Ten Plant-Based Medicines That Altered the Course of Human History

Photo by Joydeep | CC BY-SA 3.0

10. Vincristine & Vinblastine

Vincristine and vinblastine are two related chemotherapeutic drugs used to treat cancer. Vincristine is used most often to treat non-Hodgkin’s and Hodgkin’s lymphoma. Vinblastine is also used to treat Hodgkin’s lymphoma as well as non-small cell lung cancer, bladder cancer, and many other cancers. Before vincristine and vinblastine were exotic-sounding chemotherapeutic agents, they were simple alkaloids dwelling comfortably within the Madagascar periwinkle plant (otherwise known as Catharanthus reseus if you want to impress your friends).

The aboriginal people of Madagascar had long used this member of the periwinkle family to treat the condition now known as diabetes. In the 1950s, a Canadian physician named Dr. Robert Noble set out to isolate the compound responsible for the Madagascar periwinkle’s proposed blood sugar-lowering effects.1

Dr. Noble’s research showed that instead of lowering blood sugar the Madagascar periwinkle lowered white blood cell count. However, this observation led to the extraction and isolation of the offending alkaloids: vincristine and vinblastine. It wasn’t long before Dr. Noble and his colleagues inferred a potential use for these alkaloids in the battle against blood cancers.2 One such blood cancer, lymphoma, is characterized by an overproduction of abnormal white blood cells. Thus, an alkaloid that could inhibit the growth of white blood cells represented an exciting new pharmacologic avenue for treating lymphoma.

Vincristine and vinblastine both inhibit cancer cells by binding to the protein tubulin found in the cell’s nucleus. This binding interferes with the process of cell division and growth known as mitosis. Unfortunately, the interference is not isolated to cancer cells and affects healthy cells as well. The reason that the cancer is preferentially killed stems from the rapidly accelerated rate of mitosis and cell division characteristic of cancer cells.

So as it turned out, rather than isolating a new diabetic medication, Dr. Noble discovered the first two anticancer drugs derived from the natural world and approved for use in humans.

Photo by Jason Hollinger CC BY 2.0
Photo by Jason Hollinger | CC BY 2.0

9. Paclitaxel

Paclitaxel is another anticancer drug derived from the natural world. Paclitaxel is used to treat lung, pancreatic, ovarian, and breast cancers. In contrast to the accidental discovery of the anticancer properties of vinca alkaloids, paclitaxel’s discovery resulted from a targeted research effort.

In 1958 the National Cancer Institute funded a program with the purpose of screening substances for anticancer properties. In 1962 bark from a Washington state Pacific yew tree, Taxus brevifolia, was collected and delivered to the lab of Dr. Monroe E. Wall in Research Triangle Park, North Carolina. Dr. Wall and his team went on to discover that the Pacific yew tree bark inhibited tumor growth.3 The team continued work with the Pacific yew until, in 1971, researchers isolated the compound responsible for the Pacific yew’s anticancer properties. Dr. Wall named this substance “paclitaxel.”

It wasn’t until 1992 after researchers had worked out a way to generate the compound synthetically, that paclitaxel was approved for use in humans. Paclitaxel, like the vinca alkaloids, targets the protein tubulin. However, rather than merely disrupting the process of division, paclitaxel arrests it. Paclitaxel essentially over-stabilizes the dividing cell, which in turn leads to cell death.

Photo by Jeevan Jose | CC BY-SA 4.0
Photo by Jeevan Jose | CC BY-SA 4.0

8. Reserpine

Reserpine has been a component of Hindu ayurvedic medicine for centuries. Derived from the Rauwolfia serpentine root, reserpine was traditionally used to treat insanity, hypertension, and insomnia. It wasn’t until the 1950s that Dr. Emil Schlittler isolated the primary active alkaloid, reserpine, from Rauwolfia serpentine.4

Reserpine depletes the neurotransmitters norepinephrine, serotonin, and dopamine available to nerve cells by inhibiting the vesicular monoamine transporter. This depletion of neurotransmitters results in decreased blood pressure and provides a level of sedation. Reserpine was first marketed as a treatment for high blood pressure and as a calming medication for schizophrenia. In modern medicine, reserpine has been replaced by more tolerable medications and is almost never used.

Photo by Kurt Stüber | CC BY-SA 3.0
Photo by Kurt Stüber | CC BY-SA 3.0

7. Digoxin

The purple foxglove plant, Digitalis purpurea, was known for its toxic qualities for centuries before Dr. William Withering identified its use in the treatment of heart disease in the late 1700s.5

Historical accounts suggest that the discovery occurred as Dr. Withering cared for a particular patient who was dying from congestive heart failure, a syndrome then known as “dropsy.” Dr. Withering had exhausted all currently available treatments, and in an act of desperation Dr. Withering’s patient went to an herbalist who provided a secret mixture of herbs. Remarkably, not only did Dr. Withering’s patient survive after consuming the herbal concoction, he improved dramatically. Bewildered, Dr. Withering tracked the herbalist down and demanded to know the secret. The herbalist, after initial resistance, finally relented and shared the ingredients with Dr. Withering, one of which was foxglove.

The active glycoside, digoxin, responsible for foxglove’s medicinal effects was not identified until 1875. Digoxin, isolated from Digitalis lanata, inhibits the sodium-potassium pump in heart cells, increasing the force of heart muscle contraction. Congestive heart failure is a condition that can be simplistically conceptualized as resulting from a failing pump, thus a pump-enhancing medication such as digoxin provided significant clinical utility in some subsets of heart failure.

Interestingly, in overdose digoxin produces a yellow-green shift in vision. Vincent van Gogh suffered from epilepsy and was likely treated, as was customary in the mid to late 1800s, with digoxin. Some scholars argue that the yellow hue in his most famous works, including “The Starry Night,” was the result of an over-eager dosing regimen by his treating physician.6

Photo by Alex Popovkin | CC BY 2.0
Photo by Alex Popovkin | CC BY 2.0

6. Pilocarpine

Dr. Symphronio Coutinhou, a Brazilian physician, observed aboriginal people in South America consume the leaves of the Pilocarpus jaborandi plant to induce salivation. Dr. Coutinhou recognized the possible therapeutic use of these leaves and in the year 1873 he collected specimens to bring with him on a visit to Europe. It was in Europe that the active alkaloid, pilocarpine, was isolated from Pilocarpus jaborandi and found to have, among other effects, profound drool-inducing properties.7

Pilocarpine is a parasympathomimetic, which means that it stimulates the muscarinic receptors of the parasympathetic nervous system. This stimulation has a wide range of effects but pilocarpine was primarily used for two effects in particular: inducing salivation and lowering intraocular pressure. These effects made pilocarpine the treatment of choice for dry mouth and glaucoma for many years.

Photo by Tom Oates | CC BY-SA 3.0
Photo by Tom Oates | CC BY-SA 3.0

5. Atropine

Atropine, like pilocarpine, is an alkaloid that acts on the parasympathetic nervous system. However, unlike pilocarpine, atropine is a parasympatholytic, inhibiting rather than stimulating the parasympathetic nervous system.

Atropine is derived from the plant Atropa belladonna and has been used as a medicinal supplement for at least two millennia.8 One of the many effects of atropine on the human body is the dilation of the pupils when placed in the eyes. In the first century BCE, Cleopatra used atropine extracts to dilate her pupils because large pupils were considered attractive (of note, the pupil naturally dilates when an individual is sexually attracted to a potential mate). The practice of atropine induced pupil dilation fell out of favor in the early centuries of the Common Era, but saw a resurgence during the Renaissance in the 1400s.

Atropine’s effects on the pupils can take around seven days to reverse so when your optometrist dilates your eyes he or she is likely using the shorter-acting tropicamide (a parasympatholytic) or phenylephrine (a sympathomimetic). If, however, your optometrist is using atropine and you’re stumbling around for a week after your yearly check up it may be time to open up the yellow pages and find yourself a new eye doctor.

Photo by Ethel Aardvark | CC BY 3.0
Photo by Ethel Aardvark | CC BY 3.0

4. Curare

In the 1500s European explorers arrived in South America, bringing European imperialism and exotic diseases to the tribes of South America. Conflict soon arose and European firearms were met with, among other weapons, barbed tip arrows coated in a substance that would later be identified as the alkaloid curare.

Curare is a powerful acetylcholine receptor antagonist; it blocks all action of the receptor. One of the many roles of acetylcholine receptors are to stimulate the contraction of muscles, including the diaphragm. The diaphragm acts as a bellows to move air in and out of the lungs. Needless to say, it may be an understatement to call curare’s inactivation of the diaphragm (as well as all other muscles) the proverbial salt in the barbed-arrow wound of the unfortunate European explorer who found himself on the business end of this South American weapon.

Unsurprisingly, an arrow that stopped a man from breathing was newsworthy and word about the poison-tipped arrows quickly traveled back to Europe. In 1735 Charles Marie de la Condamine collected samples of the curare poison from the plant Chondodendron tomentosum during his trip to Ecuador.7 The samples were transported back to Europe where curare was formerly analyzed and studied.

Curare would traverse great geographic and chronologic distances to find a home in the pharmacologic armamentarium of a Dr. Abram Bennett and his electroconvulsive therapy (ECT) clinic in 1940s Nebraska. ECT is a procedure by which a seizure is induced using electrical stimulation. The therapy is used to treat severe depression among other conditions. However, in the early 1940s the therapeutic seizure sometimes had the pesky side effect of causing vertebral fractures. Curare, however, allowed patients to be anesthetized, temporarily paralyzed (with assisted breathing), and treated without the danger of a seizure-related vertebral fracture. Thus, rather than providing another potential source of depression (a vertebral fracture), curare allowed patients to experience the pure antidepressant effect of ECT.

Public Domain
Public Domain

3. Quinine

Quinine is an alkaloid found in the bark of the Cinchona calisaya tree that has been used to treat malaria since the 1600s. Incan legend tells the story of a feverish man lost in the jungle (ostensibly thanks to a malarian-drunk mosquito). The unfortunate Incan man was said to have been unduly parched thanks to his pyrexic predicament and found himself facing the awful choice of quenching his thirst in a dirty puddle or perishing with a mouth as dry as the Saharan desert. The man fell to his knees and drank thirstily from the brackish water, noting its bitter taste before passing out from exhaustion. Upon awaking, the man found that his fever had broke.

The Incan man shared his discovery with his fellow villagers and the bitter taste was linked to the cinchona (“quina-quina” in the local dialect) tree bark spoiling the puddle. Incan medicine men noted the unpleasantly bitter taste of the quina-quina bark so they mixed sugar in with the water for their patients, creating the forerunner of tonic water (gin would come later).

It wasn’t long before a Jesuit priest took note of the Incan’s use of the quina-quina bark and subsequently began shipping the rebranded “Jesuit’s bark,” as it would come to be known, back to Europe. When the bark was used to cure King Charles II in the late 1600s, quinine became the staple treatment for malaria.9

Quinine would not be identified as the active alkaloid in quina-quina bark until the 1820s. Quinine works by interfering with the malaria-causing parasite’s ability to digest hemoglobin (a rather important component of our red blood cells).

Photo by Dinkum | CC0
Photo by Dinkum | CC0

2. Morphine

Morphine is an alkaloid component of the opium latex contained within the Papaver somniferum poppy flower. Some scholars believe that opium has been used medicinally as a treatment for pain for around four millennia.10 Morphine acts on opioid receptors in the brain to produce profound analgesia.

In the 1500s opium was a key ingredient in a pain-killing mixture known as “laudanum.” In 1804 morphine was isolated from opium by a German pharmacist named Friedrich Serturner. And in 1827 the company that would later become Merck began mass-producing morphine.

Bayer tweaked Merck’s morphine structure and created diacetylmorphine. Bayer marketed diacetylmorphine (almost twice as potent as morphine) under the name “heroin” in 1874. Marketed as a non-addictive substitute for morphine (whoops!), heroin was available for retail until 1924.

CC BY-SA 3.0
CC BY-SA 3.0

1. Aspirin

Hippocrates, of the famous oath, documented the benefits of white willow bark, Salix alba, in the treatment of headache, fever, and pain in the 400s BCE. It wasn’t until 1763, however, that Edward Stone at the University of Oxford isolated salicylic acid from salicin, the active ingredient of white willow bark.11

Many years and many experiments later, chemists at Bayer acetylated a version of salicin from the plant Filipendula ulmaria to create acetylsalicylic acid (or “ASA” as every medical student with writer’s cramp documents for short). Acetylsalicylic acid would be branded “Aspirin” in 1899 and would remain the chief antipyretic (fever reducer) and analgesic (pain reliever) used by pyretic and algesic patients the world over until early versions of Tylenol and Advil came on the scene in the 1950s and 60s.

References

  1. Ahmed MF, Kazim SM, Ghori SS, et al. Antidiabetic Activity of Vinca rosea Extracts in Alloxan-Induced Diabetic Rats. Int J Endocrinol. 2010;2010:1-6. doi:10.1155/2010/841090.
  2. Noble RL. The discovery of the vinca alkaloids–chemotherapeutic agents against cancer. Biochem Cell Biol Biochim Biol Cell. 1990;68(12):1344-1351.
  3. Newton DE. Chemistry of Drugs. New York: Facts on File; 2007. http://search.ebscohost.com/login.aspx?direct=true&scope=site&db=nlebk&db=nlabk&AN=229592. Accessed September 1, 2016.
  4. Raviña Rubira E. The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. Weinheim: Wiley-VCH; 2011.
  5. Wade OL. Digoxin 1785-1985. I. Two hundred years of digitalis. J Clin Hosp Pharm. 1986;11(1):3-9.
  6. Wolf P. Creativity and chronic disease Vincent van Gogh (1853-1890). West J Med. 2001;175(5):348-348. doi:10.1136/ewjm.175.5.348.
  7. Sneader W. Drug Discovery: A History. Hoboken, N.J: Wiley; 2005.
  8. Brighetti A. From belladonna to atropine. Il Policlin Sezione Prat. 1966;73(35):1171-1174.
  9. Achan J, Talisuna AO, Erhart A, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10(1):144. doi:10.1186/1475-2875-10-144.
  10. Norn S, Kruse PR, Kruse E. History of opium poppy and morphine. Dan Med Årb. 2005;33:171-184.
  11. Sneader W. The discovery of aspirin: a reappraisal. BMJ. 2000;321(7276):1591-1594.

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