Modeling the Atrial Fibrillation Side Effects of Interleukin-11
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Transcript of Modeling the Atrial Fibrillation Side Effects of Interleukin-11
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Computational Biology Final Project, Bar-Ilan
UniversityAugust 2004
(Administered for Treating Thrombocytopenia and Various Diseases)
Smadar Horowitz & Moran Elishmereni
Guidance:
Prof. Zvia Agur Dr. Hila Harpak
Yuri Kheiffez
IMBM
Modeling the Atrial Fibrillation Side Effects of
Interleukin-11
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Chemotherapy-Induced Thrombocytopenia
Reason - chemotherapeutic agents eliminate megakaryocytes and platelet precursors that are part of thrombopoiesis (platelet production).
Side effects - abnormal bleeding, bruising, spots on the skin, headaches.
Introduction
A low level of platelet formation or platelets in plasma due to administration of
chemotherapy.
Thrombocytopenia is a dose-limiting side
effect of chemotherapy.
How do we treat it?
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Transfusion of Platelets
Introduction
Treatment
Chemotherapy-Induced Thrombocytopenia
Most common treatment.
Required every few days.
Risk of infections and immunologic reaction.
Expensive.
Platelet Growth Factors
Interleukin 11
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A protein of 178 amino acids, molecular mass of 19 kDa.Secreted by bone marrow & intestine.Main biological activity : stimulation of megakaryocyte proliferation and increased platelet production.
Introduction
Interleukin 11 (IL-11)A pleiotropic cytokine / growth factor.
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A protein of 179 amino acids, molecular mass of 19 kDa.Secreted by bone marrow & intestine.Main biological activity : stimulation of megakaryocyte proliferation and increased platelet production.
Introduction
Interleukin 11 (IL-11)A pleiotropic cytokine / growth factor.
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A protein of 179 amino acids, molecular mass of 19 kDa.Secreted by bone marrow & intestine.Main biological activity : stimulation of megakaryocyte proliferation and increased platelet production.
Introduction
Interleukin 11 (IL-11)A pleiotropic cytokine / growth factor.
megakaryocyte
platelets
RBC
WBC
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IL-11
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Introduction
Interleukin 11 (IL-11)
Succeeds in
elevating platelet count!
Great Solution!
So what’s
the catch?
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Side effects
Edema (59%)
Asthenia (50%)
Dyspnea (48%)
Conjunctival redness (19%)
Anemia (<15%)
Pleural effusion (<15%)
Interleukin 11 (IL-11)
Introduction
Common Adverse Events
Usually manageable and reversible with
drug discontinuation, but may become
severe
AF- Atrial Fibrillation (<15%)
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Side-effects
Edema (59%)
Asthenia (50%)
Dyspnea (48%)
Conjunctival redness (19%)
Anemia (<15%)
Pleural effusion (<15%)
Interleukin 11 (IL-11)
Introduction
AF- Atrial Fibrillation (<15%)
Less-common Adverse Event
Usually severe, life-threatening, and
irreversible
What is Atrial
Fibrillation?
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Normal Sinus Rhythm
Introduction
Electrical impulses are fired through the heart, creating a predictable wave of stimulation and contraction.
Heart beat:
60-100 bpm
regular
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Introduction
Multiple atrial sites fire impulses in a random fashion, creating many uncoordinated contractions.
Heart beat:
120-180 bpm
erratic, ineffective and rapid
Atrial Fibrillation (AF)
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Atrial Fibrillation (AF)
Introduction
The most common
arrhythmic disorder
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Atrial Fibrillation (AF)
Introduction
Leads to serious complications such as heart
failure and blood clots.
Causes 15% of all strokes.
Prevalence rises with advanced
age or history of cardiac disorder.
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The Problem
IL-11 is rarely administered due to all of the side-effects.
IL-11 is not administered at all in elderly or cardiac
impaired patients due to risk of AF .
IL-11 Induces AF
IL-11 AF
life-threatening side-effect
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The Problem
IL-11 Induces AF
IL-11 AF
Major Problem!
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The Problem
IL-11 Induces AF
IL-11 AF
How can we allow the safe use of IL-11
anyway?
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Purpose of the Project
Mathematical Model
Creation of a
Simulating IL-11
induced AFI. Treatment protocol- dosage & time of administration.
II. Personal characteristics of the patient.
Risk of AF (%) in a specific patient
treated with IL-11
InputOutput
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Purpose of the Project
Mathematical Model
Creation of a
Simulating IL-11
induced AF
Phases:
I. Understand the Physiological Mechanism of IL-11-induced AF.
II. Adjust the Mechanism & Write Appropriate Equations.
III. Analyze the Equations and Find Parameters.
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Mathematical Model: (I) Physiological Mechanism
IL-11 Na+ & Fluid
Retention
Atrial Enlargement and Stretch
AF
Activation of Stretch-
Dependant Channels &
Faster Depolarization
IL-11 Induces AF: How?
Direct Effect on Kidney or
Compensatory Response of
Kidney (RAAS)
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IL-11 Na+ & Fluid
Retention
Atrial Enlargement and Stretch
AF
Mathematical Model: (II) Adjusting Mechanism
IL-11 plasma concentration = IL-11 dosage.
IL-11 Dose
IL-11 Conc.
X
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IL-11 Na+ & Fluid
Retention
Atrial Enlargement and Stretch
AF
IL-11 plasma concentration = IL-11 dosage.
IL-11 Dose
IL-11 Conc.
X
We don’t know how Fluid Retention occurs: Assume a mediating factor Y formed as a result of IL-11 activity and leading to FR.
Mathematical Model: (II) Adjusting Mechanism
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IL-11 Na+ & Fluid
Retention FR
Atrial Enlargement and Stretch
AF
IL-11 plasma concentration = IL-11 dosage.
IL-11 Dose
IL-11 Conc.
X
We don’t know how Fluid Retention occurs: Assume a mediating factor Y formed as a result of IL-11 activity and leading to FR.
Factor Y
Mathematical Model: (II) Adjusting Mechanism
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IL-11 AF
IL-11 plasma concentration = IL-11 dosage.
IL-11 Dose
IL-11 Conc.
X
We don’t know how Fluid Retention occurs: Assume a mediating factor Y formed as a result of IL-11 activity and leading to FR.
Factor Y
Fluid Retention (or Atrial Volume) highly correlate with occurrence of AF.
Na+ & Fluid
Retention FR
Atrial Enlargement and Stretch
Mathematical Model: (II) Adjusting Mechanism
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IL-11 AF
IL-11 plasma concentration = IL-11 dosage.
IL-11 Dose
IL-11 Conc.
X
We don’t know how Fluid Retention occurs: Assume a mediating factor Y formed as a result of IL-11 activity and leading to FR.
Factor Y
Fluid Retention (or Atrial Volume) highly correlate with occurrence of AF.
Na+ & Fluid
Retention FR
Mathematical Model: (II) Adjusting Mechanism
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IL-11 AFIL-11 Dose
IL-11 Conc.
X
Factor Y
Na+ & Fluid
Retention FR
Mathematical Model: (II) Adjusting Mechanism
Personalized Data entered:
Age
History of cardiac disorder
History of alcohol use
Obesity
Personalized Parameters
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IL-11 AFIL-11 Dose
IL-11 Conc.
X
Factor Y
Na+ & Fluid
Retention FR
1 2 4
1
2
3
4
3Adm(X)
Mathematical Model: (II) Writing Equations
Personalized Parameters
)),(()(
)()(21
rsedParametePersonaliztFRftAF
tYftFR
YXX
X
dt
dY
XXAdmdt
dX
mm
m
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)),(()(
)()(21
rsedParametePersonaliztFRftAF
tYftFR
YXX
X
dt
dY
XXAdmdt
dX
mm
m
1
2
3
4
How
Mathematical Model: (III) Analysis of Equations and Parameters
Deriving the Analytical Solutions:
FR (t)
Y (t)
How?
X (t)
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Mathematical Model: (III) Analysis of Equations and Parameters
XXAdmdt
dX
)24(24
)1(24
1
1)(
nt
n
ee
etX
Initial Dose of IL-11 is
known
Day (0,1,2…
)
1
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2
Mathematical Model: (III) Analysis of Equations and Parameters
YXX
X
dt
dYmm
m
21
24
)1(24)24(
1
1)(
e
eeuX
nnu
t
mm
mut du
XuX
uXeetY
021)(
)()(
Values of m X1/2
are unknown!
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3
Mathematical Model: (III) Analysis of Equations and Parameters
)()( tYftFR
normFRtkYtFR )()(
normFRtFRtkY )()(
A B
H = (A – B)2 0
Solution: Curve
fitting (Aspire H to a
minimal value)
We want to find the
parameters of A so
that A and B are close
First Phase: Linear
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Mathematical Model: (III) Analysis of Equations and Parameters
To find minimum of H we use a numerical method:
Steepest Descent Method
X(n+1) = X(n) - f (X(n))
nniii
i
xxfxxxxxf
x
f ,...,,...,,,,..., 1111
Start at random point.
Get direction of steepest descent.
Move in this direction.
Repeat until minimum is found.
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Mathematical Model: (III) Analysis of Equations and Parameters
H
Iterations
H reaches
minimum value!
Parameter values of Y(t)
are: 9984.2
7496.0
8444.0
0375.0
21
X
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Mathematical Model: (III) Analysis of Equations and Parameters
normFRtkYtFR )()(
We found parameters- function is known!
Defined by normal plasma
volume- 5.5 L
Not enough data - we cannot use interpolation to define FR(t).
First Phase: Linear
Later Phase: Unknown
We remain only with linear equation.
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Mathematical Model: Achievements
1 32
X (t) Y (t) FR (t)
Deriving the Analytical Solutions:
Future studies will allow us to create a more complete and accurate model…
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In Conclusion
Cancer
Interleukin-11
Chemotherapy
Chemotherapy-Induced
Thrombocytopenia
AFMathematica
l Modelfor IL-11 induced AF
DISEASE TREATMENT
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We wish to thank the following people for their contribution to the
project:
... תודה על ההקשבה
Prof. Zvia Agur Dr. Hila
Harpak Yuri Kheiffez
Dr. Ron Unger Dr. Yehudit Sonn
Dr. Nethaniel Horowitz Dr. Yitzhak Kehatt Prof. Amir Pelleg
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References
1. Age-dependent atrial remodeling induced by recombinant human interleukin-11: implications for atrial flutter/fibrillation. Jiang Xu, 2002.
2. A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Tepler I, 1996.
3. A phase I trial of recombinant human interleukin-11 (neumega rhIL-11 growth factor) in women with breast cancer receiving chemotherapy. Gordon MS, 1996.
4. Tolerability and side-effect profile of rhIL-11. Smith J.
5. Hematopoietic, immunomodulatory and epithelial effects of interleukin-11. Shwertzshlag US, 1999.
6. Mechanism and amelioration of recombinant human interleukin-11 (rhIL-11)-induced anemia in healthy subjects. Dykstra KH, 2000.
7. Pharmacokinetics of [125I]-recombinant human interleukin-11: 1. Absorption, distribution and excretion after subcutaneous administration to male rats. Uchida T, 1998.
8. Pharmaco-economic analysis of oprelvekin solid tumor patients receiving chemotherapy. Scott B. Cantor, Ph.D.