Plants used to treat infectious disease - II

1. Plants used to treat infectious disease - II Antimalarials

2. Malaria • Known since antiquity - Roman thought “bad air” • Still the world's most prevalent disease with 40% of the world’s population at risk • 500 million infected with malaria and 100 million experience a malaria illness each year • 2 to 3 million people die each yr from malaria, and at least one million of these are young children • Today largely confined to tropical and subtropical countries in Asia, Africa, Central + South America

3. Malaria • Caused by unicellular parasites in genus Plasmodium - 4 species of Plasmodium: P. vivax, P. ovale, P. malariae, P. falciparium - P. falciparum cause of most fatalities • Spread by bite of female Anopheles mosquito • Parasite multiplies in liver and released in blood stream • Invade red blood cells - multiply and rupture RBC • Cycle repeats every few days -symptoms fever, chills, anemia....death

6. Fever bark tree • Genus Cinchona native to the slopes of the Andes Mountains in South America • Small evergreen trees belong to the Rubiaceae, the coffee family • Called quina-quina by the Incas • 38 species Cinchona - several used to treat malaria

7. Use of Quina-quina • Fever reducing powers of the tree were well known to the Incas who shared knowledge with Jesuit missionaries • many variations on this story including the discovery of the medicinal properties by the Jesuits themselves • Bark of tree used for many medicinal purposes • Analgesic, Anaesthetic, Antibacterial, Anti-malarial, Anti-microbial, Anti-parasitic, Antiseptic, Astringent, Febrifuge, Muscle-relaxant

8. Small specimen of Cinchona pubescens in the Rubiaceae

9. Cinchona sp.

10. Jesuit’s bark • Jesuits used bark to treat people with malaria • In 1638 - Countess of Cinchon, wife of the Viceroy of Peru - miraculous recovery spread reputation of the bark • Years later Linnaeus named the genus Cinchona in honor of the countess • By the end of the 17th century the powdered bark of the quina-quina tree was the standard treatment for malaria

11. Quinine • In 1820 two French scientists isolated the alkaloid quinine • Within a few years purified quinine was available commercially • Demand for the bark increased even more • 36 alkaloids in Cinchona bark - 4 have anti-malarial properties • Quinine is the most effective

12. Quinine

13. Cinchona • Bark of wild Cinchona species may yield up to 7% quinine - cultivated species as much as 15% • British started plantations in India and Dutch in Java in the 1860s to 1870s • Java soon became the leading producer of quinine - accounting for 95% of the commercial supply

14. Physiological action • Quinine kills parasite in blood stream • 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

15. 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

16. 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

17. 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

18. Chloroquinine • Today the most widely used drug for malaria is chloroquine which is less toxic and more effective than quinine - mefloquine another synthetic • Widespread use of chloroquine has resulted in chloroquine-resistant strains of the parasites • Parasites becoming resistant to other drugs as well • Quinine often used for these infections in combination with other drugs - quinine also used for complicated malaria

20. Artemisinin Artemesia annua

21. Artemesia annua • Recently scientists have been investigating anti-malarial properties of plant Artemesia annua, wormwood, annual wormwood, sweet wormwood, sweet Annie, qinghao • Herbaceous annual native to Asia - probably China - often considered a weed • Plant became naturalized in many countries and now almost a worldwide distribution

22. Artemesia annua Sweet Annie Sweet wormwood Annual wormwood Qinghao

23. Traditional uses of qinghao • Used for treating malaria for over 2000 yrs • Mentioned in an early medical treatise that has been dated at 168 BC • Mentioned in Chinese Handbook of Prescriptions for Emergency Treatments of 340 AD for the treatment of fevers • Modern scientific studies on this plant began in the late 1960s and artemisinin isolated in 1972

24. Artemesinin • Sesquiterpene lactone with an endoperoxide bridge • Artemisinin and derivatives are being called endoperoxides

25. Distribution of artemisinin • Essential oils of Artemisia annua contain at least 40 volatile oils and several nonvolatile sesquiterpenese - 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

26. Current uses • Artemisinin and derivatives are effective in treating chloroquinine resistant strains of Plasmodium • Artemisinin is being used in China, Vietnam, Thailand, Myanmar (Burma) where multi-drug resistance has occurred • Clinical trials on-going in many areas

27. Artemisinin • Advantages - clear parasites from blood faster than other drugs • Disadvantages • short half life so high rates of reinfections • 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