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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:

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Modeling the atrial fibrillation side effects of interleukin 11

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:

Prof. Zvia Agur Dr. Hila Harpak Yuri Kheiffez

IMBM


Chemotherapy induced thrombocytopenia

Introduction Interleukin-11

Chemotherapy-Induced Thrombocytopenia

A low level of platelet formation or platelets in plasma due to administration of chemotherapy.

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.

Thrombocytopenia is a dose-limiting side effect ofchemotherapy.

How do we treat it?


Treatment

Introduction Interleukin-11

Chemotherapy-Induced Thrombocytopenia

Treatment

Platelet Growth Factors

X

  • Most common treatment.

  • Required every few days.

  • Risk of infections and immunologic reaction.

  • Expensive.

Transfusion of Platelets

Interleukin 11


Introduction Interleukin-11

Interleukin 11 (IL-11)

A pleiotropic cytokine / growth factor.

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

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

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.

RBC

megakaryocyte

WBC

platelets


IL-11 Interleukin-11


Introduction Interleukin-11

Interleukin 11 (IL-11)

Succeeds in elevating platelet count!

So what’s the catch?

Great Solution!


Side effects

Introduction Interleukin-11

Interleukin 11 (IL-11)

Side effects

Common Adverse Events

Usually manageable and reversible with drug discontinuation, but may become severe

Edema (59%)

Asthenia (50%)

Dyspnea (48%)

Conjunctival redness (19%)

Anemia (<15%)

Pleural effusion (<15%)

AF- Atrial Fibrillation (<15%)


Side effects1

Introduction Interleukin-11

Interleukin 11 (IL-11)

Side-effects

Edema (59%)

Asthenia (50%)

Dyspnea (48%)

Conjunctival redness (19%)

Anemia (<15%)

Pleural effusion (<15%)

What is Atrial Fibrillation?

Less-common Adverse Event

Usually severe, life-threatening, and irreversible

AF- Atrial Fibrillation (<15%)


Introduction Interleukin-11

Normal Sinus Rhythm

Electrical impulses are fired through the heart, creating a predictable wave of stimulation and contraction.

Heart beat:

60-100 bpm

regular


Introduction Interleukin-11

Atrial Fibrillation (AF)

Multiple atrial sites fire impulses in a random fashion, creating many uncoordinated contractions.

Heart beat:

120-180 bpm

erratic, ineffective and rapid


Introduction Interleukin-11

Atrial Fibrillation (AF)

The most common arrhythmic disorder


Introduction Interleukin-11

Atrial Fibrillation (AF)

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 Interleukin-11

IL-11 Induces AF

AF

IL-11

life-threatening side-effect

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 .


The Problem Interleukin-11

IL-11 Induces AF

AF

IL-11

Major Problem!


The Problem Interleukin-11

IL-11 Induces AF

AF

IL-11

How can we allow the safe use of IL-11 anyway?


Purpose of the Project Interleukin-11

Creation of a

Mathematical Model

Output

Input

Simulating IL-11 induced AF

  • Treatment protocol- dosage & time of administration.

  • Personal characteristics of the patient.

Risk of AF (%) in a specific patient treated with IL-11


Purpose of the Project Interleukin-11

Creation of a

Mathematical Model

Simulating IL-11 induced AF

  • Phases:

  • Understand the Physiological Mechanism of IL-11-induced AF.

  • Adjust the Mechanism & Write Appropriate Equations.

  • Analyze the Equations and Find Parameters.


Mathematical Model: (I) Physiological Mechanism Interleukin-11

IL-11 Induces AF: How?

IL-11

Na+ & Fluid Retention

Atrial Enlargement and Stretch

AF

Direct Effect on Kidney or Compensatory Response of Kidney (RAAS)

Activation of Stretch-Dependant Channels & Faster Depolarization


Mathematical Model: (II) Adjusting Mechanism Interleukin-11

IL-11

IL-11 Dose

IL-11 Conc. X

Na+ & Fluid Retention

Atrial Enlargement and Stretch

AF

IL-11 plasma concentration = IL-11 dosage.


Mathematical Model: (II) Adjusting Mechanism Interleukin-11

IL-11

IL-11 Dose

IL-11 Conc. X

Na+ & Fluid Retention

Atrial Enlargement and Stretch

AF

IL-11 plasma concentration = IL-11 dosage.

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 Interleukin-11

IL-11

IL-11 Dose

IL-11 Conc. X

FactorY

Na+ & Fluid Retention FR

Atrial Enlargement and Stretch

AF

IL-11 plasma concentration = IL-11 dosage.

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 Interleukin-11

IL-11

IL-11 Dose

IL-11 Conc. X

FactorY

Na+ & Fluid Retention FR

Atrial Enlargement and Stretch

AF

IL-11 plasma concentration = IL-11 dosage.

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.

Fluid Retention (or Atrial Volume) highly correlate with occurrence of AF.


Mathematical Model: (II) Adjusting Mechanism Interleukin-11

IL-11

IL-11 Dose

IL-11 Conc. X

FactorY

Na+ & Fluid Retention FR

AF

IL-11 plasma concentration = IL-11 dosage.

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.

Fluid Retention (or Atrial Volume) highly correlate with occurrence of AF.


Mathematical Model: (II) Adjusting Mechanism Interleukin-11

Personalized Parameters

IL-11

IL-11 Dose

IL-11 Conc. X

FactorY

Na+ & Fluid Retention FR

AF

Personalized Data entered:

Age

History of cardiac disorder

History of alcohol use

Obesity


Mathematical Model: (II) Writing Equations Interleukin-11

Personalized Parameters

Adm(X)

1

2

3

4

IL-11

IL-11 Dose

IL-11 Conc. X

FactorY

Na+ & Fluid Retention FR

AF

1

2

3

4


Mathematical Model: (III) Analysis of Equations and Parameters

Deriving the Analytical Solutions:

How

How?

X (t)

1

Y (t)

2

FR (t)

3

4


Mathematical Model: (III) Analysis of Equations and Parameters

1

Initial Dose of IL-11 is known

Day (0,1,2…)


Mathematical Model: (III) Analysis of Equations and Parameters

2

Values of   m X1/2are unknown!


Mathematical Model: (III) Analysis of Equations and Parameters

3

First Phase: Linear

We want to find the parameters of A so that A and B are close

Solution: Curve fitting (Aspire H to a minimal value)

A

B

0

H = (A – B)2


Mathematical Model: (III) Analysis of Equations and Parameters

To find minimum of H we use a numerical method:

SteepestDescentMethod

X(n+1) = X(n) -   f (X(n))

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 reaches minimum value!

H

Iterations

Parameter values of Y(t) are:


Mathematical Model: (III) Analysis of Equations and Parameters

First Phase: Linear

We found parameters- function is known!

Defined by normal plasma volume- 5.5 L

Later Phase: Unknown

Not enough data - we cannot use interpolation to define FR(t).

We remain only with linear equation.


Mathematical Model: Achievements (III) Analysis of Equations and Parameters

Deriving the Analytical Solutions:

1

2

3

X (t)

Y (t)

FR (t)

Future studies will allow us to create a more complete and accurate model…


In Conclusion (III) Analysis of Equations and Parameters

DISEASE

TREATMENT

Cancer

Chemotherapy

Chemotherapy-Induced Thrombocytopenia

Interleukin-11

Mathematical Model

for IL-11 induced AF

AF


We wish to thank the following people for their contribution to the project:

Prof. Zvia Agur Dr. Hila Harpak Yuri Kheiffez

Dr. Ron Unger Dr. Yehudit Sonn Dr. Nethaniel Horowitz Dr. Yitzhak Kehatt Prof. Amir Pelleg

תודה על ההקשבה ...


References to the project:

  • Age-dependent atrial remodeling induced by recombinant human interleukin-11: implications for atrial flutter/fibrillation. Jiang Xu, 2002.

  • A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Tepler I, 1996.

  • A phase I trial of recombinant human interleukin-11 (neumega rhIL-11 growth factor) in women with breast cancer receiving chemotherapy. Gordon MS, 1996.

  • Tolerability and side-effect profile of rhIL-11. Smith J.

  • Hematopoietic, immunomodulatory and epithelial effects of interleukin-11. Shwertzshlag US, 1999.

  • Mechanism and amelioration of recombinant human interleukin-11 (rhIL-11)-induced anemia in healthysubjects. Dykstra KH, 2000.

  • Pharmacokinetics of [125I]-recombinant human interleukin-11: 1. Absorption, distribution and excretion after subcutaneous administration to male rats. Uchida T, 1998.

  • Pharmaco-economic analysis of oprelvekin solid tumor patients receiving chemotherapy. Scott B. Cantor, Ph.D.


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