CLINICAL TRIAL

CARDIOVASCULAR DISEASES

The clinical trial for cardiovascular diseases was conducted at the Department of Cardiology, Dr. Saiful Anwar General Hospital-Brawijaya University, School of Medicine, Malang, East Java, Indonesia in 2015 with Prof. H. Djanggan Sargowo, MD., Ph.D., FACC, FESC, FAPSC as Chief Investigator.

SUBJECTS

This clinical trial is using a true experimental study research method with pre-test and post-test design that recruited:

  • 35 Stable Angina Pectoris subjects
  • 37 High-risk heart disease subjects, according to Framingham Risk Score > 20

AGE

Average age of the subjects was 65 years.

DOSAGE & DURATION

Dosage       : 3×1 capsule/day

Duration   : 90 days*

*as an adjuvant therapy to the standard therapy that was regularly administered by subjects in accordance to their needs.


BIOMARKERS

The biomarkers measured during the pretest and post test:

  1. Inflammation: Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), and C-Reactive Protein (CRP)
  2. Oxidative Stress: Malondialdehyde (MDA) and Superoxide Dismutase (SOD)
  3. Lipid Profile: Total Cholesterol (TC), Triglycerides (TG), Low-density Lipoprotein (LDL) and High-density Lipoprotein (HDL)
  4. Endothelial Dysfunction: Circulating Endothelial Cell (CEC) and Endothelial  Progenitor Cell (EPC)
  5. Diabetes: Glycated Hemoglobin (HbA1c).

Clinical Trial Results

Effect of PsP Administration on Inflammatory Biomarkers, i.e. IL-6, TNF-α and CRP

Atherosclerosis in Angina Pectoris involves a chronic inflammatory process that occurs at every stage of atherosclerosis. Therefore, measurements of TNF-α, CRP, and IL-6 levels  as inflammatory biomarker were performed to determine the effect of PsP on the inflammatory process.

Figure 1. Effect of PsP Administration on IL-6 Levels in Groups of Patients with Stable Angina Pectoris and High-Risk Cardiovascular Disease


Figure 2. Effect of PsP Administration on TNF-α and CRP Levels in Groups of Patients with Stable Angina Pectoris and High-Risk Cardiovascular Disease

Biomarker measurements after 90 days of the use of PsP as an adjuvant therapy to the standard therapy demonstrated a significant decrease of IL-6, TNF-α, and CRP levels. Thus, PsP does act as anti-inflammatory agent in suppressing atherosclerosis progress.

Effect of PsP Administration on Oxidative Stress, i.e. MDA, SODs and NO

Parameters of oxidative stress measurement are MDA, SODs and NO. MDA and NO are biomarkers that indicate the presence of lipid peroxidation by Reactive Oxygen Species (ROS), while SODs performs in suppressing oxidative stress by catalyzing the reaction of superoxide anion (O2–) dismutation into hydrogen peroxide.

Figure 3. Effect of PsP Administration on MDA, SODs and NO Levels in Groups of Patients with Stable Angina Pectoris and High-Risk Cardiovascular Disease

Biomarker measurements after 90 days of the use of PsP as an adjuvant therapy to the standard therapy showed adjustments on the following values:

  • a decrease in the MDA level
  • an increase in the SODs level
  • a decrease in the NO level compared to prior to PsP administration.

This data suggests that oxidative stress is suppressed by PsP administration.

Effect of PsP Administration on Lipid Profiles, i.e. TC, LDL, TG and HDL

In this clinical trial the lipid biomarkers were measured to discover about the condition of dyslipidemia, which has an important role in the increase of heart disease risk through high levels of  LDL and TG, and low HDL levels.

Figure 4. Effect of PsP Administration on Total Cholesterol and LDL Levels in Groups of Patients with Stable Angina Pectoris and High-Risk Cardiovascular Disease

Figure 5. Effect of PsP Administration on TG and HDL Levels in Groups of Patients with Stable Angina Pectoris and High-Risk Cardiovascular Disease

Biomarker measurement after 90 days of the use of PsP as an adjuvant therapy to the standard therapy showed adjustments on the following values:

  • a decrease in Total cholesterol, LDL and TG levels
  • no increase in HDL level

Thus, PsP may help improve the condition of dyslipidemia.

Effect of  PsP Administration on the Endothelial Dysfunction Biomarkers, i.e., CECs and EPCs

Endothelial dysfunction biomarkers measured during this clinical trial were:

  • Circulating Endothelial Cells (CECs)
  • Endothelial Progenitor Cells (EPCs)

The CEC counts in patients with acute coronary syndromes correlate with endothelial dysfunction and with the prothrombotic state, hence, CECs can act as a blood-based biomarker of cardiovascular diseases. CECs are considered to reflect the occurrence of endothelial defects and vascular disruption, and serve as a biomarker that answers to both diagnostic and prognostic needs. CECs are rarely found in normal healthy individuals, in the order of < 3 cells/ml.

In parallel is the hypothesis that EPCs are restorative/regenerative cells, possible destined to replace/renew damaged areas of the intima.

Thus it can be concluded that CECs is a biomarker of vascular damage. High levels of CECs indicate endothelial damage whereas EPCs is a vascular repair biomarker.

Figure 6. Effect of PsP administration on CECs and EPCs levels in Groups of Patients with Stable Angina Pectoris and High-Risk Cardiovascular Disease CECs

The significant reduction of  CEC in this study, for both high risk and stable angina patients suggest the improvement of endothelial dysfunction in atherosclerosis after PsP administration.


The decreased numbers of CECs indicate an improvement in endothelial cells; therefore, in cases of increase of CECs numbers such as in cardiovascular disease and its risk factors, i.e. unstable angina, acute myocardial infarction, stroke, diabetes mellitus, critical limb ischemia, a decrease in the number of CECs is expected to happen.

This study results shows a significant reduce of CEC but also EPC. As the CEC is reduced, so there is minimal detachment of endothel and injury in endothelial cells, suggesting that the endothelial cells do not need high turnover rate to maintain vessel homeostasis, and will not induce the mobilization of EPC. In myocardial infarction, EPC markedly increased with peak values on day 7, and returned to baseline within 60 days.


Since this study was only 90 days, the significant reduction of EPC remains a debate whether because of the minimal endothelial injury that was not enough to induce EPC mobilization, or decreasing EPC mobilization due to effect of β-glucan. Whereas, the research of  Hristov M. et al., states that within 3 – 4 weeks EPCs have formed monolayers with endothelial appearance.

Thus, PsP administration does improve endothelial function by its antioxidant effects.

Effect of PsP Administration on Diabetes Mellitus HbA1C Biomarker Profile

In this clinical trial one of the biomarker profiles of Diabetes Mellitus, Glycated (Glycosylated) Hemoglobin, known as HbA1c, was also measured. The HbA1c represents blood glucose levels that react with the 120 day old hemoglobin of red blood cells. Increased levels of glycated hemoglobin has been associated with cardiovascular disease, nephropathy, and retinopathy in diabetes mellitus.

Figure 7. Effect of PsP administration on Diabetes Mellitus HbA1C biomarker profile in Group of Patients with Stable Angina Pectoris and High-Risk Cardiovascular Disease

Biomarker measurements after 90 days of PsP administration to the standard therapy showed that:
PsP was able to decrease the HbA1c level in both groups of study subjects, i.e. groups of patients with Stable Angina Pectoris and High Risk Heart Diseases.

Decreased number of CECs and decreased in HbA1c levels prove that PsP may be administered by Diabetes Mellitus patients to prevent further vascular complications.

Conclusion

This clinical trial concludes that:
PsP can be used as secondary preventive therapy for patients with Stable Angina Pectoris and as primary preventative therapy for patients with High Risk Heart Disease (according to the Framingham Risk Score > 20).