Download Infectious Diseases

Plants used to treat infectious
disease - II
Antimalarials
Malaria
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History
Statistics
Caused by unicellular parasites in genus
Plasmodium
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Plasmodium vivax,
Plasmodium ovale,
Plasmodium malariae
P. falciparum cause of most fatalities
Spread by bite of female Anopheles mosquito
Fever bark tree
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Genus Cinchona native to the slopes of the Andes
Mountains in South America
Member of the Rubiaceae, the coffee family
Called quina-quina by Incas
38 species Cinchona - several used to treat malaria
Small specimen
of Cinchona
pubescens in
the Rubiaceae
Cinchona sp.
Historical use of quina-quina
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Well known to Incas
Shared with Jesuits
Bark of tree used for many medicinal
purposes
 analgesic, anaesthetic, antibacterial, antimalarial, anti-microbial, anti-parasitic,
antiseptic, astringent, febrifuge, musclerelaxant
Jesuit’s bark
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Jesuit’s bark
1638 - Countess of Cinchon, wife of the Viceroy of
Peru
Linnaeus named the genus Cinchona
Late 17th century - standard treatment for malaria
Quinine
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1820 - alkaloid quinine isolated
Purified quinine soon available
Demand for the bark increased
36 alkaloids in Cinchona bark - 4 have antimalarial properties
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Quinine is the most effective
Quinine yields
Plantations
Quinine
Physiological action
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Quinine kills parasite in blood stream
Also effective as a prophylactic to prevent
initial infection of red blood cells in travelers
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"gin and tonic” one of the earliest prophylactics
Not 100% effective
Quinine mode of action
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Parasite feeds on hemoglobin - Breaks down
globin proteins into a.a. in lysosomes - heme
converted to a non-toxic product by parasite
Quinine accumulates in lysosome of parasite in
RBC
Quinine binds to heme and inhibits conversion of
heme to non- toxic product
Heme-quinine complex highly toxic to parasite
May function by disrupting lysosome membrane
Side effects
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Ringing in the ears, possible hearing loss
Dizziness
Gastrointestinal upset: nausea, vomiting,
diarrhea, abdominal pain
Rashes
Visual disturbances - blurred vision
More serious side effects in rare cases
Synthetics
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During World War II synthetics were developed
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In 1944 Robert Woodward and William Doering
synthesized quinine from coal tar
Several synthetics have similar mode of action to
quinine
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Chloroquine
Mefloquine
Piperaquine
Chloroquine
Chloroquinine
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Chloroquine is less toxic and more effective
than quinine
Most widely used drug for malaria
Widespread use of chloroquine has resulted
in chloroquine-resistance
Parasites becoming resistant to other drugs
as well
Piperaquine – seeing increased use in
chloroquine resistant areas
Artemisinin
Artemesia annua
Artemesia annua
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Artemesia annua, wormwood, annual
wormwood, sweet wormwood, sweet Annie,
qinghaosu
Member of the Asteraceae (sunflower family)
Herbaceous annual native to Asia
Plant became naturalized in many countries
and now almost a worldwide distribution
Often considered a weed
Artemesia annua
Sweet Annie
Sweet wormwood
Annual wormwood
Qinghaosu
Traditional uses of qinghaosu
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Used for treating malaria for over 2,000 yrs
Mentioned in an early medical treatise that has been
dated at 168 BC
Mentioned in Chinese Handbook of Prescriptions for
Emergency Treatments from 340 AD for the
treatment of fevers
Modern scientific studies on this plant began in the
late 1960s and artemisinin isolated in 1972
Artemesinin
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Sesquiterpene lactone
with an endoperoxide
bridge
Artemisinin and
derivatives are being
called endoperoxides
Distribution of artemisinin
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Essential oils of Artemisia annua contain at
least 40 volatile oils and several nonvolatile
sesquiterpenes components - artemisinin is
one of these
The essential oils are found in glandular
trichomes on the leaves, stems, and flowers
Artemisinin content appears to be highest in
the trichomes of the flowers
Artemesinin derivatives and semisynthetics
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Dihydroartemesinin (DHA) – reduced lactol
derivative
Artemether – semi-synthetic derivative
Arteether – semi-synthetic derivative
Artesunate – semi-synthetic derivative
Artelinate – semi-synthetic derivative
Current uses
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Artemisinin and derivatives are effective in
treating chloroquinine resistant strains of
Plasmodium
Artemisinin and/or derivatives used in China,
Vietnam, Thailand, Myanmar (Burma) where
multi-drug resistance has occurred
Clinical trials on-going in many areas
Combined therapy with piperaquine being
used in many areas
Artemisinin
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Advantages - clear parasites from blood
faster than other drugs
Disadvantages
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short half life so high rates of reinfection
poor oral bioavailability
liver stages are not affected so not good as a
prophylactic or for radical cures (eradicating
the dormant liver stage for P. vivax and ovale
Derivatives should help overcome these