1. CIRCULAT IN CHRONIC ISCHEMIC HEART DISEASE

3. Genetic Modulator

5. Pennsylvania State University, 2007 Faculty of Medicine 187 modulated genes with Circulat August, 2007 STUDY

6. Evaluation of the changes in the genetic expression after CIRCULAT Objective: To reveal the underlying molecular mechanisms to the biological activity of the Circulat .

7. Gene Expression

11. CIRCULAT: Gene expression modulator

14. Results Stable Angina Pectoris Estudio realizado en 83 pacientes Mejoría significativa 85%

15. Male, 64 years: evolution ‘years’ After 6 month treatment Clinical Outcomes of Diabetic Foot Management with Circulat (Example of Study’s photographic evidence)

16. Female, 61 years, evolution ‘months’ After 6 months treatment Diabetic Foot

17. Male, 58 years, evolution 6 months Diabetic Foot After 4 months’ treatment

18. After 2 1/2 months of treatment Male, 56 years, evolution “years” Diabetic Foot

19. After 9 months of treatment Female, 65 years, evolution 15 days Diabetic Foot

20. After 3 months of treatment Female, 59 years, evolution 7 months Diabetic Foot

21. Female, 67 years, evolution 2 years. After 7 months of treatment Diabetic Foot

22. Female, 61 years, evolution “months” After 6 months of treatment Diabetic Foot

23. After 2 months of treatment Female, 49 years, evolution 1 year Diabetic Foot

24. After 9 months of treatment Male, 44 years, evolution 1 month Diabetic Foot

25. After 2 months of treatment Male, 46 years, evolution 4 months. Diabetic Foot

26. Male, 62 years. Evolution“years” After 1 months of treatment Diabetic Foot

27. Female, 47 years. Evolution “months” After 4 months of treatment Diabetic Foot

28. Female, 79 years: evolution 2 years After 6 year treatment Photographic Evidence Varicose Ulcer

29. Female, 42 years: evolution 14 months After 5 month treatment Photographic Evidence Varicose Ulcer

30. Female, evolution 30 years Photographic Evidence Varicose Ulcer After 7 month treatment After 1 month treatment

31. Male, evolution 1 years Photographic Evidence Varicose Ulcer After 2 month’s treatment

32. Photographic Evidence Varicose Ulcer Before After

33. Photographic Evidence Varicose Ulcer Before After

34. CMA Lecherías H.C. 22728 Dra. Luz Méndez Photographic Evidence Arterial Ulcer Before After

35. CMA Sta Mónica HC: 4097 Dra.. Gladys Vargas Photographic Evidence Arterial Ulcer Before After

36. CMA Lechería H.C. 22.970 Dra.. Luz Méndez Photographic Evidence Arterial Ulcer Before After

37. CMA Lechería H.C. 26629 Dra. Luz Méndez Photographic Evidence Varicose Ulcer Before After

38. CMA SabanaGrande H.C: 57.394 Dra.: Runi Molina Photographic Evidence Varicose Ulcer Before After

39. CMA Sabana Grande H.C. 30.195 Dra. Runi Molina Photographic Evidence Varicose Ulcer Before After

40. CMA Barquisimeto H.C. 28.212 Dr. Rolando Sequera Photographic Evidence Varicose Ulcer Before After

41. CMA Lechería H.C. 26.213 Dra. Magaly Tinoco Photographic Evidence Varicose Ulcer Before After

42. CMA Lechería H.C. 18970 Dr. Nerio Villalobos Photographic Evidence Varicose Ulcer Before After

43. CMA Lechería H.C. 19.121 Dra. Mª Osorio Photographic Evidence Varicose Ulcer Before After

44. CMA Lechería H.C. 12.316 Dr. Wilfredo Sánchez Photographic Evidence Varicose Ulcer Before After

45. CMA Sabana Grande H.C. 57.943 Dra. Edith González Photographic Evidence Varicose Ulcer Before After

46. CIRCULAT Study in Chronic Ischemic Heart Disease Patrick J. Lynch, 2006

47. Background: Endothelial Damage NORMAL ARTERY ATHEROSCLEROTIC PLAQUE NARROWED ARTERY ENDOTHELIUM SMOOTH MUSCLE SMOOTH MUSCLE CELLS MACROPHAGES TRANSFORMED INTO FOAM CELLS LIPIDS, CALCIUM CELLULAR DEBRIS FIBROUS CAP. ENDOTHELIUM DAMAGE ENDOTHELIAL DYSFUNCTION MECHANICAL STREESS HYPERTENSION VASOCONSTRICTION PERIPHERAL VASCULAR RESISTANCE

48. Relevant Mortality Rates in Venezuela

49. Chronic Ischemic Heart Disease GSPECT Assessment (Independant Lab) Treadmill Imaging

50. Chronic Ischemic Heart Disease GSPECT Assessment (Independant Lab) Assessment

51. GSPECT Cardio-Diagnostic Imaging (Source: www.yale.edu/imaging/) Annualized Cardiac Events Risk Treatment Implications (majority of patients) <1% risk of cardiac death and MI Risk factor modification (RFM) in addition to current regimen Low risk of cardiac death; Intermediate risk of MI Aggressive RFM/medical treatment Intermediate-to-high risk of both cardiac death/MI Catheterization (possible revascularization)/RFM Normal Mildly Normal Moderately / Severely Abnormal anterior inferior septal lat anterior inferior base apex apex lat septal base

52. Chronic Ischemic Heart Disease treatment with complex herbal formulation Study Roberto Guzmán, José Olalde, Francis Amendola, Oswaldo del Castillo Results: Good response (17 out of 20 initial patients) to therapy was observed in 85% of the patients ( p ≤ 6.104e-05; %=99.9999) as determined by Wilcoxon. No patient suffered adverse events or died during the studied period. *Results r anging between six months and one year; in first 20 out of 30 total Patients under study + + = = = One Patient Diffuse Captation Lateral Wall Qualitative 20 Patients * 3 Patients Same Perfusion Defect Quantitative One Patient Diffuse Captation Inferior Wall Qualitative 15 Patients Perfusion Defect Quantitative 3 Patients Same Captation Lateral / Inferior Wall Qualitative 17 Patients Improvement 15 Quant + 2 Qual 3 Patients No Improvement

53. Study Aditional Hightlights (1)

54. Study Aditional Hightlights (2)

55. PD%: 40 29 APR 2009 16 SEP 2009 PD%: Post–Effort Perfusion Damage Percentage GSPECT Image PD%: 35 Control 6 months Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Total 452 post-treatment 386 Time (sec) pre-treatment 66 Increase (sec) 6 month treatment Patient 1

56. PD%: 45 13 MAY 2009 28 OCT 2009 GSPECT Image PD%: 30 Control 6 months PD%: Post–Effort Perfusion Damage Percentage 7 JUL 2010 PD%: 15 One year Chronic Ischemic Heart Disease One year treatment study Funtional Capacity Time (sec) Patient unable to carry out the test due physical limitations Patient 2

57. GSPECT Image PD%: 20 20 MAY 2009 28 OCT 2009 PD%: 10 Control 6 months PD%: Post–Effort Perfusion Damage Percentage 16 JUN 2010 PD%: 10 One year Chronic Ischemic Heart Disease One year treatment study Funtional Capacity Time (sec) Total 442 post-treatment 366 Time (sec) pre-treatment 76 Increase (sec) 6 month treatment Patient 3

58. GSPECT Image PD%: 70 03 JUN 2009 11 NOV 2009 PD%: 60 Control 6 months PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Total 200 post-treatment 155 Time (sec) pre-treatment 45 Increase (sec) 6 month treatment Patient 4

59. GSPECT Image PD%: 30 06 MAY 2009 07 OCT 2009 PD%: 25 Control 6 months 09 JUL 2010 PD%: 0 One year PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease One year treatment study Funtional Capacity Time (sec) Total 615 post-treatment 486 Time (sec) pre-treatment 81 Increase (sec) 6 month treatment 48 Increase (sec) 1 year treatment Patient 5

60. GSPECT Image PD%: 30 06 MAY 2009 07 OCT 2009 PD%: 20 Control 6 months 09 JUN 2010 PD%: 20 One year PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease One year treatment study Funtional Capacity Time (sec) Total 662 post-treatment 553 Time (sec) pre-treatment 88 Increase (sec) 6 month treatment 14 Increase (sec) 1 year treatment Patient 6

61. PD%: 15 29 APR 2009 16 SEP 2009 PD%: Post–Effort Perfusion Damage Percentage GSPECT Image PD%: 15 Control 6 months Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Total 609 post-treatment 555 Time (sec) pre-treatment 54 Increase (sec) 6 month treatment Patient 7

62. PD%: 10 14 JUL 2009 11 NOV 2009 GSPECT Image PD%: 5 Control 6 months 28 JUL 2010 PD%: 5 One year PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease One year treatment study Funtional Capacity Time (sec) Total 491 post-treatment 433 Time (sec) pre-treatment 68 Increase (sec) 6 month treatment -10 Decrease (sec) 1 year treatment Patient 8

63. PD%: 20 14 JUL 2009 11 NOV 2009 PD%: 20 Control 6 months 04 AGO 2010 PD%: 20 One year PD%: Post–Effort Perfusion Damage Percentage GSPECT Image Chronic Ischemic Heart Disease One year treatment study Funtional Capacity Time (sec) Total 676 post-treatment 516 Time (sec) pre-treatment 132 Increase (sec) 6 month treatment 28 Increase (sec) 1 year treatment Patient 9

64. PD%: 60 13 MAY 2009 07 OCT 2009 GSPECT Image PD%: 35 Control 6 months 02 JUN 2010 PD%: 20 One year PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease One year treatment study Funtional Capacity Time (sec) Total 428 post-treatment 339 Time (sec) pre-treatment 89 Increase (sec) 6 month treatment Patient 10

65. PD%: 25 12 AGO 2009 08 DEC 2009 PD%: Post–Effort Perfusion Damage Percentage GSPECT Image PD%: 15 Control 6 months Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Total 373 post-treatment 323 Time (sec) pre-treatment 50 Increase (sec) 6 month treatment Patient 11

66. PD%: 15 14 JUL 2009 02 DEC 2009 GSPECT Image PD%: 0 Control 6 months 04 AGO 2010 PD%: 0 One year PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease One year treatment study Funtional Capacity Time (sec) Total 570 post-treatment 432 Time (sec) pre-treatment 83 Increase (sec) 6 month treatment 55 Increase (sec) 1 year treatment Patient 12

67. PD%: 25 23 JUL 2009 02 DEC 2009 PD%: Post–Effort Perfusion Damage Percentage GSPECT Image PD%: 20 Control 6 months Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Patient unable to carry out the test due physical limitations Patient 13

68. GSPECT Image PD%: 70 11 MAR 2010 15 SEP 2010 PD%: 55 Control 6 months PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Total 235 post-treatment 209 Time (sec) pre-treatment 26 Increase (sec) 6 month treatment Patient 14

69. GSPECT Image PD%: 95 04 MAR 2010 15 SEP 2010 PD%: 90 Control 6 months PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Patient unable to carry out the test due physical limitations Patient 15

70. GSPECT Image PD%: 35 10 MAR 2010 1 SEP 2010 PD%: 35 Control 6 months PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Patient unable to carry out the test due physical limitations Patient 16 * * Slight Qualitative Perfusion Improvement determined by diffuse radioisotope captation in lateral wall

71. GSPECT Image PD%: 50 17 MAR 2010 15 SEP 2010 PD%: 35 Control 6 months PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Total 254 post-treatment 333 Time (sec) pre-treatment -79 Decrease (sec) 6 month treatment Patient 17

72. GSPECT Image PD%: 50 17 MAR 2010 06 SEP 2010 PD%: 35 Control 6 months PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Total 549 post-treatment 479 Time (sec) pre-treatment 70 Increase (sec) 6 month treatment Patient 18

73. GSPECT Image PD%: 45 03 MAR 2010 01 SEP 2010 PD%: 45 Control 6 months PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Total 620 post-treatment 610 Time (sec) pre-treatment 10 Increase (sec) 6 month treatment Patient 19 * * Important Qualitative Perfusion Improvement determined by diffuse radioisotope captation in inferior wall

74. GSPECT Image PD%: 15 10 MAR 2010 15 SEP 2010 PD%: 15 Control 6 months PD%: Post–Effort Perfusion Damage Percentage Chronic Ischemic Heart Disease Six month treatment study Funtional Capacity Time (sec) Patient unable to carry out the test due physical limitations Patient 20

75. Cardiac Stent Alternatives: Associated Risk

76. Stem cells: Future Alternative ?

77. CIRCULAT IP Protection USA Patent: Circulatory Disorders and Diabetes Russian Patent: Method of elaboration; Circulatory Disorders and Diabetes Mexican Patent: Circulatory Disorders and Diabetes 17 International patents (12/USA; 4/Russia; 1/Mexico)

78. Early results in the administration of CIRCULAT have shown it to be therapeutically efficacious, accessible and safe in the treatment of chronic ischemic heart disease. Evidence of CIRCULAT’s efficacy was determined by state-of-the-art Gamma Single Photon Emission Computerized Tomography (GSPECT) images. CIRCULAT is the only known orally administered treatment capable of obtaining myocardial reperfusion in chronic ischemic heart disease. Conclusions

80. Description of Circulat

82. Potential Synergetic Contribution Potential Synergetic Contribution (SC) Number of active principles (n) The synergetic potential of a complex herbal formulation -such as CIRCULAT- is provided by the interactions of the active principles present in each phytoceutical and can be mathematically expressed by SC value below.

83. US FREE SALES CERTIFICATE

86. VENEZUELAN PHARMACOPEIA

87. GUIA SPILVA - CIRCUFORTE

88. VENEZUELAN FDA CERTIFICATION AS A NATURAL MEDICINE

92. Origin & Philosophical Background

94. Circulat 187 genes I 52 E 44 O 14 45 Organization Fraction Intelligence Fraction Common to 2 or 3 Fractions Energy Fraction CIRCULAT’s Synergistic -Gene Modulating- Capacity The formulation modulates 32 additional genes than the sum of formulas’ individual fractions + + + = modulates 155 genes ∑ = modulates 187 genes; while ( )

95. International Publications e CAM: Part I, II and III. Systemic Theory & Systemic Medicine (2005). e CAM: Part IV. The Praxis (2005). Investigación Clínica Sept. 2005 (vol. 46, sup. 2). Phytotherapy Research: Gene Expression (2 007). Phytotherapy Research: Diabetic Foot (2008). Phytopharm 2010 (Abstracts Book) Ischemic Cardiopathy.