Transcript PowerPoint-Präsentation

Seminar sehari
Uji Klinik Obat Herbal dalam
Meningkatkan Kualitas Hidup
Prof Dr dr M.T.Kamaluddin, MSc, SpFK
Bagian Farmakologi
Fakultas Kedokteran Unsri
1
Palembang, 23 Februari 2013
How to use herbal products ;
efficaceous - safe
Awareness
• Increasing use
• > 80 % world pop
Acceptability
• Market
• Quality
• Collection, handling, processing,
production
• Price
Herbal products
Abuse
• Hazards
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Adulteration
• Social problems
Clinical Trials of some Herbal Products
Documented improvements
Several problems not applicable to synthetic drugs
often influence the quality of herbal drugs :
1. Herbal drugs are usually mixtures of many constituents.
2. The active principle(s) is (are), in most cases unknown.
3. Selective analytical methods or reference compounds
may not be available commercially.
4. Plant materials are chemically and naturally variable.
5. Chemo-varieties and chemo cultivars exist.
6. The source and quality of the raw material are variable.
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Differences in medicinal products
Chemical – Herbal
Chemical products
Herbal products
• First chemical products
derived from herbal
pattern
• Long-time experience in
phytotherapy
• Application of plants or
parts of plants is
historically the basis for
any therapy
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Differences in medicinal products
Chemical – Herbal
Chemical products
Herbal products
• Defined substance(s) as
active ingredient(s)
• Whole plant extract as
active ingredient
• This active ingredient is
chemically synthetizised
and exactly
characterized
• These extracts are
complex multisubstance
mixtures
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Differences in medicinal products
Chemical – Herbal
Chemical products
Herbal products
• Defined doses of the
active ingredient must
have equivalent efficacy
in every final product
• Every substance of the
extract may contribute
to the efficacy (and
tolerability) of the
extract
• Pharmacokinetic
studies are nearly
impossible to perform
due to multisubstance
character
• Pharmacokinetic
studies are easy to
perform due to
monosubstance
character
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Differences in medicinal products
Chemical – Herbal
Chemical products
Herbal products
Products with the same
active ingredient must
guarantee the same
efficacy
Products with an extract
of the same plant from
different manufacturers
may differ in efficacy
and tolerability
– proven by studies
respective to
bioavailability or
bioequivalence
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Differences in medicinal products
Herbal – Herbal
Herbal extracts of the same plant may
be different in
efficacy and tolerability !
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Differences in medicinal products
Herbal – Herbal
Herbal extracts are characterized by:
 Kind of extract
– Fluid extract
– Spissum extract
– Dried extract
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Differences in medicinal products
Herbal – Herbal
Herbal extracts are characterized by:
 Extractive agent
– Influences the kind and amount of extracted
substances (lipohilic or hydrophilic)
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Differences in medicinal products
Herbal – Herbal
Herbal extracts are characterized by:
 Drug-Extract-Ratio (DER)
– How many drug is used to get 1 g of extract?
More or less concentrated!
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Differences in medicinal products
Herbal – Herbal
Herbal extracts are characterized by:
 Composition of the extract itself
– respective to quality and quantity of all
contained substances
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Dependency of the composition of a herbal extract
from manufacturing and quality parameters
drug
extracting agent
content of active substance
content of water
cutting size
specific extracting agent
concentration
amount
portion of powder
flow rate
homogeneity
herbal extract
extraction time
filling quantity
extraction pressure
filling height /
density
extraction temperature
method of extraction
batch size
manufact. process
static pressure
facility
Differences in medicinal products
Herbal – Herbal
• Efficacy and safety of a herbal extract
depends on its very special quality!
• Extracts from the same part of the same
plant can show different clinical properties
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Differences in medicinal products
Herbal – Herbal
Results of clinical studies with an extract of
manufacturer A are not automatically valid
for the extract of manufacturer B
The preparation of an extract and the
production process for the medicinal
product is based on a very special
knowledge in each company!
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Standardization and quality control of herbal crude
drugs –WHO (1996a and b, 1992), is the process
involved in the physicochemical evaluation of crude
drug covering aspects:
• selection and handling of crude material,
• safety, efficacy and stability assessment of
finished product,
• documentation of safety and risk based on
experience, provision of product information to
consumer and product promotion.
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Attention in quality indices such as:
1. Macro and microscopic examination:
For Identification of right variety and search of adulterants.
2. Foreign organic matter: This involves removal of matter other
than source plant to get the drug in pure form.
3. Ash values: These are criteria to judge the identity and
purity of crude drug – Total ash, sulphated ash, water
soluble ash and acid insoluble ash etc.
4. Moisture content: Checking moisture content helps reduce errors
in the estimation of the actual weight of drug material. Low moisture
suggests better stability against degradation of product.
5. Extractive values:
These are indicative weights of the extractable chemical constituents
of crude drug under different solvents environment.
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6. Crude fibre: This helps to determine the woody material
component, and it is a criterion for judging purity.
7. Qualitative chemical evaluation: This covers
identification and characterization of crude drug with
respect to phytochemical constituent. It employs different
analytical technique to detect and isolate the active
constituents. Phytochemical screening techniques involve
botanical identification, extraction with suitable solvents,
purification, and characterization of the active constituents
of pharmaceutical importance.
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8. Chromatographic examination: Include identification of
crude drug based on the use of major chemical
constituents as markers.
9. Quantitative chemical evaluation: To estimate the
amount of the major classes of constituents.
10. Toxicological studies: This helps to determine the
pesticide residues, potentially toxic elements, safety
studies in animals like LD50 and Microbial assay to
establish the absence or presence of potentially harmful
microorganisms.
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Naturally occurring anxiolytic substances from
aromatic plants of genus citrus
Pimenta, Flávia Cristina Fernandes 1*, Correia, Nadja de Azevedo 2, Albuquerque, Katy Lísias Gondin Dias 2, De Sousa, Damião Peregrino 3, Da Rosa, Marine Raquel Diniz
4, Pimenta, Martina Bragante Fernandes 5, Diniz, Margareth de Fátima Formiga Melo 6 and De Almeida, Reinaldo Nóbrega 2
1Departamento de Medicina Interna, Centro de Ciências Médicas, Universidade Federal da Paraíba, Brazil. 2Departamento de Fisiologia e Patologia, Centro de Ciências da
Saúde, Universidade Federal da Paraíba, Brazil. 3Departamento de Fisiologia, Universidade Federal de Sergipe, São Cristóvão-SE, Brazil. 4Departamento de Fonoaudiologia,
Centro de Ciências da Saúde, Universidade Federal da Paraíba, Brazil. 5Faculdade de Medicina Nova Esperança – PB, Brazil. 6Departamento de Ciências Farmacêuticas,
Centro de Ciências da Saúde, Universidade Federal da Paraíba, Brazil.
Accepted 8 September, 2011
Currently, anxiety is one of the most common mental disorders affecting humanity and its prevalence is increasing.
Anxiolytic substances occupy a prominent post in the ranking of the most utilized drugs by man. However, the
anxiolytic drugs have an unfavorable risk/benefit ratio, especially benzodiazepines. Several medicinal plants have
been used in traditional folk medicine for their anxiolytic or sedative properties. It is well reported in the literature that
aromatic substances have the power to influence emotional states in humans. Several plants rich in essential oil have
been used in the treatment of anxiety. In addition, a great number of essential oils are currently in use as
aromatherapy agents to relieve stress and depression. These oils are considered a holistic complementary therapy
utilized for increased comfort and reduce stress. For this reason, we performed a literature review used papers
indexed in Elsevier Science Direct and PubMed a source of research. The dates were collected of reviewed studies
from 2000 to 2011 using essential oils of genus citrus with anxiolytic effects in preclinical models and clinical studies.
Ethnopharmacological data has confirmed the popular use of plant species of the genus Citrus with sedatives,
hypnotics, tranquilizers and anti-epileptics activities to treat disorders of the central nervous system. Given these
assumptions, this paper aims to describe the principal evidence in the literature about the use of essential oils of
genus citrus with anxiolytic effects in preclinical models and clinical studies.
Key words: Genus citrus , anxiolytic effects, preclinical models, clinical studies of anxiety.
Journal of Medicinal Plants Research Vol. 6(3), pp. 342-347, 23 January, 2012
Clinical Trials
Table 1. Preclinical studies of essentials oils from genus Citrus and
their effects on the central nervous system.
Herbs/essential oil
Linalool
Species
Mice
Reference
Linck et al. (2010)
Citrus bergamia oil
Effect
Anxiolytic, increased social interaction
and decreased aggressive behavior
Anxiolytic
Rat
Carvalho-Freiras and
Costa (2002), Pultrini et
al. (2006), Saiyudthong
and Marsden (2010 )
Cittrus aurantium oil
Anxiolytic, sedative and anticonvulsive
Rat
Leite et al. (2008) Mice
Blanco et al. (2009)
Faturi et al. (2010)
Cymbopogon citrates- Anxiolytic, sedative and Anticonvulsive
Citrus grass oil
Citrus sinensis oil
Anxiolytic
Citrus lemon oil
Anti-stress, Sedative
Mice
Citrus latifolia and C.
reticulata oil
Mice
Anti-stress and anxiolytic
Journal of Medicinal Plants Research Vol. 6(3), pp. 342-347, 23 January, 2012
Rat
Mice
Komiya et al. (2006)
Fukumoto et al.
(2008)
Gargano et al. (2008)
Citrus Bergamia
(Bergamot)
Italy
Citrus Lemon
Italy - Asia
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Clinical Trials
Table 2. Clinical studies of the essential oils of orange
( Citrus sinensis ).
Experimental design
35 patients were exposed to odor
orange and the state anxiety was
measured through questionnaires.
50 patients were exposed to odor
orange and the state anxiety was
measured through questionnaires
81 patients were exposed to odor
orange and the state anxiety was
assessed through questionnaires.
Effect
Reduced levels of stateanxiety in female.
Reference
Lehrner et al.
(2000)
Lehrner et al.
Lower levels of state
(2005)
anxiety, more positive
mood and a higher level of
calmness
Toet et al. (2010)
No effects on the
anticipatory anxiety
Journal of Medicinal Plants Research Vol. 6(3), pp. 342-347, 23 January, 2012
Clinical Trials
Autoimmune diseases and immunomodulant plant
M. M. Akram 1, M. Saim Jamil 1, Zahid Mehmood 2, Khan Usmanghani 1, Iqbal Azhar 4, Muhammad Akram 5, H. M. Asif 3 and
Umar Iqbal 1
1Shifa ul Mulk Memorial Hospital, Hamdard University, Karachi, Pakistan. 2Department of Chemistry and Biochemistry, University of
Agriculture, Faisalabad, Pakistan. 3Department of Pharmacy, The Islamia University of Bahawalpur, Pakistan. 4Department of
Pharmacognosy, University of Karachi, Pakistan. 5Department of Pharmacy, University of Sargodha, Pakistan.
Accepted 4 November, 2011
The immune system in general responds appropriately to the presence of
foreign antigens. Body immune system protects the body against invading
organisms. In an autoimmune disease, immune system attacks healthy cells in
body by mistake. Autoimmune diseases can affect many parts of the body.
Various plants are used to strengthen the immunity due to their
immunomodulatory activities. In this article, autoimmune diseases, description
of autoimmune diseases, and plants used as immunomodulant agent has
given.
Key words: Autoimmune diseases, immunomodulatory activity, medicinal plants, research study.
Journal of Medicinal Plants Research Vol. 6(7), pp. 1100-1105, 23 February, 2012
Clinical Trials
Table 3. Autoimmune classification.
Disease
Juvenile insulin-dependent diabetes
Pernicious anemia
Addison's disease
Idiopathic hypoparathyroidism
Autoimmune hemolytic anemia
Idiopathic thrombocytopenic purpura
Idiopathic neutropenia
Vitiligo
Chronic active hepatitis
Goodpasture's syndrome
Rheumatoid arthritis
Sjogren's syndrome
Systemic lupus erythematosus
Myasthenia gravis
Grave’s disease
Thyroiditis
Insulin-resistant diabetes
Asthma
Antibody against
Pancreatic islet cells
Gastric parietal cells
Adrenal cells
Parathyroid cells
Erythrocytes
Platelets
Neutrophils
Melanocytes
Nuclei of hepatocytes
Basement membranes
Gamma globulin, virus-related antigens
Nuclei and centromeres
Nuclei, DNA, RNA, erythrocytes, etc
Acetylcholine receptors
Thyroid-stimulating hormone receptor
Thyroid
Insulin receptor
Journal of Medicinal Plants
Research Vol. 6(7), pp. 1100-1105,
Beta-2 adrenergic receptors
23 February, 2012
Clinical Trials
Table 4. Research study
Plant/title
Ginseng
Activity
W. somnifera
Ocimum sanctum
In one study, it has been evaluated that ginseng polysaccharide decreases the expression of
TNF-α and interferon-gamma (IFN-γ), and regulate the function of lymphocytes in enteric
mucosal immune system in collagen-induced arthritis (CIA) rats. This study indicates that
ginseng polysaccharide could be used in the treatment of autoimmune disease (Hongyan et al.,
2011)
It has been studied that aqueous extract of O. basilicum is a powerful natural
immunomodulatory spice influencing various types of immune-responses and have potential
health effects (Tsai1 et al., 2011).
It has been studied that T. cordifolia has immunomodulatory properties, and is used for the
treatment of jaundice, skin diseases, diabetes and anemia (Chopra et al., 1982).
In one study, it has been evaluated that T. cordifolia improves the phagocytic and bactericidal
activities in patients suffering from polymorphism in surgical jaundice (Thatte et al., 1989). In
one study, effect of feeding T. cordifolia has been observed in broiler birds which were
immunosuppressed with cyclophosphamide, and found a significant rise in antibody titer
against ND virus with augmentation of inflammatory reaction to skin contact sensitivity test
(Kolte et al., 2007). Rege et al. (1989) and Bishavi et al. (2002) have proved the
hepatoprotective effect of T. cordifolia .
Akram et al. (2010) studied the immunomodulant effect of W. somnifera
Modulates humoral immune response (Kujur, 2001; Krishnamohan et al., 1997; Kumar, 2003)
A. racemosus
Stimulates both humoral and cell mediated immune responses (Kuttan et al., 1992).
O. basilicum
T. cordifolia
Journal of Medicinal Plants Research Vol. 6(7), pp. 1100-1105, 23 February, 2012
Panax quinquefolius foliage and fruit
Asparagus racemosus (Satavar, Shatavari, or Shatamull)
27Withania somnifera
Tinospora cordifolia
Clinical Trials
Main constituents of Hedera helix L.
Triterpensaponins
COO R
H
 -L-rhamnose)1
2  -L-arabinose)1
O
H
HOCH2
 -hederin:
hederacoside
C:C:
hederacoside
R
R=H
=R1(β-D-glucose)6
= 1( -D-glucose)6
–1(1(β-D-glucose)4
 -D-glucose)4 1(– 1(α-L-rhamnose)
 -L-rhamnose)
Hedera rhombea, Aizu,
Fukushima pref., Japan
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Osimum basilicum, lemon Basil
PROSPAN®
Dried extract of Ivy leaves (DER 5-7.5 : 1)
Efficacy and safety for this extract has been proved in
various clinical studies
secretolytic
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broncholytic
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cough relieving
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Documented improvements
Objective (Lung function)
Subjective
- vital capacity (VC),
- forced vital capacity (FVC),
- forced expiratory volume/sec. (FEV1),
- intrathoracic gas volume (ITGV),
- residual volume (RV),
- airway resistance (RAW, obstruction
marker)
- peak expiratory flow (PEF)
- coughing frequency
- coughing intensity
- painful coughing
- sputum production
- expectoration
- dyspnoea
- general well-being
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How to increase ß2-adrenergic effects on living
cells?
accumulation of
receptor-ligandcomplexes
ligand (L)
RL-complex
in lipid rafts
(coated pit)
ß2-adrenergic
receptor (R)
clathrin
endocytosis
α-hederin
recycling
early endosome
degradation
degradation
Inhibition of internalization of 2-adrenergic receptors
in pulmonary epithelial cells (A549)
by -hederin.
control,
untreated
10µM terbutaline 20 min
pretreatment with 1µM
-hederin for 24 h, then
10 µM terbutaline 20 min
Prospan: mode of action
-hederin influences regulatory processes
of ß2-adrenergic receptors:
-hederin inhibits redistribution as well as
internalisation of even redistributed ß2adrenergic receptors after ligand binding.
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Ivy: Mode of action – consequences I
An increased ß2-adrenergic receptor density and an increased
signal transduction lead to an increased production of cAMP:
 increased exocytosis of surfactant in pulmonary epithelial
cells (alveolar type II cells) (secretolytic effect, decrease in
mucus viscosity, decrease in coughing intensity and
frequency).
lamellar
bodies
ß2-adrenergic
receptor
surfactant
PKA
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cAMP
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Ivy: Mode of action – consequences II
An increased ß2-adrenergic receptor density and an increased
signal transduction lead to an increased production of cAMP:
 decrease in intracellular [Ca2+i] with subseeding bronchial
muscle relaxation (formation of less active myosin kinase via
phosphorylation by phosphokinase A).
Ca2+ channel
cAMP
ß2-adrenergic
receptor
[Ca2+i]
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Ivy - Resorption
In vitro (CaCo-2-cells)
0,45
0,4
0,35
0,3
0,25
0,2
0,15
0,1
0,05
0
0
50
Transport
α-Hederin
Transport
ofofalpha-hederin
C
kumulierte Konzentration
[µg/ml]
cumulated concentration [µg/ml]
Transport
of Hederacosid
C
Transport
of Hederacosid
100
0,6
0,5
0,4
0,3
0,2
0,1
0
0
20
40
60
80
time [min]
time(min)
[min]
Time
Time (min)
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100
Ivy - Resorption
In vivo – first results
alpha-hederin
• discovered in blood of treated animals and
humans
• the amount of hederacosid C given in an extract
seems to support the concentration of alphahederin in blood (prodrug??)
Actually: Ongoing works on the sensitivity of
analytical methods for further clarification
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Ivy- mode of action
-hederin
increased β2 –adrenergic stimulation
lung epithelium
bronchial muscle
surfactantproduction
Ca++
(intracellular)
secretolytic
broncholytic
dilatation of bronchial
musculature
reduction of
mucus viscosity
Expectorant
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Ivy: Effect on ß2-receptors in general
In theory -hederin supports indirectly the
stimulaton of all ß2-receptors
but
given by the smooth and indirect effect, a
result will only be seen in those organs with a
pathological condition
(e.g. ivy will have no bronchiolytic effect in case of
„normal“ bronchial muscles)
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Conclusion
• Plants contain of some chemical
substances that synergistically delivered
their effects to biological systems
• It would no obviously affect the living
cells and could be observed as clinical
effects
Thank you
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Thank you
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