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Antimicrobial drug use in food-producing animals and associated human health risks: what, and how strong, is the evidence?
Antimicrobial resistance is a public health threat. Because antimicrobial consumption in food-producing animals contributes to the problem, policies restricting the inappropriate or unnecessary agricultural use of antimicrobial drugs are important. However, this link between agricultural antibiotic use and antibiotic resistance has remained contested by some, with potentially disruptive effects on efforts to move towards the judicious or prudent use of these drugs.
The goal of this review is to systematically evaluate the types of evidence available for each step in the causal pathway from antimicrobial use on farms to human public health risk, and to evaluate the strength of evidence within a ‘Grades of Recommendations Assessment, Development and Evaluation‘(GRADE) framework. The review clearly demonstrates that there is compelling scientific evidence available to support each step in the causal pathway, from antimicrobial use on farms to a public health burden caused by infections with resistant pathogens. Importantly, the pathogen, antimicrobial drug and treatment regimen, and general setting (e.g., feed type) can have significant impacts on how quickly resistance emerges or spreads, for how long resistance may persist after antimicrobial exposures cease, and what public health impacts may be associated with antimicrobial use on farms. Therefore an exact quantification of the public health burden attributable to antimicrobial drug use in animal agriculture compared to other sources remains challenging.
Even though more research is needed to close existing data gaps, obtain a better understanding of how antimicrobial drugs are actually used on farms or feedlots, and quantify the risk associated with antimicrobial use in animal agriculture, these findings reinforce the need to act now and restrict antibiotic use in animal agriculture to those instances necessary to ensure the health and well-being of the animals.
What Are Terpenes?
Terpenes, also known as isoprenoids are the largest and most diverse group of naturally occurring compounds that are mostly found in plants but larger classes of terpenes such as sterols and squalene can be found in animals. They are responsible for the fragrance, taste, and pigment of plants. 1 Terpenes are classified on the basis of organization and number of isoprene units it contains (see footnote 1). An isoprene unit is a building block of terpenes that is a gaseous hydrocarbon that contains the molecular formula C5H8 (see footnote 1). Terpenes and terpenoids are terms that are often used interchangeably but the two terms have slight differences terpenes are an arrangement of isoprene units that are naturally occurring, volatile, unsaturated 5-carbon cyclic compounds that give off a scent or a taste to defend itself from organisms that feed off of certain types of plants (see footnote 1). Terpenes have many functions in plants such as a thermoprotectant, signaling functions, and not limited to, pigments, flavoring, and solvents but also have various medicinal uses (Yang et al. 2012). Table 15.1 shows the different types of terpenes discussed in this chapter along with an example of that terpene.
Different types of terpenes and their properties
|Classification||Carbon atoms||Species produced from||Medicinal uses||References|
|Monoterpenes||C10||Quercus ilex||Fragrances, repellent||Loreto et al. (2002)|
|Sesquiterpenes||C15||Helianthus annuus||Treat malaria, treat bacterial infections, and migraines||Chadwick et al. (2013)|
|Diterpenes||C20||Euphorbia, salvia miltiorrhiza||Anti-inflammatory, cardiovascular diseases||Vasas and Hohmann (2014), Zhang et al. (2012)|
|Triterpenes||C30||Centella asiatica||Wound healing, increases circulation||James and Dubery (2009)|
Plants that Carry Medicinal Terpene
Terpene is a natural compound with various medical properties and found in both plants and animals (Gershenzon 2007). Among natural products that mediate antagonistic and beneficial interactions within the organism, terpene play a variety of roles (Gershenzon 2007). Terpene protects many living organisms like microorganisms, animals and plants from abiotic and biotic stresses (Gershenzon 2007). Terpene can ward off pathogens, predators, and competitors. Living organisms use terpene for multiple reasons like medicinal purposes and communications about food, mates, or enemies (Gershenzon 2007). It is impressive how different organisms use terpene for common purposes even though terpene contain many forms and varieties (Gershenzon 2007).
So far only a small percentage of terpene is investigated (Franklin et al. 2001). Cannabis is one of the most common sources for the medicinal terpene (Franklin et al. 2001). This plant contains many medicinal properties like anticancer, antimicrobial, antifungal, antiviral, antihyperglycemic, analgesic, anti-inflammatory, and antiparasitic (Franklin et al. 2001). Terpene is also used to enhance skin penetration, prevent inflammatory diseases (Franklin et al. 2001). Nowadays modern medication use large scales of terpene for various treatment drugs (Franklin et al. 2001).
There are commonly used plants like tea (Melaleuca alternifolia), thyme, Cannabis, Salvia lavandulifolia (Spanish sage), citrus fruits (lemon, orange, mandarin) etc. that provide wide range of medicinal values (Perry et al. 2000). Tea tree oil has increased in popularity in recent years when it comes to alternative medicine (Perry et al. 2000). Tea tree oil is a volatile essential oil and is famous for its antimicrobial properties, and acts as the active ingredient that is used to treat cutaneous infections (Carson et al. 2006) Apart from the flavor that gives to food, essential oil contain antimicrobial properties (Bound et al. 2015). Thyme is one of plants that synthesize terpene alcohols and phenols which contain powerful antibacterial and antifungal properties (Bound et al. 2015). Terpene synthesized from cannabis also long served as medicines (Perry et al. 2000). They also contain psychoactive properties and used against many infectious diseases (Perry et al. 2000). is famous for anti-dementia (current memory-enhancing) drugs by enhancing cholinergic activity via inhibition of cholinesterase (Perry et al. 2000). In vitro examination method was used to study the effects of constituent terpenes on human erythrocyte acetylcholinesterase (Perry et al. 2000). Some of the medicinal properties of terpenes are listed in Table 15.2 .
Medicinal Properties of terpenes from different sources
|Tea tree||Contains the active ingredient to treat cutaneous infections||Carson et al. (2006)|
|Thyme||Possesses powerful antibacterial and antifungal properties||Bound et al. (2015)|
|Cannabis||Possesses psychoactive properties and used against many infectious diseases||Friedman et al. (2006)|
|Spanish sage||Enhances memory and is used in anti-dementia drugs||Lopresti (2016)|
|Citrus fruits||Drugs against pediculosis||Mehlhorn et al. (2011)|
|Citral||Antibacterial and antifungal effects||Silva et al. (2008)|
|Lemongrass||Insect repellent||Silva et al. (2008)|
Properties Associated with Terpene
Important properties associated with terpene are difficult to overstress (Franklin et al. 2001). There are many important uses with terpene and these include anti-insect properties, antimicrobial properties and anti-herbivore properties (Franklin et al. 2001). Terpene can be extracted through plants and thorough some insects (Franklin et al. 2001).
Without using harsh chemicals that could potentially contain side effects, terpene is a healthy alternative to ward off insects (Franklin et al. 2001). There have been many pesticides made for killing domestic pests like lice, or mites (Franklin et al. 2001). In these cases, it is very important to make sure that these pesticides do not affect humans in harmful ways (Franklin et al. 2001). There are many options like shampoo, sprays, lotions that were manufactured against pests that include one or more terpenes that are employed in the instant invention (Franklin et al. 2001). These naturally occurring terpenes are generally not modified they were used in their raw form and the environment protection agency in the USA classified as “GRAS” which mean Generally Regards as Safe (Franklin et al. 2001).
Certain terpene is highly effective against both lice and lice eggs and there is a less than significant chance of resistance developing against this terpene based pesticides reason for this is their observed modes of action (Franklin et al. 2001). Unlike other types of pediculosis medication this terpene based instant inventions are not neurotoxins (Franklin et al. 2001) Terpenes are also used combined with terpene aldehyde called citral. Citral derives from an essential oil that is extracted from lemongrass ( ) (Franklin et al. 2001). Citral possesses antibacterial and antifungal properties, while lemongrass possesses anti-insect properties (Franklin et al. 2001).
A series of anti-insect formulation contain many terpenes (Franklin et al. 2001) Most of these pesticides are a mix of terpene and citral (Franklin et al. 2001). Table 15.3 consists of what these terpenes include.
Terpenes added in anti-insect formulations
|Limonene||This is strongly preferred. Limonene enhances the properties of other terpenes||Redistilled limonene has less odor, more stable than d -limonene||Franklin et al. (2001)|
|Beta-ionone||Antibacterial and antifungal properties||Beta-ionone has prophylactic value.||Mikhlin et al. (1983)|
|Geraniol||Similar level activity like beta-ionone. Geraniol possesses antibacterial and antifungal properties.||Geraniol gives a pleasant fragrance.||Chen and Viljoen (2010)|
|Eugenol||This is also the active terpene in clove oil. This possesses anesthetic properties which help with the itching that comes with bug bites. Also contain antibacterial and antifungal properties||Contain a distinct fragrance which is like geraniol||Franklin et al. (2001)|
|Myrcene||Possesses antifungal, antibacterial properties||Famous for its fragrance properties||Filipowicz et al. (2003)|
Antimicrobial properties or the ability to kill or stop growth of a microorganism in terpenes are commonly used in traditional and modern medicine (Himejima et al. 1992). There are many terpenes with antimicrobial activities (Himejima et al. 1992). The following plants produce terpenes which have antimicrobial properties: Pinus ponderosa (Pinaceae), spices (sage, rosemary, caraway, cumin, clove, and thyme), Cretan propolis, Helichrysum italicum, Rosmarinus officinalis, and so on (Himejima et al. 1992). These antimicrobial terpenes can also be used against food borne pathogen like , , and (Himejima et al. 1992).
cell extract contain wide-ranging antimicrobial activities (Himejima et al. 1992). After steaming and distillation from Pinus ponderosa cell extract, a distillate and a residue are obtained (Himejima et al. 1992). The distillate consists of monoterpenes and some sesquiterpenes while the residue consists of four diterpene acids (Himejima et al. 1992). It was also reported that when a physical damage is caused to the pine tree or any other terpene containing tree from insect attacks, resin which contains terpene secret to protect the tree from further damage (Himejima et al. 1992).
Five different kinds of terpene can be isolated from , they are, the diterpenes, 14,15-dinor-13-oxo-8(17)-labden-19-oic acid and a mixture of labda-8(17),13E-dien-19-carboxy-15-yl oleate, palmitate and triterpene (Popova et al. 2009). Spectroscopic analysis and chemical evidence has been used to establish the structures of the different compounds (Popova et al. 2009). These compounds that were isolated from terpene was tested for its antimicrobial activity against bacteria like gram positive and gram negative (Popova et al. 2009). It was all tested for human pathogenic fungi which has broad-spectrum antimicrobial activity (Popova et al. 2009).
essential oil was analyzed using gas chromatography and mass spectrometry to fraction into terpene and terpenoid. Fifty two compounds, including hydrocarbons of the oil α-pinene (10.2%), α-cedrene (9.6%) aromadendrene (4.4%), β-caryophyllene (4.2%), and limonene (3.8%), neryl acetate (11.5%), 2-methylcyclohexyl pentanoate (8.3%), 2-methylcyclohexyl octanoate (4.8%), and geranyl acetate (4.7%) were identified (Mastelic et al. 2017).
The smallest of terpenes are monoterpenes . They contain the compound C10H16, come from different flowers, fruits and leaves and are known as the main component of essential oils, fragrances and many structural isomers (see footnote 1). Monoterpenes are also the most fragrant of all the classes of terpenes (see footnote 1). Examples for the types of monoterpenes found in natural scents are α-pinene, which imparts scent to pine trees, and limonene from citrus plants (see footnote 1).
What is thought to be one of the main purposes of monoterpenes is to attract pollinators or to serve the purpose of repelling other organisms from feeding off of plants. They also may be related to the flowering process of the plants (Loreto et al. 2002). They are isolated from their plant sources by distillation with steam and have a boiling points in the range of 150 °C to 185 °C (see footnote 1). Monoterpenes are purified using fractional distillation at pressures that are reduced or use another process in order to form a crystalline derivative (see footnote 1).
Monoterpene Emission Under Heat Stress
Many studies test the hypothesis of high emissions of monoterpenes under high temperatures using the leaves of Quercus ilex, also known as evergreen oak (Table 15.1 ). The evergreen tree is native to the Mediterranean area where it has to survive under hot and dry conditions and synthesis of these monoterpenes may have been an adaptive mechanism for the plants to survive under heat stress. 2 This tree does not emit isoprenes but it emits monoterpenes and is able to handle different environmental stresses such as drought, salt, and heat (see footnote 2). A particular study done by Loreto et al. (2002) were conducted to visualize monoterpene production in response to high temperatures and to see if thermotolerance is increased with monoterpenes (Loreto et al. 2002). In this study, the leaves were exposed in 5 °C intervals ranging from the temperatures 30 °C to 55 °C and leaves were kept under conditions in which inhibited or allowed monoterpenes to synthesize (Loreto et al. 2002). The results that were found in this experience was a discovery of seven most abundant monoterpenes which was emitted at the maximum temperature of 35 °C and decreased its abundance over time as the temperatures increased and α-pinene had the greatest abundance of emittance at 35 °C as well as other terpenes but greatly reduced over higher temperatures (Loreto et al. 2002). At 55 °C the monoterpenes, myrcene and limonene had higher emission rates compared to temperatures around 35 °C (Loreto et al. 2002). Photosynthesis was also decreased when the leaves were exposed to any temperature that was higher than 30 °C and at 55 °C showed a loss of CO2 and recovery occurred around 30 °C (Loreto et al. 2002). Overall, the monoterpenes showed that their optimal temperature for emission was around 30 °C (Loreto et al. 2002). Researchers prove that the emission of monoterpenes is under enzymatic control due to their optimal temperatures (Loreto et al. 2002).
Sesquiterpenes , containing the chemical formula C15H24, are much larger compounds than monoterpenes and are much more stable in comparison. 3 They are isolated by distillation with steam or by extraction and purified by methods such as vacuum fractional distillation or gas chromatography (see footnote 1). Oxidation or rearrangement of isoprene units that are made to sesquiterpenes produce the corresponding sesquiterpenoids (see footnote 1). Sesquiterpenes are naturally occurring and found in plants , fungi, and insects and act as a defensive mechanism or attract mates with pheromones in insects (see footnote 1). Acyclic compounds of sesquiterpenes such as farnesans can be used as a natural pesticide for insects and also as pheromones for some insects and mammals such as elephants, to attract mates or to mark their territory (see footnote 1).
Sesquiterpenes have a vital role in plant growth hormones and signaling properties in response to its environment (Giraudat 1995). Abscisic acid has a role in plants such as development, germination, cell division, and synthesis of protein storage and signalling (Giraudat 1995). It also plays a role in plants in response to various environmental stresses. It regulates the closure of the stoma by regulating ion channels and exchange of water across the plasma membrane (Giraudat 1995). Cyclic ADP-ribose signals abscisic acid in response to drought-stressing conditions from the environment (Giraudat 1995). Abscisic acid is not unique to plants, it has shown to be present in the central nervous system of other organisms such as pigs and may play a role in humans as a pro-inflammatory cytokine and stimulator of insulin release in the human pancreas (Chadwick et al. 2013). Gossypol is a sesquiterpene that is found in cotton plants. It has anticancer properties and can potentially inhibit fertility in male humans which is why it must be removed from essential oils and various other products before human use or consumption. Avarol, a sesquiterpenoid that has shown to have antimicrobial and antifungal uses, is effective against the AIDS virus in humans (see footnote 3). 4
The medicinal properties of sesquiterpenes typically come from flowering plants that are included in the Asteraceae family, which include, but not limited to sunflowers, marigolds, and daisies. This family of flowers is a significant resource for potent sesquiterpene lactones, which are usually found in the leaves and the flower portion of plants and are constantly being produced at high levels (Chadwick et al. 2013). The role of sesquiterpenes in these flowering plants are not solely made for human use but for the purpose of protecting the plant from predators and are produced de novo in response to microbial attack and ultraviolet ray protection (Chadwick et al. 2013). Their bitter taste is a defense mechanism against herbivores from feeding on them but some have sweet tastes or tastes that are pleasant to certain organism for the purpose of spreading their seeds and being fertilized in different areas (Chadwick et al. 2013). Sesquiterpenes have many uses in traditional, western medicine because they contain so many anticancer, antiplasmodial, and anti-inflammatory activities (Chadwick et al. 2013). Sesquiterpenes lactones are able to reduce stomach ulcers in some people and are also present in powerful antimalarial drugs (Chadwick et al. 2013). Artemisinin, a metabolite produced from Artemisia annua, which contains sesquiterpene lactone produced in the roots and shoots of the plants, is used in drugs to treat malaria (Chadwick et al. 2013). Other uses of this family of flowers is for treatment of bacterial infections, migraines, and to improve skin (Chadwick et al. 2013). Lettuce opium has been used for many years as a painkiller (Chadwick et al. 2013).
Diterpenes are naturally occurring chemical compounds that contain the molecular formula, C20H32. Diterpenes have physiologically active groups such as vitamin A activity well as plant growth hormones that regulate germination, flowering and switch reproductive cycles (from asexual to sexual reproduction) of plants (Lee et al. 2015). They can also be classified as a phytol, which is an oxygenated acyclic diterpene. Over 650 diterpenoids have been isolated from Euphorbia plants, which is a very diverse genus of flowering plants (Popova et al. 2009). Diterpenes have many therapeutic benefits such as antitumor, cytotoxic, and anti-inflammatory (Vasas and Hohmann 2014). They are present in anticancer drugs such as taxol, and the tumor promoter, phorbol (Vasas and Hohmann 2014).
Tanshinones are a class of diterpenes that are isolated from dried roots or rhizomes of an herb in traditional Chinese medicine called also known as Danshen or Tanshen (Zhang et al. 2012). Tanshinones were first isolated in the 1930s, and since then, more than 90 chemicals have been identified and split up into two groups: 40 lipophilic and 50 hydrophilic compounds (Zhang et al. 2012). Tanshinones have recently been extensively researched for their anticancer properties in vitro and in vivo (Zhang et al. 2012). Their potential use as an anticancer drug comes from their broad range of activities such as anti-proliferation and inhibiting adhesion, migration, and invasion (Zhang et al. 2012). Analogues of tanshinone have been synthesized in many clinical trials because they have many anticancer attributes (Lee et al. 2015). This herb has been used in many Asian countries for preventative and therapeutic solutions to many diseases such as heart disease, vascular diseases, and arthritis (Zhang et al. 2012). Tanshinones may also reduce inflammation and increase immune responses (Zhang et al. 2012).
Cafestol and kahweol are diterpene alcohols that are found in the oil derived from coffee beans. These chemical structures are very similar but only differ by an extra double bond that is present in kahweol’s chemical structure. 5 Researchers have reported that coffee lowers the risk of depression in women, prostate cancer in men, stroke, diabetes, and some cancers (see footnote 5). It is thought that the anti-inflammatory and antioxidant properties of these particular diterpenes are responsible for such events (see footnote 5). Coffee benefits the liver as well by lowering liver enzymes that are in response to inflammation and damage and may offer some protection against liver cancer as well (see footnote 5). The adverse result of these diterpenes is that they raise cholesterol level, but it seems to be limited to coffee that has been unfiltered and has oily droplets of cafestol and kahweol (see footnote 5). Filtered coffee may not have much impact on cholesterol levels (see footnote 5).
Triterpenes are composed of three or six isoprene units and have the chemical formula C30H48 which includes steroids and sterols with squalene being the biological precursor of all triterpenes (see footnote 1). Triterpenes are produced by animals, plants, and fungi. They play a role as precursors to steroids in animal and plant organisms, and are derived from mevalonic acid (see footnote 1). Saponins come from the skins of many plants and have emulsion like properties that make them excellent detergents in the human digestive system (see footnote 1). Chemical structures of steroid saponins are similar to hormones that are produced in the human body (see footnote 1).
The medicinal uses of triterpenes are not quite as recognized as other different types of terpenes but their uses are being continuously investigated by researchers. Their properties have been studied for anticancer, antioxidant, antiviral, and anti-atherosclerotic activities (Nazaruk and Borzym-Kluczyk 2015). Some studies have shown that there is promising potential for the use of triterpenes for people with diabetes by aiming to reduce glucose levels and also by reducing sweetness inhibitors in sweet and high calorie foods (Nazaruk and Borzym-Kluczyk 2015). Saponins have detoxification properties and act as a diuretic for the kidneys and wound healing properties (Nazaruk and Borzym-Kluczyk 2015).
Tetraterpenes are also known as carotenoids that have the molecular formula C40H56 and can be in the category of terpenes because they are made from isoprene units. 6 Most carotenoids are highly unsaturated and for this reason, they are extremely difficult to isolate and purify (see footnote 1). They are found in all different types of fungi, bacteria, and plants and mainly responsible for red, yellow, or orange fat-soluble plant and animal pigments (see footnote 6). One of the most crucial and common tetraterpene is beta-carotene that contributes to the yellow pigment in carrots. It is important to mammals especially because it is a precursor in producing vitamin A and other important terpenoids for vision (see footnote 1).
Higher order terpenes have been shown to increase thermotolerance (Singsaas 2001). The permeability of the thylakoid membranes increase at higher temperatures and this happens by an increase in cyclic photophosphorylation around photosystem II (Singsaas 2001). When the temperature of the atmosphere continues to rise, the photophosphorylation system is not able to keep up with protons leaking, which causes the transmembrane gradient to drop and a reduction in ATP synthesis occurs (Singsaas 2001). All these events can potentially cause lowering in the Rubisco activation state due to an inhibition of RuBP regeneration (Singsaas 2001).
The MEP pathway , also known as the non-mevalonate pathway or methylerythritol phosphate pathway, is a metabolic pathway for isoprenoid biosynthesis that creates the products isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). This pathway occurs in the chloroplasts and produce monoterpenes, specific sesquiterpenes, diterpenes, and carotenoids (Zhang et al. 2012). The vital application of this pathway is to develop antimicrobial agents to target diseases such as malaria and sexually transmitted diseases (Hunter 2007). Since this pathway does not occur in humans, it is a valuable resource to develop antibacterial and antiparasitic drugs (Seemann et al. 2009).
The first steps of this pathway involve pyruvate and d -glyceraldehyde 3-phosphate to produce DOXP which is catalyzed by 1-deoxy- d -xylulose-5-phosphate (DXS) (Hunter 2007). 1-Deoxy- d -xylulose-5-phosphate reductoisomerase, otherwise known as IspC, coverts DOXP to MEP. From MEP, it reacts with CTP to create 4-diphosphocytidyl-2C-methyl- d -erythritol (Hunter 2007). A phosphate is released in this reaction and then reacts with ATP-dependent IspE to make 4-diphosphocytidyl-2C-methyl- d -erythritol 2-phosphate and ADP and then reacts with the enzyme IspF to create 2C-methyl- d -erythritol 2,4-cyclodophosphate (Hunter 2007). The enzyme requires metal cations. Then finally, in the least understood step of the reaction, the two enzymes, IspG and IspH make the two products, IPP and DMAPP by using a two-electron reduction (Hunter 2007). The pathway is regulated by control of repression or activation of gene expression via feedback loops within the pathway or by effector molecules which target an enzyme or downstream activities (Hunter 2007).
The MVA pathway or mevalonic acid pathway occurs in the cytosol. It is responsible for the synthesis of sterols, specific sesquiterpenes, and also may play a role in the synthesis of transhinones (Zhang et al. 2012). In gram-positive bacteria, the genes in the metabolic pathways such as MVA are organized into operons and are thought to be regulated by transcription (Hunter 2007).
The use of cannabis is increasing for medicinal uses that commonly treat pain, the side effects of chemotherapy in cancer patients such as nausea, anxiety and depression, and its uses and benefits are continuously being researched by scientists (Cathcart et al. 2015). There are at least 80 compounds that come from the cannabis plant that are regarded as cannabinoids that cause psychotropic effects in the human brain due to CB1 receptors (Klein et al. 2011). The main active ingredient, delta-9-tetrahydrocannabinol, otherwise known as THC, is a psychoactive agent and is a focus for controversy in society because it binds to the human endocannabinoid receptors in areas of the brain such as the hippocampus and the frontal cortex, which are responsible for memory, cognition and attention. 7 How THC works is by taking the place of endocannabinoids, naturally occurring chemicals in the human body (see footnote 7). One of the most common and well known molecules that THC replaces in the human body is called anadamide (see footnote 7). To this day, scientists are researching to discover the exact role of this molecule in the human body.
Cannabidiol, or CBD is also a common ingredient in cannabis but compared to THC, it is a non-psychoactive and it can potentially reduce the effects of THC (Klein et al. 2011). CBD does not bind to the same receptors as THC does in the human body and it works by inhibiting FAAH or the enzyme fatty acid amide hydroxyls (see footnote 7). This enzyme is responsible for degrading anadamide in the body and by inhibiting FAAH, CBD increases natural endocannabinoids already in the human system (Klein et al. 2011). CBD is thus an agent that works for depression, anxiety and neuroprotective effects (Klein et al. 2011).
What are major components in cannabis are the monoterpenes that are responsible for many different medicinal properties. One of the main uses for THC is the potential for cancer treatment and can play a role in reducing size of tumors (see footnote 7). THC can also reduce inflammation caused by certain diseases in patients. Other conditions that THC can help but are not limited to are ADHD, Arthritis, migraines, and glaucoma (see footnote 7). 8 It can also improve the symptoms in individuals that suffer from HIV by helping their appetite and thus causing weight again, improving their depression symptoms and their quality of life (Lutge et al. 2013).
Terpenes have been shown to have a favorable antiplasmodial activity. With the rising malarial infections and drug resistance, terpenes have gained more attention towards it through antiplasmodial activity (Nogueira and Lopes 2011). The interesting mechanism behind the terpene activity is that it binds to the hemin part of infected erythrocytes and kills the parasite just like the famous antimalarial drug chloroquine (Orjih et al. 1981 Kayembe et al. 2012). Hemin is made of iron which is necessary for the plasmodium development in the erythrocytes. Though hemin breaking enzymes are not yet found in plasmodium, it could be one reason why hemin binding accounts for parasite lysis (Ginsburg and Demel 1984). Another study suggests that drug-hemin complex binds to phospholipid layers thereby disrupting the respective membrane structure and causing cell lysis (Ginsburg and Demel 1984). Moreover, it is also known that hemin can affect the carbohydrate metabolism of the parasites, which could lead to lysis of parasites (Rodriguez and Jungery 1986). Thus, terpenes can be designed to be promising drugs for malaria.
Different kinds of terpenes show different effects on the parasites. For instance, beta-myrcene the most common terpenes, is proven to have in vitro antiplasmodial activity (Kpoviessi et al. 2014). Beta-myrcene from , the plant which is high in terpenes, does not show an anti plasmodial effect but extracts from stem, leaves, and seeds of clove basil showed a good antiplasmodial activity (Small 2017 Kpoviessi et al. 2014). Additionally, it was also reported to have antitrypanosomal activity when tested against (Habila et al. 2010). This data leads to the fact that terpenes are effective against pathogenic Protista.
Limonene regarded as the second most commonly found terpene, also possesses antiplasmodial activity against . Limonene achieves its goal by targeting the intermediates of the active isoprenoid pathway of the parasite. Isoprenoid pathway plays a major role in parasite survival by mediating cell signaling, protein translation and several other biological processes (Jordão et al. 2011). Specifically, the isoprenic products that are inhibited from being synthesized are dolichol and ubiquinone (Goulart et al. 2004). The isoprenoid pathway of parasites is distinct from that found in mammals, which makes limonene a reliable constituent of antimalarial drug (Goulart et al. 2004). Thus, the host cell pathway will not be affected by the administration of the drug.
Pinene, commonly found monoterpene in pine trees is composed of two classes𠅊lpha-pinene and beta-pinene. Both the classes of pinene were reported to be effective against the W2 strain of , which is resistant to chloroquine (Boyom et al. 2010). Of particular interest is the increase in antiplasmodial activity of pinene in cumin seed oil with increase in the distillation time. The study concluded that the optimal distillation time for increased antimalarial activity is 0𠄵 and 5𠄷.5 min (Zheljazkov et al. 2015). Further investigation is needed to ascertain if distillation time is just increasing the yield of pinenes in the oil or improving the bioactivity of pinenes.
The next most abundant terpene, caryophyllene has the ability to both prevent and cure malaria. Caryophyllene is an active component of insect repellents especially for mosquitoes and other blood-feeding Diptera (Maia and Sarah 2011). Recent studies ensured that silver nanoparticles synthesized from caryophyllene are highly effective against (Kamaraj et al. 2017). Thus, terpenes could be a safer and a cost effective alternative for malarial treatment.
The emerging viral diseases have necessitated the research for new effective antiviral agents such as terpenes . As a result, scientists evaluated various terpenes for their properties, among which monoterpenes showed a good result. Monoterpenes are terpene classes that possess two isoprene units. They form a major constituent of essential oils in plants which indicates monoterpenes play a major role in defense for plants (Grabmann 2005). A 2005 study evaluated the in vitro antiviral activity of several essential oils extracted from South American plants (Duschatzky et al. 2005). The oil extracts were tested against three major human viruses—herpes simplex virus-1 (HSV1), dengue virus type 2, and Junin virus. The oils that were proved to be virucidal were mainly composed of monoterpenes, namely, carvone, carveol limonene, alpha- and beta-pinene, caryophylene, camphor, beta-ocimene, and one sesquiterpene which is germacrene (Duschatzky et al. 2005). A similar study in 2008 analyzed the essential oils of seven plants from Lebanon for in vitro antiviral activity (Loizzo et al. 2008). The viruses under investigation were HSV1 and severe acute respiratory syndrome corona virus (SARS CoV). The results were positive for antiviral effects, and the major constituents were alpha- and beta-pinene, beta-ocimene, and 1,8-cineole (Loizzo et al. 2008). Following this, a 2009 study on also had similar results which suggested 1,8-cineole, α-pinene, caryophyllene oxide, and sabinene to be the major components of virucidal oils (Alim et al. 2009). Functional data from these studies reveal that a few monoterpenes are shared by various plants for antiviral properties (Alim et al. 2009). These shared monoterpenes could be of importance as they are present universally.
Of particular interest is the single main monoterpene that is contributing to the virucidal activity. This was studied by Astani et al. (2009) using eucalyptus, tea tree, and thyme essential oil extracts (Astani et al. 2009). They suggested that monoterpene hydrocarbons have a slightly higher virulent activity compared to the monoterpene alcohols against HSV-1. The monoterpenes with the highest virucidal activity were identified to be alpha-pinene and alpha-terpineol (Astani et al. 2009). The mechanism behind the virucidal activity was suggested to be direct inactivation of free viral particles. However, the study concluded that more than isolated single monoterpenes, a mixture of monoterpenes are more effective and possessed lesser toxicity to host cells (Astani et al. 2009). This was further bolstered by another study which evidenced the virucidal property of a combination of monoterpenes obtained from (Zamora et al. 2016). The activity was tested against a human flavivirus West Nile virus. The results were positive both in vivo and in vitro. The underlying mechanism was predicted to be induced cell cycle arrest at G0 or G1 phase. This indicates that a mixture of monoterpenes could act as a better antiviral agent rather than a single monoterpene (Zamora et al. 2016). Recent studies have shown that triketone-terpene adducts also exert antiviral, antimicrobial and antitumor activity (Chen et al. 2017). These adducts are obtained from Myrtaceae as secondary metabolites in the form of sesquiterpenes called myrtucomvalones A, B, and C. The terpene adducts successfully inhibited the respiratory syncytial virus (RSV) (Chen et al. 2017).
The bioactive terpenes present in various plants have shown various results for antiviral property. It would therefore be important to look for various plant source rather than various monoterpenes for therapeutic purposes. Researchers are also focusing on synthesizing terpene hybrid from fungal sources as they are presumed to have antiviral and UV protective properties (Yuan et al. 2017). Terpene synthesis from fungi can lead to cost effective and limited labor methods (Yuan et al. 2017).
The medicinal benefits of terpenes are not limited to pathogenic diseases. Terpenes are widely acclaimed for their anticancer activity too. An early 1997 study concluded that a combination of monoterpenes, diterpenes and sesquiterpenes can be effectively used to treat cancers that occur in colon, brain, prostate gland, and bones. 9 It also claimed that administration of terpenes in humans inhibited the growth of prostate cancer cells and sensitized the tumor in such a way it becomes susceptible to radiotherapy (see footnote 9). The major advantage of this treatment was that, the drug can be administered through several routes among which oral and topical were most preferred (see footnote 9).
Among the different kinds of terpenes, limonene is well recognized as an anticancer agent. Limonene is a bioactive food component found in citrus peels, orange peels, and several other citrus fruits (Jirtle et al. 1993). Studies have reported limonene to exhibit strong cancer inhibition activity both in vitro and in vivo. The mechanism behind limonene activity is still under investigation. A study by Jirtle et al. (1993) reported that limonene acts through induction of transforming growth factor B-1 and mannose-6-phosphate/insulin-like growth factor II receptors (Jirtle et al. 1993). In contrast a study by Bishayee and Rabi 2009) suggested that limonene eliminates cancer cells by induction of apoptosis (Bishayee and Rabi 2009). Structural studies on limonene reported that they are lipophilic and have the tendency to be deposited in fatty tissues when administered orally. This indicates that limonene can act as an excellent chemopreventive drug for cancer as it can be deposited in the body (Miller et al. 2010). Another study in 2013 concluded that limonene acts by suppressing the expression of breast tumor cyclin D1 (Miller et al. 2013). This lead to cell cycle arrest and mitigated proliferation of cancer cells in women with early stages of breast cancer (Miller et al. 2013). Recent study showed that limonene from pinecones can kill lung cancer cells in vitro by apoptotic mechanism that is activated through caspase-3 pathway (Lee et al. 2017). These findings indicate a novel application of limonene towards fighting and preventing cancer. Not just limonene, but also its metabolite perillyl alcohol is also said to exhibit antitumor activity in pancreatic cell lines through apoptotic mechanisms (Sobral et al. 2014 Dalessio et al. 2014).
Apart from limonene, the terpene thymoquinone has all been widely studied for its chemoprotective and chemotherapeutic activity. Thymoquinone is found to be an active constituent of the volatile oils of an annual herbaceous plant called (black cumin) (Majdalawieh et al. 2017). The pathways affected by thymoquinone to exert its antitumor properties are p53, PPARγ, MAPK, NF-㮫, PI3K/AKT, and STAT3 signaling pathways (Majdalawieh et al. 2017). Thymoquinone has been proved to be anticancerous against several cancers such as breast cancer, skin cancer, non–small cell lung cancer, bile duct cancer, and brain cancer. The basic mechanisms underlying the cancer inhibition is apoptosis and cell cycle arrest (Sobral et al. 2014 Khader and Eckl 2014). Most of the cancer related studies were performed using thermoquinone obtained from the N. sativa extracts. A 2012 study showed that thermoquinone can be obtained in larger amounts from the mint family, namely, Monarda didyma and Monarda media (Taborsky et al. 2012). Thus, thermoquinone from alternative sources has to be tested for its precious potential in cancer therapy.
Other terpenes that have reported cytotoxic effects on cancer cells include alloocimene, camphor, beta-myrcene, pinene, alpha- and gamma-thujaplicin, terpinene, thymohydroquinone, carvone, camphene, and cymene (Sobral et al. 2014). Terpenes being natural compounds are unlikely to affect the healthy cells or create a side effect, which attracts many researchers to exploit its capability in cancer treatment.
Diabetes is one of the widely prevalent diseases in the world. It is affecting both children and adults in both developing and developed nations (You and Henneberg 2016 Narayan et al. 2000). The social and economic burden of diabetes continues to grow and it is expected to rise rapidly in developing countries (Sarwar et al. 2010). In USA, diabetes is one of the leading causes for visual impairment, limb amputation, renal diseases, heart diseases and death (Saddinne et al. 1999). Diabetes can be of two types—type 1 (where the immune system of the body acts against the insulin-producing organs) and type 2 (where the insulin produced cannot be used by the body or insulin is produced in low amounts). 10 Although there are several medications available, their use is limited due to their adverse effects. Some of the commonly found side-effects include low blood sugar, vomiting, nausea, diarrhea, bloating, and weight gain. 11 This led to the research for natural products to be used as effective antidiabetic medication. Phytochemicals from the medicinal plants have been recommended for treating type 2 diabetes, of which terpene forms a major constituent (Jung et al. 2006).
Medicinal plants of Oriental Morocco were studied for their antidiabetic property in rats. The report showed that terpenes, terpene diols, and terpene diol glucosides form major components of the extracts of plants under study (Bnouham et al. 2010). A similar study on medicinal plant and their natural products that were reported from 2001 was conducted by Jung et al. 2006. This study was focused on non–insulin-dependent diabetes mellitus (type 2), and it proved that terpenes along with few other secondary metabolites such as alkaloids and flavonoids exhibit antidiabetic potential (Jung et al. 2006).
The most promising terpene compound for treating diabetes is called andrographolide which is a diterpenoid lactone (Brahmachari 2017). This compound forms the major component of the leaves of the small herbaceous plant . A. paniculata is an Asian plant that has already been reported to be used in traditional medicines for its therapeutic nature (Brahmachari 2017). The terpenoid acts by reducing the plasma glucose and increasing the utilization of glucose by the body in diabetes mellitus rats (Gupta et al. 2008). The actual mechanism by how it does this is it activates the alpha-adrenoreceptors to increase the release of an opioid peptide beta-endomorphin (Brahmachari 2017) which is reported to be secreted in low amounts in diabetic rats (Forman et al. 1985). This increased secretion in turn activates the opioid μ-receptors. These receptors can effectively curb the hepatic gluconeogenesis (glucose synthesis from non-carbohydrate precursors) and elevate the utilization of glucose by muscles. Finally, this results in a reduced plasma glucose concentration (Brahmachari 2017). Andrographolide is also observed to prevent the secondary complications of diabetes such as diabetic retinopathy, a condition that will lead to blindness (Brahmachari 2017). It significantly weakens the retinal angiogenesis and inflammation during the development of the disease (Brahmachari 2017). Moreover, it can also fix the impaired or extended estrous cycle in diabetic rats (Reyes et al. 2006). Andrographolide was orally administered in all the above studies. This indicates its efficiency for being used as a lead molecule in the future drugs designed for treating diabetes mellitus.
Another widely known terpene is curcumin obtained from which commonly called turmeric (Nabavi et al. 2015). It exhibits high antidiabetic property and acts by quashing the oxidative stress and inflammation. By regulating the polyol pathway, it can also reduce the plasma glucose and levels of glycosylated hemoglobin (Nabavi et al. 2015). Moreover, curcumin is also reported to activate the enzymes present in the liver that are essential for glycolysis, gluconeogenesis, and lipid metabolism (Zhang et al. 2013). Alike andrographolide, curcumin is also reported to reduce the complications of diabetes (Nabavi et al. 2015), for example, liver disorder which is a common manifestation of diabetes type 2 (Zhang et al. 2013). Curcumin treats these disorders by reducing the liver weight and lipid peroxidation products. Further, it is also reported to normalize the levels of fetuin-A in serum that contributes to insulin resistance and fatty liver in diabetic rats (Zhang et al. 2013). Other complications that can be attenuated by curcumin include diabetes associated—retinopathy, microangiopathy, neuropathy, and nephropathy (Zhang et al. 2013). These findings confirm that curcumin is likely to be used in the future for diabetes treatment.
Depression has become a serious health concern by contributing to the emerging mental and emotional disorders throughout the world. It is hitting both the developed and developing countries. Depression can pave way to various health issues from alcoholism to heart diseases (Holden 2000). It is also said to increase the rate of mortality significantly in breast cancer patients (Hjerl et al. 2003). Moreover, depression immobilizes its victims thereby leading to economic loss (Holden 2000). By analyzing the social and economic burdens caused by depression, researchers have stepped out towards finding novel stress-relieving drugs. Synthetic drugs have serious side-effects and unintended interactions with the body that negatively affects the treatment outcome (Jawaid et al. 2011). Hence this necessitated the need for natural drugs. Terpenes serves as one of the most relevant bioactive compound for treating depression and therefore can open doors for designing natural or synthetic antidepressant drugs (Bahramsoltani et al. 2015).
Twenty-five percentage of antidepressant drugs prescribed by doctors are obtained from herbs through various extracts (Saki et al. 2014). To estimate the important compounds contributing to the antidepressant effect, Saki et al. (2014) performed an electronic database based study. The results revealed that terpenes formed a major part of the extracts of medicinal plants that exerted antidepressant effects (Saki et al. 2014). Thus, scientists focused on identifying the active principles of plant extracts contributing to the antistress effects. Different plant had different acting compounds.
Among the several terpenes, linalool and beta-pinene are commonly found to be active principles (both Guzmán-Gutiérrez et al. 2015 Guzmán-Gutiérrez et al. 2012). They were discovered from the extracts of medicinal plants and and flowers of lavender (Appleton 2012 Guzmán-Gutiérrez et al. 2012 Guadarrama-Cruz et al. 2008). These monoterpenes act by interacting with the 5HT1A receptors of the serotonergic pathway. Serotonins are important in the fact that their release and re-uptake levels can be altered to overcome stress (Chaouloff 2000 Guzmán-Gutiérrez et al. 2012). They also interact with adrenergic receptors of the body that play a major role in stress-induced behavioral changes (Pandey et al. 1995 Guzmán-Gutiérrez et al. 2015). Another interesting finding is the interaction of beta-pinene with dopaminergic receptors namely D1 receptors. This is the mechanism followed by most of the antidepressant drugs available in the market (Guzmán-Gutiérrez et al. 2015). A more interesting study would be to examine the beta-pinene and linalool efficiency through inhalation tests. This is because these monoterpenes are aromatic compounds that generally have an enhanced activity when inhaled as they can directly hit the central nervous system (Guzmán Gutiérrez et al. 2014).
Apart from monoterpenes, sesquiterpenes also exhibit antidepressant effects. One striking example is beta-caryophyllene which was proved to ameliorate the depressive symptoms in mice (Bahi et al. 2014). The underlying mechanism of this compound is binding to a receptor called CB2 and activating it. CB2 is found in the brain and immune cells and plays a major role in regulating depressive-related disorders (Bahi et al. 2014). Thus beta-caryophyllene curbs depression by acting as a CB2 receptor agonist (Bahi et al. 2014).
Other terpenes that have effective antidepressant properties include hyperforin which is present in the extracts of (Subhan et al. 2010). It has been shown that the extracts of H. perforatum differ in their antidepressant potential with the difference in concentration of hyperforin present in the extract (Laakmann et al. 1999). Similar to many other antidepressants hyperforin acts by inhibiting the neuronal uptake of mood regulators such as serotonin, dopamine and norepinephrine. In addition, it also has its own unique mechanism of controlling depression by inhibiting the neurotransmitters GABA and l -glutamate uptake (Müller et al. 2001).
Another fascinating antidepressant plant is , which is a short perennial herb. This plant not only reduces the stress and anxiety levels but also improves the symptoms of depression in humans (Bhattacharyya et al. 2007). The major components of Valeriana extracts are terpenoids called maaliol, patchouli alcohol, and 8-acetoxypatchouli alcohol (Subhan et al. 2010). The terpenoid-less extract of Valeriana was found to be devoid of antidepressant activity which indicates that terpenes are the active components involved in reducing the depression (Subhan et al. 2010).
Uses in Folk Medicine
Folk medicine has always been an eye-opener for designing novel drugs for diseases. To be more specific, almost three-fourths of the plant-based drugs were created based on the knowledge of folk medicine (Table 15.4 ) (Efferth et al. 2008). Realizing this fact, western worlds are now turning back into old medicines and bioactive plant components to treat modern diseases (Efferth et al. 2007, 2008). This has boosted the export rates of Chinese medicinal products (based on traditional Chinese medicine) from China to other developed nations. Plants used in traditional Chinese medicine (TCM) are being extensively studied for their secondary metabolites and their therapeutic properties (Efferth et al. 2007). One of the active principles of TCM products is terpenes (Liu and Jiang 2012). Due to their large availability and diversity, terpenes contribute the most to industrial and medicinal applications among all the secondary metabolites of plants (Zwenger and Basu 2008).
Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance
Many different definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare-associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided.
© 2011 European Society of Clinical Microbiology and Infectious Diseases. No claim to original US government works.
The emergence and increasing prevalence of bacterial strains that are resistant to available antibiotics demand the discovery of new therapeutic approaches. Targeting bacterial virulence is an alternative approach to antimicrobial therapy that offers promising opportunities to inhibit pathogenesis and its consequences without placing immediate life-or-death pressure on the target bacterium. Certain virulence factors have been shown to be potential targets for drug design and therapeutic intervention, whereas new insights are crucial for exploiting others. Targeting virulence represents a new paradigm to empower the clinician to prevent and treat infectious diseases.
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There are a few mechanisms by which antiprotozoan drugs target infectious protozoans (Table 2, below). Some are antimetabolites, such as atovaquone, proguanil, and artemisinins. Atovaquone, in addition to being antifungal, blocks electron transport in protozoans and is used for the treatment of protozoan infections including malaria, babesiosis, and toxoplasmosis. Proguanil is another synthetic antimetabolite that is processed in parasitic cells into its active form, which inhibits protozoan folic acid synthesis. It is often used in combination with atovaquone, and the combination is marketed as Malarone for both malaria treatment and prevention.
Artemisinin, a plant-derived antifungal first discovered by Chinese scientists in the 1970s, is quite effective against malaria. Semisynthetic derivatives of artemisinin are more water soluble than the natural version, which makes them more bioavailable. Although the exact mechanism of action is unclear, artemisinins appear to act as prodrugs that are metabolized by target cells to produce reactive oxygen species (ROS) that damage target cells. Due to the rise in resistance to antimalarial drugs, artemisinins are also commonly used in combination with other antimalarial compounds in artemisinin-based combination therapy (ACT).
Several antimetabolites are used for the treatment of toxoplasmosis caused by the parasite Toxoplasma gondii. The synthetic sulfa drug sulfadiazine competitively inhibits an enzyme in folic acid production in parasites and can be used to treat malaria and toxoplasmosis. Pyrimethamine is a synthetic drug that inhibits a different enzyme in the folic acid production pathway and is often used in combination with sulfadoxine (another sulfa drug) for the treatment of malaria or in combination with sulfadiazine for the treatment of toxoplasmosis. Side effects of pyrimethamine include decreased bone marrow activity that may cause increased bruising and low red blood cell counts. When toxicity is a concern, spiramycin, a macrolide protein synthesis inhibitor, is typically administered for the treatment of toxoplasmosis.
Two classes of antiprotozoan drugs interfere with nucleic acid synthesis: nitroimidazoles and quinolines. Nitroimidazoles, including semisynthetic metronidazole, which was discussed previously as an antibacterial drug, and synthetic tinidazole, are useful in combating a wide variety of protozoan pathogens, such as Giardia lamblia, Entamoeba histolytica, and Trichomonas vaginalis. Upon introduction into these cells in low-oxygen environments, nitroimidazoles become activated and introduce DNA strand breakage, interfering with DNA replication in target cells. Unfortunately, metronidazole is associated with carcinogenesis (the development of cancer) in humans.
Another type of synthetic antiprotozoan drug that has long been thought to specifically interfere with DNA replication in certain pathogens is pentamidine. It has historically been used for the treatment of African sleeping sickness (caused by the protozoan Trypanosoma brucei) and leishmaniasis (caused by protozoa of the genus Leishmania), but it is also an alternative treatment for the fungus Pneumocystis. Some studies indicate that it specifically binds to the DNA found within kinetoplasts (kDNA long mitochondrion-like structures unique to trypanosomes), leading to the cleavage of kDNA. However, nuclear DNA of both the parasite and host remain unaffected. It also appears to bind to tRNA, inhibiting the addition of amino acids to tRNA, thus preventing protein synthesis. Possible side effects of pentamidine use include pancreatic dysfunction and liver damage.
The quinolines are a class of synthetic compounds related to quinine, which has a long history of use against malaria. Quinolines are thought to interfere with heme detoxification, which is necessary for the parasite’s effective breakdown of hemoglobin into amino acids inside red blood cells. The synthetic derivatives chloroquine, quinacrine (also called mepacrine), and mefloquine are commonly used as antimalarials, and chloroquine is also used to treat amebiasis typically caused by Entamoeba histolytica. Long-term prophylactic use of chloroquine or mefloquine may result in serious side effects, including hallucinations or cardiac issues. Patients with glucose-6-phosphate dehydrogenase deficiency experience severe anemia when treated with chloroquine.
|Table 2. Common Antiprotozoan Drugs|
|Mechanism of Action||Drug Class||Specific Drugs||Clinical Uses|
|Inhibit electron transport in mitochondria||Naphthoquinone||Atovaquone||Malaria, babesiosis, and toxoplasmosis|
|Inhibit folic acid synthesis||Not applicable||Proquanil||Combination therapy with atovaquone for malaria treatment and prevention|
|Sulfonamide||Sulfadiazine||Malaria and toxoplasmosis|
|Not applicable||Pyrimethamine||Combination therapy with sulfadoxine (sulfa drug) for malaria|
|Produces damaging reactive oxygen species||Not applicable||Artemisinin||Combination therapy to treat malaria|
|Inhibit DNA synthesis||Nitroimidazoles||Metronidazole, tinidazole||Infections caused by Giardia lamblia, Entamoeba histolytica, and Trichomonas vaginalis|
|Not applicable||Pentamidine||African sleeping sickness and leishmaniasis|
|Inhibit heme detoxification||Quinolines||Chloroquine||Malaria and infections with E. histolytica|
Think about It
Interactive resources for schools
Medicines which prevent the immune response of the body from destroying a transplanted organ
A distinct part of the cell, such as the nucleus, ribosome or mitochondrion, which has structure and function.
A thin, flexible sheet-like structure that acts as a lining or a boundary in an organism.
A bacterium, virus, or other microorganism, capable of causing disease.
Single-celled organism. Has a cell wall, cell membrane, cytoplasm. Its DNA is loosely-coiled in the cytoplasm and there is no distinct nucleus
A list of often difficult or specialised words with their definitions.
Reusable protein molecules which act as biological catalysts, changing the rate of chemical reactions in the body without being affected themselves
The basic unit from which all living organisms are built up, consisting of a cell membrane surrounding cytoplasm and a nucleus.
Cells - the fundamental unit of life
Living organisms are made up of cells. Understanding the structures and functions of cells is the key to understanding how whole organisms work and interact with the world around them.
How does your body recognise an invading pathogen? How do cells communicate so they can act as a coordinated whole? Why are transplanted organs rejected without immunosuppressant drugs? What are the differences between your cells and those of bacteria?
The size and structure of cells varies enormously, but there are many common features. The cell surface membrane forms a barrier between the contents of the cell and the environment. Membranes also surround all the organelles inside the cell. The structure of these membranes affects the functioning of almost every aspect of the cell.
Cells act as biological factories, producing many different substances which need to be exported to different regions of the cell or the body. Often these substances are produced as a result of signals from inside or outside the cell itself.
Cells display complex identification systems on their surfaces, and these act as part of overall cell communication. These systems are sometimes used by pathogens to gain entry to cells – and both surface identification systems and internal communication cascades can be used as targets for drugs in the battle against disease.
A cell contains a hundred or more chemical reactions, each contained by membranes and controlled by enzymes.
Graphene and graphene-based composite have exclusive electronic, biological, mechanical, as well as unique optical properties. Researchers nowadays have developed various transistors based on graphene molecules, for use in the biomedical field such as biosensing via fluorescence, cell growth and its differentiation for the treatment of many diseases. The formation of a unique biosensor based on graphene has strong functionalization under various physiological conditions with a loss in few properties. As an emerging field, research on nanomaterial scaffolds of graphene for the implementation of stem cell culture deserves notable attention. To build therapeutics on the basis of graphene, researchers might standardize its derivatives as well as check functionalization of this on the biological field to know the response of cells to many graphene derivatives. Graphene may come up as a unique nanoparticle to be used in the biomedical study by efficient association with various branches of science.
Prehistoric times Edit
Plants, including many now used as culinary herbs and spices, have been used as medicines, not necessarily effectively, from prehistoric times. Spices have been used partly to counter food spoilage bacteria, especially in hot climates,   and especially in meat dishes which spoil more readily.  Angiosperms (flowering plants) were the original source of most plant medicines.  Human settlements are often surrounded by weeds used as herbal medicines, such as nettle, dandelion and chickweed.   Humans were not alone in using herbs as medicines: some animals such as non-human primates, monarch butterflies and sheep ingest medicinal plants when they are ill.  Plant samples from prehistoric burial sites are among the lines of evidence that Paleolithic peoples had knowledge of herbal medicine. For instance, a 60 000-year-old Neanderthal burial site, "Shanidar IV", in northern Iraq has yielded large amounts of pollen from eight plant species, seven of which are used now as herbal remedies.  A mushroom was found in the personal effects of Ötzi the Iceman, whose body was frozen in the Ötztal Alps for more than 5,000 years. The mushroom was probably used against whipworm. 
Ancient times Edit
In ancient Sumeria, hundreds of medicinal plants including myrrh and opium are listed on clay tablets. The ancient Egyptian Ebers Papyrus lists over 800 plant medicines such as aloe, cannabis, castor bean, garlic, juniper, and mandrake.  From ancient times to the present, Ayurvedic medicine as documented in the Atharva Veda, the Rig Veda and the Sushruta Samhita has used hundreds of pharmacologically active herbs and spices such as turmeric, which contains curcumin.   The Chinese pharmacopoeia, the Shennong Ben Cao Jing records plant medicines such as chaulmoogra for leprosy, ephedra, and hemp.  This was expanded in the Tang Dynasty Yaoxing Lun.  In the fourth century BC, Aristotle's pupil Theophrastus wrote the first systematic botany text, Historia plantarum.  In around 60 AD, the Greek physician Pedanius Dioscorides, working for the Roman army, documented over 1000 recipes for medicines using over 600 medicinal plants in De materia medica. The book remained the authoritative reference on herbalism for over 1500 years, into the seventeenth century. 
Middle Ages Edit
In the Early Middle Ages, Benedictine monasteries preserved medical knowledge in Europe, translating and copying classical texts and maintaining herb gardens.   Hildegard of Bingen wrote Causae et Curae ("Causes and Cures") on medicine.  In the Islamic Golden Age, scholars translated many classical Greek texts including Dioscorides into Arabic, adding their own commentaries.  Herbalism flourished in the Islamic world, particularly in Baghdad and in Al-Andalus. Among many works on medicinal plants, Abulcasis (936–1013) of Cordoba wrote The Book of Simples, and Ibn al-Baitar (1197–1248) recorded hundreds of medicinal herbs such as Aconitum, nux vomica, and tamarind in his Corpus of Simples.  Avicenna included many plants in his 1025 The Canon of Medicine.  Abu-Rayhan Biruni,  Ibn Zuhr,  Peter of Spain, and John of St Amand wrote further pharmacopoeias. 
Early Modern Edit
The Early Modern period saw the flourishing of illustrated herbals across Europe, starting with the 1526 Grete Herball. John Gerard wrote his famous The Herball or General History of Plants in 1597, based on Rembert Dodoens, and Nicholas Culpeper published his The English Physician Enlarged.  Many new plant medicines arrived in Europe as products of Early Modern exploration and the resulting Columbian Exchange, in which livestock, crops and technologies were transferred between the Old World and the Americas in the 15th and 16th centuries. Medicinal herbs arriving in the Americas included garlic, ginger, and turmeric coffee, tobacco and coca travelled in the other direction.   In Mexico, the sixteenth century Badianus Manuscript described medicinal plants available in Central America. 
19th and 20th centuries Edit
The place of plants in medicine was radically altered in the 19th century by the application of chemical analysis. Alkaloids were isolated from a succession of medicinal plants, starting with morphine from the poppy in 1806, and soon followed by ipecacuanha and strychnos in 1817, quinine from the cinchona tree, and then many others. As chemistry progressed, additional classes of pharmacologically active substances were discovered in medicinal plants.   Commercial extraction of purified alkaloids including morphine from medicinal plants began at Merck in 1826. Synthesis of a substance first discovered in a medicinal plant began with salicylic acid in 1853.  Around the end of the 19th century, the mood of pharmacy turned against medicinal plants, as enzymes often modified the active ingredients when whole plants were dried, and alkaloids and glycosides purified from plant material started to be preferred.  Drug discovery from plants continued to be important through the 20th century and into the 21st, with important anti-cancer drugs from yew and Madagascar periwinkle. 
Medicinal plants are used with the intention of maintaining health, to be administered for a specific condition, or both, whether in modern medicine or in traditional medicine.   The Food and Agriculture Organization estimated in 2002 that over 50,000 medicinal plants are used across the world.  The Royal Botanic Gardens, Kew more conservatively estimated in 2016 that 17,810 plant species have a medicinal use, out of some 30,000 plants for which a use of any kind is documented. 
In modern medicine, around a quarter [a] of the drugs prescribed to patients are derived from medicinal plants, and they are rigorously tested.   In other systems of medicine, medicinal plants may constitute the majority of what are often informal attempted treatments, not tested scientifically.  The World Health Organization estimates, without reliable data, that some 80 percent of the world's population depends mainly on traditional medicine (including but not limited to plants) perhaps some two billion people are largely reliant on medicinal plants.   The use of plant-based materials including herbal or natural health products with supposed health benefits, is increasing in developed countries.  This brings attendant risks of toxicity and other effects on human health, despite the safe image of herbal remedies.  Herbal medicines have been in use since long before modern medicine existed there was and often still is little or no knowledge of the pharmacological basis of their actions, if any, or of their safety. The World Health Organization formulated a policy on traditional medicine in 1991, and since then has published guidelines for them, with a series of monographs on widely used herbal medicines.  
Medicinal plants may provide three main kinds of benefit: health benefits to the people who consume them as medicines financial benefits to people who harvest, process, and distribute them for sale and society-wide benefits, such as job opportunities, taxation income, and a healthier labour force.  However, development of plants or extracts having potential medicinal uses is blunted by weak scientific evidence, poor practices in the process of drug development, and insufficient financing. 
All plants produce chemical compounds which give them an evolutionary advantage, such as defending against herbivores or, in the example of salicylic acid, as a hormone in plant defenses.   These phytochemicals have potential for use as drugs, and the content and known pharmacological activity of these substances in medicinal plants is the scientific basis for their use in modern medicine, if scientifically confirmed.  For instance, daffodils (Narcissus) contain nine groups of alkaloids including galantamine, licensed for use against Alzheimer's disease. The alkaloids are bitter-tasting and toxic, and concentrated in the parts of the plant such as the stem most likely to be eaten by herbivores they may also protect against parasites.   
Modern knowledge of medicinal plants is being systematised in the Medicinal Plant Transcriptomics Database, which by 2011 provided a sequence reference for the transcriptome of some thirty species.  The major classes of pharmacologically active phytochemicals are described below, with examples of medicinal plants that contain them.     
Alkaloids are bitter-tasting chemicals, very widespread in nature, and often toxic, found in many medicinal plants.  There are several classes with different modes of action as drugs, both recreational and pharmaceutical. Medicines of different classes include atropine, scopolamine, and hyoscyamine (all from nightshade),  the traditional medicine berberine (from plants such as Berberis and Mahonia), [b] caffeine (Coffea), cocaine (Coca), ephedrine (Ephedra), morphine (opium poppy), nicotine (tobacco), [c] reserpine (Rauvolfia serpentina), quinidine and quinine (Cinchona), vincamine (Vinca minor), and vincristine (Catharanthus roseus).  
The opium poppy Papaver somniferum is the source of the alkaloids morphine and codeine. 
The alkaloid nicotine from tobacco binds directly to the body's Nicotinic acetylcholine receptors, accounting for its pharmacological effects. 
Anthraquinone glycosides are found in medicinal plants such as rhubarb, cascara, and Alexandrian senna.   Plant-based laxatives made from such plants include senna,  rhubarb  and Aloe. 
The cardiac glycosides are powerful drugs from medicinal plants including foxglove and lily of the valley. They include digoxin and digitoxin which support the beating of the heart, and act as diuretics. 
The foxglove, Digitalis purpurea, contains digoxin, a cardiac glycoside. The plant was used on heart conditions long before the glycoside was identified.  
Polyphenols of several classes are widespread in plants, having diverse roles in defenses against plant diseases and predators.  They include hormone-mimicking phytoestrogens and astringent tannins.   Plants containing phytoestrogens have been administered for centuries for gynecological disorders, such as fertility, menstrual, and menopausal problems.  Among these plants are Pueraria mirifica,  kudzu,  angelica,  fennel, and anise. 
Many polyphenolic extracts, such as from grape seeds, olives or maritime pine bark, are sold as dietary supplements and cosmetics without proof or legal health claims for beneficial health effects.  In Ayurveda, the astringent rind of the pomegranate, containing polyphenols called punicalagins, is used as a medicine. 
Angelica, containing phytoestrogens, has long been used for gynaecological disorders.
Polyphenols include phytoestrogens (top and middle), mimics of animal estrogen (bottom). 
Terpenes and terpenoids of many kinds are found in a variety of medicinal plants,  and in resinous plants such as the conifers. They are strongly aromatic and serve to repel herbivores. Their scent makes them useful in essential oils, whether for perfumes such as rose and lavender, or for aromatherapy.    Some have medicinal uses: for example, thymol is an antiseptic and was once used as a vermifuge (anti-worm medicine). 
Thymol is one of many terpenes found in plants. 
Medicinal plants demand intensive management. Different species each require their own distinct conditions of cultivation. The World Health Organization recommends the use of rotation to minimise problems with pests and plant diseases. Cultivation may be traditional or may make use of conservation agriculture practices to maintain organic matter in the soil and to conserve water, for example with no-till farming systems.  In many medicinal and aromatic plants, plant characteristics vary widely with soil type and cropping strategy, so care is required to obtain satisfactory yields. 
Medicinal plants are often tough and fibrous, requiring some form of preparation to make them convenient to administer. According to the Institute for Traditional Medicine, common methods for the preparation of herbal medicines include decoction, powdering, and extraction with alcohol, in each case yielding a mixture of substances. Decoction involves crushing and then boiling the plant material in water to produce a liquid extract that can be taken orally or applied topically.  Powdering involves drying the plant material and then crushing it to yield a powder that can be compressed into tablets. Alcohol extraction involves soaking the plant material in cold wine or distilled spirit to form a tincture. 
Traditional poultices were made by boiling medicinal plants, wrapping them in a cloth, and applying the resulting parcel externally to the affected part of the body. 
When modern medicine has identified a drug in a medicinal plant, commercial quantities of the drug may either be synthesised or extracted from plant material, yielding a pure chemical.  Extraction can be practical when the compound in question is complex. 
Plant medicines are in wide use around the world.  In most of the developing world, especially in rural areas, local traditional medicine, including herbalism, is the only source of health care for people, while in the developed world, alternative medicine including use of dietary supplements is marketed aggressively using the claims of traditional medicine. As of 2015, most products made from medicinal plants had not been tested for their safety and efficacy, and products that were marketed in developed economies and provided in the undeveloped world by traditional healers were of uneven quality, sometimes containing dangerous contaminants.  Traditional Chinese medicine makes use of a wide variety of plants, among other materials and techniques.  Researchers from Kew Gardens found 104 species used for diabetes in Central America, of which seven had been identified in at least three separate studies.   The Yanomami of the Brazilian Amazon, assisted by researchers, have described 101 plant species used for traditional medicines.  
Drugs derived from plants including opiates, cocaine and cannabis have both medical and recreational uses. Different countries have at various times made use of illegal drugs, partly on the basis of the risks involved in taking psychoactive drugs. 
Plant medicines have often not been tested systematically, but have come into use informally over the centuries. By 2007, clinical trials had demonstrated potentially useful activity in nearly 16% of herbal medicines there was limited in vitro or in vivo evidence for roughly half the medicines there was only phytochemical evidence for around 20% 0.5% were allergenic or toxic and some 12% had basically never been studied scientifically.  Cancer Research UK caution that there is no reliable evidence for the effectiveness of herbal remedies for cancer. 
A 2012 phylogenetic study built a family tree down to genus level using 20,000 species to compare the medicinal plants of three regions, Nepal, New Zealand and the South African Cape. It discovered that the species used traditionally to treat the same types of condition belonged to the same groups of plants in all three regions, giving a "strong phylogenetic signal".  Since many plants that yield pharmaceutical drugs belong to just these groups, and the groups were independently used in three different world regions, the results were taken to mean 1) that these plant groups do have potential for medicinal efficacy, 2) that undefined pharmacological activity is associated with use in traditional medicine, and 3) that the use of a phylogenetic groups for medicines in one region may predict their use in the other regions. 
The World Health Organization (WHO) has been coordinating a network called the International Regulatory Cooperation for Herbal Medicines to try to improve the quality of medical products made from medicinal plants and the claims made for them.  In 2015, only around 20% of countries had well-functioning regulatory agencies, while 30% had none, and around half had limited regulatory capacity.  In India, where Ayurveda has been practised for centuries, herbal remedies are the responsibility of a government department, AYUSH, under the Ministry of Health & Family Welfare. 
WHO has set out a strategy for traditional medicines  with four objectives: to integrate them as policy into national healthcare systems to provide knowledge and guidance on their safety, efficacy, and quality to increase their availability and affordability and to promote their rational, therapeutically sound usage.  WHO notes in the strategy that countries are experiencing seven challenges to such implementation, namely in developing and enforcing policy in integration in safety and quality, especially in assessment of products and qualification of practitioners in controlling advertising in research and development in education and training and in the sharing of information. 
Drug discovery Edit
The pharmaceutical industry has roots in the apothecary shops of Europe in the 1800s, where pharmacists provided local traditional medicines to customers, which included extracts like morphine, quinine, and strychnine.  Therapeutically important drugs like camptothecin (from Camptotheca acuminata, used in traditional Chinese medicine) and taxol (from the Pacific yew, Taxus brevifolia) were derived from medicinal plants.   The Vinca alkaloids vincristine and vinblastine, used as anti-cancer drugs, were discovered in the 1950s from the Madagascar periwinkle, Catharanthus roseus. 
Hundreds of compounds have been identified using ethnobotany, investigating plants used by indigenous peoples for possible medical applications.  Some important phytochemicals, including curcumin, epigallocatechin gallate, genistein and resveratrol are pan-assay interference compounds, meaning that in vitro studies of their activity often provide unreliable data. As a result, phytochemicals have frequently proven unsuitable as lead compounds in drug discovery.   In the United States over the period 1999 to 2012, despite several hundred applications for new drug status, only two botanical drug candidates had sufficient evidence of medicinal value to be approved by the Food and Drug Administration. 
The pharmaceutical industry has remained interested in mining traditional uses of medicinal plants in its drug discovery efforts.  Of the 1073 small-molecule drugs approved in the period 1981 to 2010, over half were either directly derived from or inspired by natural substances.   Among cancer treatments, of 185 small-molecule drugs approved in the period from 1981 to 2019, 65% were derived from or inspired by natural substances. 
Plant medicines can cause adverse effects and even death, whether by side-effects of their active substances, by adulteration or contamination, by overdose, or by inappropriate prescription. Many such effects are known, while others remain to be explored scientifically. There is no reason to presume that because a product comes from nature it must be safe: the existence of powerful natural poisons like atropine and nicotine shows this to be untrue. Further, the high standards applied to conventional medicines do not always apply to plant medicines, and dose can vary widely depending on the growth conditions of plants: older plants may be much more toxic than young ones, for instance.      
Pharmacologically active plant extracts can interact with conventional drugs, both because they may provide an increased dose of similar compounds, and because some phytochemicals interfere with the body's systems that metabolise drugs in the liver including the cytochrome P450 system, making the drugs last longer in the body and have a more powerful cumulative effect.  Plant medicines can be dangerous during pregnancy.  Since plants may contain many different substances, plant extracts may have complex effects on the human body. 
Quality, advertising, and labelling Edit
Herbal medicine and dietary supplement products have been criticized as not having sufficient standards or scientific evidence to confirm their contents, safety, and presumed efficacy.     A 2013 study found that one-third of herbal products sampled contained no trace of the herb listed on the label, and other products were adulterated with unlisted fillers including potential allergens.  
Where medicinal plants are harvested from the wild rather than cultivated, they are subject to both general and specific threats. General threats include climate change and habitat loss to development and agriculture. A specific threat is over-collection to meet rising demand for medicines.  A case in point was the pressure on wild populations of the Pacific yew soon after news of taxol's effectiveness became public.  The threat from over-collection could be addressed by cultivation of some medicinal plants, or by a system of certification to make wild harvesting sustainable.  A report in 2020 by the Royal Botanic Gardens, Kew identifies 723 medicinal plants as being at risk of extinction, caused partly by over-collection.