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®


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

s

-10.0-20

-10

0

10

20

30

40

50

60

70

80

90

100

110

-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


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.

0

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


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


360

340

320

300

280

260

p=0.0001

p=0.01710.3%

19.4%


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)





360

340

320

300

280

260

p=0.0001

p=0.01710.3%

19.4%


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)





360

340

320

300

280

260

p=0.0001

p=0.01710.3%

19.4%


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.


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




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



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




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



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




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



p=0.017

p=0.0410.0%

11.0%

3%

5%

6.1%

Experimental Protocol


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.


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.

¿?

0 0

1.0

2.0

3.0

10

20

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

e

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


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


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.

+34 928 734 [email protected]

C/ Las Mimosas 8, 35118 Agüimes.

Las Palmas. Spain

Award winning innovation for increased physical and mental …€¦ · Nootropics boost cognitive...

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