PRODUCTION OF MEDICINAL PLANTS
The therapeutical
value of a medicinal
presence
or
of
one
more
plant
constituents
depends on the
possessing
certain
medicinal
use
physiological and pharmacological activity.
SOURCES OF MEDICINAL PLANTS:
1- WILD
The
collection
of
wild
plants
for
is
frequently accompanied by certain drawbacks (disadvantages):
i- Wild plants are distributed over unlimited areas and are
not confined to limited locality.
ii- The difficulty in collecting wild plants as they
usually
iii-
The
home
growing
difficulty
of
the
convenient
in deserts,
of
forests
transportation
desired
plant
is
when
far
or seas.
the
away
v- Ignorance
natural
from
any
means of transport.
iv- Continuous collection may lead to extinction or
serious
are
to a
deficiency in supplies.
of
collectors
may
lead
to
the
following
disadvantages:
1-Admixture
of
the
desired
plant
with
other
plants
(Adulteration).
2-Collection of the desired plant in the wrong period of
growth.
3-Collection of the desired organs of the desired
with
plant
undesired organs.
4-Drying of the collected plants under drastic
conditions.
The results of that is, the collected drug fails to give
maximum
therapeutic activity.
5-Insufficiency of wild plants to fulfil the demands of the
market and pharmaceutical industries.
1
6-Collection from wild plants helps monopolies.
II- CULTIVATED PLANTS
Advantages:
1-Cultivation affords good means of controlling purity of the
end product.
2-Cultivation
affords
good
means
to
control
processes
of
collection, drying, preparation and storage in controlled farm
where these preparations are carried out by trained workers
instead of being left to primitive treatments of unskilled
collectors.
2- Cultivation affords good means to concentrate a large number
of
plants
in
relatively
small
area,
thus
simplifying
collection and transportation.
3- Cultivation helps to control factors affecting drug activity
as hybridization, polyploidy, selection and mutation.
4- Production
of
medicinal
plants
by
cultivation
assures
regular supplies and breakdown monopolies.
5- Cultivation
of
medicinal
plants
near
the
pharmaceutical
factories for manufacturing is advantage where the fresh
drugs can be taken directly from the field into the factory
or
laboratory
for
immediate
use.
Thus
preventing
deterioration of the drugs by careless handling or temporary
storage and lower the costs of transportation.
Disadvantages:
1- The high cost of production.
2- Loss of plants due to adverse weather conditions such as
flood, draught or rain in harvesting season.
3-Fungal and virus diseases may also cause losses.
4-Damage of the plant by attack of insects.
2
5-Medicinal
plants
require
a
particular
environment
not
readily obtainable under cultivation.
FACTORS CAUSING VARIABILITY IN DRUG ACTIVITY
The
content
of
therapeutically
active
constituents
and
the
ratio between different constituents of drugs are not static
but vary in the living plants according to the interaction of
factors inside and outside the organisms.
Variation
may
be
caused
by
genetic
factors
or
by
the
differences in the environmental conditions under which the
plant is grown.
Variation
may
also
results
from
the
methods
used
in
collection, preparation, drying and storage of crude vegetable
drugs
I-GENETIC FACTORS
Each living cell contains in its nucleus as a rule 2 sets of
chromosomes.
The
genes
which
carry
the
characteristic
morphological,
histological, taxonomical and biochemical properties of the
plant
are
associated
in
groups
on
the
chromosomes.
Accordingly, the heredity characters are a function of the
chromosome
number
and
the
genes
present
in
the
nucleus.
Therefore, any genetic difference is accompanied by different
species and different varieties of the drug. These differences
3
will lead to differences in the amount, type or properties of
the active constituents produced.
Different species or varieties can be easily differentiated
morphologically
difference
is
and
taxonomically.
little,
But,
biochemical
when
the
variations
genetic
only
occur
without any morphological differences giving rise to chemotype.
Examples of Chemo-type:
1-The bitter and sweat almond trees can not be distinguished
except
by
the
fact
that, the
seeds
of
the
former (bitter
almond) contain bitter glycoside amygdalin while the seeds of
the latter (sweat almond) are free of amygdalin .
2-Dubosia
myoporoides
growing
in
north
Australia
produces
chiefly hyoscine while plants of the same species from the
south Australia produce chiefly hyoscyamine.
3-Eucalyptus
dives yields an oil that varies greatly in odour
and chemical content from tree to tree although the trees are
morphologically identical and growing side by side.
In each chemo-type, there are certain specific enzymes, differ
from those present in the other chemo-type. These different
enzymes indicate certain different reactions with different
pathway to give rise to a certain end product.
The
Difference
in
enzyme
action
is
due
to
the
genetic
difference in the plant.
Therefore, any change in these genetic factors will lead to
changes in the amount and type of active constituents. This
explain the importance of the gene as information part that
4
direct the organism (plant) to produce the wanted or desired
product(s) and this is known by made-to-order product.
A- POLYPLOIDY
Each
living
chromosomes.
cell
contains
If
mitosis
in
its
occurs
nucleus
(i.e.
2
sets
duplication
of
of
chromosomes within the nucleus with no division of the cell
2n→ 4n), a condition arises in the nucleus when it contains
more than its normal complement of chromosomes. This condition
is termed POLYPLOIDY.
METHODS OF POLYPLOIDY:
1- Physically
This is carried out by treating the cells, usually seeds or
buds with heat.
2- Chemically
By using colchicine or other specific chemical agents.
Treating the seeds with colchicine will lead to increase of
the number of chromosomes (polyploidy).
This activity of colchicine is due to:
1-Interaction
of
colchicine
with
the
disulfide
bonds
of
protein present in tissues.
2-By inhibition of the conversion of the globular protein to
fibrous protein.
The
effect
of
chromosome
number
on
the
constituents
medicinal plants can be shown as follows:
A-Datura stramonium in 4n , there is increase of
60-150% of tropane
alkaloids over 2n.
B-In Opium also polyploidy increase the percentage
of morphine up to 100%, 3n plants are especially high.
5
of
B-HYBRIDISATION:
In plant breeding, hybridization forms a possible means of
combining in a single variety the desirable characters of
two different varieties or species and producing new and
desirable
characters
not
found
in
either
parent.
Hybridization is used to produce plants that resist diseases
and contain much more percentage of active constituents.
EXAMPLES:
A-Hybrids of Cinchona are produced showing increase in the
yield of quinine.
A
hybrid
produced
by
crossing
Cinchona
succirubra
with
Cinchona ledgeriana yields a bark, which contains 11-12% of
alkaloids
while
the
parent
species
yielded
3-4%
and
5.1%,
respectively, of alkaloids.
B- the genus Datura, the effect of hybridization on the
chemical constituents is illustrated by crossing:
Datura ferox
x Datura stramonium
Datura stramonium normally contains hyoscyamine and hyoscine
in a ratio of 2:1 at the flowering period.
Datura ferox contains hyoscine with some meteloidine.
The result of hybridization is the formation of plants larger
than either of plants and containing hyoscine as the principal
alkaloid which only small amounts of other bases.
Generally, Crossing cause changes in the genes of the new
hybrid leading to an increase in the active constituents.
C-SELECTION:
Although the members of any
population of the plant may be
more or less closely related, the samples will be genetically
6
heterogeneous to some extent due to genetic differences from
individual to other.
If the members showing the most desirable characteristics are
chosen and crossed, a desired second population may result
which will exhibit a tendency toward improvement with that
particular desirable quality.
Continued
selection
individuals
greater
may
and
cultivation
result
response
in
toward
a
of
the
population,
improvement
most
which
in
desirable
will
the
show
particular
desirable quality chosen.
In
drug
production.
The
purpose
of
selection
work
is
to
exclude dispensable types of low productive ability or of low
therapeutic
value
and
to
isolate
high
quality
plants
by
selective breeding.
In selection, high-grade parent plants of the same genus, the
same species and the same variety are chosen.
Example:
Selection work on Cinchona ledgeriana with about 5% alkaloidal
content, has produced types which yield bark with up to 15%
alkaloids.
In
nature,
some
strains
of
a
given
microbe
are
active
in
producing antibiotics while other strains are inactive.
Careful
selection
of
active
strains
is
important
to
all
industries which use microbes to produce toxins, vaccines and
which use microbes to perform certain chemical reactions in
Pharmaceutical industries.
7
D-MUTATION:
It is a change in the nature of a gene. This change may cause
the gene to lose its function partially or completely or it
may cause the gene to do a different job.
This may lead to biochemical differences.
Mutation can be brought about by:
1-Ionizing radiation; e.g. -rays ,  and -rays, radio active
isotopes.
2-Non-ionizing radiation; e.g. U.V
3-Certain mutagenic chemical agent.
Mutation will give mutants, which contain high percentage of
active constituents.
Example:
Penicillin
is
produced
from
the
fungus
Penicillium
chrysogenum. The original strain of this fungus produces 100
units of penicillin per ml of culture media. -ray treatment
of this strain gives mutants, which produce 500 units per ml
of the medium.
UV treatment of the latter produce mutants which produce 1000
units per ml of the medium.
Not all mutations are produced artificially; they may also
arise spontaneously in nature.
N.B: Mutation and selection together play a basic role in the
development
of
resistance
to
chemotherapeutic
agents
by
containing
an
pathogenic microbes.
When
a
microbe
is
cultured
in
a
medium
antibiotic to which it is sensitive, the great majority of the
organisms
will
be
eliminated
by
individuals will survive.
8
the
antibiotic
but
a
few
The organisms, which survive, are mutants resistant to the
antibiotic.
The resistant organisms are free to multiply and grow giving
rise to a new population, which is resistant.
II –ECOLOGIC FACTORS
1-LIGHT AND TEMPERATURE
A- Light
is
a
therefore,
very
important
deficiency
of
factor
light
(in
for
photosynthesis;
cloudy
weather)
will
cause a decrease in the amount of carbohydrates produced in
the leaves.
Carbohydrates
biosynthesis
serve
as
of
the
the
initial
secondary
starting
material
metabolites
for
(Active
constituents). Therefore, if the plant is placed in a short
day
light,
synthesis
of
carbohydrates
and
consequently
the
active constituents become very low.
Example:
Digitalis contains cardiac glycosides, If the biosynthesis of
carbohydrate is diminished, the aglycone-sugar linkage does
not formed, so the percentage of the glycoside decreases and
thus the activity of Digitalis also decreased.
B-Change in temperature may also affect the plant growth by
affecting
the
rate
of
chemical
reactions.
Lower
or
higher
temperatures than the optimum temperature for enzymes cause
suppression of enzymatic action.
9
2-LATITUDE
The
effect
of
latitude
is
apparent
in
the
case
of
fat
production by plants.
Fats from tropical plants contain mainly saturated fatty acids
(Palm oil, Cocoa butter). But fats from subtropical plants
contain a larger proportion of unsaturated fatty acids.
Also The Indian Hemp , in tropical regions it gives narcotic
resins, while in other regions it is free from narcotic resin
and gives only fibers.
3-ALTITUDE
Thymus vulgaris and Mentha piperita produce less volatile oils
in higher altitudes than they do when grown in low lands.
The
yield
of
Valerian
roots
is
3-5
times
higher
in
the
mountains than in the low lands. Therefore, the altitude is
greatly affects the percentage of active constituents.
4-Minerals, Water and Oxygen
Minerals
are
functioning
of
essential
plants.
for
plant
growth
They
serve
as
and
biochemical
catalysts
and
cell
constituents.
Deficiency of certain minerals will decrease the production of
active constituents.
The air capacity of soil is inversely proportional to water
capacity (i.e. increase of water cause decrease in oxygen),
since good aeration is essential for root development; soil
must not contain high amount of water.
10
5-PLANT GROWTH
REGULATORS (Plant Hormones)
The growth of the plants is regulated by a specific chemical
substances . They are known as plant hormones.
Five of growth regulators are well known:
A-Auxins
B-Gibberellins
C-Cytokinins
D-Abscisic acid and its derivatives.
E-Ethylene
Auxins ,Gibberellins, and Cytokinins
while
Abscisic
acid
and
its
are growth promoters,
derivatives
and
Ethylene
are
growth inhibitors.
These substances occur in all higher plants, and are specific
in their action and active in very low concentration.
They are responsible for:
1-Cell elongation and enlargement.
2-Regulation of cell division.
3-Cell differentiation.
4-Organogensis.
5-Dormancy (not actively growing).
I-GROWTH PROMOTORS
A-AUXINS
They are growth promoting substances as:
Auxin A
isolated from human urine.
Auxin B isolated from cereal products.
Auxins have the same properties as Indole Acetic Acid (IAA)
Several and similar acids and precursors of IAA have been
CH 2-COOH
N
H
IAA
11
reported as natural products as
-Indole Acetaldehyde
CH2CN
CH2-CO-COOH
N
H
N
H
Indole acetonitrile
Indole pyruvic acid
Their effect is shown in:
a-Cell elongation i.e. stem length
b-Inhibition
of
root
growth
and
production
roots.
Synthetic Auxins:
CH2-COOH
O-CH2-COOH
Cl
NAA
Cl
Naphthalene -1-Ace tic Acid
2.4-dichlorophe noxy ace tic acid
CH2-CH2-CH2-COOH
N
Indole -3-butyric acid
12
of
adventitious
In the plant oxidative degradation of the IAA is
IAA Oxidase
IAA
oxidative degradation
inhibited by
caffeic acid
quercetin
chlorogenic
acid
OH
HO
HO
HO
CH
CH
O
OH
COOH
OH
OH O
Caffeic acid
qurecetin
controlled by IAA oxidase. These compounds inhibit the action
of the enzyme and hence stimulate the growth.
Monophenols
enzyme
as
p-coumaric
acid
promote
the
action
of
the
(IAA oxidase) and so inhibit the growth.
HO
CH
CH
COOH
p-coumaric acid
IAA
may
conjugate
with
aspartic
acid,
glycine,
sugars,
glutamic acid and stored in this form (inactive form).
Uses of auxins:
1- In low concentrations they accelerate the rooting of woody
and herbaceous cuttings.
2- In high concentrations act as selective herbicides or weed
killer.
13
Applications of Auxins:
-
In
Cinchona
cutting
Indole-3-butyric
acid
was
successful
with cinchona cuttings saving some from 2-3 years compared
with growth from seeds.
- In Biogenetic studies
They use auxins to induce root formation on isolated leaves
such as those of Nicotiana and Datura species,
2,4-dichlorophenoxy
acetic
dicotyledons
in
while
acid
suitable
is
found
to
concentration
be
toxic
having
to
little
effect on monocotyledons. So ,it can be used to destroy such
dicotyledon weeds as Dandelion.
N.B. Certain carbamate and urea derivatives have an opposite
effect and can be used to destroy grass without serious injury
to dicotyledonous crops.
Applications of the effect of Auxins on secondary metabolites:
1- Mentha piperita
When treated with NAA (using seedlings or young plants) they
gave in the mature plants an increased yield (30-50%) of oil
which contain 4.5-9 % more menthol.
2-Datura species
No marked effect on the alkaloid formation or on the type of
alkaloids. But it shows an increase in trichome production
particularly in non-glandular branched trichomes.
3-Ergot
Increase in the alkaloid production was observed in some Ergot
strains, when treated with various auxins (IAA, NAA, 2,4-D,
indole propionic acid).
14
4-Anthraquinones
Cell grown in presence of NAA produce more anthraquinones, but
those with 2,4-D as a sole auxin do not appear to have no
beneficial effect on the production of sennosoides in Cassia
angustifolia.
B-GIBBERELLINS
This
group
Japanese
of
in
plant
growth
connection
with
regulators
the
Bakanae
was
discovered
(Foolish
by
Seedling)
disease of Rice.
Range of Gibberellins was involved and are distinguished as
Causative organism is
Gibberella fugikuroi
isolation of the active
material
Gibberellin
GA1+, GA2, GA3
GA3
……….etc.
= Gibberellic acid and produced commercially by Fungal
cultivation.
Applications of Gibberellins:
Gibberellins
have
been
used
to
treat
many
plants,
which
contain useful secondary metabolites e.g.
1-Volatile oils and Terpenoids
Treatment
of
volatile
oil
producing
plants
with
GA,
their
yield was increased by 40%. But it has been noticed that in
some cases as Mentha pipereta the volatile oil was decreased
due to reduction of glandular trichomes.
15
2-Alkaloids
The seeds of tropane alkaloid producing species when treated
with
adjusted
dose
of
GA,
could
increase
the
alkaloidal
content.
Other alkaloid containing plants which have been subjected to
GA treatment are:
Catharanthus
roseus
(Vinca)
showed
gradually
a
lowering
of
alkaloidal content and some changes in relative proportion of
vinblastine to other alkaloids.
Rauwolfia serpentina, lowering of alkaloid concentration was
observed and the effect increases with the dose
III- Cell division hormones (Cytokinins)
Auxins
enlargement
process,
and
and
gibberellins
although
there
are
they
other
are
concerned
influence
substances,
with
cell
cell-multiplication
which
have
a
more
specific effect on cell division (Cytokinesis)
Action of cytokenin
1- cell division in tissue
2- regulate the pattern and frequency of organ production as
well as position and shape.
3- Much employed in tissue culture to promote the formation of
adventitious buds and shoots from undifferentiated cells.
e.g.
HN CH2
O
N
N
N
N
H
16
Kinetin (6-furfurylamino purine) has not isolaated from plants
Zeatin
[6-
(4-hydroxy-3-methylbut-2enyl)
–
amino
purine]
CH3
HN CH2
CH C
CH2OH
N
N
N
N
H
isolated from the maize embryos at the milky stage.
Growth inhibitors
Natural growth inhibitors are present in plants and affect

Bud opening

Seed germination

Development of Dormancy
e.g.
Abscisic acid
H3C
CH3
(ABA)
CH3
OH
COOH
O
CH3
isolated from the fungus Cenospora rosicola.
2- Ethylene.

Ethylene include growth response

It was demonstrated that ethylene evolved by stored apples
inhibit the growth of potato shoots enclosed with them.

It has a role in fruit opening.
A compound which gives rise to a typical ethylene response in
plants is (2-chloro ethyl) – phosphoric acid (ethephon)

At
low
conc.
Ethylene
increase
the
Sennoside
conc.
In
Cassia angustifolia

When
applied
with
Digitalis
lanata
tissue
culture
cardinolide accumulation is decreased.

Ethephon is now used to enhance the flow of rubber latex.
17
6- PRECURSORS
They
are
intermediate
synthesizing
plant
substances
during
the
normally
formation
produced
steps
of
by
the
active
constituents.
The yield of a desired compound is sometimes increased by
adding one or more of the precursors normally produced by the
developing organisms.
7-PARASITES
Medicinal
plants
are
subjected
to
infectious
diseases.
Microbes and viruses attack them, causing disturbances of the
metabolic processes.
This
will
lead
to
decrease
in
the
amount
of
active
to
develop
constituents.
In
many
cases,
plant
breeders
have
been
able
strains of various plants which are resistant to the more
common infectious diseases of plants.
8-ALLELOPATHY
Living
organisms
exert
an
influence
upon
each
other.
This
interaction is called ALLELOPATHY and it may be BENEFICIAL
(SYMBIOSIS) or DETRIMENTAL (DESTRUCTIVE OR ANTIBIOSIS).
Examples of Symbiosis:
1- Artemisia
species
(Family
Asteraceae)
has
a
beneficial
influence on the development and growth of Atropa belladonna
increasing the yield in both plants and the percentage of
alkaloids.
2- Ripe
apples
exhale
ethylene,
unripe apples.
18
which
helps
maturation
of
Examples of Antibiosis:
1-The growth of Aatropa belladonna and Datura stramonium
is
strongly
Inhibited
when
the
plants
are
cultivated
with
Mustard plants.
2-Encelia species ( Family Asteraceae)
produces 3-acetyl-6-methoxy benzaldehyde, which is
inhibitory to other plants in the area.
ALLELOPATHIC ACTION IN BACTERIA
1- Nitrogen fixing bacteria living symbiotically with plants
belonging to family Leguminosae.
2- Antibiotics-producing
microorganisms
have
detrimental
effect on bacteria (antibiosis).
CHANGES TAKING PLACE IN DRUGS SUBSEQUENT TO COLLECTION AND
DRYING
Water lost by evaporation disturbs the equilibrium between the
cell contents and leads to the diffusion of the enzymes. The
acid cell sap diffuses into the plasma due to alteration in
the permeability of the membrane enclosing it.
I-DESIRABLE CHANGES:
1- Naturally; many alkaloids present in the living plants in
the form of alkaloidal tannate.
Examples:
a) Atropine
tannate;
hydrolysis
of
this
salt
gives
free
atropine and tannic acid.
It was found that, the mydriatic effect of the free alkaloid
is more than atropine tannate. Therefore, the decomposition of
the alkaloidal tannate is desirable.
19
b) Tea; its main active constituent in the leaves is caffeine
alkaloid present as caffeine tannate.
The tea prepared from fresh leaves contains less caffeine than
that
prepared
drying
and
enzymes
from
storage,
break
up
dried
leaves.
fermentation
caffeine
This
takes
tannate
is
because,
place
into
during
caffeine
during
which
free.
Therefore, the percentage of caffeine in dried leaves is more.
2- Freshly collected Vanilla pods do not contain free vanillin
and are odourless.
After drying, fermentation process leads to formation of free
vanillin with the characteristic odour.
CHO
CHO
Enzyme
OCH3
OCH3
OH
O-glucose
Vanillin Glucoside
Free Vanillin
3- Essential oil of Wintergreen (methyl salicylate)
O-glucose
OH
Enzyme
COOCH3
Oil of wintergreen
COOCH3
Methyl salicylate
gaultherin
20
4-Rhubarb
On
storage,
oxidation
of
anthranol
or
anthrone
to
give
anthraquinones which have the characteristic laxative effect.
OH
O
Oxidation
Anthranol
O
Oxidation
H
Anthrone
O
OH
Anthraquinone
II- UNDESIRABLE CHANGES
1-Glycosides are decomposed by enzymes with the formation of
compounds which are often medicinally inactive.
Example:Digitalis leaves contain cardiac glycosides. The sugar
part
is
essential
for
the
therapeutic
glycosides.
21
activity
of
the
Digitalis Lanata
lanatoside A
- acetyl
-glucose
Purpurea glycoside A
deacetyl lanatoside A
Acetyl digitoxin
- acetyl
-glucose
Digitoxin
-3 digitoxose
Digitoxigenin
-3 digitoxose
Digitoxin
-glucose
purpurea glycoside A
Digitalis purpurea
Enzymes
are
capable
for
decomposing
the
glycosides,
thus
rendering the leaves inactive.
2-Valerian:
The fresh drug contains bornyl isovaleriate (therapeutically
active) which is odourless.
Enzyme
action
decomposes
the
ester
into
borneol
isovalerianic acid which has a characteristic odour.
H3C
H3C
H3C
H3C
CH
CH 2 COO.C 10H17
enzyme
hydrolysis
Bornyl isovalerianate
odourless
CH
CH 2 COOH
isovalerianic acid
characteristic odour
+
C10H18O
borneol
22
and
3- Bitter almond contains amygdalin.
O-glucose-glucose
C6H5
CH
H
C O-glucose+glucose
CN
CN
Amygdalin
mandelonitrile
CHO
HCN +
CHO
CN
toxic
benzaldehyde
Bronasine
23