Role of Alternative Medicine in Pandemic H1N1 Influenza

What is swine influenza?
A respiratory disease caused by a type of
influenza virusvirus- Novel H1N1
Human cases of the novel H1N1 influenza
(swine flu) have been identified in more
than 192 countries, including India.
As of 25 October 2009, worldwide there
have been more than 440,000 laboratory
confirmed cases of pandemic influenza
H1N1 2009 and over 5700 deaths
reported to WHO (WHO Update72).
What are the symptoms of
swine influenza?
H1N1 has two genes from flu
viruses that normally circulate in
pigs in Europe and Asia and bird
(avian) genes and human genes.
It is a "quadruple reassortant"
virus.
CDC, Atlanta
Latest WHO Update
(3 November 2009)
H1N1 Infection
(as on 3 November, 2009)
According to the Ministry of Health of
Ukraine, the country has now
recorded more than 250 000 cases of
influenzainfluenza-like illness, with 235
patients requiring intensive care.
As of 2 November, 70 deaths from
acute respiratory illness have been
reported.
High risk groups /
CoCo-morbidities
Prevention at Various Levels
Star Anise :
Source of Tamiflu
Therapy
Tamiflu:
(3R,4R,5S)-ethyl 4-acetamido-5-amino-3-(pentan-3-yloxy)cyclohex-1enecarboxylate; 30 synthetic steps from shikimic acid, extracted from spice; neuraminidase
inhibitor; oral intake possible
Derived from Star Anise (Illicium
(Illicium verum)
verum)
ORIGIN:
ORIGIN: Central America, China, India, Indonesia,
Italy, Morocco, South America, Spain
PARTS USED: Seed pod
Relenza:
(4S,5R,6R)-5-acetamido-4-guanidino-6-((1R,2R)-1,2,3-trihydroxypropyl)-5,6dihydro-4H-pyran-2-carboxylic acid; neuraminidase inhibitor; specific inhalation system
developed; discovery by computer-aided drug design/discovery
Oseltamivir
Star Anise
Star anise is a source of shikimic acid, which is used
to produce the antianti-flu drug tamiflu. It also contains
anethole, which gives them their licoricelicorice-like flavor.
Chinese star anise has been used as a spice and
medicine for over 3000 years.
Star anise has been used in Chinese and Ayurvedic
medicine and cooking for centuries. Both cultures
use it as a breath freshener and digestive.
It's soothing to the stomach and is often used in
cough medications. Star anise is usually used
together with ginger and clove to treat nausea and
vomiting.
Shikimic
Acid
to
Oseltamivir
Are oseltamivir and zanamivir the
solution?
Common Adverse Drug Reactions (ADRs)
associated with Oseltamivir Therapy
Nausea
Vomiting
Diarrhea
abdominal pain
headache.
Other ADRs reported in post marketing surveillance :
hepatitis and elevated liver enzymes, rash, allergic reactions
including anaphylaxis, and StevensStevens-Johnson syndrome.
toxic epidermal
necrolysis
cardiac arrhythmia
Seizure
Confusion
Aggravation of diabetes
Haemorrhagic colitis
Weighing CostCost-Benefit Ratio
There are concerns that oseltamivir may cause dangerous
psychological, neuropsychiatric side effects, including self harm
harm in
some users.
These dangerous side effects occur more commonly in children
than in adults.
This stems from cases in Japan, where the drug is most heavily
prescribed, consuming 60% of the world's production.
In March 2007, Japan's Health Ministry warned that
oseltamivir should not be given to those aged 10 to 19. The
Ministry had previously decided, in May 2004, to include
neurological and psychological disorders as possible adverse
effects, including: impaired consciousness, abnormal behavior,
and hallucinations.
In November 2006, the United States Food and Drug
Administration (FDA) amended the warning label to include the
possible side effects of delirium, hallucinations, or other related
related
behavior.
Vaccines 2009
• An inactivated vaccine (containing
killed virus.
• Approved for use in people 6 months of
age and older, including healthy people,
people with chronic medical conditions and
pregnant women.
• The 2009 H1N1 flu shot is being made in
the same way that the seasonal flu shot is
made.
• A vaccine made with live, weakened
viruses that do not cause the flu
(sometimes called LAIV for "live
attenuated influenza vaccine").
• LAIV is approved for use in healthy
people 2 years to 49 years of age who are
not pregnant. Manufactured in US by
MedImmune,
• Antibodies produced after ca. 2 weeks.
Why alternatives are needed?
Alternatives
Why Herbals offer Promise?
WHO Estimates
Molecular Drugs
Herbal Drugs
Mostly therapeutic
Both preventive and therapeutic
Symptomatic treatment
Holistic treatment (by and large)
High toxicity
Low toxicity
Target specific sites
Multiplicity of sites of action
Induce biochemical shock
Renders compensatory effect
Artificial combinations generated, yet Natural combinations, low toxicity
(Whole extracts or polyherbal
toxic
formulations)
• Nearly 70% of the world population is still dependent on
plants
• Renewed interest in plants:
• Western medicine…..Costly and not a solution for all
diseases
• Plants: Leads for new drugs
• New Chemical Entities (NCEs)
• Synthesized
THE GOLDEN
TRIANGLE
Promising Plants
Arora et al., 2006
Methods of Herb Delivery
Holistic Concepts in Herbal Drug Development
• Integration
• Formulation
Good Source Practice (GSP)
Good Agriculture Practice (GAP)
Good Field Collection Practice (GFCP)
Good Laboratory Practice (GLP)
GMP etc.
• Regulatory requirements
World’
World’s Major Herbal Traditions
EUROAMERICA N
JAPA NESE
KEMPU
OTHE R
INDE GENOUS
SYSTEMS
Arora et al., 2009 eCAM communicated
Ocimum sanctum (Lamiaceae)
•
•
•
•
•
The plant as a whole, is a treasure house of
potent compounds.
Oleanolic acid, ursolic acid, rosmarinic acid,
eugenol, carvacrol, linalool, and β-caryophyllene.
Ocimum extracts are used in ayurvedic remedies for
common colds, headaches, stomach disorders, inflammation,
heart disease, various forms of poisoning, and malaria.
Fresh leaves also cure chronic fever and when mixed with
honey and ginger juice, it is useful in cough, bronchitis.
Immunomodulatory action.
Tinospora cordifolia
•
•
•
•
(Menispermaceae)
Picrotene and bergenin found in the plant.
Traditionally used as remedy for influenza.
Immunomodulatory activity.
Enhancement in humoral immunity.
Bergenin
Dimethylallyl pyrophosphate
Ursolic acid
Rosmarinic acid
Camellia sinensis
Glycyrrhiza glabra
(Papilionaceae)
Green Tea
• Mulathee
• Triterpine, saponins, Glycyrrhizic acid, anti-viral
compounds.
• Stimulate macrophages.
• Efficacy against the influenza A virus that is mediated by
stopping the virus replication.
• Inactivates virus particles.
•
•
•
•
•
Undergone minimal oxidation during processing.
Particularly rich in polyphenolic compounds and catechins.
The compounds strongly inhibit
adsorption of the viruses on RBCs.
Green tea has ability to enhance
humoral and cell-mediated immunity.
Useful for preventing influenza by inhibiting
Flu replication, using potentially
direct virucidal effect.
Glycyrrhizic acid
Panax quinquefolius
Ginkgo biloba (Ginkgoaceae)
•
•
•
•
Native of China
150 million years old, endangered sp.
Leaves
Flavonoid glycosides and terpenoids
(ginkgolides, bilobalides).
• Increases peripheral and cerebral blood flow
• antioxidant
• Immuno-stimulant.
• Ginsenoside, Protopanaxadiol
• Ginseng prevent s colds.
• Effectively provide immunity to individuals against
influenza.
• Rhizome
• Adaptogenic
Ginsenoside
Protopanaxadiol
Ginkgolides
Bilobalides
Mentha piperita
Echinacea (Asteraceae)
(Labiatae)
• Native to North America
• All parts of plant used
• Contains Polysaccharides, phenols, alkylamides
and Cichoric acid.
• Immunostimulant, non-specific
• Helps infections (resistance and treatment), esp.
upper respiratory. Helps patients recover faster .
• Increase antibody production, raise white blood cell
counts, and stimulate the activity of key white blood
cells.
• Long history of use in Europe
• Leaf, essential oil.
• Principal components of the oil are menthol, menthone
and menthyl acetate.
• Menthol is virucidal against Influenza.
• Leaves possess anti-Influenza A activity.
Pulegone
Menthone
Phyllanthus emblica
Azadirachta indica
(Euphorbiaceae)
• Amla (Hindi).
• Indian gooseberry is a common constituent of most of
the polyherbal formulations.
• Antiviral activity against Hepatitis B virus and A and B
influenza virus.
• Apoptosis induction.
(Meliaceae)
• Leaves, seeds, oil.
• Seed contains Azadirachtin.
• Neem has traditionally been used as an antiviral
substance.
• Viral replication hindered.
• May serve to be potent against Influenza.
Kaempferol
Azadirachtin
Ellagic_acid
HPLC profile NEEM seeds
Alium sativum (Alliaceae)
• Lahsan (Hindi).
• Grand conductors of the body’s immune symphony.
• Garlic has been used for hundreds of years to treat
fungal, parasitic, and viral infections.
• Efficiently acts as virucidal in early stages of
infection.
• In-vitro anti-influenza activity proven.
Aegle marmelos(Rutaceae)
• Aegelin, Marmorosin, β-sitosterol, Tembamide.
• Stem, bark, root, leaves and fruit have medicinal virtues.
• Oil from Bael gives relief from recurrent cold and
respiratory infection.
• Imperorins from Indian variety is a potent anti-viral.
Aegelin
β-sitosterol
Actaea racemosa
Zingiber officinale (Zingiberaceae)
(Black cohosh)
• Ginger root.
• Zingerone (allicin, alliin, and ajoene), shogaols and
gingerols.
• Anti-influenza agents, anti influenza cytokine, TNFα.
• Beneficial in inflammatory reactions triggered by virus.
•
•
•
•
•
•
•
Native to North America
Roots and rhizomes (underground stem)
Remedy for colds, cough.
Putrid sore throats.
Curative for the headache of influenza.
Proved potent during last pandemic
influenza of 1918.
Zingerone
Gingerols
Sophora flavescens
Centella asiatica
(Sophora)
(Apiaceae)
Medicinal Uses:
•
• Roots are regionally called ku shen or kushenin.
• Flavonoids
• Quinolizidine alkaloids matrine (MT) and
oxymatrine (OMT), have been reported to exhibit
anti-viral activity.
• Efficacy against H1N1 infection.
•
•
•
•
•
Constituents:
•
•
Common name: Brahma-manduki;
Mandukaparni
Distribution: Low lying marshy regions
of the Himalayas
Toddalia asiatica
•
Hydrocotylin
Asiaticoside
Oxy-asiaticoside
Ganoderma: The Magical Mushroom
(Rutaceae)
• Seed
• Treatment of malaria, sprains, cough, fever, neuralgia,
epilepsy, dyspepsia and other disease conditions.
• Benzophenanthridine alkaloids, coumarins,
cyclohexylamides and terpenoids.
• The essential oil from the plant is highly potent antimicrobial agent.
Leprosy
Insecticidal
Brain tonic
Tuberculosis
Skin diseases
Behavioural radioprotection
• Ganoderma is one of the well known Traditional Chinese
Medicine which has been found to be effective on a
number of modern health problems.
• How Ganoderma can help in preventing Swine-Flu
Symptoms?
–
–
–
–
–
–
–
Preventing Coldness or Chill
Preventing Cough
Preventing Body Fatigue
Anti inflammatory properties of Ganoderma prevent fever
Head aches and Body Aches
Sore throat
Stuffy nose
Chemical Fingerprinting and
Characterization of
Phytochemicals
• Thin Layer Chromatography
• High Performance Thin Layer Chromatography (HPTLC)
• High Performance Liquid Chromatography (HPLC)
– Analytical and
– Preparative
• LC-MS
• LC-MS/MS
• Gas Chromatography
• GC-MS
• NMR
• UV-visible spectroscopy
• Capillary electrophoresis
Issues in Herbal Drug
Development
• Availability of good quality raw material
• Authentication of raw material
• Availability of chemical standards
• Authenticated and proper standardization
• Methodology of single chemical based herbal drugs
and polyherbal formulations or poly-chemical herbal
compositions
• Quality control parameters
• Reproducibility
• Animal Studies and mode of dispersions
Bioactivity-Guided Fractionation
and Isolation of Phytoconstituents
Spectroscopical
data on line
Spectroscopical
data off line
Synthesis
LC/UV
LC/MS
LC/NMR
Medicinal Plants
with Antiviral
H1N1
Properties
Extracts
Fractions
Bioassay
Bioassay
LC/UV
LC/MS
Structure
elucidation
LC/NMR
Pure Constituents
Toxicology
Structure
Modification
Bioassay
Herbal Drugs: Preparing for Future
Pandemics
Develop preparations either as single molecules
or comprising of multiple molecules and
evidence –based analysis for future pandemics.
Make existing preparations molecular-defined.
Investigate synergism.
Develop specific preparation(s) which
accelerate therapy and recovery.
Develop non-specific adaptogenic preparations
with a wide spectrum of activity against
viruses.
Every Cloud has a Silver Lining!
• Dr. RK Sharma, Sc ‘F’ & Joint Director, INMAS
• Dr. RP Tripathi, Director, INMAS
• Defence Research and Development
Organization (DRDO)
• All my PhD students Rohit, Jyoti, Atlar, Manish,
Poonam and Deepti.
Thank you