CA2179183C - Interleukin-1 receptor antagonist decreases severity of acute pancreatitis - Google Patents
Interleukin-1 receptor antagonist decreases severity of acute pancreatitis Download PDFInfo
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- CA2179183C CA2179183C CA002179183A CA2179183A CA2179183C CA 2179183 C CA2179183 C CA 2179183C CA 002179183 A CA002179183 A CA 002179183A CA 2179183 A CA2179183 A CA 2179183A CA 2179183 C CA2179183 C CA 2179183C
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Abstract
A method for treating acute pancreatitis comprising administering an effective amount of Interleukin-1 receptor antagonist (IL-1ra) or a pharmaceutically acceptable salt thereof to a person afflicted with that condition.
Description
i .~..:
'' ~ 2~19~~~
-1_ zbrrERLSOxIx-i RscRPTOR aNTaGOx~xsT
D8CR8A888 SL~'VERIT OF ACDTB PAHCREATITI$
TSCHHICAh BIBLD
The present invention relates to a method for treating acute pancreatitis.
B11C~CGROQIID OF T8B I3IVEDiTIOl7 Acute pancreatitis is a common clinical problem which remains evasive of specific therapy.l Each year more than l5,00o admissions to (1.S. hospitals are caused by acute pancreatitis.
It is most often caused by alcoholism or biliary tract disease. Less commonly, 3t is associated with hyperlipemia, hyperparathyroidism, abdominal trauma, vasculitis or uremia- The average length of hospitalization for the disease is 12.4 days, with a significant number of patients staying much longer because of associated complications.
There are rio medical therapies or pharmacologic agent: cusrontly available which have been shown to decrease the severity, duration, complication rate, or mortality for this common Z5 disease. Over the past decade, a somatostatin analog has undergone several clinical, as well as laboratory trials, in an attempt to show beneficial f t effects of suppressing pancreatic exocrine function pharmacologically during acute pancreatitis. The majority of investigators have shown beneficial effects only with treatment prior to the onset of pancreatitis, and disappointing results when somatostatin was given after the acute inflammatory process had started.~~3~i With more recent understanding of the complex mechanisms of tissue and cellular injury to associated with inflammatory processes, such as sepsis,s it is reasonable to assume that many of these inflammatory processes are not spec3.fic to sepsis syndromes alone. several authors have suggested that much of the intrinsic pancreatic damage seen in acute pancreatitis is due to the release of toxic substances from macrophages and other white blood cells which migrate into the damaged gland.s~~~a,s,t0,11.I1 These substances are known as cytokines and are now well known as 2o mediators of inflammation and tissue injury.
A curious aspect of acute panereatitis is the systemic response which is seen following inflammation initiated within the pancreas. Acute pulmonary, renal, and hepatic failure, generalized water retention, hypocalcamia, hypoxia, and aCid/base disturbances are all possible complications of pancreatitis. The mechanism for 2r79I831 complications of pancreatitis. The mechanism Eor the involvement of these other organ systems is unclear, but probably involves activation of the cytokine cascade, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) in a manner not significantly different Erom sepsis syndromes.lz,i3,1l,15 gerum levels of these peptides have been shown to correlate to a high degree with the severity of acute pancreatitis in humans, and can also be demonstrated within pancreatic ascites.~z~IS
The administration of IL-1 to rabbitsl~.ia,ts,z~ and primateszr has been shown to result in hypotension, tachycardia, lunq edema, renal failure, and, eventually, death, depending on the dose. These signs and symptoms are similar to those demonstrated by patients with severe acute pancreatitis. When the serum from the IL-1 treated animals 'is examined, the elevation of a0 other cytokines is evident, mimicking the levels seen in acute pancreatitis in humans.tl~IZ There is a large body of evidence currently ava liable which supports the role of IL-1 as a major mediator oP
the systemic response to diseases such as sepsis and pancreatitis and as an activator of the remaining members of the cytokine cascade.5 ~Fischer et al.zs demonstrated that the administration of a naturally occurring antagonist to IL-1 will significantly blunt the cytokine cascade and improve survival in baboons given a lethal doss of live bacteria. In this study, IL-1 receptor antagonist (IL-lra) signifioantly attenuated the decrease in mean arterial pressure and cardiac output and improved survival over control. The systemic IL-1 and IL-6 responses observed as a result of the bacteremia were to diminished significantly, correlating with a decrease in the systemic response to the sepsis.
Studies by Aiura et al.~° have shown that IL-lra is protective in a rabbit model of hypotensive gram-positive septic shock. The administration of IL-lra in this animal model has been shown to maintain mean arterial pressure compared to control, as well as decreasing lung water and maintaining urine output. This work demonstrated the role of IL-1 and the protective role oP IS~-ire in gram-positive shock which was thought to be due to a separate mechanism Erom gram-negative shock. The common pathway for the systemic manifestations of these two different models of shock has been shown to involve IL-1 as a central mediator. Evidence is mounting for the x~i~ pE Z~-1 as the principal mediator in a patient s clinical response to multiple diP~ererit i t "' .
;.~ . 2179183 stresses regardless of the etiology (including acute pancreatitis).
U.S. patents 4,522,827 and 4,902,708 disclose methods of treating acute pancreatitis.
FFowever, none of these patents take into effect the specific pathology of the disease, thereby proposing treatments which are not specific and are directed to the symptoms only, not the underlyittg mechanism.
U.S. patent 5,196,402 discloses the use of S-adenosyl methionine for the use of treatment of pancreatitis in the context of a complication in the graft rejection in pancreas transplant, a Very uncommon procedure. The patent does not address acute paricreatitis as a disease in the nontransplant patient. The vast majority of oases of pancreatitis are not associated with pancreatic transplants.
Treatments are needed which take into account that the local, as well as systemic, effects seen during acute pancreatitis are due to activation of the cytokine cascade whereby proximal inhibition of this cascade will decrease the severity of the inflammatory process.
2179183' -b-8D~8LARY OF THH IN'vEDtTION AND ADVANTAGES
According to the present invention, a method for treating acute paricreatitis is provided.
The method comprisag adminiutering to a pwrson afflicted with that condltiori an effective amount of Interleukin-1 receptor antagonist (IL-ire) or a pharmaceutically acceptable salt thereof.
Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in corinectlon with the accompanying drawings wherein:
FIGURE 1 is a graph showing the pancreatic wet weight in controls (shaded), IL-ire lOmg/kg pretreatment (solid), IL-Ira 10 mg/kg post treatment (diagonal), arid untreated disease control (cross-hatching) with .* indicating p<0.01 compared to no treatment;
FIGURE ,2 is a graph showing the serum amylase levels in groups as in Figure 1 with indicating p<0.05 compared to no treatments FIGURE 3 is a graph shoWirig the scrum lipase levels in groups as in Figure 1 with indicating p<0.0001 Compared to no treatment;
;.
~~, . 2~1~~g~
_,_ FIGURE 4 is a graph showing the serum interleWcin-6 levels in groups as in figure 1 with * indicating p<0.0001 compared to no treatment; and FIGURE 5 is a graph showing the serum TFN
levels in groups as in Figures 1 with * indiaati.ng P<0.0001 compared to rio treatment.
DET1~1I3~ED DESCRIPTION OF THH PREFERRED EMDODIlfENT
IL-lra is a naturally occurring peptide secreted by macrophages in response to many of the same stimuli which cause the secretion of IL-1 itself. IL-Ira is the only known naturally occurring antagonist to the cytokines and recognizes receptors on various cell types and blocks IL-1 mediated responses by occupying the receptor.~~,l8,~s,ao,xi In humans, IL-ira is a naturally occurring group of molecules; three forms have been characterized (two glycosylated and one non-glycosylated).
a0 According to the present invention, a person afflicted with that condition is administered an effective amount of Interleukin-1 receptor antagonist (IL-Ira) or a pharmaceutically acceptable salt thereof.
The safety of IL-Ira after intravenous administration has been demonstrated during the past three years in mice, rats, rabbits, dogs, _$_ primates, and hutnans,t~~t9,2~,2t,a2,23,2! In no7Cma1 volunteers, IL-Ira has been demonstrated to have a half-life of approximately two hours after intravenous administration and the plasma clearance of IL-ire appeared to correlate with creative clearance.~5 Hence, there already exists a regimen for Ih-lra administration for humans.
The IL-Ira to be used can be administered in aombi.riation with other drugs or singly consistent c~ith good medical practice. The other drugs can be somatostatln or an analog (i.e., Saridostatinm) and prostaglandin inhibitors (1.e., non-steroidal, anti-inflammatory drugs such as aspirin, indomethacin, ibuprofen, etc.).
Z5 Additionally, steroids or other drugs designed to suppress the immune system and other synthetia or recombinant antagonists or blockers to cytokines (e.g., soluble fNF receptors, soluble IL-I
receptors, soluble i'L-6 receptors or others;
monoclonal antibodies to IL-1, IL-6, TNF or others, etc.) can be administered. Further, nitric oxide inhibitors or antagonists, fr~s radical scavengc;rs or anti-oxidants, antagonists or M ockers of complement, ecosinoids or their antagonists and antibiotics, as appropriate, can also be administered.
-9_ The IL-ire is administered and dosed in acoordancs with good medical praotica, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, and other factors known to medlcai practitioners. The "effective amount's for purposes herein is thus determined by such considerations as era known in the art.
In the method of the present invention, the IL-lra can he administered in various ways. It should be noted that the IL-Ira can be administered as the compound or as pharmaceutically acceptable salt and can be administered along or in combination with pharmaceutically acceptable carriers. The compounds can be administered orally or parenterally including intravenous, intraperitoneally, intranasal and subcutaneous administration. Implants of the compounds are also ao useful. The patient' being treated is a warm-blooded animal and, in particular, mammals including man.
When administering the IL-ire parenterally, the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders Por recoristitution into sterile injectable solutions ar dispersions. The carrier can be a solvent or 2~~9~~~
-lo-dispersing medium containing, for example, water., ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suixabl~ mixtures th~rool, and vagotabls oils.
Proper fluidity can be maintained, Eor example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Nonaqueous vehicles such a cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems far compound compositions. Additionally, various additives which enhance the stability, sterility, and isotonicity of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can he added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
In many eases, it will be desirable to inolude isotonic agents, foz example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
r According to thw prwswnt invwntion, howovwr, any vehicle, diluent, or additive used would have to be coippatible with the compounds.
Sterile injoctable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.
A pharmacological formulation of the IL-Ira can be administered to the patient iri an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as polymer matrices, liposomes, and microspheres. An implant suitable for use in the present invention can 'take the form of a pellet which slowly dissolves after being implanted or a biocompatible delivery module well known to those skilled in the art. Such well known dosage foams and modules are designed such that the active ingredients are slowly released over a period of several days to several weeks.
Examples of well-known implants and modules useful in the present invention include:
U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No.
4, 486,194, which discloses a therapeutic device for administering medicants through the skin; U.S.
Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at . a precise infusion rate; O.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery;
U.S. Patent No. 4,439,196, which discloses an osaotic drug delivery system having mufti-chamber compart~asnts; and U.S. Patent No. 4,475,19b, which discloses an osmotic drug delivery system.
Many other such implants, delivery systems, and modules are well known to those skilled in the art.
A pharmacological formulation of the IL-ire utilized in the present invention can be administered orally to the patient. conventional methods such as administering the compounds in tablets, suspensions, solutions, emulsions, capsules, powders, syrups and the like are usable.
Known techniques which deliver the IL-ire orally or intravenously and retain the biological activity are preferred.
In one embodiment, the IL-lra can be administered initially by intravenous injection to bring blood levels of IL-lra to a suitable level.
The patient s IL-lra levels are then maintained by an oral dosage form, although other forms of administration, dependent upon the patient s condition and as indicated above, can be used. The guantity of IL-Ira to be administered will vary for the patient being treated and will vary from about 10o ng/kg of body weight to 100 mg/kg of body weight per day and preferably will be from 10 Etg/kg to to mg/kg per day.
In one preferred embodiment, if the patient is diagnosed with severe acute pancreatitis, then the patient will be aggressively treated for 72 hours and will receive intravenously a loading dose of 100 mg in a total volume of 10m1 2o followed by a 72-hour continuous infusion. The continuous infusion will consist of 2.Omg/kg/hr.
The infusion will be done by preparing loOml of the drug in saline for each 12-hour period. It will be infused by utilizing a volumetric infusion pump at 95 a rats of 8.a m1/hr. Any res;dual IL-Ira at the end of the 12 hours will be infused before the subsequent 12-hour infusion is initiated. At the ~
-14' completion of the 72-hour infusion, the patient is evaluated and, based on the patients condition, infusion will be continued, administration switched to oral dosage, or the drug discbntinued.
The practice and. utility of the present invention is shown in the following example:
liATBRIALB AND HETHOD$
The specification and claims provide 7.0 guidance for the use of the invention in humans.
The Tnvestic~tor~s fi~ndbook26 provided by the National Cancer Institute (page 23) indicates that the starting dose for Phasc I trials is based on the mouse equivalent LDlo. Farther, the manual 15 (page 22) indicates that anfmal studies carried out prior to Phase I trials provide the investigator with a prediction of the likely effects.~7 Therefore, the presented rodent model data is not only acceptable in determining human doses and 2o protocols, but is considered highly predictive.
Acute edematous, necrotizing pancreatitis vas induced in adult male Swiss mice weighing more than 35 grams using caerulein - an analog of cholecystokinin. Mice were divided into four 25 groups with three of the groups receiving caerulein So pg/kg by intraperitoneal (IP) injection in dour /e ~~7'~1~~
doses over three hours as previously described.z~~~9~l2,ae,2s Group 1 was a control group (n-9) which received only IP sal.ina injoetiono. Group z (n=1z) was an untreated disease control. Group 3 (n=12) received three injections (10 mg/kg/hr) starting one hour prior induction of pancreatitis_ Group 4 (n=12) received three injections (10 mg/kg/hr) starting one hour after induction of pancreatitis.
The IL-Ira used in this study is produced in E. colt by Synergen Corporation (Boulder, Co) by utilizing recombinant DNA technology and is identical to the non-glycosylated human form of human IL-lra except for the addition of one terminal methionine amino acid.
After nine hours, all animals were euthanized, the blood collected, and the pancreata surgically excised and weighed. Serum was assayed 2o for amylase, lipase, IL-6, and TNF levels_ Each pancreas was fixed, stained, and grnded histologically in a blinded fashion for interstitial edema, granulocyte Infiltration, acinar vacuolization, and acinar sell necrosis as described previously.7.27.2e Additionally, serum levels of IL-Ira Were determined, therefore allowing comparisons between dosage, serum level, r' 2179183 -ls-systemic cytokine response, and degree of pancreatic damage.
IL-6, Il-1, IL-ira,and TNF were measured by commercially available ELISA kits (Genzyme Corp., Boston, MA). All specimens were run in triplicate. Serum levels of amylase and lipase were measured on a Kodak Ectachem 700 automated analyzer (Eastman Kodak Company, Rochester, NY).
tIistologic slides were prepared as is known in the art after rapid excision and subsequent fixation in 10~ formalin. The tissues were paraffin embedded as is known in the art and then stained with Hematoxylin and Eosin in a standard fashion. These slides were examined and graded in a blinded fashion by a board cartified pathologist.
Results In these experiments, acute pancreatitis was induced in 45 mice using aaerulein. Acute edematous, necrotizing pancreatitis is present within an hour of caerulein injection and reaches a peak effect approximately nine hours later. Ay treating mice with IL-Ira prior to or after the induction of panereatitie, applicants were able to show a significant decrease in pancreatic wet weight (p<.O1), serum amylase (p<.o5), lipase (p<.0001), and IL-6 (p<.0001) as shown in Figures ~ I79I ~~
1-4 and Table I, respectively. TNF (p<0.0001) was also signlfi.oantly reduced (Figure S). All statistics noted are significant by two-tailed W3leoxon test. Additionally, these was a decrease in tha number of polymorphonuclear white blood cells (PMNs) within the capillaries of the lungs and pancreas. Histologie studies of these pancreata were performed in a blinded fashion and showed a significant decrease (p<.05) in total organ edema, acinar necrosis, acinar vacuolization, and inflammation in those animals treated with IL-lra. An important finding in these experiments was that treatment with IL-Ira within two hours after the onset of pancreatitis was neariy as protective as pretreatment.
These series of experiments were repeated using both higher and lower does of I1-lRa. In one experiment, all animals received IL-ira at a dose oP 100 mg/kg/hrX3. All the previous findings were confirmed, but no significant benefit could be found with the higher dose. When the dose o! IL-ira was decreased to 1 mg/kg/hrx3, the benefita were seen in all categories except amylase levels. This dose, however, did not show quite as much decrease in wet weight or the levels of IL-6 and TNF as did the 10 mg/kg/hrx3 dose. These dose response experiments confirm the efficacy of IL-ira :, ~,;, 2i7918~
. .
in the treatment of pancreatitis when proper levels of the drug are maintained.
Tha example provides guidance for the use of the invention in humans. The imvest3qgtor~s H_~~ boo 26 provided by the National. Cancer Institute (page 23) indicates that the starting dose for Phase I trials is based on the mouse equivalent LDlp. In fact, Phase T trials of IL-ira have been completed.~~ Further, the manual (page 1U 22) indicates that animal studies carried out prior to Phase I trials provide the investigator with a prediction of the.likely effects.lZ Therefore, the presented rodent model data is not only acceptable iri determining human doses arid protocols but is considered highly predictive. Based on the available data from the Phase I trials and Phase II
trials in the treatment of sepsis3~ combined With the present invention allows the treatment of pancreatitis in humans.
2o Further, the cytokine activation in fulminant pancreatitis is similar to that of sepsis. The blockade of the cascade applicants have shown is similar to that shown in animal and human studies using IL-ira for sepsis. A better understanding of the role played by specific cytokines in this systemic reaction has provided insight into effective therapies for severe -ls-pancreatitis, in particular the therapeutic use of IL-lra in acute pancreatitis.
The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be 1n the nature of Words of description rather than of limitation.
Obviously, many modifications ~ arid variations of the present invention ase possible ~in light of the above teachings. It is, therefore,. to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.
TABLE I
(m5) (5U) (IU) (ng/kg)(ng/kgD
1 188*0.1 220Ct156 1715158 5415 6319 t.04* #1756* i3155* *51* #30*
1.02** *2393** *1685** *il* * #3**
#.04** 4494** 12648** *17* * #10**
Results are exp ressed as mean t SEM, significance ted if 0.05 by two -tailed4lilcoxcn accep p <
test.
* compared to control (Group 1) ** compared eated pancreatitis (Group to untr 2D
.; ' ~ ; , ' 21 l 918 J . v,:i, ;
i . r: t, :; i ' . : ~. . ; ' ;~;,,. ; , .
:;
:'.~.~.:;1 :.
REFERENCES
1. LeBCIa SD, GorBlick S, Hodlin IH, NeW
Perspectives on Acute Pancreatitis. Scan. .7 Gastroenterol 1992:27 Suppl 192:29-38.
2. Murayama KM, Drew JB, and Joehl RJ: Does somatostatin analogue prevent experimental acute pancreatitis? Arch burg 1990;125:1570-1572.
'' ~ 2~19~~~
-1_ zbrrERLSOxIx-i RscRPTOR aNTaGOx~xsT
D8CR8A888 SL~'VERIT OF ACDTB PAHCREATITI$
TSCHHICAh BIBLD
The present invention relates to a method for treating acute pancreatitis.
B11C~CGROQIID OF T8B I3IVEDiTIOl7 Acute pancreatitis is a common clinical problem which remains evasive of specific therapy.l Each year more than l5,00o admissions to (1.S. hospitals are caused by acute pancreatitis.
It is most often caused by alcoholism or biliary tract disease. Less commonly, 3t is associated with hyperlipemia, hyperparathyroidism, abdominal trauma, vasculitis or uremia- The average length of hospitalization for the disease is 12.4 days, with a significant number of patients staying much longer because of associated complications.
There are rio medical therapies or pharmacologic agent: cusrontly available which have been shown to decrease the severity, duration, complication rate, or mortality for this common Z5 disease. Over the past decade, a somatostatin analog has undergone several clinical, as well as laboratory trials, in an attempt to show beneficial f t effects of suppressing pancreatic exocrine function pharmacologically during acute pancreatitis. The majority of investigators have shown beneficial effects only with treatment prior to the onset of pancreatitis, and disappointing results when somatostatin was given after the acute inflammatory process had started.~~3~i With more recent understanding of the complex mechanisms of tissue and cellular injury to associated with inflammatory processes, such as sepsis,s it is reasonable to assume that many of these inflammatory processes are not spec3.fic to sepsis syndromes alone. several authors have suggested that much of the intrinsic pancreatic damage seen in acute pancreatitis is due to the release of toxic substances from macrophages and other white blood cells which migrate into the damaged gland.s~~~a,s,t0,11.I1 These substances are known as cytokines and are now well known as 2o mediators of inflammation and tissue injury.
A curious aspect of acute panereatitis is the systemic response which is seen following inflammation initiated within the pancreas. Acute pulmonary, renal, and hepatic failure, generalized water retention, hypocalcamia, hypoxia, and aCid/base disturbances are all possible complications of pancreatitis. The mechanism for 2r79I831 complications of pancreatitis. The mechanism Eor the involvement of these other organ systems is unclear, but probably involves activation of the cytokine cascade, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) in a manner not significantly different Erom sepsis syndromes.lz,i3,1l,15 gerum levels of these peptides have been shown to correlate to a high degree with the severity of acute pancreatitis in humans, and can also be demonstrated within pancreatic ascites.~z~IS
The administration of IL-1 to rabbitsl~.ia,ts,z~ and primateszr has been shown to result in hypotension, tachycardia, lunq edema, renal failure, and, eventually, death, depending on the dose. These signs and symptoms are similar to those demonstrated by patients with severe acute pancreatitis. When the serum from the IL-1 treated animals 'is examined, the elevation of a0 other cytokines is evident, mimicking the levels seen in acute pancreatitis in humans.tl~IZ There is a large body of evidence currently ava liable which supports the role of IL-1 as a major mediator oP
the systemic response to diseases such as sepsis and pancreatitis and as an activator of the remaining members of the cytokine cascade.5 ~Fischer et al.zs demonstrated that the administration of a naturally occurring antagonist to IL-1 will significantly blunt the cytokine cascade and improve survival in baboons given a lethal doss of live bacteria. In this study, IL-1 receptor antagonist (IL-lra) signifioantly attenuated the decrease in mean arterial pressure and cardiac output and improved survival over control. The systemic IL-1 and IL-6 responses observed as a result of the bacteremia were to diminished significantly, correlating with a decrease in the systemic response to the sepsis.
Studies by Aiura et al.~° have shown that IL-lra is protective in a rabbit model of hypotensive gram-positive septic shock. The administration of IL-lra in this animal model has been shown to maintain mean arterial pressure compared to control, as well as decreasing lung water and maintaining urine output. This work demonstrated the role of IL-1 and the protective role oP IS~-ire in gram-positive shock which was thought to be due to a separate mechanism Erom gram-negative shock. The common pathway for the systemic manifestations of these two different models of shock has been shown to involve IL-1 as a central mediator. Evidence is mounting for the x~i~ pE Z~-1 as the principal mediator in a patient s clinical response to multiple diP~ererit i t "' .
;.~ . 2179183 stresses regardless of the etiology (including acute pancreatitis).
U.S. patents 4,522,827 and 4,902,708 disclose methods of treating acute pancreatitis.
FFowever, none of these patents take into effect the specific pathology of the disease, thereby proposing treatments which are not specific and are directed to the symptoms only, not the underlyittg mechanism.
U.S. patent 5,196,402 discloses the use of S-adenosyl methionine for the use of treatment of pancreatitis in the context of a complication in the graft rejection in pancreas transplant, a Very uncommon procedure. The patent does not address acute paricreatitis as a disease in the nontransplant patient. The vast majority of oases of pancreatitis are not associated with pancreatic transplants.
Treatments are needed which take into account that the local, as well as systemic, effects seen during acute pancreatitis are due to activation of the cytokine cascade whereby proximal inhibition of this cascade will decrease the severity of the inflammatory process.
2179183' -b-8D~8LARY OF THH IN'vEDtTION AND ADVANTAGES
According to the present invention, a method for treating acute paricreatitis is provided.
The method comprisag adminiutering to a pwrson afflicted with that condltiori an effective amount of Interleukin-1 receptor antagonist (IL-ire) or a pharmaceutically acceptable salt thereof.
Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in corinectlon with the accompanying drawings wherein:
FIGURE 1 is a graph showing the pancreatic wet weight in controls (shaded), IL-ire lOmg/kg pretreatment (solid), IL-Ira 10 mg/kg post treatment (diagonal), arid untreated disease control (cross-hatching) with .* indicating p<0.01 compared to no treatment;
FIGURE ,2 is a graph showing the serum amylase levels in groups as in Figure 1 with indicating p<0.05 compared to no treatments FIGURE 3 is a graph shoWirig the scrum lipase levels in groups as in Figure 1 with indicating p<0.0001 Compared to no treatment;
;.
~~, . 2~1~~g~
_,_ FIGURE 4 is a graph showing the serum interleWcin-6 levels in groups as in figure 1 with * indicating p<0.0001 compared to no treatment; and FIGURE 5 is a graph showing the serum TFN
levels in groups as in Figures 1 with * indiaati.ng P<0.0001 compared to rio treatment.
DET1~1I3~ED DESCRIPTION OF THH PREFERRED EMDODIlfENT
IL-lra is a naturally occurring peptide secreted by macrophages in response to many of the same stimuli which cause the secretion of IL-1 itself. IL-Ira is the only known naturally occurring antagonist to the cytokines and recognizes receptors on various cell types and blocks IL-1 mediated responses by occupying the receptor.~~,l8,~s,ao,xi In humans, IL-ira is a naturally occurring group of molecules; three forms have been characterized (two glycosylated and one non-glycosylated).
a0 According to the present invention, a person afflicted with that condition is administered an effective amount of Interleukin-1 receptor antagonist (IL-Ira) or a pharmaceutically acceptable salt thereof.
The safety of IL-Ira after intravenous administration has been demonstrated during the past three years in mice, rats, rabbits, dogs, _$_ primates, and hutnans,t~~t9,2~,2t,a2,23,2! In no7Cma1 volunteers, IL-Ira has been demonstrated to have a half-life of approximately two hours after intravenous administration and the plasma clearance of IL-ire appeared to correlate with creative clearance.~5 Hence, there already exists a regimen for Ih-lra administration for humans.
The IL-Ira to be used can be administered in aombi.riation with other drugs or singly consistent c~ith good medical practice. The other drugs can be somatostatln or an analog (i.e., Saridostatinm) and prostaglandin inhibitors (1.e., non-steroidal, anti-inflammatory drugs such as aspirin, indomethacin, ibuprofen, etc.).
Z5 Additionally, steroids or other drugs designed to suppress the immune system and other synthetia or recombinant antagonists or blockers to cytokines (e.g., soluble fNF receptors, soluble IL-I
receptors, soluble i'L-6 receptors or others;
monoclonal antibodies to IL-1, IL-6, TNF or others, etc.) can be administered. Further, nitric oxide inhibitors or antagonists, fr~s radical scavengc;rs or anti-oxidants, antagonists or M ockers of complement, ecosinoids or their antagonists and antibiotics, as appropriate, can also be administered.
-9_ The IL-ire is administered and dosed in acoordancs with good medical praotica, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, and other factors known to medlcai practitioners. The "effective amount's for purposes herein is thus determined by such considerations as era known in the art.
In the method of the present invention, the IL-lra can he administered in various ways. It should be noted that the IL-Ira can be administered as the compound or as pharmaceutically acceptable salt and can be administered along or in combination with pharmaceutically acceptable carriers. The compounds can be administered orally or parenterally including intravenous, intraperitoneally, intranasal and subcutaneous administration. Implants of the compounds are also ao useful. The patient' being treated is a warm-blooded animal and, in particular, mammals including man.
When administering the IL-ire parenterally, the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders Por recoristitution into sterile injectable solutions ar dispersions. The carrier can be a solvent or 2~~9~~~
-lo-dispersing medium containing, for example, water., ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suixabl~ mixtures th~rool, and vagotabls oils.
Proper fluidity can be maintained, Eor example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Nonaqueous vehicles such a cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems far compound compositions. Additionally, various additives which enhance the stability, sterility, and isotonicity of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can he added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
In many eases, it will be desirable to inolude isotonic agents, foz example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
r According to thw prwswnt invwntion, howovwr, any vehicle, diluent, or additive used would have to be coippatible with the compounds.
Sterile injoctable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.
A pharmacological formulation of the IL-Ira can be administered to the patient iri an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as polymer matrices, liposomes, and microspheres. An implant suitable for use in the present invention can 'take the form of a pellet which slowly dissolves after being implanted or a biocompatible delivery module well known to those skilled in the art. Such well known dosage foams and modules are designed such that the active ingredients are slowly released over a period of several days to several weeks.
Examples of well-known implants and modules useful in the present invention include:
U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No.
4, 486,194, which discloses a therapeutic device for administering medicants through the skin; U.S.
Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at . a precise infusion rate; O.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery;
U.S. Patent No. 4,439,196, which discloses an osaotic drug delivery system having mufti-chamber compart~asnts; and U.S. Patent No. 4,475,19b, which discloses an osmotic drug delivery system.
Many other such implants, delivery systems, and modules are well known to those skilled in the art.
A pharmacological formulation of the IL-ire utilized in the present invention can be administered orally to the patient. conventional methods such as administering the compounds in tablets, suspensions, solutions, emulsions, capsules, powders, syrups and the like are usable.
Known techniques which deliver the IL-ire orally or intravenously and retain the biological activity are preferred.
In one embodiment, the IL-lra can be administered initially by intravenous injection to bring blood levels of IL-lra to a suitable level.
The patient s IL-lra levels are then maintained by an oral dosage form, although other forms of administration, dependent upon the patient s condition and as indicated above, can be used. The guantity of IL-Ira to be administered will vary for the patient being treated and will vary from about 10o ng/kg of body weight to 100 mg/kg of body weight per day and preferably will be from 10 Etg/kg to to mg/kg per day.
In one preferred embodiment, if the patient is diagnosed with severe acute pancreatitis, then the patient will be aggressively treated for 72 hours and will receive intravenously a loading dose of 100 mg in a total volume of 10m1 2o followed by a 72-hour continuous infusion. The continuous infusion will consist of 2.Omg/kg/hr.
The infusion will be done by preparing loOml of the drug in saline for each 12-hour period. It will be infused by utilizing a volumetric infusion pump at 95 a rats of 8.a m1/hr. Any res;dual IL-Ira at the end of the 12 hours will be infused before the subsequent 12-hour infusion is initiated. At the ~
-14' completion of the 72-hour infusion, the patient is evaluated and, based on the patients condition, infusion will be continued, administration switched to oral dosage, or the drug discbntinued.
The practice and. utility of the present invention is shown in the following example:
liATBRIALB AND HETHOD$
The specification and claims provide 7.0 guidance for the use of the invention in humans.
The Tnvestic~tor~s fi~ndbook26 provided by the National Cancer Institute (page 23) indicates that the starting dose for Phasc I trials is based on the mouse equivalent LDlo. Farther, the manual 15 (page 22) indicates that anfmal studies carried out prior to Phase I trials provide the investigator with a prediction of the likely effects.~7 Therefore, the presented rodent model data is not only acceptable in determining human doses and 2o protocols, but is considered highly predictive.
Acute edematous, necrotizing pancreatitis vas induced in adult male Swiss mice weighing more than 35 grams using caerulein - an analog of cholecystokinin. Mice were divided into four 25 groups with three of the groups receiving caerulein So pg/kg by intraperitoneal (IP) injection in dour /e ~~7'~1~~
doses over three hours as previously described.z~~~9~l2,ae,2s Group 1 was a control group (n-9) which received only IP sal.ina injoetiono. Group z (n=1z) was an untreated disease control. Group 3 (n=12) received three injections (10 mg/kg/hr) starting one hour prior induction of pancreatitis_ Group 4 (n=12) received three injections (10 mg/kg/hr) starting one hour after induction of pancreatitis.
The IL-Ira used in this study is produced in E. colt by Synergen Corporation (Boulder, Co) by utilizing recombinant DNA technology and is identical to the non-glycosylated human form of human IL-lra except for the addition of one terminal methionine amino acid.
After nine hours, all animals were euthanized, the blood collected, and the pancreata surgically excised and weighed. Serum was assayed 2o for amylase, lipase, IL-6, and TNF levels_ Each pancreas was fixed, stained, and grnded histologically in a blinded fashion for interstitial edema, granulocyte Infiltration, acinar vacuolization, and acinar sell necrosis as described previously.7.27.2e Additionally, serum levels of IL-Ira Were determined, therefore allowing comparisons between dosage, serum level, r' 2179183 -ls-systemic cytokine response, and degree of pancreatic damage.
IL-6, Il-1, IL-ira,and TNF were measured by commercially available ELISA kits (Genzyme Corp., Boston, MA). All specimens were run in triplicate. Serum levels of amylase and lipase were measured on a Kodak Ectachem 700 automated analyzer (Eastman Kodak Company, Rochester, NY).
tIistologic slides were prepared as is known in the art after rapid excision and subsequent fixation in 10~ formalin. The tissues were paraffin embedded as is known in the art and then stained with Hematoxylin and Eosin in a standard fashion. These slides were examined and graded in a blinded fashion by a board cartified pathologist.
Results In these experiments, acute pancreatitis was induced in 45 mice using aaerulein. Acute edematous, necrotizing pancreatitis is present within an hour of caerulein injection and reaches a peak effect approximately nine hours later. Ay treating mice with IL-Ira prior to or after the induction of panereatitie, applicants were able to show a significant decrease in pancreatic wet weight (p<.O1), serum amylase (p<.o5), lipase (p<.0001), and IL-6 (p<.0001) as shown in Figures ~ I79I ~~
1-4 and Table I, respectively. TNF (p<0.0001) was also signlfi.oantly reduced (Figure S). All statistics noted are significant by two-tailed W3leoxon test. Additionally, these was a decrease in tha number of polymorphonuclear white blood cells (PMNs) within the capillaries of the lungs and pancreas. Histologie studies of these pancreata were performed in a blinded fashion and showed a significant decrease (p<.05) in total organ edema, acinar necrosis, acinar vacuolization, and inflammation in those animals treated with IL-lra. An important finding in these experiments was that treatment with IL-Ira within two hours after the onset of pancreatitis was neariy as protective as pretreatment.
These series of experiments were repeated using both higher and lower does of I1-lRa. In one experiment, all animals received IL-ira at a dose oP 100 mg/kg/hrX3. All the previous findings were confirmed, but no significant benefit could be found with the higher dose. When the dose o! IL-ira was decreased to 1 mg/kg/hrx3, the benefita were seen in all categories except amylase levels. This dose, however, did not show quite as much decrease in wet weight or the levels of IL-6 and TNF as did the 10 mg/kg/hrx3 dose. These dose response experiments confirm the efficacy of IL-ira :, ~,;, 2i7918~
. .
in the treatment of pancreatitis when proper levels of the drug are maintained.
Tha example provides guidance for the use of the invention in humans. The imvest3qgtor~s H_~~ boo 26 provided by the National. Cancer Institute (page 23) indicates that the starting dose for Phase I trials is based on the mouse equivalent LDlp. In fact, Phase T trials of IL-ira have been completed.~~ Further, the manual (page 1U 22) indicates that animal studies carried out prior to Phase I trials provide the investigator with a prediction of the.likely effects.lZ Therefore, the presented rodent model data is not only acceptable iri determining human doses arid protocols but is considered highly predictive. Based on the available data from the Phase I trials and Phase II
trials in the treatment of sepsis3~ combined With the present invention allows the treatment of pancreatitis in humans.
2o Further, the cytokine activation in fulminant pancreatitis is similar to that of sepsis. The blockade of the cascade applicants have shown is similar to that shown in animal and human studies using IL-ira for sepsis. A better understanding of the role played by specific cytokines in this systemic reaction has provided insight into effective therapies for severe -ls-pancreatitis, in particular the therapeutic use of IL-lra in acute pancreatitis.
The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be 1n the nature of Words of description rather than of limitation.
Obviously, many modifications ~ arid variations of the present invention ase possible ~in light of the above teachings. It is, therefore,. to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.
TABLE I
(m5) (5U) (IU) (ng/kg)(ng/kgD
1 188*0.1 220Ct156 1715158 5415 6319 t.04* #1756* i3155* *51* #30*
1.02** *2393** *1685** *il* * #3**
#.04** 4494** 12648** *17* * #10**
Results are exp ressed as mean t SEM, significance ted if 0.05 by two -tailed4lilcoxcn accep p <
test.
* compared to control (Group 1) ** compared eated pancreatitis (Group to untr 2D
.; ' ~ ; , ' 21 l 918 J . v,:i, ;
i . r: t, :; i ' . : ~. . ; ' ;~;,,. ; , .
:;
:'.~.~.:;1 :.
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Claims (7)
1. A use of an effective amount of Interleukin-1 receptor antagonist (IL-lra) or a pharmaceutically acceptable salt thereof for treating acute pancreatitis in a patient.
2. The use of claim 1 wherein the IL-lra is suspended in an acceptable carrier.
3. The use of claim 1 wherein the effective amount of IL-lra is from 100 ng/kg body weight to 100 mg/kg body weight of the patient per day.
4. The use of claim 3 wherein the effective amount of IL-lra is administerable initially by an intravenous injection to bring blood levels of IL-lra to a suitable level after which the patients IL-lra levels are maintainable.
5. The use of claim 4 wherein the IL-lra is administerable (a) intravenously as a loading dose of 100 mg in a total volume of 10ml followed by (b) a 72 hour continuous infusion.
6. The use of claim 5 wherein the 72 hour continuous infusion consists of 2.0mg/kg/hr.
7. The use of claim 1 further comprising, in combination with the IL-lra, a somatostatin, prostaglandin inhibitor, immunosuppressive drug, cytokine agonist, cytokine blocker, nitric oxide inhibitor or antagonist, free radical scavenger or anti-oxidant, antagonist or blocker of complement, ecosinoid or its antagonist or an antibiotic.
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| US167,698 | 1980-07-11 | ||
| US08/167,698 US5508262A (en) | 1993-12-15 | 1993-12-15 | Interleukin-1 receptor antagonist decreases severity of acute pancreatitis |
| PCT/US1994/014572 WO1995016706A1 (en) | 1993-12-15 | 1994-12-15 | Interleukin-1 receptor antagonist decreases severity of acute pancreatitis |
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| CA2179183A1 CA2179183A1 (en) | 1995-06-22 |
| CA2179183C true CA2179183C (en) | 2006-12-05 |
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| CA002179183A Expired - Fee Related CA2179183C (en) | 1993-12-15 | 1994-12-15 | Interleukin-1 receptor antagonist decreases severity of acute pancreatitis |
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| US (2) | US5508262A (en) |
| EP (1) | EP0734395A4 (en) |
| JP (1) | JPH09510434A (en) |
| CA (1) | CA2179183C (en) |
| WO (1) | WO1995016706A1 (en) |
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| US5874424A (en) * | 1995-12-20 | 1999-02-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
| US6008217A (en) * | 1995-12-20 | 1999-12-28 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
| US6204261B1 (en) | 1995-12-20 | 2001-03-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β Converting enzyme inhibitors |
| US6159460A (en) * | 1988-05-27 | 2000-12-12 | Amgen Inc. | Method for treating interleukin-1 mediated diseases |
| US5075222A (en) | 1988-05-27 | 1991-12-24 | Synergen, Inc. | Interleukin-1 inhibitors |
| US6858409B1 (en) | 1988-05-27 | 2005-02-22 | Amgen Inc. | Nucleic acids encoding interleukin-1 inhibitors and processes for preparing interleukin-1 inhibitors |
| US5508262A (en) * | 1993-12-15 | 1996-04-16 | University Of South Florida | Interleukin-1 receptor antagonist decreases severity of acute pancreatitis |
| US6420522B1 (en) | 1995-06-05 | 2002-07-16 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
| US5723116A (en) * | 1995-01-06 | 1998-03-03 | University Of South Florida | Decreased mortality of severe acute pancreatitis following proximal cytokine blockade |
| GB9512100D0 (en) * | 1995-06-14 | 1995-08-09 | Sandoz Nutrition Ltd | Improvements in or relating to organic compounds |
| US5843904A (en) * | 1995-12-20 | 1998-12-01 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1βconverting enzyme |
| US5972880A (en) * | 1996-03-07 | 1999-10-26 | Arthro Lab Inc. | Method of treatment of osteoarthritis with interleuken-1 receptor antagonist |
| US6416753B1 (en) * | 1996-03-15 | 2002-07-09 | The General Hospital Corporation | Method for modulating apoptosis |
| ES2615357T3 (en) * | 1996-12-06 | 2017-06-06 | Amgen Inc. | Combination therapy using an IL-1 inhibitor to treat IL-1 mediated diseases |
| US6294170B1 (en) | 1997-08-08 | 2001-09-25 | Amgen Inc. | Composition and method for treating inflammatory diseases |
| US6063600A (en) * | 1997-05-23 | 2000-05-16 | Uab Research Foundation | DNA encoding canine interleukin-1 receptor antagonist |
| US6294655B1 (en) | 1998-04-03 | 2001-09-25 | Hyseq, Inc. | Anti-interleukin-1 receptor antagonist antibodies and uses thereof |
| US6426191B1 (en) | 1998-04-03 | 2002-07-30 | Hyseq, Inc. | Assays involving an IL-1 receptor antagonist |
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| US4475196A (en) * | 1981-03-06 | 1984-10-02 | Zor Clair G | Instrument for locating faults in aircraft passenger reading light and attendant call control system |
| US4447233A (en) * | 1981-04-10 | 1984-05-08 | Parker-Hannifin Corporation | Medication infusion pump |
| US4439196A (en) * | 1982-03-18 | 1984-03-27 | Merck & Co., Inc. | Osmotic drug delivery system |
| US4522827A (en) * | 1982-07-02 | 1985-06-11 | Knoll Ag | Method of treating acute pancreatitis with isometheptene |
| US4447224A (en) * | 1982-09-20 | 1984-05-08 | Infusaid Corporation | Variable flow implantable infusion apparatus |
| US4487603A (en) * | 1982-11-26 | 1984-12-11 | Cordis Corporation | Implantable microinfusion pump system |
| US4486194A (en) * | 1983-06-08 | 1984-12-04 | James Ferrara | Therapeutic device for administering medicaments through the skin |
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| US5080646A (en) * | 1988-10-03 | 1992-01-14 | Alza Corporation | Membrane for electrotransport transdermal drug delivery |
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| US5167616A (en) * | 1989-12-14 | 1992-12-01 | Alza Corporation | Iontophoretic delivery method |
| WO1992012724A1 (en) * | 1991-01-17 | 1992-08-06 | The Upjohn Company | Method of preventing and treating insulin dependent diabetes mellitus |
| US5220018A (en) * | 1991-04-10 | 1993-06-15 | Merck & Co., Inc. | Cholecystokinin antagonists |
| US5225182A (en) * | 1991-10-31 | 1993-07-06 | Sharma Yash P | Vectored drug delivery system using a cephaloplastin linking agent and a methed of using the system |
| US5508262A (en) * | 1993-12-15 | 1996-04-16 | University Of South Florida | Interleukin-1 receptor antagonist decreases severity of acute pancreatitis |
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1993
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1996
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| JPH09510434A (en) | 1997-10-21 |
| WO1995016706A1 (en) | 1995-06-22 |
| EP0734395A1 (en) | 1996-10-02 |
| US5919444A (en) | 1999-07-06 |
| CA2179183A1 (en) | 1995-06-22 |
| US5508262A (en) | 1996-04-16 |
| EP0734395A4 (en) | 1997-03-19 |
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