Award winning innovation for increased physical and mental …€¦ · Nootropics boost cognitive...
Transcript of Award winning innovation for increased physical and mental …€¦ · Nootropics boost cognitive...
Award winning innovation for increased physical and mental energy
SCIENCE BASED NATURAL INGREDIENTS
WHITEPAPER
I. INTRODUCTION 3
II. PRECLINICAL STUDIES ON ZYNAMITE® 4
III. CLINICAL STUDIES ON ZYNAMITE® 6 SPORTS PERFORMANCE 6
MENTAL ENERGY 8
IV. REGULATORY 9
V. MANUFACTURING PROCESS 9
VI. BIBLIOGRAPHY 10
INDEX
Nektium | Zynamite® | 3
I. INTRODUCTION
Zynamite® gives sustained focus
and increases mental and physical
energy without any negative side
effects like jitters, nausea, anxiety
or increased blood pressure.
WHAT DO TIRED PEOPLE NEED?Stressed or fatigued people lack enthusiasm and mostly feel exhausted and desperate. What they desire is a sustained boost of energy that improves physical performance, concentration, attention, alertness and mood.
THE PROBLEM WITH CAFFEINEBecause of the mental energy and focus provided by caffeine, billions of cups of coffee are consumed daily to assist people to cope. However, caffeine is addictive and most people consume too much of it and suffer from its side effects and withdrawal symptoms1.
IDEAL FOR SPORTS PERFORMERSZynamite® is doping free and ideal for sports professionals or weekend warriors who are aiming to increase their physical and mental energy performance.
What is Zynamite®?
How does Zynamite® work?
Zynamite® is protected
Zynamite® is Nektium’s patent pending proprietary Mangifera indica extract standardized to ≥ 60% mangiferin.
Mangifera indica, the common mango tree, is cultivated extensively in the tropical and subtropical regions of the world. Infusions and decoctions of mango leaves are used in traditional health systems and have been known for centuries for their health benefits2,3.
Zynamite® is a COMT inhibitor that activates brain waves and increases Long-Term Potentiation in a remarkably similar pattern to caffeine4,5. While caffeine antagonizes adenosine receptors, Zynamite® acts non-selectively on multiple CNS targets to stimulate brain activity without causing side-effects.
Zynamite® is protected by 3 pending patents:
1. Compositions for Enhancing Brain Activity
2. Compositions for Reducing Craving, Enhancing Mood &
Decreasing Stress
3. Compositions for Improving Sports Performance
Zynamite®
Nektium | Zynamite® | 4
WIRELESS EEG
The Central Nervous System (CNS) activities of Zynamite® were investigated using cutting- edge neurophysiological studies including in vivo functional electroencephalogram (EEG) in four brain regions, for six brain wave frequency ranges. In collaboration with Professor Wilfried Dimpfel, Justus-Liebig University, Giessen, Germany, the EEG of Zynamite® was compared to that of caffeine. Results demonstrated that the pattern of electrical activation for both Zynamite® and caffeine are remarkably similar in the brain frontal cortex and in the hippocampus4,5. The colored bars represent the six frequency bands studied.
CNS SCREEN
Furthermore, detailed in vitro studies were performed, looking at 90 different CNS targets.
Conclusion
Zynamite® crosses the blood brain barrier and has a strikingly similar brain activity activation on EEG to caffeine.
- Zynamite® combined with caffeine has a synergistic effect.
- Zynamite® and caffeine have two have different molecular mechanisms of action.
- Zynamite® is a COMT inhibitor. COMT modulates the levels of dopamine, serotonin and nor-epinephrine.
II. PRECLINICAL STUDIES ON ZYNAMITE®
Saline
Front. cortex Hippocampus
Zynamite®
Caffeine
% frombaseline
100
80
60
100
80
60
100
Wireless EEG
CNS Screen
COMT inhibition
% Inhibition of Control Specific Binding-30 -20 -10 10 20 30 40 50 60 70 80 90 1000
C0X1 (h)
Thresholdfor a “hit”
5-lipoxygenase (h)
PDE1B (h)
PDE3A (h)
PDE5 (h) (non-selective)
phosphatase 1B (h) (PTP1B)
phosphatase CDC25A(h)
PKCα (h)
AChE (h)
COMT (h)
GABA transaminase (h)
MAO-B (h) r. enzyme
MAO-A (h)
tyrosine hydroxylase (h)
ATPase (Na+/K+) (h)
CENP-E (h)
Eg5 (h)
HDAC3 (h)
HDAC4 (h)
HDAC6 (h)
HDAC11 (h)
sirtuin 2 (h) (inhibitor e�ect)
sirtuin 1 (h) (inhibitor e�ect)
PDE4 (h)
Test Concentration: 1.0E-05 M
% In
hib
itio
n o
f C
ont
rol V
alue
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-10.0-20
-10
0
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-9.5 -9.0 -8.0 -7.5 -7.0 -6.5 -6.0 -5.5 -5.0 -4.5-8.5
Log SUP_Mn_REP_2017(M)
Top: 100Bottom: -1nH: 2.4IC50: 2.6E-6
Nektium | Zynamite® | 5
LONG-TERM POTENTIATION
The effect of Zynamite® was tested in Long-Term Potentiation (LTP) in the rat hippocampus, which is the area of the brain responsible for memory. LTP enables the brain to form memories and helps athletes to automate coordination skills6. In a study comparing the effect of Zynamite®, caffeine and the combination of Zynamite® + caffeine on LTP, Zynamite® had a greater effect on LTP than caffeine, while the combination of Zynamite® + caffeine demonstrated a remarkable synergy in increasing LTP4,5.
Conclusion
- Zynamite® increased Long-Term Potentiation more than caffeine.
- Zynamite® can increase attention, learning and memory and can thus be considered as a nootropic that can be used to completely replace caffeine or dramatically reduce the dose of caffeine in a product.
II. PRECLINICAL STUDIES ON ZYNAMITE®
TOXICOLOGY
To confirm the safety of ingestion of Zynamite®, Nektium commissioned a 90-day in vivo repeat dose oral gavage toxicity study of Zynamite®. Based on the observations made the No Observed Adverse Effect Level (NOAEL) was determined as follows. NOAEL: 2000 mg/kg bw/day.
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10 20 30 40 50 60 70 80 90 100 110 120
1
2
3
4
amplitude[mV]
time[min]
Ex-vivo
TBS
Zynamite® Zynamite®+ Ca�eineCa�eineControl
LTP
Nektium | Zynamite® | 6
After acute (48 hours) and prolonged (15 days) supplementation with a low dose of 140mg Zynamite® + 50mg Luteolin intake and a high dose of 420mg Zynamite® + 150mg Luteolin intake, taken eight hourly, 12 physically active young men performed repeated bicycle ergometer Wingate sprint tests7. In a second study, the effect of 140mg Zynamite® intake, taken eight hourly for 48 hours was tested a) with 50mg Luteolin and b) with 600mg Quercetin. 30 young athletes (13 women) performed Wingate sprints8. In a third trial, muscle biopsies of cyclists during sprints were taken to study the physiological mechanism of action of Zynamite® at molecular level in muscle tissue. Peak power output (PPO), mean power output (MPO), oxygen uptake (VO
2), respiratory
variables, cerebral vascular reactivity, muscle oxygenation and cerebral oxygenation were analysed after exhaustion and after exhaustion followed by bilateral isquemia-reperfusion (IR), a model for simulation of fatigue. Both Zynamite® formulations enhanced exercise sprint performance, likely by improving brain oxygenation and allowing a higher muscle extraction of oxygen. These effects were observed following 48h and 15 days of supplementation without significant
differences between the two doses tested7.
III. CLINICAL STUDIES ON ZYNAMITE®
CLINICAL STUDIES ON SPORTS PERFORMANCE
Sports performance is a major arena for caffeine replacement products because around 80% of sports performance products contain caffeine as an ergogenic aid, often in combination with nootropics. In collaboration with Professor Dr. Jose López Calbet, University of Las Palmas, Spain, the effect of Zynamite® on performance and muscle fatigue was studied in three randomized, double-blind, placebo-controlled trials in caffeine-free formulations containing polyphenols, commonly used as antioxidants in sports products.
Improved Performance (MPO)after 30sec sprint
Improved Performance (MPO)after 60sec sprint
Improved Performance (PPO)after ischemia
Placebo Zynamite® + Luteolin
525
375
450
300
225
Wingate
5%(p=0.009)
15%(p=0.04)
IR + Wingate
MP
O (
W)
pro
lon
ged
sp
rin
t: 6
0s
afte
r is
chem
ia
MP
O W
ing
ate t
est
s (W
)
PP
O (
W)
275
225
250
200
150 175
Placebo
7%(p=0.008)
6%(p=0.007)
Zynamite®+ Luteolin
Zynamite®+ Quercetin
Placebo Zynamite®+ Luteolin
Zynamite®+ Quercetin
360
340
320
300
280
260
p=0.0001
p=0.01710.3%
19.4%
Placebo Zynamite® + Luteolin
525
375
450
300
225
Wingate
5%(p=0.009)
15%(p=0.04)
IR + Wingate
MP
O (
W)
pro
lon
ged
sp
rin
t: 6
0s
afte
r is
chem
ia
MP
O W
ing
ate t
est
s (W
)
PP
O (
W)
275
225
250
200
150 175
Placebo
7%(p=0.008)
6%(p=0.007)
Zynamite®+ Luteolin
Zynamite®+ Quercetin
Placebo Zynamite®+ Luteolin
Zynamite®+ Quercetin
360
340
320
300
280
260
p=0.0001
p=0.01710.3%
19.4%
Placebo Zynamite® + Luteolin
525
375
450
300
225
Wingate
5%(p=0.009)
15%(p=0.04)
IR + Wingate
MP
O (
W)
pro
lon
ged
sp
rin
t: 6
0s
aft
er
isch
em
ia
MP
O W
ing
ate
test
s (W
)
PP
O (
W)
275
225
250
200
150 175
Placebo
7%(p=0.008)
6%(p=0.007)
Zynamite®+ Luteolin
Zynamite®+ Quercetin
Placebo Zynamite®+ Luteolin
Zynamite®+ Quercetin
360
340
320
300
280
260
p=0.0001
p=0.01710.3%
19.4%
Nektium | Zynamite® | 7
MEAN POWER OUTPUT (MPO)
Compared to placebo, MPO was improved in
athletes taking Zynamite® + Luteolin in the 30s
Wingate test by 5% (p=0.009), while in the
Wingate test following IR, the improvement was
15% (p=0.04).
Compared to placebo, MPO was improved in
athletes taking Zynamite® formulations in the
prolonged 60s sprint by 6% (p=0.007) for
Zynamite® + Luteolin and 7% (p=0.008) for
Zynamite® + Quercetin.
PEAK POWER OUTPUT (PPO)
Compared to placebo, PPO was improved
in athletes taking Zynamite® formulations in
sprints performed at high exhaustion following
IR, by 10.3% for Zynamite® + Luteolin and 19.4%
for Zynamite® + Quercetin.
OXYGEN UPTAKE (VO
2MAX) AND
BRAIN OXYGENATION
Zynamite® + Quercetin improved VO2max by
6.1%, with a corresponding increase in brain oxygenation of 11% in women.
MUSCLE OXYGENATION
After the ingestion of 140mg of Zynamite® + Luteolin, the quadriceps muscle tissue oxygenation index (TOI) during sprint exercise was 3% lower (p= 0.007) after 48h and 5% lower (p= 0.09) after 15 days, indicating enhanced muscle O
2 extraction.
PAIN PERCEPTION
Pain perception was reduced in Zynamite® in formulations compared to placebo (p= 0.068).
Conclusion
Nektium’s sports performance studies
demonstrate that Zynamite® has better ergogenic activity than caffeine, without cardiovascular or other side effects. Zynamite® is doping-free, tested against WADA list of doping agents.
III. CLINICAL STUDIES ON ZYNAMITE®
8sWarm-up sprints
6 minMen: 100W
Women: 80W
RestingBlood sample (BS)
2 min
recovery
3 minrecovery
5 min
recovery
30sWingate
30sWingate
60sSprint
15sSprint
4 minrecovery
Lactate Pre30s before sprint
BS
BS1 min
BS5 min
BS5 min
20s
Occlusion
10s recoverywithout
occlusion
Lactate1 min post-sprint
VO2max
during repeated sprints
Muscle Oxygenation Pain Perception
Brain Oxygenationaverage of 5 sprints
2500
2300
2400
2200
2100
Placebo
p=0.011
p=0.12
Zynamite®+ Luteolin
Zynamite®+ Quercetin
Placebo Zynamite® + Luteolin
66
60
62
54
52
48h
p=0.007
p=0.09
15 days
TO
I Q
uad
rice
ps
mu
scle
(%
)
64
56
58
66
64
62
60
58
56
TO
I fr
on
tal l
ob
e (
%)
VO
2m
ax
(mL
/min
) W
om
en
Placebo Zynamite®+ Luteolin
Zynamite®+ Quercetin
p=0.017
p=0.0410.0%
11.0%
3%
5%
6.1%
2500
2300
2400
2200
2100
Placebo
p=0.011
p=0.12
Zynamite®+ Luteolin
Zynamite®+ Quercetin
Placebo Zynamite® + Luteolin
66
60
62
54
52
48h
p=0.007
p=0.09
15 days
TO
I Q
uad
rice
ps
mu
scle
(%
)
64
56
58
66
64
62
60
58
56
TO
I fr
on
tal l
ob
e (
%)
VO
2m
ax
(mL
/min
) W
om
en
Placebo Zynamite®+ Luteolin
Zynamite®+ Quercetin
p=0.017
p=0.0410.0%
11.0%
3%
5%
6.1%
Placebo Zynamite®
+ Luteolin&Zynamite®
+ Quercetin+Tigernuts
7,3
p=0.068
7,1
6,9
6,7
6,5
6,3
6,1
5,9
5,7
5,5
Pai
n ar
bitra
ry u
nits
Pain perception
Placebo Zynamite®
+ Luteolin&Zynamite®
+ Quercetin+Tigernuts
7,3
p=0.068
7,1
6,9
6,7
6,5
6,3
6,1
5,9
5,7
5,5
Pain
arb
itra
ry u
nit
s
Pain perception
2500
2300
2400
2200
2100
Placebo
p=0.011
p=0.12
Zynamite®+ Luteolin
Zynamite®+ Quercetin
Placebo Zynamite® + Luteolin
66
60
62
54
52
48h
p=0.007
p=0.09
15 days
TO
I Q
uad
rice
ps
mu
scle
(%
)
64
56
58
66
64
62
60
58
56
TO
I fr
on
tal l
ob
e (
%)
VO
2m
ax
(mL
/min
) W
om
en
Placebo Zynamite®+ Luteolin
Zynamite®+ Quercetin
p=0.017
p=0.0410.0%
11.0%
3%
5%
6.1%
Experimental Protocol
Nektium | Zynamite® | 8
MOOD AND STRESS
The study showed that Zynamite® significantly reduced fatigue after only 1.5 hours, analyzed with the Profile of Mood States questionnaire (POMS). Zynamite® reduced stress during the Calculation Performance Tests, evidenced by Galvanic skin response.
HEART RATE VARIABILITY AND BLOOD PRESSURE
Zynamite® had no side effects and no change in heart-rate variability or blood pressure over the course of the study - variables typically affected by caffeinated products.
EEG
During performance of two cognitively demanding challenges, a Number Sequence Test (NST) and a Number Connection Test (NCT), Zynamite® had a significant activating effect on the brain compared to placebo as determined by frequency analysis of the changes in electrical activity across six brain wave frequency ranges (colour coded) in the EEG of the association cortex (change from time-averaged baseline assigned as 100% **p<0.05, ***p<0.001.
PSYCHOMETRIC TESTS
Reaction time was significantly faster for
Zynamite® compared to placebo. Conclusion
The results of these clinical studies demonstrate that Zynamite® enhances attention, reduces mental fatigue and improves reaction time - results typically shown for caffeine. The advantage of Zynamite® is that this extract also reduced stress, and there were no side-effects, including no changes in heart rate or blood pressure.
III. CLINICAL STUDIES ON ZYNAMITE®
CLINICAL STUDIES ON MENTAL ENERGY
Nootropics boost cognitive function and memory and improve reaction time, focus and performance with no negative rebound effects, like those experienced from caffeine. Popularity for nootropics has increased significantly in recent years. The nootropic effect of 500mg Zynamite® was studied in two randomized, double blind, placebo-controlled cross-over pilot clinical trials. 16 participants took Zynamite® compared to placebo.
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0 0
1.0
2.0
3.0
10
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Ski
n r
esis
tan
ce (μs
)
Sco
re f
or
fati
gu
e
0
1.0
2.0
3.0
Sco
re f
or
fati
gu
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before intake
Decreased stress(Galvanic skin response)
Reduced fatigue No effect on heart rate
after intake
p=0.05
before intake after intake before intake after intake
p=0.015 p=0.05
PlaceboZynamite®
70
NST NCT
Placebo
NCTNST
[%]
of r
efer
ence
0h
90
110
130
150
NST: Number Sequence TestNCT: Number Connection Test
** p<0.05*** p<0.001
Delta
Theta
Alpha 1
Alpha 2
Beta 1
Beta 2
**
***
***
***
***
**
**
**
**
Zynamite®
Human EEG
Zynamite®
p=0.016
Placebo Zynamite®Placebo% o
f m
ax. r
each
able
res
ult
s
Calculation performance Reaction time
Tim
e in
sec
.
10
30
40
50
60
20
0
0.32
0.34
0.36
0.30
0.28
p=0.048
Placebo Zynamite®
0
0h
20
1,5h 0h 1,5h 0h 1,5h
40
60
80
SDNNHR RMSSDHR: Heart RateSDNN: standard deviation of NN intervalsRMSSD: square root of the mean squared dierence of successive NNs
Blood Pressure (mm Hg)and pulse/Heart rate (bpm)
Reduced fatigue
Reaction time
Decreased stressGalvanic skin response
Heart Rate Variability
Nektium | Zynamite® | 9
Mango leaves have a well-established food and beverage use throughout the tropics of the world where mango trees are cultivated. They are also listed as food supplement in Italy, France and Belgium. Specific countries that were notified for the marketing of mango leaf extract (60% mangiferin) under the brand name Zynamite® include: Italy, France, Belgium, Germany and Finland. Furthermore the authorities of Australia and New Zealand were notified as well.
DNA BARCODING: IDENTIFICATION OF SPECIES
The botanical raw material used for Zynamite®
first undergoes macroscopic inspection to ensure it conforms with reference plant material. DNA barcoding by the Royal Botanical Garden, Madrid, is used to positively confirm its botanical identity. Additionally, UPLC chromatographic profiles are used to confirm the presence of characteristic markers and to quantify the content of mangiferin.
QUALITY ASSURANCE & CERTIFICATIONS
Zynamite® is the result of high quality botanical raw material combined with meticulous manufacturing procedures. Nektium’s facilities and production processes strictly comply with cGMP (independently audited and certified annually) and rigorous quality control programs that ensure a high-quality product. Nektium Pharma S.L. is authorized by the Spanish Health & Food Agency for the production of botanical and fruit extracts in conformance with RD 1712/1991 and Spanish Regulations.
IV. REGULATORY
V. MANUFACTURING PROCESS
Nektium Pharma SL holds GMP certification (ES19/85835) and FSSC 22000 Food Safety System Certification (ES19/86276) by SGS
Nektium | Zynamite® | 10
1. Snel, J. & Lorist, M. M. Effects of Caffeine on Sleep and Cognition. Progress in Brain Research. 190, 105–117 (2011).
2. Ross, Ivan A. Medicinal Plants of the World. Volume 1: Chemical Constituents, Traditional and Modern Medicinal Uses. Humana Press. 2nd edn. DOI: 10.1007/978-1-59259-365-1 (2003).
3. Khandare, M. S. Mango (Mangifera indica Linn) A medicinal and holy plant. Journal of Medicinal Plants Studies. 4(4): 44-46 (2016).
4. Dimpfel, W., Wiebe, J., Gericke, N. & Schombert, L. Synergy Between Mango Leaf Extract (Zynamite®) and Caffeine with Respect to Stimulation of the Central Nervous System in Rats. Synergy Forum, 9-10, Bonn, Germany (2018).
5. Dimpfel, W., Wiebe, J., Gericke, N. & Schombert, L. Zynamite® (Mangifera indica leaf extract) and Caffeine Act in a Synergistic Manner on Electrophysiological Parameters of Rat Central Nervous System. Food and Nutrition Sciences, 9, 502-518 (2018).
6. Patten, A.R., Sickmann, H., Hryciw, B.N., Kucharsky, T., Parton, R., Kernick, A., & Christie, B.R. Long-term Exercise is Needed to Enhance Synaptic Plasticity in the Hippocampus. Learning & Memory. 20, 642–7 (2013).
7. Gelabert-Rebato, M., Wiebe, J.C., Martin-Rincon, M., Galvan-Alvarez, V., Curtelin, D., Perez-Valera, M., Habib, J.J., Pérez-López, A., Vega, T., Morales-Alamo, D., & Calbet, J.A.L. Enhancement of Exercise Performance by 48 Hours, and 15-Day Supplementation with Mangiferin and Luteolin in Men. Nutrients, 11 (2), 344 (2019).
8. Gelabert-Rebato, M., Wiebe, J.C., Martin-Rincon, M., Gericke, N., Perez-Valera, M., Curtelin, D., Galvan-Alvarez, V., Lopez-Rios, L., Morales-Alamo, D., & Calbet, J.A.L. Mangifera indica L. leaf Extract (Zynamite®) in Combination with Luteolin or Quercetin Enhances VO
2peak and Peak Power Output,
and Preserves Skeletal Muscle Function During Ischemia-Reperfusion in Humans. Frontiers in Physiology, 9, 740 (2018).
VI. BIBLIOGRAPHY
SCIENCE BASED NATURAL INGREDIENTS
© Nektium Pharma S.L.
The information contained in this publication is provided in good faith for B2B customers only, and is based on our current knowledge. No legally binding
promise or warranty regarding the suitability of our products for any specific use is made. These statements have not been evaluated by the Food and Drug Administration or by EFSA. This product is not intended to diagnose, treat, cure or prevent any disease. Nektium Pharma S.L. will not assume any
expressed or implied liability in connection with any use of this information. Rev. 4. 2019.
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