ZYNAMITE® under the looking glass:
We take a closer look at Nektium’s latest science based innovation
Question and Answer interview with Dr. Julia Wiebe
Research and Development Director: Nektium Pharma, Spain
Zynamite® is the latest product from your new product development pipeline and the ingredient has already won an important award. Can you briefly describe what it is and what it does?
Zynamite® is our patent-pending proprietary extract of Mangifera indica leaves (mango) and it is a highly versatile nutraceutical ingredient for the enhancement of mental and physical energy. The convergent results of our in-vitro, ex-vivo, in-vivo studies, toxicological studies and 5 double-blind, randomized placebo controlled clinical studies demonstrate that Zynamite® is not only safe and free of cardiovascular and other side-effects, but it has nootropic and ergogenic effects. The nootropic activities include enhanced mental activation, calculation performance, faster reaction time, and reduced stress and fatigue, while the sports performance activities include increased power output, brain and muscle oxygenation, and VO2max.
Why were you interested in developing a product from mango leaves and can you tell us a bit more about how your product development process unfolded for this ingredient?
Four years ago, after noting the worrying global trend of increasing adverse reactions from excessive consumption of highly caffeinated products, our R&D and innovation team began a global search for a safe and effective ingredient that could not only replace caffeine, but be superior to caffeine. The highly challenging research imperative we committed to was to develop a rapidly acting botanical extract with nootropic and sports performance activities, free of cardiovascular and other side-effects, and without addictive and tolerance potential.
We are fortunate that Dr. Nigel Gericke, a medical doctor and ethnobotanist was part of our discovery and innovation team and under his guidance we started the challenging quest for a botanical with these unique attributes. Our search involved extensive reviews of the international ethnobotanical literature, of the uses of plants in the traditions of Ayurvedic Medicine and Traditional Chinese Medicine, and reviews of Nektium’s own ethnobotanical records from European, Russian, Amazonian, and African plants.
An initial selection of fifty botanical candidates was made and reviewed in terms of safety, potential efficacy, plant chemistry, pharmacology, sustainability of supply, and cost of production among other criteria. Multivariate analysis revealed an intriguing pattern among the candidate plants, revealing that a cluster of disparate species contained appreciable concentrations of the flavone mangiferin. Since there was a well-established safe food and beverage use of leaves of the mango, Mangifera indica, which are rich in mangiferin, we decided to make a proprietary standardized extract of the leaves, and then took this special extract (M52P), which we later trademarked as Zynamite®, into pre-clinical and clinical research.
Can you briefly share the results of your pre-clinical and clinical research on Zynamite®?
We first did a Long-Term Potentiation ex-vivo study which demonstrated that Zynamite® displayed a similar Long-Term Potentiation activity to caffeine in the hippocampus of rats. This classical pharmacology indicates potential in enhancing memory and attention.
We conducted cutting edge in-vivo studies on the effect of Zynamite® on brain electrical activity (EEG) from the frontal cortex, hippocampus, striatum and reticular formation of nine rats. From this study we could conclude that bioactive compounds in Zynamite® cross the blood brain barrier to give a similar pattern of stimulation of the central nervous system to caffeine. Since Zynamite®, combined with caffeine, results in a synergistic stimulant action, we could conclude that the two have different molecular mechanisms of action, which we confirmed through receptor binding studies.
Zynamite® can thus be characterized as a novel natural nootropic that can be used to replace caffeine. The synergy of Zynamite® in combination with low doses of caffeine can also be exploited to dramatically reduce the dose of caffeine in a product. These results have been published (Dimpfel et al. 2018).
We have completed 5 RCT clinical trials in humans with Zynamite®, and a further two clinical studies on sports performance that will be concluded by the 4th quarter of 2019. Two clinical trials demonstrated the mental activation activity of Zynamite® through changes in brain cortical electrical activity (quantitative EEG) in response to cognitive challenges. We could also show improvement of reaction and exclude negative cardiovascular effects, with no changes in blood pressure or heart rate variability.
After seeing these positive CNS results we wanted to interrogate the ergogenic effect of Zynamite® in two caffeine-free patent pending formulations. Professor Jose López Calbet, one of Europe’s leading academic sports physiologists was the Principal Investigator of these randomized, double blind, placebo-controlled studies conducted at the University of Las Palmas in Spain. These studies focused on power output, oxygen consumption and cerebral oxygenation. Mean power output and peak power output, typical measures of athletic performance during exercise, were studied. The results were astounding! Zynamite® containing formulations were shown to exert a remarkable ergogenic effect in fatigued male and female subjects, increased both peak and mean power output and also increases peak VO2 (oxygen consumption) and brain oxygenation during prolonged sprinting. The results of these two studies have been published (Gelabert-Rebato, M. et al. 2018, and Gelabert-Rebato, M. et al. 2019).
That sounds like a powerful ingredient! How does it actually work in the body?
Zynamite® is a complex standardized polymolecular ingredient that acts non-selectively on multiple CNS targets to achieve its profound mental activation effect. We studied the binding and enzyme inhibition of Zynamite® on 90 CNS targets, and found that the major bioactive in Zynamite®, mangiferin, is a COMT inhibitor enhancing endogenous noradrenergic and dopaminergic signaling. Interestingly, mangiferin did not bind to adenosine receptors, or inhibit PDE4, activities found for caffeine, and contributing to adverse effects of caffeine in high doses. Interestingly, COMT-inhibitors are targets for treating addiction, as we discovered that Zynamite® does not cause dependence or tolerance. It can further be extrapolated from our ex-vivo LTP study that modulation of glutamatergic signaling plays a role, while attenuation of prominent alpha-2 wave in the in-vivo EEG supports that there is modulation of dopaminergic signaling.
Metabolomic and transcriptomic studies have shown that isolated mangiferin enhances the expression and activity of succinate dehydrogenase, leading to increased ATP production. At the transcriptional level, mangiferin induced mRNAs of mitochondrial genes and their transcriptional factors. These data suggest that mangiferin upregulates mitochondrial oxidative capacity.
So, it looks like Zynamite® works similar to caffeine but through an entirely different mechanism and doesn’t have the negative side effects of caffeine? This is an ingredient sports fanatics will love! Is it safe to use?
Yes, you’re right, we are very excited by the enormous potential of this disruptive innovation! Zynamite® does not have any negative side effects, it has a better ergogenic activity than caffeine. If we look at results for caffeine in sports performance, the increase of power output reported is around 2-4% (in those studies that showed an effect at all, some studies showed no effect) while Zynamite® improved power output 5-7% in fatigued conditions, and 11-19% in the most extreme fatigue of exercise post ischaemia-reperfusion.
We invested in two in-vivo toxicology studies on Zynamite®, a 14-day repeat dose study, and a 90-day repeat dose study with the USA company AIBMR. Both studies proved that Zynamite® did not cause adverse physical, behavioral or histological effects in rats in the highest daily doses used of 2000mg/kg bw/day. Our toxicology research has been submitted for publication. Zynamite® is also doping-free, tested for the presence of WADA-banned substances by NSF International, and is non-addictive.
What do you plan for the future of Zynamite®?
We anticipate a great future for Zynamite®. It´s an innovation with enormous potential. We expect the ingredient to be widely used in place of caffeine for its nootropic and ergogenic activities in diverse finished products by men and women of all ages. This is the perfect time for a lifestyle ingredient that can enhance mental energy, focus and concentration, and physical performance and endurance.
Nektium has invested a great deal in the research supporting the ingredient and the protection of intellectual property. In addition to trade secrets relating to the extract process, Zynamite® is protected by three international patent applications. Our strategy is to build Zynamite® into a strong, perennial evidence-based brand through continued investment in clinical studies.