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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:

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Modeling the Atrial Fibrillation Side Effects of Interleukin-11

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  1. 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

  2. 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?

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. IL-11

  8. Introduction Interleukin 11 (IL-11) Succeeds in elevating platelet count! So what’s the catch? Great Solution!

  9. 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%)

  10. 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%)

  11. 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

  12. 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

  13. Introduction Atrial Fibrillation (AF) The most common arrhythmic disorder

  14. 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.

  15. 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 .

  16. The Problem IL-11 Induces AF AF IL-11 Major Problem!

  17. The Problem IL-11 Induces AF AF IL-11 How can we allow the safe use of IL-11 anyway?

  18. 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

  19. 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.

  20. 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

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 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.

  26. 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

  27. 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

  28. Mathematical Model: (III) Analysis of Equations and Parameters Deriving the Analytical Solutions: How How? X (t) 1 Y (t) 2 FR (t) 3 4

  29. Mathematical Model: (III) Analysis of Equations and Parameters 1 Initial Dose of IL-11 is known Day (0,1,2…)

  30. Mathematical Model: (III) Analysis of Equations and Parameters 2 Values of   m X1/2are unknown!

  31. 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

  32. 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.

  33. Mathematical Model: (III) Analysis of Equations and Parameters H reaches minimum value! H Iterations Parameter values of Y(t) are:

  34. 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.

  35. 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…

  36. In Conclusion DISEASE TREATMENT Cancer Chemotherapy Chemotherapy-Induced Thrombocytopenia Interleukin-11 Mathematical Model for IL-11 induced AF AF

  37. 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 ...

  38. 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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