Final Study Report of the 30-day placebo controlled study of Quell-Gel Softgels, a proprietary formula containing vitamin D3, turmeric extract, omega 3 rich fish oil, GLA, tocotrienols, hydroxytyrosol, astaxanthin, potassium and organic hemp seed oil.


Quell-Gel Softgels provided by Tishcon Corp., Westbury, NY, contain in the 4 softgel daily dose, vitamin D3 (as cholecalciferol) 100mcg, potassium 51mg, curcuminoids-cyclodextrin complex (cava curcumin®; curcuma longa rhizome) 2000mg, fish oil concentrate (TG; Epax®) 1700mg- EPA (TG) 900mg and DHA (TG) 200mg, other omega-3’s 250mg, total omega-3 (TG) 1350mg, gamma linoleic acid (Sonova®)-400) 38mg, mixed tocotrienols (Evnol™) 50mg, hydroxytyrosol (HT Essence®) 25mg, astaxanthin (Natural; AstaZine®) 12mg, organic hemp seed oil 56mg. Participants were advised to take four Quell-Gel Softgels daily with meals.

 

Abstract:

Background: Inflammation plays a key role and an early step in the pathogenesis of endothelial function, thereby increasing the risk of cardiovascular disease(CVD). We assessed the efficacy for improving cardiovascular health (blood pressure, inflammation and endothelial reactivity) over a 4-week intervention period in individuals with Pre-Hypertension.

Methods: We performed a double-blinded, placebo-controlled, randomized clinical trial to investigate cardiovascular effects of Quell-Gel Softgels with 80 individuals (30 men and 50 women). The mean age of participants was 48.8 + 16.0 years. Participants were enrolled and randomized to Quell-Gel or placebo and followed for 4 weeks.  Paired and Independent T-tests were used to analyze the mean differences between and within groups. Repeated Measures ANOVA with Pairwise comparisons using Tukey's test was used to analyze the effect of Quell-Gel on blood pressure (BP) changes among genders in both groups.

Results: The primary endpoints of the study were the effect on inflammatory markers (IL-6, CRP) at 4 weeks, endothelial function and blood pressure. There was a significant reduction in mean SBP at 4 weeks in the Quell-Gel group compared to baseline [mean±SD 4.7 + 6.8 (p=0.002)]. Relative to placebo, Quell-Gel subjects showed a significant decrease in High sensitivity C Reactive Protein (hsCRP) (-0.49±1.9 vs + 0.51±2.5, p=0.059).  EPA Levels and the Omega3 fatty acid (FA) index significantly increased in the active treatment relative to the placebo group, (+16.75 ±15.4 vs + 0.67±8.75, p<=0.001). The study also demonstrated a blunted increase in IL-6 in those taking Quell-Gel (+0.2 vs +0.4 in placebo, p=0.60).

Conclusion: Inflammatory markers were reduced or blunted by Quell-Gel Softgels, with a robust increase in both EPA levels and the fatty acid index.  Furthermore, systolic BP was reduced by Quell-Gel Softgels over 4 weeks with concurrent improvement in endothelial function.

 


Introduction:

Coronary artery disease (CAD) is the leading cause of mortality in developed countries, accounting for approximately 43.2% of all deaths in US (1).  Inflammation plays a key role in the pathogenesis of atherosclerosis by causing endothelial dysfunction, which is an earliest vascular anomaly. Oxidative stress and local hypoxia lead to inflammation by the generation of oxygen free radicals which decreases the bioavailability of nitric oxide (NO) leading to the endothelial dysfunction. (2) In pre-hypertensive and metabolic syndrome, which includes obesity, hyperlipidemia, and impaired glucose intolerance, lowering inflammation has been shown to substantially reduce the risk of developing CVD. (3).

It is estimated that 20–50% of the European population use complementary or alternative therapy to treat disease or to help prevent its onset (4). In Britain, approximately 40% of general practitioners provide complementary therapies for their patients (5). Recent studies have shown that supplemental foods reported having anti-inflammatory and anti-oxidant effects (6, 7,8,9). The Mediterranean diet contains high nutrient contents of antioxidant polyphenols, vitamins, omega 3 (EPA) and omega 6 fatty acids, and carotenoids which reduces the risk of CVD (7). Omega- 3 {Eicosapentaneoic acid (EPA)} and omega-6 {gamma-linoleic acid (GLA)}, rich in vegetable oils, help reduce inflammation (7). Curcumin, a yellow pigment substance, which is an active ingredient of turmeric (Curcuma longa) exhibits anti-inflammatory activity by regulating a number of different molecules that play a role in inflammation like transcription factors, cytokines, protein kinases, adhesion molecules, and enzymes. (8) Astaxanthin is a ketocarotenoid, an antioxidant rich in salmon and shrimp, which protects cells from damage improving the immune system functions and helps to balance free radicals to reduce oxidative stress. (9) Early research suggests that taking astaxanthin by mouth reduces blood fats called triglycerides and increases high-density lipoprotein (HDL or "good") cholesterol in people with high cholesterol (9).  Dietary intake to promote vegetable consumption via such initiatives is challenging because compliance with these diets is poor. In a 3 month randomized, intervention study, only 21% of participants achieved a suitable daily consumption of fruit and vegetables after dietary counseling. This poor adherence is related, in part, to the time required to prepare these foods and/or the cost implications (10). Although convenient vegetable juices are readily available on the market, those were avoided due to their cost and undesired taste. Hence, there is a need for inexpensive dietary supplements which makes easy consumption and adherence to the supplements. Dietary supplements like aged garlic extract have been known to reduce the risk of CVD, including endothelial function, blood pressure, and cholesterol (11). Although previous studies have demonstrated the anti-inflammatory effect of supplement food, their role in improving the endothelial function thereby blood pressure is unclear. This current study investigates whether complex of Curcuminoids, EPA, Astaxanthin, and GLA (Quell-Gel Softgels) supplementation improves inflammation, endothelial function and blood pressure.  This combination could decrease risk of CVD by downregulating the inflammation in pre-hypertensive individuals and those at risk of becoming hypertensive.


Methods: 

Study population and randomization: 

Our study is a randomized placebo-controlled single center double-blinded study. The research study is approved by the Institutional Review Board (IRB) of the Los Angeles Biomedical Research Institute at Harbor- UCLA Medical Center. 80 patients (Figure 1) were enrolled in the study after obtaining informed consent. We enrolled patients between age 18-75 years who have BP 121-140/81-90 mm Hg on average and Body Mass Index (BMI) 18-40. Participants were followed for 4weeks.

Exclusion criteria: We excluded patients who had chronic diseases including cancer or rheumatologic disorders, weight in excess of 350 pounds, bleeding disorder, any history of myocardial infarction or all types of revascularization procedures, second or third degree heart block with or without a pacemaker, angina pectoris of any type, concurrent potentially life-threatening arrhythmia or symptomatic arrhythmia, clinically significant valvular heart disease, history of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, (with the exception of localized basal cell carcinoma of the skin) serum creatinine > 2.0 mg/dl, or concurrent enrollment in another placebo-controlled trial.

Evaluation of Cardiovascular risk factors: In all subjects, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded after resting for 5 minutes with back support, feet flat, and arm bared at heart level. Subjects were instructed to abstain from smoking, alcohol, use of mouthwash, and to fast at least 12 hours before sample drawing. Venous blood samples of all patients were drawn after admission in a fasting state. Outcomes were measured at baseline and 4 weeks, which includes testing blood pressure, endothelial function, EPA, Omega 3 and Omega 6 FA indexes, IL-6 and CRP.

Measurement of Brachial flow-mediated dilatation (bFMD): Endothelial function was assessed non-invasively by Flow-Mediated Dilatation (FMD) which reflects changes in the brachial artery diameter after regional ischemia by a trained technician who was blinded to the treatment allocation. The diameter of the brachial artery is measured by high-resolution external vascular ultrasound (UNEXEF18G, Unex Co Ltd, Nagoya, Japan) using a 10-MHz linear-array transducer) in response to an increase in blood flow, (causing shear-stress) during reactive hyperemia (induced by cuff inflation and then deflation). This leads to endothelium-dependent dilatation. The artery is scanned and the diameter measured during these conditions; at baseline, and during reactive hyperemia. Hyperemia is induced by inflation and then deflation of a sphygmomanometer cuff around the limb, distal to the scanned part of the artery.  The time required to obtain a high-quality baseline scan varies between 1 and 10 min. The cuff inflation period of 5 min was initially decided to produce adequate hyperemia to allow flow-mediated dilatation, but not to compromise patient comfort. Shorter inflation periods do not seem to produce significant flow-mediated dilatation. The usual scanning period used in our laboratory is 30 seconds before and 2min after the cuff deflation. FMD was calculated as the percentage change of the arterial diameter from baseline to maximum dilation. bFMD is measured at baseline, and at 4 weeks.

Quell-Gel therapy information:

Quell-Gel Softgels were provided by Tishcon, Westbury, NY\. Contained in 4 softgels:

1.Cavacurcumin (Wacker)- 2000mg,

2.Astaxanthin  - 12mg ( Astazine)

3.Omega 3 – 1350mg,

4.Gamma Lionoleic acid -38mg GLA,

5.Tocotrienols – 50mg Tocotrienols,

6. Hydroxy Tyrosol (Wacker)- 25mg Hydroxy Tyrosol,

7.Vitamin D3- 100mcg,

8.Potassium 51mg.

 

Statistical analysis:  Continuous normally distributed data were expressed as means + SDs. Within each group (i.e. Quell-Gel Solftgels and placebo), changes in BP, bFMD and inflammatory markers (IL-6 and CRP) from baseline values were analyzed by paired and unpaired students t test. EPA, Omega 3 and Omega 6 fatty acid indexes between groups and between baseline and follow-up were assessed with paired and independent t tests. A value of P < 0.05 was considered statistically significant. All statistical analyses were performed with SAS 9.4 software.

 

Results:  Eighty Participants (30 men and 50 women; mean age of 48.8 + 16.0 years) completed baseline and 4 weeks visit, where baseline and follow-up blood pressure indexes were assessed

(Table 1).  Of 80 patients, 40 were randomized into the active group and 40 into the placebo group. There were 24 females in each group. 4 patients were lost to follow-ups among 80 patients. (Figure 1)

There was a significant reduction in mean SBP at 4 weeks in Quell-Gel group compared to baseline [mean ± SD 4.7 + 6.8 (p=0.002)]. (Table 2).  

Relative to placebo, Quell-Gel Group subjects showed a significant decrease in High sensitivity C Reactive Protein (hsCRP) (-0.49±1.9 vs + 0.51±2.5, p=0.059). (Table 3A) The study also demonstrated a blunted increase in interleukin-6 (IL-6) in those taking Quell-Gel (+0.2 vs +0.4 in placebo, p=0.60). (Table 3A).  EPA Levels and the Omega3 fatty acid (FA) index significantly increased in the active treatment relative to the placebo group, (+16.75 ±15.4 vs + 0.67±8.75, p<=0.001). (Table 3B).

There was a significant increase of 0.605+/- 3.30 in FMD among Quell-Gel subjects as compared to a decrease of -0.459+/- 2.40 in the placebo, p=0.03 (Table 4).

 

 

Discussion: 

Our study demonstrates a significant reduction in SBP by improving the endothelial function measured by bFMD.  Inflammation is a result of major consequences of RAS imbalance and oxidative stress which leads to vascular remodeling and endothelial dysfunction. Due to this remodeling, Angiotensin II (AT1) receptor level increases the production of cell adhesion and accumulation of monocytes, which transform into macrophages and foam cells. These secrete inflammatory markers (IL6, CRP), which promotes vascular remodeling (2). Thus, inflammation takes part in the system engaged with the pathophysiology of hypertension, and consequently increases the risk of CAD (Figure 2).

C-reactive protein (CRP), an acute phase reactant which reflects the stages of inflammation, is an independent risk factor in CVD. CRP induces the synthesis of plasminogen activator inhibitor- 1 (PAI-1) and known to be actively involved in thrombosis during the atherosclerotic process. (19) One of the recent studies demonstrates that monocytes exhibit increased production of IL-6 in response to CRP (17). In healthy individuals, high levels of circulatory IL-6 are at increased risk of development and progression of ischemic heart disease (IHD). (18)  CRP, IL6 and its biomarkers have diagnostic and prognostic values in CVD. Our current study demonstrated the rise in interleukin-6 (IL-6) was slowed with Quell-Gel, and CRP changed significantly in the active group.

Omega 3 FA are rich in salmon, tuna, walnuts, soyabeans, tofu, flaxseed and vegetable oils. The diet rich in EPA consumption has been associated with improved cardiovascular function in terms of anti-inflammatory properties, improving endothelial function and its antithrombotic properties reduces major coronary events, peripheral artery disease. (22) EPA and Omega 3 FA index contribute to protective actions towards athero Quell-Gel sclerosis and cardiovascular health by reducing or blunting the inflammatory markers by Quell-Gel over 4 weeks.

One basic etiology for arterial wall alterations is oxidative stress, an imbalance between free radicals and anti-oxidants which leads to decreasing the bioavailability of Arginine, Adenosine Tri-Phosphate (ATP) and Nitric oxide (NO) and ultimately resulting in endothelial dysfunction and atherosclerosis (13,14,15,16). Endothelial dysfunction is characterized by reduced vasodilation, a proinflammatory state, and prothrombic properties, which increases the risk of CVD, such as hypertension, coronary artery disease, chronic heart failure, peripheral artery disease, diabetes, and chronic renal failure. (21) A recent study presented that endothelial dysfunction, which was measured by bFMD, is a strong and independent predictor of CAD (20). Several prospective studies have suggested that vitamin D deficiency increases the risk of hypertension and ischemic heart disease.  In our current study, endothelial function is improved in patients who received Quell-Gel Softgels with Vitamin D and Omega-3, and thereby SBP improved as well. High SBP strongly correlates to CVD risk and a reduced life expectancy (4,5,12). In pre-hypertensive and metabolic syndrome patients, lowering hypertension substantially reduces the risk of developing cardiovascular diseases. Together, these findings validate that Quell-Gel Softgels with Vitamin D and antioxidants like tocotrienols, and hydroxytyrosol exhibits an anti-inflammatory effect by downregulating the inflammatory markers (IL6, CRP).  This in turn improves endothelial function and blood pressure across the 4-week treatment period. Such observations highlight the importance and growing need for accessible and effective anti-inflammatory interventions.

Limitations: The current study has several limitations. First, this is a short-term follow-up study, but based on the favorable results, a longer study is warranted. Second, patients had different background dietary patterns.  There are multiple components of Quell-Gel therapy, and we were not able to assess which individual components contributed to each individual improvement in CV health.  Additional research is necessary to examine whether Quell-Gel is associated with the reduction of future cardiac events.

Conclusion: Interventions that control biological inflammation, as well as restore endothelium function, reduce blood pressure and slow down atherosclerosis are highly likely to improve long term cardiovascular health.  Such observations highlight the importance and growing need for accessible and effective nutraceutical interventions.

 

References:

1.     Heart Disease and Stroke Statistics-2019 At-a-Glance. Available from: https://healthmetrics.heart.org/wp-content/uploads/2019/02/At-A-Glance-Heart-Disease-and-Stroke-Statistics-%E2%80%93-2019.pdf

2.     Castellon X, Bogdanova V. Chronic Inflammatory Diseases and Endothelial Dysfunction. Aging Dis. 2016;7(1):81-9. Published 2016 Jan 2. doi:10.14336/AD.2015.0803

3.     Rapsomaniki et al., 2014, Jupiter, Cantos

4.     Fisher P, Ward A (1994) Medicine in Europe: complementary medicine in Europe. BMJ 309: 107–111. 2.

5.     Schmidt K, Jacobs P, Barton A (2002) Cross-cultural differences in GPs’ attitudes towards complementary and alternative medicine: a survey comparing regions of the UK and Germany. Complement Ther Med 10: 141-147

6.     Michael J. Puglisi, Maria Luz Fernandez; Modulation of C-Reactive Protein, Tumor Necrosis Factor-α, and Adiponectin by Diet, Exercise, and Weight Loss, The Journal of Nutrition, Volume 138, Issue 12, 1 December 2008, Pages 2293–2296, https://doi.org/10.3945/jn.108.097188T richopoulou Antonia, Bamia Christina, Trichopoulos Dimitrios. Anatomy of health effects of Mediterranean diet: Greek EPIC prospective cohort study BMJ 2009; 338: b2337

7.     Widmer RJ, Flammer AJ, Lerman LO, Lerman A. The Mediterranean diet, its components, and cardiovascular disease. Am J Med. 2014;128(3):229-38.

8.     Aggarwal, B.B. and Harikumar, K.B. 2009. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. The International Journal of Biochemistry & Cell Biology 41(1), pp. 40–59.

9.     Fassett RG, Coombes JS. Astaxanthin: a potential therapeutic agent in cardiovascular disease. Mar Drugs. 2011;9(3):447-65. Published 2011 Mar 21. doi:10.3390/md9030447

10.  Couch SC, Saelens BE, Levin L, et al. The efficacy of a clinic-based behavioral nutrition intervention emphasizing a DASH-type diet for adolescents with elevated blood pressure. J Pediatr. 2008; 152: 494–501.

11.  Suguru Matsumoto, Rine Nakanishi, Dong Li, Anas Alani, Panteha Rezaeian, Sach Prabhu, Jeby Abraham, Michael A Fahmy, Christopher Dailing, Ferdinand Flores, Sajad Hamal, Alexander Broersen, Pieter H Kitslaar, Matthew J Budoff; Aged Garlic Extract Reduces Low Attenuation Plaque in Coronary Arteries of Patients with Metabolic Syndrome in a Prospective Randomized Double-Blind Study, The Journal of Nutrition, Volume 146, Issue 2, 1 February 2016, Pages 427S–432S, https://doi.org/10.3945/jn.114.202424

12.  Huang AVita JAVenema RCKeaney JF Jr. Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. J Biol Chem. 2000 Jun 9;275(23):17399-406.

13.  Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, et al. (1995). Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation, 91: 2488-2496 [PubMed]

14.  Falk E (2006). Pathogenesis of atherosclerosis. J Am Coll Cardiol, 47: C7-12 [PubMed]

15.  Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MF, et al. (1999). Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest, 103: 1597-1604 [PMC free article] [PubMed]

16.  Kullo IJ, Gau GT, Tajik AJ (2000). Novel risk factors for atherosclerosis. Mayo Clin Proc, 75: 369-380 [PubMed]

17.Li JJ1, Fang CH. C-reactive protein is not only an inflammatory marker but also a direct cause of cardiovascular diseases

18. Brasier, A.R., Recinos, A. and Eledrisi, M.S. 2002. Vascular inflammation and the renin-angiotensin system. Arteriosclerosis, Thrombosis, and Vascular Biology 22(8), pp. 1257–1266.

19. Husain K, Hernandez W, Ansari RA, Ferder L. Inflammation, oxidative stress and the renin-angiotensin system in atherosclerosis. World J Biol Chem. 2015;6(3):209-17

20. Anderson, T.J., Uehata, A., Gerhard, M.D., et al. 1995. A close relation of endothelial function in the human coronary and peripheral circulations. Journal of the American College of Cardiology 26(5), pp. 1235–1241.

21. Endemann, D.H., and Schiffrin, E.L. 2004. Endothelial dysfunction. Journal of the American Society of Nephrology 15(8), pp. 1983–1992.

22. Mohebi-Nejad A, Bikdeli B. Omega-3 supplements and cardiovascular diseases. Tanaffos. 2014;13(1):6–14.

 

Quell Tables and Graphs_Page_1.jpg
Quell Tables and Graphs_Page_2.jpg
Quell Tables and Graphs_Page_3.jpg
Quell Tables and Graphs_Page_4.jpg
Quell Tables and Graphs_Page_5.jpg