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:

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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:

Prof. Zvia Agur Dr. Hila Harpak Yuri Kheiffez

IMBM


Introduction

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?


Introduction

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 (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 (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.

RBC

megakaryocyte

WBC

platelets


IL-11


Introduction

Interleukin 11 (IL-11)

Succeeds in elevating platelet count!

So what’s the catch?

Great Solution!


Introduction

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%)


Introduction

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

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

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

Atrial Fibrillation (AF)

The most common arrhythmic disorder


Introduction

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

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

IL-11 Induces AF

AF

IL-11

Major Problem!


The Problem

IL-11 Induces AF

AF

IL-11

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


Purpose of the Project

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

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

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

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

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

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

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

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

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

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

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

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

  • 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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