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Research on curcumin* continues to grow at a staggering pace with over 10,000 publications demonstrating myriad benefits including antioxidant protection, brain health, healthy inflammation and joint health, cardiovascular protection, liver function and healthy blood sugar metabolism.1 Because curcumin can modulate so many biochemical and cell signaling pathways, it has a bright future as a potent nutraceutical for condition-specific formulas provided its applications are tempered by a systematic approach that supports its benefits at every stage of product development. The importance of this cannot be overstated because of criticisms that can impact consumer perception about curcumin despite the large amount of published research showing the contrary.2 Developing a stepwise approach to research and formulation that translates into focused results targeted for consumer needs and claim substantiation is a critical step in product development. Those steps include:
1. Evaluating curcuminoid profile for efficacy is the first step
The curcumin and curcuminoids are often used interchangeably but the active compounds in turmeric are actually three curcuminoids: curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Natural turmeric powder and extracts should contain all three curcuminoids and is easily verifiable by standard analytical methods like HPLC. Adulterated or synthetic formulas would typically show up as a single peak. The approximate profile of curcuminoids found in turmeric root is 70-80% curcumin, 18-25% demethoxycurcumin, and 2-5% bisdemethoxycurcumin. Prior to conducting any research, verifying the presence and/or profile of curcuminoids is extra insurance that future clinical outcomes are successful.
2. Bioavailability and efficacy are linked so plan for it
Curcuminoids are poorly soluble in aqueous environments, which has a direct impact on bioavailability and the ability of the active compounds to reach target tissues. It is estimated that only one percent of curcuminoids are absorbed from standard powder extracts. These conditions often limit the clinical impact of curcuminoids. To compensate for this, large doses may be needed but this can reduce consumer compliance. In other words, no matter what dose is used, it may not translate into a benefit because it is not absorbed.
That’s why enhanced forms of curcumin are replacing standard forms. With the increased availability of enhanced formulas, it is important that proper analytical methods be followed and the results assessed accordingly. That means determining guidelines by which bioavailability is measured – one of the most important is establishing baseline blood levels of curcuminoids. If the dose of standard or control does not show in serum samples the dose being used is, perhaps, too low. How relevant or accurate are the findings when a rise in serum levels of curcuminoids from an enhanced formula is compared to, essentially, zero levels from standard powder? Controlling for factors that can affect the outcome is also important. Were the subjects fasted or given a meal that can affect absorption? Are they an appropriate population? Are you using proper, validated analytical methods like area under the curve (AUC) and standard pharmacokinetic measures that are commonly found in pharmaceutical models? All these factors are critical because they form the basis as to how bioavailability translates into efficacious dosages that consumers find acceptable.
Even after curcumin is absorbed, the challenge of rapid metabolism needs to be addressed. There are various schools of thought on how – and what – to measure. Is it free curcumin? Curcuminoids? Its conjugates? The reality is that the science around the metabolism of curcuminoids and their activity in the body once absorbed is still unclear. But what is known is that, despite its rapid metabolism, curcuminoids in some form are reaching the tissues where they are having some kind of functional benefit as seen in many studies. And, in the case of enhanced curcumin, those effects are greater than an equivalent dose of standard powder.
3. Build a foundation for successful human studies and product formulation
After addressing the challenges around solubility, absorption, and metabolism, a well-designed research program helps ensure focused outcomes. With curcumin’s ability to modulate so many cellular targets which are the most appropriate to help ensure successful outcomes during human studies and use for dietary supplements? Unlike drugs, that target specific pathways, curcuminoids are a complex group of moleculesthat target multiple pathways. Because curcumin shows such a broad “reactivity,” it is important to understand its cellular activity as a starting point. Curcumin research needs to follow a stepwise process to build a solid foundation for a strong formula that supports efficacy and claims.
Creating a foundation for human studies starts with nutrigenomics research – the scientific study of the interaction of nutrition and genes, especially with regard to the prevention or treatment of disease. Nutrigenomics provides insight into mechanism of action and effects on cellular targets that can provide the direction for future research and eventually finished formulas targeting specific categories.
In vivo research is the next step for establishing efficacious outcomes. Whereas nutrigenomics can provide the direction of future research, in vivo research will validate those effects seen at the cellular level that warrant further investigation. In vivo research is the link that helps to establish:
At this point, based on all the completed nutrigenomic and in vivo research, a clear direction on what to study – and how – in human clinical trials can be established. Prior to human studies it is also important to carefully consider other lifestyle or environmental factors that can affect study outcomes. For example, if study outcomes are intended to be more “universally” accepted or focused on specific lifestyle issues within a population, geography may need to be de ned. The majority of curcumin’s benefits may not be an acute effect and, therefore, the duration of the study must be considered. Dosage may vary depending on a specific condition. Finally, understanding how disease influences biomarkers – like cytokines or prostaglandins for inflammation – compared to healthy subjects and how curcumin may impact them differently is also important. All of these initiatives should use validated methods to measure and analyze that are accepted by the scientific community and regulatory agencies. All of this research prior to launching a human study provides a better understanding of the limitations and opportunities that can be leveraged to increase the likelihood of successful outcomes.
FloMeD study – An example of successful clinical outcomes based on a systematic
approach to research
OmniActive’s FloMeD study evaluated the impact of CurcuWIN on healthy circulation using flow mediated dilation* and demonstrated a 37% increase in vasodilation for improved cardiovascular health in healthy subjects.3 This improvement also translates into a reduction of cardiovascular disease risk of up to 50 percent. The results of this study were borne out of a systematic approach to research. It began with developing OmniActive’s UltraSOL system to improve solubility and bioavailability of poorly absorbed nutrients, and applying this to curcumin/turmeric extract. The result is a high bioavailable form of curcumin formulated to contain all three curcuminoids as found naturally in turmeric. In a well-controlled clinical study CurcuWIN increased relative absorption of total curcuminoids 46-times over standard curcumin and was signi cantly more bioavailable than other enhanced forms.4
Subsequent preclinical research indicated that CurcuWIN affects key markers of vascular function – endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) – and provided clues into how CurcuWIN can potentially improve vascular function. In vivo models further established indications for dose, safety and tolerability. When weaved together, all of this research and product development CurcuWIN’s signi cant impact in a healthy population at a low dose.
Curcumin has a bright future in science and supplements
Curcumin’s benefits are numerous due to its ability to target multiple cellular pathways. However, not all of its actions are relevant – maintaining curcumin’s place in the market as an effective nutraceutical requires focusing on its most promising potentials. Challenges around formulation are being addressed by the industry and establishing “guidelines” to assess bioavailability will provide meaningful results across different platforms. Despite its high metabolic conversion, we know that curcumin, and potentially its metabolites, work. Studies evaluating total curcuminoids and formulas preserving curcuminoid activity can help support their role as efficacious agents in the dietary supplement industry. To ensure healthy outcomes and build strong claims, research on curcumin should follow a stepwise process that begins with preclinical work and provides the launch point for appropriate, well designed human studies that are important to claim substantiation in the dietary industry.
* Flow mediated dilation is a process that re ects the ability of blood vessels to relax during increased blow ow and is a useful tool to assess endothelial function.
CurcuWIN and UltraSOL are trademarks of OmniActive Health Technologies, Ltd.
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©2017 OmniActive Health Technologies
This article is available in the Spring 2017 issue of Nutraceuticals Now