Medicinal Plants
There is documentation from 4000 years ago that plants have been used to treat diseases
In the US, 25% of all prescription drugs are from plants or based on plant-derived compounds.
50% if fungal compounds are included
Herbal Medicine is still very big in many parts of the world.
There’s an Amazonian Conservation team working with indigenous people in Suriname to identify their herbal plants and protect them from habitat destruction and global warming.
Preserves the knowledge.
All our plant-based prescription drugs started out as herbal remedies somewhere.
Knowledge that the plant has healing properties
in literature or word of mouth
Isolation and structural characterization of the active component(s).
Mode of Action
Clinical Trials
Drug Development
Phenolics
Aspirin and related NSAIDs
Terpenoids
eg. steroid
Alkaloid
Contains Nitrogen
Are usually basic (alkaline) and taste bitter
Pronouced actions on the nervous system
quinine, caffeine, nicotine, cocaine, ephedrine
Active components were found to be steroid-type compounds
affects Na+K+ATPase
A diuretic
Used to treat Congestive Heart Failure
Does not cure the disease, just treats the symptoms
Digitoxin is the prescription drug
individualized doses
William Withering was an English Clergyman that studied a herbal tea that was used to treat “dropsy”
It contained 20 plants
He found that the active principle was foxglove
Dropsy is a condition characterized by severe bloating due to fluid accumulation
AKA Congestive Heart Failure
80 million aspirin tablets are taken every day in the US
Aspirin doesn’t come from a willow tree or occur naturally
2500 years ago the Greeks used an infusion from white willow (Salix Alba) bark to treat rheumatism, fever, and pain
Many Native American tribes had independently discovered the healing powers of willow bark
1839: Salicin was identified in willow bark extracts by German chemists
Aromatic ring with a sugar group
Salicylic acid (SA) was synthesized in labs in Germany to treat gout and rheumatism
Salicin is converted to SA in the stomach naturally (the aromatic ring loses the sugar group)
Other plants contain SA too including Spirea and wintergreen
Acetyl Salicylic acid was more palatable and had fewer side effects
Acetyl Salicylic acid is what aspirin actually is
Aspirin is an analgesic (pain-killer), antipyretic (fever breaker), and anti-inflammatory
Aspirin is easy to make in a laboratory, its cheap, and effective
British Biochemist, John Vane showed that aspirin inhibits prostaglandin synthesis (1970)
Arachidonate acid (the precursor of prostaglandins) is synthesized in mammals from linoleic acid (18:2)
Prostaglandin: considered to be a “local hormone,” stimulates inflammation, regulates blood flow
Made on site
Prostaglandin synthase has 2 different catalytic activities, one is cyclooxygenase (COX) activity.
Aspirin irreversibly inhibits COX activity which is how it decreases inflammation, pain, and fever
Arachidonate cannot bind in the groove to get converted to a Prostaglandins
Other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Like Ibuprofen and Naproxen
Thousands of compounds have been synthesized in the lab, based on aspirin as a prototype
The use of aspirin for pain and inflammation has been, to a certain extent, superseded by other NSAIDs
NSAIDs are more gentle on the stomach
Because aspirin inhibits COX activity it inhibits the biosynthesis of thromboxanes (later in the prostaglandin pathways)
Thromboxanes are used in blood clotting
This is the basis for the effect of aspirin in preventing blood clots (thrombi)
Aspirin is taken daily by millions of people to reduce blood clots, heart attacks, and stroke
Salicylic Acid is known to have some positive health effects
in fact, aspirin is metabolized in the human body into Salicyclic acid very quickly (within a minute)
3 billion people get parasitic diseases a year
Malaria comes from the Italians’ belief that it was caused by “Bad Air”
The worse of these is Malaria which affects millions a year
Estimated there are half a billion clinical cases of Malaria a year
Usually confined to tropical/subtropical regions
Plasmodium: is the causative organism (protest) of malaria
4 species are responsible for most of the cases
Plasmodium is transmitted from person to person by a mosquito vector
Life Cycle of a Plasmodium
When a female, Anopheles mosquito, harboring the malaria parasite in her salivary glands, bites an individual, the sporozoite stage of the parasite is injected. The sporozoites are carried to the liver in the bloodstream
In the liver, merozoites are produced and released into the bloodstream
The merozoites invade RBCs and multiply
After a period of time the RBCs rupture, releasing a new generation of merozoites, which then infect other RBCs. The cycle is synchronous with the simultaneous rupture of RBCs and release of merozoites and toxins, causing the periodic fever and chills
Male and female gametocytes are formed in some RBCs. If the gametocytes are ingested when an Anopheles mosquito bites an infected individual, they can complete sexual reproduction and begin the infection cycle anew.
Cinchona: contains quinine for the treatment of malaria
Make tea with the bark
Also called the fever bark tree
Thought to have been used 1st in Peru
Documented use in the early 1600s
Knowledge of the tree and samples of the bark was taken to Europe by Jesuit missionaries in the 17th century, then we went worldwide.
The active ingredient was 1st isolated by French scientists in 1820
1880: the 1st determination that malaria was a parasitic disease
1896: confirmed transmission of the parasite by a mosquito to human
1944: the 1st synthetic version (Chloroquine) is made
The occupation of Java during WWII by the Japanese shut down the major supplier by quinine to the world
Quinine and chloroquine both block the life cycle of the Plasmodium at the red blood cell stage
Chloroquine - used extensively
less toxic and more effective than Quinine
Primaquine
Mefloquine and many more
There are some problems associated with Plasmodium developing resistance to quinine and its derivative
So other plants are being studied
Artemisia Annus contains Artemisinin which is a sesquiterpenoid lactone, with an endo-peroxide bridge
Fewer side effects than the quinines
Kills the parasite in the RBC stage, but not the Liver stage so cannot be taken as a prophylactic
Artemisia is a Chinese plant that is grown in controlled growth rooms
The World Health Organization recommends using artemisinin in quinine-resistant malaria areas
However, the 1st case of resistance has been confirmed near the Thailand/Laos Border
The search for more plants/drugs continues
You can run mosquito control
insecticide
bed nets
decreasing the amount of standing water
Vaccines are also in the works.
The active components of the Catharanthus are the Vinca Alkaloids.
The whole plant is used.
1950: Canadian Scientists received a sample of Vinca leaves from Jamaica, which was thought to be useful for treating diabetes.
They tested extracts of the plant on lab rats
The rats were all dead in 3 days
They had all died of bacterial and fungal diseases
Analysis of the dead rats showed low WBC counts
1961: the FDA approves the use of Vinblastine
1963: the FDA approves the use of Vincristine
Used in the treatment of leukemias and other cancers of the lymphatic system
The two main alkaloids are Vinblastine (VLB) and Vincristine (VCR)
In the plant, Vinblastine is probably formed first and vincristine is formed later as an oxidized product
VLB has a methyl group (CH3) while VCR has an aldehyde group (CHO) instead
Vinblastine: used in combination with other drugs to treat generalized Hodgkin’s disease, and various lymphomas
Vincristine: used to treat acute lymphocytic diseases, and used in combination with other drugs to treat Hodgkin’s disease, lymphosarcoma, etc.
The yield of the vinca alkaloids is 0.0002% from the leaves
VCR is more biologically active but found in smaller quantities
To satisfy the demand, the plant is collected from natural sources and cultivated sources in Madagascar, Australia, South Africa, South America, West Indies, India, and the Southern US.
It takes over 500 kg of Vinca leaves to get 1 g of VCR
Vinblastine and Vincristine block mitosis
They prevent the polymerization of the tubulin so that cells go into metaphase arrest
Taxol is now known as Paclitaxel
Only found in the bark
Taxus translates to yew
A member of the gymnosperm phylum and the Taxaceae family
The Pacific yew has no cones but fleshy “berries” (still NOT a fruit but an aril)
1958: the National Cancer Institute commissioned USDA (United States Department of Agriculture) Botanists to collect samples from 30,000 plants
1962: Extracts from bark, twigs, and needles of the Pacific yew were tested
1963: Extracts of bark showed biological activity (it slowed the growth of cancer cells in culture)
1971: The chemical structure of a complex diterpene was determines
C47H51NO14 → molecular weight 854 g
1979: the mode of action was shown to be different from that of the Vinca Alkaloids
1983: National Cancer Institute commenced phase 1 trials, although taxol was in very short supply
1994 (April): The FDA approves use for metastatic breast cancer that has recruited within 6 months of initial chemotherapy
1994: Two groups simultaneously publish the total synthesis of taxol
Taxol promoted the polymerization of microtubules but prevents depolymerization (so no daughter cells are formed)
Initially used to treat cancer patients who were terminal
Some showed no further growth of ovarian tumors, and some tumors even shrunk.
Taxol is particularly effective against solid tumors
Metastatic breast cancer that has recruited within 6 months of initial chemotherapy
Since taxol was in short supply during the phase 1 trials, further research was delayed.
Difficulties in getting enough taxol for experimental use
Only found in the bark and removing the bark kills the tree
It took six 100-year-old trees to get enough taxol to treat one person
This reinforced the desperate need for alternative sources of taxol
Taxol has 11 stereocenters in the molecule so technically 2048 stereoisomers could exist
Making it from scratch in the Lab is too difficult to be profitable
Maybe we can find a similar compound in related species
The European Yew had a compound that contained the complicated ring structure in the needles.
We can work off the ring from the European Yew and try to convert it to Taxol
Taxol was BMS’s strongest performer in 1995 with 62% sales increase over the previous year
In 2000 annual sales reached $1.6 billion
The European Yew has a less restrictive growing range
The needles can be harvested repeatedly without killing the tree
It is much easier to do semi-synthesis than the total synthesis
Many of these come from plants
These are called “Botanicals” or “Herbal”
These are not regulated the same way as drugs or foods.
The Food and Drug Administration (FDA) in the US regulates food and drugs but does not regulate the production of dietary supplements
You can’t actually make claims, just suggestions
St. John’s Wort: used for treating mild depression, (mood enhancer)
Echinacea: used for “healthy immune function”
Sometimes problems can arise because dietary supplements have not been tested properly
The FDA will then issue a warning
In extreme cases, they will remove a product from the market
Ephedra is the source of the alkaloid ephedrine
Ephedrine was 1st identified in 1887 and added to modern prescription drugs during the 1920s
Decongestant effects due to relaxation of bronchial muscles, CNS stimulant that acts similar to adrenaline
When taken in excess they give the same effects as the illegal drug “ecstasy”
In excess, it causes heart attack, strokes, seizures
It was banned in the US in 2004
Supplement companies quickly tried to get this overturned, taking the case all the way to the supreme court.
They were unsuccessful
This is also one reason allergy medication is now sold over the counter
It contains pseudoephedrine which has the same effects as ephedrine
With fewer stimulation effects
In addition, it is an ingredient for making illegal methamphetamines
There is documentation from 4000 years ago that plants have been used to treat diseases
In the US, 25% of all prescription drugs are from plants or based on plant-derived compounds.
50% if fungal compounds are included
Herbal Medicine is still very big in many parts of the world.
There’s an Amazonian Conservation team working with indigenous people in Suriname to identify their herbal plants and protect them from habitat destruction and global warming.
Preserves the knowledge.
All our plant-based prescription drugs started out as herbal remedies somewhere.
Knowledge that the plant has healing properties
in literature or word of mouth
Isolation and structural characterization of the active component(s).
Mode of Action
Clinical Trials
Drug Development
Phenolics
Aspirin and related NSAIDs
Terpenoids
eg. steroid
Alkaloid
Contains Nitrogen
Are usually basic (alkaline) and taste bitter
Pronouced actions on the nervous system
quinine, caffeine, nicotine, cocaine, ephedrine
Active components were found to be steroid-type compounds
affects Na+K+ATPase
A diuretic
Used to treat Congestive Heart Failure
Does not cure the disease, just treats the symptoms
Digitoxin is the prescription drug
individualized doses
William Withering was an English Clergyman that studied a herbal tea that was used to treat “dropsy”
It contained 20 plants
He found that the active principle was foxglove
Dropsy is a condition characterized by severe bloating due to fluid accumulation
AKA Congestive Heart Failure
80 million aspirin tablets are taken every day in the US
Aspirin doesn’t come from a willow tree or occur naturally
2500 years ago the Greeks used an infusion from white willow (Salix Alba) bark to treat rheumatism, fever, and pain
Many Native American tribes had independently discovered the healing powers of willow bark
1839: Salicin was identified in willow bark extracts by German chemists
Aromatic ring with a sugar group
Salicylic acid (SA) was synthesized in labs in Germany to treat gout and rheumatism
Salicin is converted to SA in the stomach naturally (the aromatic ring loses the sugar group)
Other plants contain SA too including Spirea and wintergreen
Acetyl Salicylic acid was more palatable and had fewer side effects
Acetyl Salicylic acid is what aspirin actually is
Aspirin is an analgesic (pain-killer), antipyretic (fever breaker), and anti-inflammatory
Aspirin is easy to make in a laboratory, its cheap, and effective
British Biochemist, John Vane showed that aspirin inhibits prostaglandin synthesis (1970)
Arachidonate acid (the precursor of prostaglandins) is synthesized in mammals from linoleic acid (18:2)
Prostaglandin: considered to be a “local hormone,” stimulates inflammation, regulates blood flow
Made on site
Prostaglandin synthase has 2 different catalytic activities, one is cyclooxygenase (COX) activity.
Aspirin irreversibly inhibits COX activity which is how it decreases inflammation, pain, and fever
Arachidonate cannot bind in the groove to get converted to a Prostaglandins
Other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Like Ibuprofen and Naproxen
Thousands of compounds have been synthesized in the lab, based on aspirin as a prototype
The use of aspirin for pain and inflammation has been, to a certain extent, superseded by other NSAIDs
NSAIDs are more gentle on the stomach
Because aspirin inhibits COX activity it inhibits the biosynthesis of thromboxanes (later in the prostaglandin pathways)
Thromboxanes are used in blood clotting
This is the basis for the effect of aspirin in preventing blood clots (thrombi)
Aspirin is taken daily by millions of people to reduce blood clots, heart attacks, and stroke
Salicylic Acid is known to have some positive health effects
in fact, aspirin is metabolized in the human body into Salicyclic acid very quickly (within a minute)
3 billion people get parasitic diseases a year
Malaria comes from the Italians’ belief that it was caused by “Bad Air”
The worse of these is Malaria which affects millions a year
Estimated there are half a billion clinical cases of Malaria a year
Usually confined to tropical/subtropical regions
Plasmodium: is the causative organism (protest) of malaria
4 species are responsible for most of the cases
Plasmodium is transmitted from person to person by a mosquito vector
Life Cycle of a Plasmodium
When a female, Anopheles mosquito, harboring the malaria parasite in her salivary glands, bites an individual, the sporozoite stage of the parasite is injected. The sporozoites are carried to the liver in the bloodstream
In the liver, merozoites are produced and released into the bloodstream
The merozoites invade RBCs and multiply
After a period of time the RBCs rupture, releasing a new generation of merozoites, which then infect other RBCs. The cycle is synchronous with the simultaneous rupture of RBCs and release of merozoites and toxins, causing the periodic fever and chills
Male and female gametocytes are formed in some RBCs. If the gametocytes are ingested when an Anopheles mosquito bites an infected individual, they can complete sexual reproduction and begin the infection cycle anew.
Cinchona: contains quinine for the treatment of malaria
Make tea with the bark
Also called the fever bark tree
Thought to have been used 1st in Peru
Documented use in the early 1600s
Knowledge of the tree and samples of the bark was taken to Europe by Jesuit missionaries in the 17th century, then we went worldwide.
The active ingredient was 1st isolated by French scientists in 1820
1880: the 1st determination that malaria was a parasitic disease
1896: confirmed transmission of the parasite by a mosquito to human
1944: the 1st synthetic version (Chloroquine) is made
The occupation of Java during WWII by the Japanese shut down the major supplier by quinine to the world
Quinine and chloroquine both block the life cycle of the Plasmodium at the red blood cell stage
Chloroquine - used extensively
less toxic and more effective than Quinine
Primaquine
Mefloquine and many more
There are some problems associated with Plasmodium developing resistance to quinine and its derivative
So other plants are being studied
Artemisia Annus contains Artemisinin which is a sesquiterpenoid lactone, with an endo-peroxide bridge
Fewer side effects than the quinines
Kills the parasite in the RBC stage, but not the Liver stage so cannot be taken as a prophylactic
Artemisia is a Chinese plant that is grown in controlled growth rooms
The World Health Organization recommends using artemisinin in quinine-resistant malaria areas
However, the 1st case of resistance has been confirmed near the Thailand/Laos Border
The search for more plants/drugs continues
You can run mosquito control
insecticide
bed nets
decreasing the amount of standing water
Vaccines are also in the works.
The active components of the Catharanthus are the Vinca Alkaloids.
The whole plant is used.
1950: Canadian Scientists received a sample of Vinca leaves from Jamaica, which was thought to be useful for treating diabetes.
They tested extracts of the plant on lab rats
The rats were all dead in 3 days
They had all died of bacterial and fungal diseases
Analysis of the dead rats showed low WBC counts
1961: the FDA approves the use of Vinblastine
1963: the FDA approves the use of Vincristine
Used in the treatment of leukemias and other cancers of the lymphatic system
The two main alkaloids are Vinblastine (VLB) and Vincristine (VCR)
In the plant, Vinblastine is probably formed first and vincristine is formed later as an oxidized product
VLB has a methyl group (CH3) while VCR has an aldehyde group (CHO) instead
Vinblastine: used in combination with other drugs to treat generalized Hodgkin’s disease, and various lymphomas
Vincristine: used to treat acute lymphocytic diseases, and used in combination with other drugs to treat Hodgkin’s disease, lymphosarcoma, etc.
The yield of the vinca alkaloids is 0.0002% from the leaves
VCR is more biologically active but found in smaller quantities
To satisfy the demand, the plant is collected from natural sources and cultivated sources in Madagascar, Australia, South Africa, South America, West Indies, India, and the Southern US.
It takes over 500 kg of Vinca leaves to get 1 g of VCR
Vinblastine and Vincristine block mitosis
They prevent the polymerization of the tubulin so that cells go into metaphase arrest
Taxol is now known as Paclitaxel
Only found in the bark
Taxus translates to yew
A member of the gymnosperm phylum and the Taxaceae family
The Pacific yew has no cones but fleshy “berries” (still NOT a fruit but an aril)
1958: the National Cancer Institute commissioned USDA (United States Department of Agriculture) Botanists to collect samples from 30,000 plants
1962: Extracts from bark, twigs, and needles of the Pacific yew were tested
1963: Extracts of bark showed biological activity (it slowed the growth of cancer cells in culture)
1971: The chemical structure of a complex diterpene was determines
C47H51NO14 → molecular weight 854 g
1979: the mode of action was shown to be different from that of the Vinca Alkaloids
1983: National Cancer Institute commenced phase 1 trials, although taxol was in very short supply
1994 (April): The FDA approves use for metastatic breast cancer that has recruited within 6 months of initial chemotherapy
1994: Two groups simultaneously publish the total synthesis of taxol
Taxol promoted the polymerization of microtubules but prevents depolymerization (so no daughter cells are formed)
Initially used to treat cancer patients who were terminal
Some showed no further growth of ovarian tumors, and some tumors even shrunk.
Taxol is particularly effective against solid tumors
Metastatic breast cancer that has recruited within 6 months of initial chemotherapy
Since taxol was in short supply during the phase 1 trials, further research was delayed.
Difficulties in getting enough taxol for experimental use
Only found in the bark and removing the bark kills the tree
It took six 100-year-old trees to get enough taxol to treat one person
This reinforced the desperate need for alternative sources of taxol
Taxol has 11 stereocenters in the molecule so technically 2048 stereoisomers could exist
Making it from scratch in the Lab is too difficult to be profitable
Maybe we can find a similar compound in related species
The European Yew had a compound that contained the complicated ring structure in the needles.
We can work off the ring from the European Yew and try to convert it to Taxol
Taxol was BMS’s strongest performer in 1995 with 62% sales increase over the previous year
In 2000 annual sales reached $1.6 billion
The European Yew has a less restrictive growing range
The needles can be harvested repeatedly without killing the tree
It is much easier to do semi-synthesis than the total synthesis
Many of these come from plants
These are called “Botanicals” or “Herbal”
These are not regulated the same way as drugs or foods.
The Food and Drug Administration (FDA) in the US regulates food and drugs but does not regulate the production of dietary supplements
You can’t actually make claims, just suggestions
St. John’s Wort: used for treating mild depression, (mood enhancer)
Echinacea: used for “healthy immune function”
Sometimes problems can arise because dietary supplements have not been tested properly
The FDA will then issue a warning
In extreme cases, they will remove a product from the market
Ephedra is the source of the alkaloid ephedrine
Ephedrine was 1st identified in 1887 and added to modern prescription drugs during the 1920s
Decongestant effects due to relaxation of bronchial muscles, CNS stimulant that acts similar to adrenaline
When taken in excess they give the same effects as the illegal drug “ecstasy”
In excess, it causes heart attack, strokes, seizures
It was banned in the US in 2004
Supplement companies quickly tried to get this overturned, taking the case all the way to the supreme court.
They were unsuccessful
This is also one reason allergy medication is now sold over the counter
It contains pseudoephedrine which has the same effects as ephedrine
With fewer stimulation effects
In addition, it is an ingredient for making illegal methamphetamines