modeling the atrial fibrillation side effects of interleukin-11
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Modeling the Atrial Fibrillation Side Effects of Interleukin-11. (Administered for Treating Thrombocytopenia and Various Diseases). Smadar Horowitz & Moran Elishmereni. Computational Biology Final Project, Bar-Ilan University August 2004. Guidance: - PowerPoint PPT PresentationTRANSCRIPT
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
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?
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
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.
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.
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
IL-11
Introduction
Interleukin 11 (IL-11)
Succeeds in
elevating platelet count!
Great Solution!
So what’s
the catch?
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%)
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?
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
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)
Atrial Fibrillation (AF)
Introduction
The most common
arrhythmic disorder
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.
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
The Problem
IL-11 Induces AF
IL-11 AF
Major Problem!
The Problem
IL-11 Induces AF
IL-11 AF
How can we allow the safe use of IL-11
anyway?
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
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.
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)
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
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
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
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
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
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
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
)),(()(
)()(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)
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
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!
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
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.
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
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.
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…
In Conclusion
Cancer
Interleukin-11
Chemotherapy
Chemotherapy-Induced
Thrombocytopenia
AFMathematica
l Modelfor IL-11 induced AF
DISEASE TREATMENT
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
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.