The amazing couple
for an actual relief from ache.
These statements may not comply with your country’s laws and regulations or with Reg. EC n.
1924/2006 and have not been evaluated by the Food and Drug Administration. The products are notintended to diagnose, treat, cure or prevent any disease. Marketers of finished products containing
this ingredient are responsible for ensuring compliance with the applicable legal framework.

2

Index4

Facing a global healthproblem, with the helpof nature

7

Ginger, the power of nature
to modulate healthy
inflammatory response9

Acmella: from Sardinia
a “made in Italy” biomass,powered by Indena

13

The amazing couple: ginger
and acmella working together
for ache management

1.

Facing a global healthproblem, with the helpof nature
As highlighted by the most authoritative official sources, such as
WHO or IASP (International Association for the Study of Pain), pain
is an enormous global health problem.

Globally, it has been estimatedthat 1 in 5 adults suffer from pain
and that another 1 in 10 adults
are diagnosed with chronic paineach year1.
4

https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC3201926/#B1
1

Pain affects all populations, regardless of age, sex, income,race/ethnicity, or geography and the four largest causes of pain arecancer, osteo- and rheumatoid arthritis, operations and injuries,and spinal problems.

2
https://www.packagedfacts.com/
Pain-Management-Consumer10595686/

Despite advances in medicine and numerous
agents that counteract pain, millions of people
continue to suffer. That’s why researchand remedies for pain management
is a priority for public health.

Recent analysis revealed 5 top trends in pain managementfor 20172:

23%

Growth in alternative therapies: as of 2016, roughly
23% of adults trust homeopathic medicine,and 22% prefer alternative medicine to standard
medical practices;Heavier focus on health and diet: health anddiet tools — ranging from functional foods andbeverages to organic and natural and beyond —have a signiﬁcant role to play in satiating that
hunger and achieving the universal goal of a more
fulﬁlled life;
Exercise and weight management as a partof broader treatment;
Rising interest in homeopathic and functional
pain medication: makers and marketers should
consider adding homeopathic or herbal qualities
that can help users feel like they are doing
something healthy for their entire body and notjust eradicating their pain;

Caffeine for more than just coffee.

An important help may come from nature, forinstance from plants whose active ingredients
could selectively act on cannabinoid CB2
receptors, such as cannabidiol, which represent
an attractive target in obtaining ananti-inflammatory and analgesic effect without
central nervous system side-effects.

Indena has been focused for years in developing
an innovative product which
could give an actual relief from ache:

Mitidol®

Today it’s available, thanks to a coupleof botanicals working together in a very
effective way:

ginger (Zingiber officinale)
and acmella (Acmella oleracea L.).

6

2.

Ginger, the powerof nature to modulate
healthy inﬂammatory
response
Ginger (Zingiber officinale Roscoe) rhizome is one of the hot
spices belonging to Zingiberaceae family, a herbaceous perennial
plant native to Southern Asia.

Ginger rhizome is extensively
consumed as a spice in foods
and beverages because of its
characteristic pungency andpiquant ﬂavor. It is used in a variety
of foods and also in carbonateddrinks, in liquors and as a preservein sugar syrup (murabba).
Ginger is an excellent source of several bioactive phenolics,
including non-volatile pungent compounds such as gingerols,paradols, shogaols, and zingerones.
It is also used in traditional oriental medicine (Ayurvedic,Chinese, and Unani systems of medicine) since antiquity to treat
different diseases that include rheumatoid arthritis, sprains andmuscular aches, sore throat, nausea, constipation and indigestion,
fever, infectious diseases, and helminthiasis.
Ginger is particularly valued in medicine as a carminative andstimulant to the gastrointestinal tract and it's known to increase
the motility of the gastrointestinal tract and has antibacterial,
antiviral, analgesic, and antipyretic properties.

7

The pungency of the fresh ginger rhizome is due
to gingerols, of which the major pungent principleis [6]-gingerol (1-[40-hydroxy-30-methoxyphenyl]5-hydroxy-3-decanone), an oily liquid, and the mostabundant constituent among the gingerols.

OO

HOOH

OH

6-Gingerol(Pungent compoundin fresh ginger)

OCH3
HO
The pungencyOCHof dried or cooked ginger is due to3
nonvolatile phenylpropanoid-derived compounds
from gingerols, namely, shogaols. The less pungentzingerone is also producedOfrom gingerols during drying
process. Ginger also contains acrid resinous substances(5–8%).
OHOO
HOO

Shogaol(Pungent constituentof ginger producedon drying or cooking)Gingerols and shogaols
are the main components
of ginger extracts.

The major properties of ginger compounds
include immune modulatory, anti-inﬂammatory, anti-tumorigenic,
anti-hyperglycemic, and antilipidemic actions.3

8Krishnapura Srinivasan, Ginger
rhizomes (Zingiber officinale): A
spice with multiple health beneficial potentials, PharmaNutrition 5(2017) 18–28
3

3.

Acmella: from Sardinia
a “made in Italy” biomass,
powered by Indena
Acmella is a flowering herb species in Asteraceae o Compositae'sfamily. It is grown as an ornamental or medicinal plant andattracts fireflies when in bloom. A small, erect plant, it grows
quickly and bears gold or red inflorescences. It is frost-sensitive
but perennial in warmer climates.

The whole plant is used as a
medicinal remedy in various partsof the world.
9Acmella has been used for centuries to treat oral pain becauseof its analgesic properties. The leaves and inflorescence are usedas household medicine to treat oral and throat diseases.

Acmella flower is then also known as the"tootache plant". When chewed, the leaves
and flowers generate a tingling sensation
to the lips and tongue.

This sensation is caused by the action of spilanthol, an
isobutylamide compound that promotes local anesthetic action
treating the toothache.4

60

Spilanthes (Compositae or Asteraceae) is a genus
comprising of over 60 species.

Spilanthes (Compositae or Asteraceae) is a genus comprisingof over 60 species and Spilanthes acmella, has been well
documented for its uses as spice, antiseptic, antibacterial,antifungal, antimalarial treatment, and as remedy for toothache,flu, cough, rabies diseases, and tuberculosis.5
Despite being a remedy used for centuries in the territories
of origin, acmella has not been widely exploited in nutraceuticals
so far.

Indena has been one of the firstcompany to study in depth
the efficacy of that plant throughIndena’s usual scientific approach.
Mitidol® is the result of thisresearch commitment that goesback many years.

104Mariangela Rondanelli, Federica
Fossari, Viviana Vecchio, Valentina Braschi, Antonella Riva, Pietro
Allegrini, Giovanna Petrangolini,
Giancarlo Iannello, Milena Anna
Faliva, Gabriella Peroni, Mara
Nichetti, Clara Gasparri, Daniele
Spadaccini, Vittoria Infantino,
Sakina Mustafa, Tariq Alalwan,
Simone Perna, Acmella oleracea
for pain management, Fitoterapia
140 (2020) 104419

5Suchita Dubey, Siddhartha Maity,Mahendra Singh, Shubhini A.
Saraf, and Sudipta Saha, Phytochemistry, Pharmacology andToxicology of Spilanthes acmella:
A Review, Advances in Pharmacological Sciences Volume 2013,
Article ID 423750, 9 pages

As quality of raw material is one of the most important
prerequisite for a quality extract, Indena had to finda good acmella’s biomass for Mitidol® production.
Considering the poor quality of biomass coming from thetropical or far east countries, the company decided toinvest in a proprietary cultivation looking for the mostsuitable farmland in Italy.

Since three years, in the Italian region ofSardinia the company grows its own
Spilanthes acmella plants, which give

excellent biomass in termsof purity and quality thanks
to organic and sustainable
farming practices.

11

For the first time a “made in Italy”
acmella has been produced and it’s
one of the point of strength and of
peculiarity of Indena’s Mitidol®.
Acmella’s main constituents are lipophilic alkylamides oralkamides bearing different numbers of unsaturated hydrocarbons(alkenes and alkynes), such as spilanthol, which is the main
compound isolated from many parts of this plant, particularlyflowers.

Spilanthol has many biological activities,
including analgesic, antinociceptive,

antioxidant, anti-inﬂammatory,
antiwrinkle.6

ON
H
Spilanthol(2E, 6Z, 8E)-N-isobutyIdeca-2,6,8-trienamide

12M. Rondanelli, et al., Acmellaoleracea for pain management,
Fitoterapia 140 (2020) 104419 –già citata sopra.

6

4.

The amazing couple:
acmella and ginger
working together
for ache management
As reported by literature data, both Zingiber officinale and Acmellaoleracea extracts can be useful as inflammation and ache modulators.
Indena’s innovative solution is to exploit the synergy of theamazing couple, through the rational combination of the twostandardized extracts, which have been proven to provide a
healthy inflammatory and ache relief support action.
Starting from such an idea and considering Indena's pioneeringcommitment to acmella and the availability of quality raw materials
from its crops in Sardinia, the company has made technologicalefforts to associate the two botanical extracts together, with thepurpose of create a unique and very effective product.

The result of that effort is Mitidol®,the combination of ginger andacmella with an innovative
formulation which blends the twooily liquid extracts in a uniquefine-powder ingredient.
13

Mitidol®’s mechanism of action and efficacy have been reported ina study very recently published (January 2020).7
In the study, the new food-grade formulation of Acmella oleracea
and Zingiber officinale was tested in two in-vitro assays in order toverify its effect on endocannabinoid system.
Endocannabinoid system includes CB1 receptors, foundprimarily in the brain and in central nervous system, and CB2
receptors which are mostly in the peripheral organs, especiallyin cells associated to the immune system.
Endocannabinoid system is linked to many human organism
functions, among which are immune or cardiovascular ones,
neuroprotection, fertility, memory and pain modulation.
FAAH (= Fatty Acid Amide Hydrolase) is an enzyme which breaks
down anandamide (AEA=N-Arachidonoylethanolamine), an
endogenous cannabinoid, able to activate both CB1 (brain andCNS) and CB2 (periferical organs) receptors: FAAH inhibition
leads then to long-lasting effect of AEA.
The mentioned study on Mitidol® includes a cell-based assay inhuman recombinant Cannabinoid 2 Receptor cells, in order toevaluate a possible agonist effect on those receptors, and a Fatty
Acid Amide Hydrolase inhibition activity assay, to evaluate potential
inhibition of that hydrolase, which, as said, is responsible fordegradation of the endogenous cannabinoid anandamide.

From the evidence that emerged in theexperiments made in the study, the combinationof the two extracts in the Mitidol® formulation
has a proven double effect on ache relief
support: a direct one thanks to the interaction withCB2 receptors, the same target on which
the CBD – cannabidiol acts; and an indirect effectthrough the inhibition of FAAH enzyme.
Conditions affecting joint health are very common nowadays, forexample osteoarthritis is ranked as the 11th highest contributor
to global disability in the world and is predicted to become thefourth leading cause of disability worldwide by 2020.8147
Giovanna Petrangolini, FabioDonzelli, Davide Berlanda, Pietro
Allegrini, Andrea Rossignoli,Michela Stucchi, Antonella Riva,
Targeting Cannabinoid Receptors
and Fatty Acid Amide Hydrolase:
An Innovative Food-Grade Delivery System of Zingiber officinale
and Acmella oleracea Extracts as
Natural Adjuvant in Pain Management, J Nutr Food Sci, Vol. 9 Iss.
5 No: 766

Cross M, Smith E, Hoy D, et al.
The global burden of hip andknee osteoarthritis: estimates from the Global Burdenof Disease 2010 study. AnnRheum Dis. 2014;73(7):13231330. doi:10.1136/annrheumdis-2013-204763
8Care and management of knee OA pain remains very complex.
Despite advances in medicine and numerous agents thatcounteract knee OA pain, millions of people continue to sufferfrom it.
Recently, attention has been given in the identification of novel
botanicals interventions supporting pain relief, like ginger andacmella do. Therefore, they’re dietary botanicals supplements
potentially useful in supporting ache relief also in case of OA.
In this area, an important one-month human study has beenvery recently completed to show Mitidol®’s efficacy in supportingknee functionality and comfort.99
Mariangela Rondanelli, Antonella Riva, Pietro Allegrini, Milena
Anna Faliva, Maurizio Naso,
Gabriella Peroni, Mara Nichetti,
Clara Gasparri, Daniele Spadaccini, Giancarlo Iannello, Infantino
Vittoria, Teresa Fazia, Luisa
Bernardinelli, Simone Perna, Manuscript accepted for publication

The human study involved 50 subjects with knee challenges
who’ve got a 30-day supplementation with Mitidol®.
The main results include both individual and objective evidences.
Individuals report: a remarkable support in the relief fromache starting from 7 days; optimization of knee function,
confirmed with 2 different tests (Lhysolm scale and WOMACscale); improvement of the quality of life (SF-36 questionnaire)and of the physical wellbeing. This last health progress resulted
in a consequent reduction of BMI - Body Mass Index, since themore comfort people feel, the more they move. At the same time,
objectively parameters show that Mitidol® maintains a healthy
inflammatory response after 1 month of supplementation:- 12,7 % ESR - Erythrocyte Sedimentation Rate, and -36,4% CRP high sensitivity C-Reactive Protein.

In conclusion, these results
suggest a strong rationale for theuse of Mitidol®, the combinationof Zingiber officinale and Acmellaoleracea, as a natural adjuvant insupporting ache relief.
Moreover, Mitidol® is also a smart
formulation which combines 2 oily
extracts in a powder ingredient,suitable for easy development andmanufacture of solid oral dosage
forms (e.g. capsules, tablets).

15

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