a
considerable proportion of early deaths in
acute pancreatitis, is largely mediated by
inflammatory mediators secondary to
excessive IL-18 that is in turn generated via
upregulated and disinhibited caspase-1 action
within the inflamed, necrotic pancreas [4].
IL-18 is an 18 kDa active cytokine generated
by proteolytic cleavage of an inactive 24 kDa
form, pro-IL-18, by the action of caspase-1
[3, 4, 10, 11] (Figure 1). IL-18 plays a central
role in both adaptive, antigen driven
immunity and innate, pathogen associated
molecular pattern, pathogen associated
molecular pattern, driven inflammation [10,
11].
Notable synthesis of IL-18 occurs in articular
chondrocytes, keratinocytes, Kupfer cells,
macrophages, osteoblasts, and synovial cells
[12]. Exceptional levels, up to 1,000 times the
upper reference limit, are seen in rheumatoid
arthritis, and particularly adult-onset Still's
disease [12].
In experimental pancreatitis induced by
retrograde instillation of sodium taurocholate
into the common duct in rats, lung injury
ensues consequent to the provoked
pancreatitis, as it often does in human
pancreatitis. If these rats are given an
experimental intraperitoneal caspase-1
inhibitor, lowered indexes of lung injury were
seen commensurate with the lowered
circulating IL-18 [13].
In patients with chronic pancreatitis,
circulating IL-18 levels are considerably
elevated [4, 5, 6, 7]. Acute pancreatitis is
associated with a 5-fold increase in
circulating IL-18 [7] and levels are roughly
proportional to acute pancreatitis severity [8,
9] and immunohistochemistry of pancreas
tissue shows elevated IL-18 content [5].
Tumor necrosis factor-alpha (TNF) levels are
likewise elevated in pancreatitis. TNF and IL-
18 levels tend to parallel each other [8, 9]
supporting the suggestion that following daily
TNF levels in acute pancreatitis patients
might provide fast feedback on patient
trajectory allowing faster response and
preemptive interventions to impending
deterioration. It is suspected but has not been
established that elevated IL-18 or TNF
presage clinical deterioration. This matter
needs further study.
Figure 1. Schematic diagram of how disulfiram and
ritonavir have been shown to act at two separate steps
in path to generation of active interleukin-1beta and
interleukin-18 with consequent inflammation in
pancreatitis.
dsRNA: double stranded RNA
NLR: nod-like receptor, intracellular receptors of
similar function to the outer cell membrane toll-like
receptors
TLR toll-like receptor
TNF: tumor necrosis factor-alpha
VEGF: vascular endothelial growth factor

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352
Multiorgan dysfunction becomes more
common as IL-18 level rises [14]. Ascitic
fluid associated with acute pancreatitis has
massive IL-18 content [14].
Ritonavir
A schema of how ritonavir and disulfiram
inhibit the IL-18 activation process is
depicted in Figure 1. Ritonavir is a 721 Da,
short half-life (several hours]), hepatically
eliminated, orally active HIV protease
inhibitor used to treat HIV infection since
1996. In addition to inhibiting the HIV
protease, ritonavir is a potent inhibitor of
human liver P450-3A4 activity and has been
shown to block the conversion of inactive, 45
kDa pro-caspase-1 to active, 20 kDa subunits
that dimerize to form catalytically active
caspase-1 [15, 16, 17].
Disulfiram
Disulfiram is a 296 Da, long half-life (days),
hepatically eliminated, orally active
acetaldehyde dehydrogenase inhibitor used
since 1950s to help recovering alcoholics
abstain from drinking alcohol by generating
high and extremely unpleasant levels of
acetaldehyde should alcohol be consumed
during treatment. Disulfiram also inhibits
several caspases important for inflammation,
among them caspase-1 [18], as depicted in
Figure 1.
Captopril
In vitro, the oldest angiotensin converting
enzyme (ACE) inhibitor in clinical use,
captopril, also showed caspase-1 inhibiting
effects in nM range [19] and could be
considered as well for clinical use in lowering
IL-18 destructive activity in pancreatitis if
rodent studies confirmed benefit in
experimental pancreatitis.
Conclusion
If pre-clinical and murine studies support the
projected pancreatitis protection and IL-18
lowering effect of captopril, disulfiram, or
ritonavir, clinical study of these in acute
pancreatitis patients who are showing
multiorgan signs, elevated IL-18, and
deteriorating course under standard treatment,
should be considered.
Received January 28
th
, 2008 - Accepted
February 15
th
, 2008
Keywords Captopril; Caspase 1; Disulfiram;
Inflammation; Interleukin-18; Pancreatitis;
Ritonavir
Conflict of interest The author has no
potential conflicts of interest
Correspondance
Richard Eric Kast
University of Vermont
2 Church Street
Burlington, VT 05401
USA
Phone: +1-802.863.2462
Fax: +1-802.863.2462
E-mail: rekast@email.com
Document URL: http://www.joplink.net/prev/200805/08.html
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