ULINASTATIN IN THE MANAGEMENT OF SEPSIS & ACUTE …
Transcript of ULINASTATIN IN THE MANAGEMENT OF SEPSIS & ACUTE …
ULINASTATIN IN THE MANAGEMENT OF SEPSIS & ACUTE PANCREATITIS
DR PUNIT D. GHETIA
MD , IDCCM (MUMBAI)
CONSULTANT INTENSIVIST , BANKERS HEART INSTITUTE
Ulinastatin is a kind of glycoprotein extracted from human urinewhich acts as a Urinary Trypsin Inhibitor (UTI).
Physical Information:Ulinastatin for Injection is available as a clear, colourless liquid. Itcontains UTI of not less than 45,000 units per ml and not less than2500 units per mg protein.
Chemical Information:Molecular Weight: Ranges from 62 kDa to 72 kDa
ULINASTATIN
Pharmaceutical Information:
Appearance: White or light yellow lyophilized powder or clear colourless liquidpH: 6-8Sterility: SterileAssay: 90% to 110% of label claimShelf life: 2 years under the storage conditions at 2°C-8°C
MOLECULAR BASIS OF SEPSIS
Complement systemC3, C4, C9Factor BC1 inhibitorC4b - binding proteinMannose - binding protein
Coagulation and fibrinolyticsystemFibrinogen, PlasminogenTissue plasminogen activatorUrokinase, Protein S, VitronectinPlasminogen-activator inhibitor-1
TNF-alpha
NeutrophilElastase
UTI
UTIUTI
UlinastatininhibitsNeutrophil
elastasePlasminThrombinCathepsinKallikreinTrypsinTryptaseChymotrypsinSIRS
USAGE RATIONALEPRE-CLINICAL STUDIES
URINARY TRYPSIN INHIBITOR REDUCES INFLAMMATORY RESPONSE IN KIDNEY INDUCED BY LIPOPOLYSACHHARIDE
ROLE OF ULINASTATIN IN DOWNREGULATION OF TNF-α
Masaaki, U et al. Journal of Bioscience andBioengineering, 2007, Vol. 104, No. 4, 315-320
Absence of Ulinastatin gene increases organ injury induced by bacterial endotoxin
WT LPS
UTI (-/-) LPS
p<0.01KIDNEY
WT LPS
UTI (-/-) LPS
p<0.01LIVER
Ken-Ichiro I, et al. Mol Pharmacol67:673–680, 2005
WT LPS
UTI (-/-) LPS
p<0.01LUNG
WT : Wild type miceUTI (-/-) : Knock out mice without UTI gene
URINARY TRYPSIN INHIBITOR PROTECTS AGAINST SYSTEMIC INFLAMMATION INDUCED BY LIPOPOLYSACCHARIDE
Hiroshi Kobayashi et al. The Journal of Infectious Diseases 2005; 191:930–8
ULINASTATIN IMPROVES SURVIVAL LPS
LPS + UTI 25
LPS + UTI 50
ULINASTATIN SUPPRESSES LIPOPOLYSACCHARIDE-INDUCED LETHALITY THROUGH DOWN-REGULATION OF TUMOR NECROSIS FACTOR–Α AND INTERLEUKIN-1Β IN MACROPHAGES.
0 6 12
8
18 24 0
50
100
Kaplan Meier survival curve
SU
RV
IVA
L
USAGE RATIONALE: CLINICAL STUDIES
A prospective, multicentric, double-blind, randomized, phase III clinical study to comparethe efficacy and safety of I.V. Ulinastatin vs. placebo along with standard supportive care in subjects of severe sepsis
n=114
10
D.R. Karnad et.al, Intensive Care Medicine; April 2014
Indian Experience
Multicenter
Seven sites at various locations in India
Medical or Surgical ICUs
Site City ICU
B Y L Nair Hospital & T N Medical College Mumbai Medical
Lokmanya Tilak Muncipal General Hospital & Medical College
Mumbai Medical
Maulana Azad Medical College New Delhi Medical
Vardhaman Mahavir Medical College and Safdarjung Hospital
New Delhi Surgical
Jehangir Hospital & Research Center Pune Medical/Surgical
NDMVP Samaj Medical College & Hospital Nashik Medical/Surgical
Bhatia Hospital Mumbai Medical/Surgical
STUDY DESIGN
Randomization
Subjects were randomised in a 1:1 ratio
Double blind
Opaque sealed envelope for each subject
Treatment
Ulinastatin
200,000 IU dissolved in 250 ml normal saline
IV infusion over one hour - twice a day (10 – 14 hours apart) x 5 days.
Placebo
Dissolved in 250 ml normal saline
IV infusion over one hour - twice a day (10 – 14 hours apart) x 5 days.
STUDY DESIGN
1. Age between 18-60 years and Weight <135kg
2. Evidence of infection
3. Presence of systemic inflammatory response syndrome (SIRS)
4. At least one organ system failure
All four criteria must be present at enrollment
INCLUSION CRITERIA
Absolute mortality reduction 13%Relative reduction in mortality 66%
PRIMARY END-POINT: 28 DAY ALL CAUSE MORTALITY
SECONDARY END POINTS: ONSET OF NEW ORGAN DYSFUNCTION
New onset organ dysfunction or worsening from baseline
Placebo Ulinastatin
P value
(n=59) (n=55)
Cardiovascular 9 4 0.18
Respiratory 8 4 0.27
Hematological 7 4 0.41
Hepatic 3 2 1
Renal 4 2 0.68
Central Nervous System 3 2 1
Total No. of patients with New Onset of organ dysfunction
26 10 0.003
There was a significant reduction in the onset of new organ dysfunction, 26% Absolute reduction
SECONDARY END POINTS:VENTILATOR-FREE DAYS & DURATION OF HOSPITALISATION
Decrease in duration of ventilation is highly suggestive of efficacy of Ulinastatin
Reduces cost of care – important end point from pharmaco-economic perspective
Decrease in Hospital stay is highly suggestive of better efficacy in UTI group
ULINASTATIN IN SEPSIS
Inhibition of the cytokines, reduction in the levels of TNF-α and Interleukin-6
Suppresses the activity of neutrophil elastaseand prevents the incidence of DIC
Prevents progression to MOD’s in Sepsis
Reduces New onset organ-dysfunction.
Reduces overall mortality in sepsis
CLINICAL STUDIES
N= 50 Group A: Received 2 lac IU of UlinastatinGroup B: Placebo
J of Evolution of Med and Dent Sci/ eISSN- 2278-4802, pISSN- 2278-4748/ Vol. 3/ Issue 53/Oct 16, 2014
CONCLUSION OF STUDY :Prevents progression to MOD’s in Sepsis Reduces New onset organ-dysfunction.Reduces overall mortality in sepsis
Ulinastatin in the treatment acute pancreatitis
ULINASTATIN IN THE TREATMENT ACUTE PANCREATITIS: A MULTICENTRIC CLINICAL TRIAL
A multicenter randomized controlled clinical trial, N = 94
Stratified by AHNP(=ACUTE HEMORRAGIC NECROTISING PANCREATITIS) or AEP(= ACUTE EDEMATOUS PANCREATITIS)
patients were randomly allocated into either the treatment group (with ulinastatin) or the control group
Ulinastatin was shown to be effective in treating AEP and AHNP with few adverse effects.
in cases of AEP, the cured rates for ulinastatin were 83.3%.
Global effective rate for ulinastatin in the treatment of AHNP 78.6%
Ulinastatin is a broad-spectrum enzyme inhibitor
ULINASTATIN FOR PANCREATITIS AFTER ERCP: A RANDOMIZED CONTROLLED TRIAL
N = 406 Patients
2.9% of subjects on ulinastatin and 7.4% on placebo developed pancreatitis (p=0.041).
Incidence of hyperenzymemia was significantly lower in the ulinastatin group than in the placebo group
Clin Gastroenterol Hepatol. 2005;3:376.
A PROSPECTIVE, MULTICENTER, DOUBLE-BLIND, RANDOMIZED, PHASE III CLINICAL STUDY TO COMPARE THE EFFICACY AND SAFETY
OF INTRAVENOUS ULINASTATIN VERSUS PLACEBO ALONG WITH STANDARD SUPPORTIVE CARE IN SUBJECTS WITH MILD OR SEVERE
ACUTE PANCREATITIS
P. Abraham et.al;JAPI 2013;Aug(61)
DEFINITIONS
Mild acute pancreatitis
APACHE II score <8, with no extrapancreatic manifestation or
complication
Severe acute pancreatitis
APACHE II score ≥8, with or without any organ failure or local
complication
STUDY DESIGN
Randomization
1:1 ratio
Double blind
Opaque sealed envelopes
Treatment
Ulinastatin
200,000 IU dissolved in 100 mL 5% dextrose or 0.9% saline IV injection over one hour every 12 hours for 5 days
Placebo
Dissolved in 100 mL 5% dextrose or 0.9% saline IV injection over one hour every 12 hours for 5 days
INCLUSION CRITERIA
I. Age 18-70 years (both inclusive)
II. Any two of the following three:
1. Abdominal pain characteristic of acute pancreatitis
2. Serum amylase and/or lipase ≥3 times upper limit of normal
3. Characteristic findings of acute pancreatitis on USG, contrast-
enhanced CT or MRI
III. Elevated serum CRP level
EXCLUSION CRITERIA
1. Pregnancy or breast-feeding
2. Evidence of chronic pancreatitis on imaging (calcification,
ductal irregularity or dilatation)
3. Subjects requiring immediate surgery (within 7 days)
4. Moribund state in which death was perceived to be
imminent (≤24 hours)
5. Participation in another investigational study within 30
days before current study
EFFICACY END POINTS
Primary end-points
Reduction in serum CRP on Day 7 from commencement of IP
administration
Secondary end-points
Mortality
Prevention of new-onset organ failure
Hospital stay (days) till discharge in survivors
CONSORT DIAGRAM
Mild pancreatitis Severe pancreatitis
Group Ulinastatin(n=30)
Placebo (n=32)
p value
Ulinastatin(n=35)
Placebo(n=32)
p value
CRP Day 7Median (IQR)
22.6(0.1 - 144.8)
11.17(0.3 -
145.3)
.942 12 (1 - 430) 10 (0.3 -165)
.71
CRP changeD0 - D7 Median (IQR)
15.52(-12.17 -
135.4)
8.46(-70 - 112)
.344 7.15(-100 -
126)
9.9(-24 -168)
.71
RESULTS: PRIMARY END-POINT
Mild pancreatitis Severe pancreatitis
Group Ulinastatin
(n=30)Placebo (n=32)
p value
Ulinastatin(n=35)
Placebo(n=32)
p value
MortalityNo. (%)
1 (3.3%) 0 .48 1 (2.8%) 6 (18.7%) .048
New-onset organ dysfunction No. (%)
5 (16.7%) 4 (12.5%) .74 12 (34.3%)29
(90.6%).0026
Hospital stay (days) Median (IQR)
7 (5 - 22) 8 (5 - 15) .0749
(6 - 22)10
(6 - 22).207
Adverse events
33 35 0.62 23 45 .000013
RESULTS: SECONDARY END-POINTS
CONCLUSIONS
The 22-day all-cause mortality was reduced significantly from 18.8% in the placebo group to 2.8% in the Ulinastatin group in the severe pancreatitis subjects.
CONCLUSIONS
New-onset organ failure decreased from 90% in the placebo group to 34% in the Ulinastatin group; this was statistically significant.
CONCLUSIONS
Hospital stay was shorter in the Ulinastatin group.
The reduction of Serum CRP was comparable in the two treatment groups.
No infusion-related toxicity was seen in any of the study subjects in either group.
Incidence of adverse events were significantly less in the Ulinastatin group compared to the Placebo group.
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