Hypericum perforatum

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Common St John's wort (Hypericum perforatum) is a flowering plant of the genus Hypericum. In humans, it is a medicinal herb with antidepressant, antibacterial, antioxidant, neuroprotective, and potent anti-inflammatory properties as well as potential anti-cancer and antiviral properties.[1][2] Clinical evidence supports the use of St John's wort preparations as a treatment for depression and certain other conditions.[1][3] However, it is toxic to certain species of livestock when ingested and is also considered a weed when growing wild. Hypericum perforatum is indigenous to Europe but has spread worldwide as an invasive species, including to temperate and subtropical regions of Turkey, Ukraine, Russia, the Middle East, India, and China.

Other names for St John's wort include Tipton's weed, rosin rose, goatweed, chase-devil, or Klamath weed.[4] In common speech, the name St John's wort may be used to refer to any species of the genus Hypericum. Therefore, H. perforatum is sometimes called Common St John's wort or Perforate St John's wort in order to differentiate it.

Botanical description

Translucent dots on the leaves

Hypericum perforatum is a yellow-flowering, stoloniferous or sarmentose, perennial herb indigenous to Europe. It has been introduced to many temperate areas of the world and grows wild in many meadows. The herb's common name comes from its traditional flowering and harvesting on St John's day, 24 June. The genus name Hypericum is derived from the Greek words hyper (above) and eikon (picture), in reference to the plant's traditional use in warding off evil by hanging plants over a religious icon in the house during St John's day. The species name perforatum refers to the presence of small oil glands in the leaves that look like windows, which can be seen when they are held against the light.[4]

St John's wort is a perennial plant with extensive, creeping rhizomes. Its stems are erect, branched in the upper section, and can grow to 1 m high. It has opposing, stalkless, narrow, oblong leaves that are 12 mm long or slightly larger. The leaves are yellow-green in color, with transparent dots throughout the tissue and occasionally with a few black dots on the lower surface.[4] Leaves exhibit obvious translucent dots when held up to the light, giving them a ‘perforated’ appearance, hence the plant's Latin name.

Its flowers measure up to 2.5 cm across, have five petals, and are colored bright yellow with conspicuous black dots. The flowers appear in broad cymes at the ends of the upper branches, between late spring and early to mid summer. The sepals are pointed, with glandular dots in the tissue. There are many stamens, which are united at the base into three bundles. The pollen grains are ellipsoidal.[4]

When flower buds (not the flowers themselves) or seed pods are crushed, a reddish/purple liquid is produced.

Ecology

St John's wort reproduces both vegetatively and sexually. It thrives in areas with either a winter- or summer-dominant rainfall pattern; however, distribution is restricted by temperatures too low for seed germination or seedling survival. Altitudes greater than 1500 m, rainfall less than 500 mm, and a daily mean January (in Southern hemisphere) temperature greater than 24 degrees C are considered limiting thresholds. Depending on environmental and climatic conditions, and rosette age, St John's wort will alter growth form and habit to promote survival. Summer rains are particularly effective in allowing the plant to grow vegetatively, following defoliation by insects or grazing.

The seeds can persist for decades in the soil seed bank, germinating following disturbance.[5]

Invasive species

Although Hypericum perforatum is grown commercially in some regions of south east Europe, it is listed as a noxious weed in more than twenty countries and has introduced populations in South and North America, India, New Zealand, Australia, and South Africa.[5] In pastures, St John’s wort acts as both a toxic and invasive weed.[6] It replaces native plant communities and forage vegetation to the dominating extent of making productive land nonviable{{ safesubst:#invoke:Unsubst||date=__DATE__ |$B= {{#invoke:Category handler|main}}{{#invoke:Category handler|main}}[citation needed] }} or becoming an invasive species in natural habitats and ecosystems. Ingestion by livestock can cause photosensitization, central nervous system depression, spontaneous abortion, and can lead to death. Effective herbicides for control of Hypericum include 2,4-D, picloram, and glyphosate. In western North America three beetles Chrysolina quadrigemina, Chrysolina hyperici and Agrilus hyperici have been introduced as biocontrol agents.

Livestock

Poisoning

In large doses, St John's wort is poisonous to grazing livestock (cattle, sheep, goats, horses).[6] Behavioural signs of poisoning are general restlessness and skin irritation. Restlessness is often indicated by pawing of the ground, headshaking, head rubbing, and occasional hindlimb weakness with knuckling over, panting, confusion, and depression. Mania and hyperactivity may also result, including running in circles until exhausted. Observations of thick wort infestations by Australian graziers include the appearance of circular patches giving hillsides a ‘crop circle’ appearance, it is presumed, from this phenomenon. Animals typically seek shade and have reduced appetite. Hypersensitivity to water has been noted, and convulsions may occur following a knock to the head. Although general aversion to water is noted, some may seek water for relief.

Severe skin irritation is physically apparent, with reddening of non-pigmented and unprotected areas. This subsequently leads to itch and rubbing, followed by further inflammation, exudation, and scab formation. Lesions and inflammation that occur are said to resemble the conditions seen in foot and mouth disease. Sheep have been observed to have face swelling, dermatitis, and wool falling off due to rubbing. Lactating animals may cease or have reduced milk production; pregnant animals may abort. Lesions on udders are often apparent. Horses may show signs of anorexia, depression (with a comatose state), dilated pupils, and injected conjunctiva.

Diagnosis

Increased respiration and heart rate is typically observed while one of the early signs of St John's wort poisoning is an abnormal increase in body temperature. Affected animals will lose weight, or fail to gain weight; young animals are more affected than old animals. In severe cases death may occur, as a direct result of starvation, or because of secondary disease or septicaemia of lesions. Some affected animals may accidentally drown. Poor performance of suckling lambs (pigmented and non-pigmented) has been noted, suggesting a reduction in the milk production, or the transmission of a toxin in the milk.

Photosensitisation

Most clinical signs in animals are caused by photosensitisation.[7] Plants may induce either primary or secondary photosensitisation:

  • primary photosensitisation directly from chemicals contained in ingested plants
  • secondary photosensitisation from plant-associated damage to the liver.

Araya and Ford (1981) explored changes in liver function and concluded there was no evidence of Hypericum-related effect on the excretory capacity of the liver, or any interference was minimal and temporary. However, evidence of liver damage in blood plasma has been found at high and long rates of dosage.

Photosensitisation causes skin inflammation by a mechanism involving a pigment or photodynamic compound, which when activated by a certain wavelength of light leads to oxidation reactions in vivo. This leads to lesions of tissue, particularly noticeable on and around parts of skin exposed to light. Lightly covered or poorly pigmented areas are most conspicuous. Removal of affected animals from sunlight results in reduced symptoms of poisoning.

Medical uses

Major depressive disorder

St John's wort is widely known as a herbal treatment for depression. In some countries, such as Germany, it is commonly prescribed for mild to moderate depression, especially in children and adolescents.[8] Specifically, Germany has a governmental organization called Commission E which regularly performs rigorous studies on herbal medicine. It is proposed that the mechanism of action of St. John's wort is due to the inhibition of reuptake of certain neurotransmitters.[4] The best studied chemical components of the plant are hypericin and pseudohypericin.

An analysis of twenty-nine clinical trials with more than five thousand patients was conducted by Cochrane Collaboration. The review concluded that extracts of St John's wort were superior to placebo in patients with major depression. St John's wort had similar efficacy to standard antidepressants. The rate of side-effects was half that of newer SSRI antidepressants and one-fifth that of older tricyclic antidepressants.[9] A report[9] from the Cochrane Review states:

The available evidence suggests that the Hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; and c) have fewer side-effects than standard antidepressants.

Other medical uses

St John's wort is being studied for effectiveness in the treatment of certain somatoform disorders. Results from the initial studies are mixed and still inconclusive; some research has found no effectiveness, other research has found a slight lightening of symptoms. Further study is needed and is being performed.

A major constituent chemical, hyperforin, may be useful for treatment of alcoholism, although dosage, safety and efficacy have not been studied.[10][11] Hyperforin has also displayed antibacterial properties against Gram-positive bacteria, although dosage, safety and efficacy has not been studied.[12] Herbal medicine has also employed lipophilic extracts from St John's wort as a topical remedy for wounds, abrasions, burns, and muscle pain.[11] The positive effects that have been observed are generally attributed to hyperforin due to its possible antibacterial and anti-inflammatory effects.[11] For this reason hyperforin may be useful in the treatment of infected wounds and inflammatory skin diseases.[11] In response to hyperforin's incorporation into a new bath oil, a study to assess potential skin irritation was conducted which found good skin tolerance of St John's wort.[11]

A randomized controlled trial of St John's wort found no significant difference between it and placebo in the management of ADHD symptoms over eight weeks. However, the St John's wort extract used in the study, originally confirmed to contain 0.3% hypericin, was allowed to degrade to levels of 0.13% hypericin and 0.14% hyperforin. Given that the level of hyperforin was not ascertained at the beginning of the study, and levels of both hyperforin and hypericin were well below that used in other studies, little can be determined based on this study alone.[13] Hypericin and pseudohypericin have shown both antiviral and antibacterial activities. It is believed that these molecules bind non-specifically to viral and cellular membranes and can result in photo-oxidation of the pathogens to kill them.[4]

A research team from the Universidad Complutense de Madrid (UCM) published a study entitled "Hypericum perforatum. Possible option against Parkinson's disease", which suggests that St John's wort has antioxidant active ingredients that could help reduce the neuronal degeneration caused by the disease.[14][15][16][17]

Recent evidence suggests that daily treatment with St John's wort may improve the most common physical and behavioural symptoms associated with premenstrual syndrome.[18]

St John's wort was found to be less effective than placebo, in a randomized, double-blind, placebo-controlled trial, for the treatment of irritable bowel syndrome.[19]

St John's wort alleviated age-related long-term memory impairment in rats.[20]

Adverse effects and drug interactions

St John's wort is generally well tolerated, with an adverse effect profile similar to placebo.[21] The most common adverse effects reported are gastrointestinal symptoms, dizziness, confusion, tiredness and sedation.[22][23] It also decreases the levels of estrogens, such as estradiol, by speeding up its metabolism, and should not be taken by women on contraceptive pills as it upregulates the CYP3A4 cytochrome of the P450 system in the liver.[24]

St John's wort may rarely cause photosensitivity. This can lead to visual sensitivity to light and to sunburns in situations that would not normally cause them.[21] Related to this, recent studies concluded that the extract reacts with light, both visible and ultraviolet, to produce free radicals, molecules that can damage the cells of the body. These can react with vital proteins in the eye that, if damaged, precipitate out, causing cataracts.[25] Another study found that in low concentrations, St. John's wort inhibits free radical production in both cell-free and human vascular tissue, revealing antioxidant properties of the compound. The same study found pro-oxidant activity at the highest concentration tested.[26]

St John's wort is associated with aggravating psychosis in people who have schizophrenia.[27]

Consumption of St. John's wort is discouraged for those with bipolar disorder. There is concern that people with major depression taking St. John’s wort may be at a higher risk for mania.[28]

While St. John's wort shows some promise in treating children, it is advised that it be only done with medical supervision. [28]

The interactions that Saint Johns Wort has with other medications is also well studied and has yielded significant results of drug interactions with medications such as Selective Serotonin Re-uptake Inhibitor (SSRI) antidepressants, warfarin, and birthcontrol. Combining both SJW and SSRI depressants can lead to increased serotonin levels causing a potentially fatal serotonin syndrome.[29] SJW will reduce the effects of warfarin and lead to thrombosis.[30] Combining estrogen containing oral contraceptives with SJW can lead to decreased efficacy of the contraceptive and eventually unplanned pregnancies.[31] These are just a few of the drug interactions that SJW posess. It is also known to decrease the efficacy of HIV medications, Cholesterol medications, as well as transplant medications.[32] It is because of these dangerous drug interactions that it is imperative to speak with your Doctor or Pharmacist before starting any alternative medicines.

Pharmacokinetic interactions

St John's wort has been shown to cause multiple drug interactions through induction of the cytochrome P450 enzymes CYP3A4 and CYP2C9, and CYP1A2 (females only). This drug-metabolizing enzyme induction results in the increased metabolism of certain drugs, leading to decreased plasma concentration and potential clinical effect.[33] The principal constituents thought to be responsible are hyperforin and amentoflavone.

St John's wort has also been shown to cause drug interactions through the induction of the P-glycoprotein (P-gp) efflux transporter. Increased P-gp expression results in decreased absorption and increased clearance of certain drugs, leading to lower plasma concentration and potential clinical efficacy.[34]

Examples of drugs causing clinically significant interactions with St John's wort
Class Drugs
Antiretrovirals Non-nucleoside reverse transcriptase inhibitors, protease inhibitors
Benzodiazepines Alprazolam, midazolam
Hormonal contraception Combined oral contraceptives
Immunosuppressants Calcineurin inhibitors, cyclosporine, tacrolimus
Antiarrhythmics Amiodarone, flecainide, mexiletine
Beta-blockers Metoprolol, carvedilol
Calcium channel blockers Verapamil, diltiazem, amlodipine
Statins (cholesterol-reducing medications) Lovastatin, simvastatin, atorvastatin
Others Digoxin, methadone, omeprazole, phenobarbital, theophylline, warfarin, levodopa, buprenorphine, irinotecan
Reference: Rossi, 2005; Micromedex

For a complete list, see CYP3A4 ligands and CYP2C9 ligands.

Pharmacodynamic interactions

In combination with other drugs that may elevate 5-HT (serotonin) levels in the central nervous system (CNS), St John's wort may contribute to serotonin syndrome, a potentially life-threatening adverse drug reaction.[35]

Drugs that may contribute to serotonin syndrome with St John's wort
Class Drugs
Antidepressants MAOIs, TCAs, SSRIs, SNRIs, mirtazapine
Opioids Tramadol, pethidine (meperidine), Levorphanol
CNS stimulants Phentermine, diethylpropion, amphetamines, sibutramine, cocaine
5-HT1 agonists Triptans
Psychedelic drugs Methylenedioxymethamphetamine (MDMA), LSD, Dimethyltryptamine (DMT), MDA, 6-APB
Others Selegiline, tryptophan, buspirone, lithium, linezolid, 5-HTP, dextromethorphan
Reference:[35]

Detection in body fluids

Hypericin, pseudohypericin, and hyperforin may be quantitated in plasma as confirmation of usage and to estimate the dosage. These three active substituents have plasma elimination half-lives within a range of 15–60 hours in humans. None of the three has been detected in urine specimens.[36]

Chemical constituents

The plant contains the following:[37][38]

The naphthodianthrones hypericin and pseudohypericin along with the phloroglucinol derivative hyperforin are thought to be among the numerous active constituents.[4][39][40][41] It also contains essential oils composed mainly of sesquiterpenes.[4]

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Mechanism of action

St. John's wort (SJW), similarly to other herbal products, contains a whole host of different chemical constituents that may be pertinent to its therapeutic effects.[37] Hyperforin and adhyperforin, two phloroglucinol constituents of SJW, are TRPC6 receptor agonist and, consequently, they induce noncompetitive reuptake inhibition of monoamines (specifically, dopamine, norepinephrine, and serotonin), GABA, and glutamate when they activate this receptor.[3][42][2] It inhibits reuptake of these neurotransmitters by increasing intracellular sodium ion concentrations.[3] Moreover, SJW is known to downregulate the β1 adrenoceptor and upregulate postsynaptic 5-HT1A and 5-HT2A receptors, both of which are a type of serotonin receptor.[3] Other compounds may also play a role in SJW's antidepressant effects such compounds include: oligomeric procyanidines, flavonoids (quercetin), hypericin, and pseudohypericin.[3][43][44][45]

In humans, the active ingredient hyperforin is a monoamine reuptake inhibitor which also acts as an inhibitor of PTGS1, Arachidonate 5-lipoxygenase, SLCO1B1 and an inducer of cMOAT. Hyperforin is also a powerful anti-inflammatory compound with anti-angiogenic, antibiotic, and neurotrophic properties.[42][2][46] Hyperforin also has an antagonistic effect on NMDA receptors, a type of glutamate receptor.[2] According to one study, hyperforin content correlates with therapeutic effect in mild to moderate depression.[47] Moreover, a hyperforin-free extract of St John's wort (Remotiv) may still have significant antidepressive effects.[48][49] The limited existing literature on adhyperforin suggests that, like hyperforin, it is a reuptake inhibitor of monoamines, GABA, and glutamate.[50]

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Compound Conc.[37]
[38][51]
log P PSA pKa Formula MW CYP1A2
[Note 1]
CYP2C9
[Note 2]
CYP2D6
[Note 3]
CYP3A4
[Note 4]
PGP
[Note 5]
t1/2[51] (h) Tmax[51] (h) Cmax[51] (mM) CSS[51] (mM) Notes/Biological activity[Note 6]
Phloroglucinols (2-5%)
Adhyperforin 0.2-1.9 10-13 71.4 8.51 C36H54O4 550.81 ? ? ? ? ? ? ? ? ? Inhibits reuptake of: 5-HT, DA, NE, GABA and Glu via TRPC6 activation[52]
Hyperforin 2-4.5 9.7-13 71.4 8.51 C35H52O4 536.78 +[53] +[53]/-[54] -[54] + + 3.5-16 2.5-4.4 15-235 53.7 Serves as a TRPC6 and PXR agonist. Reuptake inhibitor of 5-HT (205nM), DA (102nM), NE (80nM), GABA (184nM), Glu (829nM), Gly and Ch (8.5μM). Angiogenesis, COX-1 (300nM), 5-LO (90nM), SIRT1 (15μM), SIRT2 (28μM) and MRSA (1.86μM) inhibitor.
Naphthodianthrones (0.03-3%)
Hypericin[55] 0.003-3 7.5-10 156 6.9±0.2 C30H16O8 504.44 0 -
(3.4 μM)
- (8.5 μM) -
(8.7 μM)
? 2.5-6.5 6-48 0.66-46 ? Is a topoisomerase II,[56] PKA (10μM), PKC (27nM), CK1 (3μM), CK2 (6nM), MAPK (4nM), EGFR (35nM), InsR (29nM), PI3K (180nM), DBH (12.4μM), DNA polymerase A (14.7μM), HIV-1 RT (770nM), COMT, MAOA (68μM) and MAOB (420μM), succinoxidase (8.2μM), GSR (2.1nM), GPx (5.2μM), GST (6.6μM) and CuZnSOD (5.25μM) inhibitor.[51][55] Binds to the NMDA receptor (Ki=1.1μM), μ-opioid, κ-opioid, δ-opioid, 5-HT6, CRF1, NPY-Y1, NPY-Y2 and σ receptors.[55] Exhibits light-dependent inhibitory effects on HIV-1 and cancers.[55]
Pseudohypericin 0.2-0.23 6.7±1.8 176 7.16 C30H16O9 520.44 ? ? ? ? ? 24.8-25.4 3 1.4-16 0.6-10.8[57] Photosensitiser and antiretroviral like hypericin.[58][59] PKC inhibitory effects in vitro.[60]
Flavonoids (2-12%)
Amentoflavone
[61]
0.01-0.05 3.1-5.1 174 2.39 C30H18O10 538.46 ? -
(35 nM)
- (24.3 μM) -
(4.8 μM)
? ? ? ? ? Serves as a fatty acid synthase (FASN) inhibitor,[62][63][64] kappa opioid antagonist,[65] and a negative allosteric modulator at the benzodiazepine site of the GABAA receptor.[66]
Apigenin 0.1-0.5 2.1±0.56 87 6.63 C15H10O5 270.24 ? ? ? ? ? ? ? ? ? Benzodiazepine receptor ligand (Ki=4μM) with anxiolytic effects.[67] Also has anti-inflammatory, anticancer, cancer-preventing and antioxidant effects.[68][69]
Catechin 2-4 1.8±0.85 110 8.92 C15H14O6 290.27 ? ? ? ? ? ? ? ? ? Anticancer, antioxidant, cardioprotective and antimicrobial.[70][71] Cannabinoid receptor CB1 ligand.[72]
Epigallocatechin ? -0.5-1.5 131 8.67 C15H14O6 290.27 ? ? ? ? ? 1.7±0.4a 1.3-1.6a ? ? Found in higher concentrations in Green tea. Antioxidant. CB1 receptor ligand (Ki=35.7 μM).[72]
Hyperoside 0.5-2 1.5±1.7 174 6.17 C21H20O12 464.38 ? ? -[73] (3.87μM) ? ? ? ? ? ? Has anti-fungal effects in vitro (against the plant pathogens P. guepini and Drechslera),[74] neuroprotective effects via the PI3K/Akt/Bad/BclXL signalling pathway in vitro,[75] anti-inflammatory effects via NF-κB inhibition in vitro,[76] D2 receptor-dependent antidepressant-like effects in vivo,[77] and antiglucocorticoid-like effects in vitro.[78]
Kaempferol[79] ? 2.1±0.6 107 6.44 C15H10O6 286.24 ? ? ? +/-[Note 7] ? ? ? ? ? Inhibits the following: inflammation (via NF-κB and STAT1 inhibition),[80] cancer, HDAC,[81] bacteria, viruses, protozoa and fungi.[82] It is also known to prevent cardiovascular disease and cancer.[82]
Luteolin ? 2.4±0.65 107 6.3 C15H10O6 286.24 - ? ? ? ? ? ? ? ? Has anti-inflammatory, anticancer, anti-allergic and antioxidant effects.[83][84] May also have positive effects on people with autism spectrum disorders.[85] Potent non-selective competitive inhibitor of PDE1-5.[86]
Quercetin[87][88] 2-4 2.2±1.5 127 6.44 C15H10O7 302.24 -
(7.5 μM)
b
- (47 μM)
b
- (24 μM)
b
- (22 μM)
b
- 20-72c 8c ? ? Has anti-cancer, anti-inflammatory, anti-allergic, anti-asthmatic, antihypertensive, analgesic, neuroprotective, gastroprotective, anti-diabetic, cardiovascular disease-preventing, antioxidant, antidepressant-like (in rat models of depression), anxiolytic-like, sedative, antimicrobial and athletic performance-promoting effects.[88] Non-selective PDE1-4 inhibitor that is slightly selective for PDE3/4 over PDE1/2.[89]
Rutin 0.3-1.6 1.2±2.1 266 6.43 C27H30O16 610.52 ? ? ? ? ? ? ? ? ? Has anticancer, cardioprotective, nephroprotective, antioxidant, anti-inflammatory, antidiabetic, procognitive and antilipidaemic effects.[90]
Phenolic acids (~0.1%)
Caffeic acid 0.1 1.4±0.4 77.8 3.64 C9H8O4 180.16 ? ? ? -[91] ? ? ? ? ? Anticancer, hepatoprotective, antibacterial and antioxidant effects reported.[92]
Chlorogenic acid <0.1% -0.36±0.43 165 3.33 C16H18O9 354.31 0 0 0 0 ? ? ? ? ? Antibacterial, anticancer and antioxidant effects have been demonstrated.[93]
Acronyms and symbols
Acronym/Symbol Meaning
MW Molecular weight in g•mol−1.
PGP P-glycoprotein
t1/2 Elimination half-life in hours
Tmax Time to peak plasma concentration in hours
Cmax Peak plasma concentration in mM
CSS Steady state plasma concentration in mM
Partition coefficient. These values are experimental values taken from ChemSpider and [94] (the access dates are both 13–15 December 2013) where available or, if they are not available approximations are taken from [www.chemaxon.com/download/marvin/for-end-users/ ChemAxon MarvinSketch] 6.1.4 & [95]
PSA Polar surface area of the molecule in question in square angstroms2). Obtained from PubChem (the access date is 13 December 2013).
Conc. These values pertain to the approximation concentration (in %) of the constituents in the fresh plant material
- Indicates inhibition of the enzyme in question.
+ Indicates an inductive effect on the enzyme in question.
0 No effect on the enzyme in question.
5-HT 5-hydroxytryptamine — synonym for serotonin.
DA Dopamine
NE Norepinephrine
GABA γ-aminobutyric acid
Glu Glutamate
Gly Glycine
Ch Choline
a Pharmacokinetic data for ECG comes from a study[96] of its pharmacokinetics after oral administration of green tea.
b Comes from this source.[54]
c Pharmacokinetic data for quercetin comes from a study[97] using pure oral quercetin, not a SJW extract.

Notes:

  1. In brackets is the IC50/EC50 value depending on whether its an inhibitory or inductive action being exhibited, respectively.
  2. As with last note
  3. As with last note
  4. As with last note
  5. As with last note
  6. Values given in brackets are IC50/EC50 depending on whether it's an inhibitory or inductive action the compound displays towards the biologic target in question. If it pertains to bacterial growth inhibition the value is MIC50
  7. Depends on the time frame: short-term administration causes inhibition; long-term causes induction via PXR

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See also

References

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Further reading

  • British Herbal Medicine Association Scientific Committee (1983). British Herbal Pharmacopoeia. West Yorkshire: British Herbal Medicine Association. ISBN 0-903032-07-4.
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External links

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