Plants used to treat infectious disease - II
Antimalarials
Malaria
History Statistics Caused by unicellular parasites in genus
Plasmodium Plasmodium vivax, Plasmodium ovale, Plasmodium malariae P. falciparum cause of most fatalities
Spread by bite of female Anopheles mosquito
Fever bark tree
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
Small specimen of Cinchona pubescens in the Rubiaceae
Cinchona sp.
Historical use of quina-quina
Well known to Incas Shared with Jesuits Bark of tree used for many medicinal
purposes analgesic, anaesthetic, antibacterial, anti-
malarial, anti-microbial, anti-parasitic, antiseptic, astringent, febrifuge, muscle-relaxant
Jesuit’s bark
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
1820 - alkaloid quinine isolated Purified quinine soon available Demand for the bark increased 36 alkaloids in Cinchona bark - 4 have anti-
malarial properties Quinine is the most effective
Quinine yields Plantations
Quinine
Physiological action
Quinine kills parasite in blood stream Also effective as a prophylactic to prevent
initial infection of red blood cells in travelers "gin and tonic” one of the earliest prophylactics Not 100% effective
Quinine mode of action
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
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
During World War II synthetics were developed In 1944 Robert Woodward and William Doering
synthesized quinine from coal tar Several synthetics have similar mode of action to
quinine Chloroquine Mefloquine Piperaquine
Chloroquine
Chloroquinine
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
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 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
Sesquiterpene lactone with an endoperoxide bridge
Artemisinin and derivatives are being called endoperoxides
Distribution of artemisinin 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 semi-synthetics Dihydroartemesinin (DHA) – reduced lactol
derivative Artemether – semi-synthetic derivative Arteether – semi-synthetic derivative Artesunate – semi-synthetic derivative Artelinate – semi-synthetic derivative
Current uses
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
Advantages - clear parasites from blood faster than other drugs
Disadvantages 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
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